The Japan Registry for Adult Subjects of Spinal Muscular Atrophy (jREACT-SMA): Protocol for a Longitudinal Observational Study

Introduction

Spinal muscular atrophy (SMA) is an autosomal recessive genetic neuromuscular disorder with progressive muscle weakness and atrophy mainly caused by lower motor neuron degeneration resulting from decreased levels of the survival motor neuron (SMN) protein [1,2]. The SMN gene is an SMA-determining gene mapped to chromosome 5q13 [3]. Patients with 5q-SMA have the loss of SMN1 or an SMN1 point mutation and at least one copy of the highly homologous gene, SMN2 [3,4]. SMN2 differs from SMN1 by only 11 nucleotides (7 in intron 6, 2 in intron 7, 1 in coding exon 7, and 1 in noncoding exon 8) [3,5-7], resulting in the alteration of splicing regulation and exclusion of exon 7 [5]. SMN2 produces lower levels of the full-length SMN transcript [8], whereas SMN exon 7–skipped mRNA produces unstable protein, which is rapidly degraded [9].

SMA is one of the rare diseases affecting patients across a broad age range that is designated as an intractable disease [10] and a specific pediatric chronic disease [11]. The incidence of infantile-onset SMA (type I SMA) in Japan is 0.27 per 10,000 live births, and the number of Japanese patients with SMA is assumed to be approximately 1500 [12].

Before 2017, no disease-modifying therapy was available that could influence the clinical course of SMA [13]. Because patients with a higher copy number of SMN2 tend to develop SMA with later onset and/or show relatively milder symptoms [9,14], increasing the level of full-length functional SMN protein from SMN2 is expected to alleviate symptoms in patients with SMA [15]. Nusinersen is an antisense oligonucleotide drug that selectively corrects the splicing of SMN2 pre-mRNA to produce increased amounts of functional SMN protein [15,16]. The efficacy and safety of nusinersen were demonstrated in clinical trials (some including Japanese patients) in infants and children aged 0-15 years with SMA [17-21]. A clinical trial to assess the efficacy of an investigational higher dose of nusinersen in patients with SMA, including patients aged ≥18 years, is also ongoing (ClinicalTrials.gov NCT04089566). In Japan, nusinersen was approved for the treatment of infantile-onset type I SMA in July 2017, and subsequently, its indications were expanded to later-onset types II, III, and IV SMA. In addition, onasemnogene abeparvovec, a gene replacement therapy, was approved in March 2020 for patients with SMA aged under 2 years old, and risdiplam, an oral, once-daily splicing modifier, was approved in June 2021 for patients aged 2 months or older.

The natural history of SMA has changed over the last decade due to improvements in care; in particular, the survival of critically ill infants with type I SMA has increased [22,23]. In addition, these new treatments are expected to improve the prognosis of SMA, suggesting that the number of adult patients with SMA will possibly increase. Neuromuscular symptoms, including muscle weakness, progress more slowly in adult patients with later-onset SMA compared with patients with infantile-onset SMA [24,25]. Therefore, long-term clinical follow-up of treated patients and the natural history of SMA are essential to assess the effectiveness of the treatment, particularly the improvement and/or maintenance of motor functions. Registry and multicenter observational studies of SMA that include adult patients have been reported or are ongoing in several countries [26-30]. At the planning and launch stage of this research, nusinersen was the only treatment option for patients with SMA in Japan. However, the administration regimen of nusinersen for later-onset SMA is different between Japan and other countries. In Japan, the treatment regimens used in the ENDEAR study [18] (4 loading doses and once every 4 months for the maintenance dose with adjustment for age) and in the CHERISH study [19] (3 loading doses and once every 6 months for the maintenance dose) have been approved for infantile-onset SMA and later-onset SMA, respectively. However, in other countries, only the ENDEAR treatment regimen has been approved for all types, including later-onset SMA. As such, the effectiveness of nusinersen in adult patients has not been fully assessed in Japan in both clinical trials and clinical practice. Therefore, it is important to systematically collect longitudinal clinical data, including the natural history of SMA in adult patients. As more treatment options have become available, we expect to gain a better understanding of the pathophysiology of SMA and clinical data to support treatment decisions obtained from long-term clinical follow-up in adult patients with and without treatment.

Here, we describe the protocol for a longitudinal observational study in adult patients with SMA who have been diagnosed with 5q-SMA, which is being conducted with the aim of establishing a new registry (Japan Registry for Adult Subjects of Spinal Muscular Atrophy [jREACT-SMA]). The study will lead to a better understanding of the natural history of SMA, as well as the long-term effectiveness of disease-modifying therapies in Japan.

Methods

Study Design

The jREACT-SMA study is a longitudinal (prospective and retrospective) observational registry study with a 60-month prospective follow-up being conducted at 19 investigational sites in Japan, including university hospitals, specialist centers, and tertiary hospitals (Figure 1). Patient data are collected from multiple centers because treatment for SMA is not centralized in Japan. The planned number of patients was 100, which takes into consideration the feasibility of enrolling patients; however, registration of additional patients is permitted (Textbox 1).

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Sample Selection

Patients who fulfill the following inclusion criteria are eligible for enrollment (Textbox 1): diagnosed with SMA, as defined by the Diagnostic Criteria of the Research Committee for Spinal Muscular Atrophy from the Ministry of Health, Labour and Welfare of Japan [31]; aged ≥18 years; genetically confirmed deletion or mutations of the SMN1 gene (5q-SMA), as well as at least 1 copy of the SMN2 gene; able to attend the investigational sites at least once a year during the follow-up period; and able to understand the purpose of the study and provide written informed consent. Patients who had any condition (such as psychiatric disorders) that would make it difficult to comply with study requirements and patients who were deemed by the investigators to be unsuitable for study enrollment are excluded.

Patients will be enrolled regardless of treatment status. The requirement for treatment is decided by the investigators independently from the study, taking into account each patient’s preference and medical condition. Disease-modifying therapies are administered according to the approved administration regimen.

Measurements and Planned Outcomes

Motor function scales and patient-reported outcomes (PRO)/quality-of-life (QOL) outcomes are the primary end points of the study. By partly referring to the TREAT-NMD SMA Registries Core Dataset [32], registration, demographics, genetic diagnosis, motor functions, PRO/QOL data, and other clinical data have been or will be collected (Table 1, data that are highly encouraged to be collected are shown in italics). All data have been or will be obtained from medical records or at regular visits. Further details and the schedule of data collection are shown in Table 1, and free-text columns are available for investigators to collect data other than those listed. Any adverse events for patients treated with each of the disease-modifying therapies are to be reported according to the standard safety report procedures in the respective all-case surveillance studies.

Data Collection

The jREACT-SMA study uses the Research Electronic Data Capture system, operated by the ARO Data Coordinating Center, Department of Advanced Medicine, Nagoya University Hospital (Nagoya, Japan) and the Department of Neurology, Nagoya University Graduate School of Medicine (Nagoya, Japan), to register patients and collect/centralize data. The Research Electronic Data Capture system can be accessed securely by the investigators and study-related personnel only.

Information that can identify patients is anonymized at data entry. Anonymized data are labeled with an identifying code to reidentify patients. The identifying codes linking patients with their anonymized data are securely stored at each investigational site. The investigators are responsible for saving source data and ensuring the quality of data at each investigational site.

Data Analysis

Demographics at baseline and clinical characteristics at first visit will be summarized. Time-to-event outcomes (survival status and time to tracheostomy) will be analyzed using the Kaplan-Meier method. Continuous variables will be summarized by descriptive statistics, including arithmetic mean, standard deviation, minimum, 25% quartile, median, 75% quartile, maximum, and proportion of missing values. Categorical variables will be analyzed using Wilcoxon signed-rank test with the number and percentage in each category. Additional analyses referring to specific research questions may be conducted and will be described in a statistical analysis plan. The statistical analysis plan will be completed by database lock. Interim and final analyses are planned.

Ethics and Dissemination

The study is being conducted in compliance with the Declaration of Helsinki, Ethical Guidelines for Medical and Health Research Involving Human Subjects, and the Act on the Protection of Personal Information. Written informed consent has been or will be obtained from all patients, including agreement for publication. If patients withdraw informed consent, the patients’ data will be excluded from the data set as much as possible. The study is registered at the University Hospital Medical Information Network Center Clinical Trials Registry (UMIN000042015). Collaborative investigational sites must obtain approval from their own relevant ethics committees before starting the study. Prior to patient screening, a contract research organization (Mebix, Inc.), funded by Biogen Japan Ltd, reviewed study responsibilities with the investigators and study-related personnel.

Ethics Approval

The study is led by Nagoya University, and the protocol was approved on September 28, 2020 (approval 2020-0289) by the ethical review committee of Nagoya University.

Results

Patient registration started in December 2020 and was planned to end in May 2022 (Textbox 1 and Figure 2). As of May 2022, 113 patients had been enrolled, and patient registration has been extended to December 2022. Data from the first visit (first visit at the investigational site regardless of diagnosis, with or without treatment; data before diagnosis could be inputted) to registration were and will be retrospectively collected. Data at registration and during the follow-up period were and will be prospectively collected at least once a year until November 2025 (maximum 60 months). Data analyses will be conducted when all data have been collected. Results are expected to be available in 2026 and the study is expected to be completed by March 2027 (Figure 2).

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Discussion

Expected Findings

This protocol is for the first longitudinal (prospective and retrospective) observational study in Japanese adult patients with SMA, regardless of treatment status, with the aim of establishing a new registry named jREACT-SMA. Using the results from the jREACT-SMA study, we expect to gain a better understanding of the pathophysiology of SMA and clinical data to support treatment decisions for overcoming potential therapeutic limitations in adult patients with SMA.

Outside of Japan, other registry or observational studies have been or will be reporting real-world clinical data—including motor function scales such as the 6-minute walk test, the Hammersmith Functional Motor Scale–Expanded, and the Revised Upper Limb Module—in adult patients with SMA [26-30]. In addition, some of these studies will provide PRO and sociodemographic data [28]. However, data in Japanese patients with SMA are still required because the administration regimen of nusinersen for later-onset SMA is different between Japan and other countries. Several registries of patients with SMA are currently in operation in Japan, but no data have been reported yet. The Spinal Muscular Atrophy Research & Treatment Consortium [33] has been established for patients with SMA and health care professionals to share information regarding new clinical trials and investigator-initiated trials promptly and to help conduct the trials efficiently. The Rare Disease Data Registry of Japan [34] has been established to centralize clinical information and biological samples from the Japan Agency for Medical Research and Development [35] and the intractable disease research groups of the Ministry of Health, Labour and Welfare. Distinct from these registries in Japan, the jREACT-SMA study will provide longitudinal prospective and retrospective follow-up data in adult patients with SMA, including both adult patients who transitioned from pediatric SMA and patients with adult-onset SMA.

In this jREACT-SMA study, patients who do not wish to receive active treatments are registered, as well as patients who have been or are being treated with disease-modifying therapies. Longitudinal observation of SMA in Japanese adult patients is limited [36], and the inclusion of untreated patients in jREACT-SMA will provide valuable information about the natural history of adults with SMA. In addition, because nusinersen was approved in Japan based on the results of clinical trials in infants and children with SMA who were aged ≤9 years at screening [17-19], the effectiveness of nusinersen in adult patients has not been fully assessed in Japan. As mentioned above, the administration regimen of nusinersen in Japan differs from other countries. The number of loading doses and the administration interval were defined by a pharmacokinetics simulation using data from patients with types II and III SMA. Therefore, information on patients treated with the Japan-approved administration regimen may provide further important insights into the optimization and validation of therapeutic protocols for Japanese adult patients with SMA. The comprehensive analyses from the jREACT-SMA study will allow us to address current gaps in our knowledge of the natural history of SMA, as well as the long-term effectiveness of disease-modifying therapies in adult patients.

Strengths and Limitations

The jREACT-SMA study is the first multicenter, long-term, longitudinal observational study to establish a registry for Japanese adult patients, which will better reflect real-world clinical settings. Most core hospitals that provide specialized treatment for SMA in Japan were included in the study. The only patients who will be excluded are those who have any condition that would make it difficult to comply with the study requirements and those who are deemed by the investigators to be unsuitable for study enrollment. A broad range of data will be collected, including patient background, clinical characteristics, and clinical measures such as motor functions and PRO/QOL, as well as physiological and blood tests. Only adult patients are eligible for the study; this allows examination of the clinical course of the disease in this population of patients with SMA, whose numbers are expected to increase as pediatric patients survive longer. In addition, both patients treated with disease-modifying therapies and untreated patients have been enrolled, which will enable a better understanding of the natural history of SMA and the long-term effectiveness of the therapies during adulthood.

However, several limitations of the study need to be considered. First, we are not able to include all Japanese patients with SMA. Of note, the number of untreated patients to be registered may not be proportionate to their population in Japan because they make fewer hospital visits and are therefore less likely to be enrolled. Second, we cannot identify patients who have not yet been diagnosed with SMA, which makes it difficult to understand the full context of SMA in Japan from the jREACT-SMA study. Third, we may not be able to obtain information longitudinally if patients change hospitals during the data collection period (eg, if a patient moves from a participating hospital to a nonparticipating hospital, we are not able to obtain complete prospective data). Fourth, the baseline of the outcome measures may not be assessed appropriately or could be partly missing in the case of participants who started disease-modifying therapies before enrollment, meaning that data were collected retrospectively. Additionally, follow-up data could be partly missing in the case of participants who stopped regular visits. Fifth, the planned number of patients, especially untreated patients, is small; therefore, it may be difficult to analyze the effectiveness of disease-modifying therapies compared with the natural history of SMA. Sixth, although PRO/QOL are some of the primary end points, it is difficult to demonstrate that benefits in PRO/QOL result from intervention because of the absence of an age- and SMA type–matched control group in the study and the potential for response bias. Seventh, respiratory management (requirement for invasive/noninvasive ventilatory support) is proposed by physicians based on their treatment policy, knowledge, and experience, and the final decision is made by patients/caregivers. Therefore, outcomes relating to artificial ventilation should be carefully interpreted. Finally, the quantity of data (ie, number of patients with data in each category) may vary for different variables because although data collection is highly encouraged or optional, it is not mandatory.

Conclusions

The jREACT-SMA study will contribute to a better understanding of the natural history of the disease and the long-term effectiveness of disease-modifying therapies with the aim of establishing a database of Japanese adult patients with SMA.