A Phase 1 Study of DD01 in Overweight/Obese Subjects With T2DM and NAFLD

Study Overview
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Brief Summary
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This is a Phase 1, first in human (FiH), randomized, double-blind, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) study to investigate the safety, tolerability, PK and PD of DD01 administered by subcutaneous (SC) injection in overweight/obese subjects with type 2 diabetes (T2DM) and nonalcoholic fatty liver disease (NAFLD). The study will be conducted in 2 Parts (Part A and B), with up to 8 cohorts included in each part (Part A; Cohorts A1 to A8 and Part B; Cohorts B2 to B8).

Detailed Description
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Part A (SAD): In Part A, subjects will receive a single dose of study drug, and the safety and efficacy of DD01 will be evaluated in overweight/obese subjects with T2DM. Part B (MAD): In Part B, subjects will receive once-weekly doses of the study drug for 4 weeks, and the safety and efficacy of DD01 will be evaluated in overweight/obese subjects with T2DM and NAFLD.

Official Title
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A Phase 1, Randomized, Double-blind, Placebo-controlled, Single and Multiple Dose Study to Assess Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DD01 in Overweight/Obese Subjects With T2DM and NAFLD

Conditions
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NAFLD, Overweight and Obesity, Type2 Diabetes

Intervention / Treatment
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* Drug: DD01
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Part A Inclusion Criteria: Type 2 diabetes ≥ 12 months. Treatment with diet and exercise or metformin monotherapy on stable dose for 3 months prior to screening HbA1c ≤ 10%). Body Mass Index (BMI) ≥ 25 and ≤ 40.0 kg/m2 Part B Inclusion Criteria Type 2 diabetes ≥ 12 months. Treatment with diet and exercise or metformin monotherapy on stable dose for 3 months prior to screening HbA1c ≤ 10% BMI ≥ 30 kg/m2 and ≤ 40.0 kg/m2 Waist circumference ≤ 57 inches Controlled attenuation parameter by FibroScan Liver fat fraction ≥ 10% by magnetic resonance imaging (MRI) Part A Exclusion Criteria: History of type 1 diabetes mellitus (T1DM) History of acute proliferative retinopathy or maculopathy, severe gastroparesis, and/or severe neuropathy, in particular autonomic neuropathy, as judged by the Investigator. Uncontrolled hypertension Treatment with antihypertensive medication and statins not stable during the past 2 months prior to screening Treatment with thyroid hormones not stable during the past 3 months prior to screening History of any weight control treatment, including over-the-counter and herbal medication and supplements, or any medication with a labeled indication for weight loss or weight gain within 3 months prior to screening History of surgical treatment for obesity History of heart disease History of renal disease History or current diagnosis of acute or chronic pancreatitis or factors for pancreatitis, such as a history of cholelithiasis (without cholecystectomy) or alcohol abuse A history of or active chronic liver disease due to alcohol, auto-immune, HIV, HBV or active HCV-infection or NASH History of major depression, anxiety, suicidal behavior or attempts, or other psychiatric disorder requiring medical treatment Personal or family history of medullary thyroid carcinoma (MTC) or a genetic condition that predispose to MTC (i.e., multiple endocrine neoplasia type 2) Administration of Vaccines/Immunizations within 14 days prior to first dosing or if scheduled during the study. Vaccination for COVID-19 is allowed during the study if a washout period of 5 days after vaccine administration is followed before dosing. History of any major surgery within 6 months prior to screening Participation in any other clinical interventional study receiving active treatment within 30 days or 5 half-lives prior to screening, whichever is longer History of alcohol or illicit drug abuse including marijuana Existence of any surgical or medical condition that, in the judgment of the Investigator, might interfere with the investigational product PART B Exclusion Criteria History of type 1 diabetes mellitus (T1DM) History of acute proliferative retinopathy or maculopathy, severe gastroparesis, and/or severe neuropathy, in particular autonomic neuropathy, as judged by the Investigator Uncontrolled hypertension (treatment with medications must be stable) History of any weight control treatment History of surgical treatment for obesity History of heart disease History of renal disease Subjects with a history or clinically significant active disease of the gastrointestinal, cardiovascular, hepatic, neurological, renal, pancreatic, immunological, dermatological, endocrine, genitourinary or hematological system. History or current diagnosis of acute or chronic pancreatitis History of major depression, anxiety, suicidal behavior or attempts, or other psychiatric disorder requiring medical treatment History of alcohol or illicit drug abuse including marijuana Existence of any surgical or medical condition that, in the judgment of the Investigator, might interfere with the investigational product Any history of clinically significant chronic liver disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Interventional Model Description: Part A - Cohorts A1, A2, A3, A4, A5, A6, A7 & A8 Part B - Cohorts B2, B3, B4, B5, B6, B7 & B8
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A1 - Single Ascending Dose<br>DD01 Dose 1 (N=6) Placebo (N=2) Subcutaneous injection | Drug: DD01<br>* The active of DD01 is a synthetic peptide, administered in a 1mL volume for injection.<br>Drug: Placebo<br>* Placebo drug of DD01, administered in a 1mL volume for injection<br>|
| Experimental: Group A2, Single Ascending Dose<br>DD01 Dose 2 (N=6) Placebo (N=2) Subcutaneous injection | Drug: DD01<br>* The active of DD01 is a synthetic peptide, administered in a 1mL volume for injection.<br>Drug: Placebo<br>* Placebo drug of DD01, administered in a 1mL volume for injection<br>|
| Experimental: Group A3, Single Ascending Dose<br>DD01 Dose 3 (N=6) Placebo (N=2) Subcutaneous injection | Drug: DD01<br>* The active of DD01 is a synthetic peptide, administered in a 1mL volume for injection.<br>Drug: Placebo<br>* Placebo drug of DD01, administered in a 1mL volume for injection<br>|
| Experimental: Group A4, Single Ascending Dose<br>DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection | Drug: DD01<br>* The active of DD01 is a synthetic peptide, administered in a 1mL volume for injection.<br>Drug: Placebo<br>* Placebo drug of DD01, administered in a 1mL volume for injection<br>|
| Experimental: Group B2 - Multiple Ascending Dose<br>DD01 Dose 2 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks | Drug: DD01<br>* The active of DD01 is a synthetic peptide, administered in a 1mL volume for injection.<br>Drug: Placebo<br>* Placebo drug of DD01, administered in a 1mL volume for injection<br>|
| Experimental: Group B3 - Multiple Ascending Dose<br>DD01 Dose 3 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks | Drug: DD01<br>* The active of DD01 is a synthetic peptide, administered in a 1mL volume for injection.<br>Drug: Placebo<br>* Placebo drug of DD01, administered in a 1mL volume for injection<br>|
| Experimental: Group B4 - Multiple Ascending Dose<br>DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks | Drug: DD01<br>* The active of DD01 is a synthetic peptide, administered in a 1mL volume for injection.<br>Drug: Placebo<br>* Placebo drug of DD01, administered in a 1mL volume for injection<br>|
| Experimental: Group B5 - Multiple Ascending Dose<br>DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks | Drug: DD01<br>* The active of DD01 is a synthetic peptide, administered in a 1mL volume for injection.<br>Drug: Placebo<br>* Placebo drug of DD01, administered in a 1mL volume for injection<br>|
| Experimental: Group B6 - Multiple Ascending Dose<br>DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks | Drug: DD01<br>* The active of DD01 is a synthetic peptide, administered in a 1mL volume for injection.<br>Drug: Placebo<br>* Placebo drug of DD01, administered in a 1mL volume for injection<br>|
| Experimental: Group A5, Single Ascending Dose<br>DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection | Drug: DD01<br>* The active of DD01 is a synthetic peptide, administered in a 1mL volume for injection.<br>Drug: Placebo<br>* Placebo drug of DD01, administered in a 1mL volume for injection<br>|
| Experimental: Group A6, Single Ascending Dose<br>DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection | Drug: DD01<br>* The active of DD01 is a synthetic peptide, administered in a 1mL volume for injection.<br>Drug: Placebo<br>* Placebo drug of DD01, administered in a 1mL volume for injection<br>|
| Experimental: Group A7, Single Ascending Dose<br>DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection | Drug: DD01<br>* The active of DD01 is a synthetic peptide, administered in a 1mL volume for injection.<br>Drug: Placebo<br>* Placebo drug of DD01, administered in a 1mL volume for injection<br>|
| Experimental: Group A8, Single Ascending Dose<br>DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection | Drug: DD01<br>* The active of DD01 is a synthetic peptide, administered in a 1mL volume for injection.<br>Drug: Placebo<br>* Placebo drug of DD01, administered in a 1mL volume for injection<br>|
| Experimental: Group B7 - Multiple Ascending Dose<br>DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks | Drug: DD01<br>* The active of DD01 is a synthetic peptide, administered in a 1mL volume for injection.<br>Drug: Placebo<br>* Placebo drug of DD01, administered in a 1mL volume for injection<br>|
| Experimental: Group B8 - Multiple Ascending Dose<br>DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks | Drug: DD01<br>* The active of DD01 is a synthetic peptide, administered in a 1mL volume for injection.<br>Drug: Placebo<br>* Placebo drug of DD01, administered in a 1mL volume for injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events and serious adverse events |  | Part A - 43 days | 
| Number of participants with treatment-related adverse events and serious adverse events (TEAEs) |  | Part B - 57 days | 
| Number of participants with clinically significant abnormalities in clinical laboratory values |  | Part A - 43 days | 
| Number of participants with clinically significant abnormalities in clinical laboratory values |  | Part B - 57 days | 
| Number of participants with clinically significant abnormalities in physical examinations |  | Part A - 43 days | 
| Number of participants with clinically significant abnormalities in physical examinations |  | Part B - 57 days | 
| Number of participants with clinically significant abnormalities in vital signs |  | Part A - 43 days | 
| Number of participants with clinically significant abnormalities in vital signs |  | Part B - 57 days | 
| Blood Pressure assessed by 24-hour ambulatory blood pressure monitoring (ABPM) |  | Part A - 43 days | 
| Blood Pressure assessed by 24-hour ambulatory blood pressure monitoring (ABPM) |  | Part B - 57 days | 
| Heart Rate assessed by 24-hour ambulatory electrocardiography monitoring reader) |  | Part A - 43 days | 
| Heart Rate assessed by 24-hour ambulatory electrocardiography monitoring reader) |  | Part B - 57 days | 
| Number of participants with clinically significant abnormalities in 12-lead ECGs |  | Part A - 43 days | 
| Number of participants with clinically significant abnormalities in 12-lead ECGs |  | Part B - 57 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed blood/plasma concentration of DD01 | Maximum observed blood/plasma concentration (Cmax) | Part A - 43 days | 
| Maximum observed blood/plasma concentration of DD01 | Maximum observed blood/plasma concentration (Cmax) | Part B - 57 days | 
| Time of the maximum observed blood/plasma concentration of DD01 | Time of the maximum observed blood/plasma concentration (Tmax) | Part A - 43 days | 
| Time of the maximum observed blood/plasma concentration of DD01 | Time of the maximum observed blood/plasma concentration (Tmax) | Part B - 57 days | 
| Apparent blood/plasma terminal elimination half life of DD01 | Apparent blood/plasma terminal elimination half life (t1/2) | Part A - 43 days | 
| Apparent blood/plasma terminal elimination half life of DD01 | Apparent blood/plasma terminal elimination half life (t1/2) | Part B - 57 days | 
| Termination elimination rate constant of DD01 | Termination elimination rate constant (kel) | Part A - 43 days | 
| Termination elimination rate constant of DD01 | Termination elimination rate constant (kel) | Part B - 57 days | 
| Apparent total blood/plasma clearance of DD01 | Apparent total blood/plasma clearance (CL/F) | Part A - 43 days | 
| Apparent total blood/plasma clearance of DD01 | Apparent total blood/plasma clearance (CL/F) | Part B - 57 days | 
| Apparent volume of distribution of DD01 | Apparent volume of distribution(Vz/F) | Part A - 43 days | 
| Apparent volume of distribution of DD01 | Apparent volume of distribution(Vz/F) | Part B - 57 days | 
| Area under the blood/plasma concentration time curve from time zero to the time of the last quantifiable concentration of DD01 | Area under the blood/plasma concentration time curve from time zero to the time of the last quantifiable concentration (AUC0-t) | Part A - 43 days | 
| Area under the blood/plasma concentration time curve from time zero to the time of the last quantifiable concentration of DD01 | Area under the blood/plasma concentration time curve from time zero to the time of the last quantifiable concentration (AUC0-t) | Part B - 57 days | 
| Area under the blood/plasma concentration time curve from time zero to 144 hours postdose of DD01 | Area under the blood/plasma concentration time curve from time zero to 144 hours postdose (AUC0-144) | Part A - 43 days | 
| Area under the blood/plasma concentration time curve from time zero to 144 hours postdose of DD01 | Area under the blood/plasma concentration time curve from time zero to 144 hours postdose (AUC0-144) | Part B - 57 days | 
| Area under the blood/plasma concentration time curve from time zero to 216 hours postdose of DD01 | Area under the blood/plasma concentration time curve from time zero to 216 hours postdose (AUC0-216) | Part A - 43 days | 
| Area under the blood/plasma concentration time curve from time zero to 216 hours postdose of DD01 | Area under the blood/plasma concentration time curve from time zero to 216 hours postdose (AUC0-216) | Part B - 57 days | 
| Area under the blood/plasma concentration time curve from time zero to 168 hours postdose of DD01 | Part B only: Area under the blood/plasma concentration time curve from time zero to 168 hours postdose (AUC0-168) | Part B - 57 days | 
| Number of participants with antidrug antibodies (ADAs) |  | Part A - 43 days | 
| Number of participants with antidrug antibodies (ADAs) |  | Part B - 57 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver Disease