A multicenter, randomized, blinded, placebo controlled, phase II study to evaluate the safety and efficacy of cell therapy based with artificially expanded CD4+CD25+CD127- regulatory lymphocytes and anti-CD20 antibody in pediatric patients with presymptomatic diabetes type 1 (stage 1)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Poltreg S.A.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18], Diseases [C] - Immune System Diseases [C20]

Trial duration

28 Jan 2025 → ongoing

Decision date (initial)

2024-07-22

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Equity capital of the sponsor · Agencja Badań Medycznych

External identifiers

EU CT number

2023-505226-33-00

ClinicalTrials.gov

NCT06688331

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Prophylaxis

To assess the safety and efficacy of the treatment used in the separate groups of pediatric participants with DM1 stage 1 treated with two-dose combination regimen of Tregs and rituximab over placebo, rituximab alone, and Tregs alone.

Secondary objectives 1

1. To evaluate the key T1DM focused clinical parameters of diabetes development, including HbA1c, clinically important hypoglycemic episodes, TIR, C peptide AUC, immunologic markers, plasma insulin levels,and quality of life measures

Conditions and MedDRA coding

Presymptomatic diabetes type 1 (stage 1)

Regulatory references

Scientific advice from competent authorities

Poltreg S.A.

EMA paediatric investigation plan (PIP)

EMEA-002737-PIP01-19, EMEA-000000-PIP00-00

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Age 3-18
2. 5 ≤ BMI ≤ 95 percentile (acc. to OLAF or WWF in the case of children under six years old) with a lower weight threshold of 20 kg
3. 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)
4. Insulin independence
5. C-peptide levels ≥ 1.0 ng/ml in fasting and post-stimulation tests increase ≥ 100%
6. 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)
7. HbA1c level (%) <5,7% (acc. to ADA)
8. Positive autoantibody titres (ICA, IAA, GAD, IA-2/ICA512, ZnT8) - low titers of two or more antibodies (2 times the normal or higher); 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)
9. 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])
10. 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
11. Venous access to guarantee blood donation

Exclusion criteria 38

1. Refusal to participate in the trial or lack of a signed informed consent form
2. Suspicion or diagnosis for a type of diabetes other than type 1 diabetes mellitus
3. Age under 3 or above 18
4. 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)
5. C-peptide levels < 1.0 ng/ml fasting and in post-stimulation tests increase < 100%
6. Glucose levels in venous blood ≥ 100mg% fasting
7. Glucose levels in venous blood after 1 and 2 hours in OGTT ≥ 200mg%
8. Glycated hemoglobin level (HbA1c) in venous blood ≥ 5,7%
9. BMI < 5th percentile or > 95th percentile for age or body weight < 20 kg
10. History of hypersensitivity to anti-CD20 or other components of the preparation
11. History of hypersensitivity to penicillin and/or streptomycin
12. 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.
13. Active infection with the EBV or CMV virus (positive IgM)
14. Any fungal, parasitic, viral, or bacterial infection
15. History of past or active cancer
16. 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
17. Elevated thrombotic activity/history of thrombosis episode
18. Any disease reported in the medical history prior to inclusion in the trial that has required continuous treatment for more than 3 months with medication directly affecting the immune system (e.g., immunosuppressive, immunomodulatory or immunostimulatory therapy). This does not include chronic treatment with drugs without a primary immunological mechanism of action.
19. Diagnosed autoimmune disease other than type 1 diabetes mellitus, including a history of Hashimoto's disease and coeliac disease
20. Taking anti-diabetic medication (including insulin) in the last 4 weeks prior to trial inclusion
21. History of retinopathy
22. History of hypertension
23. Current or history of albuminuria
24. 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
25. Breastfeeding
26. 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
27. Excessive anxiety of the participant or his/her legal representatives regarding the procedures used in the trial
28. Any medical problem that, in the opinion of the investigator, may adversely affect the participant's health if included in the trial
29. Legal representatives and/or children over the age of 15 with an identified alcohol and/or psychoactive substance addiction
30. History of disease of unknown etiology
31. History of Creutzfeldt-Jacob disease
32. History of progressive dementia or degenerative neurological disease, including of unknown origin
33. History of taking hormones derived from the human pituitary gland (e.g., growth hormone)
34. Treatment with immunosuppressants
35. History of corneal, scleral, and dural transplant or undocumented neurosurgery
36. History of occurrence of risk factors related to the participant's travel, where there is a possibility of exposure to regional infectious diseases
37. Physical signs that indicate the risk of an infectious disease
38. History of xenogeneic transplant

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Percentage of participants in each group who are still in stage 1 type 1 diabetes mellitus, i.e., presence of autoantibodies and normoglycemia or in stage 2 type 1 diabetes mellitus, i.e., presence of autoantibodies, dysglycemia or stage 3 at the end of the trial.
2. Number of adverse events reported 1 year, 2 years after the first dose of Tregs and at the end of the trial comparing to control arms

Secondary endpoints 7

1. Pace of diabetes development. 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)
2. 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 comparing to control arms
3. Daily average 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 in each arm of the trial
4. Number of participants per arm 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%]
5. Assessment of the incidence and severity of adverse events associated with the administration of Treg preparation or anti-CD20 antibody, primarily the effects of immunosuppression: incidence of infections of any etiology and de novo tumors detected
6. Number of days from day 0 to the day of first dysglycemia (stage 2 of type 1 diabetes mellitus) in each group.
7. Cumulative diabetes incidence [only the progression to stage 3 considered as diabetes incidence].

Investigational products

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

Test 2

Placebo 1

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Poltreg S.A.

Sponsor organisation

Poltreg S.A.

Address

Ul. Botaniczna 20

City

Gdansk

Postcode

80-298

Country

Poland

Scientific contact point

Organisation

Poltreg S.A.

Contact name

Information desk

Public contact point

Organisation

Poltreg S.A.

Contact name

Information desk

Third parties 4

Locations

1 EU/EEA country · 10 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 46 files

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

Application history

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