| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 19.1 |
| 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 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045242 |
| E.1.2 | Term | Type II diabetes mellitus |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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| 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 determine whether ITCA 650 is non-inferior either to empagliflozin or to glimepiride in reducing glycosylated hemoglobin (HbA1c) or weight in patients with type 2 diabetes (T2D) following 65 weeks of treatment. The non-inferiority margins are 0.3% and 1.5 kg, for HbA1c and weight, respectively. If non-inferiority is demonstrated, then ITCA 650 will be tested for corresponding superiority. |
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| E.2.2 | Secondary objectives of the trial |
Following 65 weeks of treatment of either ITCA 650, empagliflozin, or glimepiride:
Key secondary objective:
- To compare % of patients in each arm with decrease in HbA1c ≥1.0% and ≥2 kg weight loss
Other secondary objectives:
- To compare % of patients in each arm who need rescue and % of patients in each arm achieving treatment to goal defined as HbA1c <7%
- To compare % of patients in each arm achieving treatment to goal defined as HbA1c ≤6.5%
- To determine the overall safety and tolerability of ITCA 650 compared with empagliflozin and with glimepiride
- To determine the change in fasting plasma glucose in patients on ITCA 650 compared with empagliflozin and glimepiride
- Time to rescue will also be conducted using the log-rank test and Kaplan-Meier curve for ITCA vs. empagliflozin and ITCA vs. glimepiride
- To characterize treatment satisfaction, as measured by the patient reported outcome questionnaire [DTSQ] with ITCA 650 compared with empagliflozin and with glimepiride |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Understanding of the study procedures and conditions of the protocol and agreement to participate in the study by providing a signed and dated informed consent prior to any study-specific procedures.
2. Male or female patients 18 to 80 years old, inclusive.
3. Diagnosis of T2D ≥ 3 months prior to the Screening Visit.
4. Body mass index (BMI) between ≥ 25 to ≤ 45 kg/m2 at the Screening Visit.
5. Stable body weight (not varying by >10%) ≥ 3 months prior to the Screening Visit.
6. Glycosylated hemoglobin A1c (HbA1c) ≥7.5 and ≤10.5%. One re-test of this parameter is allowed prior to Visit 2.
7. Calcitonin <50 ng/L (50 pg/mL) at the Screening Visit.
8. On a stable (≥ 3 months prior to the Screening Visit) treatment regimen of metformin monotherapy of ≥1500 mg/day.
9. Agreement to maintain the same dose of background metformin from the Screening Visit to the end of the study (unless a change is clinically indicated).
10. Women may be enrolled if all of the following criteria (in addition to other criteria) are met: they are not pregnant; they are not breast feeding; and they do not plan on becoming pregnant during the study.
11. Women of childbearing potential (WOCBP) must have a negative pregnancy test at the Screening Visit. Women are considered to be of childbearing potential unless they meet one of the following criteria as documented by the Investigator:
• They have had a hysterectomy or tubal ligation prior to signing the informed consent form (ICF); or
• They are post-menopausal, defined for women ≤ 50 years old as ≥ 2 years since their last menstrual period and for women >50 years old as ≥ 1 year since their last menstrual period.
12. WOCBP must agree to use an adequate method of contraception during the study and for 1 additional menstrual cycle after the Follow-up visit. Women practicing abstinence or whose partner(s) is (are) sterile should be considered to be of childbearing potential. Adequate methods of contraception for WOCBP include: oral, implanted or injectable contraceptive hormones; mechanical products (intrauterine device); or barrier methods (diaphragm, condoms, cervical cap) with spermicide. The patient’s understanding of this requirement must be documented by the Investigator.
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| E.4 | Principal exclusion criteria |
Diabetes Therapy or History
1. History of type 1 diabetes, diabetes that is the result of pancreatic injury, or secondary forms of diabetes, (eg, Cushing’s syndrome) and/or acute metabolic complications such as diabetic ketoacidosis or hyperosmolar state (coma)
2. Participation in a clinical study involving ITCA 650
3. Treatment with any GLP-1 receptor agonist within 6 months prior to Screening or at any time in the past if therapy was discontinued due to gastrointestinal intolerance. This includes treatment during participation in a clinical study
4. Treatment with any of the following antidiabetic agents within 3 months prior to Screening: sodium-glucose cotransporter-2 inhibitors, sulfonylureas, dipeptidyl peptidase-4 inhibitors, alpha glucosidase inhibitors, meglitinides, thiazolidinediones, bile acid sequestrants (eg, colesevelam), dopamine receptor agonists (eg, bromocriptine), amylin analogues (eg, pramlitide), or insulin. NOTE: History of short term (<14 days) use of insulin is allowed as long as the last dose was administered more than 2 weeks prior to the Screening
5. FPG >270 mg/dL (15 mmol/L). One re-test of this parameter is allowed prior to randomization
6. Significant symptomatic hyperglycemia: polyuria, polydipsia, unexplained weight loss
History
7. Any condition, clinically significant laboratory abnormality or therapy, which might pose a risk to the patient, or interfere with the conduct of the study or interpretation of the safety and efficacy data
8. Alcohol or substance abuse within 1 year prior to Screening
9. Treatment with an investigational drug within 30 days prior to screening or 5 half-lives (whichever is longer); participation in a clinical study involving an investigational product or non-approved use of a drug or device or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study
10. History of hypersensitivity to exenatide, empagliflozin, or glimepiride or to one of its excipients
11. Contraindications or warnings according to the specific labels for metformin, empagliflozin, or glimepiride therapy
Endocrine
12. History of medullary thyroid cancer or a family or personal history of multiple endocrine neoplasia type 2
13. Presence of a thyroid nodule, detected on a physical examination that has not been fully evaluated
14. Thyroid-stimulating hormone outside of normal limits at Screening. One re- test of this parameter is allowed prior to inclusion
15. Thyroid hormone therapy that has not been stable for ≥6 weeks prior to Screening
Cardiovascular
16. History or evidence, within the last 6 months prior to the Screening Visit, of any of the following: myocardial infarction, coronary revascularization (coronary artery bypass grafting or percutaneous coronary intervention), unstable angina, cerebrovascular accident or stroke
17. Uncontrolled hypertension: sitting systolic blood pressure ≥180 mmHg and /or sitting diastolic blood pressure >100 mmHg at Screening (may be repeated after 15 minutes and exclusion will be based on the last measurement)
18. Congestive heart failure (Grade III and IV acc. to NYHA classification)
Renal
19. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at the Screening
Hepatic/Pancreatic/Gastrointestinal
20. History or evidence of acute or chronic pancreatitis
21. History of weight loss surgery
22. History of current infectious liver disease including hepatitis B or hepatitis C virus. Patients who have isolated, positive anti-hepatitis B surface antibody may be included
23. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) or alkaline phosphatase 3 × above upper limit of normal (ULN) at Screening
24. Bilirubin 2 × above ULN at Screening
25. Fasting triglycerides ≥500 mg/dL at Screening
Oncologic/Neoplastic
26. History of malignancy (not including basal or squamous cell carcinoma of the skin) within the past 5 years; patients who have been disease free for 5 years may be included
Immune System
27. History or evidence of immunocompromised status, including but not limited to individuals who have undergone organ transplantation or who are known to be positive for the HIV
28. Requires treatment with immunosuppressant therapy. Low dose methotrexate (≤7.5 mg/week) for the treatment of rheumatoid arthritis is allowed
Other Medical Conditions
29. Donation of 1 unit (500 mL) or more of blood, significant blood loss equaling at least 1 unit of blood or transfusion within 30 days prior to Screening
30. Poor mental function or any other reason to expect patient difficulty in complying with the study requirements
31. Chronic (>10 consecutive days) treatment with systemic corticosteroids within 8 weeks prior to screening (intra-nasal, intra-articular, intra-ocular, inhaled or topical steroids are permitted)
32. Requires treatment with weight-loss medications
33. Requires treatment with medications that affect GI motility |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
PRIMARY EFFICACY ENDPOINTS:
Co-primary endpoints:
- Change from baseline in HbA1c at Week 65.
- Change from baseline in weight at Week 65. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
KEY SECONDARY EFFICACY ENDPOINT
- Percentage of patients with a decrease in HbA1c ≥1.0% and ≥2 kg weight loss at Week 65.
OTHER SECONDARY EFFICACY ENDPOINTS:
- Percentage of patients who need rescue during the 65-week period.
- Percentage of patients with treatment to goal defined as HbA1c <7% at Week 65.
- Percentage of patients with treatment to goal defined as HbA1c ≤6.5% at Week 65.
- Change from baseline in FPG at Week 65.
- PROs: DTSQ scores. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 65
Exception applicable for:
- "Percentage of patients who need rescue during the 65-week period": during the treatment period
- "PROs: DTSQ scores": during the treatment period
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| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| 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 |
| Pharmacokinetic/pharmacodynamic and exenatide antibody testing to be performed on the ITCA 650 arm in the USA only. No sites in the EU will participate in this testing. |
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| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 71 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Brazil |
| Canada |
| France |
| Germany |
| Italy |
| Korea, Republic of |
| Netherlands |
| Russian Federation |
| Spain |
| Sweden |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 2 |
| 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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