Phase I/II randomized clinical trial of allogeneic adipose tissue-derived mesenchymal stromal cells systemic infusion in severe systemic sclerosis MSC-AT-SSc

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

8 Jan 2025 → ongoing

Decision date (initial)

2024-11-21

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

PHRC 2020

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety

To evaluate the safety one month after allogeneic 2x106 MSC(AT)/kg intravenous administration once or twice at 3 months interval (M0, M3) in severe SSc patients

Secondary objectives 6

1. - Safety during the infusion, within the first 24 hours of infusion and during all study follow-up.
2. - Efficacy signals to inform future studies, using outcome measures on skin sclerosis, lung function and quality of life, previously validated in SSc or used in other cell therapy trials.
3. - Analysis of the response to treatment, Progression-free survival (PFS), Global Rank Composite Score (GRCS) at M3, M6 and M12 and ACR Provisional Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis (CRISS) for early SSc patients at M3, M6, and M12.
4. - Analysis of the overall survival and assess causes of death.
5. - Impact of allogeneic MSC(AT) iv once or twice at 3 months interval on the immune response, including immunophenotyping and alloimmunization up to M6 after starting therapy.
6. - Cost effectiveness of the allogeneic MSC(AT) infusion once or twice versus no treatment in severe SSc patients.

Conditions and MedDRA coding

Systemic sclerosis

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 1) Provide signed and dated informed consent
2. 2) Willing to comply with all study procedures and be available for the duration of the study;
3. 3) Male or female, aged ≥ 18 years and ≤ 80 years of age
4. 4) SSc patients according to American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2013 classification criteria for SSc
5. 5) Severe disease with either: a) disease duration of 2 years or less with a modified Rodnan skin score (mRSS) ≥ 20 and (abnormal CRP > 5 mg/l and/or hemoglobin < 11 g/dL), or b) mRSS ≥ 15 without any restriction as to disease duration plus at least one major organ involvement as defined by: (1) respiratory involvement consisting of lung diffusion capacity for carbon monoxide (DLCO) and/or forced vital capacity (FVC) < 80% predicted and evidence of interstitial lung disease (chest X-ray and/or high resolution computed tomography (HRCT) scan) and/or moderate Pulmonary hypertension with baseline resting systolic pulmonary arterial pressures > 35 mmHg and below 50 mmHg by cardiac echocardiography, or mean pulmonary artery pressure > 20 mmHg and < 40 mm Hg on right heart catheterization; (2) renal involvement consisting of past renal crisis, microangiopathic hemolytic anemia, and/or renal insufficiency not explained by other causes than SSc; (3) cardiac involvement consisting of reversible congestive heart failure, atrial or ventricular rhythm disturbances such as recurrent episodes of atrial fibrillation or flutter, recurrent atrial paroxysmal tachycardia, 2nd or 3rd degree AV-block, mild to moderate pericardial effusion and/or presence of MRI involvement (Increased T1 or T2 mapping, late gadolinium enhancement, septal D sign) . All causes of organ involvement should be attributed to SSc.
6. 6) Contraindication, inadequate response or unwillingness to undergo AHSCT (determined by patient and physician judgement)
7. 7) Contraindication, inadequate response or unwillingness or adverse events necessitating discontinuation of conventional immunosuppressive therapy, except for MMF and methotrexate);
8. 8) Women of reproductive potential must use highly effective contraception;
9. Men of reproductive potential must use condoms
10. 10) Health insurance

Exclusion criteria 14

1. 1. Age < 18 years or > 80 years
2. 2. Pregnancy or unwillingness to use adequate contraception;
3. 3. Life-threatening end-organ damage defined as: DLCO (corrected for hemoglobin) < 30% predicted; Left ventricular ejection fraction < 40% by cardiac echocardiography; Pulmonary hypertension with baseline resting systolic pulmonary arterial pressures > 50 mmHg by cardiac echocardiography, or mean pulmonary artery pressure > 40 mmHg on right heart catheterization; glomerular filtration rate < 30mL/min
4. 4. Active or chronic Hepatitis (ASAT, ALAT > 3 upper limit normal)
5. 5. Neoplasms of less than 5 years, except for basal cell or in situ cervix carcinoma or concurrent myelodysplasia,
6. 6. Uncontrolled hypertension
7. 7. Uncontrolled acute or chronic infection
8. 8. HIV-1 or HIV-2 infection
9. 9. BMI < 16.5 kg/m2
10. 10. Severe psychiatric disorder
11. 11. Bone marrow insufficiency, defined as neutropenia < 1 x 109/L, thrombopenia < 50 x 109/L, anemia < 8 g/dL, lymphopenia < 0,5 x 109/L
12. 12. Inability to provide informed consent
13. 13. Patient included in another interventional clinical trial
14. 14. Patient under tutelle

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The rate of treatment-related Severe Adverse Events (SAE) defined as Adverse Events (AE) of grade equal or above 3 using the NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0 classification, at one month after each infusion (M1, M4).

Secondary endpoints 11

1. - Rate of treatment-related SAE defined as AE of grade equal or above 3 CTCAE v5.0 at time and within the first 24 hours of infusion and during all follow-up at: M0, M3, M6, M9 and M12
2. - Main efficacy endpoint: modified Rodnan Skin Score (mRSS) difference between M0 and M12.
3. - Other efficacy disease related endpoints : o mRSS at M3, M6 and M9 o WHO performance status (PS) and Health-Related Quality of Life (HRQoL) questionnaires : Scleroderma-Health Assessment Questionnaire (SHAQ), the Short Form (36) health survey (SF-36v2) and EQ-5D-5L at M0, M3, M6, and M12; o Forced Vital Capacity (FVC) and Diffusing capacity of Lung for carbon monoxide (DLCO) at M0, M6 and M12.
4. - PFS at M12, with progression defined as any of the following: decreased in FVC > 10% or in DLCO > 15%; decrease in LVEF% > 15%; decrease in weight > 15%; decrease in creatinine clearance > 30%; increased mRSS > 25% ; and/or increase in SHAQ> 0.5.
5. - GRCS values at M3, M6, and M12.
6. - CRISS values for early SSc patients at M3, M6, and M12.
7. - Overall survival at M12
8. - Myeloid and lymphocyte sub-populations in all included patients at M0, M1, M3, M4, M6.
9. - Alloimmunization in all included patients through the detection and identification of donor-specific anti-HLA antibodies at M0, M3 and M6
10. - Extra-Cost per QALY (quality-adjusted Life Year) gained by unique and repeated IV infusion of allogeneic MSC(AT) in severe SSc after 12 months.
11. - Extra-Cost per SAE of grade above or equal to 3 CTCAE avoided by unique and repeated IV infusion of allogeneic MSC(AT) in severe SSc after 12 months.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

1 Avenue Claude Vellefaux

City

Paris

Postcode

75010

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr Dominique Farge-Bancel

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr Dominique Farge-Bancel

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications