| 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 |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| 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 | 100000004861 |
|
| 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 demonstrate that tirzepatide 10 mg and/or 15 mg administered once weekly (QW) are noninferior to semaglutide 1 mg QW for glycemic control (mean change in HbA1c from baseline) at 40 weeks |
|
| E.2.2 | Secondary objectives of the trial |
- To demonstrate that tirzepatide 5 mg administered once weekly (QW) is noninferior to semaglutide 1 mg QW for glycemic control (mean change in HbA1c from baseline) at 40 weeks
- To demonstrate that tirzepatide 5 mg, 10 mg, and/or 15 mg QW is superior to semaglutide
1 mg QW at 40 weeks for the following:
- Mean change in body weight from baseline
- Mean change in HbA1c from baseline
- Proportion of patients with HbA1c target values of <7.0 % (53 mmol/mol)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
[1] Have been diagnosed with T2DM based on the World Health Organization classification or other locally applicable diagnostic standards
[2] Have HbA1c ≥7.0% (≥53 mmol/mol) to ≤10.5% (≤91 mmol/mol), as determined by the central laboratory at Visit 1
[3] Are of stable weight (±5%) ≥3 months preceding Visit 1 and agree to not initiate a diet and/or exercise program during the study with the intent of reducing body weight, other than the lifestyle and dietary measures for diabetes treatment
[4] Have body mass index (BMI) ≥25 kg/m2 at Visit 1
[5] Have been on stable diabetes treatment with metformin ≥1500 mg/day during the 3 months prior to Visit 1 and between Visits 1 and 3
[6] Are 18 years old or of an acceptable age to provide informed consent according to local regulations, whichever is older
Male patients
- Male patients should be willing to use reliable contraceptive methods throughout the study and for at least 3 months after last injection
Female patients:
- Female patients not of childbearing potential due to surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation), congenital anomaly (that is, Mullerian agenesis), or menopause
o Women with an intact uterus are deemed postmenopausal if they are at least 45 years old and
have not taken hormones or oral contraceptives within the last year and had cessation of menses
for at least 1 year
OR
have had at least 6 months and less than 12 months of spontaneous amenorrhea with follicle-stimulating hormone (FSH) and estradiol levels consistent with a postmenopausal state (FSH ≥40 mIU/mL and estradiol <30 pg/mL).
o Female patients of childbearing potential (not surgically sterilized and between menarche and 1-year postmenopausal) must
-test negative for pregnancy at Visit 1 based on a serum pregnancy test
AND
- if sexually active, agree to use 2 forms of effective contraception, where at least 1 form is highly effective for the duration of the trial and for 30 days thereafter).
- not be breastfeeding
[7] In the investigator’s opinion, are well motivated, capable, and willing to
(a) perform finger-stick BG monitoring, including scheduled BG profiles with up to 7 measurements in 1 day
(b) learn how to self-inject study drugs (tirzepatide or semaglutide), as required for this protocol (visually impaired persons who are not able to perform the injections must have the assistance of a sighted individual trained to inject the study drug; persons with physical limitations who are not able to perform the injections must have the assistance of an individual trained to inject the study drug)
(c) inject tirzepatide or semaglutide once weekly
(d) maintain study diaries, as required for this protocol
(e) sufficiently understand one of the provided languages of the country such that they will be able to complete the patient questionnaires
|
|
| E.4 | Principal exclusion criteria |
[1] Have type 1 diabetes mellitus (T1DM)
[2] Have a history of chronic or acute pancreatitis any time prior to study entry (Visit 1)
[3] Have a history of any of the following:
- proliferative diabetic retinopathy,
OR
- diabetic maculopathy,
OR
- nonproliferative diabetic retinopathy that requires acute treatment (a dilated fundoscopic examination performed by an ophthalmologist or optometrist between Visit 2 and Visit 3 is required to confirm eligibility)
[4] Have a history of ketoacidosis or hyperosmolar state/coma
[5] Have a history of severe hypoglycemia and/or hypoglycemia unawareness within the 6 months prior to Visit 1
[6] Have a known clinically significant gastric emptying abnormality (for example, severe diabetic gastroparesis or gastric outlet obstruction), have undergone or plan to have during the course of the study: gastric bypass (bariatric) surgery or restrictive bariatric surgery (for example, Lap-Band®), or chronically take drugs that directly affect GI motility
[7] Have any of the following cardiovascular (CV) conditions within 2 months prior to Visit 1: acute myocardial infarction, cerebrovascular accident (stroke), or hospitalization due to congestive heart failure (CHF)
[8] Have a history of New York Heart Association Functional Classification IV CHF
[9] Have acute or chronic hepatitis, signs and symptoms of any liver disease other than nonalcoholic fatty liver disease (NAFLD), or alanine aminotransferase (ALT) level >3.0 times the upper limit of normal (ULN) for the reference range, as determined by the central laboratory at study entry. Patients with NAFLD are eligible to participate in this trial if their ALT level is ≤3.0 times the ULN for the
reference range
[10] Have an estimated glomerular filtration rate <45 mL/min/1.73 m2 (or lower than the country-specific threshold for discontinuing metformin therapy per local label), calculated by Chronic Kidney Disease-Epidemiology as determined by central laboratory at Visit 1
[11] Have evidence of a significant, uncontrolled endocrine abnormality (for example, thyrotoxicosis or adrenal crises), in the opinion of the investigator
[12] Have family or personal history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN2)
[13] Have a serum calcitonin level of ≥35 ng/L, as determined by central laboratory at Visit 1
[14] Have known or suspected hypersensitivity to trial product(s) or related products
15] Have evidence of a significant, active autoimmune abnormality (for example, lupus or rheumatoid arthritis) that, in the opinion of the investigator, is likely to require concurrent treatment with systemic glucocorticoids in the next 12 months
[16] Have had a transplanted organ (corneal transplants [keratoplasty] allowed) or awaiting an organ transplant
[17] Have a history of an active or untreated malignancy or are in remission from a clinically significant malignancy (other than basal or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for less than 5 years
[18] Have any hematological condition that may interfere with HbA1c measurement (for example, hemolytic anemias, sickle cell disease)
[19] Have been treated with any antihyperglycemic medication (other than metformin) within the 3 months prior to Visit 1. An exception is for the use of insulin for gestational diabetes or short-term use (<14 days) for acute conditions such as acute illness, hospitalization, or elective surgery
[20] Have been treated with prescription drugs that promote weight loss (for example, Saxenda [liraglutide 3.0 mg], Xenical® [orlistat], Meridia® [sibutramine], Acutrim® [phenylpropanolamine], Sanorex® [mazindol], Adipex® [phentermine], BELVIQ® [lorcaserin], Qsymia® phentermine/topiramate combination], Contrave® [naltrexone/bupropion], or similar other body weight loss medications
including over-the-counter [OTC] medications [for example, allī®]) within 3 months prior to Visit 1 and/or between study entry (Visit 1) and randomization (Visit 3)
[21] Are receiving chronic (>2 weeks or 14 days) systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, or inhaled preparations) or have received such therapy within 1 month of Visit 1 or between Visits 1 and 3
[22] Are currently enrolled in any other clinical study involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study
[23] Have participated, within the last 30 days, in a clinical study involving an investigational product. If the previous investigational product has a long halflife, 5 half-lives or 30 days (whichever is longer), should have passed prior to screening
[24] Have previously completed or withdrawn from this study or any other study investigating tirzepatide
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Mean change in HbA1c from baseline |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
-Mean change in HbA1c from baseline
-Mean change in body weight from baseline
- Proportion of patients with HbA1c target values
of <7.0% (53 mmol/mol) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 |
| Each dose of tirzepatide will be double blinded. Semaglutide will be open label. |
|
| 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 | 4 |
| 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 | 12 |
| 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 | 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Israel |
| Mexico |
| United States |
|
| 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
|
| End of the study is the date of the last visit or last scheduled procedure shown in the protocol for the last patient. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 4 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| 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 | 22 |
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