Frexalimab in preservation of endogenous insulin secretion compared to placebo in adults, adolescents and children on top of Insulin therapy (FABULINUS)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Sanofi-Aventis Recherche & Developpement

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

2 Feb 2024 → ongoing

Decision date (initial)

2025-06-11

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Sanofi-Aventis Research & Development

External identifiers

EU CT number

2022-500531-36-00

WHO UTN

U1111-1275-9618

ClinicalTrials.gov

NCT06111586

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Others, Pharmacodynamic, Dose response, Pharmacokinetic, Safety

To demonstrate the efficacy of different doses of frexalimab in comparison with placebo and in addition to standard of care (SOC) on endogenous insulin secretion in participants with newly diagnosed T1D over a 52-week period aged 12-21 y.o. in Part B and 6-11 y.o. in Part C

Secondary objectives 5

1. To evaluate the efficacy of frexalimab in comparison to placebo and on top of SOC on glycemic control and endogenous insulin secretion in participants with newly diagnosed T1D aged 12-21 y.o. in Part B and 6- 11 y.o. in Part C
2. To evaluate the safety and tolerability of frexalimab versus placebo in all participants
3. To characterize pharmacokinetics (PK) of frexalimab in all participants
4. To evaluate the potential for immunogenicity of frexalimab in all participants
5. To assess the impact of frexalimab treatment on caregiver- and/or patient-reported clinical outcome measurements in all participants

Conditions and MedDRA coding

Type 1 diabetes mellitus

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002945-PIP03-23

Plan to share IPD

Yes

IPD plan description

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysys plan and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting can be found at: https://vivli.org

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Participants who meet the criteria of T1D according to American Diabetes Association
2. Initiated exogenous insulin replacement therapy not longer than 90 days prior to screening visit at which random C-peptide will be assessed (V1).
3. Receiving at least one of the following T1D standard of care (SOC), insulin hormone replacement therapy o one or multiple daily injections (MDI) of basal insulin, prandial insulin and/or premixed insulin, or o continuous subcutaneous insulin infusion (CSII)
4. Participants must be positive for at least 1 of the following T1D autoantibodies confirmed by medical history and/or obtained at study screening: o Glutamic acid decarboxylase (GAD-65) o Insulinoma Antigen-2 (IA-2) o Zinc-transporter 8 (ZnT8) or o Insulin (if obtained not later than 10 days after exogenous insulin therapy initiation)
5. Have random C-peptide levels ≥ 0.2 nmol/L determined at screening visit.
6. 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
7. Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
8. Participants body weight at screening must be at least 20 kg.

Exclusion criteria 19

1. 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.
2. 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.
3. 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.
4. 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).
5. History or current hypogammaglobulinemia.
6. 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).
7. 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).
8. 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.
9. 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.
10. 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
11. Systemic corticosteroids (duration >7 days), adrenocorticotropic hormone 1 month prior to screening.
12. Any IV, IM or SC administered biologic treatments, < 3 months or < than 5 half-lives (whichever is longer), prior to randomization.
13. 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.
14. Any non-live (inactivated, mRNA, recombinant, conjugate, toxoid) vaccine administered less than 28 days prior to randomization.
15. Other medications not compatible or interfering with IMP at discretion of investigator.
16. Any immunosuppressive therapy within 12 weeks prior to randomization
17. Course of Thymoglobulin®, teplizumab or other immunomodulatory treatments at any time.
18. 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.
19. Abnormal laboratory test(s) at screening.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 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.)
2. 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.)

Secondary endpoints 44

1. Time in range (70-180 mg/dL), assessed by study CGM at W52 and W104(part B)
2. Time in tight range (TITR, 70 – 140 mg/dL), assessed by study CGM at W52 and W104(part B)
3. Change from baseline to W104 in mean 2h mixed meal tolerance test (MMTT) stimulated C-peptide concentration, calculated from AUC(Part B)
4. 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)
5. 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)
6. 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)
7. Change from baseline to W52 and W104 in insulin dose [IU/kg/day] (part B)
8. Change from baseline to W52 and W104 in insulin dose [IU/kg/day](part B)
9. HbA1c level and its change from baseline at W52 and W104(part B)
10. Proportion of participants with HbA1c ≤6.5% and requiring no injections of exogenous insulin at W52 and W104(part B)
11. Proportion of participants with HbA1c ≤6.5% and requiring ≤0.25 IU of insulin at W52 and W104(part B)
12. Proportion of participants with HbA1c <7% at W52 and W104(part B)
13. Incidence of treatment emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events of special interest (AESIs) and TEAEs leading to treatment discontinuation
14. Number of participants with at least one hypoglycemic event
15. Number of participants with at least one hyperglycemic episode
16. Number of participants with at least one diabetic ketoacidosis (DKA) event
17. Number of participants with clinically significant changes in vital signs, electrocardiogram (ECG), and/or laboratory evaluation
18. Height and growth rate over time (for participants <18 y.o. at screening)
19. Frexalimab plasma concentrations over time and PK parameters
20. Incidence of anti-drug antibodies (ADAs) over time
21. Change from baseline to W52 and W104 in PedsQL Diabetes Symptoms domain score (all participants≥8 y.o.) (part B)
22. Change from baseline to W52 and W104 in Pediatric Quality of Life (PedsQL) Diabetes Management domain score (all participants≥8 y.o.) (part B)
23. Change from baseline to W52 and W104 in Problem Areas In Diabetes (PAID) total score (all participants)(part B)
24. Change from baseline to W52 and W104 in Diabetes Treatment Satisfaction Questionnaires (DTSQs) total and item scores (all participants)(part B)
25. Change from baseline to W52 and W104 in PAID immediate and theoretical domain scores (caregivers of all participants 6-17 y.o.)(part B)
26. Change from baseline to W52 and W104 in DTSQs Total and item scores (caregivers of all participants 6-17 y.o.)(part B)
27. Time in range (70-180 mg/dL), assessed by study CGM at W26 and W52(part C)
28. Time in tight range (TITR, 70 – 140 mg/dL), assessed by study CGM at W26 and W52(part C)
29. Change from baseline to W52 in mean 2h mixed meal tolerance test (MMTT) stimulated C-peptide concentration, calculated from AUC(Part C)
30. 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)
31. 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)
32. 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)
33. Change from baseline to W26 and W52 in IDAA1c score(part C)
34. Change from baseline to W26 and W52 in insulin dose [IU/kg/day] (part C)
35. HbA1c level and its change from baseline at W26 and W52(part C)
36. Proportion of participants with HbA1c ≤6.5% and requiring no injections of exogenous insulin at W26 and W52(part C)
37. Proportion of participants with HbA1c ≤6.5% and requiring ≤0.25 IU of insulin at W26 and W52(part C)
38. Proportion of participants with HbA1c <7% at W26 and W52(part C)
39. Change from baseline to W26 and W52 in PedsQL Diabetes Symptoms domain score (all participants≥8 y.o.) (part C)
40. Change from baseline to W26 and W52 in PedsQL Diabetes Management domain score (all participants≥8 y.o.) (part C)
41. Change from baseline to W26 and W52 in Problem Areas In Diabetes (PAID) total score (all participants)(part C)
42. Change in PedsQL Diabetes Symptoms and Management domains scores (caregivers of participants 6 -7 y.o.) from baseline to W26 and W52 (Part C)
43. Change from baseline to W26 and W52 in PAID immediate and theoretical domain scores (caregivers of all participants 6-17 y.o.)(part C)
44. Change from baseline to W26 and W52 in DTSQs Total and item scores (caregivers of all participants 6-17 y.o.)(part C)

Investigational products

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

Test 1

Placebo 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Sanofi-Aventis Recherche & Developpement

Sponsor organisation

Sanofi-Aventis Recherche & Developpement

Address

82 Avenue Raspail

City

Gentilly

Postcode

94250

Country

France

Scientific contact point

Organisation

Sanofi-Aventis Research & Development

Contact name

Clinical Sciences and Operations

Public contact point

Organisation

Sanofi-Aventis Research & Development

Contact name

Clinical Sciences and Operations

Third parties 10

Locations

13 EU/EEA countries · 62 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 473 files

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

Application history

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