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).

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.

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.

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.

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.

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.

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.

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.

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.

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.