| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| High sugar levels in the blood |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067585 |
| E.1.2 | Term | Type 2 diabetes mellitus |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the effect of MEDI0382 titrated up to a dose level of 300 μg on glucose control versus placebo after 32 days of treatment |
|
| E.2.2 | Secondary objectives of the trial |
• To characterise the safety profile and tolerability of MEDI0382 titrated up to a dose level of 300 μg during dosing and follow-up in subjects with T2DM and renal impairment
• To assess the effects of MEDI0382 titrated up to a dose level of 300 μg on additional measures of glycaemic control versus placebo after 32 days of treatment
• To assess the effects of MEDI0382 titrated up to a dose level of 300 μg on weight versus placebo after 32 days of treatment
• To characterise the PK profile and immunogenicity of MEDI0382 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 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/m2 (inclusive) at screening
5. HbA1c range of 6.5 % to 10.5% (inclusive) at screening
6. Renal impairment with eGFR ≥ 30 and < 60 mL/min/1.73m2 at screening. At least 16 subjects (40%) are required to have a screening eGFR ≥30 and < 45 mL/min/1.73m2 and at least 16 subjects (40%) are required to have screening eGFR ≥45 and < 60 mL/min/1.73m2. eGFR will be determined by the chronic kidney disease-epidemiology collaboration (CKD-EPI) equation. In instances where the eGFR estimated during the screening period is outside the range expected from the subject’s medical history, the subject may be re-tested once.
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 nonsterilized male partner must be using at least one highly effective method of contraception from screening and up to 4 weeks after the last dose of investigational product. It is strongly recommended for the male partner of a female subject to also use male condom plus spermicide throughout this period. Cessation of contraception after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. |
|
| E.4 | Principal 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 ECG, which in the opinion of the investigator, would compromise the subject’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 subject who has received another investigational product as part of a clinical study or a 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 subject who has received any of the following medications within the specified timeframe prior to the start of the study (Visit 2)
o 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, bupropionnaltrexone, phentermine-topiramate, phentermine, lorcaserin) within 30 days (or 5 half-lives of the drug) prior to the start of dosing (Visit 4)
o 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)
o 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)
o 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)
o 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.Subjects who have undergone a renal transplant
8.Subjects with suspicion of acute or subacute renal function deterioration (eg, subjects 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 subjects with any of the following results:
o Aspartate transaminase (AST) ≥ 3 × upper limit of normal (ULN)
o Alanine transaminase (ALT) ≥ 3 × ULN
o Total bilirubin ≥ 2 × ULN
12.Poorly controlled hypertension defined as:
o Systolic BP > 180 mm Hg
o Diastolic BP ≥ 100 mm Hg
after 10 minutes of seated rest and confirmed by repeated measurement at screening. Subjects who fail BP screening criteria may be considered for 24-hour ABPM at the discretion of the investigator. Subjects 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 subjects 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 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. Subjects 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percentage change in glucose area under the curve (AUC) as measured by a standardised mixed meal tolerance test (MMTT) from baseline (Day -5) to the end of 32 days of treatment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1) Measures of safety and tolerability (AEs/SAEs, vital signs, postural blood pressure [BP] changes, ECG, laboratory test results)
2) Change in mean 24-hour pulse rate, systolic and diastolic blood pressure from baseline (Day -5) to the end of dosing at each dose level (Days 4, 11, 18, and 32)
3) Change in HbA1c from baseline (Day 1) to the end of 32 days of treatment (Day 32)
4) Change in fasting glucose from baseline (Day 1) to the end of 32 days of treatment (Day 32)
5) Change in percentage of time spent within a target glucose range of 70 mg/dL (3.9 mmol/L) to 180 mg/dL (10 mmol/L) over a 7-day period at baseline (Days -8 to - 2) to the final week of treatment (Days 26-32)
6) Percentage and absolute change in body weight from baseline (Day 1) to the end of 32 days of treatment (Day 33)
7) PK endpoints: AUC over a dosing duration, maximum observed concentration (Cmax), time to Cmax (Tmax), trough plasma concentration (Ctrough)
8) Development of anti-drug antibodies (ADA) and titre (if confirmed positive) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) 7) 8) Refer to schedule of events
2) Days 4, 11, 18, and 32
3) 4) Day 32
5) Days 26-32
6) End of treatment |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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