Exposure-Response Study of Siplizumab in Adults with New Onset Type 1 Diabetes: A 12-Month, Randomized, Single-Blind, Placebo-Controlled Trial
- Trial ID
- 2023-506837-31-00
- Protocol
- TCD601F201
- Sponsor
- Itb-Med AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the effect of 12 weeks of **siplizumab** treatment on beta-cell function in adults recently diagnosed with new onset type 1 diabetes (T1D) compared to placebo at week 52. This is clinically relevant as preserving beta-cell function can potentially improve glycemic control and reduce the progression of T1D.
Secondary objectives include:
- Assessing the incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) as compared to placebo.
- Quantifying clinical and laboratory measures of diabetic disease and glycemic indices of siplizumab compared to placebo.
- Assessing the effect of siplizumab on the incidence of local and systemic infections, particularly opportunistic infections.
- Measuring pharmacokinetic (PK) and pharmacodynamic (PD) activity of siplizumab in subjects with T1D.
Participants
The clinical trial involves a total of **30 participants** diagnosed with **new onset type I diabetes**. The study population comprises both male and female adults aged between **18 to 45 years**. Participants were selected based on their ability to understand the study requirements and provide informed consent, as well as a diagnosis of type I diabetes by a qualified healthcare provider within 100 days of randomization. The trial does not include a vulnerable population. Participants are required to have a positive test for at least one diabetes-related autoantibody and a peak stimulated C-peptide level greater than 0.2 pmol/mL following a mixed-meal tolerance test. They must agree to adhere to strict glycemic control guidelines and use continuous glucose monitoring throughout the study. Additionally, participants are expected to be up to date with immunizations or agree to receive routine immunizations as per local guidelines. The trial does not specify any particular lifestyle considerations such as diet or physical activity.
Plans and Procedures
The clinical trial is a **randomized**, single-blind, placebo-controlled study designed to evaluate the effect of **siplizumab** on beta-cell function in adults with new onset type 1 diabetes. The trial is set to last for 12 months, with the primary objective being to assess the change in mean 4-hour stimulated C-peptide area under the curve (AUC) following a mixed-meal tolerance test (MMTT) at week 52 compared to placebo. Participants will be randomly assigned to receive either siplizumab or a placebo, with the treatment administered via intravenous, subcutaneous, or intramuscular routes.
The study will commence with a screening visit to confirm eligibility based on inclusion criteria such as age, diagnosis of type 1 diabetes within 100 days, and positive autoantibody status. Following successful screening, participants will be enrolled and randomized. The trial will include several follow-up visits to monitor safety and efficacy, with assessments including hemoglobin A1c levels, insulin usage, and incidence of hypoglycemic episodes. The end-of-study visit will occur at week 52, where final evaluations will be conducted to determine the primary and secondary endpoints.
Participant involvement is expected to last for the entire 12-month duration of the trial. However, conditions such as non-compliance with study protocols, adverse events, or withdrawal of consent may lead to early termination from the study. Throughout the trial, participants will be required to adhere to strict glycemic control guidelines and use continuous glucose monitoring (CGM) devices. The trial aims to provide valuable insights into the potential benefits of siplizumab in preserving beta-cell function in individuals with new onset type 1 diabetes.
Treatment
The clinical trial involves the administration of **Siplizumab**, a solution for injection/infusion, as the experimental medication. Siplizumab is administered intravenously, subcutaneously, or intramuscularly, with a maximum daily dose of 0.48 mg/kg and a total maximum dose of 6.24 mg/kg over a 12-month period. The pharmaceutical form is a solution for injection/infusion, and the active substance is derived from a protein of other origin. The trial aims to assess the effect of Siplizumab on beta-cell function in adults recently diagnosed with type 1 diabetes.
**Cetirizine Dihydrochloride** is used as an auxiliary treatment in the study. It is provided in the form of film-coated tablets, with each tablet containing 10 mg of the active substance. The route of administration is oral, and the maximum daily dose is 10 mg. Cetirizine Dihydrochloride is a chemical substance and is not a pediatric formulation. The product is manufactured by GENERICS [UK] LIMITED.
**Paracetamol** is also included as an auxiliary treatment. It is available as 500 mg film-coated tablets, administered orally. The maximum daily dose is 1000 mg. Paracetamol is a chemical substance, and the product is manufactured by HALEON IRELAND LIMITED. It is not a pediatric formulation and serves as a standard-of-care therapy in the trial.
**0.9% Normal Saline** is utilized as a placebo in the study. It is administered intravenously over a 12-month period. The saline solution does not contain any active pharmaceutical ingredient and serves as a control to compare the effects of the experimental medication. The use of normal saline is standard in clinical trials to ensure blinding and to provide a baseline for evaluating the efficacy of the experimental treatment.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the change from baseline in mean 4-hour stimulated **C-Peptide** area under the curve (AUC) following a mixed-meal tolerance test (MMTT), compared to placebo at week 52. This measurement will provide insight into the effect of siplizumab on beta-cell function in adults recently diagnosed with type 1 diabetes.
Secondary endpoints include a variety of parameters: changes from baseline in hemoglobin A1c (HbA1c) levels, exogenous insulin usage, and the incidence and severity of hypoglycemic episodes over time. Additionally, partial remission will be measured by insulin dose-adjusted HbA1c, and changes in fasting and postprandial blood glucose concentrations will be assessed by treatment arm. The incidence and severity of ketoacidosis, as well as CGM-derived Ambulatory Glucose Profiles (AGPs), will also be evaluated. Further assessments include 4-hour and 2-hour MMTT C-peptide AUC, peak concentration, and the percentage of subjects with C-peptide levels ≥0.2 pmol/mL.
Safety and tolerability will be monitored through reported adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs), graded per CTCAE criteria. The incidence, frequency, and severity of infection-related AEs/SAEs will also be recorded. Serial measurements of serum siplizumab concentrations, total lymphocyte counts, and T-cell subsets over time will be conducted to further understand the pharmacokinetics and pharmacodynamics of the treatment.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Able to understand the study requirements and provide written informed consent before any study assessment is performed.
- Male or female between 18 to 45 years of age.
- A diagnosis of T1D by a qualified healthcare provider based on ADA guidelines ≤ 100 days of randomization.
- Positive for at least one diabetes-related autoantibody against: Glutamate decarboxylase (GAD-65), Insulin, if obtained prior and up to 10 days of the onset of exogenous insulin therapy, Insulinoma antigen-2 (IA-2), Zinc transporter-8 (ZnT8), or Islet cell autoantibodies against cytoplasmic proteins in the beta cell (ICA).
- Peak stimulated C-peptide level >0.2 pmol/mL (200 pmol/L) following a two-hour mixed-meal tolerance test (MMTT) during Screening (Visit 1).
- Agreement to follow local, regional, or national guidelines for strict glycemic control with targets of HbA1c ≤ 53 mmol/mol (≤ 7.0%).
- Agreement to use CGM from screening until the end of the study/Week 52
- Up to date immunization status or agreement to receive routine immunizations according to current country and/or regional guidelines and agree to comply with the guidelines for immunosuppressed individuals and those with chronic disease prior to randomization and receipt of study drug.
Exclusion Criteria
- Inability or unwillingness to provide written informed consent or comply with the study protocol.
- History of and/or suspected intolerance, hypersensitivity, severe reactions, or anaphylaxis to human/humanized monoclonal antibodies or any components of the formulation of siplizumab or its excipients.
- History of significant allergy (e.g., anaphylaxis) to milk or soy proteins.
- History of recent [within 3 Months of Screening (Visit 1)] or ongoing serious uncontrolled bacterial, viral, fungal, or other opportunistic infections, including: • Human immunodeficiency virus (HIV) • Current or prior infection with hepatitis B (HBV), as indicated by positive HBsAg or positive HBcAb • Current or prior hepatitis C (HCV), unless treated with anti-viral therapy with achievement of a sustained virologic response (undetectable viral load (VL) 12 weeks after cessation of therapy) • Positive Interferon Gamma Release Assay (IGRA) TB test, e.g., Quantiferon-TB Gold or Quantiferon-TB Gold Plus tests • Active infection with EBV as defined by EBV viral load ≥ 10,000 copies per 106 PBMCs or ≥ 2,000 copies per mL of whole blood • Active infection with Cytomegalovirus (CMV) as defined by CMV viral load ≥ 10,000 IU or copies per mL of whole blood or plasma
- Any of the following laboratory abnormalities at Screening (Visit 1). Abnormal screening values may be confirmed by a repeat test prior to randomization: • White blood count (WBC) < 3 x 10^9/L • Absolute Lymphocyte Count (ALC) < 800 cells/µL • Platelet count <150 x 10^9/L • Hemoglobin < 100 g/L • ALT ≥ 2x upper limit of normal (ULN) • AST ≥ 2x ULN
- Current or prior (within 6 months) treatment that is known to alter the natural history of T1D or immunologic status, including high-dose inhaled, extensive topical or systemic glucocorticoids.
- Active participation in an investigational drug trial within the last six weeks prior to screening.
- Current or prior (within 14 days of Visit 1 MMTT) use of any medication known to influence glucose tolerance (e.g., atypical antipsychotics, diphenylhydantoin, thiazide, or other potassium-depleting diuretics, β-adrenergic blockers, niacin).
- Current or prior (within the last 28 days of Visit 1 MMTT) use of metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, DPP-IV inhibitors or amylin.
- Previous or current diagnosis of malignancy, except adequately treated cervical carcinoma in situ and adequately treated non-metastatic basal and squamous cell carcinoma.
- History of bone marrow transplantation (BMT) / stem cell transplantation or solid organ transplantation.
- History or diagnoses of other autoimmune disease, including disease associated with lymphopenia, with the exception of stable thyroid or celiac disease.
- History of significant cardiovascular disease (including history of myocardial infarction, angina, use of anti-anginal medicines (e.g., nitroglycerin), or abnormal stress test).
- Vaccination with a live attenuated vaccine (e.g., varicella, measles, mumps, rubella, cold-attenuated intranasal influenza vaccine, bacillus Calmette- Guérin, and smallpox) within 28 days of dosing (Day 0).
- Past or current medical problems or findings from physical examination or laboratory testing, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant’s ability to comply with study requirements or that may affect the quality or interpretation of the data obtained from the study.
- Current diagnosed mental illness (e.g., severe depression), current diagnosed or self-reported drug, or alcohol abuse that, in the opinion of the investigator, would interfere with the participant’s ability to comply with study requirements.
- Women who are pregnant, lactating, or planning on pregnancy during the study.
- Women of child-bearing potential who are unwilling to use a medically acceptable form of contraception until study Week 52. Contraception is required for 14 days prior to randomization. Highly effective contraception methods include: • Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. • Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject. • Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example, hormone vaginal ring or transdermal hormone contraception. • Placement of long-acting reversible contraceptives or intrauterine device or intrauterine system. In case of use of oral contraception women should have been stable on the same brand (or generic equivalent) for a minimum of 3 months before taking study treatment. Women are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to screening. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of childbearing potential.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 Oct 2022 | 12 |
 Italy | Not Recruiting | 01 Oct 2022 | 15 |
 Spain | Not Recruiting | 01 Oct 2022 | 20 |
 Sweden | Not Recruiting | 01 Oct 2022 | 66 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Cetirizin Mylan 10 mg film-coated tablets | Other | FILM-COATED TABLETS | ORAL | 10 | 1 | PRD597552 |
Paracetamol 500 mg Film Coated Tablets | Other | FILM COATED TABLETS | ORAL | 1000 | 1 | PRD8757963 |
0,9% normal saline | Placebo | N/A | INTRAVENOUS | — | 12 | N/A |