Galcanezumab Add-on in Refractory Cluster Headache

Galcanezumab Add-on in Refractory Cluster Headache | 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 Research Article Galcanezumab Add-on in Refractory Cluster Headache Georgios Karagiorgis, Savvas Christofilos, Christina Deligianni, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4390027/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Cluster headache (CH), currently one of the most painful conditions, lacks a well-established, disease specific, and mechanism-based prophylactic treatment. Galganezumab, a monoclonal antibody targeting the calcitonin gene-related peptide, reduced the weekly attacks of CH in one randomized, placebo-controlled trial for the prevention of episodic CH (eCH), but this effect was not detected in people with chronic CH (cCH). Objective: To explore the efficacy and safety of galcanezumab for the prevention of CH in people with refractory CH in a real-world setting. Methods: In this observational study, we systematically monitored the efficacy and safety outcomes of adjunctive therapy in patients with refractory CH (failure of ≥3 prophylactic treatments) who received galcanezumab (120–360 mg monthly) for 3 consecutive months. A detailed headache diary with monthly in-person follow-ups was used. All participants received intermediate treatment with oral steroids or a great occipital nerve block ≥2 months before starting galcanezumab treatment. Results: Data from 11 people with CH (eCH n=5, cCH, n=6) were collected. After galcanezumab treatment, the average number of weekly CH attacks and weekly days with any symptomatic treatment for CH decreased significantly from 16.0±9.4 and 6.50±3.59 before treatment to 1.8±1.32 (p=0.002) and 1.8±3.36 (p=0.001) at month 3 of treatment, respectively.Two participants with cCH showed no change in the number of attacks with galcanezumab. No serious adverse events were recorded. Conclusion: These data, along with those of previous real-world reports, suggest that galcanezumab may help people with refractory CH as an add-on treatment. Episodic Cluster Headache Chronic Cluster Headache Galcanezumab Calcitonin Gene-Related Peptide Treatment Figures Figure 1 INTRODUCTION Cluster headache (CH) is one of the most serious pain conditions in medicine today, affecting nearly 0.1% of the general population and presenting with recurrent, exclusively unilateral, and severe periorbital headache attacks lasting 30–180 minutes and accompanied by restlessness, agitation, and ipsilateral autonomic features.(1,2) Typically, CH attacks occur in clusters or bouts with unpredictable cyclical periodicity followed by headache-free periods. There are two subforms of CH, the episodic CH (eCH) and the chronic CH (cCH). The former (eCH) is characterized by repetitive daily attacks that last for weeks to months, followed by at least a 3-month remission period, whereas the latter (cCH) lasts longer than one year, with remission lasting for less than 3 months. (3)The pathophysiology of CH is poorly understood except for critical information based on animal, clinical, and neuroimaging studies. According to these studies, the peripheral endings of the trigeminal nerve surrounding the dural vessels together with the autonomic trigeminal reflex control ipsilateral pain and autonomic symptoms, while the hypothalamus supervises circadian and circannual attacks and may also contribute to the induction of attacks.(4) Current management of CH includes acute treatments aimed at quickly aborting CH attacks (e.g., sumatriptan subcutaneous or oxygen inhalation), intermediate treatments (e.g., steroids or occipital nerve blockage) aimed at temporarily alleviating the onset of attacks, and prophylactic treatments aimed at enhancing and perpetuating the effect of intermediate treatments for as long as possible. (5)Paradoxically, there is no disease-specific or mechanism-based prophylactic treatment for CH. Repurposed drugs are currently used (e.g., verapamil, lithium, or topiramate), but there is limited evidence of their efficacy. (6) However, there is strong evidence that calcitonin gene-related peptide (CGRP) is involved in the pathophysiology of CH. CGRP is elevated during spontaneous CH attacks and is normalized after symptomatic treatment. (7)In addition, CGRP triggers a CH attack in those experiencing an ongoing period of CH activity (bout). (8) Galcanezumab, a monoclonal antibody that targets the ligand CGRP, was more efficacious than placebo in reducing CH attacks per week at a dose of 300 mg SC in one randomized controlled study in which people with eCH participated.(9) However, in another randomized clinical trial involving people with cCH, galcanezumab was not effective at reducing weekly attacks compared to a placebo. (10) Despite these contradictory findings, eCH or cCH patients are treated with galcanezumab daily, either as an additional treatment or as monotherapy, without safety concerns.(11,12) We sought to monitor the effects of galcanezumab in a series of patients with intractable CH in a real-world setting. MATERIALS AND METHODS This is a monocenter, observational, and longitudinal survey. Patients suffering from eCH or cCH were diagnosed according to the International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria,(13) between December 2020 and November 2023. Participants with cCH had to fulfill the criteria for intractable CH(14), and those with eCH had to have failed to respond to at least three prophylactic treatments. After the initial visit and treatment, the participants were followed up every 4 weeks and instructed to keep a headache diary for 3 months after the first dose of galcanezumab. All patients received 240 or 360 mg of galcanezumab sc monthly for 3 consecutive months. Intermediate treatment with either per os methypresolone 16 mg/day for 3 days or a great occipital nerve block with lidocaine was administered to eCH patients but more than 2 months before the start of galcanezumab treatment. Patients with cCH did not receive any kind of intermediate treatment. In the absence of an observed response following the initial 240 mg dose, the dosage was increased to 360 mg for the second and third administrations. Previously used preventive treatments for CH were continued. We collected demographic data (such as age and sex), headache features (including affected side, onset time, duration of cCH, and duration of cluster in eCH), comorbidities (such as smoking), number of failed and current preventive treatments, number of weekly days with acute medications, and frequency of headache attacks at initial presentation and on follow-up visits. The qualitative variables are presented as frequencies, and the quantitative variables are presented as the means with standard deviations. The efficacy variables were compared using chi-square tests and Student’s t tests. The data were analyzed using SPSS 25 (IBM Corp., Armonk, NY, USA). The study was carried out according to the Declaration of Helsinki and after approval of the Ethics Committee of the Aeginitio Hospital (AΔA: 9ΡΔ146Ψ8Ν2-Ι9Μ). All participants signed an informed consent form. The treatments were approved and fully reimbursed by the (Hellenic) National Health System after a special application. RESULTS Eleven people with CH (cCH, n = 6 and eCH, n = 5) were monitored for three months. The CH subtypes were not significantly associated with age, affected side, smoking status, headache attacks per week, years since onset, or previous treatments (p > 0.005). The baseline characteristics of the participants and treatments are illustrated in Table 1 . All participants with eCH received interim treatment with either steroids (oral methylprednisolone 160 mg per day for three consecutive days) or a great occipital nerve block (GONB) with 2% lidocaine or both. Table 1 Baseline Characteristics of Study Participants cCH (n = 6) eCH (n = 5) All (n = 11) Mean age (yrs) 45.3 47.3 46.3 Smoking (n) 4 4 8 Mean disease duration (yrs) 11.3 16.6 13.5 Mean duration of chronic form (yrs) 6 - - Mean bout duration (months) - 3 - Mean No of current prophylactic treatments 2.3 0.6 1.9 Verapamil (n) 5 3 4 Lithium (n) 2 0 2 Topiramate (n) 3 0 3 Mean No of failed previous prophylactic treatments 5.6 2.8 4.4 Verapamil (n) 6 5 11 Lithium (n) 5 2 7 Topiramate (n) 5 4 9 GONB (n) 6 4 8 Steroids (n) 6 2 6 Gabapentin (n) 2 0 2 Pregabalin (n) 1 0 1 Table 2 Weekly attacks and days with symptomatic treatment cCH (n = 6) eCH (n = 5) All (n = 11) p Mean number of cluster headache attacks per week Baseline 20 11.4 16 Month-1 4.5 3 3.8 0.005 Month-2 3.5 0.6 2.2 0.003 Month-3 3.5 0 1.8 0.002 Number of days with symptomatic treatment per week Baseline 5.6 7.6 6.5 Month-3 0.8 3 1.8 0.001 The number of headache attacks per week before and during treatment with galcanezumab is illustrated in Fig. 1 . After add-on galcanezumab treatment, the average number of weekly headache attacks decreased significantly from 16.0 ± 9.4 before treatment to 3.8 ± 2.32 (p = 0.005) at the 1-month follow-up. Two participants showed no change in the number of attacks with galcanezumab treatment (one with eCH and one with cCH), but in the remaining participants, a ≥ 50% reduction in weekly CH attacks was recorded; thus, the efficiency rate was 82%. We compared the weekly number of attacks with the baseline number of attacks after galcanezumab treatment. A significant main effect of time was revealed between attacks at baseline and each of the three months, showing that galcanezumab treatment significantly decreased the number of attacks per week at months 1, 2, and 3 with respect to baseline (all p < 0.01). However, when the number of attacks per week at month 1 after treatment onset was compared with the number of attacks per week at months 2 and 3, no significant main effect of time was shown (p > 0.05). (Fig. 1 ). The participants had a stable response to treatment, with a significantly reduced number of acute attacks at 3 months compared to baseline (p < 0.001). The number of days for which symptomatic medications were received showed a significant declining trend from 6.50 ± 3.59 to 1.8 ± 3.36 (p = 0.001). Symptomatic medications included oxygen (n = 4), sumatriptan sc (n = 11), or both (n = 4). Galcanezumab eliminated bouts in all 5 eCH patients, two of whom were treated with galcanezumab exclusively, after failing to improve with verapamil, topiramate and other treatments in previous bouts or in the current bout (they had a two-month trial with these treatments). Galcanezumab decreased the weekly mean number of attacks from 11.4 at baseline to 3, 0.6 and 0 at months 1, 2 and 3, respectively. The dose of galcanezumab used to treat eCH was 240 mg monthly for all participants. In participants with cCH, galcanezumab decreased the weekly number of CH attacks from 20.0 at baseline to 4.5, 3.5 and 3.5 at months 1, 2 and 3, respectively. All cCH participants received galcanezumab as an add-on treatment at monthly doses of either 240 mg or 360 mg. A higher dose was used at months 2 and 3 in two cCH patients who did not respond to treatment with the lower dose, but no additional effect was observed. None of the participants reported any significant or serious adverse events (AEs) that resulted in treatment discontinuation, even those treated with the higher dose (360 mg/month). The only AE recorded was mild pain and/or discomfort at the injection site in 9 out of 33 injections (27.3%) and 4 out of 11 treated people (36.3%). Blood tests, including liver enzyme tests, did not reveal any abnormalities. The entire treatment (galcanezumab along with conventional treatments) was well tolerated. DISCUSSION In this observational, real-world study, which included 11 patients with intractable CHs who were treated with 240–360 mg of galcanezumab daily for 3 consecutive months, the number of headache attacks decreased significantly from 16.0 at baseline to 1.8 at month 3 of treatment, without notable AEs, apart from injection side pain and/or discomfort. Thus, people with CH who fail standard therapy may benefit from galcanezumab before trying other more expensive treatment options, such as neuromodulation techniques. However, the data of this case series should be considered with caution because of the limited sample size and the short follow-up period. Longer, larger, randomized, and placebo-controlled trials are required to determine the efficacy and safety of galcanezumab in treating CH. The results from the follow-up of this series of patients cannot confirm whether the additional treatment with galcanezumab had a different effect on one or the other type of CH, e.g., eCH or cCH. Although headache attacks disappeared three months after treatment in all patients with eCH, it is not certain whether this was a result of the treatment or the natural course of the disease. Although efficacy was visible as early as the first week of treatment, it remained stable without further reduction in weekly CH attacks throughout the three months. Other real-world evidence studies support our findings. In a large case series of 47 participants with eCH, 240 mg SC galcanezumab was administered (36 patients who received add-on treatment). The number of weekly attacks decreased from 7.0 at baseline to 0.0 at week 4 posttreatment, and the number of days with acute medication use per week decreased from 7.0 to 0.0. Constipation was reported by 11 participants (30.6%). (12) In an observational multicenter survey, 14 people with eCH received 240 mg galcanezumab SC for two consecutive cluster bouts. In the first bout, treatment reduced the total headache attacks from 7.0 at baseline to 0.0 at week 3, and in the second bout, it reduced the total headache attacks from 7.0 at baseline to 2.0 at week 3. Most of the participants had received a transitional treatment before galcanezumab. No serious adverse effects (AEs) were recorded. (15) In another report, nine people with refractory CH were treated with 240 mg galcanezumab monthly during a refractory cluster bout. Five out of six participants with cCH showed a ≥ 50% reduction in weekly attack frequency at month 3 of treatment. In participants with cCH, the bout ended a mean of 17.3 days after galcanezumab initiation. One-third of the participants reported mild AEs, but none of them discontinued treatment.(16) Finally, a recent observational study included 22 people with cCH who had tried more than 6 preventive therapies (including off-label onabotulinum toxin A). After treatment with 240 mg of galcanezumab monthly, the median monthly attack frequency decreased from 60 to 31. Of the 15 patients with 3 months of follow-up, seven had a 50% reduction in attack frequency, and four had a 75% reduction in attack frequency. AEs, including constipation, asthenia, and flu-like symptoms, were reported by 52% of the participants and were mild. (17) In conclusion, this case series, along with previous ones, indicates that treatment with galcanezumab, alone or as an add-on, might be considered an option to manage people with refractory CH. This finding also indicates that the effect of galcanezumab on refractory CH should be tested with a placebo-controlled design. DECLARATIONS Competing Interests GK has received travel grants from Novartis, Teva, and Pfizer. SC and IS have no disclosures. CD received an International Headache Society 2021 research grant, and she is a member of the Executive Board of the European Headache Federation. SV received travel grants from Abbot, Bayer and Pfizer. DDM has received honoraria, research, and travel grants from AbbVie, Genesis Pharma, Eli Lilly, Lundbeck, Merk, Novartis, Pfizer, Roche, and Teva Pharmaceuticals; participated in clinical trials for AbbVie, Amgen, Cefaly, Electrocore, Eli Lilly, Genesis Pharma, Lundbeck, Mertz, Novartis, Pfizer and Teva Pharmaceuticals as principal investigators; and is President of the board of the Hellenic Headache Society, member of the management group of the Headache Scientific Panel and of Coordinating Panel on Functional Neurological Disorders at the European Academy of Neurology. Founding There was no finding for this study. Ethical statement Approval was obtained from the ethics committee of Aeginition Hospital (AΔA: 9ΡΔ146Ψ8Ν2-Ι9Μ). All participants signed an informed consent form. The treatments were approved and fully reimbursed by the (Hellenic) National Health System after a special application. All procedures used in this study adhere to the tenets of the Declaration of Helsinki. ACKNOWLEDGMENTS There are no acknowledgments. REFERENCES Martelletti P, Mitsikostas DD. Cluster headache: a quasirare disorder needing a reappraisal. Journal of Headache and Pain. 2015;16(1). Kim SA, Choi SY, Youn MS, Pozo-Rosich P, Lee MJ. Epidemiology, burden and clinical spectrum of cluster headache: a global update. Cephalalgia [Internet]. 2023 Sep 1 [cited 2024 Jan 26];43(9). Available from: https://pubmed.ncbi.nlm.nih.gov/37728577/ May A, Schwedt TJ, Magis D, Pozo-Rosich P, Evers S, Wang SJ. Cluster headache. Nat Rev Dis Primers [Internet]. 2018 Mar 1 [cited 2024 Jan 26];4. Available from: https://pubmed.ncbi.nlm.nih.gov/29493566/ Wei DY, Goadsby PJ. Cluster headache pathophysiology - insights from current and emerging treatments. Nat Rev Neurol [Internet]. 2021 May 1 [cited 2024 Jan 26];17(5):308–24. Available from: https://pubmed.ncbi.nlm.nih.gov/33782592/ Magis D. Emerging treatments for cluster headache: hopes and disappointments. Curr Opin Neurol [Internet]. 2019 Jun 1 [cited 2024 Jan 26];32(3):432–7. Available from: https://pubmed.ncbi.nlm.nih.gov/30893102/ May A, Evers S, Goadsby PJ, Leone M, Manzoni GC, Pascual J, et al. European Academy of Neurology guidelines on the treatment of cluster headache. Eur J Neurol [Internet]. 2023 Oct 1 [cited 2024 Jan 26];30(10):2955–79. Available from: https://pubmed.ncbi.nlm.nih.gov/37515405/ Snoer A, Vollesen ALH, Beske RP, Guo S, Hoffmann J, Fahrenkrug J, et al. Calcitonin-gene related peptide and disease activity in cluster headache. Cephalalgia [Internet]. 2019 Apr 1 [cited 2024 Jan 26];39(5):575–84. Available from: https://pubmed.ncbi.nlm.nih.gov/30854880/ Vollesen ALH, Snoer A, Beske RP, Guo S, Hoffmann J, Jensen RH, et al. Effect of Infusion of Calcitonin Gene-Related Peptide on Cluster Headache Attacks: A Randomized Clinical Trial. JAMA Neurol [Internet]. 2018 Oct 1 [cited 2024 Jan 26];75(10):1187–97. Available from: https://pubmed.ncbi.nlm.nih.gov/29987329/ Goadsby PJ, Dodick DW, Leone M, Bardos JN, Oakes TM, Millen BA, et al. Trial of Galcanezumab in Prevention of Episodic Cluster Headache. N Engl J Med [Internet]. 2019 Jul 11 [cited 2024 Jan 26];381(2):132–41. Available from: https://pubmed.ncbi.nlm.nih.gov/31291515/ Dodick DW, Goadsby PJ, Lucas C, Jensen R, Bardos JN, Martinez JM, et al. Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: Results from 3-month double-blind treatment. Cephalalgia [Internet]. 2020 Aug 1 [cited 2024 Jan 26];40(9):935–48. Available from: https://pubmed.ncbi.nlm.nih.gov/32050782/ Láinez MJA, Schoenen J, Stroud C, Bardos J, Bangs M, Kemmer P, et al. Tolerability and safety of galcanezumab in patients with chronic cluster headache with up to 15 months of galcanezumab treatment. Headache [Internet]. 2022 Jan 1 [cited 2024 Jan 26];62(1):65–77. Available from: https://pubmed.ncbi.nlm.nih.gov/34806783/ Mo H, Kim BK, Moon HS, Cho SJ. Real-world experience with 240 mg of galcanezumab for the preventive treatment of cluster headache. J Headache Pain [Internet]. 2022 Dec 1 [cited 2024 Jan 26];23(1). Available from: https://pubmed.ncbi.nlm.nih.gov/36209047/ Olesen J. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia [Internet]. 2018 Jan 1 [cited 2023 Apr 20];38(1):1–211. Available from: https://pubmed.ncbi.nlm.nih.gov/29368949/ Mitsikostas DD, Edvinsson L, Jensen RH, Katsarava Z, Lampl C, Negro A, et al. Refractory chronic cluster headache: a consensus statement on clinical definition from the European Headache Federation. Journal of Headache and Pain. 2014;15(1). Hong Y, Kang MK, Moon HS, Kim BK, Cho SJ. Preventive therapy with galcanezumab for two consecutive cluster bouts in patients with episodic cluster headache: an observational multicenter study. J Headache Pain [Internet]. 2023;24:136. Available from: https://doi.org/10.1186/s10194-023-01661-7 Membrilla JA, Torres-Ferrus M, Alpuente A, Caronna E, Pozo-Rosich P. Efficacy and safety of galcanezumab as a treatment of refractory episodic and chronic cluster headache: Case series and narrative review. Headache. 2022 Nov 1;62(10):1395–405. Lamas Pérez R, Millán-Vázquez M, González-Oria C. Efficacy and safety of galcanezumab as chronic cluster headache preventive treatment under real world conditions: Observational prospective study. Cephalalgia [Internet]. 2024 Mar 19 [cited 2024 Mar 23];44(3). Available from: https://pubmed.ncbi.nlm.nih.gov/38501892/ Additional Declarations Competing interest reported. GK has received travel grants from Novartis, Teva, and Pfizer. SC and IS have no disclosures. CD received an International Headache Society 2021 research grant, and she is a member of the Executive Board of the European Headache Federation. SV received travel grants from Abbot, Bayer and Pfizer. DDM has received honoraria, research, and travel grants from AbbVie, Genesis Pharma, Eli Lilly, Lundbeck, Merk, Novartis, Pfizer, Roche, and Teva Pharmaceuticals; participated in clinical trials for AbbVie, Amgen, Cefaly, Electrocore, Eli Lilly, Genesis Pharma, Lundbeck, Mertz, Novartis, Pfizer and Teva Pharmaceuticals as principal investigators; and is President of the board of the Hellenic Headache Society, member of the management group of the Headache Scientific Panel and of Coordinating Panel on Functional Neurological Disorders at the European Academy of Neurology. 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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-4390027","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":303650980,"identity":"810f8d6f-57b4-4e25-a2d6-94567813ac98","order_by":0,"name":"Georgios Karagiorgis","email":"","orcid":"","institution":"Aeginitio Hospital, National and Kapodistrian University of Athens","correspondingAuthor":false,"prefix":"","firstName":"Georgios","middleName":"","lastName":"Karagiorgis","suffix":""},{"id":303650981,"identity":"9a1871db-8f9f-4261-8caa-ad9d80ea027a","order_by":1,"name":"Savvas Christofilos","email":"","orcid":"","institution":"Aeginitio Hospital, National and Kapodistrian University of Athens","correspondingAuthor":false,"prefix":"","firstName":"Savvas","middleName":"","lastName":"Christofilos","suffix":""},{"id":303650984,"identity":"57faf0b9-0e49-40bf-81a3-472d86fca574","order_by":2,"name":"Christina Deligianni","email":"","orcid":"","institution":"Aeginitio Hospital, National and Kapodistrian University of Athens","correspondingAuthor":false,"prefix":"","firstName":"Christina","middleName":"","lastName":"Deligianni","suffix":""},{"id":303650987,"identity":"4b98bc60-7dd3-452d-a794-3c469842b5e2","order_by":3,"name":"Ioanna Spanou","email":"","orcid":"","institution":"Aeginitio Hospital, National and Kapodistrian University of Athens","correspondingAuthor":false,"prefix":"","firstName":"Ioanna","middleName":"","lastName":"Spanou","suffix":""},{"id":303650990,"identity":"a4f518dd-0113-42eb-8c4d-f7f72982f79b","order_by":4,"name":"Sofia Vassilopoulou","email":"","orcid":"","institution":"Aeginitio Hospital, National and Kapodistrian University of Athens","correspondingAuthor":false,"prefix":"","firstName":"Sofia","middleName":"","lastName":"Vassilopoulou","suffix":""},{"id":303650994,"identity":"5ced7f9f-3850-4804-9e00-5aef846e6d4c","order_by":5,"name":"Dimos-Dimitrios D. Mitsikostas","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIiWNgGAWjYDCCA4wNDAwGCRDOByK1NDaAtbAxMDDOIE4LA8gaiBZmHmJ08F073P7wR0GanPz85sefbdts5Bn41z7Aq0XydmJjM49BjrHBMTYz6dy2NMMGiecGeLUYgLQwGFQkbmBjMGPObTvM2CBxDL/DQFoafwC1zG9j//zZsu2wPVFaGoAOS2w4xmMgzdh2OLGBvw2/FpBfZvMYpAH9klMm2XMuLblNgg2/Fr7b6Q8+/viTLCfffHzzhx9lNrb9/AQchgnYJBJI1cLAf4BkLaNgFIyCUTC8AQC+9kkXBMnXvQAAAABJRU5ErkJggg==","orcid":"","institution":"Aeginitio Hospital, National and Kapodistrian University of Athens","correspondingAuthor":true,"prefix":"","firstName":"Dimos-Dimitrios","middleName":"D.","lastName":"Mitsikostas","suffix":""}],"badges":[],"createdAt":"2024-05-08 14:40:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4390027/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4390027/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57033875,"identity":"e64463b7-759b-4ae7-85c5-cfe59a314222","added_by":"auto","created_at":"2024-05-23 18:24:21","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":181212,"visible":true,"origin":"","legend":"\u003cp\u003eNumbers of cluster headache attacks per week before and after add-on treatment with 240-360 mg sc galcanezumab monthly in 11 people with intractable cluster headache. A significant reduction was recorded at month 1, which remained stable for the next two months but without further improvement. Chronic cluster headache cases (cCH, n=6); episodic cluster headache cases (eCH, n=5).\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4390027/v1/5e178f33db56417a9666ab55.jpeg"},{"id":58873040,"identity":"475f1de6-6fda-40c5-a543-cf2910028043","added_by":"auto","created_at":"2024-06-22 21:16:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":485285,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4390027/v1/93718230-29ff-47bb-b687-4dbfee1e8148.pdf"}],"financialInterests":"Competing interest reported. GK has received travel grants from Novartis, Teva, and Pfizer.\nSC and IS have no disclosures.\nCD received an International Headache Society 2021 research grant, and she is a member of the Executive Board of the European Headache Federation.\nSV received travel grants from Abbot, Bayer and Pfizer.\nDDM has received honoraria, research, and travel grants from AbbVie, Genesis Pharma, Eli Lilly, Lundbeck, Merk, Novartis, Pfizer, Roche, and Teva Pharmaceuticals; participated in clinical trials for AbbVie, Amgen, Cefaly, Electrocore, Eli Lilly, Genesis Pharma, Lundbeck, Mertz, Novartis, Pfizer and Teva Pharmaceuticals as principal investigators; and is President of the board of the Hellenic Headache Society, member of the management group of the Headache Scientific Panel and of Coordinating Panel on Functional Neurological Disorders at the European Academy of Neurology.","formattedTitle":"\u003cp\u003eGalcanezumab Add-on in Refractory Cluster Headache\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eCluster headache (CH) is one of the most serious pain conditions in medicine today, affecting nearly 0.1% of the general population and presenting with recurrent, exclusively unilateral, and severe periorbital headache attacks lasting 30\u0026ndash;180 minutes and accompanied by restlessness, agitation, and ipsilateral autonomic features.(1,2) Typically, CH attacks occur in clusters or bouts with unpredictable cyclical periodicity followed by headache-free periods. There are two subforms of CH, the episodic CH (eCH) and the chronic CH (cCH). The former (eCH) is characterized by repetitive daily attacks that last for weeks to months, followed by at least a 3-month remission period, whereas the latter (cCH) lasts longer than one year, with remission lasting for less than 3 months. (3)The pathophysiology of CH is poorly understood except for critical information based on animal, clinical, and neuroimaging studies. According to these studies, the peripheral endings of the trigeminal nerve surrounding the dural vessels together with the autonomic trigeminal reflex control ipsilateral pain and autonomic symptoms, while the hypothalamus supervises circadian and circannual attacks and may also contribute to the induction of attacks.(4) Current management of CH includes acute treatments aimed at quickly aborting CH attacks (e.g., sumatriptan subcutaneous or oxygen inhalation), intermediate treatments (e.g., steroids or occipital nerve blockage) aimed at temporarily alleviating the onset of attacks, and prophylactic treatments aimed at enhancing and perpetuating the effect of intermediate treatments for as long as possible. (5)Paradoxically, there is no disease-specific or mechanism-based prophylactic treatment for CH. Repurposed drugs are currently used (e.g., verapamil, lithium, or topiramate), but there is limited evidence of their efficacy. (6)\u003c/p\u003e \u003cp\u003eHowever, there is strong evidence that calcitonin gene-related peptide (CGRP) is involved in the pathophysiology of CH. CGRP is elevated during spontaneous CH attacks and is normalized after symptomatic treatment. (7)In addition, CGRP triggers a CH attack in those experiencing an ongoing period of CH activity (bout). (8) Galcanezumab, a monoclonal antibody that targets the ligand CGRP, was more efficacious than placebo in reducing CH attacks per week at a dose of 300 mg SC in one randomized controlled study in which people with eCH participated.(9) However, in another randomized clinical trial involving people with cCH, galcanezumab was not effective at reducing weekly attacks compared to a placebo. (10)\u003c/p\u003e \u003cp\u003eDespite these contradictory findings, eCH or cCH patients are treated with galcanezumab daily, either as an additional treatment or as monotherapy, without safety concerns.(11,12) We sought to monitor the effects of galcanezumab in a series of patients with intractable CH in a real-world setting.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003eThis is a monocenter, observational, and longitudinal survey. Patients suffering from eCH or cCH were diagnosed according to the International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria,(13) between December 2020 and November 2023. Participants with cCH had to fulfill the criteria for intractable CH(14), and those with eCH had to have failed to respond to at least three prophylactic treatments. After the initial visit and treatment, the participants were followed up every 4 weeks and instructed to keep a headache diary for 3 months after the first dose of galcanezumab. All patients received 240 or 360 mg of galcanezumab sc monthly for 3 consecutive months. Intermediate treatment with either per os methypresolone 16 mg/day for 3 days or a great occipital nerve block with lidocaine was administered to eCH patients but more than 2 months before the start of galcanezumab treatment. Patients with cCH did not receive any kind of intermediate treatment. In the absence of an observed response following the initial 240 mg dose, the dosage was increased to 360 mg for the second and third administrations. Previously used preventive treatments for CH were continued. We collected demographic data (such as age and sex), headache features (including affected side, onset time, duration of cCH, and duration of cluster in eCH), comorbidities (such as smoking), number of failed and current preventive treatments, number of weekly days with acute medications, and frequency of headache attacks at initial presentation and on follow-up visits. The qualitative variables are presented as frequencies, and the quantitative variables are presented as the means with standard deviations. The efficacy variables were compared using chi-square tests and Student\u0026rsquo;s t tests. The data were analyzed using SPSS 25 (IBM Corp., Armonk, NY, USA).\u003c/p\u003e \u003cp\u003e The study was carried out according to the Declaration of Helsinki and after approval of the Ethics Committee of the Aeginitio Hospital (AΔA: 9ΡΔ146Ψ8Ν2-Ι9Μ). All participants signed an informed consent form. The treatments were approved and fully reimbursed by the (Hellenic) National Health System after a special application.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eEleven people with CH (cCH, n\u0026thinsp;=\u0026thinsp;6 and eCH, n\u0026thinsp;=\u0026thinsp;5) were monitored for three months. The CH subtypes were not significantly associated with age, affected side, smoking status, headache attacks per week, years since onset, or previous treatments (p\u0026thinsp;\u0026gt;\u0026thinsp;0.005). The baseline characteristics of the participants and treatments are illustrated in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. All participants with eCH received interim treatment with either steroids (oral methylprednisolone 160 mg per day for three consecutive days) or a great occipital nerve block (GONB) with 2% lidocaine or both.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionNumber\"\u003e\n\u003cp\u003eBaseline Characteristics of Study Participants\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ecCH (n\u0026thinsp;=\u0026thinsp;6)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eeCH (n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAll (n\u0026thinsp;=\u0026thinsp;11)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMean age (yrs)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e46.3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSmoking (n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMean disease duration (yrs)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13.5\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMean duration of chronic form (yrs)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMean bout duration (months)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMean No of current prophylactic treatments\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVerapamil (n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLithium (n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTopiramate (n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMean No of failed previous prophylactic treatments\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVerapamil (n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLithium (n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTopiramate (n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGONB (n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSteroids (n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGabapentin (n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePregabalin (n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eWeekly attacks and days with symptomatic treatment\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ecCH (n\u0026thinsp;=\u0026thinsp;6)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eeCH (n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAll (n\u0026thinsp;=\u0026thinsp;11)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ep\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eMean number of cluster headache attacks per week\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBaseline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMonth-1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.005\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMonth-2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.003\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMonth-3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.002\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eNumber of days with symptomatic treatment per week\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBaseline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMonth-3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eThe number of headache attacks per week before and during treatment with galcanezumab is illustrated in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. After add-on galcanezumab treatment, the average number of weekly headache attacks decreased significantly from 16.0\u0026thinsp;\u0026plusmn;\u0026thinsp;9.4 before treatment to 3.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.32 (p\u0026thinsp;=\u0026thinsp;0.005) at the 1-month follow-up. Two participants showed no change in the number of attacks with galcanezumab treatment (one with eCH and one with cCH), but in the remaining participants, a\u0026thinsp;\u0026ge;\u0026thinsp;50% reduction in weekly CH attacks was recorded; thus, the efficiency rate was 82%. We compared the weekly number of attacks with the baseline number of attacks after galcanezumab treatment. A significant main effect of time was revealed between attacks at baseline and each of the three months, showing that galcanezumab treatment significantly decreased the number of attacks per week at months 1, 2, and 3 with respect to baseline (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). However, when the number of attacks per week at month 1 after treatment onset was compared with the number of attacks per week at months 2 and 3, no significant main effect of time was shown (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). The participants had a stable response to treatment, with a significantly reduced number of acute attacks at 3 months compared to baseline (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The number of days for which symptomatic medications were received showed a significant declining trend from 6.50\u0026thinsp;\u0026plusmn;\u0026thinsp;3.59 to 1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.36 (p\u0026thinsp;=\u0026thinsp;0.001). Symptomatic medications included oxygen (n\u0026thinsp;=\u0026thinsp;4), sumatriptan sc (n\u0026thinsp;=\u0026thinsp;11), or both (n\u0026thinsp;=\u0026thinsp;4).\u003c/p\u003e\n\u003cp\u003eGalcanezumab eliminated bouts in all 5 eCH patients, two of whom were treated with galcanezumab exclusively, after failing to improve with verapamil, topiramate and other treatments in previous bouts or in the current bout (they had a two-month trial with these treatments). Galcanezumab decreased the weekly mean number of attacks from 11.4 at baseline to 3, 0.6 and 0 at months 1, 2 and 3, respectively. The dose of galcanezumab used to treat eCH was 240 mg monthly for all participants. In participants with cCH, galcanezumab decreased the weekly number of CH attacks from 20.0 at baseline to 4.5, 3.5 and 3.5 at months 1, 2 and 3, respectively. All cCH participants received galcanezumab as an add-on treatment at monthly doses of either 240 mg or 360 mg. A higher dose was used at months 2 and 3 in two cCH patients who did not respond to treatment with the lower dose, but no additional effect was observed.\u003c/p\u003e\n\u003cp\u003eNone of the participants reported any significant or serious adverse events (AEs) that resulted in treatment discontinuation, even those treated with the higher dose (360 mg/month). The only AE recorded was mild pain and/or discomfort at the injection site in 9 out of 33 injections (27.3%) and 4 out of 11 treated people (36.3%). Blood tests, including liver enzyme tests, did not reveal any abnormalities. The entire treatment (galcanezumab along with conventional treatments) was well tolerated.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this observational, real-world study, which included 11 patients with intractable CHs who were treated with 240\u0026ndash;360 mg of galcanezumab daily for 3 consecutive months, the number of headache attacks decreased significantly from 16.0 at baseline to 1.8 at month 3 of treatment, without notable AEs, apart from injection side pain and/or discomfort. Thus, people with CH who fail standard therapy may benefit from galcanezumab before trying other more expensive treatment options, such as neuromodulation techniques. However, the data of this case series should be considered with caution because of the limited sample size and the short follow-up period. Longer, larger, randomized, and placebo-controlled trials are required to determine the efficacy and safety of galcanezumab in treating CH.\u003c/p\u003e \u003cp\u003eThe results from the follow-up of this series of patients cannot confirm whether the additional treatment with galcanezumab had a different effect on one or the other type of CH, e.g., eCH or cCH. Although headache attacks disappeared three months after treatment in all patients with eCH, it is not certain whether this was a result of the treatment or the natural course of the disease. Although efficacy was visible as early as the first week of treatment, it remained stable without further reduction in weekly CH attacks throughout the three months.\u003c/p\u003e \u003cp\u003eOther real-world evidence studies support our findings. In a large case series of 47 participants with eCH, 240 mg SC galcanezumab was administered (36 patients who received add-on treatment). The number of weekly attacks decreased from 7.0 at baseline to 0.0 at week 4 posttreatment, and the number of days with acute medication use per week decreased from 7.0 to 0.0. Constipation was reported by 11 participants (30.6%). (12) In an observational multicenter survey, 14 people with eCH received 240 mg galcanezumab SC for two consecutive cluster bouts. In the first bout, treatment reduced the total headache attacks from 7.0 at baseline to 0.0 at week 3, and in the second bout, it reduced the total headache attacks from 7.0 at baseline to 2.0 at week 3. Most of the participants had received a transitional treatment before galcanezumab. No serious adverse effects (AEs) were recorded. (15) In another report, nine people with refractory CH were treated with 240 mg galcanezumab monthly during a refractory cluster bout. Five out of six participants with cCH showed a\u0026thinsp;\u0026ge;\u0026thinsp;50% reduction in weekly attack frequency at month 3 of treatment. In participants with cCH, the bout ended a mean of 17.3 days after galcanezumab initiation. One-third of the participants reported mild AEs, but none of them discontinued treatment.(16) Finally, a recent observational study included 22 people with cCH who had tried more than 6 preventive therapies (including off-label onabotulinum toxin A). After treatment with 240 mg of galcanezumab monthly, the median monthly attack frequency decreased from 60 to 31. Of the 15 patients with 3 months of follow-up, seven had a 50% reduction in attack frequency, and four had a 75% reduction in attack frequency. AEs, including constipation, asthenia, and flu-like symptoms, were reported by 52% of the participants and were mild. (17)\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eIn conclusion, this case series, along with previous ones, indicates that treatment with galcanezumab, alone or as an add-on, might be considered an option to manage people with refractory CH. This finding also indicates that the effect of galcanezumab on refractory CH should be tested with a placebo-controlled design.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"DECLARATIONS","content":"\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGK\u0026nbsp;\u003c/strong\u003ehas received travel grants from Novartis, Teva, and Pfizer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSC\u003c/strong\u003e and \u003cstrong\u003eIS\u003c/strong\u003e have no disclosures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCD\u003c/strong\u003e received an International Headache Society 2021 research grant, and she is a member of the Executive Board of the European Headache Federation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSV\u003c/strong\u003e received travel grants from Abbot, Bayer and Pfizer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDDM\u0026nbsp;\u003c/strong\u003ehas received honoraria, research, and travel grants from AbbVie, Genesis Pharma, Eli Lilly, Lundbeck, Merk, Novartis, Pfizer, Roche, and Teva Pharmaceuticals; participated in clinical trials for AbbVie, Amgen, Cefaly, Electrocore, Eli Lilly, Genesis Pharma, Lundbeck, Mertz, Novartis, Pfizer and Teva Pharmaceuticals as principal investigators; and is President of the board of the Hellenic Headache Society, member of the management group of the Headache Scientific Panel and of Coordinating Panel on Functional Neurological Disorders at the European Academy of Neurology.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFounding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere was no finding for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eApproval was obtained from the ethics committee of Aeginition Hospital (A\u0026Delta;A: 9\u0026Rho;\u0026Delta;146\u0026Psi;8\u0026Nu;2-\u0026Iota;9\u0026Mu;). All participants signed an informed consent form. The treatments were approved and fully reimbursed by the (Hellenic) National Health System after a special application. All procedures used in this study adhere to the tenets of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere are no acknowledgments.\u003c/p\u003e"},{"header":"REFERENCES","content":"\u003col\u003e\n\u003cli\u003eMartelletti P, Mitsikostas DD. Cluster headache: a quasirare disorder needing a reappraisal. Journal of Headache and Pain. 2015;16(1).\u003c/li\u003e\n\u003cli\u003eKim SA, Choi SY, Youn MS, Pozo-Rosich P, Lee MJ. Epidemiology, burden and clinical spectrum of cluster headache: a global update. Cephalalgia [Internet]. 2023 Sep 1 [cited 2024 Jan 26];43(9). Available from: https://pubmed.ncbi.nlm.nih.gov/37728577/\u003c/li\u003e\n\u003cli\u003eMay A, Schwedt TJ, Magis D, Pozo-Rosich P, Evers S, Wang SJ. Cluster headache. Nat Rev Dis Primers [Internet]. 2018 Mar 1 [cited 2024 Jan 26];4. Available from: https://pubmed.ncbi.nlm.nih.gov/29493566/\u003c/li\u003e\n\u003cli\u003eWei DY, Goadsby PJ. Cluster headache pathophysiology - insights from current and emerging treatments. Nat Rev Neurol [Internet]. 2021 May 1 [cited 2024 Jan 26];17(5):308\u0026ndash;24. Available from: https://pubmed.ncbi.nlm.nih.gov/33782592/\u003c/li\u003e\n\u003cli\u003eMagis D. Emerging treatments for cluster headache: hopes and disappointments. Curr Opin Neurol [Internet]. 2019 Jun 1 [cited 2024 Jan 26];32(3):432\u0026ndash;7. Available from: https://pubmed.ncbi.nlm.nih.gov/30893102/\u003c/li\u003e\n\u003cli\u003eMay A, Evers S, Goadsby PJ, Leone M, Manzoni GC, Pascual J, et al. European Academy of Neurology guidelines on the treatment of cluster headache. Eur J Neurol [Internet]. 2023 Oct 1 [cited 2024 Jan 26];30(10):2955\u0026ndash;79. Available from: https://pubmed.ncbi.nlm.nih.gov/37515405/\u003c/li\u003e\n\u003cli\u003eSnoer A, Vollesen ALH, Beske RP, Guo S, Hoffmann J, Fahrenkrug J, et al. Calcitonin-gene related peptide and disease activity in cluster headache. Cephalalgia [Internet]. 2019 Apr 1 [cited 2024 Jan 26];39(5):575\u0026ndash;84. Available from: https://pubmed.ncbi.nlm.nih.gov/30854880/\u003c/li\u003e\n\u003cli\u003eVollesen ALH, Snoer A, Beske RP, Guo S, Hoffmann J, Jensen RH, et al. Effect of Infusion of Calcitonin Gene-Related Peptide on Cluster Headache Attacks: A Randomized Clinical Trial. JAMA Neurol [Internet]. 2018 Oct 1 [cited 2024 Jan 26];75(10):1187\u0026ndash;97. Available from: https://pubmed.ncbi.nlm.nih.gov/29987329/\u003c/li\u003e\n\u003cli\u003eGoadsby PJ, Dodick DW, Leone M, Bardos JN, Oakes TM, Millen BA, et al. Trial of Galcanezumab in Prevention of Episodic Cluster Headache. N Engl J Med [Internet]. 2019 Jul 11 [cited 2024 Jan 26];381(2):132\u0026ndash;41. Available from: https://pubmed.ncbi.nlm.nih.gov/31291515/\u003c/li\u003e\n\u003cli\u003eDodick DW, Goadsby PJ, Lucas C, Jensen R, Bardos JN, Martinez JM, et al. Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: Results from 3-month double-blind treatment. Cephalalgia [Internet]. 2020 Aug 1 [cited 2024 Jan 26];40(9):935\u0026ndash;48. Available from: https://pubmed.ncbi.nlm.nih.gov/32050782/\u003c/li\u003e\n\u003cli\u003eL\u0026aacute;inez MJA, Schoenen J, Stroud C, Bardos J, Bangs M, Kemmer P, et al. Tolerability and safety of galcanezumab in patients with chronic cluster headache with up to 15 months of galcanezumab treatment. Headache [Internet]. 2022 Jan 1 [cited 2024 Jan 26];62(1):65\u0026ndash;77. Available from: https://pubmed.ncbi.nlm.nih.gov/34806783/\u003c/li\u003e\n\u003cli\u003eMo H, Kim BK, Moon HS, Cho SJ. Real-world experience with 240 mg of galcanezumab for the preventive treatment of cluster headache. J Headache Pain [Internet]. 2022 Dec 1 [cited 2024 Jan 26];23(1). Available from: https://pubmed.ncbi.nlm.nih.gov/36209047/\u003c/li\u003e\n\u003cli\u003eOlesen J. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia [Internet]. 2018 Jan 1 [cited 2023 Apr 20];38(1):1\u0026ndash;211. Available from: https://pubmed.ncbi.nlm.nih.gov/29368949/\u003c/li\u003e\n\u003cli\u003eMitsikostas DD, Edvinsson L, Jensen RH, Katsarava Z, Lampl C, Negro A, et al. Refractory chronic cluster headache: a consensus statement on clinical definition from the European Headache Federation. Journal of Headache and Pain. 2014;15(1).\u003c/li\u003e\n\u003cli\u003eHong Y, Kang MK, Moon HS, Kim BK, Cho SJ. Preventive therapy with galcanezumab for two consecutive cluster bouts in patients with episodic cluster headache: an observational multicenter study. J Headache Pain [Internet]. 2023;24:136. Available from: https://doi.org/10.1186/s10194-023-01661-7\u003c/li\u003e\n\u003cli\u003eMembrilla JA, Torres-Ferrus M, Alpuente A, Caronna E, Pozo-Rosich P. Efficacy and safety of galcanezumab as a treatment of refractory episodic and chronic cluster headache: Case series and narrative review. Headache. 2022 Nov 1;62(10):1395\u0026ndash;405.\u003c/li\u003e\n\u003cli\u003eLamas P\u0026eacute;rez R, Mill\u0026aacute;n-V\u0026aacute;zquez M, Gonz\u0026aacute;lez-Oria C. Efficacy and safety of galcanezumab as chronic cluster headache preventive treatment under real world conditions: Observational prospective study. Cephalalgia [Internet]. 2024 Mar 19 [cited 2024 Mar 23];44(3). Available from: https://pubmed.ncbi.nlm.nih.gov/38501892/\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Episodic Cluster Headache, Chronic Cluster Headache, Galcanezumab, Calcitonin Gene-Related Peptide, Treatment","lastPublishedDoi":"10.21203/rs.3.rs-4390027/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4390027/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003eBackground:\u003c/em\u003e Cluster headache (CH), currently one of the most painful conditions, lacks a well-established, disease specific, and mechanism-based prophylactic treatment. Galganezumab, a monoclonal antibody targeting the calcitonin gene-related peptide, reduced the weekly attacks of CH in one randomized, placebo-controlled trial for the prevention of episodic CH (eCH), but this effect was not detected in people with chronic CH (cCH).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eObjective:\u003c/em\u003e\u003cstrong\u003e \u003c/strong\u003eTo explore the efficacy and safety of galcanezumab for the prevention of CH in people with refractory CH in a real-world setting.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMethods:\u003c/em\u003e\u003cstrong\u003e \u003c/strong\u003eIn this observational study, we systematically monitored the efficacy and safety outcomes of adjunctive therapy in patients with refractory CH (failure of ≥3 prophylactic treatments) who received galcanezumab (120–360 mg monthly) for 3 consecutive months. A detailed headache diary with monthly in-person follow-ups was used. All participants received intermediate treatment with oral steroids or a great occipital nerve block ≥2 months before starting galcanezumab treatment.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eResults:\u003c/em\u003e Data from 11 people with CH (eCH n=5, cCH, n=6) were collected. After galcanezumab treatment, the average number of weekly CH attacks and weekly days with any symptomatic treatment for CH decreased significantly from 16.0±9.4 and 6.50±3.59 before treatment to 1.8±1.32 (p=0.002) and 1.8±3.36 (p=0.001) at month 3 of treatment, respectively.Two participants with cCH showed no change in the number of attacks with galcanezumab. No serious adverse events were recorded.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConclusion:\u003c/em\u003e\u003cstrong\u003e \u003c/strong\u003eThese data, along with those of previous real-world reports, suggest that galcanezumab may help people with refractory CH as an add-on treatment.\u003c/p\u003e","manuscriptTitle":"Galcanezumab Add-on in Refractory Cluster Headache","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-23 18:24:03","doi":"10.21203/rs.3.rs-4390027/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8be59937-fd26-4c00-9830-7c3784f29a7c","owner":[],"postedDate":"May 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-22T21:08:21+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-23 18:24:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4390027","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4390027","identity":"rs-4390027","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}