A Study to Look at the Effect MEDI0382 Has on Blood Sugar in People With Type 2 Diabetes and Kidney Problems and Also to Check That MEDI0382 is Well Tolerated

Study Overview
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Brief Summary
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A study to look at the effect MEDI0382 has on blood sugar in people with type 2 diabetes and kidney problems and also to check that MEDI0382 is well tolerated.

Official Title
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A Phase 2a, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of MEDI0382 in Subjects With Type 2 Diabetes Mellitus and Renal Impairment

Conditions
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Type II Diabetes Mellitus, Renal Insufficiency

Intervention / Treatment
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* Drug: MEDI0382
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 and < 85 years at screening. Signed and dated written informed consent (with the exception of consent for genetic and nongenetic research) prior to performing any protocol-related procedures, including screening evaluations. Diagnosed with type 2 diabetes mellitus (T2DM) with glucose control managed with any insulin and/or oral therapy combination where no significant dose changes of oral therapy of more than 50% have occurred in the 3 months prior to screening Body mass index (BMI) between 25 and 45 kg/m^2 (inclusive) at screening Haemoglobin A1c (HbA1c) range of 6.5 % to 10.5% (inclusive) at screening Renal impairment with estimated glomerular filtration rate (eGFR) ≥ 30 and < 60 mL/min/1.73 m^2 at screening. Approximately 16 participants (40%) are required to have a screening eGFR ≥30 and < 45 mL/min/1.73 m^2 and at least 16 participants (40%) are required to have screening eGFR ≥45 and < 60 mL/min/1.73 m^2. Females of childbearing potential must have a negative pregnancy test at screening and randomisation, and must not be lactating. Women of childbearing potential who are sexually active with a non-sterilized male partner must be using at least one highly effective method of contraception from screening and up to 4 weeks after the last dose study drug. Exclusion Criteria: History or presence of significant medical or psychological conditions, including substance dependence/abuse, or significant abnormalities in laboratory parameters or vital signs including electrocardiogram (ECG), which in the opinion of the investigator, would compromise the participant's safety or successful participation in the study. As an example, severe anaemia (haemoglobin < 7.0 g/dL) could be exclusionary due to blood sampling required by the protocol, at the discretion of investigator. Concurrent participation in another interventional study of any kind and repeat randomisation in this study is prohibited. Any participant who has received another study drug as part of a clinical study or a glucagon-like peptide-1 (GLP-1) analogue-containing preparation within the last 30 days or 5 half-lives of the drug (if known; whichever is longer) at the time of Visit 2. Any participant who has received any of the following medications within the specified timeframe prior to the start of the study (Visit 2) Herbal preparations within 1 week prior to the start of dosing (Visit 4) or drugs licensed for control of body weight or appetite (eg, orlistat, bupropion-naltrexone, phentermine-topiramate, phentermine, lorcaserin) within 30 days (or 5 half-lives of the drug) prior to the start of dosing (Visit 4) Aspirin (acetylsalicylic acid) at a dose greater than 150 mg once daily and within the last 3 days prior to the start of the run-in period (Visit 2) Paracetamol (acetaminophen) or paracetamol-containing preparations at a total daily dose of greater than 3000 mg and within the last 3 days prior to the start of the run-in period (Visit 2) Ascorbic acid (vitamin C) supplements at a total daily dose of greater than 1000 mg and within the last 3 days prior to the start of the run-in period (Visit 2) Opiates, domperidone, metoclopramide, or other drugs known to alter gastric emptying and within 2 weeks prior to the start of dosing (Visit 4) Severe allergy/hypersensitivity to any of the proposed study treatments or excipients Symptoms of acutely decompensated blood glucose control (eg, thirst, polyuria, weight loss), a history of type 1 diabetes mellitus or diabetic ketoacidosis Participants who have undergone a renal transplant Participants with suspicion of acute or subacute renal function deterioration (eg, participants with large fluctuations of creatinine values documented within the 6 months prior to screening) Significant inflammatory bowel disease, gastroparesis, or other severe disease or surgery affecting the upper gastrointestinal (GI) tract including weight-reducing surgery and procedures) which may affect gastric emptying or could affect the interpretation of safety and tolerability data History of acute or chronic pancreatitis Significant hepatic disease (except for non-alcoholic steatohepatitis or nonalcoholic fatty liver disease without portal hypertension or cirrhosis) and/or participants with any of the following results: Aspartate transaminase (AST) ≥ 3 × upper limit of normal (ULN) Alanine transaminase (ALT) ≥ 3 × ULN Total bilirubin ≥ 2 × ULN Poorly controlled hypertension defined as: Systolic blood pressure (BP) > 180 mm Hg Diastolic BP ≥ 100 mm Hg Participants who fail BP screening criteria may be considered for 24-hour ambulatory blood pressure monitoring (ABPM) at the discretion of the investigator. Participants who maintain a mean 24-hour systolic BP ≤ 180 or diastolic BP < 100 mm Hg with a preserved nocturnal dip of > 15% will be considered eligible Unstable angina pectoris, myocardial infarction, transient ischemic attack or stroke within 3 months prior to screening, or participants who have undergone percutaneous coronary intervention or a coronary artery bypass graft within the past 6 months or who are due to undergo these procedures at the time of screening Severe congestive heart failure (New York Heart Association Class III or IV) Basal calcitonin level > 50 ng/L at screening or history/family history of medullary thyroid carcinoma or multiple endocrine neoplasia History of neoplastic disease within 5 years prior to screening, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer Any positive results for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody, and human immunodeficiency virus (HIV) antibody Nephrotic range proteinuria defined as spot urine albumin creatinine ratio (ACR) > 250 mg/mmol at screening History of substance dependence, alcohol abuse, or excessive alcohol intake (defined as an average weekly intake of > 21 alcoholic drinks for men or > 10 alcoholic drinks for women) within 3 years prior to screening, and/or a positive screen for drugs of abuse or alcohol at screening or on Day -5. Participants who use tricyclic antidepressants or benzodiazepines for an established clinical indication may be permitted to enter the study based upon the judgement of the investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 84 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: Parallel Assignment
Interventional Model Description: Randomised, Double-Blind, Placebo-Controlled
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MEDI0382<br>Participants will receive subcutaneous (SC) dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days. | Drug: MEDI0382<br>* Participants will receive subcutaneous MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.<br>|
| Placebo Comparator: Placebo<br>Participants will receive SC dose of placebo matched to MEDI0382 once daily for 32 days. | Drug: Placebo<br>* Participants will receive SC placebo matched to MEDI0382 once daily for 32 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Plasma Glucose Area Under the Concentration Time-curve From Time 0 to 4 Hours (AUC0-4 Hrs) as Measured by Mixed-meal Tolerance Test (MMTT) to Day 32 | The MMTT involved the consumption of a standardised liquid meal (a nutritional supplement containing the components of fat, carbohydrate, and protein, which make up a standard MMTT) within 15 minutes, and timed serial blood samples obtained for measurement of glucose and parameters related to glucose metabolism through 240 minutes after consumption of the standardized meal (with no additional food intake during this time). | Zero minutes before and 15, 30, 45, 60, 90, 120, 180, and 240 minutes after consumption of the standardised meal on Day -5 (Baseline) and Day 32 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. | Day 1 through Day 60 | 
| Number of Participants With Abnormal Vital Signs Reported as TEAEs | Number of participants with abnormal vital signs reported as TEAEs is reported. Vital sign measurements were obtained after the participant had rested in the supine position for at least 10 minutes at the recording time. Abnormal vital signs is defined as any abnormal finding in the vital sign parameters (blood pressure, pulse rate, body temperature, and respiratory rate). | Day 1 through Day 60 | 
| Change From Baseline in Postural Blood Pressure | The change difference is the change from Day 1 to Day 32 in the difference between systolic blood pressure (SBP) or diastolic blood pressure (DBP) values in standing and supine positions. For this outcome measure, participants with difference (standing-supine) in DBP or SBP on Day 1 and Day 32 were analyzed. For few participants either DBP or SBP was recorded eg, standing DBP was not recorded on Day 1 for 2 participants in Placebo arm and 1 participant in MEDI0382 arm; standing SBP was not recorded on Day 32 for a participant in the Placebo arm. | Baseline (Day 1) through Day 32 | 
| Number of Participants With Abnormal Electrocardiograms (ECGs) Reported as TEAEs | Number of participants with abnormal ECGs reported as TEAEs is reported. Abnormal ECGs is defined as any abnormal findings in heart rate, RR interval, PR interval, QRS, axis, ST-T morphology, and QT intervals from the primary lead of the digital 12-lead ECG. | Day 1 through Day 60 | 
| Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs | Number of participants with abnormal clinical laboratory parameters reported as TEAEs is reported. Abnormal clinical laboratory parameters defined as any abnormal finding during analysis of serum chemistry, hematology, and urine. | Day 1 through Day 60 | 
| Number of Participants With Treatment-emergent Adverse Events of Special Interest (TEAESIs) | An adverse event of special interest (AESI) was one of scientific and medical interest specific to understanding of the study drug and may require close monitoring and rapid communication by the investigator to the sponsor. | Day 1 through Day 60 | 
| Change From Baseline in Mean 24-hrs Pulse Rate to the End of Each Dosing Level | Change from baseline in mean 24-hrs pulse rate to the end of each dosing levels: Day 5 for 50 μg; Day 12 for 100 μg, Day 19 for 200 μg, and Day 32 for 300 μg. | Day -5 (Baseline) and on Days 5, 12, 19, and 32 | 
| Change From Baseline in Mean 24-hrs Systolic and Diastolic Blood Pressure to the End of Each Dosing Level | Change from baseline in mean 24-hrs systolic and diastolic blood pressure to the end of each dosing levels: Day 5 for 50 μg, Day 12 for 100 μg, Day 19 for 200 μg, and Day 32 for 300 μg. | Day -5 (Baseline) and on Days 5, 12, 19, and 32 | 
| Change From Baseline in Haemoglobin A1c (HbA1c) to Day 32 | Change from baseline in haemoglobin A1c (HbA1c) is reported. | Day 1 (Baseline) and Day 32 | 
| Change From Baseline in Fasting Glucose to Day 32 | Change from baseline in fasting glucose is reported. | Day 1 (Baseline) and Day 32 | 
| Change From Baseline in Percentage of Time Spent Within a Target Glucose Range Over a 7-day Period to the Final Week of Treatment | Change from baseline in percentage of time spent within a target glucose range over a 7-day period to the final week of treatment is reported. Target glucose range was considered as 70 mg/dL (3.9 mmol/L) to 180 mg/dL (10 mmol/L). | Baseline (Days -8 to -2), Days 5 to 11, Days 12 to 18, Days 19 to 25, and Days 26 to 32 (final week of treatment) | 
| Percent Change Frome Baseline in Body Weight to Day 33 | Percent change from baseline in body weight is reported. | Day 1 (Baseline) and Day 33 | 
| Change From Baseline in Absolute Body Weight to Day 33 | Change from baseline in absolute body weight is reported. | Day 1 (Baseline) and Day 33 | 
| Area Under the Plasma Concentration Time Curve Over a Dosing Duration (AUCτ) of MEDI0382 at 300 μg | Area under the plasma concentration time curve over a dosing duration (AUCτ) of MEDI0382 at 300 μg is reported. | Predose and at 0.5, 1, 2, 4, 6, 8, and 24 hrs postdose on Day 32 | 
| Maximum Observed Serum Concentration (Cmax) of MEDI0382 at 300 μg | Maximum observed serum concentration (Cmax) of MEDI0382 at 300 μg is reported. | Predose and at 0.5, 1, 2, 4, 6, 8, and 24 hrs postdose on Day 32 | 
| Time to Observed Maximum Serum Concentration (Tmax) of MEDI0382 at 300 μg | Time to observed maximum serum concentration (Tmax) of MEDI0382 at 300 μg is reported. | Predose and at 0.5, 1, 2, 4, 6, 8, and 24 hrs postdose on Day 32 | 
| Trough Plasma Concentration (Ctrough) of MEDI0382 | Trough concentration is the lowest concentration reached by a drug before the next dose is administered. Trough plasma concentration of MEDI0382 is reported. | Days 1, 5, 12, and 19: Predose; and Day 32: Predose and at 0.5, 1, 2, 4, 6, 8, and 24 hrs postdose (Day 33) | 
| Number of Participants With Positive Anti-drug Antibodies (ADA) Titre to MEDI0382 | Number of participants with positive Anti-drug antibodies (ADA) Titre to MEDI0382 is reported. | Pre-dose on Days 1, 12, and 32 and on Day 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes Mellitus, MEDI0382, Renal Impairment, Glucose concentration, Hemoglobin A1c