| 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 body weight versus placebo |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the effect of MEDI0382 titrated up to a dose level of 300 μg versus placebo
on energy intake during ad libitum lunchtime meals
• To assess the effect of MEDI0382 titrated up to a dose level of 300 μg versus placebo on TEE, AEE, and REE
• To assess the effect of a 16-day period of MEDI0382 titrated up to a dose level of 300 μg versus placebo on REE
• To assess the effect of MEDI0382 titrated up to a dose level of 300 μg versus placebo on TEE
• To assess the effect of MEDI0382 titrated up to a dose level of 300 μg on measures of body weight and composition versus placebo
• To assess the effect of MEDI0382 titrated up to a dose level of 300 μg on glucose homeostasis versus placebo
Please refer to the Protocol for full details of the Secondary objectives. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1 Subjects aged ≥ 30 and ≤ 75 years at screening
2 Provision of signed and dated written informed consent (except for consent for genetic and non-genetic research and additional optional assessments) prior to any protocol-related procedures
3 Body Mass Index > 28 and ≤ 40 kg/mˆ2 at screening
4 Glycated haemoglobin (HbA1c) ≤ 8.0% at screening
5 Diagnosed with T2DM with glucose control managed with metformin, with or without a DPPIV inhibitor, SGLT2i, sulfonylurea, or glitinide, where no significant dose change (increase or decrease > 50%) has occurred in the 3 months prior to screening; if the subject is on dual therapy, a 4-week washout of the non-metformin therapy (DPPIV inhibitor, SGLT2i, sulfonylurea or glitinide) will be required prior to Visit 4
6 Female subjects of childbearing potential must have a negative pregnancy test at screening and randomisation, and must not be lactating
7 Female subjects of childbearing potential who are sexually active with a non-sterilised male partner must be using at least one highly effective method of contraception from screening and must agree to continue using such precautions up until 4 weeks after the last dose of investigational product |
|
| E.4 | Principal exclusion criteria |
1 History of, or any existing condition(s) that, in the opinion of the investigator, would interfere with evaluation of the investigational product, put the subject at risk, influence the subject’s ability to participate or affect the interpretation of the results of the study and/or any subject unable or unwilling to follow study procedures
2 Any subject with a cardiac pacemaker or implanted/portable electronic device
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 (whichever is longer) at the time of screening (Visit 1)
4 Any subject who has received any of the following medications within the specified time frame prior to Visit 2: herbal preparations or drugs licensed for control of body weight or appetite (eg, orlistat, bupropion, naltrexone, phentermine-topiramate, phentermine, lorcaserin, opiates, domperidone, metoclopramide, or other drugs known to alter gastric emptying)
5 Concurrent participation in another study with an investigational product and prior randomisation in this study is prohibited
6 Severe allergy/hypersensitivity to any of the proposed study treatments, excipients, or standardised meals
7 Symptoms of acutely decompensated blood glucose control (eg, thirst, polyuria, weight loss), a history of type 1 diabetes mellitus or diabetic ketoacidosis, or if the subject has been treated with daily SC insulin within 90 days prior to screening
8 Abnormal thyroid stimulating hormone (TSH) level of < 0.03 mIU/L or > 10 mIU/L confirmed on two consecutive tests
9 Regularly engage in high intensity exercise at least three times per week or have done so in the prior three months
10 Clinically significant inflammatory bowel disease, gastroparesis or other severe disease or surgery affecting the upper GI tract (including weight-reducing surgery and procedures) which may affect gastric emptying or could affect the interpretation of safety and tolerability data
11 Acute or chronic pancreatitis with or without amylase > 1000 IU/L and/or lipase > 600 IU/L at screening
12 Significant hepatic disease (except for nonalcoholic steatohepatitis or nonalcoholic fatty liver disease without portal hypertension or cirrhosis) and/or subjects with any of the following results at screening:
(a) Aspartate transaminase (AST) ≥ 3 × upper limit of normal (ULN)
(b) Alanine transaminase (ALT) ≥ 3 × ULN
(c) Total bilirubin ≥ 2 × ULN
13 Impaired renal function defined as estimated glomerular filtration rate (eGFR) < 45 mL/minute/1.73 mˆ2 at screening (GFR estimated according to the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) or the Modification of Diet in Renal Disease (MDRD) using MDRD Study Equation isotope dilution mass spectrometry-traceable [SI units])
14 Poorly controlled hypertension defined as:
(a) Systolic BP > 180 mm Hg
(b) Diastolic BP or > 100 mm Hg
After 10 minutes of supine rest and confirmed by repeated measurement at screening. Subjects who fail BP screening criteria may be considered for 24-hour ambulatory blood pressure monitoring at the discretion of the investigator. Subjects who maintain a mean 24-hour BP ≤ 180/100 mmHg with a preserved nocturnal dip of > 15% will be considered eligible
15 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
16 Severe congestive heart failure (New York Heart Association Class III or IV)
17 Basal calcitonin level > 50 ng/L at screening or history/family history of medullary thyroid carcinoma or multiple endocrine neoplasia
18 History of neoplastic disease within 5years prior to screening, except for adequately treated basal cell, squamous cell skin cancer, or in situ cervical cancer
19 Any positive results for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV) antibody
20 Substance dependence or history of alcohol abuse and/or excess alcohol intake
21 Involvement of any AstraZeneca, MedImmune, contract research organization (CRO), or National Institute for Health Research/Wellcome Trust Cambridge Clinical Research Facility employee or their close relatives |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percentage change in body weight in kg from Day 17 to 59 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1) Percentage and absolute change in total energy intake in kJ from the ad libitum lunch from Day 16 to 32 and Day 16 to 59
2) Percentage and absolute change in TEE, AEE, and REE as measured by whole room indirect
calorimetry in kJ per kg of fat body mass from Day 15 to 58
3) Percentage and absolute change in REE as measured by hood indirect calorimetry in kJ per kg of fat body mass in kJ from Day 16 to 32
4) Percentage and absolute change in total energy expenditure as measured by doubly labelled water in kJ per kg of fat body mass from baseline (Day 17) to the end of treatment (Day 58 or 59)
5) -Absolute change in body weight in kg from Day 17 to 59
-Change in absolute and percentage change in total body fat mass as measured by DXA in kg from Day -1 to 59
-Change in absolute and percentage change in total body fat mass: lean mass ratio as measured by DXA from Day -1 to 59
6) -Change in fasting glucose during a MMTT from Day -1 to 59
-Percentage change in glucose AUC during a MMTT from Day -1 to 59
7) During treatment and follow-up:
• Vital signs
• ECGs
• Safety laboratory analysis
• TEAEs and TESAEs
8) Development of ADA and titre (if confirmed ADA-positive) during treatment and follow up |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) 2) 3) 4) 5) 6) Refer to schedule of study Procedures
7) 8) During treatment and follow-up |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Single blind followed by Double blind treatment period |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | 8 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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