{"paper_id":"9a8cb982-2c1a-4eaa-b2f6-3e00f7b00613","body_text":"Ishikawa et al. Reproductive Health           (2024) 21:12  \nhttps://doi.org/10.1186/s12978-024-01739-8\nSTUDY PROTOCOL Open Access\n© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom-\nmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nReproductive Health\nEfficacy and safety of a novel \npain management device, AT-04, \nfor endometriosis-related pain: study protocol \nfor a phase III randomized controlled trial\nHiroshi Ishikawa1,2*, Osamu Yoshino3, Fuminori Taniguchi4, Tasuku Harada4, Mikio Momoeda5, Yutaka Osuga6, \nTamiki Hikake7, Youko Hattori8, Michiko Hanawa7, Yosuke Inaba7, Hideki Hanaoka7 and Kaori Koga1,2 \nAbstract \nBackground Endometriosis-related pain encompassing dysmenorrhea, dyspareunia, and chronic pelvic pain, \nreduces the quality of life in premenopausal women. Although treatment options for endometriosis alleviate this pain, \napproximately one-third of women still experience pain even after receiving treatment, indicating the need for novel \napproaches to pain relief in those women. The Angel Touch device (AT-04) is a portable magnetic fields irradiation \ndevice that incorporates a combination of mixed alternative magnetic fields at 2 kHz and 83.3 MHz. A phase III trial \nconfirmed the efficacy and safety of AT-02, a prototype of AT-04, for pain relief in patients with fibromyalgia.\nMethods This is a phase III, multicenter, prospective, randomized, sham device-controlled, double-blind, paral-\nlel study. The participants will be premenopausal women aged > 18 years who have endometriosis-related pain \nwith at least moderate severity. Considering dropouts, 50 participants have been deemed appropriate. Eligible \nwomen will be centrally registered, and the data center will randomly allocate them in a 1:1 ratio to the interven-\ntion and control groups. Women in the intervention group will receive electromagnetic wave irradiation generated \nby AT-04 and those who in the control group will wear a sham device for 16 weeks, and both groups will wear AT-04 \nfor another 4 weeks. The primary outcome measure is the change in the Numeric Rating Scale score at 16 weeks \ncompared with the baseline. Secondary outcome measures are efficacy for pelvic pain including dysmenorrhea \nand non-menstrual pain, and chronic pelvic pain not related to menstruation, dysmenorrhea, and dyspareunia, \nand improvement of quality of life during the study period. Safety will be evaluated by device defects and the fre-\nquency of adverse events. The study protocol has been approved by the Clinical Study Review Board of Chiba Uni-\nversity Hospital, Chiba, Japan, and will be conducted in accordance with the principles of the Declaration of Helsinki \nand the Japanese Clinical Trials Act and relevant notifications.\nDiscussion This study aims to develop a novel method of managing endometriosis-related pain. The AT-04 \nis an ultralow-invasive device that can be used without inhibiting ovulation, suggesting potential benefits to women \nof reproductive-age.\nTrial registration number Japan Registry of Clinical Trials (jRCTs032230278).\n*Correspondence:\nHiroshi Ishikawa\nishikawa@chiba-u.jp\nFull list of author information is available at the end of the article\n\nPage 2 of 11Ishikawa et al. Reproductive Health           (2024) 21:12 \nKeywords Endometriosis, Chronic pain, Quality of life, Pain management, Electromagnetic radiation, Patient reported \noutcome measures\nPlain language summary \nEndometriosis is a chronic inflammatory disorder that negatively impacts reproductive health via endometriosis-\nrelated pain, infertility, and endometriosis-associated ovarian cancer. Although current therapeutic options for endo-\nmetriosis are effective for the endometriosis-related pain, approximately one-third of women still experience pain \neven after receiving treatment, indicating the need for novel approaches to pain relief in those women. This is the first \nrandomized controlled trial to investigate the efficacy and safety of a novel portable pain management device, AT-04, \nthat incorporates a combination of mixed alternating magnetic fields, for endometriosis-related pain. This is a mul-\nticenter, prospective, sham device-controlled, double-blind, parallel study. Enrolled women will have undergone \nstandard hormonal treatment for endometriosis at baseline, and this allows for assessing whether the device remains \neffective when used in conjunction with existing treatment methods. The study also will explore the impact of AT-04 \non reducing the size of ovarian endometriotic cysts that reflect the activity of endometriosis. The study reflects \nthe strong desire by physicians to liberate women from the unbearable pain associated with endometriosis. The sole \nefficacy of AT-04 in treating endometriosis-related pain is difficult to evaluate as there is a possibility that menstrual \ncycles may influence the assessment of pain and quality of life. However, the study findings regarding the effective-\nness of AT-04 for the treatment of endometriosis-related pain may benefit women with endometriosis who have pain \nthat is not effectively relieved by other treatments. Consequently, it may contribute to the improvement of reproduc-\ntive health within society.\nBackground\nEndometriosis is a progressive, chronic inflammatory \ndisorder that affects approximately 10% of women of \nreproductive age. It generally develops in late adoles -\ncence to early adulthood, and the associated symptoms \noften appear in the late twenties and early thirties [1 ]. \nWomen with endometriosis experience endometri -\nosis-related pain, encompassing dysmenorrhea, dys -\npareunia, and chronic pelvic pain, which reduces \ntheir quality of life and decreases labor productivity. \nAlthough endometriosis-related infertility and ovarian \nmalignant tumors arising from ovarian endometriotic \ncysts are also important, controlling endometriosis-\nrelated pain is of utmost importance when treating \nendometriosis [2 ]. Current standard treatments for \nendometriosis include progestin-based hormonal treat -\nments, such as combined oral contraceptive (OC) pills, \ngonadotropin-releasing hormone (GnRH) analogs, \nand laparoscopic surgeries [3 ]. Analgesics and tradi -\ntional Chinese medicines are also prescribed to relieve \nendometriosis-related pain; however, these treatments \nmay be completely ineffective or insufficient in some \nwomen, even if appropriate treatments are admin -\nistered [4 ]. Additionally, endometriosis-related pain \noften persists even after laparoscopic excision of endo -\nmetriotic lesions, indicating that controlling disease \nprogression does not necessarily lead to pain relief. \nWorsening pain symptoms can trigger anxiety and \ndepression, leading to a further decrease in quality of \nlife and labor productivity [5 ].\nEndometriosis severity does not necessarily correlate \nwith pain intensity, indicating that pain development in \npatients with endometriosis involves complex mecha -\nnisms. Hence, in addition to lowering the pain threshold \ndue to persistent chronic pelvic pain, chronic inflamma -\ntion, peripheral and central pain generators, endocrine \nchanges, and structural alterations in the peripheral and \ncentral nervous systems are also associated with pain [6]. \nUpregulation of vascular endothelial factors and nerve \ngrowth factors as well as proliferation of sensory nerves \nin local endometriotic lesions may also be associated \nwith pain [7]. Furthermore, the presence of treatment-\nresistant endometriosis-related pain may indicate the \nprogression of local endometriotic lesions.\nThe Angel Touch device (AT-04,  ait®, developed by \nPeace of Mind Co., Ltd., Kumamoto, Japan) is a port -\nable magnetic fields irradiation device that incorporates \na combination of mixed alternative magnetic fields at \n2  kHz and 83.3  MHz (magnetic field energy is approxi -\nmately one-third of the Earth’s magnetic field). Local pain \nrelief may be achieved by carefully using this device on \nthe affected area. Animal experimental data has revealed \nthat the pain control mechanism of this device involves \nthe regulation of nerve growth factors, local inhibition of \ninflammatory cytokines, and activation of the descending \ninhibitory system [8]. These are the possible mechanisms \nthat control endometriosis-related pain. A phase III clini-\ncal trial confirmed the efficacy and safety of AT-02, a \nprototype of AT-04, for pain relief in patients with fibro -\nmyalgia [9]. Moreover, a pilot study using AT-04 for pain \n\nPage 3 of 11\nIshikawa et al. Reproductive Health           (2024) 21:12 \n \nrelief from dysmenorrhea in five women with endometri-\nosis conducted in our laboratory revealed that dysmenor-\nrhea significantly improved without any adverse events, \nand the size of the endometriotic cysts significantly \ndecreased (data not shown). These results prompted the \nneed for large-scale validation studies to identify the effi -\ncacy and safety of AT-04 for pain relief in women with \nendometriosis.\nMethods\nAim\nThe aim of this study is to explore the efficacy and safety \nof AT-04 in women with endometriosis-related pain.\nDesign and setting\nThis is a phase III, sham-controlled, double-blind, par -\nallel-group study. This study will be conducted in the \nChiba University Hospital and its affiliated facilities, The \nUniversity of Tokyo Hospital, University of Yamanashi \nHospital, Fukuoka University, KASHIWAZAKI OB/GYN \nCLINIC, Iryohojinshadan Seijunkai Juno Vesta Clinic \nHatta, TSUBAKI Women’s Clinic, and Yokosuka Haruko \nLady’s Clinic. Details of the participating research facili -\nties are provided in Additional file 1.\nStudy participants\nInclusion criteria\nParticipants must fulfil the following inclusion criteria:\n1. Premenopausal women aged ≥ 18 years at the time of \nobtaining consent\n2. Patients clinically diagnosed with endometriosis \nmeeting one of the following criteria (additional \ndiagnosis required if the disease recurs after surgery):\na. laparoscopy or laparotomy performed within \n5 years of the start of treatment\nb. magnetic resonance imaging or ultrasonogra -\nphy (transvaginal, transabdominal, or transrec -\ntal) performed within 1 year prior to the start of \ntreatment\nc. pelvic and rectal examination performed prior to \nthe start of treatment\n3. Patients with dysmenorrhea or pelvic pain believed \nto be caused by endometriosis, with at least one \nassessed by the principal investigator to be moderate \nor higher on the Biberoglu and Behrman (B&B) rat -\ning scale before the start of treatment [10]\n4. Patients with an average Numeric Rating Scale (NRS) \nscore ≥ 4 for endometriosis-related pain within \n28 days before obtaining consent [10]\n5. Patients who have not initiated any new treatment \nfor endometriosis or made changes to their existing \ntreatment (including prescription details, dosage, and \nadministration) within 28 days before obtaining con -\nsent\n6. Patients who, based on the assessment of the princi -\npal investigator, show no evidence of acute endome -\ntriosis deterioration within 28 days before obtaining \nconsent.\n7. Patients who provide written consent to participate \nin the study.\nExclusion criteria\nPatients meeting the following criteria will be excluded:\n (1) Use of the following drugs within 8 weeks prior \nto obtaining consent: clinical trial or investiga -\ntional drugs, GnRH analogs, danazol and aro -\nmatase inhibitors, and selective estrogen recep -\ntor modulators\n (2) Previous use of alternating magnetic field therapy \ndevices, including the study devices\n (3) Patients who routinely use non-steroidal anti-\ninflammatory drugs (NSAIDs)\n (4) Patients with ovarian endometriotic cysts > 10 cm \nin diameter and aged > 40 years\n (5) History of bilateral oophorectomy\n (6) Significant or unexplained irregular uterine \nbleeding determined by the principal investigator\n (7) Patients with uterine fibroids who may require \nnew treatment during the study period in the \nopinion of the principal investigator\n (8) Irritable bowel syndrome and/or lower abdomi -\nnal pain due to severe interstitial cysts\n (9) Patients with a history of, or complications of, \nsevere hepatic disorder, jaundice, renal disorder, \ncardiovascular, endocrine system, metabolic, pul-\nmonary, gastrointestinal, neurological, or urolog-\nical diseases, immune disorders, psychiatric dis -\neases (especially depression-like symptoms), and \nsuicide attempts due to such disorders\n (10) Patients using life-supporting medical electri -\ncal equipment such as artificial heart lungs and \npacemakers\n (11) Patients using medical electrical equipment, such \nas electrocardiographs\n (12) Patients participating in clinical trials or clinical \nstudies on other drugs or medical devices\n (13) Patients requiring hospitalization for treatment\n\nPage 4 of 11Ishikawa et al. Reproductive Health           (2024) 21:12 \nParticipant screening\nConsent will be obtained from eligible participants \n28–35 days before randomization. The examination items \nat screening will encompass the following items:\n(1) Participant characteristics at the baseline, including \nthe date of consent, patient identification code, age, \nheight (cm), weight (kg), body mass index (BMI), \nmedical history, comorbidities, prior treatments, \nand physical findings, including major symptoms of \nendometriosis, gravidity, and parity\n(2) Vital signs, including systolic and diastolic blood \npressure and body temperature\n(3) Evaluation of subjective and objective pain symp -\ntoms\n(4) Determination of the average NRS score for the \n4 weeks preceding the visit\n(5) Evaluation of the B&B score\n(6) Ultrasound examination to identify ovarian endo -\nmetriotic cysts and other endometriotic lesions. \nFor assessment of ovarian endometriotic cysts, the \nmaximum diameter of each cyst and their perpen -\ndicular diameter will be measured, and the calcu -\nlated volume  (cm3) will be recorded.\n(7) Monitoring the occurrence of adverse events\n(8) Documentation of concomitant medications and \ntherapies.\nDiscontinuation criteria\nThe study will be terminated if any of the following crite -\nria are met during the study period:\n(1) Occurrence of unexpected severe illnesses or condi-\ntions, including physical disability or death, events \nthat may lead to physical disability or death, hospi -\ntalization or extension of hospital stay, and congeni-\ntal disorders or abnormalities in the next generation\n(2) Frequent occurrence of predictable severe condi -\ntions that significantly exceed expectations\n(3) Serious adverse events for which a causal relation -\nship cannot be excluded\n(4) Reports indicating significant changes in the inci -\ndence, frequency, and conditions of disease occur -\nrence\n(5) Reports indicating the potential occurrence of can -\ncer, other serious diseases, disabilities, or death\n(6) Information suggesting a lack of efficacy in the trial\n(7) Information on measures implemented to pre -\nvent manufacturing, importation, or sale, as well \nas recall, disposal, or other actions to prevent the \noccurrence or spread of health and hygiene hazards \nfor commercial products having the same effect as \nthe tested devices.\nStudy device\nThe AT-04 is a minimally invasive device comprising a \ncontroller and a dual-coil emitter assembly powered by a \n3.7-V battery (Fig.  1a). The dual emitter simultaneously \ngenerates alternating magnetic fields. Detailed instruc -\ntions, in Japanese, for using the device are provided in \nthe Additional file. Briefly, participants are instructed to \nattach two pads to the left and right sides of the lower \nabdomen and then press the start button to generate local \nelectromagnetic waves (Fig. 1b). The device automatically \nFig. 1 Study device and location for applying pads. a Actual photo of the AT-04. The appearance of the test device (AT-04) and the sham device \n(S-02) is identical, and it is impossible to distinguish the two based on their external features. b Location for applying pads. Participants will attach \nthe pads themselves to both sides of their lower abdomens. The grey circle indicates the basic location for applying the pads\n\nPage 5 of 11\nIshikawa et al. Reproductive Health           (2024) 21:12 \n \nstops after 30  min. If participants experience pain in \nareas other than those mentioned above, they can attach \nthe remaining two pads to the affected area(s). The test \nand sham devices will be provided free of charge by Peace \nMind Co. Ltd., Kumamoto, Japan.\nInterventions\nThe study design is shown in Fig.  2. After obtain -\ning consent, eligibility for this study will be confirmed \nthrough screening tests. Central enrolment and rand -\nomized assignment will be conducted at the data center \nusing a 1:1 ratio to minimize bias. The actual treatment \ngroup will use the AT-04 and the control group will use \nthe S-02, a sham device, for 16  weeks. At the 16-week \nvisit, participants will be asked to bring their device for \nreplacement with a new device (all actual devices). To \nensure blinding after replacement with the actual device \nat week 16, participants will be informed, at the time of \nobtaining their consent to participate, that the feeling of \nuse may vary depending on the device under study. The \npads will be applied to at least two sites on the lower \nabdomen, including the uterine and ovarian areas; if \nthere are other painful areas, two additional pads (a max -\nimum of four sites) will be applied to those areas.\nOutcome measures\nPrimary outcome\nThe primary outcome of this study is the change in the \nNRS score for endometriosis-related pain collected at \neach visit and at the end of the double-blind period \n(after 16  weeks) compared with the baseline score at \nthe start of treatment.\nSecondary outcomes\nThe secondary outcomes of this study are summarized \nin Table 1. Measurements will be conducted at the base -\nline and at 4, 6, 12, 16, and 20  weeks after treatment \ninitiation. Longitudinal pain during the study period \nwill be recorded using electronic patient-reported \noutcomes (ePRO). The B&B scale, a specialized scor -\ning system for evaluating endometriosis-related pain, \nwill be employed. It consists of a rating based on the \npatient’s self-assessment of pelvic pain, dysmenorrhea, \nand dyspareunia (Bourdel et  al. 2014). The quality of \nlife of the participants will be evaluated using the Endo -\nmetriosis Health Profile-30 (EHP-30) and the EuroQol \n5-Dimension (EQ-5D) Health-Related Quality of Life \n(HRQoL) Questionnaire.\nFig. 2 Overview of the study design. After providing consent, eligible women will be randomly assigned to the treatment group, utilizing \nAT-04, or the control group, utilizing S-02. Participants will use these devices for 16 weeks (double-blind period), after which they will use AT-04 \nfor an additional 4 weeks (actual device usage period)\n\nPage 6 of 11Ishikawa et al. Reproductive Health           (2024) 21:12 \nObservation, examination, and evaluation items at each visit \n(Table 2)\nTreatment using the test device will commence on Day 1, \nand the NRS, B&B, EHP-30, and EQ-5D scores will also \nbe collected on Day 1. NRS scores will be assessed by \nparticipants recalling their endometriosis-related pelvic \npain over the 4 weeks prior to the visit. The following \nitems will be assessed at the visits in weeks 4, 8, 12, 16, \nand 20 after the initiation of the trial:\n (1) Height and BMI\n (2) Vital signs, including systolic and diastolic blood \npressure and body temperature\n (3) Subjective and objective pain symptoms\n (4) Average NRS score for the 4 weeks preceding the \nvisit\n (5) Maximum and average NRS scores during men -\nstruation within the 4 weeks preceding the visit\n (6) Maximum and average NRS scores for periods \nother than menstruation within the 4 weeks pre -\nceding the visit\n (7) B&B, EHP-30 score, and EQ-5D scores\n (8) Ultrasonography to identify ovarian endometri -\notic cysts and other endometriotic lesions. Ovar -\nian endometriotic cysts will be evaluated using \nthe same measurements as the screening exami -\nnation\n (9) Occurrence of adverse events\n (10) Concomitant medications and therapies.\nIn the event of discontinuation of the device by a par -\nticipant, the reasons for discontinuation will be included \nin addition to the observation items mentioned above.\nParticipant diary\nPaper-based records and ePRO will be used to collect \ndaily data, including the presence or absence of menstru -\nation, number of devices used, quantity of device pads \nused, NRS scores (reflecting maximum pain in the pre -\nceding 24  h before input), utilization of analgesics, and \nthe occurrence of adverse events.\nAssignment of interventions and blinding\nAfter obtaining consent, eligible participants confirmed \nthrough screening tests will be randomized. The ran -\ndomization at a 1:1 ratio will be conducted at the data \ncenter to achieve central registration and minimize bias. \nFor the random allocation, the minimization method \nwill be employed, adjusting for the trial facility and the \npresence or absence of low dose estrogen-progestin and \nprogestin treatment within each group. The principal \ninvestigator will initiate protocol treatments for partici -\npants determined to be ‘eligible’ according to the rand -\nomization results. Therefore, the trial participants and \nprincipal investigator will be blinded to interventions \nafter assignment.\nStatistical analysis\nThe baseline characteristics for participants in each \ngroup will be summarized, presenting frequencies and \nTable 1 Secondary outcomes in this study\n*Baseline was defined as a point before treatment initiation\n# Pain during menstruation including menstrual pain and other pelvic pain\n$ eRPO: Electronic Patient-Reported Outcomes; NRS: Numeric Rating Scale\n**Time at the end of the treatment period\nOutcomes Evaluation tools Time points\nEfficacy for pain Pelvic pain NRS score Comparison baseline* with 4, 8, 12, \nand 20 weeks after treatment initiation\nPain during menstruation# NRS score by  ePRO$ From treatment initiation to end of treatment\nPain other than menstruation NRS score by  ePRO$ From treatment initiation to end of treatment\nChronic pelvic pain not related \nto menstruation, dysmenorrhea, \nand dyspareunia\nBiberoglu & Behrman (B&B) scale Comparison baseline* with 4,8,12, \nand 20 weeks after treatment initiation\nQuality of life Endometriosis Health Profile-30 (EHP-30) \nscore\nComparison baseline* with 4, 8, 12, \nand 20 weeks after treatment initiation\nHealth-related quality of life (EQ-5D) Comparison baseline* with 4, 8, 12, \nand 20 weeks after treatment initiation\nEfficacy for endo-\nmetriosis lesions\nSize of ovarian endometriotic \ncysts\nTransvaginal ultrasound Comparison baseline* with 16 weeks \nafter treatment initiation**\nSafety of the device The frequency and proportion \nof malfunctions and adverse \nevents in the test device\n\nPage 7 of 11\nIshikawa et al. Reproductive Health           (2024) 21:12 \n \nTable 2 Study schedule for observation, inspection, and evaluation\n\nPage 8 of 11Ishikawa et al. Reproductive Health           (2024) 21:12 \npercentages for categorical variables and summary sta -\ntistics (number of cases, mean, standard deviation, and \nminimum, median, and maximum values) for continu -\nous variables. For group comparisons, Pearson’s Chi-\nsquared test will be used for categorical variables, Fisher’s \nexact test will be applied for cells with an expected fre -\nquency < 5% and > 20%, and the t-test or Mann–Whitney \nU test will be used for continuous variables.\nA two-tailed 5% significance level will be used. A two-\ntailed Student’s t-test will assess the primary outcome \n(null hypothesis: the difference in NRS score change \nbetween the treatment and control groups equals zero; \nalternative hypothesis: the difference in NRS score \nchange between the treatment and control groups is not \nequal to zero). Rejection of the null hypothesis and adop -\ntion of the alternative hypothesis will occur if p < 0.05.\nAdditionally, an analysis of variance with the alloca -\ntion factor as a fixed effect will be performed as a sen -\nsitivity analysis, and the Wilcoxon rank-sum test will \nbe performed for a non-parametric analysis. The sec -\nondary endpoint analysis will be similar to the primary \nendpoint analysis. For the safety endpoint, frequencies \nand proportions of the patients with adverse events will \nbe presented for each group. Exact two-sided 95% con -\nfidence intervals, assuming a binomial distribution, will \nbe calculated for each group, and Fisher’s exact test will \nbe used to compare groups. All statistical analyses will be \nperformed using SAS version 9.4 or higher (SAS Institute \nJapan Ltd, Tokyo).\nSample size calculation\nThe sample size calculation is based on the findings \nof a randomized controlled trial assessing the effect \nof the AT-02, a prototype of the AT-04, in patients \nwith fibromyalgia [9]. Anticipated placebo effects of \nthe sham device are approximately 14%. In previous \nopen trials for dysmenorrhea, participants with NRS \nscores ≥ 6 before treatment initiation experienced a \nsignificant reduction in NRS scores by 1.73 as the total \neffect, encompassing the true effect and placebo effect. \nAssuming a true effect of 1.49 and attributing 14% as \nthe placebo effect, the calculated placebo effect will \nbe 0.24. The standard deviation of the actual device \nwas approximately 1.8, and that of the sham device \nwas approximately 0.3. Employing a two-sided non-\npaired t-test, the effect size was set to 0.969, alpha was \nset to 0.05, and power was set to 0.9. A sample size of \n24 participants per group, totalling 48 participants, is \nrequired to achieve a conservative beta error. Consider -\ning potential dropouts, a sample size of 50 is deemed \nappropriate.\nData management\nThe principal investigator and collaborating physicians \nwill utilize Electronic Data Capture (EDC) to produce, \nmanage, and revise the study report. External data col -\nlection will be facilitated through ePRO. The source \nmaterials include: (1) informed consent forms and \nTable 2 (continued)\n● Represents the examination and assessment items to be performed at each visit\n# 1: Acceptable range of the required tests at Day 1, as indicated by 〇, are 14 days. Treatment using test device starts at Day 1\n# 2: Consent from the participants must be obtained at least 28 days before the start of the study\n# 3: Participants recall and assess the level of pain experienced over the past 4 weeks at each visit\n# 4: Data collected through the electronic Patient Reported Outcome (ePRO) system will be used for the assessment\n# 5: The participant diary will start recording from the date of consent. Recordings until the day before Day1 will be on paper diary, while from Day1 onwards, record \nwill be collected by ePRO\nBMI: body mass index; NRS: Numeric rating Scale; B&B: Biberoglu and Behrman; EHP-30: Endometriosis Health Profile-30; EQ-5D: EuroQol 5-Dimension\n\nPage 9 of 11\nIshikawa et al. Reproductive Health           (2024) 21:12 \n \ndocuments providing information to the study partici -\npants; (2) documents containing participant baseline \ndata, including patient charts, nursing documents, \nlaboratory results, and imaging results; (3) documents \non the use of testing devices; and (4) documents and \nrecords related to necessary tests under the Clinical \nTrials Act of Japan.\nMonitoring\nConsidering the study’s risk profile, both on-site and \noff-site monitoring will be carried out in adherence to \nthe quality control protocols of the facilities. Monitor -\ning personnel are required to compile reports on signifi -\ncant findings, including diseases and noncompliance, or \nprovide summaries of the factual circumstances. Impor -\ntantly, they must refrain from disclosing information \nacquired during their duties without valid reasons.\nDiscussion\nThis randomized trial aims to evaluate the efficacy of \nAT-04, a novel pain management device, in treating \nendometriosis-related pain. The AT-04 generates weak \nalternating magnetic fields, providing effective local pain \nrelief. Women who have undergone standard hormonal \ntreatment for endometriosis at baseline will be enrolled. \nThis allows for assessment of whether the device remains \neffective when used in conjunction with existing treat -\nment methods. Additionally, recruitment of women \nwho have not undergone existing treatments can be \nchallenging.\nCurrent therapies for endometriosis-related pain have \nseveral advantages and disadvantages. NSAIDs are the \nfirst-choice analgesics, and traditional Chinese medicines \nare frequently used for pain control [11]. While these \ndrugs have few side effects and are generally well toler -\nated, their analgesic effects vary among individuals. Hor -\nmonal treatments using low-dose OC, progestins, and \nGnRH analogs have demonstrated efficacy in improving \nendometriosis-related pain [12]. However, continuous \nuse of hormonal treatments may be challenging if women \nwish to become pregnant due to impaired ovulation. \nMoreover, each hormonal treatment has specific adverse \neffects. The use of OCs is associated with pulmonary \nembolism and deep venous thrombosis. Long-term use \nof GnRH analogs is restricted due to the significant loss \nof bone mineral density. Dienogest administration may \nlead to persistent abnormal uterine bleeding, impacting \na woman’s quality of life. While laparoscopic surgeries are \nfrequently performed to remove endometriotic lesions, \na significant number of recurrences have been observed. \nThe loss of the ovarian reserve after laparoscopic excision \nof ovarian endometriotic cysts negatively affects women \nwith infertility [13].\nApproximately one-third of women with endometri -\nosis-related pain experience poor pain control, which \naffects their daily lives. Consequently, several thera -\npeutic options have been developed to alleviate pain \nthrough diverse mechanisms. Oral GnRH antagonists \nsuch as relugolix, elagolix, and linzagolix have proven \neffective for short-term endometriosis-related pain \n[14]. Combination therapy with relugolix and low-dose \nestrogen and progestin has shown significant improve -\nment in endometriosis-related pain without serious \nadverse events [15]. Supplementation of antioxidant \nvitamins has been effective in significantly reducing \ninflammatory markers and pelvic pain scores in women \nwith endometriosis [16]. Additionally, a combination \nof N-acetyl cysteine, alpha-lipoic acid, bromelain, and \nzinc, which have antioxidant action upstream of the \ncyclooxygenase-2 pathway, has shown effectiveness in \ncontrolling endometriosis-related pain [17]. Although \nopioids are generally not recommended for pain relief \nin women with endometriosis, opioid prescriptions \nhave been identified for women diagnosed with endo -\nmetriosis within the past year in the United States [18]. \nWomen with endometriosis have a four-fold greater \nrisk of chronic opioid use compared to those without \nendometriosis [19]. Psychological interventions, such \nas cognitive-behavioral therapy, mindfulness therapy, \nyoga, psychoeducation, and progressive muscular \nrelaxation, significantly reduce endometriosis-related \npain [20]. Chinese acupuncture has also demonstrated \neffectiveness in pain control for endometriosis [21].\nImproving the HRQoL of women with endometriosis \nis another important aspect of patient-centered nar -\nrative medicine. Therefore, this study aims to evaluate \nHRQoL using the EHP-30 and EQ-5D scoring systems. \nThe EHP-30 is a valid and reproducible measure of \nHRQoL in women with endometriosis, consisting of 30 \nquestions divided into five categories: pain, control and \npowerlessness, social support, emotional well-being, \nand self-image [22, 23]. The EQ-5D is a generic instru -\nment for describing HRQoL in daily life, evaluating \ndaily life in five dimensions: mobility, self-care, usual \nactivities, pain/discomfort, and anxiety/depression \n[24].\nThis study has some potential limitations that need \nconsideration. First, it is challenging to determine the \nsole efficacy of AT-04 in treating endometriosis-related \npain since all eligible women would have already been \ndiagnosed with endometriosis, and most would have \nundergone treatment for endometriosis. Second, the \nNRS and HRQoL measurements may vary during the \n\nPage 10 of 11Ishikawa et al. Reproductive Health           (2024) 21:12 \nstudy period due to hormonal fluctuations associated \nwith the menstrual cycle; this may impact the assessment \nof pain and quality of life. Finally, there is a possibility of \ninsufficient pain relief by AT-04 because the study targets \nwomen with an NRS score ≥ 4 with moderate endome -\ntriosis-related pain. The effectiveness of pain relief may \nbe comparatively weak in women with moderate pain. \nFurthermore, this study will be held in Japan. The rele -\nvance to other countries, race, ethnicities and cultures is \nanother limitation.\nConclusion\nIn summary, this randomized study has the potential \nto develop a novel method of managing endometriosis-\nrelated pain. The AT-04 is an ultralow-invasive device \nthat can be used without inhibiting ovulation in women \nwith endometriosis. The mechanism of pain manage -\nment using the AT-04 is distinctly different to that of \nexisting treatments; this suggests potential efficacy in \nthe treatment of women with endometriosis-related \npain.\nAbbreviations\nAT-04  Angel Touch device 04\nBMI  Body mass index\nB&B  Biberoglu and Behrman\nEDC  Electronic data capture\nEHP-30  Endometriosis Health Profile-30\nePRO  Electronic patient-reported outcomes\nEQ-5D  The EuroQol 5-dimension\nGnRH  Gonadotropin-releasing hormone\nHRQoL  Health-related quality of life\nNRS  Numeric Rating Scale\nNSAIDs  Non-steroidal anti-inflammatory drugs\nOC  Oral contraceptive\nSupplementary Information\nThe online version contains supplementary material available at https:// doi. \norg/ 10. 1186/ s12978- 024- 01739-8.\nAdditional file 1. The study protocol has been approved by the Clinical \nStudy Review Board of Chiba University Hospital, Chiba, Japan, and regis-\ntered by the Japan Registry of Clinical Trials (jRCTs032230278, https:// jrct. \nniph. go. jp/). An overview of this research is publicly available through the \nJapan Registry of Clinical Trials.\nAdditional file 2. The participant consent form has been approved by the \nClinical Study Review Board of Chiba University Hospital, Chiba, Japan, and \nregistered by the Japan Registry of Clinical Trials (jRCTs032230278, https:// \njrct. niph. go. jp/). An overview of this research is publicly available through \nthe Japan Registry of Clinical Trials.\nAcknowledgements\nWe thank Mr. Eisaku Yamauchi, an executive officer of Peace of Mind Co., Ltd., \nfor his cooperation and suggestions for the study protocol. We thank Editage \n(www. edita ge. com) for English language editing.\nAuthor contributions\nHI designed the study, created figures and tables, and wrote drafting of the \nmanuscript. OY, FT, TH, MM, and YO provided suggestions for the design of the \nstudy protocol. TH is a monitoring supervisor and designed the monitoring \nmethod. YH is a case registration and assignment supervisor. MH is a data \nmanagement manager. YI is a statistical expert and designed the statistical \nmethods. HH is responsible for the research planning support and coordina-\ntion, and operational support. KK, the principal investigator, designed the \nstudy, planned the study protocol, and critically revised the manuscript for \nintellectual content.\nFunding\nThis study is conducted with research grants obtained from the 2022 Growth-\nOriented Small and Medium-Sized Enterprises Research and Development \nSupport Project (Go-Tech Project) supported by the Ministry of Economy, \nTrade and Industry in Japan.\nAvailability of data and materials\nThe detailed study protocols and a participant consent form, which are \ndescribed in Japanese, are available in the Additional file 1 and 2, respectively.\nDeclarations\nEthics approval and consent to participate\nThe study protocol has been approved by the Clinical Study Review Board of \nChiba University Hospital, Chiba, Japan, and registered by the Japan Registry \nof Clinical Trials (jRCTs032230278, https:// jrct. niph. go. jp/). An overview of this \nresearch is publicly available through the Japan Registry of Clinical Trials. The \nstudy will be conducted in accordance with the principles of the Declaration \nof Helsinki and the Japanese Clinical Trials Act enacted in 2017 (https:// www. \nmhlw. go. jp/ file/ 06- Seisa kujou hou- 10800 000- Iseik yoku/ 00002 13334. pdf) and \nrelevant notifications. Principal investigators and study co-investigators in this \nstudy will obtain informed written consent from the study participants. They \nwill create case report forms using EDC in accordance with the requirements \nof clinical research methods and relevant guidelines. Participant identification \nwill be conducted solely using a unique participant identification number. \nDocuments containing personal information of the participants will be treated \nas confidential documents by the principal investigator. Only the principal \ninvestigator and co-investigators will have access to the final dataset.\nConsent for publication\nNot applicable.\nCompeting interests\nAll authors have no competing interests in relation to this study.\nAuthor details\n1 Department of Obstetrics and Gynecology, Graduate School of Medi-\ncine, Chiba University, Inohana 1-8-1, Chuo-Ku, Chiba 260-8670, Japan. \n2 Department of Obstetrics and Gynecology, Chiba University Hospital, \nChiba 260-8677, Japan. 3 Department of Obstetrics and Gynecology, University \nof Yamanashi Graduate School of Medicine, Yamanashi 409-3898, Japan. \n4 Department of Obstetrics and Gynecology, Faculty of Medicine, Tottori \nUniversity, Tottori 683-8504, Japan. 5 Department of Obstetrics and Gyne-\ncology, Aiiku Hospital, Tokyo 105-8321, Japan. 6 Department of Obstetrics \nand Gynecology, The University of Tokyo Graduate School of Medicine, \nTokyo 113-8655, Japan. 7 Chiba University Clinical Research Center, Chiba \nUniversity Hospital, Chiba 260-8677, Japan. 8 Data Center, Chiba University \nHospital, Chiba 260-8677, Japan. \nReceived: 4 January 2024   Accepted: 15 January 2024\nReferences\n 1. Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic dis-\nease: clinical challenges and novel innovations. Lancet. 2021;397:839–52.\n 2. Bulun SE, Yilmaz BD, Sison C, et al. Endometriosis. Endocr Rev. \n2019;40:1048–79.\n 3. Zondervan KT, Becker CM, Koga K, et al. Endometriosis. Nat Rev Dis Prim-\ners. 2018;4:9.\n 4. Brown J, Crawford TJ, Datta S, et al. Oral contraceptives for pain associated \nwith endometriosis. Cochrane Database Syst Rev. 2018;5:CD001019.\n\nPage 11 of 11\nIshikawa et al. Reproductive Health           (2024) 21:12 \n \n 5. Laganà AS, La Rosa VL, Rapisarda AMC, et al. Anxiety and depression in \npatients with endometriosis: impact and management challenges. Int J \nWomens Health. 2017;9:323–30.\n 6. Morotti M, Vincent K, Becker CM. Mechanisms of pain in endometriosis. \nEur J Obstet Gynecol Reprod Biol. 2017;209:8–13.\n 7. Maddern J, Grundy L, Castro J, et al. Pain in endometriosis. Front Cell \nNeurosci. 2020;14: 590823.\n 8. Kohno T, Takaki K, Kishita K, et al. Neuromodulation through magnetic \nfields irradiation with AT-04 improves hyperalgesia in a rat model of \nneuropathic pain via descending pain modulatory systems and opioid \nanalgesia. Cell Mol Neurobiol. 2023;43:4345.\n 9. Oka H, Miki K, Kishita I, et al. A multicenter, prospective, randomized, \nplacebo-controlled, double-blind study of a novel pain management \ndevice, AT-02, in patients with fibromyalgia. Pain Med. 2020;21:326–32.\n 10. Bourdel N, Alves J, Pickering G, Ramilo I, Roman H, Canis M. Systematic \nreview of endometriosis pain assessment: how to choose a scale? Hum \nReprod Update. 2014;21(1):136–52.\n 11. Balan A, Moga MA, Dima L, et al. An overview on the conservative man-\nagement of endometriosis from a naturopathic perspective: phytochemi-\ncals and medicinal plants. Plants (Basel). 2021;10:587.\n 12. Kalaitzopoulos DR, Samartzis N, Kolovos GN, et al. Treatment of endome-\ntriosis: a review with comparison of 8 guidelines. BMC Womens Health. \n2021;21:397.\n 13. Tang Y, Li Y. Evaluation of serum AMH, INHB combined with basic FSH \non ovarian reserve function after laparoscopic ovarian endometriosis \ncystectomy. Front Surg. 2022;9: 906020.\n 14. Yan H, Shi J, Li X, et al. Oral gonadotropin-releasing hormone antagonists \nfor treating endometriosis-associated pain: a systematic review and \nnetwork meta-analysis. Fertil Steril. 2022;118:1102–16.\n 15. Giudice LC, As-Sanie S, Arjona Ferreira JC, et al. Once daily oral relugolix \ncombination therapy versus placebo in patients with endometriosis-\nassociated pain: two replicate phase 3, randomised, double-blind, studies \n(SPIRIT 1 and 2). Lancet. 2022;399:2267–79.\n 16. Santanam N, Kavtaradze N, Murphy A, et al. Antioxidant supplementa-\ntion reduces endometriosis-related pelvic pain in humans. Transl Res. \n2013;161:189–95.\n 17. Lete I, Mendoza N, de la Viuda E, et al. Effectiveness of an antioxidant \npreparation with N-acetyl cysteine, alpha lipoic acid and bromelain in \nthe treatment of endometriosis-associated pelvic pain: LEAP study. Eur J \nObstet Gynecol Reprod Biol. 2018;228:221–4.\n 18. As-Sanie S, Soliman AM, Evans K, et al. Short-acting and long-acting \nopioids utilization among women diagnosed with endometriosis in the \nUnited States: a population-based claims study. J Minim Invasive Gynecol. \n2021;28:297-306.e2.\n 19. Chiuve SE, Kilpatrick RD, Hornstein MD, et al. Chronic opioid use and \ncomplication risks in women with endometriosis: a cohort study in US \nadministrative claims. Pharmacoepidemiol Drug Saf. 2021;30:787–96.\n 20. Samami E, Shahhosseini Z, Khani S, et al. Pain-focused psychological \ninterventions in women with endometriosis: a systematic review. Neu-\nropsychopharmacol Rep. 2023;43:310–9.\n 21. Xu Y, Zhao W, Li T, et al. Effects of acupuncture for the treatment of \nendometriosis-related pain: a systematic review and meta-analysis. PLoS \nONE. 2017;12: e0186616.\n 22. Hansen KE, Lambek R, Røssaak K, et al. Health-related quality of life in \nwomen with endometriosis: psychometric validation of the Endome-\ntriosis Health Profile 30 questionnaire using confirmatory factor analysis. \nHum Reprod Open. 2022;2022:hoab042.\n 23. Pokrzywinski RM, Soliman AM, Chen J, et al. Achieving clinically meaning-\nful response in endometriosis pain symptoms is associated with improve-\nments in health-related quality of life and work productivity: analysis of 2 \nphase III clinical trials. Am J Obstet Gynecol. 2020;222:592.e1-592.e10.\n 24. Yoshino O, Suzukamo Y, Yoshihara K, et al. Quality of life in Japanese \npatients with dysmenorrhea or endometriosis-associated pelvic \npain treated with extended regimen ethinylestradiol/drospirenone \nin a real-world setting: a prospective observational study. Adv Ther. \n2022;39:5087–104.\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in pub-\nlished maps and institutional affiliations.","source_license":"CC0","license_restricted":false}