Scleroderma, Diffuse
Conditions
Keywords
Diffuse cutaneous systemic sclerosis (dcSSc), Scleroderma, Diffuse, revised Composite Response Index in Systemic Sclerosis (rCRISS), modified Rodnan skin score (mRSS), forced vital capacity (FVC)
Brief summary
The purpose of this study is to evaluate the efficacy, safety and tolerability of rapcabtagene autoleucel (administered once following lymphodepletion) in participants with severe refractory diffuse cutaneous systemic sclerosis relative to rituximab.
Detailed description
This is a phase 2, multi-part, five-year, randomized, open-label, assessor-blinded, multicenter study to evaluate the efficacy and safety of rapcabtagene autoleucel versus rituximab in participants with severe refractory diffuse cutaneous systemic sclerosis (dcSSc). This study comprises two cohorts: * A Lead-in Cohort enrolling participants to receive rapcabtagene autoleucel. * A Randomized Cohort enrolling participants to receive rapcabtagene autoleucel or rituximab. Participants in the rituximab arm whose disease is not fully controlled may receive rapcabtagene autoleucel treatment once the participant is confirmed to be eligible per protocol. After end of study, participants who received rapcabtagene autoleucel infusion will enter a long-term follow-up (LTFU) period after rapcabtagene autoleucel infusion. This LTFU will be described in a separate study protocol.
Interventions
BIOLOGICALrapcabtagene autoleucel
single infusion of rapcabtagene autoleucel after lymphodepleting therapy with fludarabine (adjusted based on renal impairment) and cyclophosphamide daily for 3 days.
BIOLOGICALrituximab
rituximab intravenous infusion (i.v.) as per protocol
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
The study investigator and the participant will be unblinded to the study treatment. A blinded assessor will perform the efficacy assessments to minimize bias in data collection.
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Participant must fulfill the 2013 American College of Rheumatology/ European League Against Rheumatism classification criteria for systemic sclerosis and meet the diffuse cutaneous SSc (dcSSc) subset classification according to LeRoy. 2. Disease onset from the first non-Raynaud symptoms attributable to SSc (e.g., puffy hands, scleroderma, digital ulcers, arthralgia, dyspnea) within 7 years prior to the Screening visit. 3. Severe, progressive systemic sclerosis disease defined by at least one of the following: * Progressive systemic sclerosis-associated interstitial lung disease * Severe, progressive systemic sclerosis skin disease * Clinically significant systemic sclerosis-associated cardiac involvement at Screening 4. All recommended vaccinations received according to institutional, local or global guidelines for immuno-compromised patients.
Exclusion criteria
1. Any condition during Screening that could prevent a complete washout of medications as required per protocol or could otherwise make the participant ineligible for anti-CD19 CAR-T therapy and further participation in the study, as judged by the Investigator. 2. Participants with history of hypersensitivity to excipients in rapcabtagene autoleucel or to rituximab. 3. Any participant for whom treatment with rituximab is clinically inappropriate in the opinion of the investigator. 4. Any medical conditions that are not related to SSc that, in the opinion of the Investigator, would jeopardize the ability of the participant to tolerate lymphodepletion and anti-CD19 CAR-T cell therapy. 5. Rheumatic disease other than dcSSc, (except secondary Sjogren's syndrome or scleroderma myopathy),including limited cutaneous systemic sclerosis (lcSSc) or sine scleroderma at Screening. 6. Participants with pre-existing pulmonary hypertension. 7. Significant renal pathology at Screening. 8. Participants with uncontrolled stage II hypertension at Screening. 9. Vaccination with live attenuated vaccines within 6 weeks prior to randomization. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Achievement of a treatment response as per the Revised Composite Response Index in Systemic Sclerosis 50 (rCRISS50) definition at Week 52. | Week 52 | To demonstrate the superiority of rapcabtagene autoleucel as a single infusion compared to rituximab, with respect to the proportion of participants achieving a Revised Composite Response Index in Systemic Sclerosis 50 (rCRISS50) response at Week 52. This response is assessed across 5 assessment domains: (1) modified Rodnan Skin Score (mRSS), (2) Health Assessment Questionnaire Disability Index (HAQ-DI), (3) patient global assessment (PGA), (4) physician global assessment (PhGA) and (5) percent-predicted forced vital capacity (FVC%). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in Forced Vital Capacity (FVC)% predicted at Week 52 | Baseline, Week 52 | Change from baseline in FVC % predicted |
| Change from baseline in modified Rodnan Skin Score (mRSS) at Week 52. | Baseline, Week 52 | The modified Rodnan Skin Score (mRSS) is a clinical tool used to assess skin thickness in patients with systemic sclerosis (scleroderma). It involves palpating the skin and rating its thickness on a scale from 0 to 3 across 17 different body sites. The total score is the sum of the individual scores from all 17 sites, ranging from 0 (normal) to 51 (severe). |
| Change from baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 52. | Baseline, Week 52 | The Health Assessment Questionnaire Disability Index (HAQ-DI) is a widely used tool to measure a patient's level of functional ability and disability. It consists of 20 questions that cover eight domains of daily living activities: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Each question is rated on a scale from 0 (without difficulty) to 3 (unable to do). |
| Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Up to end of study, assessed up to approximately 5 years | The distribution of adverse events will be done via the analysis of frequencies for Adverse Event (AEs) and Serious Adverse Event (SAEs) through the monitoring of relevant clinical and laboratory safety parameters. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Czechia, Denmark, France, Germany, Hungary, Israel, Italy, Japan, Mexico, Netherlands, Singapore, South Korea, Spain, Switzerland, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Outcome results
None listed