Mesenchymal Stromal Cells to Treat Type 1 Diabetes in Children and Adolescents

Study Overview
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Brief Summary
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This is a combined phase 1 and 2 study in 66 subjects, male or female, between 7-21 years of age that have recently (< 6 months) been diagnosed with type 1 diabetes. The first phase 1 part of the study includes six subjects openly receiving allogeneic Wharton's jelly derived mesenchymal stromal cells as the Advanced Therapy Medicinal Product (ATMP) Protrans, three each in the age ranges 7-11 and 12-18.The second part is a randomized, double-blinded placebo-controlled phase 2 study in parallel design comparing allogeneic Wharton's jelly derived mesenchymal stromal cells treatment (as Protrans) to placebo in children and adolescent subjects (7-21 years of age) diagnosed with type 1 diabetes, The primary objectives of this study will be to investigate the safety, tolerance and efficacy after an allogieneic infusion of Wharton's jelly derived mesenchymal stromal cells.

Official Title
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A Double-blinded, Randomized, Parallel, Placebo-controlled Trial of Wharton's Jelly-derived Allogeneic Mesenchymal Stromal Cells to Treat Type 1 Diabetes in Children and Adolescents

Conditions
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Type1diabetes

Intervention / Treatment
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* Biological: the ATMP Protrans


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent for participation of the study (for subjects below 18 years of age also from both caregivers), given before undergoing any study-specific procedures Clinical history compatible with type 1 diabetes diagnosed less than 6 months before enrolment In the first part of the study, six subjects, three between 7-11 and three between 12-18 years of age (both groups inclusive at both ends), will be included. The sixty subjects in the second part of the study are stratified by age (12-21 and 7-11 years, respectively) and randomized to one of two treatment arms (active or placebo), with a 6-month safety delay for the younger stratum. Mentally stable and, in the opinion of the investigator, able to comply with the procedures of the study protocol. Fasting plasma C-peptide concentration >0.12 nmol/L. Subjects of child-bearing potential must agree to using adequate contraception until one year after the administration of WJMSC/Placebo. Adequate contraception is as follows: oral (except low-dose gestagen (lynestrenol and noretisteron), injectable or implanted hormonal contraceptives. intrauterine device intrauterine system (for example progestin-releasing coil) vasectomized male (with appropriate postvasectomy documentation of the absence of sperm in the ejaculate) Exclusion Criteria: Subjects with body weight >100 kg Subjects with unstable cardiovascular status incl. NYHA class III/IV or symptoms of angina pectoris. Subjects with uncontrolled hypertension (≥160/105 mmHg). Subjects with active on-going infections. Subjects with latent or previous as well as on-going therapy against tuberculosis, or exposed to tuberculosis or has traveled in areas with a high risk of tuberculosis or mycosis within the last 3 months. Subjects with serological evidence of infection with HIV, Treponema pallidum, hepatitis B antigen (subjects with serology consistent with previous vaccination and a history of vaccination are acceptable), or hepatitis C. Subjects with any systemic immune suppressive treatment Subjects with a known demyelinating disease or with symptoms or physical examination findings consistent with possible demyelinating disease. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. Subjects with known, or previous, malignancy. Taking oral anti-diabetic therapies or any other concomitant medication which may interfere with glucose regulation other than insulin. Subjects with GFR <60 ml/min/1.73 m2 body surface. Subject with any condition or any circumstance that, in the opinion of the investigator, would make it unsafe to undergo treatment with MSC. Known hypersensitivity against any excipients, i.e., dimethyl sulfoxide (DMSO).

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 21 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Wharton's jelly derived mesenchymal stromal cells (Protrans)<br>Cells are dissolved in saline and given intravenously over a period of 20-40 min. 100 million cells to subjects < 50 kg and 200 million cells to subjects 50-100 kg (>100 kg is an exclusion criterion). | Biological: the ATMP Protrans<br>* Protrans consists of Wharton's jelly derived mesenchymal stromal cells<br>|
| Placebo Comparator: Placebo<br>Placebo (saline) is given intravenously over a period of 20-40 min. | Biological: the ATMP Protrans<br>* Protrans consists of Wharton's jelly derived mesenchymal stromal cells<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety at one year evaluated as adverse events | Safety parameters will be evaluated at each study visit and recorded as adverse events. | One year | 
| Safety at five years evaluated as adverse events | Safety parameters will be evaluated at each study visit and recorded as adverse events. | Five years | 
| Efficacy measured as change in C-peptide Area under the curve to a mixed mealtolerance test. | Change in C-peptide Area under the curve (AUC) (0-120 min) for mixed meal tolerance test (MMTT) at 12 months following Protrans/Placebo infusion when compared to test performed before the start of treatment (baseline). | One year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin independency | The proportion of study participants independent of insulin at 6 months | One year | 
| Insulin independency | The proportion of study participants independent of insulin at 12 months | One year | 
| Low insulin needs | The proportion of study participants with daily insulin needs <0.25 U/kg at 6 months | 6 months | 
| Low insulin needs | The proportion of study participants with daily insulin needs <0.25 U/kg at 12 months | 12 months | 
| Insulin needs | Insulin requirement/kg body weigh at 6 months | 6 months | 
| Insulin needs | Insulin requirement/kg body weigh at 12 months | 12 months | 
| HbA1c | HbA1c at 6 months | 6 months | 
| HbA1c | HbA1c at 12 months | 12 months | 
| Time in target | Time in target (4-8 mmol/l) as measured by flash glucose monitoring for 14 days at 6 months | 6 months | 
| Time in target | Time in target (4-8 mmol/l) as measured by flash glucose monitoring for 14 days at 12 months | 12 months | 
| Time in range | Time in target (3.9-10 mmol/l) as measured by flash glucose monitoring for 14 days at 6 months | 6 months | 
| Time in range | Time in target (3.9-10 mmol/l) as measured by flash glucose monitoring for 14 days at 12 months | 12 months | 
| C-peptide | Change in C-peptide Area under the curve (AUC) (0-120 min) for mixed meal tolerance test (MMTT) at 6 months following Protrans/Placebo infusion when compared to test performed before the start of treatment (baseline). | 6 months | 
| Change in peak C-peptide | Change in peak C-peptide concentration during the first 6 months | 6 months | 
| Change in peak C-peptide | Change in peak C-peptide concentration during the first 12 months | 12 months |