Multiple Ascending Dose Study of MHS552 in Adults With Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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The purpose of this two-part multiple ascending dose study is to evaluate the safety and tolerability of multiple doses of MHS552 in adults with type 1 diabetes mellitus. Participants will be treated for 4 or 12 weeks followed by an 8 week follow-up period

Detailed Description
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This is a Phase 1b, randomized, investigator and participant blinded, placebo controlled, multiple ascending dose (MAD) study in adults with type 1 diabetes mellitus (adults aged 18-45 years, inclusive, diagnosed with T1DM within 5 years at the time of screening). This MAD study will be conducted in two sequential parts, Part A and Part B. In Part A, after an screening period of up to 28 days, participants will be randomized (in a 3:1 ratio) to MHS552 or placebo administered subcutaneously (s.c.) weekly for four weeks of treatment. Part A will consist of up to 3 cohorts (low, medium, high dose), with approximately 4-8 participants completing each cohort (total of approximately 16 participants). Participants will be followed-up during 8 weeks post last dose. The total duration of study participation of Part A is approximately 106 Days. In Part B, after a screening period of up to 28 days, approximately 12 participants will be randomized (in a 2:1 ratio) to MHS552 or placebo administered s.c. weekly for 12 weeks of treatment (dose level 4). Participants will be followed-up during 8 weeks post last dose with End of Study (EoS) visit at Day 134. The total duration of study participation of Part B is approximately 162 Days.

Official Title
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A Randomized, Investigator and Participant Blinded, Placebo Controlled, Multiple Ascending Dose, Two Part Design Study to Assess the Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Effects of MHS552 in Adults With Type 1 Diabetes Mellitus (T1DM)

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Drug: MHS552
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult men and women ages 18 to 45, inclusive, body weight between ≥40 to ≤150 kg, inclusive, with T1DM, a maximum of 5 years from T1DM diagnosis at screening. Evidence of one or more T1DM autoantibody(ies) including glutamic acid decarboxylase (anti GAD), protein tyrosine, phosphatase-like protein (anti-IA-2); zinc transporter 8 (anti-ZnT8); islet cell (cytoplasmic) (anti-ICA) Residual pancreatic β-cell function (fasting C-peptide >100 pmol/L [0.30 ng/mL] or random C peptide >200 pmol/L [0.60 ng/mL]) Exclusion Criteria: History of hypersensitivity to drugs of similar biological class, IL-2 protein analogues, or immunoglobulin (IgG1) proteins, hypersensitivity to any components of the study drug, or history of severe hypersensitivity reaction or anaphylaxis to biological agents, e.g. human monoclonal antibody. Use of other investigational drugs or use of immunosuppressive agents at the time of enrollment, or within 5 half-lives of enrollment, or until the expected PD effect has returned to baseline, whichever is longer; or longer if required by local regulations. Diabetes forms other than autoimmune type 1 such as maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of the adult (LADA), acquired diabetes (secondary to medications or surgery), type 2 diabetes by judgement of the investigator. Diabetic ketoacidosis within 2 weeks. Polyglandular auto-immune disease, including but not limited to: Addison's disease, pernicious anemia, celiac sprue and psoriasis. Treated, stable Hashimoto's thyroiditis is not exclusionary. History of capillary leak syndrome (CLS). Ongoing, and up to 2 weeks prior to screening, initiation of medications or change in dose of medications that may affect glucose control (e.g, systemic steroids, thiazides, beta blockers). Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Cohort 1 - MHS552 low dose<br>Participants will receive MHS552 low dose once weekly subcutaneously for 4 weeks | Drug: MHS552<br>* MHS552 will be administered once weekly as subcutaneous injection for 4 (Part A) or 12 weeks (Part B)<br>|
| Placebo Comparator: Part A: Cohort 1, 2, 3 - Placebo<br>Participants will receive placebo once weekly subcutaneously for 4 weeks | Drug: Placebo<br>* Placebo will be administered once weekly as subcutaneous injection for 4 (Part A) or 12 weeks (Part B)<br>|
| Experimental: Part A: Cohort 2 - MHS552 medium dose<br>Participants will receive MHS552 medium dose once weekly subcutaneously for 4 weeks | Drug: MHS552<br>* MHS552 will be administered once weekly as subcutaneous injection for 4 (Part A) or 12 weeks (Part B)<br>|
| Experimental: Part A: Cohort 3 - MHS552 high dose<br>Participants will receive MHS552 high dose once weekly subcutaneously for 4 weeks | Drug: MHS552<br>* MHS552 will be administered once weekly as subcutaneous injection for 4 (Part A) or 12 weeks (Part B)<br>|
| Experimental: Part B: MHS552<br>Participants will MHS552 (dose to be determined) once weekly subcutaneously for 12 weeks | Drug: MHS552<br>* MHS552 will be administered once weekly as subcutaneous injection for 4 (Part A) or 12 weeks (Part B)<br>|
| Placebo Comparator: Part B: Placebo<br>Participants will receive placebo once weekly subcutaneously for 12 weeks | Drug: Placebo<br>* Placebo will be administered once weekly as subcutaneous injection for 4 (Part A) or 12 weeks (Part B)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Adverse events (AEs) and Serious Adverse events (SAEs) | Numbers of participants with AEs and SAEs including vital signs, electrocardiograms (ECG) and laboratory results | Part A: up to 12 weeks; Part B: up to 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under Plasma Concentration-time Curve calculated to the end of a dosing interval (AUCtau) for MHS552 | Characterize the AUCtau profile following multiple doses of MHS552 | Part A: up to Day 78; Part B: up to Day 134 | 
| Maximum ObservBlood Concentrations (Cmax) for MHS552 | Characterize the Cmax profile following multiple doses of MHS552 | Part A: up to Day 78; Part B: up to Day 134 | 
| Time to Reach Maximum Blood Concentrations (Tmax) of MHS552 | Characterize the Tmax profile following multiple doses of MHS552 | Part A: up to Day 78; Part B: up to Day 134 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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type 1 diabetes mellitus, T1DM