Treatment of Refractory Systemic Lupus Erythematosus by Allogeneic Mesenchymal Stem Cells Derived From the Umbilical Cord

Study Overview
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Brief Summary
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Systemic lupus erythematosus (SLE) is a rare (prevalence: 40- 50/100 000 persons) heterogeneous auto-immune and auto-inflammatory disease (AD), affecting both sexes and all races, with a peak incidence / prevalence among black people and a predilection for women in the 3rd-4th decade of life. SLE is characterized by successive periods of flares and remission, which may all vary in duration and quality. Prognosis of severe forms of SLE, which affect lung, heart or brain in addition to renal involvement, has improved, but still evolution remains pejorative in a subset of patients whose 10 years mortality remains 10-15%, even in tertiary referral centers. For 20 years, no new prospective clinical trial in the course of SLE has demonstrated its effectiveness. New biological therapies have not yet made the long awaited breakthrough in the treatment of severe SLE and only anti-Blys monoclonal antibody has gained indication in moderately active SLE. In addition, serious adverse side effects (progressive multifocal leukoencephalopathy) observed with several biologics in AD patients has dampened their expected benefits. For SLE subjects resistant to 1er or 2nd line conventional treatment, there is a need to develop more effective therapies with fewer long term side effects, based on new immunomodulatory and immunosuppressive strategies. According to their in vitro immunomodulatory properties and ability to induce tissue repair mechanisms, mesenchymal stem cells (MSC) have been proposed as a new therapy for several AD, including SLE. The use of allogeneic umbilical cord-derived MSC is based on experimental and human clinical data, particularly produced by Nanjing team (Pr Sun) in China. It is also logical to select SLE patients with the same severity criteria as those used worldwide to validate the efficacy of anti-Blys therapies. Similarly, the analysis of the expected results should take into account criteria similar or comparable to those used for the pivotal clinical trials. This trial is a unique opportunity to set up collaboration between Saint-Louis APHP, clinical expert center for cell therapy in AD, and University College London for cell manufacturing.

Official Title
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Treatment of Refractory Systemic Lupus Erythematosus by Injection of Allogeneic Mesenchymal Stem Cells Derived From the Umbilical Cord

Conditions
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Lupus Erythematosus, Stem Cell Transplant

Intervention / Treatment
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* Biological: mesenchymal stem cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years and < 70 years. Diagnosis of Systemic Lupus Erythematosus (SLE) according to the ACR criteria with positive antinuclear antibodies. Subjects with sustained disease activity defined by a SELENA- SLEDAI SLE activity index ≥ 6 at baseline, Inefficacy or adverse effects necessitating discontinuation of first and second line therapies of SLE including: a. Prednisone orally ≥ 6 mg / day (or equivalent) for at least 28 days. b. At least one or more of the following immunosuppressive therapies for 3 months in total: i- Cyclophosphamide, iv bolus ≥500 mg / month for 3 months minimum ii- Mycophenolate mofetil, orally or equivalent at a dose> 2000 mg / day for at least 90 days iii- Azathioprine orally at a dose> 2 mg / kg / day for at least 90 days; iv- Methotrexate orally or parenterally, at doses > 20mg / week for at least 90 days; v- Leflunomide orally, at a dose of> 10-mg / day for at least 90 days; vi- Rituximab (anti-CD20) intravenous bolus 375 mg / m2, once a week for four weeks or total dose of 1 g twice a day for two weeks vii- Cyclosporine orally, at a dose of 2.5-5 mg / kg / day, for at least 90 days; viii- Belimumab intravenously at monthly bolus of 10 mg / kg infusion), for at least 3 months. Patient who received treatment of SLE at stable doses for a minimum of 30 days prior to eligibility, including one of the following treatments: prednisone (or equivalent) alone or combined with antimalarial treatment, an anti-inflammatory steroidal and / or an immunosuppressant. Negative pregnancy test for women of childbearing age. For men and women : Using effective contraceptive methods during treatment and within 3 months after the end of treatment for men with her partner of childbearing age Signed Informed Consent. Affiliation to social security. Exclusion Criteria: 1- Pregnancy, breastfeeding or lack of appropriate contraception during study duration Presence of: Renal failure: calculated creatinine clearance of <30 ml / min Cardiac failure: clinical signs of congestive heart failure; left ventricular ejection fraction <40% on echocardiography; uncontrolled ventricular arrhythmia; Hepatitis defined by abnormal levels of transaminases (AST, ALT> 2 x normal) not related to disease activity. Respiratory disease: mean PAP> 50 mmHg (echocardiography), respiratory failure defined by a resting blood pressure of oxygen at PaO 2 < 70 mmHg and / or PaCO2 > 50 mmHg without oxygen Severe psychiatric disorders, including severe psychosis related to SLE, which would prevent to give informed consent or to undergo the procedure. Active neoplasia or concomitant myelodysplasia, except for basal cell carcinoma or squamous cell carcinoma or in situ cervix carcinoma. Bone marrow failure defined by neutropenia <0.5.109/L, thrombocytopenia <30. 109 / L, anemia < 8 g / dL, lymphopenia CD4 + <200 x 106 / L caused by another disease than SLE. Acute or chronic uncontrolled infection: HIV 1/2, HTLV-1/2, Hepatitis B (HBsAg surface antigen), Hepatitis C with positive PCR Patient having received belimumab within 2 months of belimumab within 2 months of Baseline, or having received rituximab or other B cell depleting biologic therapy within 6 months of Baseline Current substance abuse or recent (within 60 days) history of substance abuse Patient in periods of exclusion from the national roster of researchers Patient with Linguistic or psychological incapacity to sign informed consent Patient already included in another study at the same time. Poor patient compliance. Patient under legal protection.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: mesenchymal stem cells<br>Phase I-II, Allogeneic Umbilical Cord derived-MSCs injected by slow intravenous infusion according to the weight of the recipient and patient groups in the study, at doses of: 1.10^6 CSM / kg 2.10^6 CSM / kg 4.10^6 CSM / kg 1 injection during 30min to 1h by Intravenous infusion | Biological: mesenchymal stem cells<br>* Allogeneic Umbilical Cord derived-MSCs injected by slow intravenous infusion according to the weight of the recipient and patient groups in the study, at doses of: 1.10^6 CSM / kg 2.10^6 CSM / kg 4.10^6 CSM / kg 1 injection during 30min to 1h by Intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity of allogeneic MSC injection according to CTCAE | Immediate tolerance as assessed after the first allogeneic MSC injection, according to standards CTCAE side effects. An injection will be considered as not tolerated for any toxicity criteria above grade ≥ 3. | 10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity of allogeneic MSC injection according to CTCAE Month 1 | Tolerance according to side effects defined by CTCAE standards (Miller Results of cancer treatment Cancer 1981; 47 (1): 207 - 214). Treatment-related toxicity will be analyzed according to the international World Health Organization (WHO) (maximum degree of toxic attacks by the body). An injection will be considered as not tolerated for any toxicity criteria above grade ≥ 3. | 1 month | 
| Toxicity of allogeneic MSC injection according to CTCAE Month 3 | Tolerance according to side effects defined by CTCAE standards (Miller Results of cancer treatment Cancer 1981; 47 (1): 207 - 214). Treatment-related toxicity will be analyzed according to the international World Health Organization (WHO) (maximum degree of toxic attacks by the body). An injection will be considered as not tolerated for any toxicity criteria above grade ≥ 3. | 3 months | 
| Toxicity of allogeneic MSC injection according to CTCAE Month 6 | Tolerance according to side effects defined by CTCAE standards (Miller Results of cancer treatment Cancer 1981; 47 (1): 207 - 214). Treatment-related toxicity will be analyzed according to the international World Health Organization (WHO) (maximum degree of toxic attacks by the body). An injection will be considered as not tolerated for any toxicity criteria above grade ≥ 3. | 6 months | 
| Toxicity of allogeneic MSC injection according to CTCAE Month 12 | Tolerance according to side effects defined by CTCAE standards (Miller Results of cancer treatment Cancer 1981; 47 (1): 207 - 214). Treatment-related toxicity will be analyzed according to the international World Health Organization (WHO) (maximum degree of toxic attacks by the body). An injection will be considered as not tolerated for any toxicity criteria above grade ≥ 3. | 12 months | 
| Proportion of subjects with Clinical Response Month 3 | Proportion of subjects with Major Clinical Response (MCR) and the proportion of subjects with Partial Response Clinic (PCR) | 3 months | 
| Proportion of subjects with Clinical Response Month 6 | Proportion of subjects with Major Clinical Response (MCR) and the proportion of subjects with Partial Response Clinic (PCR) | 6 months | 
| Proportion of subjects with Clinical Response Month 9 | Proportion of subjects with Major Clinical Response (MCR) and the proportion of subjects with Partial Response Clinic (PCR) | 9 months | 
| Proportion of subjects with Clinical Response Month 12 | Proportion of subjects with Major Clinical Response (MCR) and the proportion of subjects with Partial Response Clinic (PCR) | 12 months | 
| Disease activity measured by the BILAG index Month 3 | Disease activity measured by the British Isles Lupus Assessment Group (BILAG) index (min=0 to max=72). The higher value is the higher is the disease activity. | 3 months | 
| Disease activity measured by SELENA-SLEDAI Month 3 | Disease activity measured by the Safety of Estrogens in Lupus National Assessment study (SELENA) of the Systemic lupus erythematosus disease activity index (SLEDAI) (min=0 to max=105). The higher value is the higher is the disease activity. | 3 months | 
| Disease activity measured by SELENA-SLEDAI Month 6 | Disease activity measured by the Safety of Estrogens in Lupus National Assessment study (SELENA) of the Systemic lupus erythematosus disease activity index (SLEDAI) (min=0 to max=105). The higher value is the higher is the disease activity. | 6 months | 
| Disease activity measured by the BILAG index Month 6 | Disease activity measured by the British Isles Lupus Assessment Group (BILAG) index (min=0 to max=72). The higher value is the higher is the disease activity. | 6 months | 
| Disease activity measured by the BILAG index Month 9 | Disease activity measured by the British Isles Lupus Assessment Group (BILAG) index (min=0 to max=72). The higher value is the higher is the disease activity. | 9 months | 
| Disease activity measured by SELENA-SLEDAI Month 9 | Disease activity measured by the Safety of Estrogens in Lupus National Assessment study (SELENA) of the Systemic lupus erythematosus disease activity index (SLEDAI) (min=0 to max=105). The higher value is the higher is the disease activity. | 9 months | 
| Disease activity measured by the BILAG index Month 12 | Disease activity measured by the British Isles Lupus Assessment Group (BILAG) index (min=0 to max=72). The higher value is the higher is the disease activity. | 12 months | 
| Disease activity measured by SELENA-SLEDAI Month 12 | Disease activity measured by the Safety of Estrogens in Lupus National Assessment study (SELENA) of the Systemic lupus erythematosus disease activity index (SLEDAI) (min=0 to max=105). The higher value is the higher is the disease activity. | 12 months | 
| SRI Month 3 | SRI (Systematic lupus erythematosus Responder Index) response rate during follow-up. A SRI response is defined as a binary outcome equal to 1 if all following conditions are validated: 4 points reduction of SELENA SLEDAI-score no new BILAG A score for an organ no more than one new BILAG B score no worsening in the overall evaluation of the physician as compared to inclusion values | 3 months | 
| SRI Month 6 | SRI (Systematic lupus erythematosus Responder Index) response rate during follow-up. A SRI response is defined as a binary outcome equal to 1 if all following conditions are validated: 4 points reduction of SELENA SLEDAI-score no new BILAG A score for an organ no more than one new BILAG B score no worsening in the overall evaluation of the physician as compared to inclusion values | 6 months | 
| SRI Month 9 | SRI (Systematic lupus erythematosus Responder Index) response rate during follow-up. A SRI response is defined as a binary outcome equal to 1 if all following conditions are validated: 4 points reduction of SELENA SLEDAI-score no new BILAG A score for an organ no more than one new BILAG B score no worsening in the overall evaluation of the physician as compared to inclusion values | 9 months | 
| SRI Month 12 | SRI (Systematic lupus erythematosus Responder Index) response rate during follow-up. A SRI response is defined as a binary outcome equal to 1 if all following conditions are validated: 4 points reduction of SELENA SLEDAI-score no new BILAG A score for an organ no more than one new BILAG B score no worsening in the overall evaluation of the physician as compared to inclusion values | 12 months | 
| comorbidities Month 3 | Presence of comorbidities | 3 months | 
| comorbidities Month 6 | Presence of comorbidities | 6 months | 
| comorbidities Month 9 | Presence of comorbidities | 9 months | 
| comorbidities Month 12 | Presence of comorbidities | 12 months | 
| Quality of life Month SF-36 Month 3 | Quality of life assessed by the Short Form 36 version 2 (SF-36v2). The SF-36v2 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. | 3 months | 
| Quality of life EQ-5D Month 3 | EuroQol-5D (EQ-5D) : health status is measured in terms of five dimensions (5D); mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated from 0 to 5 and a single summary index is obtained by summing all the dimensions (min=0 to max=25). | 3 months | 
| Quality of life Month SF-36 Month 6 | Quality of life assessed by the Short Form 36 version 2 (SF-36v2). The SF-36v2 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. | 6 months | 
| Quality of life EQ-5D Month 6 | EuroQol-5D (EQ-5D) : health status is measured in terms of five dimensions (5D); mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated from 0 to 5 and a single summary index is obtained by summing all the dimensions (min=0 to max=25). | 6 months | 
| Quality of life Month SF-36 Month 9 | Quality of life assessed by the Short Form 36 version 2 (SF-36v2). The SF-36v2 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. | 9 months | 
| Quality of life EQ-5D Month 9 | EuroQol-5D (EQ-5D) : health status is measured in terms of five dimensions (5D); mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated from 0 to 5 and a single summary index is obtained by summing all the dimensions (min=0 to max=25). | 9 months | 
| Quality of life Month SF-36 Month 12 | Quality of life assessed by the Short Form 36 version 2 (SF-36v2). The SF-36v2 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. | 12 months | 
| Quality of life EQ-5D Month 12 | EuroQol-5D (EQ-5D) : health status is measured in terms of five dimensions (5D); mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated from 0 to 5 and a single summary index is obtained by summing all the dimensions (min=0 to max=25). | 12 months | 
| Steroids Month 3 | Percentage of subjects with an average dose of prednisone reduced by 25% compared to M0 | 3 months | 
| Steroids Month 6 | Percentage of subjects with an average dose of prednisone reduced by 25% compared to M0 | 6 months | 
| Steroids Month 9 | Percentage of subjects with an average dose of prednisone reduced by 25% compared to M0 | 9 months | 
| Steroids Month 12 | Percentage of subjects with an average dose of prednisone reduced by 25% compared to M0 | 12 months |