Study to Assess PK, Safety and Tolerability in Patients With DM and CKD

Study Overview
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Brief Summary
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An open-label, phase IB, multi-center study evaluating DM199 in subjects with Type 1 Diabetes or Type 2 Diabetes and Stage 3 or 4 Chronic Kidney Disease. The primary objectives of this study are to evaluate safety, tolerability, and PK profile of DM199 in these subjects.

Detailed Description
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The study evaluates the safety, tolerability, and PK profile of DM199 in subjects with T1D or T2D and with Stage 3 or Stage 4 CKD. Additionally, this study evaluates urine concentrations of KLK1 pre and post dose. Cohort 1: Subjects with T1D or T2D and Stage 3 CKD will be administered one of three DM199 doses: 3.0 ug/kg or 5.0 ug/kg or 8.0 ug/kg single SC dose. Cohort 2: Subjects with T1D or T2D and Stage 4 CKD will be administered a single 3.0 µg/kg single SC dose. Secondary and exploratory study objectives include collection and analysis of vital signs, biomarkers, eGFR, blood glucose, and ECG's.

Official Title
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A Multi-Center Open-label Investigation to Assess the Pharmacokinetics, Safety and Tolerability of DM199 in Patients With Diabetes Mellitus and Chronic Kidney Disease

Conditions
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Chronic Kidney Disease, Chronic Kidney Disease, Stage 3 (Moderate), Chronic Kidney Disease, Stage 4 (Severe), Diabetes

Intervention / Treatment
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* Drug: DM199


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is willing and able to provide informed consent for study participation. Subject is ≥ 18 years of age. Subject has an established diagnosis of T1D or T2D as determined by medical evaluation at screen. Subjects A1c <9.8% Subject is clinically stable with respect to underlying renal impairment and diabetes, as assessed by the Investigator's medical evaluation. Subject has been diagnosed with Stage 3 CKD as defined by eGFR (MDRD) between 30 - <60 or Stage 4 as defined by eGFR <30 (not on dialysis) at screening. Subject has a body mass index (BMI) between 18 to 45 kg/m2 (inclusive). Exclusion Criteria: Subject has positive drug test for drugs of abuse and/or positive alcohol breath test at screening and Day 0. Subject is unable or unwilling to comply with protocol requirements, including assessments, tests, and follow-up visits. Subject has a history of significant allergic diathesis such as urticaria, angioedema, or anaphylaxis. Subject has had any live vaccination ≤ 3 months prior to enrollment or will require vaccination during the study. Subject must not be taking an ACEi medication for 5 half-lives prior to study drug administration and for 5 days post study drug administration. Subject is unwilling or unable to limit smoking to ≤ 10 cigarettes per day (or other products that contain nicotine limited to < 200 mg of nicotine/day) during the study participation period. Subject has a current malignancy or active malignancy ≤ 3 years prior to enrollment except basal cell or squamous cell carcinoma of the skin or in situ cervical cancer that has undergone potentially curative therapy and ≥ six months have elapsed since the procedure. Subject has an active infection at the time of enrollment, and/or a history of clinically significant acute bacterial, viral, or fungal systemic infections that required systemic treatment in the last four weeks prior to enrollment. Subject has known medical history of alpha 1-antitrypsin deficiency (α1-antitrypsin deficiency). Subject has serological evidence of human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or anti-hepatitis C virus (Anti-HCV) at screen. Subject is pregnant or nursing or is planning a pregnancy during the study period. Subject is male or female of childbearing potential, is participating in sexual activity that could lead to pregnancy and is unable or unwilling to practice medically effective contraception during the study. Subject has received any investigational drug or device within 14 days (or 5 half lives, whichever is longer) prior to study drug administration on Day 1 Subject has renal artery stenosis as determine at screen with medical history. Subject has hypotension as defined by systolic blood pressure ≤ 90 and diastolic blood pressure ≤ 60 mmHg. Subject has Proteinuria: PCR>2000mg/gm (spot testing). Subject does not have adequate venous access for blood sampling. Subject has any other medical condition which, in the opinion of the Investigator, will make participation medically unsafe or interfere with the study results. Subject has any other clinically significant abnormalities in laboratory test results at screening that would, in the opinion of the Investigator, increase the subject's risk of participation, jeopardize complete participation in the study, or compromise interpretation of study data. Subject has any of the following conditions as determined by ECG or medical record: Any significant arrhythmia or conduction abnormality, which, in the opinion of the Investigators and Medical Monitor, may interfere with the safety of the subject. Subject is taking Cimetidine, St. John's Wort, or any other herbal or probiotic supplement.

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 3.0 µg/kg SC, single dose<br>n=8, study group of T1D or T2D with stage 3 CKD. separate n=8 of study group with T1D or T2D with CKD stage 4). | Drug: DM199<br>* Single SC dose<br>|
| Experimental: 5.0 µg/kg SC, single dose<br>n=8, study group of T1D or T2D with stage 3 CKD. | Drug: DM199<br>* Single SC dose<br>|
| Experimental: 8.0 µg/kg SC, single dose<br>n=8, study group of T1D or T2D with stage 3 CKD. | Drug: DM199<br>* Single SC dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as assessed by incidence, severity, and causality of adverse events |  | 11 days | 
| Tolerability as assessed by incidence and severity of AEs |  | 11 days | 
| plasma measurements of DM199 | as measured in the three different dosing groups; 3.0 ug/kg, 5.0 ug/kg, and 8.0 ug/kg. | 11 days | 
| DM199 urine concentrations of KLK1 | urine KLK1 will be measured pre and post study drug administration. | 11 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| C Reactive protein (CRP) |  | 11 days | 
| Matrix Metalloproteinase-9 (MMP-9) |  | 11 days | 
| Vascular Endothelial Growth Factor (VEGF) |  | 11 days | 
| Nitric Oxide (NO) |  | 11 days | 
| Serum creatinine |  | 11 days | 
| Cystatin C |  | 11 days | 
| neutrophil gelatinase-associated prostaglandin E2 |  | 11 days | 
| Urine Kidney Injury Molecule-1 (Kim1) |  | 11 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Chronic Kidney Disease