Study Design and Treatment
PANDA (NCT04419233) is a prospective, 2-year, multicenter PMS study conducted to collect safety, efficacy, and PK data from people with SMA treated with nusinersen in routine clinical practice in China. The study was designed based on a request by the National Medical Products Administration in China as a post-marketing requirement. All participants are to receive 12 mg nusinersen according to the approved prescribing information in China (5 ml doses per administration: four loading doses on Days 0, 14, 28, and 63, and maintenance doses administered once every 4 months thereafter). Participants are observed for 2 years following treatment initiation.
This study was performed in accordance with Title 21, United States Code of Federal Regulations (CFR) Parts 50, 54, 56, and 312 Subpart D; the International Council for Harmonisation Guideline on Good Clinical Practice (GCP) (E6); the European Union Clinical Trial Directive 2001/20/EC or Clinical Trial Regulation 536/2014; the ethical principles outlined in the Declaration of Helsinki; and/or, where applicable, European Directive 2001/20 regarding GCP in the conduct of clinical trials on medicinal products for human use and Directive 2005/28 on GCP for investigational medicinal products for human use. Ethics committee approval of all study documents was obtained prior to the start of the study at the following sites that enrolled participants: Ethics Committee (EC) of Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, China; Childrens Hospital of Fudan University, No. 399 Wanyuan Road, Minhang District, Shanghai, China; EC of Beijing Children’s Hospital, No. 56 Nanlishi Road, Xicheng District, Beijing, China; EC of Shenzhen Children’s Hospital, No. 7019, Yitian Road, Shenzhen City, Guangdong Province, China; EC of Guangzhou Woman and Children’s Medical Center, No. 9 Jinsui Road, Zhujiang New Town, Tianhe District, Guangzhou City, Guangdong Province, China; Medical Ethics Committee of Xiangya Hospital of Central South University, No. 87 Xiangya Road, Kaifu District, Changsha City, Hu’nan Province, China; EC of the First Affiliated Hospital of Fujian Medical University, No. 20 Chazhong Road, Fuzhou City, Fujian Province, China; EC of the First Hospital of Jilin University, No. 1 Xinmin Street, Changchun City, Jilin Province, China; Medical Ethics Committee of the Children’s Hospital of Zhejiang University School of Medicine, No. 3333 Binsheng Road, Binjiang District, Hangzhou City, Zhejiang Province, China; EC of Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shengyang City, Liaoning Province, China; Clinical Trial Ethical Committee of West China Second Hospital, Sichuan University, No. 20 San Duan South Renmin Road, Chengdu City, Sichuan Province, China. Informed consent was obtained from all participants or their legally authorized representative in accordance with local practice and regulations.
Participants
The decision to enroll participants in PANDA, including documentation of 5q SMA diagnosis, was made by the investigator and agreed to by the participant or their parent/legally authorized representative. Participants’ demographic data and medical/SMA disease history (including number of copies of SMN2) were obtained at baseline. Additional information about deletion mutations was captured when the SMN2 copy number was non-zero. Key exclusion criteria included hypersensitivity to nusinersen, inability to comply with study requirements, current/past treatment with nusinersen, or other unspecified reasons that, in the opinion of the investigator or sponsor, make the participant unsuitable for enrollment. Participants were considered lost to follow-up if they repeatedly failed to return for routine study visits and were unable to be contacted after three attempts by site staff.
Study Outcomes and Measurements
The primary objective of PANDA was the evaluation of nusinersen's safety in the post-marketing setting in China. To analyze the incidence of AEs and serious AEs (SAEs) during the treatment period (the primary endpoint), AEs were recorded from the time of the first LP procedure (or, for SAEs, from the time following informed consent) until study completion or discontinuation and coded according to the Medical Dictionary for Regulatory Activities, version 25.1. Investigator responsibilities included reviewing all AEs to determine seriousness and fulfillment of collection criteria, monitoring and recording all SAEs and nonserious AEs, determining the onset, resolution, and relationship to treatment of each SAE and nonserious AE, and reporting SAEs and nonserious AEs to local ethics committees as required by law. Anesthesia/sedation may have been used for the LP procedure per each participating institution's guidelines.
Secondary objectives were to assess the efficacy and PK of nusinersen. Efficacy assessments included World Health Organization (WHO) Motor Milestones, status of ventilatory support (all participants), and the Hammersmith Infant Neurological Examination (HINE) [Sects. 1 and 3 in all participants aged ≤ 24 months; Sect. 2 (HINE-2) in all participants who did not achieve walking alone according to the WHO Motor Milestones Criteria assessment at the time of the first dosing]. HINE-2 motor milestone response was defined as maintenance or improvement of baseline status in at least one motor milestone and a greater number of categories maintained or improved than categories worsened. After a participant was able to walk alone at two consecutive study visits, only the WHO Motor Milestones assessment was performed. Efficacy assessments were performed by site investigators who were trained in the performance of these assessments at the site initiation visit. The assessments were conducted as part of routine medical practice. At each visit, ventilator use within the preceding 7 days was collected. To assess PK, plasma nusinersen levels were collected from all participants pre-dose and from participants who were > 6 weeks of age at 2, 4, 8, and 24 h post-dose on Day 1 and 4 h post-dose on Day 29. Cerebrospinal fluid (CSF) nusinersen samples were collected pre-dose at each dosing visit. CSF concentrations were measured using a validated hybridization electrochemiluminescence assay (hybridization ECL assay) with a lower limit of quantitation (LLOQ) of 0.500 ng/ml.
Statistical Analyses
Safety and efficacy analyses were carried out in the safety population, defined as all participants who received at least one dose of nusinersen as of the January 4, 2023, data cutoff. Those who had an evaluable PK sample following the first injection constituted the PK analysis population. Descriptive summary statistics were calculated for continuous variables; counts and percentage were used for categorical variables. AEs were analyzed based on treatment emergence; an AE that was present prior to receiving the first dose of nusinersen that subsequently worsened in severity or was not present but subsequently appeared was classified as treatment emergent. An AE was considered “related” to the use of nusinersen sodium injection if there was a possibility that the event might have been caused by it, including a positive rechallenge, a reasonable temporal sequence between administration of the product and the event, a known response pattern of the suspected product, improvement following discontinuation or dose reduction, a biologically plausible relationship between the product and the AE, or a lack of an alternative explanation for the AE. Endpoints are summarized by age of onset of SMA symptoms; participants are divided into two subgroups: onset of SMA symptoms at ≤ 6 months of age (infantile onset) and those with onset at > 6 months (later onset).
For analysis of WHO Motor Milestones, the percentage of participants who achieved each milestone is presented at baseline and at last visit, with the two subgroups (infantile and later-onset SMA) further stratified by age at enrollment: (1) infantile-onset SMA: age at enrollment ≤ 2 years and > 2 years; (2) later-onset SMA: age at enrollment ≤ 2 years, > 2 to ≤ 6 years, and > 6 years.
For the HINE, the status at baseline and at each subsequent visit is recorded for each milestone assessed using Sect. 2; the eight milestones are summed to give a total score, which is presented over time. HINE Sect. 2 (HINE-2) was assessed in all participants who did not achieve walking alone according to the WHO motor milestone assessment at the time of the first dosing. Once a participant achieved walking alone according to the WHO motor milestone at two consecutive study visits, HINE-2 would no longer be performed. Baseline scores for Sects. 1 and 3, and individual item scores, were measured over time for each participant; the response on each item over time was summarized. Ventilator use within the preceding 7 days of study visits was summarized. Summary statistics are provided for PK results.