FrexalimAB in Preservation of Endogenous insULIN Secretion Compared to Placebo in adUlts and Adolescents on Top of inSulin Therapy (FABULINUS)

Study Overview
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Brief Summary
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This is a randomized, parallel group, double-blind Phase 2 study that consists of 2 parts. In Part A the safety of the highest dose-level of frexalimab in adults (age range 18-35 y.o.) will be established. In Part B, a dose-finding study (adolescents and young adults, 12-21 y.o.) evaluating the safety and efficacy of 3 age-adjusted dose-levels of frexalimab in comparison with placebo in participants with newly diagnosed T1D on insulin treatment. The purpose of this study is to determine safety and efficacy of different dose-levels of frexalimab, by assessment of preservation of endogenous insulin secretion in participants with newly diagnosed T1D aged 12 to 21 years compared with placebo on top of standard insulin therapy, and to determine the dose-response relationship and minimal efficacious dose in Part B. Study details include: - Screening period: at least 3 weeks and up to 5 weeks (Up to 11 days may be required to get investigational medicinal product [IMP] on site. Enrollment date of the participant must take into consideration this constraint.) - Double-blind treatment period (104 weeks): -- Main treatment period: 52 weeks -- Blinded extension: 52 weeks - Safety follow-up: 26 weeks (not applicable for participants entering the open-label study) The treatment duration will be up to 104 weeks, the total study duration will be up to 135 weeks.

Official Title
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A 52-week Randomized, Double-blind, Placebo-controlled, Multi-center Phase 2b Study With a 52-week Blinded Extension Assessing Safety and Efficacy of Frexalimab, a CD40L-antagonist Monoclonal Antibody, for Preservation of Pancreatic β-cell Function in Adults and Adolescents With Newly Diagnosed Type 1 Diabetes on Insulin Therapy

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Drug: Frexalimab
* Drug: Placebo
* Drug: Insulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants who meet the criteria of T1D according to American Diabetes Association Initiated exogenous insulin replacement therapy not longer than 90 days prior to screening visit at which random C-peptide will be assessed (V1). Receiving at least one of the following T1D standard of care (SOC), insulin hormone replacement therapy one or multiple daily injections (MDI) of basal insulin, prandial insulin and/or premixed insulin, or continuous subcutaneous insulin infusion (CSII) Participants must be positive for at least 1 of the following T1D autoantibodies confirmed by medical history and/or obtained at study screening: Glutamic acid decarboxylase (GAD-65) Insulinoma Antigen-2 (IA-2) Zinc-transporter 8 (ZnT8) or Insulin (if obtained not later than 10 days after exogenous insulin therapy initiation) Have random C-peptide levels ≥ 0.2 nmol/L determined at screening. Be vaccinated according to the local vaccination schedule. Any vaccinations should take place at least 28 days prior to randomization for non-live vaccines and at least 3 months prior to randomization for live vaccines. Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies Exclusion Criteria: Serious systemic viral, bacterial or fungal infection (eg, pneumonia, pyelonephritis), infection requiring hospitalization or IV antibiotics or significant chronic viral (including history of recurrent or active herpes zoster, acute or active cytomegalovirus (CMV), Epstein-Barr Virus (EBV) as determined at screening), bacterial, or fungal infection (eg, osteomyelitis) 30 days before and during screening. Participants with a history of invasive opportunistic infections, such as, but not limited to histoplasmosis, listeriosis, coccidioidomycosis, candidiasis, pneumocystis jirovecii, and aspergillosis, regardless of resolution. Evidence of active or latent tuberculosis (TB) as documented by medical history and examination, chest X-rays (posterior anterior and lateral), and/or TB testing. Blood testing (eg, QuantiFERON® TB Gold test) is strongly preferred; if not available, any local approved TB test is allowed. Evidence of any clinically significant, severe or unstable, acute or chronically progressive, uncontrolled infection, medical or surgical condition (eg, but not limited to, cerebral, cardiac, pulmonary, renal, hepatic, gastrointestinal, neurologic, or any known immune deficiency), or any condition that may affect participant safety in the judgment of the Investigator (including vaccinations which are not updated based on local regulation). History or current hypogammaglobulinemia. History of a systemic hypersensitivity reaction or significant allergies, other than localized injection site reaction, to any humanized mAb. Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear IgA dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis). Has other autoimmune diseases (eg, rheumatoid arthritis [RA], polyarticular juvenile idiopathic arthritis [pJIA], psoriatic arthritis [PsA], ankylosing spondylitis [AS], MS, SLE), except autoimmune thyroiditis with controlled function of thyroid gland and celiac disease (at discretion of investigator). History, clinical evidence, suspicion or significant risk for thromboembolic events, as well as myocardial infarction, stroke, antiphospholipid syndrome, other prothrombotic disorders and/or participants requiring antithrombotic treatment. Diabetes of forms other than autoimmune T1D that include but is not limited to genetic forms of diabetes, maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of the adult (LADA), secondary to medications or surgery, type 2 diabetes by judgement of the investigator. History of malignancy of any organ system, treated or untreated, within 5 years of screening, regardless of whether there is evidence of local recurrence or metastases. Systemic corticosteroids (duration &gt;7 days), adrenocorticotropic hormone 1 month prior to screening. Any IV, IM or SC administered biologic treatments, < 3 months or < than 5 half-lives (whichever is longer), prior to randomization. Any live (attenuated or viral-vector) vaccine (including but not limited to varicella zoster, oral polio, nasal influenza, rabies) within 3 months prior to randomization. Any non-live (inactivated, mRNA, recombinant, conjugate, toxoid) vaccine administered less than 28 days prior to randomization. Other medications not compatible or interfering with IMP at discretion of investigator. Any immunosuppressive therapy within 12 weeks prior to randomization. Course of Thymoglobulin®, teplizumab or other immunomodulatory treatments at any time. Any glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose co-transporter-2 and 1 (SGLT2/1) inhibitor and verapamil within 2 weeks prior to screening. Abnormal laboratory test(s) at screening. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 35 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Frexalimab Dose 1<br> | Drug: Frexalimab<br>* Intravenous (IV) Infusion at Day 1 and subcutaneous (SC) Injection from W2 to W102<br>Drug: Insulin<br>* SC injection, dose and frequency will be established and/or adjusted by investigator<br>|
| Experimental: Frexalimab Dose 2<br> | Drug: Frexalimab<br>* Intravenous (IV) Infusion at Day 1 and subcutaneous (SC) Injection from W2 to W102<br>Drug: Insulin<br>* SC injection, dose and frequency will be established and/or adjusted by investigator<br>|
| Experimental: Frexalimab Dose 3<br> | Drug: Frexalimab<br>* Intravenous (IV) Infusion at Day 1 and subcutaneous (SC) Injection from W2 to W102<br>Drug: Insulin<br>* SC injection, dose and frequency will be established and/or adjusted by investigator<br>|
| Placebo Comparator: Placebo<br>Matching Placebo | Drug: Placebo<br>* IV Infusion at Day 1 and SC Injection from W2 to W102<br>Drug: Insulin<br>* SC injection, dose and frequency will be established and/or adjusted by investigator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to W52 in mean 2h mixed meal tolerance test (MMTT) stimulated C-peptide concentration | mixed meal tolerance test (MMTT) stimulated C-peptide concentration is to be calculated from AUC | Baseline to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time in range (70-180 mg/dL blood glucose) at W52 and W104 |  | At Week 52 and Week 104 | 
| Proportion of participants who remain C-peptide positive (mean 2h MMTT stimulated C-peptide concentration ≥0.2 nmol/L) at W52 and W104 | mixed meal tolerance test (MMTT) stimulated C-peptide concentration is to be calculated from AUC | At Week 52 and Week 104 | 
| Proportion of participants with reduction from baseline to W52 and W104 of less than 10% in mean 2h MMTT stimulated C-peptide concentration | mixed meal tolerance test (MMTT) stimulated C-peptide concentration is to be calculated from AUC | From baseline to Week 52 and Week 104 | 
| Proportion of participants with partial remission at W52 and W104 (defined as insulin dose-adjusted HbA1c score ≤9.0, where it is calculated as HbA1c [%] + 4x insulin dose [IU/kg/day]) |  | At Week 52 and Week 104 | 
| Change from baseline to W52 and W104 in insulin dose [IU/kg/day] |  | From baseline to Week 52 and Week 104 | 
| HbA1c level and its change from baseline at W52 and W104 |  | From baseline to Week 52 and Week 104 | 
| Proportion of participants with HbA1c ≤6.5% and requiring no injections of exogenous insulin at W52 and W104 |  | At Week 52 and Week 104 | 
| Proportion of participants with HbA1c ≤6.5% and requiring ≤0.25 IU of insulin at W52 and W104 |  | At Week 52 and Week 104 | 
| Proportion of participants with HbA1c <7% at W52 and W104 |  | At Week 52 and Week 104 | 
| Incidence of treatment emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events of special interest (AESIs) and TEAEs leading to treatment discontinuation |  | Until Week 130 | 
| Number of participants with at least one hypoglycemic event |  | Until Week 130 | 
| Number of participants with at least one hyperglycemic episode |  | Until Week 130 | 
| Number of participants with at least one diabetic ketoacidosis (DKA) event |  | Until Week 130 | 
| Number of participants with clinically significant changes in vital signs, electrocardiogram (ECG), and/or laboratory evaluation |  | Until Week 130 | 
| Frexalimab plasma concentrations over time |  | Until Week 104 | 
| Incidence of anti-drug antibodies (ADAs) over time |  | Until Week 130 | 
| Change from baseline to W52 and W104 in PedsQL Diabetes Symptoms domain score (all participants) |  | From baseline to Week 52 and Week 104 | 
| Change from baseline to W52 and W104 in Pediatric Quality of Life (PedsQL) Diabetes Management domain score (all participants) |  | From baseline to Week 52 and Week 104 | 
| Change from baseline to W52 and W104 in Problem Areas In Diabetes (PAID) total score (all participants) |  | From baseline to Week 52 and Week 104 | 
| Change from baseline to W52 and W104 in Diabetes Treatment Satisfaction Questionnaires (DTSQs) total and item scores (all participants) |  | From baseline to Week 52 and Week 104 | 
| Change from baseline to W52 and W104 in PAID immediate and theoretical domain scores (caregivers of all participants 12-17 y.o.) |  | From baseline to Week 52 and Week 104 | 
| Change from baseline to W52 and W104 in DTSQs Total and item scores (caregivers of all participants 12-17 y.o.) |  | From baseline to Week 52 and Week 104 |