Multiple Dose Study to Evaluate the Efficacy, Safety and Pharmacodynamics of REMD-477 in Subjects With Type 1 Diabetes Mellitus

Study Overview
=================
Brief Summary
-----------------
This is a randomized, placebo-controlled, double-blind study to evaluate the efficacy, safety, and pharmacodynamics (PD) of multiple doses of REMD-477 in subjects who have Type 1 diabetes and are currently receiving insulin treatment. This study will determine whether REMD-477 can decrease daily insulin requirements and improve glycemic control after 12 weeks of treatment in subjects diagnosed with Type 1 diabetes with fasting C-peptide < 0.7 ng/mL at Screening. The study will be conducted at multiple sites in the United States. Approximately 150 subjects with type 1 diabetes on stable doses of insulin will be randomized in a 1:1:1 fashion into one of three treatment groups.

Official Title
-----------------
A Randomized, Placebo-controlled, Double-blind Study to Evaluate the Efficacy, Safety, and Pharmacodynamics of Multiple Doses of REMD-477 in Subjects With Type 1 Diabetes Mellitus

Conditions
-----------------
Type1 Diabetes Mellitus

Intervention / Treatment
-----------------
* Biological: REMD-477
* Biological: Placebo Comparator


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men and women between the ages of 18 and 65 years old, inclusive, at the time of screening; Females of non-child bearing potential must be ≥1 year post-menopausal (confirmed by a serum follicle-stimulating hormone (FSH) levels ≥ 40 IU/mL) or documented as being surgically sterile. Females of child bearing potential must agree to use two methods of contraception; Male subjects must be willing to use clinically acceptable method of contraception during the entire study; Body mass index between 18.5 and 32 kg/m2, inclusive, at screening; Diagnosed with Type 1 diabetes, based on clinical history or as defined by the current American Diabetes Association (ADA) criteria; HbA1c > 7% and < 10 % at screening; Fasting C-peptide < 0.7 ng/mL; Treatment with a stable insulin regimen for at least 8 weeks before screening with multiple daily insulin (MDI) injections or continue subcutaneous insulin infusion (CSII) Willing to use continuous CGM system (e.g. DexCom) throughout the study; Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 1.5x upper limit of normal (ULN) at screening; Able to provide written informed consent approved by an Institutional Review Board (IRB). Exclusion Criteria: History or evidence of clinically-significant disorder or condition that, in the opinion of the Investigator, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion; Significant organ system dysfunction (e.g., clinically significant pulmonary or cardiovascular disease, anemia [Hemoglobin < 10.0 g/dL], known hemoglobinopathies, and renal dysfunction [eGFR < 60 ml/min]); Any severe symptomatic hypoglycemic event associated with a seizure or requiring help from other people or medical facility in the past 6 months; Myocardial infarction, unstable angina, revascularization procedure, or cerebrovascular accident ≤12 weeks before screening; History of New York Heart Association Functional Classification III-IV cardiac disease; Current or recent (within 1 month of screening) use of diabetes medications other than insulin - subjects on an SGLT2 inhibitor should be discontinue the SGLT2 inhibitor during the Screening Period, at least 2 weeks prior to the start of the Lead-in Period; Use of steroids and/or other prescribed or over-the-counter medications that are known to affect the outcome measures in this study or known to influence glucose metabolism; Smokes > 10 cigarettes/day, and/or is unwilling to abstain from smoking during admission periods; Known sensitivity to mammalian-derived drug preparations, recombinant protein-based drugs or to humanized or human antibodies; History of illicit drug use or alcohol abuse within the last 6 months or a positive drug urine test result at screening; History of pancreatitis, pancreatic neuroendocrine tumors or multiple endocrine neoplasia (MEN) or family history of MEN; History of pheochromocytoma, or family history of familial pheochromocytoma; Known or suspected susceptibility to infectious disease (e.g. taking immunosuppressive agents or has a documented inherited or acquired immunodeficiency); Known history of positive for human immunodeficiency virus (HIV) antibodies, hepatitis B surface antigen (HbsAg), or hepatitis C antibodies (HepC Ab); Participation in an investigational drug or device trial within 30 days of screening or within 5 times the half-life of the investigational agent in the other clinical study, if known, whichever period is longer; Blood donor or blood loss > 500 mL within 30 days of Day 1; Women who are pregnant or lactating/breastfeeding; Unable or unwilling to follow the study protocol or who are non-compliant with screening appointments or study visits; Any other condition(s) that might reduce the chance of obtaining study data, or that might cause safety concerns, or that might compromise the ability to give truly informed consent Other inclusion and exclusion criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 35 mg REMD-477<br>Administered as a repeated subcutaneous (SC) doses in subjects with Type 1 Diabetes | Biological: REMD-477<br>* Administered as repeated SC doses in subjects with Type 1 Diabetes<br>|
| Experimental: 70 mg REMD-477<br>Administered as a repeated SC doses in subjects with Type 1 Diabetes | Biological: REMD-477<br>* Administered as repeated SC doses in subjects with Type 1 Diabetes<br>|
| Placebo Comparator: Matching placebo<br>Administered as a repeated SC doses in subjects with Type 1 Diabetes | Biological: Placebo Comparator<br>* Administered as a repeated SC doses in subjects with Type 1 Diabetes<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Average Daily Total Insulin Use | Change from Baseline in average daily total insulin use at Week 12 | Baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline Difference in AUC Glucose Concentrations Following Mixed Meal Tolerance Test (MMTT) - Part A Only | Difference from baseline at Week 13 in AUC glucose concentration following the Mixed Meal Tolerance Test (MMTT) after repeated doses of REMD-477. | Baseline and 13 weeks; AUC glucose timepoints: 10 minutes prior and just before (time ) initiating the mixed-meal ingestion and at 30, 60 and 120 minutes after the mixed meal ingestion. | 
| Continuous Glucose Monitoring (CGM) - Change in Average Daily 24-hour Glucose Concentration at Week 12 | Change from baseline at Week 12 in average daily 24-h blood glucose as assessed by CGM after repeated doses of REMD-477. | Baseline and 12 weeks | 
| Seven-Point Glucose Profile - Change in Average 24-h Glucose Concentrations | Change from baseline at Week 12 in the average daily 24-h blood glucose concentration as assessed by seven-point glucose profile after repeated doses of REMD-477. The 7-point blood glucose profiles includes measuring glucose via finger stick, at the following times of the day: before each meal, 2 hours after each meal, and at bedtime. The 7-point glucose profiles were obtained for 3 consecutive days before (Day 1) and for 3 consecutive days during week 12. | Baseline and 12 weeks | 
| Summary of the Product of Average Daily 24-h Glucose Ratio and Daily Insulin Use Ratio (Day 78 [Week 12]/Baseline) | The product of the ratio of average glucose (Week 12/Baseline) and ratio of average insulin use (Week 12/Baseline). | Baseline and week 12 | 
| Change in Hemoglobin A1c From Baseline at Week 13 | Change in Hemoglobin A1c from baseline at Week 13, after repeated doses of REMD-477. | Baseline and 13 weeks | 
| Percentage of Subjects With HbA1c Reduction of ≥ 0.4% at Week 13 | Proportion (percentage) of subjects who achieve HbA1c reduction of ≥ 0.4%, after repeated doses of REMD-477 | Baseline and 13 weeks | 
| Change in C-peptide Adjusted AUC Following Mixed Meal Tolerance Test (MMTT) | Change from baseline at Week 13 in the C-peptide adjusted AUC following MMTT after repeated doses of REMD-477. | Baseline and 13 weeks; AUC C-peptide timepoints: 10 minutes prior and just before (time 0) initiating the mixed-meal ingestion and at 30, 60 and 120 minutes after the mixed meal ingestion. | 
| Change in Baseline Difference in Glucagon Adjusted AUC Following Mixed Meal Tolerance Test (MMTT) - Part A Only | Change from baseline at Week 13 in glucagon adjusted AUC after MMTT challenge, after repeated doses of REMD-477. | Baseline and 13 weeks; AUC glucagon timepoints: 10 minutes prior and just before (time ) initiating the mixed-meal ingestion and at 30, 60 and 120 minutes after the mixed meal ingestion. | 
| Proportion of Subjects With Positive Anti-REMD-477 Antibodies | Proportion of subjects positive for anti-REMD-477 antibody formation. | Day 1 (pre-dose), Day 85 (Week 13) and Day 162 (Week 24) | 
| Summary of REMD-477 Plasma Concentrations | REMD-477 serum-concentration after repeated doses of REMD-477. | Baseline (Day 1 pre-dose) and Weeks 2, 5, 9, 13 and 16. | 
| Change in Hemoglobin A1c at Week 13 in Subjects With Baseline HbA1c ≥7.5% | Change in Hemoglobin A1c from baseline at Week 13, after repeated doses of REMD-477. | Baseline and 13 weeks | 
| Proportion of Subjects With Targeted Hemoglobin A1C (HbA1c) of ≤ 7.0% at Week 13 | Proportion (percentage) of subjects who achieve target HbA1c reduction of ≤ 7.0% at Week 13, after repeated doses of REMD-477 | Baseline and 13 weeks | 
| Continuous Glucose Monitoring (CGM) - Change in Percent Time Spent in Target Blood Glucose Range (70-180 mg/dL) at Week 12 | Change from baseline at Week 12 in percent time spent in target blood glucose range (70-180 mg/dL) after repeated doses of REMD-477. | Baseline and 12 weeks | 
| Continuous Glucose Monitoring (CGM) - Change in Percent Time Spent in Hyperglycemia (Blood Glucose Range >180 mg/dL) at Week 12 | Change from baseline at Week 12 in percent time spent in Hyperglycemia (Blood Glucose Range >180 mg/dL) after repeated doses of REMD-477. | Baseline and 12 weeks | 
| Continuous Glucose Monitoring (CGM) - Change in Percent Time Spent in Hypoglycemia (Blood Glucose Range <70 mg/dL) at Week 12 | Change from baseline at Week 12 in percent time spent in Hypoglycemia (Blood Glucose Range <70 mg/dL) after repeated doses of REMD-477. | Baseline and 12 weeks | 
| Continuous Glucose Monitoring (CGM) - Change in Percent Time Spent in Hypoglycemia (Blood Glucose Range <55 mg/dL) at Week 12 | Change from baseline at Week 12 in percent time spent in Hypoglycemia (Blood Glucose Range <55 mg/dL) after repeated doses of REMD-477. | Baseline and 12 weeks |