Phase IIIb, Open-label, Multi-center Study to Evaluate Safety, Tolerability and Efficacy of OAV101 Administered Intrathecally to Participants With SMA Who Discontinued Treatment With Nusinersen or Risdiplam (STRENGTH)

• ClinicalTrials.gov Identifier: NCT05386680
• Recruitment Status: Recruiting
• First Posted: May 23, 2022
• Last Update Posted: July 10, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

This is an open-label, single arm, multi-center study. Approximately 28 participants aged 2 to 12 years will be enrolled stratified as 2 to 5 years and 6 to 12 years. The study is comprised of 3 periods, Screening (up to 45 days), Treatment (1 day), and Follow-up (52 weeks).

Condition or disease	Intervention/treatment	Phase
Spinal Muscular Atrophy	Genetic: OAV101	Phase 3

Detailed Description:

During the Screening period and on Day -1 (Baseline), eligibility will be assessed, including confirmation that nusinersen (Spinraza®) or risdiplam (Evrysdi®) have not been used for the defined period (4 month and 15 days prior to Day -1 respectively). On Day - 1 (Baseline) participants will be admitted to the hospital for pre-treatment baseline procedures. Prednisolone (or equivalent) will be given and continued as per the study protocol.

Participants who meet eligibility criteria at Screening and Baseline will receive a single dose of OAV101 (1.2 x 10^14 vector genomes) by lumbar intrathecal injection on Day 1 (Treatment) and will then undergo in-patient safety monitoring over the next 24 to 48 hours, after which the participant may be discharged according to Investigator judgement.

During Follow-up, safety monitoring will continue as per the visits defined in the Assessment Schedule. Safety for participants enrolled will be evaluated by the study team together with the Data Monitoring Committee (DMC).

Final analysis will be performed after all participants have completed Week 52 or discontinued prior to Week 52. At the end of study, participants will be invited to enroll in a Novartis-sponsored long-term follow-up study to monitor long-term safety and efficacy.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 28 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase IIIb, Open-label, Single-arm, Multi-center Study to Evaluate the Safety, Tolerability and Efficacy of OAV101 Administered Intrathecally (1.2 x 10^14 Vector Genomes) to Participants 2 to 12 Years of Age With Spinal Muscular Atrophy (SMA) Who Have Discontinued Treatment With Nusinersen (Spinraza®) or Risdiplam (Evrysdi®)
• Actual Study Start Date: January 12, 2023
• Estimated Primary Completion Date: October 21, 2024
• Estimated Study Completion Date: December 6, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: OAV-101; Single intrathecal administration of OAV101 at a dose of 1.2 x 10^14 vector genomes	Genetic: OAV101; Single intrathecal administration of OAV101 at a dose of 1.2 x 10^14 vector genomes; Other Names: AVXS-101; Zolgensma

Outcome Measures

Primary Outcome Measures :

1. Number and percentage of participants reporting AEs, related AEs, SAEs, and AESIs [ Time Frame: 52 weeks ]

   An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. The occurrence of AEs must be sought by non-directive questioning of the participant at each visit during the study. Adverse events also may be detected when they are volunteered by the participant during or between visits or through physical examination findings, laboratory test findings, or other assessments.

   An AESI is primarily defined by using standard Medical Dictionary for Regulatory Activities (MedDRA) queries, and identified as follows: Hepatotoxicity, Thrombocytopenia, Thrombotic microangiopathy, Cardiac adverse events, and Dorsal root ganglia toxicity

Secondary Outcome Measures :

1. Change from baseline to Week 52 visit in the HFMSE total score [ Time Frame: 52 weeks ]
   The Hammersmith Functional Motor Scale Expanded (HFMSE) is a SMA-specific 33-item assessment that is administered by clinical evaluators in a short period of time, requires minimal equipment, and is designed to factor in patient fatigue. Each motor skill item is scored on a 3-point Likert scale from 0 (no response) to 2 (full response), with a total score range of 0 to 66. A higher score indicates a higher ability level.
2. Change from baseline to Week 52 visit in the RULM total Score [ Time Frame: 52 weeks ]
   The Revised Upper Limb Model (RULM) is a validated, SMA-specific assessment that measures motor performance in the upper limbs from childhood through adulthood in ambulatory and never ambulatory individuals with SMA. The revised version of the test consists of 19 scorable items: 18 items scored on a 0 (unable) to 2 (full achievement) scale, and one item that is scored from 0 (unable) to 1 (able). These item scores are summed to give a total score ranging from 0 to 37 points with lower scores reflecting poorer ability.
3. Change from baseline to Week 52 visit in Assessment of Caregiver Experience in ACEND instrument score [ Time Frame: 52 weeks ]
   The Assessment of Caregiver Experience in Neuromuscular Disease (ACEND) instrument quantifies the caregiver impact experienced by parents/caregivers of children affected with severe neuromuscular diseases, including children with SMA The total score is on a scale of 0 to 100 with a higher score indicating a greater impact on the caregiver.

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 12 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria

• SMA diagnosis
• Aged 2 to 12 years
• Have had at least four loading doses of nusinersen (Spinraza®) or at least 3 months of treatment with risdiplam (Evrysdi®) at Screening
• Must have symptoms of SMA as defined in the protocol

Exclusion Criteria:

• Anti Adeno Associated Virus Serotype 9 (AAV9) antibody titer using an immunoassay is reported as elevated
• Clinically significant abnormalities in test results during screening
• Contraindications for lumbar puncture procedure

• At Baseline, participants are excluded if they received:

  • nusinersen (Spinraza®) or
  • risdiplam (Evrysdi®) within a defined timeframe
• Vaccinations 2 weeks prior to administration of OAV101
• Hospitalization for a pulmonary event, or for nutritional support within 2 months prior to Screening or inpatient major surgery planned.
• Presence of an infection or febrile illness
• Requiring invasive ventilation

Contacts and Locations

Contacts

Contact: Novartis Gene Therapies Med Info (US, Latin America, Canada); +1-833-828-3947; medinfo.gtx@novartis.com

Contact: Novartis Gene Therapies Med Info (Europe, Middle East, Africa, Asia-Pacific); +353 (1) 566-2364; medinfoemea.gtx@novartis.com

Locations

United States, Massachusetts

Novartis Investigative Site; Recruiting

Boston, Massachusetts, United States, 02215

United States, Virginia

Novartis Investigative Site; Recruiting

Norfolk, Virginia, United States, 23507

United States, Wisconsin

Novartis Investigative Site; Recruiting

Madison, Wisconsin, United States, 53792-7375

Australia, Victoria

Novartis Investigative Site; Recruiting

Parkville, Victoria, Australia, 3052

Belgium

Novartis Investigative Site; Recruiting

Leuven, Belgium, 3000

Canada, Quebec

Novartis Investigative Site; Recruiting

Montreal, Quebec, Canada, H4A 3J1

France

Novartis Investigative Site; Recruiting

Bron Cedex, France, 69677

Novartis Investigative Site; Recruiting

Toulouse Cedex, France, 31059

Italy

Novartis Investigative Site; Recruiting

Roma, RM, Italy, 00168

Japan

Novartis Investigative Site; Recruiting

Kurume city, Fukuoka, Japan, 830-0011

Novartis Investigative Site; Recruiting

Shinjuku ku, Tokyo, Japan, 162 8666

Netherlands

Novartis Investigative Site; Recruiting

Utrecht, Netherlands, 3584CX

Spain

Novartis Investigative Site; Recruiting

Barcelona, Catalunya, Spain, 08035

Sponsors and Collaborators

Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT05386680
• Other Study ID Numbers: COAV101B12302
• First Posted: May 23, 2022
• Last Update Posted: July 10, 2023
• Last Verified: July 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on https://www.clinicalstudydatarequest.com/.
• URL: https://www.clinicalstudydatarequest.com/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Muscle atrophy; spinal and bulbar muscular atrophy; spinal muscular atrophy; bulbar muscular atrophy; muscle function; muscle wasting; atrophied muscle; loss of muscle strength; Zolgensma; OAV101; AVXS 101; gene therapy; SBMA; myopathy; SMA

Additional relevant MeSH terms:

Muscular Atrophy; Muscular Atrophy, Spinal; Atrophy; Spinal Cord Diseases; Pathological Conditions, Anatomical; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Central Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases