| 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 compare the change in glucose AUC as measured by a standardized MMTT in subjects treated with dapagliflozin and metformin receiving MEDI0382 or placebo for 28 days |
|
| E.2.2 | Secondary objectives of the trial |
• To compare the safety and tolerability profile of MEDI0382 (titrated up to a dose level of 300 µg SC) compared to placebo after 28 days of treatment in subjects treated with dapagliflozin and metformin
• To evaluate the PK profile of MEDI0382 and dapagliflozin (in subjects treated with dapagliflozin, metformin, and MEDI0382) and dapagliflozin (in subjects treated with dapagliflozin, metformin, and placebo)
• To evaluate the immunogenicity profile of MEDI0382 (titrated up to a dose level of 300 µg) in subjects treated with dapagliflozin and metformin receiving MEDI0382 for 28 days
• To evaluate 24-hour glucose control as measured by continuous glucose monitoring (CGM) in subjects treated with dapagliflozin and metformin receiving MEDI0382 or placebo for 28 days |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female subjects aged ≥ 18 years at screening.
2. Provision of signed and dated informed consent form (ICF) prior to any study specific procedures.
3. BMI between 25 kg/m2 and 40 kg/m2 (inclusive) at screening.
4. HbA1c range between 7.0% and 10.0% (inclusive) at the time of screening.
5. Diagnosed with T2DM and treated with of metformin monotherapy (MTD > 1 g) at least 8 weeks prior to screening or treated with stable, oral doses of dapagliflozin 10 mg and metformin (MTD > 1 g) for at least 3 months prior screening.
6. Subjects prescribed oral dual therapy with sulphonylurea, glitinide, or dipeptidyl peptidase-4 inhibitor (in addition to metformin) may be eligible to enter the study following a washout period of these medications totaling at least 28 days before initial screening evaluations have been completed.
7. Subjects treated with stable doses of metformin (MTD > 1 g) with canagliflozin (maximum dose of 300 mg/day) or metformin (MTD > 1 g) with empagliflozin (maximum dose of 25 mg/day) for at least 3 months prior to screening may be eligible to enter the study after switching to dapagliflozin 10 mg at least 2 weeks prior to Day -2
8. Female subjects of childbearing potential must have a negative pregnancy test at screening and randomization and must not be lactating.
9. Females of childbearing potential who are sexually active with a nonsterilized male partner must use at least one highly effective method of contraception from screening and must agree to continue using such precautions through to the end of the study (see Section 10.2 for accepted methods of contraception). 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 of, or any existing condition 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 who has received another investigational product not included in the protocol as part of a clinical trial or a GLP-1 analogue or other investigational SGLT2-containing preparation (excluding dapagliflozin, canagliflozin, and empagliflozin) within the last 30 days or 5 half-lives of the drug (whichever is longest) at the time of screening
3. Any subject who has received any of the following medications prior to the start of the screening period (Visit 1) or prior to the study start period (Visit 4) (see Section 4.7.2 for further details):
◦ Concurrent use of any medicinal products, or herbal or over-thecounter
(OTC) preparations licensed for control of body weight or appetite at the time of screening (Visit 1)
◦ Concurrent or previous use of drugs approved for weight loss (eg, orlistat, bupropion-naltrexone, phentermine-topiramate, phentermine, lorcaserin) within the last 30 days or 5 half-lives of the drug (whichever is longest) at the time of screening (Visit 1)
◦ Concurrent use of aspirin (acetylsalicylic acid) at a dose greater than 150 mg once daily and within the last 72 hours prior to the start of the study (Visit 4)
◦ Concurrent use of paracetamol (acetaminophen) or paracetamol containing preparations at a total daily dose of greater than 3000 mg
and within the last 72 hours prior to the start of the study (Visit 4)
◦ Concurrent use of ascorbic acid (vitamin C) supplements at a total daily
dose greater than 1000 mg and within the last 72 hours prior to the start
of the study (Visit 4)
◦ Concurrent use of opiates, domperidone, metoclopramide, or other drugs known to alter gastric emptying and within the last 72 hours prior to the start of the study (Visit 4)
4. Concurrent participation in another study of any kind and repeat randomization in this study is prohibited
5. Severe allergy/hypersensitivity to any of the proposed study treatments or excipients
6. Diagnosis of type 1 diabetes mellitus, maturity-onset diabetes of the young, or latent autoimmune diabetes of adulthood or presence of antiglutamic acid decarboxylase, anti-islet cell, or anti-insulin antibodies
7. Symptoms of acutely decompensate blood glucose control (eg, thirst, polyuria, weight loss) at screening or randomization, a history of DKA, or hyperosmolar nonketotic coma or treatment with daily SC insulin within 90 days prior to screening
8. Fasting hyperglycemia (> 250 mg/dL/ > 13.9 mmol/L) prior to randomization
9. C-peptide level < lower limit of normal (LLN)10. History of acute or chronic pancreatitis or pancreatectomy
11. Hypertriglyceridemia (> 400 mg/dL) at screening
12. 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
13. 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:
• Aspartate transaminase (AST) ≥ 3 × upper limit of normal (ULN)
• Alanine transaminase (ALT) ≥ 3 × ULN
• Total bilirubin (TBL) ≥ 2 × ULN
14. Impaired renal function defined as estimated glomerular filtration rate (eGFR) ≤ 60 mL/minute/1.73m2 at screening (eGFR according to Modification of Diet in Renal Disease [MDRD] using the isotope dilution mass spectrometry-traceable MDRD Study Equation (SI units).
15. Use of loop diuretics within 1 month prior to screening
16. Poorly controlled hypertension as defined below:
• Systolic BP > 160 mm Hg
• Diastolic BP or ≥ 100 mm Hg
After 10 minutes of supine rest and confirmed by repeated measurement at screening (Visit 1 for all subjects)
17. 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
18. Severe congestive heart failure (New York Heart Association Class III and IV)
19. Basal calcitonin level > 50 ng/L at screening or history/family history of medullary thyroid carcinoma or multiple endocrine neoplasia |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Change from baseline (Day -1) to the end of 28 days of treatment (Day 28) in glucose AUC from zero to 4 hours (AUC0 4h) as measured by a MMTT
• Percentage change from baseline (Day -1) to the end of 28 days of treatment (Day 28) in glucose AUC0 4h as measured by a MMTT |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Incidence of treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs)
• Clinically important changes in 12 lead electrocardiogram (ECG), vital signs (including 24-hour heart rate and blood pressure), physical examination, and clinical laboratory evaluations
•PK profile of both MEDI0382 and dapagliflozin administered simultaneously and dapagliflozin administered with placebo include AUC0-inf, AUC0-last and AUCtau, Cmax, tmax, t1/2, and Cl/F
• Immunogenicity as measured by the presence of antidrug antibodies (ADA) to MEDI0382 (and titer if positive) during dosing and follow up periods
• Change from baseline to the end of dosing at each dose level (Days 7, 14, and 28) in glucose AUC at 24 hours (AUC24h) as measured by CGM
• Change from baseline to the end of dosing at each dose level (Days 7, 14, and 28) in 24 hour mean glucose as measured by CGM
• Change from baseline to the end of dosing at each dose level (Days 7, 14, and 28) in standard deviation (SD) of 24 hour glucose readings as measured by CGM
• Change from baseline to Days 7, 14, and 28 in the coefficient of variation (CV) (ratio of SD:mean over 24 hours) of glucose readings as measured by CGM
• Change from baseline to Days 7, 14, and 28 in the mean amplitude of glucose excursion (MAGE) of 24-hour glucose readings as measured by CGM
• Change from baseline to Days 7, 14, and 28 in the percentage of 24 hour glucose readings obtained from CGM that fall within the euglycemic range of ≥ 70 mg/dL (≥ 3.9 mmol/L) and ≤ 180 mg/dL (≤ 10.0 mmol/L)
• Change from baseline to Days 7, 14, and 28 in the percentage of 24-hour glucose readings obtained from CGM that fall within hyperglycemic (high glucose) range of > 180 mg/dL (> 10.0 mmol/L)
• Change from baseline to Days 7, 14, and 28 in the percentage of 24 hour glucose readings obtained from CGM that fall within the hypoglycemic range of < 70 mg/dL (< 3.9 mmol/L)
• Change from baseline to Days 7, 14, and 28 in the percentage of 24 hour glucose readings obtained from CGM that fall within the clinically significant hypoglycemic range of < 54 mg/dL (3.0 mmol/L) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Refer to schedule of treatment period procedures in protocol |
|
| 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 |
| Tolerability, immunogenicity |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 | 5 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
