Nonrandomized Allocation of Steroid Therapy in Patients With Fukuyama Congenital Muscular Dystrophy: Study Protocol for a Phase II Clinical Trial

ABSTRACT

Aim

This study aimed to evaluate the efficacy and safety of steroid therapy in patients with Fukuyama congenital muscular dystrophy (FCMD).

Methods

This is a noncontrolled, nonblinded, multicenter collaborative phase 2 trial in patients with a definite diagnosis of 3‐kb insertion mutation homozygous or compound heterozygous FCMD based on genetic testing. The first part of the study evaluates efficacy; patients with homozygous FCMD were given oral prednisolone at a dose of 1 mg/kg on alternate days (0.5 mg/kg/day) for 24 weeks. The second part of the study evaluates safety; patients with homozygous and heterozygous FCMD were given oral prednisolone at a dose of 1 mg/kg on alternate days (0.5 mg/kg/day) for 48 weeks. Homozygous patients will be evaluated in the first part of the study for up to 24 weeks after prednisolone administration, after which they will continue receiving prednisolone in the second part for an additional 24 weeks. The primary endpoints were the changes in motor function evaluated using the gross motor function measure after treatment with prednisolone in the first part and the safety profiles based on the results of physical examination, vital signs, 12‐lead electrocardiography (ECG), echocardiography, ophthalmic testing, SpO₂, laboratory tests, immunological tests, and adverse events in the second part.

Discussion

Based on previous clinical research, prednisolone shows great potential as a therapeutic drug in patients with FCMD. To achieve this goal, we planned an investigator‐initiated trial to confirm the effectiveness and safety of prednisolone.

This scoping review highlights the link between atypical antipsychotics and dyslipidemia in adults with schizophrenia, identifying clozapine and olanzapine as high‐risk agents. Biomarkers and genetic polymorphisms offer promise for personalized treatment. Further research is needed on lesser‐studied drugs and predictive tools.

1. Introduction

Fukuyama congenital muscular dystrophy (FCMD) is a form of congenital muscular dystrophy accompanied by cerebral dysgenesis and ocular anomalies [1]. A 3‐kb insertion mutation in the Fukutin gene (FKTN) [2], the gene responsible for FCMD, has been identified as a founder mutation. It was recently identified as a SINE‐VNTR‐Alu (SVA)‐type retrotransposon that splices aberration owing to its exon‐trapping function. The gene product of FKTN was identified as a transferase involved in the glycosylation of α‐dystroglycan, and FKTN deficiency has been shown to disrupt a series of connections between the basement membrane and the cytoskeleton, resulting in muscular dystrophy [3]. The homozygous form of the 3‐kb insertion mutation occurs in 80% of patients with FCMD, whereas the heterozygous form is found in the remaining 20%, comprising point and nonsense mutations [3]. Since this 3‐kb insertion mutation is seen in 1/88 Japanese people as a carrier, FCMD is considered the second most common type of muscular dystrophy in Japanese children after Duchenne muscular dystrophy (DMD), affecting 2–3 infants per 100 000 births [3]. Among patients with FCMD, the maximum level of motor function achieved is crawling to walking in 20% of patients with mild severity. However, 60% of patients are typically capable of activities such as sitting and shuffling, whereas less than 20% of patients with high severity do not acquire cervical stability [4]. The maximum motor function level is usually achieved at approximately 6 years of age, after which it declines starting at 7–8 years of age, eventually making patients bedridden [5]. FCMD is an intractable disease, which typically leads to mortality at approximately 20 years of age due to respiratory failure, cardiomyopathy, and asphyxiation or aspiration pneumonia caused by dysphagia [4]. Nevertheless, Taniguchi‐Ikeda et al. [6] reported on the effectiveness of an antisense nucleic acid treatment in an animal model, and its clinical development has been planned. Compared with the available treatment strategies and clinical trials on DMD, treatment options for FCMD are known. However, the progress of research is slow because patients with FCMD are rare and limited to Japan.

In Japan, prednisolone is approved as a treatment for DMD, and randomized controlled trials have shown that it stabilizes muscle strength and function for up to 2 years, establishing it as a standard treatment [7]. The mechanisms behind the effectivity of steroids in DMD are theorized to decrease cytotoxic T cells and intracellular calcium influx, increase laminin protein expression, inhibit progression of muscle apoptosis, and improve muscle endurance through the activation of Kruppel‐like factor 15 (KLF15), a metabolic transcription factor [3]. However, this remains unclear. Phospholipase A2 (PLA2) and hematopoietic prostaglandin D synthase (H‐PGDS) have been induced around myonecrosis in DMD, suggesting the involvement of the arachidonic acid cascade, particularly prostaglandin D2 produced by H‐PGDS during the expansion of myonecrosis [2]. It has also been postulated that the arachidonic acid cascade is inhibited via the suppression of PLA2, preventing the spread of myonecrosis [3].

We hypothesized that steroid therapy would also be effective in FCMD in the same way as in DMD; thus, we planned this clinical research [8] (Tokyo Women's Medical University Ethical Review Board approval number: 160104, clinical research UMIN trial ID: UMIN000020715, Registered on: February 2016). The conventional method of assessing motor function in patients with FCMD, the FCMD Motor Function Level (9‐level scale) [9], is not suitable for intervention studies because it is unable to detect subtle changes. We examined the gross motor function measure (GMFM) [10] as a potential assessment tool for patients with FCMD with intellectual disabilities. This is primarily an observational tool with minimal instructions, which has a proven track record in the evaluation of other neuromuscular diseases. The validity of GMFM was demonstrated among patients with FCMD [5] and a revised version has also been developed [11]. In our previous clinical study [8], we initiated prednisolone administration for nine patients with genetically confirmed FCMD who exhibited motor decline (eight with homozygous FCMD, one with heterozygous FCMD; mean ± SD age: 8.1 ± 2.14 years). Motor function was evaluated before and after steroid therapy and compared using the GMFM; the overall scores improved after therapy in eight patients. The notable side effects included agrypnia (n = 3), irritability (n = 1), increased appetite (n = 1), and moon face (n = 1), and other serious adverse reactions did not occur. Although steroids lead to issues like immunosuppression with long‐term use, they have the advantage of being commercially available, orally administered, and in this case, genotype‐independent. However, our previous clinical study [8] had a small sample size and variability in the dose and duration of prednisolone administration, limiting its assessment of efficacy and safety. Nevertheless, based on the findings obtained in our clinical study on steroids, we believe that it is important to proceed with the development of prednisolone as a therapeutic drug in patients with FCMD. To achieve this goal, we planned an investigator‐initiated trial to confirm the effectiveness and safety of prednisolone.

2. Methods and Analysis

2.1. Study Design and Setting

This is a nonblinded, noncontrolled, and multicenter collaborative phase II trial. This clinical study is divided into two parts (Figure 1). The current article is based on protocol version 3.0, prepared on October 12, 2023.

FIGURE 1.

In the first part, homozygous patients will be given oral prednisolone at a dose of 1 mg/kg every other day (0.5 mg/kg/day) for 24 weeks. Homozygous patients participating in the first part will be evaluated up to 24 weeks after the start of prednisolone treatment; they will then move on to the second part, where they will continue to receive prednisolone treatment for a further 24 weeks and will be evaluated after 36 weeks of treatment. Heterozygous patients participating in the second part will receive oral prednisolone at a dose of 1 mg/kg every other day (0.5 mg/kg/day) for 48 weeks. The tapering‐off schedule at the end of prednisolone treatment is as follows: Oral prednisolone at a dose of 0.25 mg/kg every other day for 2 weeks; followed by oral prednisolone at a dose of 0.15 mg/kg every other day for 2 weeks.

2.1.1. The First Part of the Clinical Study (Efficacy Evaluation)

The study was approved by the Institutional Review Board of the Tokyo Women's Medical University (Approval number V2023012) and registered in the Japan Registry of Clinical Trials (jRCT2031230210). The first patient was enrolled on July 13, 2023, and the last patient was enrolled on November 21, 2023. This part of the clinical study will evaluate the efficacy of prednisolone in patients with 15 homozygous FCMD over 24 weeks. The first part will evaluate whether the mean change in GMFM is > 0 after 24 weeks of prednisolone treatment and whether the clinical significance of GMFM decreased after treatment. The average and standard deviation of GMFM change are assumed to be 1.11 and 1.13, respectively, based on the results of the UMIN000020715 study. Considering a one‐sided significance level of 2.5% and a dropout rate of 10%, 15 patients were required to achieve 90% power. Therefore, the sample size was set at 15 patients.

2.1.2. The Second Part of the Clinical Study (Safety Assessment)

The study was approved by the Institutional Review Board of Tokyo Women's Medical University (Approval number V2023013) and was registered in the Japan Registry of Clinical Trials (jRCT2031230211). The first patient was enrolled on July 14, 2023, and the last patient was enrolled on December 29, 2023. This part of the clinical study will evaluate the safety of prednisolone in 15 homozygous and 5 heterozygous patients with FCMD over 48 weeks. In the second part of the study, the target number of cases was set at 20. Specifically, 15 patients with homozygous FCMD were scheduled to continue treatment from the first part of the study, and 5 with the heterozygous form were scheduled to participate from the perspective of feasibility.

2.2. Study Population

2.2.1. The First Part of This Trial

The first part of this trial will include 15 patients (age range: 5–13 years) with a genetically confirmed diagnosis of homozygous FCMD with a 3‐kb insertion mutation and who meet the eligibility criteria. The study will include patients with FCMD whose upper limb function, shuffling distance, and sitting retention time were recorded during the last observation period and at two time points at least 3 months before the last observation period. Additionally, these patients must have motor function that has clearly started to regress, and these patients must have a survival expectancy of at least 1 year. Patients with the following conditions will be excluded from the study: a history of hypersensitivity to the components of the prednisolone preparation to be used; infections refractory to antibacterial agents or systemic fungal infections; peptic ulcers; tuberculosis; electrolyte abnormalities; thrombosis; acute myocardial infarction; insomnia or panic attacks; previously received other investigational or test drugs or aspirin preparations within 3 months prior to the start of prednisolone administration; previously received steroid treatment (excluding short‐term treatment for asthma, local treatment not aimed at FCMD); and other conditions deemed unsuitable for the study by the principal investigator/sub‐investigator.

2.2.2. The Second Part of This Trial

The second part of this trial will include the same 15 patients who completed the first part of the trial and an additional five patients with a genetically confirmed diagnosis of heterozygous FCMD with a 3‐kb insertion mutation who meet the eligibility criteria for confirmed regression. Heterozygous patients have a higher severity and early regression than homozygous patients. Therefore, the minimum age was lowered to 3 years in heterozygous patients, and patients with gastrostomy or nasogastric tubes were also allowed to participate.

2.3. Study Treatments and Procedures

2.3.1. The First Part of This Trial

Prednisolone will be administered orally at a dose of 1 mg/kg every other day (0.5 mg/kg/day) for 24 weeks. The dose will be calculated based on the body weight measured during the pre‐observation period throughout the study period. At the end of prednisolone administration or discontinuation, the dose will be tapered as follows: 0.25 mg/kg will be administered orally every other day for 2 weeks, followed by 0.15 mg/kg every other day for 2 weeks. These dosages were based on previous literature. There have been multiple reports of intravenous steroid administration in patients with FCMD; however, the only oral dosage that has been reported is 0.5 mg/kg every other day (0.25 mg/kg/day) in mild cases [12, 13]. In the UMIN000020715 trial, the dose was started at 0.5 mg/kg/day (0.25 mg/kg/day), and if there was no clinical improvement after 1 month, the dose was increased to 1 mg/kg every other day (0.5 mg/kg/day). In such cases where the dose was increased, improvement was evaluated using the GMFM. After completion of the trial, no significant side effects were observed in any of the nine cases, including those receiving increased doses. Notably, long‐term prednisolone use can result in a state of latent adrenal insufficiency, and its abrupt discontinuation can lead to adrenal crisis (among other issues). Thus, a rule for gradual reduction was established to ensure safety (Table 1).

TABLE 1.

Timetable and evaluation items for part 1.

Item	Preobservation period	Administration period a				Dose reduction period b	Post‐observation period b
Weeks	−4	1	4	12	24/discontinuation c	After 4 weeks from the day of starting the reduced dose	After 8 weeks from the day of starting the reduced dose
Day	35 to 28	1	28	84	168	After 28 days from the day of starting the reduced dose	After 56 days from the day of starting the reduced dose
Permissible range (days)	—	±0	±7	±7	±7	+7	+7
Consent acquisition	●
Provisional enrollment and definitive enrollment	Provisional d	Definitive
Confirmation of the Fukutin gene test results	● e
Investigational drug administration f
Age/gender/race	●
Medical history	●
Height/body weight	●			●	●		●
Concomitant drugs/concomitant therapies
Inclusion/exclusion criteria	●	●
Physical examination	●	●	●	●	●	●	●
Vital signs	●	●	●	●	●	●	●
12‐lead ECG	●	●	●	●	●		●
Echocardiography	●				●		●
Ophthalmic test g	●				●		●
SpO2	●	●	●	●	●	●	●
Hematological/biochemical tests	●	●	●	●	●	●	●
Immunological test	●				● h
Urinalysis	●	●	●	●	●	●	●
GMFM	●	●		●	●
Muscle mass evaluation i	●			●	●

^a For the first part of the study, evaluations will be performed up to 24 weeks after prednisolone therapy; consent will be acquired and definitive enrollment will be performed. Afterward, the patients will continue prednisolone therapy in the second part of the study.

^b To be performed only for patients who will not be transferred to the second part trial and who discontinued treatment. During the dose reduction period, oral prednisolone will be administered at a dose of 0.25 mg/kg on alternate days for 2 weeks followed by 0.15 mg/kg on alternate days for 2 weeks in accordance with the stipulated dose reduction upon the completion or discontinuation of prednisolone therapy.

^c Regarding tests at discontinuation, the stipulated observations and tests will be performed as soon as possible on the day after the principal investigator discontinues the trial.

^d After obtaining consent, it must be confirmed that the patient is undergoing prednisolone treatment before enrollment.

^e The PCR analysis results of DNA insertion previously conducted (prior to consent acquisition) will be confirmed.

^f The first dose will be administered after all evaluations of Week 1 are performed at the medical institution after definitive enrollment.

^g Can be performed in an inpatient setting depending on the medical system of the participating medical institution.

^h At the time of discontinuation, only Immunoglobulin G, M, and A will be measured.

ⁱ To be performed in an inpatient setting.

2.3.2. The Second Part of This Trial

Prednisolone will be administered orally at a dose of 1 mg/kg every other day.

(0.5 mg/kg/day) for 48 weeks. The administration, gradual reduction, and discontinuation of prednisolone are the same as described in the first part of the trial (Table 2).

TABLE 2.

Timetable and evaluation items for part 2.

Item	Preobservation period	Administration period a						Dose reduction period b	Post‐observation period b
Weeks	−4	1	4	12	24	36	48/discontinuation c	After 4 weeks from the day of starting the reduced dose	After 8 weeks from the day of starting the reduced dose
Day	−28	1	28	84	168	252	336	After 28 days from the day of starting the reduced dose	After 56 days from the day of starting the reduced dose
Permissible range (days)	−7	±0	±7	±7	±7	±7	±7	+7	+7
Consent acquisition d	●
Provisional enrollment and definitive enrollment d	Provisional e	Definitive
Confirmation of the Fukutin gene test results	● e
Investigational drug administration f
Age/gender/race	●
Medical history	●	●
Height/body weight	●			●	●	●	●		●
Concomitant drugs/concomitant therapies
Inclusion/exclusion criteria	●	●
Physical examination	●	●	●	●	●	●	●	●	●
Vital signs	●	●	●	●	●	●	●	●	●
12‐lead ECG	●	●	●	●	●	●	●		●
Echocardiography	●				●		●		●
Ophthalmic test g	●				●				●
SpO2	●	●	●	●	●	●	●	●	●
Hematological/biochemical tests	●	●	●	●	●	●	●	●	●
Immunological test	●				●		● h
Urinalysis	●	●	●	●	●	●	●	●	●
GMFM	●	●		●	●	●	●
Muscle mass evaluation i	●			●	●	●	●

^a In the first part of the trial, the homozygous FCMD group will undergo evaluations after 24 weeks of prednisolone administration. As Week 1 of the first part of the study is designated as the starting point, hospital visits will be made after 36 weeks.

^b To be performed also for patients who discontinued treatment. During the dose reduction period, oral prednisolone will be administered at a dose of 0.25 mg/kg on alternate days for 2 weeks followed by 0.15 mg/kg on alternate days for 2 weeks in accordance with the stipulated dose reduction at completion or discontinuation of prednisolone therapy.

^c Regarding tests at discontinuation, the stipulated observations and tests will be performed as soon as possible on the day after the principal investigator discontinues the trial.

^d Consent will be obtained from patients with homozygous FCMD, who will then undergo definitive enrollment, at or before completing the evaluations done 24 weeks after prednisolone administration (provisional enrollment is not necessary).

^e After obtaining consent from patients with heterozygous FCMD, it must be confirmed that the patient is undergoing prednisolone treatment before enrollment. The PCR analysis results of DNA insertion previously conducted (prior to consent acquisition) and the sequence analysis results for gene mutation of one allele will be confirmed. In patients without sequence analysis for gene mutation of one allele, this will be performed during the preobservation period, and the results are to be confirmed by the time of definitive enrollment.

^f For patients with homozygous FCMD, upon completing the evaluations done 24 weeks after prednisolone therapy in the first part of the study, subjects will transfer to the second part of the trial and continue to receive prednisolone therapy. For patients with heterozygous FCMD, the first dose will be administered after all evaluations of Week 1 are performed at the medical institution after definitive enrollment.

^g Can be performed in an inpatient setting depending on the medical system of the participating medical institution.

^h At the time of discontinuation, only Immunoglobulin G, M, and A will be measured.

ⁱ To be performed in an inpatient setting.

2.4. Study Endpoint

2.4.1. The First Part of This Trial

The primary endpoint of the first part of this study is the change in the GMFM before and after 24 weeks of prednisolone therapy as an assessment of efficacy. Secondary endpoints include the change in muscle mass before and after treatment as an assessment of efficacy and physical examination. Changes in muscle mass will be assessed using a Tanita BIA device (MSd‐100) manufactured by Tanita Corporation. The cross‐sectional area of total muscle tissue will be measured using the muscle cross‐sectional area index as a quantitative indicator. The proportion of muscle tissue occupied by muscle cells will be measured using the muscle density index as a qualitative indicator. In addition, magnetic resonance imaging scans of the thigh and lower leg muscles will be taken, and the degree of damage will be assessed on a scale of 0 to 4 using the Mercuri score [14] for the T1‐weighted images. There is no scale for Short‐TI Inversion Recovery images, but changes in the muscles that show high signal will be scored.

2.4.2. The Second Part of This Trial

The primary endpoints of the second part are physical examination, vital signs, 12‐lead electrocardiography, echocardiography, ophthalmological examination, SpO₂, clinical/immunological tests (Table 3), and AEs were measured as assessments of safety. AEs will be coded using the Medical Dictionary for Regulatory Activities version 27.1. Ophthalmic examinations will include intraocular pressure testing and screening for cataracts. The secondary endpoints of the second part are the changes in the GMFM and muscle mass before and after prednisolone therapy as an assessment of therapeutic efficacy.

TABLE 3.

List of hematological, biochemical, and immunological tests.

Type of test	Test items
Hematologic tests	Red blood cells, hemoglobin (Hb), hematocrit (Ht), reticulocytes (Ret), mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin (MCHC), white blood cells (WBC), platelets (Plt), WBC differential count (neutrophils, eosinophils, basophils, monocytes, and lymphocytes), fibrinogen, activated partial thromboplastin Time, and prothrombin time—international normalized ratio (PT‐INR)
Blood chemistry tests	Sodium (Na), potassium (K), calcium (Ca), chloride (Cl), inorganic phosphorus, blood urea nitrogen, creatinine (Cr), cystatin C, aspartate aminotransferase (AST), alanine transaminase (ALT), gamma‐glutamyl transferase, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), creatinine kinase (CK/CK‐MB/CK‐MM), amylase, lipase, total bilirubin, direct bilirubin, cardiac troponin T or cardiac troponin I, brain natriuretic peptide or N‐terminal proBNP (NT‐proBNP), total protein, albumin, A/G ratio, total cholesterol, neutral fats, glucose, urate, and C‐reactive proteins (CRP)
Immunological tests	HBs antigens, HCV antibodies, HIV antibodies, IgG, IgM, and IgA
Urinalysis	Glucose, occult blood, urobilinogen, protein, specific weight, osmotic pressure, sediment (red blood cells, WBC, casts), Cr, Na, K, and Cl

2.5. Statistical Analysis

2.5.1. The First Part of This Trial

The efficacy analysis set will include all subjects enrolled in the study, excluding those who did not receive prednisolone, do not meet the eligibility criteria at the time of enrollment, and do not have efficacy data. Patient characteristics (i.e., age, sex, race, medical history, height, weight, BMI, and concomitant medications) will be summarized. For the efficacy analysis, the change in GMFM 24 weeks after prednisolone therapy initiation will be summarized. The null hypothesis that the mean change in GMFM is zero (H₀: μ = 0) against the alternative hypothesis that the mean change is greater than zero (H₁: μ > 0) will be tested using a one‐sided one‐sample t‐test at a significance level of α = 0.025. Measured dates of GMFM are allowed from 7 days prior to up to 28 days after the specified date. The secondary efficacy endpoints, the changes in muscle mass will be summarized by the measurement period.

2.5.2. The Second Part of This Trial

The safety analysis set will include all subjects who received at least one dose of prednisolone among the enrolled subjects. Patient characteristics (i.e., age, sex, race, medical history, height, weight, BMI, and concomitant medications) will be summarized. As safety analysis, the number of AE cases will be counted and classified according to severity and grade for each AE and side effect in each part. Vital signs, body weight, clinical examination results, echocardiography results, SpO₂, 12‐lead ECG results, and ophthalmologic examination results will be tabulated. The ophthalmic examination results and abnormal clinical test values will also be listed. As the secondary endpoints, the change in GMFM 48 weeks after prednisolone therapy initiation will be summarized. Analyzes will be conducted using SAS software version 9.4 or later (SAS Institute Inc., Cary, NC, USA) and R version 4 or later (R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria).

2.6. Data Control and Dissemination

All data and processes will be audited by independent monitors. The study data will be published in peer‐reviewed journals using anonymized information to preserve patient confidentiality.

2.7. Ethics and Dissemination

The participants were identified using an identification code that was provided during each participant's registration and in the case report forms. Moreover, the confidentiality of the participants was maintained during the direct inspection of source documents related to the implementation of the clinical trial, in publications in medical journals, and in the submission of documents to regulatory authorities, etc.

3. Discussion

Some reports claim that steroid therapy can effectively improve the clinical symptoms of FCMD [15], specifically the temporary exacerbations of muscle weakness after viral infection [16]. More recent case reports have indicated that steroid therapy improved motor function in patients with FCMD with declining motor function [12, 13]. We believe that steroid therapy is as effective for FCMD as it is for DMD because the pathophysiology of FCMD may result from the basal lamina–sarcolemma's disruption similar to DMD [2]. Therefore, we administered steroids to patients with FCMD for 48 weeks and evaluated their efficacy and side effects. Several issues regarding steroid treatment for FCMD need to be considered, including their effect on motor function in patients with FCMD with declining motor function, the ideal timing (i.e., start and end) of steroid administration, the appropriate prednisolone dosage, and the extent of side effects associated with long‐term administration.

The purpose of this clinical trial is to clarify whether steroid therapy improves motor function in patients with FCMD, determine the appropriate steroid dosage, assess the incidence of side effects associated with long‐term administration, and determine the optimal timing for initiating treatment. The limitations of this study include its non‐randomized design, small sample size, and absence of a control group. Currently, antisense nucleic acid therapy for FCMD is under development but targets rather young patients with a 3‐kb homozygous founder mutation. Furthermore, it is still in the early stages of clinical trials, and approval will take time. Steroid therapy can be administered regardless of the FCMD genotype and can be administered to heterozygous and older patients, making it non‐competitive with future drugs. Although some issues still require further consideration, we believe that prednisolone will become a viable treatment option for FCMD for which no treatment has been established.

Author Contributions

K.I., T.S., T.I., H.N., and H.T. conceived and designed the study and were involved in the protocol development. T.I. and H.H. coordinated the regulatory aspects. H.O. and K.H. were responsible for data acquisition. M.S.O. was responsible for data analysis and interpretation. T.M. and K.I. wrote the first draft of the manuscript. All other authors read and critically reviewed the manuscript for intellectual content. All authors read and approved the final version of the manuscript.

Disclosure

Approval of the research protocol by an institutional reviewer board: The protocol for this research project has been approved by a suitably constituted Ethics Committee of the institution and it conforms to the provisions of the Declaration of Helsinki. Committee of the Institutional Review Board of the Tokyo Women's Medical University, Approval No. V2023012, V2023013.

Registry and the registration no. of the study/trial: This study was registered at the Japan Registry of Clinical Trials (jRCT2031230210, jRCT2031230211).

Consent

Legal representatives for each patient provided written informed consent prior to study participation, and patients provided voluntary assent where possible. All informed consent was obtained from the subjects and guardians.

Conflicts of Interest

T.M., T.S., K.I., M.S., Y.K. and K.I. were supported by research grants from Sarepta Therapeutics Inc. (clinical trial), Taiho Pharmaceutical Company, Limited (clinical trial) and Nippon Shinyaku Co Ltd. (clinical trial). H.N. was supported by research grants from Nippon Shinyaku Co Ltd. Other authors declare no conflicts of interest. The funding source had no role in the design, practice or analysis of this study.

Murakami T., Sato T., Ishizuka T., et al., “Nonrandomized Allocation of Steroid Therapy in Patients With Fukuyama Congenital Muscular Dystrophy: Study Protocol for a Phase II Clinical Trial,” Neuropsychopharmacology Reports 45, no. 3 (2025): e70043, 10.1002/npr2.70043.

Data Availability Statement

De‐identified individual‐level clinical and genetic data will be deposited in the Japanese Genotype–phenotype Archive under controlled access upon publication of trial results. Aggregate‐level summary data supporting the findings of this study will be made openly available in the Japan Registry of Clinical Trials (jRCT) with a permanent digital object identifier.