Frexalimab in Preservation of Endogenous Insulin Secretion Compared to Placebo in Adults, Adolescents and Children on Top of Insulin Therapy (FABULINUS)

Phase 2Active Not RecruitingNCT06111586

Sanofi197 enrolled

Overview

This is a randomized, parallel group, double-blind Phase 2 study with a blinded extension evaluating the safety and efficacy of 3 dose levels of frexalimab in comparison with placebo in participants with newly diagnosed T1D on insulin treatment. Study details include: Screening period: at least 3 weeks and up to 5 weeks. Enrollment date of the participant must take into consideration this constraint) Double-blind treatment period (104 weeks for Part A and Part B; 52 weeks for Part C): Main treatment period: 52 weeks for Parts A and B, 26 weeks for Part C Blinded extension: 52 weeks (for Part A and Part B, 26 weeks for Part C) Optional OLE period: 104 weeks for all parts Safety follow-up: 26 weeks The treatment duration will be up to 104 weeks for Part A and Part B or 52 weeks for Part C, the total study duration will be up to 135 weeks for Part A and Part B or 83 weeks for Part C. If participants enter the OLE period, the treatment duration will be up to 208 weeks for Part A and Part B or 156 weeks for Part C, and the total study duration will be 240 weeks approximately for Part A and Part B or 188 weeks for Part C.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

197

Conditions

Type 1 Diabetes Mellitus

Interventions

Eligibility

Sex: ALLMin age: 6 YearsMax age: 35 Years

Medical Language ↔ Plain English

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 visit. * 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 * Participants body weight at screening must be at least 20kg. 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, acquired or inherited bone/skeletal disorders including repeated bone fractures for unknown reason, juvenile osteoporosis, osteogenesis imperfecta, osteochondropathies, 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), that require treatment with biologic drugs (mono or polyclonal antibodies) or systemic corticosteroid therapy (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 \> 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 drugs that may be used for treatment of T1D and type 2 diabetes other than insulin including but not limited to metformin, 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.

Outcomes

Primary Outcomes

Change in mean 2h mixed meal tolerance test (MMTT) stimulated C-peptide concentration, calculated from AUC from baseline to W52 for Part B (12-21 y.o.)

mixed meal tolerance test (MMTT) stimulated C-peptide concentration is to be calculated from AUC

Time frame: Baseline to Week 52

Change in mean 2h mixed meal tolerance test (MMTT) stimulated C-peptide concentration, calculated from AUC from baseline to W26 for Part C (6-11 y.o.)

mixed meal tolerance test (MMTT) stimulated C-peptide concentration is to be calculated from AUC

Time frame: Baseline to Week 26

Secondary Outcomes

Time in range (70-180 mg/dL), assessed by CGM at W52 and W104(part B)

Time frame: 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(part B)

mixed meal tolerance test (MMTT) stimulated C-peptide concentration is to be calculated from AUC

Time frame: 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(part B)

mixed meal tolerance test (MMTT) stimulated C-peptide concentration is to be calculated from AUC

Time frame: From baseline to Week 52 and Week 104

Proportion of participants with partial remission at W52 and W104 (defined as IDAA1c score ≤9.0, where it is calculated as HbA1c [%] + 4x insulin dose [IU/kg/day])(part B)

Time frame: At Week 52 and Week 104

Change from baseline to W52 and W104 in insulin dose [IU/kg/day](part B)

Time frame: From baseline to Week 52 and Week 104

HbA1c level at Week 52 and Week 104(part B)

Time frame: at Week 52 and Week 104

Proportion of participants with HbA1c ≤6.5% and requiring no injections of exogenous insulin at W52 and W104(part B)

Time frame: At Week 52 and Week 104

Proportion of participants with HbA1c ≤6.5% and requiring ≤0.25 IU of insulin at W52 and W104(part B)

Time frame: At Week 52 and Week 104

Proportion of participants with HbA1c <7% at W52 and W104(part B)

Time frame: 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

Time frame: Until Week 130

Number of participants with at least one hypoglycemic event

Time frame: Until Week 130

Number of participants with at least one hyperglycemic episode

Time frame: Until Week 130

Number of participants with at least one diabetic ketoacidosis (DKA) event

Time frame: Until Week 130

Number of participants with clinically significant changes in vital signs, electrocardiogram (ECG), and/or laboratory evaluation

Time frame: Until Week 130

Height and growth rate over time (for participants <18 y.o. at screening)

Time frame: Until Week 130

Frexalimab plasma concentrations over time

Time frame: Until Week 104

Incidence of anti-drug antibodies (ADAs) over time

Time frame: Until Week 130

Change from baseline to W52 and W104 in PedsQL Diabetes Symptoms domain score (all participants≥8 y.o.) (part B)

Time frame: 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≥8 y.o.) (part B)

Time frame: 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)(part B)

Time frame: 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)(part B)

Time frame: 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.)(part B)

Time frame: 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.)(part B)

Time frame: From baseline to Week 52 and Week 104

Time in tight range (TITR, 70 - 140 mg/dL), assessed by CGM at W52 and W104(part B)

Time frame: Time in tight range (TITR, 70 - 140 mg/dL), assessed by CGM at W52 and W104

Change from baseline to W104 in mean 2h mixed meal tolerance test (MMTT) stimulated C-peptide concentration, calculated from AUC(part B)

Time frame: From baseline to Week 104

Change from baseline to W52 and W104 in IDAA1c score(part B)

Time frame: From baseline to Week 52

Time in range (70-180 mg/dL), assessed by study CGM at W26 and W52(part C)

Time frame: At week 26 and week 52

Time in tight range (TITR, 70 - 140 mg/dL), assessed by study CGM at W26 and W52(part C)

Time frame: At Week 26 and Week 52

Change from baseline to W52 in mean 2h mixed meal tolerance test (MMTT) stimulated C-peptide concentration, calculated from AUC(Part C)

Time frame: From baseline to week 52

Proportion of participants who remain C-peptide positive (mean 2h MMTT stimulated C-peptide concentration ≥0.2 nmol/L) at W26 and W52(part C)

Time frame: At Week 26 and Week 52

Proportion of participants with reduction from baseline to W26 and W52 of less than 10% in mean 2h MMTT stimulated C-peptide concentration(Part C)

Time frame: From baseline to week 26 and week 52

Proportion of participants with partial remission at W26 and W52 (defined as IDAA1c score ≤9.0, where it is calculated as HbA1c [%] + 4x insulin dose [IU/kg/day]) (part C)

Time frame: At week 26 and week 52

Change from baseline to W26 and W52 in IDAA1c score(part C)

Time frame: From baseline to Week 26 and Week 52

Change from baseline to W26 and W52 in insulin dose [IU/kg/day] (part C)

Time frame: From baseline to Week 26 and Week 52

HbA1c level change from baseline to Week 52 and Week 104(part B)

Time frame: From baseline to Week 52 and Week 104

Proportion of participants with HbA1c ≤6.5% and requiring no injections of exogenous insulin at W26 and W52(part C)

Time frame: At week 26 and week 52

Proportion of participants with HbA1c ≤6.5% and requiring ≤0.25 IU of insulin at W26 and W52(part C)

Time frame: At week 26 and week 52

Proportion of participants with HbA1c <7% at W26 and W52(part C)

Time frame: At week 26 and week 52

Change from baseline to W26 and W52 in PedsQL Diabetes Symptoms domain score (all participants≥8 y.o.) (part C)

Time frame: From baseline to Week 26 and Week 52

Change from baseline to W26 and W52 in [BB7.1][LS7.2]PedsQL Diabetes Management domain score (all participants≥8 y.o.) (part C)

Time frame: From baseline to Week 26 and Week 52

Change from baseline to W26 and W52 in Problem Areas In Diabetes (PAID) total score (all participants)(part C)

Time frame: From baseline to Week 26 and Week 52

Change in PedsQL Diabetes Symptoms and Management domains scores (caregivers of participants 6 -7 y.o.) from baseline to W26 and W52 (Part C)

Time frame: From baseline to Week 26 and Week 52

Change from baseline to W26 and W52 in PAID immediate and theoretical domain scores (caregivers of all participants 6-17 y.o.)(part C)

Time frame: From baseline to Week 26 and Week 52

Change from baseline to W26 and W52 [BB8.1]in DTSQs Total and item scores (caregivers of all participants 6-17 y.o.)(part C)

Time frame: From baseline to Week 26 and Week 52

HbA1c level at W26 and W52(part C)

Time frame: at Week 26 and Week 52

HbA1c level change from baseline to W26 and W52(part C)

Time frame: From baseline to Week 26 and Week 52

Frexalimab in Preservation of Endogenous Insulin Secretion Compared to Placebo in Adults, Adolescents and Children on Top of Insulin Therapy (FABULINUS)

Overview

Conditions

Interventions

Eligibility

Locations (79)

Outcomes

Primary Outcomes

Secondary Outcomes