Evaluation of the effectiveness and tolerance of tetracosactide in the treatment of post-dural puncture headaches (ESYBRECHE): A study protocol for a randomized controlled trial

Evaluation of the effectiveness and tolerance of tetracosactide in the treatment of post-dural puncture headaches (ESYBRECHE): A study protocol for a randomized controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Evaluation of the effectiveness and tolerance of tetracosactide in the treatment of post-dural puncture headaches (ESYBRECHE): A study protocol for a randomized controlled trial Celia Depaulis, Nadia Steer, Léa Garessus , Dominique Chassard, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.2.12203/v3 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Jan, 2020 Read the published version in Trials → Version 3 posted 6 You are reading this latest preprint version Show more versions Abstract Background Post-dural puncture headache (PDPH) is one of the most common complications of neuraxial anaesthesia. It limits patients’ general activity and increases length of hospital stay and use of care. It is particularly disabling during the postpartum period, when mothers have to take care of their child. Epidural blood patch is the standard treatment for PDPH. However, it is an invasive procedure that may result in rare but serious complications. Recent evidence has suggested that adrenocorticotropic hormone (ACTH) is effective in the management of PDPH. The aim of this study is to assess the efficacy and safety of tetracosactide (Synacthen ® ), a synthetic analogue of ACTH, for PDPH treatment in patients who receive neuraxial anaesthesia during labour. Method This randomised, double-blind, placebo-controlled, parallel-arm trial, is performed in two French university hospitals. Eligible patients are those suffering from postpartum PDPH, who are randomised to receive either 1 mg of tetracosactide intravenously over 20 min, or 0.9% saline (placebo). The primary endpoint is the rate of epidural blood patch within a 15-day follow-up period. Headache duration, pain intensity, reduction of general activity, increase in length of hospital stay, adverse events, analgesic use (type and duration), and number of blood patches per patient in each group are recorded. Discussion We expect a decrease in the use of epidural blood patch in those receiving tetracosactide, thus indicating a decrease in PDPH symptoms in these patients. This will define the therapeutic success of tetracosactide and the possibility to use this treatment as a non-invasive alternative to blood patch for PDPH treatment. Internal Medicine Integrative & Complementary Medicine Translational Medicine Post-dural puncture headache tetracosactide cosyntropin postpartum blood-patch epidural Figures Figure 1 Figure 2 Background Epidural analgesia is the most effective method to control pain during labour and is frequently used in France (77% of vaginal deliveries in 2010) (1). For caesarean sections, artificial deliveries, or uterine revisions, spinal anaesthesia is preferred to general anaesthesia due to the risk associated with the latter in pregnant women (such as difficult management of airway) (2). However, neuraxial anaesthesia can also lead to adverse effects, in particular post-dural puncture headache (PDPH). The incidence of PDPH following dural puncture mainly depends on the type of needle used (diameter, bevel) (3–10). For instance, incidence is reported to be between 0.7% and 4% when 24-27 G conical needles are used for spinal anaesthesia, and between 50% and 85% when large Tuohy needles are used for epidural analgesia (3,10,11). Since the incidence of dural puncture during epidural placement is reported to range from 0.04 to 6% (12), the incidence of PDPH among patients receiving these type of anaesthesia (spinal and epidural) is actually close. In addition, postpartum women are more prone to PDPH than the general population (13–15).Epidural analgesia is the most effective method to control pain during labour and is frequently used in France (77% of vaginal deliveries in 2010) (1). For caesarean sections, artificial deliveries, or uterine revisions, spinal anaesthesia is preferred to general anaesthesia due to the risk associated with the latter in pregnant women (such as difficult management of airway) (2). However, neuraxial anaesthesia can also lead to adverse effects, in particular post-dural puncture headache (PDPH). The incidence of PDPH following dural puncture mainly depends on the type of needle used (diameter, bevel) (3–10). For instance, incidence is reported to be between 0.7% and 4% when 24-27 G conical needles are used for spinal anaesthesia, and between 50% and 85% when large Tuohy needles are used for epidural analgesia (3,10,11). Since the incidence of dural puncture during epidural placement is reported to range from 0.04 to 6% (12), the incidence of PDPH among patients receiving these type of anaesthesia (spinal and epidural) is actually close. In addition, postpartum women are more prone to PDPH than the general population (13–15). PDPH is a clinical diagnosis. According to the International Headache Society, it is a severe postural, bilateral, disabling, constrictive, occipital or diffuse headache that radiates to the neck, and develops within 7 days after the dural puncture. In 66% of cases it occurs during the first 48 hours, and in 90% of cases during the first 3 days (3). PDPH is aggravated by a sitting or standing position and is relieved by lying down. Other symptoms such as neck stiffness, hearing disorders (tinnitus, hypoacusia) (16), dizziness, photophobia, nausea or vomiting, and diplopia by injury of the cranial nerve IV (17) may be associated with the headache and patients remain afebrile. Differential diagnoses are migraine, pre-eclampsia, meningitis, intracranial haemorrhage, cerebral thrombosis, pneumocephalus, and tension headaches (18,19). As described by Vandam and Dripps as early as 1956 (20), the main cause of PDPH appears to be intracranial hypotension by leakage of cerebrospinal fluid (CSF). CSF is critical in reducing impacts between the brain and the cranium during orthostatism, and the loss of this cushioning leads to headaches. Furthermore, the cerebral and meningeal vessels are stressed by the downward displacement of the brain during orthostatism. This caudal traction activates the stretch-sensitive receptors of the trigeminal nerves (frontal headache), glosso-pharyngeal and vagus nerves (occipital headache) (11,21,22), and the first three cervical nerves (arm pain or neck pain) (23). According to the Monro-Kellie theory, headaches may also be related to painful venous and arterial cerebral vasodilation which compensates for decreased CSF volume (3,21). In the inner ear, hypotension of the perilymph also causes an imbalance between endolymph and perilymph itself leading to hearing impairment, tinnitus, and/or vertigo (16,24). In most cases, dural puncture closes spontaneously without consequence. PDPH is reported to resolve in more than 50% of patients within 4 days, and in more than 70% within a week. However, headache may persist in a limited number of patients (3,20). PDPH can limit patients’ activity, increase the duration of hospital stay and use of care (25), and is particularly disabling during the postpartum period, when the mother has to take care of her child. It is therefore important to treat this syndrome. Epidural blood patch is currently the gold standard and most effective treatment for PDPH. However, the timing for this treatment remains uncertain. Some studies have suggested a greater risk of failure when administering an early blood patch although no causal link could be established (26–28). The diminished effectiveness in this case, could be explained by the severity of the CSF leak (28). Conversely, administering a delayed blood patch could increase bed rest duration. A delay of 24 to 36 hours between the onset of headaches and the completion of a blood patch seems reasonable. However, it is recommended not to delay the blood patch by more than 48 hours (29). Historically, the reported success rate after the first blood patch is around 80% (28,30). Recently, however, efficacy has been found to be lower (32% at most) (27). Moreover, it is an invasive procedure that may result in rare but serious complications such as spinal subdural hematoma (31) or permanent paraparesis and cauda equina syndrome (32). It may also trigger anxiety and discomfort in patients and can sometimes be painful (back pain, transient bradycardia). Alternative treatments have recently been studied; they aim to be less invasive or to reduce headache intensity whilst waiting for the blood patch or the disappearance of PDPH. Several lines of evidence have suggested the effectiveness of adrenocorticotropic hormone (ACTH) in the management of PDPH (33–41). Several mechanisms have been proposed to explain the effects of ACTH or its analogues on headaches. First, it has been shown by several teams that fragments of ACTH interact with opioid receptors in vitro and have morphine-like effects in vivo (42–44). Second, ACTH may increase brain β-endorphins which can change the perception of pain (35–37). Third, ACTH stimulates the adrenal cortex, which releases different hormones such as glucocorticoids, androgens, and mineralocorticoids. Glucocorticoids have an anti-inflammatory effect that may explain in part the analgesia observed after ACTH injection (38). Fourth, mineralocorticoids are responsible for fluid retention that may lead to meningeal oedema and overlapping edges of the dural puncture (36). The trial reported by Hakim found that administration of tetracosactide after accidental dural puncture in 90 parturients was associated with a significant reduction in the incidence of PDPH and requirement for epidural blood patch (39). The efficacy of tetracosactide for the treatment of PDPH in 32 patients has been reported to be 56% (95% CI [33; 79%]) (40), and to be similar to that of epidural blood patch in a study that included 28 patients (41), although 4 of the 15 in the tetracosactide group also received a blood patch. However, a randomized trial that included 18 patients did not find any efficacy of tetracosactide in the treatment of PDPH, nor in the reduction of blood patch use (45). This study was conducted among a small group of patients, and did not report any data on the interval between PDPH onset and blood patch. Taken together, efficacy evidence of ACTH analogues on PDPH remains limited with contradictory results obtained in small groups of patients. It is therefore difficult to conclude and establish a protocol for the management of PDPH. In the proposed study, we have designed a therapeutic trial to evaluate the efficacy of tetracosactide in the treatment of PDPH in 88 postpartum patients. Methods/Design 1.3.1 Aim of the study The aim of this study is to assess the efficacy and safety of tetracosactide (Synacthen ® ) in the treatment of post-dural puncture syndrome for patients who received neuraxial anaesthesia during childbirth. Our working hypothesis is that a single intravenous infusion of tetracosactide may avoid the need for epidural blood patch. To challenge this hypothesis two groups will be compared: the study group receiving an infusion of 1 mg of tetracosactide and the control group receiving a placebo (0.9% saline). Both groups receive standard analgesic treatment and epidural blood patch if needed (after a minimum of 24 h following the injection of the experimental treatment). 1.3.2 Trial Design The study is a randomised, double-blind, placebo-controlled, parallel-arm, double-centre trial. It is conducted in two different sites, both are part of the same French university hospital. Patient enrolment started in October 2016 and was expected to be completed within 2 years after the start of the study. However, this did not happen as explained in section 1.3.11. Once participants are enrolled in the study with informed consent, they are randomised into the two study arms. The study group receives 1 mg of tetracosactide intravenously whereas the control group receives 0.9% saline. Outcomes will be measured between 2 and 6 hours, on day 1, day 2, day 3, and between days 13 and 17 post-randomisation. Adverse events are collected throughout the study. 1.3.3 Primary endpoint The primary endpoint of the study is the rate of epidural blood patch within a 15-day follow-up period. That is, the number of patients who receive a blood patch within the 15-day period divided by the total number of participants included. 1.3.4 Secondary endpoint s The secondary endpoints are: duration of headache: mean number of days with headache within the 15-day follow-up period intensity of headache (11-point numerical rating scale, NRS) (46): mean NRS at day 1, 2, 3, and 15 the need for analgesic treatment (descriptive analysis of type, time interval after study treatment initiation, and duration) within the 15-day follow-up period appearance of associated features (neck stiffness, tinnitus, hypoacusia, photophobia, diplopia, dizziness, or nausea): descriptive analysis of these features within the 15-day follow-up period activity limitation (self-assessed, both qualitatively as described in Figure 1, and quantitatively on a scale from 0 to 100%): mean score at day 1, 2, 3 and 15 length of hospital stay: mean number of days spent in hospital assessed from inclusion to day 15 the number of epidural blood patches performed per patient: mean number within the 15-day follow-up period tolerance, assessed by the collection of all adverse events (type, frequency, severity) 1.3.5 Population Number of patients needed The sample size calculation is based on a previous study that investigated tetracosactide in PDPH (39) and, retrospectively, on observational data obtained from our hospital database. The primary endpoint is the rate of blood patch in the two groups. We defined the efficacy of tetracosactide as a decrease in blood patch use by 30% in the tetracosactide group, a clinically relevant difference reducing the need for invasive treatment and replacing it with an easily administered treatment that has a known safety profile. In our centre, 90% of patients with PDPH after epidural analgesia receive a blood patch. The study reported by Hakim (39) found a greater than 50% decrease in PDPH incidence and blood patch use after prophylactic treatment with tetracosactide, in a context of epidural analgesia. We therefore need to include 44 subjects in each group, given a power of 0.80 and type I error of 0.025 (α=2.5% Fisher’s exact test, power of 80%, p1=0.9; p2=0.6), to reduce blood patch requirement by 30%. Thus a total of 88 patients need to be randomised. Eligibility Patients eligible for enrolment in this clinical trial are those suffering from PDPH due to epidural analgesia, combined spinal-epidural analgesia, or spinal anaesthesia for childbirth. The headache characteristics should be as follows: within five days after delivery relieved in the supine position and/or worse while sitting or standing intense (NRS >3/10) with or without: neck stiffness, tinnitus, hypoacusia, photophobia, visual impairment, nausea or vomiting after having eliminated differential diagnosis: pre-eclampsia or eclampsia, cerebral venous thrombosis, migraine. Patients must be at least 18 years old and benefit from healthcare insurance. They also have to provide a written informed consent. Exclusion criteria Exclusion criteria are as follows: diplopia (which requires an epidural blood patch without delay) contraindication to ACTH: uncontrolled arterial hypertension, uncontrolled diabetes mellitus, acute psychosis, infectious diseases contraindication to tetracosactide: currently receiving a drug associated with an increased risk of Torsades de Pointes: astemizole, bepridil, IV erythromycin, halofantrine, pentamidine, sparfloxacine, sultopride, terfenadine, vincamine patient who received a live vaccine in the month prior to inclusion previous history of hypersensitivity to tetracosactide patient who has received tetracosactide since childbirth contraindication to epidural blood patch: HIV, HVC, leukocytosis, fever pre-eclampsia or eclampsia during the current pregnancy (may be confounding for the etiology of headache) patient who has already received a prophylactic blood patch (at the time of accidental dural puncture diagnosis) Under 18 years old or adult under guardianship Mental disorder which does not allow informed consent Patients who are enrolled in another clinical trial Consent When PDPH diagnosis is made by the anaesthesiologist, screening of patients for inclusion and exclusion criteria is performed. The investigator then presents the study to the patients. Written information is provided to the patients. Patients are given some time to think before committing to the study. Final inclusion occurs shortly after they have read the information letter, raised questions they may have, and signed the written informed consent. 1.3.6 Randomisation, blinding, and data management The anaesthesiologist checks the patient’s inclusion criteria and the absence of exclusion criteria. After signing of the informed consent, patients are randomised online using the ClinSight-Online software program (Ennov society, Paris, France). The randomisation list was compiled by a statistician, entered into the software and communicated to the pharmacist to prepare the numbered treatment kits. The randomization is performed by block stratification according to site. Patients are allocated to a treatment number (by the ClinSight software). The study is performed double-blinded; both patients and the medical team are blinded to treatment allocation. An aneaesthetic nurse prepares the treatment according to the assigned number to which the rest of the healthcare team is blinded. Patient data are collected on electronic case report forms (eCRFs). The sponsor will independently monitor both locations of this multisite trial every ten patients. This data monitoring is performed by a clinical research associate (CRA). His/her role is to check the consent form, the quality of data collection (missing data, data entry errors…), the availability of treatment at each site, the pharmacy process, and the declaration of any serious adverse event. He/she is employed by the sponsor but is independent of the investigators and is not involved in carrying out the study or interpretation of the results. Anonymized data are only accessible to the investigators, the sponsor, and other authorized persons (statistician, data manager…). They will be stored confidentially for 15 years by the sponsor. They will not be used for further studies without further patient agreement. At the end of the study, we plan to communicate trial results to participants, healthcare professionals, and the public via a peer-reviewed publication. Authors will be considered in the case of a substantial contribution to the conception or design of the study or the acquisition, analysis, or interpretation of data. They will need to have drafted the work or revised it critically. They will all approve the final version to be published. We do not expect the participation of a professional writer. Data not disclosed in the publication will not be accessible. 1.3.7 Intervention protocols During the post-partum period, patients are usually followed by midwives. In case of headache, whether an accidental dural puncture is diagnosed or not, the anaesthesiologist is informed by midwives. Therefore, any symptomatic patient is examined by an anaesthesiologist. The study investigators are the anaesthesiologists working in the maternity department of the two centres. Patients are enrolled when diagnosed with PDPH based on the anaesthesiologist’s clinical evaluation. They are randomised to receive intravenous tetracosactide or placebo. In the study group, patients receive a single intravenous injection of 1 mg tetracosactide (Synacthen ® , Sigma-Tau laboratory, Roma, Italy). Four vials containing 0.25mg tetracosactide (in 1 ml of solvent) are reconstituted in 100 ml of normal saline (0.9% NaCl). This solution is infused intravenously over 20 min. In the control group, patients receive an equal volume of normal saline: 104 ml over 20 min. The whole intervention is administered over a 20 minute course and therefore is not modifiable once begun except for the occurrence of a side effect. A side effect is defined herein as any new abnormality observed upon clinical examination, occurring during the injection. In this case, the treatment is immediately stopped but monitoring and data collection continues. Standard analgesic medication, as concomitant treatments, is also initiated in both groups from the beginning of headache, as follows: for mild headache (NRS<3/10): 1 g paracetamol and 400 mg ibuprofen orally every 6 hours for moderate headache (NRS=3): nefopam 20 mg and/or a combination of paracetamol 300 mg and opium 10 mg is given in addition every 4 hours for severe headache (NRS≥4): morphine 10 mg orally every 4 hours can be added as required These treatments are adjusted daily. The primary and secondary endpoint, including tolerance criteria, are evaluated blinded during infusion of the study treatment, 2-6 hours later, 1 day, 2 days, 3 days, and between 13 and 17 days post-treatment by the investigator. The latter is conducted by phone call in order to increase the complete follow-up. The total duration of the study is therefore 13 to 17 days. Any alternative analgesic intervention required after receiving the study treatment is reported at each time point as indicated above. The study timeline is summarised in Figure 2. Epidural blood patch is performed for patients who reported a persistent moderate to severe headache a minimum of 24 hours after administration of the study treatment and 36 hours after the dural puncture, based on the clinical appreciation of the anaesthesiologist. Epidural blood patch can be repeated twice if required (i.e. if headache does not improve or if it increases again). The anaesthesiologist performs the epidural blood patch. Autologous blood is injected into the epidural space using an 18 gauge Tuohy needle. The injection is stopped when the patient feels pressure in the lower back or pain. 1.3.8 Statistical analysis Unblinding occurs at the end of the study and once the database has been frozen. Analyses will be carried out on an intention-to-treat (ITT) basis. If data is missing from visits, we will carry forward the last value considering the pain (and others symptoms) has not improved. This is the most pessimistic scenario for this condition which usually improves spontaneously. Blood patch can only be performed at the hospital, and it is therefore very unlikely that there will be missing data regarding the primary endpoint. If a patient does not receive full treatment, she will be included in the group to which she was randomised for further ITT analysis. Statistical analyses will be performed using IBM SPSS statistics for windows (IBM corp., Armonk, NY, USA) and R (R Foundation for Statistical Computing, Vienna, Austria). All data will be checked for normal distribution using the Kolmogorov test. For normally distributed data, variables will be presented as mean ± standard deviation (SD). Non-normally distributed data will be presented as the median and interquartile range [IQR]. Categorical variables will be presented as number and percentage of the total. To compare the two groups (tetracosactide and placebo), we will use Fisher’s exact test for qualitative data and the non-parametric Mann-Whitney tests for quantitative variables. A comparison of the two groups at randomisation will identify potential bias due to unequal allocation. A multivariate logistic regression analysis will be performed to study factors independently associated with the response to tetracosactide and to control potential confounding factors. Intermediate analysis The hypothesis of a 30% difference between the two groups is conservative compared to the 50% reduction reported by Hakim (39); a difference of only 30% between the two groups should already be clinically relevant. An interim analysis is therefore planned after the enrolment of 44 patients. The overall alpha risk will be adjusted according to the Bonferroni method and will be 2.5% (5% / 2). A p value <0.025 will therefore be considered statistically significant. If this initial analysis is statistically significant (p <0.025), the independent monitoring committee may decide to stop the study without waiting for the planned recruitment. Otherwise, the study will be continued until the inclusion of 88 patients. 1.3.9 Ethical approval This trial is conducted in accordance with the protocol and in compliance with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki (1989) and Good Clinical Practice (GCP). It is also conducted in accordance with French legislation (Public Health Code; Act No. 2004-806 of August 9, 2004). It is registered in the Clinical Trial Protocol Registration and Results System: NCT02813655 (registration date: June 24, 2016). An ethics committee ( comité de protection des personnes sud Est V , CPP) has approved the study for both participating sites on April 6, 2016. The national drugs authority ( Agence Nationale de Sécurité du Médicament et des produits de santé , ANSM) authorised this trial (authorisation date: April 18, 2016). 1.3.10. Adverse events management During the study period, adverse events will be reported and recorded in the participants’ CRF. Adverse events include any new abnormality observed upon clinical examination, occurring during the study treatment injection or the follow-up period, or any allergic reaction to the treatment. The severity of adverse events will be graded as mild, moderate, severe, life threatening, or death, and the potential relationship between the adverse event and the study treatment will be assessed by clinical judgment. If an adverse event requiring hospitalisation extension or causing a medically critical situation occurs, the event will be recorded as a severe adverse event. All severe and life threatening adverse events or death will be reported to the investigator and to the sponsor within 24 hours after the information has been collected. The sponsor will report all such events to legal authorities (ANSM and CPP). The investigator must follow patients until the adverse event has been resolved. All adverse events collected will be described in the trial publication. A severe adverse event is the only reason for unblinding participants and providers before the end of the study. It will be performed by the poison control centre ( Centre anti-poison ) which is independent of the study and is the only party with access to the randomisation list. 1.3.11. Protocol amendment Because patient enrolment/inclusion was more difficult than expected, the protocol was amended (January 2017) to extend inclusion from PDPH due to a dural puncture carried out by large Tuohy needle to all postpartum PDPH, i.e. PDPH related to a large dural puncture and PDPH related to small needle (25-27G) for spinal anaesthesia. For this reason, a second amendment (November 2018) extended the inclusion period until October 10, 2021. Discussion We propose herein a protocol to investigate the use of tetracosactide, an ACTH analogue, to treat PDPH. Blood-patch is currently the gold standard for PDPH treatment, and tetracosactide could be interesting as it would reduce the need for the invasive procedure and replace it with an easily administered treatment that has a known safety profile. Given previous results obtained in small groups of patients, efficacy evidence of ACTH analogues for PDPH treatment remains limited. Initially, the inclusion was limited to PDPH due to a dural puncture carried out by a large Tuohy needle. Because patient enrolment/inclusion was more difficult than expected, the protocol was amended to extend inclusion to all postpartum PDPH. This widening of the inclusion criteria raises the issue of population heterogeneity, which we hope to limit by the randomisation process. Since the management strategy of PDPH (using blood-patch and non-invasive treatments) is not clearly defined, the rate of blood-patch varies. Rucklidge, for example, described that 50 blood-patches were received by 144 patients treated for PDPH after epidural anaesthesia over 20 years in the hospital in which he practiced (47); the blood-patch rate was therefore 35%. In the study reported by Aya et al. all patients (100%) treated for PDPH after epidural obstetric anaesthesia in their unit received a blood-patch (48). Therefore, a potential limitation of the study described herein is that the sample size could be insufficient if the rate of blood patch in the control group is lower than 90%. Trial status It is the fourth protocol version dated September 28, 2018. The study is ongoing; the first patient was included in October 2016, and in May 2019 a total of 25 patients had been enrolled. Initially we expected to finalise the study in October 2018, but we had to extend the inclusion phase until 2021 to reach a total of 88 inclusions. Due to the ongoing nature of the study and in order to avoid influencing its conduct, the final results are not presented herein. An intermediate analysis will be performed after 44 inclusions, and if there is a significant difference between the two groups concerning the primary outcome, the study will be discontinued. Conclusion We expect a decrease in the use of epidural blood patch in those receiving tetracosactide, thus indicating a decrease in PDPH symptoms for these patients. This will define the therapeutic success of tetracosactide and the possibility to use this treatment as a non-invasive alternative to blood patch for PDPH treatment. List of abbreviations ACTH Adrenocorticotropic Hormone ANSM Agence Nationale de Sécurité du Médicament et des produits de santé : the national drugs authority CPP Comité de Protection des Personnes : an ethics committee CRA Clinical Research Associate CSF Cerebrospinal Fluid eCRFs electronic Case Report Forms GCP Good Clinical Practice HIV Human Immunodeficiency Virus HCV Hepatitis C Virus IQR Interquartile Range ITT Intention-To-Treat NRS Numerical Rating Scale PDPH Post-Dural Puncture Headache SD Standard Deviation Declarations Ethics approval and consent to participate An ethics committee ( comité de protection des personnes sud Est V , CPP) has approved the study for both participating sites on 6 April 2016. Patients are given some time to think before committing to the study. Final inclusion occurs shortly after they have read the information letter, raised questions they may have, and signed the written informed consent. Consent for publication Not applicable Availability of data and materials Data sharing is not applicable to this article as no datasets were yet generated or analyzed during the current study. Competing interests The authors have no conflict of interest to declare. Funding The study is funded by grants from Fondation Apicil and Fondation de France. Funders have no role in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication. Authors’ contributions Célia Depaulis was a major contributor in writing the manuscript. Nadia Steer, Léa Garessus, Dominique Chassard and Frederic Aubrun read and approved the final manuscript. No professional writer contributed. Bibliography Kpéa L, Bonnet M-P, Le Ray C, Prunet C, Ducloy-Bouthors A-S, Blondel B. Initial Preference for Labor Without Neuraxial Analgesia and Actual Use: Results from a National Survey in France. Anesth Analg. 2015 Sep;121(3):759–66. 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The incidence and etiology of postpartum headaches: a prospective cohort study. Can J Anaesth. 2005 Nov;52(9):971–7. Bleeker CP. Postpartum post-dural puncture headache: is your differential diagnosis complete? British Journal of Anaesthesia. 2004 Sep 1;93(3):461–4. Vandam LD, Dripps RD. Long-term follow-up of patients who received 10,098 spinal anesthetics; syndrome of decreased intracranial pressure (headache and ocular and auditory difficulties). J Am Med Assoc. 1956 Jun 16;161(7):586–91. Fournet-Fayard A, Malinovsky J-M. [Post-dural puncture headache and blood-patch: theoretical and practical approach]. Ann Fr Anesth Reanim. 2013 May;32(5):325–38. Candido KD, Stevens RA. Post-dural puncture headache: pathophysiology, prevention and treatment. Best Pract Res Clin Anaesthesiol. 2003 Sep;17(3):451–69. Schabel JE, Wang ED, Glass PS. Arm pain as an unusual presentation of postdural puncture intracranial hypotension. Anesth Analg. 2000 Oct;91(4):910–912, table of contents. Lybecker H, Andersen T, Helbo-Hansen HS. The effect of epidural blood patch on hearing loss in patients with severe postdural puncture headache. J Clin Anesth. 1995 Sep;7(6):457–64. Angle P, Tang SLT, Thompson D, Szalai JP. Expectant management of postdural puncture headache increases hospital length of stay and emergency room visits. Can J Anaesth. 2005 Apr;52(4):397–402. Loeser EA, Hill GE, Bennett GM, Sederberg JH. Time vs. success rate for epidural blood patch. Anesthesiology. 1978 Aug;49(2):147–8. Paech MJ, Doherty DA, Christmas T, Wong CA, Epidural Blood Patch Trial Group. The volume of blood for epidural blood patch in obstetrics: a randomized, blinded clinical trial. Anesth Analg. 2011 Jul;113(1):126–33. Safa-Tisseront V, Thormann F, Malassiné P, Henry M, Riou B, Coriat P, et al. Effectiveness of epidural blood patch in the management of post-dural puncture headache. Anesthesiology. 2001 Aug;95(2):334–9. Les blocs périmédullaires chez l’adulte. Annales Françaises d’Anesthésie et de Réanimation. 2007 Jul;26(7–8):720–52. van Kooten F, Oedit R, Bakker SLM, Dippel DWJ. Epidural blood patch in post dural puncture headache: a randomised, observer-blind, controlled clinical trial. J Neurol Neurosurg Psychiatr. 2008 May;79(5):553–8. Verduzco LA, Atlas SW, Riley ET. Subdural hematoma after an epidural blood patch. Int J Obstet Anesth. 2012 Apr;21(2):189–92. Diaz JH. Permanent paraparesis and cauda equina syndrome after epidural blood patch for postdural puncture headache. Anesthesiology. 2002 Jun;96(6):1515–7. Foster P. ACTH treatment for post-lumbar puncture headache. Br J Anaesth. 1994 Sep;73(3):429. Kshatri AM, Foster PA. Adrenocorticotropic hormone infusion as a novel treatment for postdural puncture headache. Reg Anesth. 1997 Oct;22(5):432–4. Collier BB. Treatment for post dural puncture headache. Br J Anaesth. 1994 Mar;72(3):366–7. Cánovas L, Barros C, Gómez A, Castro M, Castro A. Use of intravenous tetracosactin in the treatment of postdural puncture headache: our experience in forty cases. Anesth Analg. 2002 May;94(5):1369. Carter BL, Pasupuleti R. Use of intravenous cosyntropin in the treatment of postdural puncture headache. Anesthesiology. 2000 Jan;92(1):272–4. Gupta S, Agrawal A. Postdural puncture headache and ACTH. J Clin Anesth. 1997 May;9(3):258. Hakim SM. Cosyntropin for prophylaxis against postdural puncture headache after accidental dural puncture. Anesthesiology. 2010 Aug;113(2):413–20. Zeger W, Younggren B, Smith L. Comparison of cosyntropin versus caffeine for post-dural puncture headaches: A randomized double-blind trial. World J Emerg Med. 2012;3(3):182–5. Hanling SR, Lagrew JE, Colmenar DH, Quiko AS, Drastol CA. Intravenous Cosyntropin Versus Epidural Blood Patch for Treatment of Postdural Puncture Headache. Pain Med. 2016 Mar 25; Terenius L. Effect of peptides and amino acids on dihydromorphine binding to the opiate receptor. J Pharm Pharmacol. 1975 Jun;27(6):450–2. Terenius L, Gispen WH, De Wied D. ACTH-like peptides and opiate receptors in the rat brain: structure-activity studies. Eur J Pharmacol. 1975 Oct;33(2):395–9. Plomp GJ, Van Ree JM. Adrenocorticotrophic hormone fragments mimic the effect of morphine in vitro. Br J Pharmacol. 1978 Oct;64(2):223–7. Rucklidge MWM, Yentis SM, Paech MJ. Synacthen Depot for the treatment of postdural puncture headache. Anaesthesia. 2004 Feb;59(2):138–41. Hjermstad MJ, Fayers PM, Haugen DF, Caraceni A, Hanks GW, Loge JH, et al. Studies comparing Numerical Rating Scales, Verbal Rating Scales, and Visual Analogue Scales for assessment of pain intensity in adults: a systematic literature review. J Pain Symptom Manage. 2011 Jun;41(6):1073–93. Rucklidge OMWM. All patients with a postdural puncture headache should receive an epidural blood patch. International Journal of Obstetric Anesthesia. 2014 May;23(2):171–4. Aya AG, Mangin R, Nouvellon E, Robert C, Ferrer JM, Eledjam JJ. [Dural puncture in obstetric analgesia. Epidemiologic features and therapeutic management]. Ann Fr Anesth Reanim. 2001 Nov;20(9):757–62. Supplementary Files SPIRITchecklistEsybreche14112019.pdf Cite Share Download PDF Status: Published Journal Publication published 08 Jan, 2020 Read the published version in Trials → Version 3 posted Editorial decision: Accept 19 Dec, 2019 Review # 1 received at journal 18 Dec, 2019 Reviewers invited by journal 17 Dec, 2019 Reviewer # 1 agreed at journal 17 Dec, 2019 Editor assigned by journal 13 Dec, 2019 Submission checks completed at journal 12 Dec, 2019 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2982","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":255462,"identity":"8bd6dd5a-55a8-4e82-a647-b1d8a64a9897","order_by":1,"name":"Celia Depaulis","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBklEQVRIiWNgGAWjYFAC5oYDQALEYjyQwGADohsP4NfCCNfCANSSBhPBr4UBroWB4TCMgRvwtzc2HvjBYC1nzn7G4MCDP+ft1rYfBtpSYxONS4vEmYMNB3sY0o0te3IMDiS23U7ediYRqOVYWm4DDi0GEkAFPAyHEzccAGlpuJ1sBiQPMDYcxq1F/mHDwT8Mh+s3nH9jcCDhz7lks/MPCWiRAMoCbUkwuAG0JYHtgJ3ZDQK2SABdfljGIN1w54xnBUC/JCeY3QDakoDHL/zthw9/fFNhLW/On7zx4Y8/dvZm59MfPvhQY4NTC9R5YAQGiWCVCXiVI3SBgT0xikfBKBgFo2BkAQAu3GyndRXpEQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-4164-0202","institution":"Hospices Civils de Lyon","correspondingAuthor":true,"prefix":"","firstName":"Celia","middleName":"","lastName":"Depaulis","suffix":""},{"id":255463,"identity":"048829f4-ff77-4018-badd-6ded73017280","order_by":2,"name":"Nadia Steer","email":"","orcid":"","institution":"Hospices Civils de Lyon","correspondingAuthor":false,"prefix":"","firstName":"Nadia","middleName":"","lastName":"Steer","suffix":""},{"id":255464,"identity":"fa59824a-ee52-4ad9-a2bd-d587678cbc04","order_by":3,"name":"Léa Garessus ","email":"","orcid":"","institution":"Hospices Civils de Lyon","correspondingAuthor":false,"prefix":"","firstName":"Léa","middleName":"","lastName":"Garessus","suffix":""},{"id":255465,"identity":"ceeaf019-1eba-49da-b18d-9878e66021cd","order_by":4,"name":"Dominique Chassard","email":"","orcid":"","institution":"Hospices Civils de Lyon","correspondingAuthor":false,"prefix":"","firstName":"Dominique","middleName":"","lastName":"Chassard","suffix":""},{"id":255466,"identity":"106e97df-4029-4f18-b70f-46b52955ad9e","order_by":5,"name":"Frederic Aubrun","email":"","orcid":"","institution":"Hospices Civils de Lyon","correspondingAuthor":false,"prefix":"","firstName":"Frederic","middleName":"","lastName":"Aubrun","suffix":""}],"badges":[],"createdAt":"2019-07-26 12:25:55","currentVersionCode":3,"declarations":"","doi":"10.21203/rs.2.12203/v3","doiUrl":"https://doi.org/10.21203/rs.2.12203/v3","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-019-4015-y","type":"published","date":"2020-01-08T12:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":264791,"identity":"acca0956-09e3-4a00-bbe8-32baf8b6119f","added_by":"auto","created_at":"2019-12-16 17:57:33","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":40859,"visible":true,"origin":"","legend":"Questionnaire for qualitative assessment of activity limitation. A simple questionnaire corresponding to the needs of a postpartum patient.","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/22315254-4eb1-441d-872d-9d57bee443d9/v3/Fig 1.jpg"},{"id":264792,"identity":"e8601909-d978-4881-8b58-53b1e4812223","added_by":"auto","created_at":"2019-12-16 17:57:33","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":78290,"visible":true,"origin":"","legend":"Schedule of enrolment, intervention, and assessment.","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/22315254-4eb1-441d-872d-9d57bee443d9/v3/Fig 2.jpg"},{"id":13482170,"identity":"8fd6f3b2-5722-4e1e-a35e-2923a7e56f46","added_by":"auto","created_at":"2021-09-16 21:49:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":455359,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2982/v3/dfcc5e43-c169-45b2-92e3-9c570d60f7bf.pdf"},{"id":264790,"identity":"c82efa5d-1522-418b-9f8a-d2d894be40ee","added_by":"auto","created_at":"2019-12-16 17:57:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":122254,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITchecklistEsybreche14112019.pdf","url":"https://assets-eu.researchsquare.com/files/22315254-4eb1-441d-872d-9d57bee443d9/v3/SPIRIT_checklist Esybreche 14112019.pdf"}],"financialInterests":"","formattedTitle":"Evaluation of the effectiveness and tolerance of tetracosactide in the treatment of post-dural puncture headaches (ESYBRECHE): A study protocol for a randomized controlled trial","fulltext":[{"header":"Background","content":"\u003cp\u003eEpidural analgesia is the most effective method to control pain during labour and is frequently used in France (77% of vaginal deliveries in 2010) (1). For caesarean sections, artificial deliveries, or uterine revisions, spinal anaesthesia is preferred to general anaesthesia due to the risk associated with the latter in pregnant women (such as difficult management of airway) (2). However, neuraxial anaesthesia can also lead to adverse effects, in particular post-dural puncture headache (PDPH). The incidence of PDPH following dural puncture mainly depends on the type of needle used (diameter, bevel) (3\u0026ndash;10). For instance, incidence is reported to be between 0.7% and 4% when 24-27 G conical needles are used for spinal anaesthesia, and between 50% and 85% when large Tuohy needles are used for epidural analgesia (3,10,11). Since the incidence of dural puncture during epidural placement is reported to range from 0.04 to 6% (12), the incidence of PDPH among patients receiving these type of anaesthesia (spinal and epidural) is actually close. In addition, postpartum women are more prone to PDPH than the general population (13\u0026ndash;15).Epidural analgesia is the most effective method to control pain during labour and is frequently used in France (77% of vaginal deliveries in 2010) (1). For caesarean sections, artificial deliveries, or uterine revisions, spinal anaesthesia is preferred to general anaesthesia due to the risk associated with the latter in pregnant women (such as difficult management of airway) (2). However, neuraxial anaesthesia can also lead to adverse effects, in particular post-dural puncture headache (PDPH). The incidence of PDPH following dural puncture mainly depends on the type of needle used (diameter, bevel) (3\u0026ndash;10). For instance, incidence is reported to be between 0.7% and 4% when 24-27 G conical needles are used for spinal anaesthesia, and between 50% and 85% when large Tuohy needles are used for epidural analgesia (3,10,11). Since the incidence of dural puncture during epidural placement is reported to range from 0.04 to 6% (12), the incidence of PDPH among patients receiving these type of anaesthesia (spinal and epidural) is actually close. In addition, postpartum women are more prone to PDPH than the general population (13\u0026ndash;15).\u003c/p\u003e\n\u003cp\u003e\u003cbr /\u003ePDPH is a clinical diagnosis. According to the International Headache Society, it is a severe postural, bilateral, disabling, constrictive, occipital or diffuse headache that radiates to the neck, and develops within 7 days after the dural puncture. In 66% of cases it occurs during the first 48 hours, and in 90% of cases during the first 3 days (3). PDPH is aggravated by a sitting or standing position and is relieved by lying down. Other symptoms such as neck stiffness, hearing disorders (tinnitus, hypoacusia) (16), dizziness, photophobia, nausea or vomiting, and diplopia by injury of the cranial nerve IV (17) may be associated with the headache and patients remain afebrile. Differential diagnoses are migraine, pre-eclampsia, meningitis, intracranial haemorrhage, cerebral thrombosis, pneumocephalus, and tension headaches (18,19).\u003c/p\u003e\n\u003cp\u003e\u003cbr /\u003eAs described by Vandam and Dripps as early as 1956 (20), the main cause of PDPH appears to be intracranial hypotension by leakage of cerebrospinal fluid (CSF). CSF is critical in reducing impacts between the brain and the cranium during orthostatism, and the loss of this cushioning leads to headaches. Furthermore, the cerebral and meningeal vessels are stressed by the downward displacement of the brain during orthostatism. This caudal traction activates the stretch-sensitive receptors of the trigeminal nerves (frontal headache), glosso-pharyngeal and vagus nerves (occipital headache) (11,21,22), and the first three cervical nerves (arm pain or neck pain) (23). According to the Monro-Kellie theory, headaches may also be related to painful venous and arterial cerebral vasodilation which compensates for decreased CSF volume (3,21). In the inner ear, hypotension of the perilymph also causes an imbalance between endolymph and perilymph itself leading to hearing impairment, tinnitus, and/or vertigo (16,24).\u003c/p\u003e\n\u003cp\u003e\u003cbr /\u003eIn most cases, dural puncture closes spontaneously without consequence. PDPH is reported to resolve in more than 50% of patients within 4 days, and in more than 70% within a week. However, headache may persist in a limited number of patients (3,20). PDPH can limit patients\u0026rsquo; activity, increase the duration of hospital stay and use of care (25), and is particularly disabling during the postpartum period, when the mother has to take care of her child. It is therefore important to treat this syndrome. Epidural blood patch is currently the gold standard and most effective treatment for PDPH. However, the timing for this treatment remains uncertain. Some studies have suggested a greater risk of failure when administering an early blood patch although no causal link could be established (26\u0026ndash;28). The diminished effectiveness in this case, could be explained by the severity of the CSF leak (28). Conversely, administering a delayed blood patch could increase bed rest duration. A delay of 24 to 36 hours between the onset of headaches and the completion of a blood patch seems reasonable. However, it is recommended not to delay the blood patch by more than 48 hours (29).\u003c/p\u003e\n\u003cp\u003e\u003cbr /\u003eHistorically, the reported success rate after the first blood patch is around 80% (28,30). Recently, however, efficacy has been found to be lower (32% at most) (27).\u0026nbsp; Moreover, it is an invasive procedure that may result in rare but serious complications such as spinal subdural hematoma (31) or permanent paraparesis and cauda equina syndrome (32). It may also trigger anxiety and discomfort in patients and can sometimes be painful (back pain, transient bradycardia).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cbr /\u003eAlternative treatments have recently been studied; they aim to be less invasive or to reduce headache intensity whilst waiting for the blood patch or the disappearance of PDPH. Several lines of evidence have suggested the effectiveness of adrenocorticotropic hormone (ACTH) in the management of PDPH (33\u0026ndash;41). Several mechanisms have been proposed to explain the effects of ACTH or its analogues on headaches. First, it has been shown by several teams that fragments of ACTH interact with opioid receptors in vitro and have morphine-like effects in vivo (42\u0026ndash;44). Second, ACTH may increase brain \u0026beta;-endorphins which can change the perception of pain (35\u0026ndash;37). Third, ACTH stimulates the adrenal cortex, which releases different hormones such as glucocorticoids, androgens, and mineralocorticoids. Glucocorticoids have an anti-inflammatory effect that may explain in part the analgesia observed after ACTH injection (38). Fourth, mineralocorticoids are responsible for fluid retention that may lead to meningeal oedema and overlapping edges of the dural puncture (36).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe trial reported by Hakim found that administration of tetracosactide after accidental dural puncture in 90 parturients was associated with a significant reduction in the incidence of PDPH and requirement for epidural blood patch (39). The efficacy of tetracosactide for the treatment of PDPH in 32 patients has been reported to be 56% (95% CI [33; 79%]) (40), and to be similar to that of epidural blood patch in a study that included 28 patients (41), although 4 of the 15 in the tetracosactide group also received a blood patch. However, a randomized trial that included 18 patients did not find any efficacy of tetracosactide in the treatment of PDPH, nor in the reduction of blood patch use (45). This study was conducted among a small group of patients, and did not report any data on the interval between PDPH onset and blood patch. Taken together, efficacy evidence of ACTH analogues on PDPH remains limited with contradictory results obtained in small groups of patients. It is therefore difficult to conclude and establish a protocol for the management of PDPH.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the proposed study, we have designed a therapeutic trial to evaluate the efficacy of tetracosactide in the treatment of PDPH in 88 postpartum patients.\u0026nbsp;\u003c/p\u003e"},{"header":"Methods/Design","content":"\u003cp\u003e\u003ca name=\"_Toc505708989\"\u003e\u003c/a\u003e\u003cstrong\u003e1.3.1 Aim of the study\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe aim of this study is to assess the efficacy and safety of tetracosactide (Synacthen\u003csup\u003e\u0026reg;\u003c/sup\u003e) in the treatment of post-dural puncture syndrome for patients who received neuraxial anaesthesia during childbirth.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur working hypothesis is that a single intravenous infusion of tetracosactide may avoid the need for epidural blood patch. To challenge this hypothesis two groups will be compared: the study group receiving an infusion of 1 mg of tetracosactide and the control group receiving a placebo (0.9% saline). Both groups receive standard analgesic treatment and epidural blood patch if needed (after a minimum of 24 h following the injection of the experimental treatment).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003ca name=\"_Toc505708990\"\u003e\u003c/a\u003e\u003cstrong\u003e1.3.2 Trial Design\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study is a randomised, double-blind, placebo-controlled, parallel-arm, double-centre trial. It is conducted in two different sites, both are part of the same French university hospital. Patient enrolment started in October 2016 and was expected to be completed within 2 years after the start of the study. However, this did not happen as explained in section 1.3.11.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOnce participants are enrolled in the study with informed consent, they are randomised into the two study arms. The study group receives 1 mg of tetracosactide intravenously whereas the control group receives 0.9% saline. Outcomes will be measured between 2 and 6 hours, on day 1, day 2, day 3, and between days 13 and 17 post-randomisation. Adverse events are collected throughout the study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003ca name=\"_Toc505708991\"\u003e\u003c/a\u003e\u003cstrong\u003e1.3.3 Primary endpoint\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe primary endpoint of the study is the rate of epidural blood patch within a 15-day follow-up period. That is, the number of patients who receive a blood patch within the 15-day period divided by the total number of participants included.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003ca name=\"_Toc505708992\"\u003e\u003c/a\u003e\u003cstrong\u003e1.3.4 Secondary endpoint\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe secondary endpoints are:\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003eduration of headache: mean number of days with headache within the 15-day follow-up period\u003c/li\u003e\n\u003cli\u003eintensity of headache (11-point numerical rating\u0026nbsp;scale, NRS) (46): mean NRS at day 1, 2, 3, and 15\u003c/li\u003e\n\u003cli\u003ethe need for analgesic treatment (descriptive analysis of type, time interval after study treatment initiation, and duration) within the 15-day follow-up period\u003c/li\u003e\n\u003cli\u003eappearance of associated features (neck stiffness, tinnitus, hypoacusia, photophobia, diplopia, dizziness, or nausea): descriptive analysis of these features within the 15-day follow-up period\u003c/li\u003e\n\u003cli\u003eactivity limitation (self-assessed, both qualitatively as described in Figure 1, and quantitatively on a scale from 0 to 100%): mean score at day 1, 2, 3 and 15\u003c/li\u003e\n\u003cli\u003elength of hospital stay: mean number of days spent in hospital assessed from inclusion to day 15\u003c/li\u003e\n\u003cli\u003ethe number of epidural blood patches performed per patient: mean number within the 15-day follow-up period\u003c/li\u003e\n\u003cli\u003etolerance, assessed by the collection of all adverse events (type, frequency, severity)\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003ca name=\"_Toc505708993\"\u003e\u003c/a\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.3.5 Population\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNumber of patients needed\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe sample size calculation is based on a previous study that investigated tetracosactide in PDPH (39) and, retrospectively, on observational data obtained from our hospital database. The primary endpoint is the rate of blood patch in the two groups. We defined the efficacy of tetracosactide as a decrease in blood patch use by 30% in the tetracosactide group, a clinically relevant difference reducing the need for invasive treatment and replacing it with an easily administered treatment that has a known safety profile.\u003c/p\u003e\n\u003cp\u003eIn our centre, 90% of patients with PDPH after epidural analgesia receive a blood patch. The study reported by Hakim (39) found a greater than 50% decrease in PDPH incidence and blood patch use after prophylactic treatment with tetracosactide, in a context of epidural analgesia. We therefore need to include 44 subjects in each group, given a power of 0.80 and type I error of 0.025 (\u0026alpha;=2.5% Fisher\u0026rsquo;s exact test, power of 80%, p1=0.9; p2=0.6), to reduce blood patch requirement by 30%. Thus a total of 88 patients need to be randomised.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients eligible for enrolment in this clinical trial are those suffering from PDPH due to epidural analgesia, combined spinal-epidural analgesia, or spinal anaesthesia for childbirth.\u003c/p\u003e\n\u003cp\u003eThe headache characteristics should be as follows:\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003ewithin five days after delivery\u003c/li\u003e\n\u003cli\u003erelieved in the supine position and/or worse while sitting or standing\u003c/li\u003e\n\u003cli\u003eintense (NRS \u0026gt;3/10)\u003c/li\u003e\n\u003cli\u003ewith or without: neck stiffness, tinnitus, hypoacusia, photophobia, visual impairment, nausea or vomiting\u003c/li\u003e\n\u003cli\u003eafter having eliminated differential diagnosis: pre-eclampsia or eclampsia, cerebral venous thrombosis, migraine.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003ePatients must be at least 18 years old and benefit from healthcare insurance. They also have to provide a written informed consent.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eExclusion criteria are as follows:\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003ediplopia (which requires an epidural blood patch without delay)\u003c/li\u003e\n\u003cli\u003econtraindication to ACTH: uncontrolled\u0026nbsp;arterial hypertension, uncontrolled diabetes mellitus, acute psychosis, infectious diseases\u003c/li\u003e\n\u003cli\u003econtraindication to tetracosactide:\n\u003cul\u003e\n\u003cli\u003ecurrently receiving a drug associated with an increased risk of Torsades de Pointes: astemizole, bepridil, IV erythromycin, halofantrine, pentamidine, sparfloxacine, sultopride, terfenadine, vincamine\u003c/li\u003e\n\u003cli\u003epatient who received a live vaccine in the month prior to inclusion\u003c/li\u003e\n\u003c/ul\u003e\n\u003c/li\u003e\n\u003cli\u003eprevious history of hypersensitivity to tetracosactide\u003c/li\u003e\n\u003cli\u003epatient who has received tetracosactide since childbirth\u003c/li\u003e\n\u003cli\u003econtraindication to epidural blood patch: HIV, HVC, leukocytosis, fever\u003c/li\u003e\n\u003cli\u003epre-eclampsia or eclampsia during the current pregnancy (may be confounding for the etiology of headache)\u003c/li\u003e\n\u003cli\u003epatient who has already received a prophylactic blood patch (at the time of accidental dural puncture diagnosis)\u003c/li\u003e\n\u003cli\u003eUnder 18 years old or adult under guardianship\u003c/li\u003e\n\u003cli\u003eMental disorder which does not allow informed consent\u003c/li\u003e\n\u003cli\u003ePatients who are enrolled in another clinical trial\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWhen PDPH diagnosis is made by the anaesthesiologist, screening of patients for inclusion and exclusion criteria is performed. The investigator then presents the study to the patients. Written information is provided to the patients. Patients are given some time to think before committing to the study. Final inclusion occurs shortly after they have read the information letter, raised questions they may have, and signed the written informed consent.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003ca name=\"_Toc505708994\"\u003e\u003c/a\u003e\u003cstrong\u003e1.3.6 Randomisation, blinding, and data management\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe anaesthesiologist checks the patient\u0026rsquo;s inclusion criteria and the absence of exclusion criteria. After signing of the informed consent, patients are randomised online using the ClinSight-Online software program (Ennov society, Paris, France). The randomisation list was compiled by a statistician, entered into the software and communicated to the pharmacist to prepare the numbered treatment kits. The randomization is performed by block stratification according to site. Patients are allocated to a treatment number (by the ClinSight software). The study is performed double-blinded; both patients and the medical team are blinded to treatment allocation. An aneaesthetic nurse prepares the treatment according to the assigned number to which the rest of the healthcare team is blinded. Patient data are collected on electronic case report forms (eCRFs). The sponsor will independently monitor both locations of this multisite trial every ten patients. This data monitoring is performed by a clinical research associate (CRA). His/her role is to check the consent form, the quality of data collection (missing data, data entry errors\u0026hellip;), the availability of treatment at each site, the pharmacy process, and the declaration of any serious adverse event. He/she is employed by the sponsor but is independent of the investigators and is not involved in carrying out the study or interpretation of the results. Anonymized data are only accessible to the investigators, the sponsor, and other authorized persons (statistician, data manager\u0026hellip;). They will be stored confidentially for 15 years by the sponsor. They will not be used for further studies without further patient agreement. At the end of the study, we plan to communicate trial results to participants, healthcare professionals, and the public via a peer-reviewed publication. Authors will be considered in the case of a substantial contribution to the conception or design of the study or the acquisition, analysis, or interpretation of data.\u0026nbsp; They will need to have drafted the work or revised it critically. They will all approve the final version to be published. We do not expect the participation of a professional writer. Data not disclosed in the publication will not be accessible.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003ca name=\"_Toc505708995\"\u003e\u003c/a\u003e\u003cstrong\u003e1.3.7 Intervention protocols\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDuring the post-partum period, patients are usually followed by midwives. In case of headache, whether an accidental dural puncture is diagnosed or not, the anaesthesiologist is informed by midwives. Therefore, any symptomatic patient is examined by an anaesthesiologist. \u0026nbsp;The study investigators are the anaesthesiologists working in the maternity department of the two centres.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatients are enrolled when diagnosed with PDPH based on the anaesthesiologist\u0026rsquo;s clinical evaluation. They are randomised to receive intravenous tetracosactide or placebo. In the study group, patients receive a single intravenous injection of 1 mg tetracosactide (Synacthen\u003csup\u003e\u0026reg;\u003c/sup\u003e, Sigma-Tau laboratory, Roma, Italy). Four vials containing 0.25mg tetracosactide (in 1 ml of solvent) are reconstituted in 100 ml of normal saline (0.9% NaCl). This solution is infused intravenously over 20 min. In the control group, patients receive an equal volume of normal saline: 104 ml over 20 min. The whole intervention is administered over a 20 minute course and therefore is not modifiable once begun except for the occurrence of a side effect. A side effect is defined herein as any new abnormality observed upon clinical examination, occurring during the injection. In this case, the treatment is immediately stopped but monitoring and data collection continues.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStandard analgesic medication, as concomitant treatments, is also initiated in both groups from the beginning of headache, as follows:\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003efor mild headache (NRS\u0026lt;3/10): 1 g paracetamol and 400 mg ibuprofen orally every 6 hours\u003c/li\u003e\n\u003cli\u003efor moderate headache (NRS=3):\u0026nbsp;nefopam 20 mg and/or a combination of paracetamol 300 mg and opium 10 mg is given in addition every 4 hours\u003c/li\u003e\n\u003cli\u003efor severe headache (NRS\u0026ge;4): morphine 10 mg orally every 4 hours can be added as required\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThese treatments are adjusted daily.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe primary and secondary endpoint, including tolerance criteria, are evaluated blinded during infusion of the study treatment, 2-6 hours later, 1 day, 2 days, 3 days, and between 13 and 17 days post-treatment by the investigator. The latter is conducted by phone call in order to increase the complete follow-up. The total duration of the study is therefore 13 to 17 days. Any alternative analgesic intervention required after receiving the study treatment is reported at each time point as indicated above. The study timeline is summarised in Figure 2.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEpidural blood patch is performed for patients who reported a persistent moderate to severe headache a minimum of 24 hours after administration of the study treatment and 36 hours after the dural puncture, based on the clinical appreciation of the anaesthesiologist. Epidural blood patch can be repeated twice if required (i.e. if headache does not improve or if it increases again). The anaesthesiologist performs the epidural blood patch. Autologous blood is injected into the epidural space using an 18 gauge Tuohy needle. The injection is stopped when the patient feels pressure in the lower back or pain.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003ca name=\"_Toc505708996\"\u003e\u003c/a\u003e\u003cstrong\u003e1.3.8 Statistical analysis\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUnblinding occurs at the end of the study and once the database has been frozen. Analyses will be carried out on an intention-to-treat (ITT) basis. If data is missing from visits, we will carry forward the last value considering the pain (and others symptoms) has not improved. This is the most pessimistic scenario for this condition which usually improves spontaneously. Blood patch can only be performed at the hospital, and it is therefore very unlikely that there will be missing data regarding the primary endpoint. If a patient does not receive full treatment, she will be included in the group to which she was randomised for further ITT analysis. Statistical analyses will be performed using IBM SPSS statistics for windows (IBM corp., Armonk, NY, USA) and R (R Foundation for Statistical Computing, Vienna, Austria). All data will be checked for normal distribution using the Kolmogorov test. For normally distributed data, variables will be presented as mean \u0026plusmn; standard deviation (SD). Non-normally distributed data will be presented as the median and interquartile range [IQR]. Categorical variables will be presented as number and percentage of the total. To compare the two groups (tetracosactide and placebo), we will use Fisher\u0026rsquo;s exact test for qualitative data and the non-parametric Mann-Whitney tests for quantitative variables. A comparison of the two groups at randomisation will identify potential bias due to unequal allocation. A multivariate logistic regression analysis will be performed to study factors independently associated with the response to tetracosactide and to control potential confounding factors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntermediate analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe hypothesis of a 30% difference between the two groups is conservative compared to the 50% reduction reported by Hakim (39); a difference of only 30% between the two groups should already be clinically relevant. An interim analysis is therefore planned after the enrolment of 44 patients. The overall alpha risk will be adjusted according to the Bonferroni method and will be 2.5% (5% / 2). A p value \u0026lt;0.025 will therefore be considered statistically significant. If this initial analysis is statistically significant (p \u0026lt;0.025), the independent monitoring committee may decide to stop the study without waiting for the planned recruitment. Otherwise, the study will be continued until the inclusion of 88 patients.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003ca name=\"_Toc505708997\"\u003e\u003c/a\u003e\u003cstrong\u003e1.3.9 Ethical approval\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis trial is conducted in accordance with the protocol and in compliance with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki (1989) and Good Clinical Practice (GCP). It is also conducted in accordance with French legislation (Public Health Code; Act No. 2004-806 of August 9, 2004). It is registered in the Clinical Trial Protocol Registration and Results System: NCT02813655 (registration date: June 24, 2016). An ethics committee (\u003cem\u003ecomit\u0026eacute; de protection des personnes sud Est V\u003c/em\u003e, CPP) has approved the study for both participating sites on April 6, 2016. The national drugs authority (\u003cem\u003eAgence Nationale de S\u0026eacute;curit\u0026eacute; du M\u0026eacute;dicament et des produits de sant\u0026eacute;\u003c/em\u003e, ANSM) authorised this trial (authorisation date: April 18, 2016).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003ca name=\"_Toc505708998\"\u003e\u003c/a\u003e\u003cstrong\u003e1.3.10. Adverse events management\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDuring the study period, adverse events will be reported and recorded in the participants\u0026rsquo; CRF. Adverse events include any new abnormality observed upon clinical examination, occurring during the study treatment injection or the follow-up period, or any allergic reaction to the treatment. The severity of adverse events will be graded as mild, moderate, severe, life threatening, or death, and the potential relationship between the adverse event and the study treatment will be assessed by clinical judgment. If an adverse event requiring hospitalisation extension or causing a medically critical situation occurs, the event will be recorded as a severe adverse event. All severe and life threatening adverse events or death will be reported to the investigator and to the sponsor within 24 hours after the information has been collected. The sponsor will report all such events to legal authorities (ANSM and CPP). The investigator must follow patients until the adverse event has been resolved. All adverse events collected will be described in the trial publication. A severe adverse event is the only reason for unblinding participants and providers before the end of the study. It will be performed by the poison control centre (\u003cem\u003eCentre anti-poison\u003c/em\u003e) which is independent of the study and is the only party with access to the randomisation list.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.3.11. Protocol amendment\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBecause patient enrolment/inclusion was more difficult than expected, the protocol was amended (January 2017) to extend inclusion from PDPH due to a dural puncture carried out by large Tuohy needle to all postpartum PDPH, i.e. PDPH related to a large dural puncture and PDPH related to small needle (25-27G) for spinal anaesthesia. For this reason, a second amendment (November 2018) extended the inclusion period until October 10, 2021.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe propose herein a protocol to investigate the use of tetracosactide, an ACTH analogue, to treat PDPH. Blood-patch is currently the gold standard for PDPH treatment, and tetracosactide could be interesting as it would reduce the need for the invasive procedure and replace it with an easily administered treatment that has a known safety profile. Given previous results obtained in small groups of patients, efficacy evidence of ACTH analogues for PDPH treatment remains limited.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInitially, the inclusion was limited to PDPH due to a dural puncture carried out by a large Tuohy needle. Because patient enrolment/inclusion was more difficult than expected, the protocol was amended to extend inclusion to all postpartum PDPH. This widening of the inclusion criteria raises the issue of population heterogeneity, which we hope to limit by the randomisation process.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSince the management strategy of PDPH (using blood-patch and non-invasive treatments) is not clearly defined, the rate of blood-patch varies. Rucklidge, for example, described that 50 blood-patches were received by 144 patients treated for PDPH after epidural anaesthesia over 20 years in the hospital in which he practiced (47); the blood-patch rate was therefore 35%. In the study reported by Aya et al. all patients (100%) treated for PDPH after epidural obstetric anaesthesia in their unit received a blood-patch (48). Therefore, a potential limitation of the study described herein is that the sample size could be insufficient if the rate of blood patch in the control group is lower than 90%.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003ca name=\"_Toc505709000\"\u003e\u003c/a\u003e\u003cstrong\u003eTrial status\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIt is the fourth protocol version dated September 28, 2018. The study is ongoing; the first patient was included in October 2016, and in May 2019 a total of 25 patients had been enrolled. Initially we expected to finalise the study in October 2018, but we had to extend the inclusion phase until 2021 to reach a total of 88 inclusions. Due to the ongoing nature of the study and in order to avoid influencing its conduct, the final results are not presented herein. An intermediate analysis will be performed after 44 inclusions, and if there is a significant difference between the two groups concerning the primary outcome, the study will be discontinued.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe expect a decrease in the use of epidural blood patch in those receiving tetracosactide, thus indicating a decrease in PDPH symptoms for these patients. This will define the therapeutic success of tetracosactide and the possibility to use this treatment as a non-invasive alternative to blood patch for PDPH treatment. \u003c/p\u003e"},{"header":"List of abbreviations","content":"\u003cp\u003eACTH Adrenocorticotropic Hormone\u003c/p\u003e\n\u003cp\u003eANSM \u003cem\u003eAgence Nationale de S\u0026eacute;curit\u0026eacute; du M\u0026eacute;dicament et des produits de sant\u0026eacute;\u003c/em\u003e\u0026nbsp;: the national drugs authority\u003c/p\u003e\n\u003cp\u003eCPP \u003cem\u003eComit\u0026eacute; de Protection des Personnes\u003c/em\u003e : an ethics committee\u003c/p\u003e\n\u003cp\u003eCRA Clinical Research Associate\u003c/p\u003e\n\u003cp\u003eCSF Cerebrospinal Fluid\u003c/p\u003e\n\u003cp\u003eeCRFs electronic Case Report Forms\u003c/p\u003e\n\u003cp\u003eGCP Good Clinical Practice\u003c/p\u003e\n\u003cp\u003eHIV Human Immunodeficiency Virus\u003c/p\u003e\n\u003cp\u003eHCV Hepatitis C Virus\u003c/p\u003e\n\u003cp\u003eIQR Interquartile Range\u003c/p\u003e\n\u003cp\u003eITT Intention-To-Treat\u003c/p\u003e\n\u003cp\u003eNRS Numerical Rating\u0026nbsp;Scale\u003c/p\u003e\n\u003cp\u003ePDPH Post-Dural Puncture Headache\u003c/p\u003e\n\u003cp\u003eSD Standard Deviation\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn ethics committee (\u003cem\u003ecomit\u0026eacute; de protection des personnes sud Est V\u003c/em\u003e, CPP) has approved the study for both participating sites on 6 April 2016. Patients are given some time to think before committing to the study. Final inclusion occurs shortly after they have read the information letter, raised questions they may have, and signed the written informed consent.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData sharing is not applicable to this article as no datasets were yet generated or analyzed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflict of interest to declare.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study is funded by grants from \u003cem\u003eFondation Apicil\u003c/em\u003e and \u003cem\u003eFondation de France.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFunders have no role in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eC\u0026eacute;lia Depaulis was a major contributor in writing the manuscript. Nadia Steer, L\u0026eacute;a Garessus, Dominique Chassard and Frederic Aubrun read and approved the final manuscript. No professional writer contributed.\u003c/p\u003e"},{"header":"Bibliography","content":"\u003col\u003e\n\u003cli\u003eKp\u0026eacute;a L, Bonnet M-P, Le Ray C, Prunet C, Ducloy-Bouthors A-S, Blondel B. Initial Preference for Labor Without Neuraxial Analgesia and Actual Use: Results from a National Survey in France. Anesth Analg. 2015 Sep;121(3):759\u0026ndash;66.\u003c/li\u003e\n\u003cli\u003eYıldırım İ, İnal MT, Memiş D, Turan FN. Determining the Efficiency of Different Preoperative Difficult Intubation Tests on Patients Undergoing Caesarean Section. Balkan Med J. 2017 Sep 29;34(5):436\u0026ndash;43.\u003c/li\u003e\n\u003cli\u003eTurnbull DK, Shepherd DB. Post-dural puncture headache: pathogenesis, prevention and treatment. Br J Anaesth. 2003 Nov;91(5):718\u0026ndash;29.\u003c/li\u003e\n\u003cli\u003eMatas SL de A. Why should we use atraumatic needles in lumbar puncture? Arquivos de Neuro-Psiquiatria. 2013 Sep;71(9B):681\u0026ndash;4.\u003c/li\u003e\n\u003cli\u003eEvans RW, Armon C, Frohman EM, Goodin DS. Assessment: prevention of post-lumbar puncture headaches: report of the therapeutics and technology assessment subcommittee of the american academy of neurology. Neurology. 2000 Oct 10;55(7):909\u0026ndash;14.\u003c/li\u003e\n\u003cli\u003eFlaatten H, Felthaus J, Kuwelker M, Wisborg T. Postural post-dural puncture headache. A prospective randomised study and a meta-analysis comparing two different 0.40 mm O.D. (27 g) spinal needles. Acta Anaesthesiol Scand. 2000 Jul;44(6):643\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eLambert DH, Hurley RJ, Hertwig L, Datta S. Role of needle gauge and tip configuration in the production of lumbar puncture headache. Reg Anesth. 1997 Feb;22(1):66\u0026ndash;72.\u003c/li\u003e\n\u003cli\u003eLavi R, Yarnitsky D, Yernitzky D, Rowe JM, Weissman A, Segal D, et al. Standard vs atraumatic Whitacre needle for diagnostic lumbar puncture: a randomized trial. Neurology. 2006 Oct 24;67(8):1492\u0026ndash;4.\u003c/li\u003e\n\u003cli\u003eHalpern S, Preston R. Postdural puncture headache and spinal needle design. Metaanalyses. Anesthesiology. 1994 Dec;81(6):1376\u0026ndash;83.\u003c/li\u003e\n\u003cli\u003eChoi PT, Galinski SE, Takeuchi L, Lucas S, Tamayo C, Jadad AR. PDPH is a common complication of neuraxial blockade in parturients: a meta-analysis of obstetrical studies. Can J Anaesth. 2003 May;50(5):460\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eDiemunsch P, Schlotterbeck H, Pottecher J. Br\u0026egrave;ches dure-m\u0026eacute;ro-arachno\u0026iuml;diennes. Conf\u0026eacute;rence d\u0026rsquo;actualisation 2003 [Internet]. SFAR. 2003; Available from: http://www.sfar.org/acta/dossier/archives/ca03/html/ca03_09/ca03_09.htm\u003c/li\u003e\n\u003cli\u003eBasurto Ona X, Uriona Tuma SM, Mart\u0026iacute;nez Garc\u0026iacute;a L, Sol\u0026agrave; I, Bonfill Cosp X. Drug therapy for preventing post-dural puncture headache. Cochrane Database Syst Rev. 2013;2:CD001792.\u003c/li\u003e\n\u003cli\u003eWu CL, Rowlingson AJ, Cohen SR, Michaels RK, Courpas GE, Joe EM, et al. Gender and post-dural puncture headache. Anesthesiology. 2006 Sep;105(3):613\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eDiaz JH. Epidemiology and outcome of postural headache management in spontaneous intracranial hypotension. Reg Anesth Pain Med. 2001 Dec;26(6):582\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eBezov D, Lipton RB, Ashina S. Post-Dural Puncture Headache: Part I Diagnosis, Epidemiology, Etiology, and Pathophysiology. Headache: The Journal of Head and Face Pain. 2010 Jun 1;50(7):1144\u0026ndash;52.\u003c/li\u003e\n\u003cli\u003ePogodzinski MS, Shallop JK, Sprung J, Weingarten TN, Wong GY, McDonald TJ. Hearing loss and cerebrospinal fluid pressure: case report and review of the literature. Ear Nose Throat J. 2008 Mar;87(3):144\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eNishio I, Williams BA, Williams JP. Diplopia: a complication of dural puncture. Anesthesiology. 2004 Jan;100(1):158\u0026ndash;64.\u003c/li\u003e\n\u003cli\u003eGoldszmidt E, Kern R, Chaput A, Macarthur A. The incidence and etiology of postpartum headaches: a prospective cohort study. Can J Anaesth. 2005 Nov;52(9):971\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eBleeker CP. Postpartum post-dural puncture headache: is your differential diagnosis complete? British Journal of Anaesthesia. 2004 Sep 1;93(3):461\u0026ndash;4.\u003c/li\u003e\n\u003cli\u003eVandam LD, Dripps RD. Long-term follow-up of patients who received 10,098 spinal anesthetics; syndrome of decreased intracranial pressure (headache and ocular and auditory difficulties). J Am Med Assoc. 1956 Jun 16;161(7):586\u0026ndash;91.\u003c/li\u003e\n\u003cli\u003eFournet-Fayard A, Malinovsky J-M. [Post-dural puncture headache and blood-patch: theoretical and practical approach]. Ann Fr Anesth Reanim. 2013 May;32(5):325\u0026ndash;38.\u003c/li\u003e\n\u003cli\u003eCandido KD, Stevens RA. Post-dural puncture headache: pathophysiology, prevention and treatment. Best Pract Res Clin Anaesthesiol. 2003 Sep;17(3):451\u0026ndash;69.\u003c/li\u003e\n\u003cli\u003eSchabel JE, Wang ED, Glass PS. Arm pain as an unusual presentation of postdural puncture intracranial hypotension. Anesth Analg. 2000 Oct;91(4):910\u0026ndash;912, table of contents.\u003c/li\u003e\n\u003cli\u003eLybecker H, Andersen T, Helbo-Hansen HS. The effect of epidural blood patch on hearing loss in patients with severe postdural puncture headache. J Clin Anesth. 1995 Sep;7(6):457\u0026ndash;64.\u003c/li\u003e\n\u003cli\u003eAngle P, Tang SLT, Thompson D, Szalai JP. Expectant management of postdural puncture headache increases hospital length of stay and emergency room visits. Can J Anaesth. 2005 Apr;52(4):397\u0026ndash;402.\u003c/li\u003e\n\u003cli\u003eLoeser EA, Hill GE, Bennett GM, Sederberg JH. Time vs. success rate for epidural blood patch. Anesthesiology. 1978 Aug;49(2):147\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003ePaech MJ, Doherty DA, Christmas T, Wong CA, Epidural Blood Patch Trial Group. The volume of blood for epidural blood patch in obstetrics: a randomized, blinded clinical trial. Anesth Analg. 2011 Jul;113(1):126\u0026ndash;33.\u003c/li\u003e\n\u003cli\u003eSafa-Tisseront V, Thormann F, Malassin\u0026eacute; P, Henry M, Riou B, Coriat P, et al. Effectiveness of epidural blood patch in the management of post-dural puncture headache. Anesthesiology. 2001 Aug;95(2):334\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eLes blocs p\u0026eacute;rim\u0026eacute;dullaires chez l\u0026rsquo;adulte. Annales Fran\u0026ccedil;aises d\u0026rsquo;Anesth\u0026eacute;sie et de R\u0026eacute;animation. 2007 Jul;26(7\u0026ndash;8):720\u0026ndash;52.\u003c/li\u003e\n\u003cli\u003evan Kooten F, Oedit R, Bakker SLM, Dippel DWJ. Epidural blood patch in post dural puncture headache: a randomised, observer-blind, controlled clinical trial. J Neurol Neurosurg Psychiatr. 2008 May;79(5):553\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eVerduzco LA, Atlas SW, Riley ET. Subdural hematoma after an epidural blood patch. Int J Obstet Anesth. 2012 Apr;21(2):189\u0026ndash;92.\u003c/li\u003e\n\u003cli\u003eDiaz JH. Permanent paraparesis and cauda equina syndrome after epidural blood patch for postdural puncture headache. Anesthesiology. 2002 Jun;96(6):1515\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eFoster P. ACTH treatment for post-lumbar puncture headache. Br J Anaesth. 1994 Sep;73(3):429.\u003c/li\u003e\n\u003cli\u003eKshatri AM, Foster PA. Adrenocorticotropic hormone infusion as a novel treatment for postdural puncture headache. Reg Anesth. 1997 Oct;22(5):432\u0026ndash;4.\u003c/li\u003e\n\u003cli\u003eCollier BB. Treatment for post dural puncture headache. Br J Anaesth. 1994 Mar;72(3):366\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eC\u0026aacute;novas L, Barros C, G\u0026oacute;mez A, Castro M, Castro A. Use of intravenous tetracosactin in the treatment of postdural puncture headache: our experience in forty cases. Anesth Analg. 2002 May;94(5):1369.\u003c/li\u003e\n\u003cli\u003eCarter BL, Pasupuleti R. Use of intravenous cosyntropin in the treatment of postdural puncture headache. Anesthesiology. 2000 Jan;92(1):272\u0026ndash;4.\u003c/li\u003e\n\u003cli\u003eGupta S, Agrawal A. Postdural puncture headache and ACTH. J Clin Anesth. 1997 May;9(3):258.\u003c/li\u003e\n\u003cli\u003eHakim SM. Cosyntropin for prophylaxis against postdural puncture headache after accidental dural puncture. Anesthesiology. 2010 Aug;113(2):413\u0026ndash;20.\u003c/li\u003e\n\u003cli\u003eZeger W, Younggren B, Smith L. Comparison of cosyntropin versus caffeine for post-dural puncture headaches: A randomized double-blind trial. World J Emerg Med. 2012;3(3):182\u0026ndash;5.\u003c/li\u003e\n\u003cli\u003eHanling SR, Lagrew JE, Colmenar DH, Quiko AS, Drastol CA. Intravenous Cosyntropin Versus Epidural Blood Patch for Treatment of Postdural Puncture Headache. Pain Med. 2016 Mar 25;\u003c/li\u003e\n\u003cli\u003eTerenius L. Effect of peptides and amino acids on dihydromorphine binding to the opiate receptor. J Pharm Pharmacol. 1975 Jun;27(6):450\u0026ndash;2.\u003c/li\u003e\n\u003cli\u003eTerenius L, Gispen WH, De Wied D. ACTH-like peptides and opiate receptors in the rat brain: structure-activity studies. Eur J Pharmacol. 1975 Oct;33(2):395\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003ePlomp GJ, Van Ree JM. Adrenocorticotrophic hormone fragments mimic the effect of morphine in vitro. Br J Pharmacol. 1978 Oct;64(2):223\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eRucklidge MWM, Yentis SM, Paech MJ. Synacthen Depot for the treatment of postdural puncture headache. Anaesthesia. 2004 Feb;59(2):138\u0026ndash;41.\u003c/li\u003e\n\u003cli\u003eHjermstad MJ, Fayers PM, Haugen DF, Caraceni A, Hanks GW, Loge JH, et al. Studies comparing Numerical Rating Scales, Verbal Rating Scales, and Visual Analogue Scales for assessment of pain intensity in adults: a systematic literature review. J Pain Symptom Manage. 2011 Jun;41(6):1073\u0026ndash;93.\u003c/li\u003e\n\u003cli\u003eRucklidge OMWM. All patients with a postdural puncture headache should receive an epidural blood patch. International Journal of Obstetric Anesthesia. 2014 May;23(2):171\u0026ndash;4.\u003c/li\u003e\n\u003cli\u003eAya AG, Mangin R, Nouvellon E, Robert C, Ferrer JM, Eledjam JJ. [Dural puncture in obstetric analgesia. Epidemiologic features and therapeutic management]. Ann Fr Anesth Reanim. 2001 Nov;20(9):757\u0026ndash;62.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Post-dural puncture headache; tetracosactide; cosyntropin; postpartum; blood-patch; epidural","lastPublishedDoi":"10.21203/rs.2.12203/v3","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.2.12203/v3","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Background\nPost-dural puncture headache (PDPH) is one of the most common complications of neuraxial anaesthesia. It limits patients’ general activity and increases length of hospital stay and use of care. It is particularly disabling during the postpartum period, when mothers have to take care of their child. Epidural blood patch is the standard treatment for PDPH. However, it is an invasive procedure that may result in rare but serious complications. Recent evidence has suggested that adrenocorticotropic hormone (ACTH) is effective in the management of PDPH. The aim of this study is to assess the efficacy and safety of tetracosactide (Synacthen ® ), a synthetic analogue of ACTH, for PDPH treatment in patients who receive neuraxial anaesthesia during labour.\nMethod\nThis randomised, double-blind, placebo-controlled, parallel-arm trial, is performed in two French university hospitals. Eligible patients are those suffering from postpartum PDPH, who are randomised to receive either 1 mg of tetracosactide intravenously over 20 min, or 0.9% saline (placebo). The primary endpoint is the rate of epidural blood patch within a 15-day follow-up period. Headache duration, pain intensity, reduction of general activity, increase in length of hospital stay, adverse events, analgesic use (type and duration), and number of blood patches per patient in each group are recorded.\nDiscussion\nWe expect a decrease in the use of epidural blood patch in those receiving tetracosactide, thus indicating a decrease in PDPH symptoms in these patients. This will define the therapeutic success of tetracosactide and the possibility to use this treatment as a non-invasive alternative to blood patch for PDPH treatment.","manuscriptTitle":"Evaluation of the effectiveness and tolerance of tetracosactide in the treatment of post-dural puncture headaches (ESYBRECHE): A study protocol for a randomized controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":3,"date":"2019-12-16 17:57:31","doi":"10.21203/rs.2.12203/v3","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accept","date":"2019-12-19T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2019-12-18T12:00:00+00:00","index":1,"fulltext":"Recommendation: Accept\nForm responses:\n---\n* Level of interest: **An article of importance in its field**\n* Quality of written English: **Acceptable**\n* Quality of figures: **Acceptable**\n* Statistical review: **No, the manuscript does not need to be seen by a statistician**\n* Declaration of competing interests: **I declare that I have no competing interests**\n\nComments to Author:\n---\n* The authors have addressed my comments; thank you!\n* The writing is clearer now, thank you! Copywriting should be sufficient to catch any remaining minor errors.\n* No further comments\n"},{"type":"reviewersInvited","content":"","date":"2019-12-17T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2019-12-17T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorAssigned","content":"","date":"2019-12-13T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2019-12-12T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":2,"date":"2019-11-19 21:26:29","doi":"10.21203/rs.2.12203/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2019-11-22T12:00:00+00:00","index":1,"fulltext":"Recommendation: Minor Revision\nForm responses:\n---\n* Level of interest: **An article of importance in its field**\n* Quality of written English: **Needs some language corrections before being published**\n* Quality of figures: **Acceptable**\n* Statistical review: **No, the manuscript does not need to be seen by a statistician**\n* Declaration of competing interests: **I declare that I have no competing interests**\n\nComments to Author:\n---\n* The authors have addressed my comments; thank you!\n* Some language editing is still required. If you require services, the journal can help suggest some\n* Regarding the statement added on Page 7, I recommend one of two options because the way it is currently written suggests the explanation is immediately following (which it is not). I would either (i) specify \"… as explained in section 1.3.11.\" so that the reader knows where to find the explanation for the change, or (ii) move up the text of the \"Protocol amendment\" section to section 1.3.2 \"Trial design\" so that the explanation for the change in trial design (i.e., inclusion criteria and extension of recruitment) is in the trial design section.\n* Regarding adverse events, are there any that were expected as potential AEs at the start of the trial and collected systematically, or are all AEs collected non-systematically (i.e., using open-ended questions)? If any were expected, can some examples be provided? Additionally, can you provide any details on plans to report the AEs that are collected in the trial publications (e.g., will you report all AEs or a subset of AEs that meet a specific criteria)?\n* Thank you for further specifying the endpoints! Most of them can now be fit into the framework, but the \"activity limitation\" outcome is still unclear. You have provided the measure (Figure 1) and domain (activity limitation), but the timepoint is not specified as for the other endpoints (I assume it is for the 15th day like most others), and it is still unclear whether this outcome will be comparing the two groups at the time point or in their change from baseline to the time point (i.e., the metric), and also whether the comparison will be made using mean or median scores, or the proportion who have a certain score (i.e., the method of aggregation).\n"},{"type":"decision","content":"Minor revision","date":"2019-11-22T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2019-11-15T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewersInvited","content":"","date":"2019-11-15T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2019-11-15T12:00:00+00:00","index":1,"fulltext":""},{"type":"checksComplete","content":"","date":"2019-11-14T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2019-08-01 03:24:26","doi":"10.21203/rs.2.12203/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2019-10-08T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2019-10-08T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2019-10-08T12:00:00+00:00","index":1,"fulltext":"Form responses:\n---\n* Level of interest: **An article whose findings are important to those with closely related research interests**\n* Quality of written English: **Needs some language corrections before being published**\n* Quality of figures: **Acceptable**\n* Statistical review: **No, the manuscript does not need to be seen by a statistician**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* Quality of written English\nPlease indicate the quality of language in the manuscript:\tNeeds some language corrections before being published: **Quality of figures\nAll images and figures within the manuscript should be genuine i.e. without evidence of manipulation. No specific feature within an image may be enhanced, obscured, moved, removed, or introduced. If you have concerns about the veracity of the figures you should choose the first option below.\tAcceptable**\n"},{"type":"decision","content":"Major revision","date":"2019-10-08T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2019-10-03T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2019-07-26T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2019-06-20T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bd6562a0-e9cd-4c5c-bf32-d64f62e5c4fe","owner":[],"postedDate":"December 16th, 2019","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":37301,"name":"Internal Medicine"},{"id":37302,"name":"Integrative \u0026 Complementary Medicine"},{"id":37303,"name":"Translational Medicine"}],"tags":[],"updatedAt":"","versionOfRecord":{"articleIdentity":"rs-2982","link":"https://doi.org/10.1186/s13063-019-4015-y","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2020-01-08 12:00:00","publishedOnDateReadable":"January 8th, 2020"},"versionCreatedAt":"2019-12-16 17:57:31","video":"","vorDoi":"10.1186/s13063-019-4015-y","vorDoiUrl":"https://doi.org/10.1186/s13063-019-4015-y","workflowStages":[]},"version":"v3","identity":"rs-2982","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"identity":"rs-2982","version":["v3"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}