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| ID | Type | Description | Link |
|---|---|---|---|
| 2023-505226-33-00 | EU Trial (CTIS) Number |
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| Name | Class |
|---|---|
| Invicta Sp. z o.o. | OTHER |
| Medical Research Agency, Poland | OTHER_GOV |
| Clinmark Clinical Research | UNKNOWN |
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The main purpose of the study is to check:
In order to confirm the effectiveness of the therapy, not all patients will receive the study treatment. The study will be a so-called blinded randomized trial. This means that in this trial, all participants will undergo the same study procedures, but the participant will be randomly assigned to one of four (4) groups that will receive different treatment regimens before entering the study.
The participant will be randomly assigned to one of four groups:
Approximately 150 patients aged 6-16 who are at risk of developing type 1 diabetes will be enrolled in the study, which will last up to 96 months. Each enrolled participant will remain in the study for up to five years.
Participants: screening of approximately 2500 high-risk subjects will be conducted until no less than 150 participants with confirmed stage 1 (preclinical) type 1 diabetes mellitus are randomized; randomization 2:1:1:2; 50 participants treated with Tregs and anti-CD20 antibody; 25 participants treated with Tregs; 25 participants treated with anti-CD20 antibody; control: 50 participants receiving placebo and sham Tregs.
Inclusion of participants: up to 36 months. Trial intervention: Total duration of the trial intervention for each participant will be approximately 3 Months. After completion of the trial intervention, participants will be monitored at the sites for the onset of type 1 diabetes mellitus for a maximum of five years counting from the first dose of Tregs.
Follow-up time: post-treatment observation of all participants to 57 months (day "0" is the day of administration of the first dose of Treg/sham preparation).
Trial time: 96 months. Trial type: Prospective randomized (phase 2), placebo-controlled, parallel group, blinded trial.
Blinding: The following roles indicated below will not be made aware of the treatment group assignment during the trial:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| TregsCD20 | Experimental | Infusion of Treg preparation at "day 0" + 4 doses of antiCD20 antibody; second infusion of Treg preparation at time "+90±30days" Interventions: ex vivo expanded CD4+CD25+CD127- regulatory T cells (Tregs) + Anti-CD20 (rituximab) | |
| Tregs only | Experimental | Infusion of Treg preparation at "day 0" + 4 doses of placebo; second infusion of Treg preparation at time "+90±30 days" |
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| CD20 only | Experimental | Infusion of Treg sham at "day 0" + 4 doses of antiCD20 antibody; second infusion of Treg sham at time "+90±30days" |
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| Control group | Placebo Comparator | Infusion of Treg sham at "day 0" + 4 doses of placebo; second infusion of Treg sham at time "+90±30days" |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| ex vivo expanded CD4+CD25+CD127- regulatory T cells (Tregs) | Biological | regulatory T cells with the phenotype CD3(+)CD4(+)CD25(high)CD127(-)doublet(-)lin(-) |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of days from day 0 to the day of first dysglycemia (stage 2 of type 1 diabetes mellitus) in each group | To assess the safety and efficacy of the treatment used in the separate groups of participants treated with combined treatment with Treg preparation and rituximab antibody or Treg preparation or rituximab antibody or the control (placebo/Tregs sham) | From day "0" (the day of administration of the first dose of Treg preparation) to the end of participation in the trial at month 60 |
| Number of adverse events reported 1 year, 2 years after the first dose of Tregs and at the end of the trial | To assess the safety and efficacy of the treatment used in the separate groups of participants treated with combined treatment with Treg preparation and rituximab antibody or Treg preparation or rituximab antibody or the control (placebo/Tregs sham) | From enrollment to the end of participation in the trial at month 60 (day "0" is the day of administration of the first dose of Treg preparation) |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of participants in each group who are in stage 2 type 1 diabetes mellitus, i.e., presence of autoantibodies, dysglycemia or stage 3 at year 1 and every year thereafter after the first dose of Tregs/placebo | Additional measures to assess the safety and efficacy of the treatment used in the separate groups of pediatric participants treated with combined treatment with Treg preparation and rituximab antibody or Treg preparation or rituximab antibody or the control (placebo/ Tregs sham) in preserving β-cell function |
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Inclusion Criteria:
Age 6-16
25 ≤ BMI ≤ 75 percentile (acc. to OLAF) with a lower weight threshold of 20 kg
Venous plasma glucose levels < 100mg% at fasting (70 to 100 mg/dl) and normal glucose tolerance test (at 120 minutes glycaemia <140 mg/dl) (acc. to PTD)
Insulin independence
C-peptide levels ≥ 1.0 ng/ml (central laboratory limit of normal) in fasting and post-stimulation tests increase ≥ 100%
Participant has not yet been diagnosed with stage 2 or 3 type 1 diabetes mellitus (no history of dysglycemia, no history of clinical symptoms of type 1 diabetes mellitus)
HbA1c level (%) <5,7% (acc. to ADA)
Positive autoantibody titres (ICA, IAA, GAD, IA-2/ICA512, ZnT8) - low titers of two or more antibodies (2-4 times the normal*); if high titer of one of the antibodies (≥ 4 times the norm, not applicable to ICA) re-screening allowed (the participant can be included in the trial only after confirming two or more antibodies)
Ability to give informed consent by the child's legal representatives (and the child himself or herself if he or she is over the age of 13 at the time of the trial [according to local law])
Ability of the child's legal representatives to manage diabetes, defined as blood glucose levels control at least three times a day and the ability to dose insulin correctly.
Venous access to guarantee blood donation
Exclusion Criteria:
Refusal to participate in the trial or lack of a signed informed consent form
Suspicion or diagnosis for a type of diabetes other than type 1 diabetes mellitus
Age under 6 or above 16
IgA deficiency or history of other diagnosed immunodeficiency (max. 7 infections/year allowed, and the prognosis should indicate that the patient will remain in the study throughout its duration)
C-peptide levels < 1.0 ng/ml fasting and in post-stimulation tests increase < 100%
Glucose levels in venous blood ≥ 100mg% fasting
Glucose levels in venous blood after 1 and 2 hours in OGTT ≥ 200mg%
Glycated hemoglobin level (HbA1c) in venous blood ≥ 5,7%
BMI < 25 or > 75th percentile for a given age or weight of less than 20 kg
History of hypersensitivity to anti-CD20 or other components of the preparation
History of hypersensitivity to penicillin and/or streptomycin
Past or active infection with HBV, HCV, HIV, HTLV I/II, mycobacterium tuberculosis, syphilis. Laboratory evidence of infection without the need for clinical signs and symptoms is sufficient for diagnosis.
Active infection with the EBV or CMV virus (positive IgM)
Any fungal, parasitic, viral, or bacterial infection
History of past or active cancer
Anemia, lymphopenia, neutropenia, or thrombocytopenia defined as a blood cell count below the lower limit of normal for age found within the last 6 weeks prior to trial inclusion
Elevated thrombotic activity/history of thrombosis episode
Any disease prior to inclusion in the trial currently requiring medication for more than 3 months in history
Diagnosed autoimmune disease other than type 1 diabetes mellitus, including a history of Hashimoto's disease and coeliac disease
Taking anti-diabetic medication (including insulin) in the last 4 weeks prior to trial inclusion
History of retinopathy
History of hypertension
Current or history of albuminuria
For women in childbearing potential/menstruating women: pregnancy (from medical interview) or unwillingness to exercise sexual restraint or use effective forms of contraception for the duration of the trial and up to 4 months after completion, if applicable.
The following contraceptive methods are acceptable: bilateral fallopian tube closure, sterilization in men, appropriate use of hormonal contraception that inhibits ovulation, hormone-releasing IUDs, and copper IUDs, male or female condoms with spermicide; and cap, uterine disc, or sponge with spermicide.
Breastfeeding
For males over 15 years of age: expressed intention to have offspring or donate sperm during the trial or within 4 months after the end of the trial, if applicable
Excessive anxiety of the participant or his/her legal representatives regarding the procedures used in the trial
Any medical problem that, in the opinion of the investigator, may adversely affect the participant's health if included in the trial
Legal representatives and/or children over the age of 15 with an identified alcohol and/or psychoactive substance addiction
History of disease of unknown etiology
History of Creutzfeldt-Jacob disease
History of progressive dementia or degenerative neurological disease, including of unknown origin
History of taking hormones derived from the human pituitary gland (e.g., growth hormone)
Treatment with immunosuppressants
History of corneal, scleral, and dural transplant or undocumented neurosurgery
History of occurrence of risk factors related to the participant's travel, where there is a possibility of exposure to regional infectious diseases
Physical signs that indicate the risk of an infectious disease
History of xenogeneic transplant
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Marta Druch, Clinical Trial Director | Contact | +48731471845 | m.druch@poltreg.com | |
| Grzegorz Orlik, Medical Director | Contact | +48790680020 | g.orlik@poltreg.com |
| Name | Affiliation | Role |
|---|---|---|
| Piotr Trzonkowski, Prof | PolTREG S.A. | Study Director |
| Artur Bossowski, Prof | Uniwersytecki Dzieciecy Szpital Kliniczny Im. L. Zamenhofa W Bialymstoku | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Uniwersytecki Dzieciecy Szpital Kliniczny Im. L. Zamenhofa W Bialymstoku | Recruiting | Bialystok | 15-269 | Poland |
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Trial type: Prospective randomized, placebo-controlled, parallel group, blinded trial.
Control method: placebo, active comparator, sham procedure.
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Blinding: The following roles indicated below will not be made aware of the treatment group assignment during the trial:
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| Anti-CD20 (rituximab) | Biological | rituximab |
|
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| Placebo | Other | intrevenous 0,9% NaCl |
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| Treg sham | Other | intrevenous 0,9% NaCl |
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| From day "0" (the day of administration of the first dose of Treg preparation) to the end of participation in the trial at month 60 |
| Total number of days from the date of diagnosis of stage 2 to the date of onset of full-blown type 1 diabetes mellitus (stage 3 of type 1 diabetes mellitus) in each group (normalized to the number of person/days in each group) | Additional measures to assess the safety and efficacy of the treatment used in the separate groups of pediatric participants treated with combined treatment with Treg preparation and rituximab antibody or Treg preparation or rituximab antibody or the control (placebo/ Tregs sham) in preserving β-cell function | From day "0" (the day of administration of the first dose of Treg preparation) to the end of participation in the trial at month 60 |
| C-peptide levels [fasting/post MMTT stimulation (AUC) 1 year, 2 years after the first dose of Tregs and then annually until the end of the trial | Additional measures to assess the safety and efficacy of the treatment used in the separate groups of pediatric participants treated with combined treatment with Treg preparation and rituximab antibody or Treg preparation or rituximab antibody or the control (placebo/ Tregs sham) in preserving β-cell function | From day "0" (the day of administration of the first dose of Treg preparation) to the end of participation in the trial at month 60 |
| Daily dose of insulin per kg body weight (DDI) 1 year, 2 years after the first dose of Tregs, and annually thereafter until the end of the trial | Additional measures to assess the safety and efficacy of the treatment used in the separate groups of pediatric participants treated with combined treatment with Treg preparation and rituximab antibody or Treg preparation or rituximab antibody or the control (placebo/ Tregs sham) in preserving β-cell function | From day "0" (the day of administration of the first dose of Treg preparation) to the end of participation in the trial at month 60 |
| Number of participants in remission 1 year, 2 years after the first dose of Tregs, and annually thereafter until the end of the trial, [remission defined as daily insulin dose is less than 0.5U/kg/day with an HbA1c level less than 6.5%] | Additional measures to assess the safety and efficacy of the treatment used in the separate groups of pediatric participants treated with combined treatment with Treg preparation and rituximab antibody or Treg preparation or rituximab antibody or the control (placebo/ Tregs sham) in preserving β-cell function | From day "0" (the day of administration of the first dose of Treg preparation) to the end of participation in the trial at month 60 |
| Assessment of the incidence and severity of adverse events associated with the administration of Treg preparation or antiCD20 antibody, primarily the effects of immunosuppression: incidence of infections of any etiology and de novo tumors detected | Additional measures to assess the safety and efficacy of the treatment used in the separate groups of pediatric participants treated with combined treatment with Treg preparation and rituximab antibody or Treg preparation or rituximab antibody or the control (placebo/ Tregs sham) in preserving β-cell function | From day "0" (the day of administration of the first dose of Treg preparation) to the end of participation in the trial at month 60 |
| Percentage of participants in each group who are still in stage 1 type 1 diabetes mellitus, i.e., presence of autoantibodies and normoglycemia | Additional measures to assess the safety and efficacy of the treatment used in the separate groups of pediatric participants treated with combined treatment with Treg preparation and rituximab antibody or Treg preparation or rituximab antibody or the control (placebo/ Tregs sham) in preserving β-cell function | From day "0" (the day of administration of the first dose of Treg preparation) to the end of participation in the trial at month 60 |
| Wojciech Mlynarski, Prof |
| Uniwersytet Medyczny W Lodzi |
| Study Chair |
| Uniwersyteckie Centrum Kliniczne | Recruiting | Gdansk | 80-211 | Poland |
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| Gornoslaskie Centrum Zdrowia Dziecka Im. Sw. Jana Pawla II Samodzielny Publiczny Szpital Kliniczny Nr 6 Slaskiego Uniwersytetu Medycznego W Katowicach | Not yet recruiting | Katowice | 40-752 | Poland |
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| Uniwersytet Medyczny W Lodzi | Recruiting | Lodz | 90-419 | Poland |
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| Uniwersytecki Szpital Dzieciecy w Lublinie | Recruiting | Lublin | 20-093 | Poland |
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| Uniwersytecki Szpital Kliniczny w Opolu | Recruiting | Opole | 45-401 | Poland |
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| Centrum Medyczne Medyk Sp. z o.o. S.K. | Recruiting | Rzeszów | 35-326 | Poland |
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| Uniwersytecki Szpital Kliniczny Im. Jana Mikulicza-Radeckiego We Wroclawiu | Recruiting | Wroclaw | 50-556 | Poland |
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| ID | Term |
|---|---|
| D003922 | Diabetes Mellitus, Type 1 |
| D011236 | Prediabetic State |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| D000069283 | Rituximab |
| ID | Term |
|---|---|
| D058846 | Antibodies, Monoclonal, Murine-Derived |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
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