Clinical trial NCT03550378: 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: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Type II Diabetes Mellitus
Renal Insufficiency
Keywords: Type 2 Diabetes Mellitus
MEDI0382
Renal Impairment
Glucose concentration
Hemoglobin A1c
Lead sponsor: MedImmune LLC
Sponsor class: INDUSTRY
First posted: 2018-06-08
Enrollment: 41
Sex: ALL
Minimum age (years): 18
Maximum age (years): 84
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomised, Double-Blind, Placebo-Controlled
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. Age ≥ 18 and \< 85 years at screening.
2. 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.
3. 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
4. Body mass index (BMI) between 25 and 45 kg/m\^2 (inclusive) at screening
5. Haemoglobin A1c (HbA1c) range of 6.5 % to 10.5% (inclusive) at screening
6. 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.
7. 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:

1. 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.
2. Concurrent participation in another interventional study of any kind and repeat randomisation in this study is prohibited.
3. 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.
4. 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)
5. Severe allergy/hypersensitivity to any of the proposed study treatments or excipients
6. Symptoms of acutely decompensated blood glucose control (eg, thirst, polyuria, weight loss), a history of type 1 diabetes mellitus or diabetic ketoacidosis
7. Participants who have undergone a renal transplant
8. 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)
9. 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
10. History of acute or chronic pancreatitis
11. 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
12. 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
13. 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
14. Severe congestive heart failure (New York Heart Association Class III or IV)
15. Basal calcitonin level \> 50 ng/L at screening or history/family history of medullary thyroid carcinoma or multiple endocrine neoplasia
16. 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
17. Any positive results for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody, and human immunodeficiency virus (HIV) antibody
18. Nephrotic range proteinuria defined as spot urine albumin creatinine ratio (ACR) \> 250 mg/mmol at screening
19. 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

Primary outcomes:
measure: 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
timeFrame: 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 outcomes:
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
timeFrame: Day 1 through Day 60
measure: Number of Participants With Abnormal Vital Signs Reported as TEAEs
timeFrame: Day 1 through Day 60
measure: Change From Baseline in Postural Blood Pressure
timeFrame: Baseline (Day 1) through Day 32
measure: Number of Participants With Abnormal Electrocardiograms (ECGs) Reported as TEAEs
timeFrame: Day 1 through Day 60
measure: Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs
timeFrame: Day 1 through Day 60
measure: Number of Participants With Treatment-emergent Adverse Events of Special Interest (TEAESIs)
timeFrame: Day 1 through Day 60
measure: Change From Baseline in Mean 24-hrs Pulse Rate to the End of Each Dosing Level
timeFrame: Day -5 (Baseline) and on Days 5, 12, 19, and 32
measure: Change From Baseline in Mean 24-hrs Systolic and Diastolic Blood Pressure to the End of Each Dosing Level
timeFrame: Day -5 (Baseline) and on Days 5, 12, 19, and 32
measure: Change From Baseline in Haemoglobin A1c (HbA1c) to Day 32
timeFrame: Day 1 (Baseline) and Day 32
measure: Change From Baseline in Fasting Glucose to Day 32
timeFrame: Day 1 (Baseline) and Day 32
measure: Change From Baseline in Percentage of Time Spent Within a Target Glucose Range Over a 7-day Period to the Final Week of Treatment
timeFrame: 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)
measure: Percent Change Frome Baseline in Body Weight to Day 33
timeFrame: Day 1 (Baseline) and Day 33
measure: Change From Baseline in Absolute Body Weight to Day 33
timeFrame: Day 1 (Baseline) and Day 33
measure: Area Under the Plasma Concentration Time Curve Over a Dosing Duration (AUCτ) of MEDI0382 at 300 μg
timeFrame: Predose and at 0.5, 1, 2, 4, 6, 8, and 24 hrs postdose on Day 32
measure: Maximum Observed Serum Concentration (Cmax) of MEDI0382 at 300 μg
timeFrame: Predose and at 0.5, 1, 2, 4, 6, 8, and 24 hrs postdose on Day 32
measure: Time to Observed Maximum Serum Concentration (Tmax) of MEDI0382 at 300 μg
timeFrame: Predose and at 0.5, 1, 2, 4, 6, 8, and 24 hrs postdose on Day 32
measure: Trough Plasma Concentration (Ctrough) of MEDI0382
timeFrame: 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)
measure: Number of Participants With Positive Anti-drug Antibodies (ADA) Titre to MEDI0382
timeFrame: Pre-dose on Days 1, 12, and 32 and on Day 60
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Research Site
city: Magdeburg
country: Germany
facility: Research Site
city: Munster
country: Germany
facility: Research Site
city: München
country: Germany
facility: Research Site
city: Dundee
country: United Kingdom
facility: Research Site
city: Edinburgh
country: United Kingdom
facility: Research Site
city: Edinburgh
country: United Kingdom
facility: Research Site
Study officials:
References:
citation: Parker VER, Hoang T, Schlichthaar H, Gibb FW, Wenzel B, Posch MG, Rose L, Chang YT, Petrone M, Hansen L, Ambery P, Jermutus L, Heerspink HJL, McCrimmon RJ. Efficacy and safety of cotadutide, a dual glucagon-like peptide-1 and glucagon receptor agonist, in a randomized phase 2a study of patients with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2022 Jul;24(7):1360-1369. doi: 10.1111/dom.14712. Epub 2022 Apr 25.