E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of type 2 diabetes mellitus (T2DM) with Inadequate Glycemic Control on Diet and Exercise |
|
E.1.1.1 | Medical condition in easily understood language |
Type 2 Diabetes Whose Sugar Levels are NOT Well Controlled by Their Current Diet and Excersise regime. |
|
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 | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10063624 |
E.1.2 | Term | Type II diabetes mellitus inadequate control |
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 |
In subjects with T2DM and inadequate glycemic control on diet and exercise, after 26 weeks:
1. To assess the A1C-lowering efficacy of ertugliflozin 15 mg q.d. plus sitagliptin 100 mg q.d. relative to placebo.
2. To assess the A1C-lowering efficacy of ertugliflozin 5 mg q.d. plus sitagliptin 100 mg q.d. relative to placebo.
3. To assess the safety and tolerability of ertugliflozin plus sitagliptin 100 mg q.d.
|
|
E.2.2 | Secondary objectives of the trial |
1. To assess the fasting plasma glucose (FPG) -lowering efficacy of ertugliflozin 15 mg q.d. plus sitagliptin 100 mg q.d. relative to placebo.
2. To assess the FPG-lowering efficacy of ertugliflozin 5 mg q.d. plus sitagliptin 100 mg q.d. relative to placebo.
3. To assess the efficacy of ertugliflozin 15 mg q.d. plus sitagliptin 100 mg q.d. on 2-hour post-meal glucose (PMG) (following a standard meal) relative to placebo.
4. To assess the efficacy of ertugliflozin 5 mg q.d. plus sitagliptin 100 mg q.d. on 2-hour PMG (following a standard meal) relative to placebo.
5. To assess the proportion of subjects at target A1C control [A1C <7% (<53 mmol/mol)] and with A1C <6.5% (48 mmol/mol) with ertugliflozin 15 mg q.d. plus sitagliptin 100 mg q.d. relative to placebo.
See protocol section 3.2 for the full list of secondary objectives. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
At Visit 1/Screening
1. Have T2DM in accordance with ADA guidelines [20] and be ≥18 years of age on the day of signing the ICF.
2. Meet one of the following criteria:
• Not on AHA for ≥8 weeks with a Visit 1/Screening A1C ≥8.0% and ≤10.5% (≥64 mmol/mol and ≤91 mmol/mol)
OR
• On single allowable AHA with a Visit 1/Screening A1C ≥7.5% and ≤10.0% (≥58 mmol/mol and ≤86 mmol/mol)
OR
• On low-dose dual combination therapy with allowable AHAs with a Visit 1/Screening A1C ≥7.5% and ≤10.0% (≥58 mmol/mol and ≤86 mmol/mol)
NOTE: Allowable AHAs prior to screening are: metformin, α-glucosidase inhibitors, sulfonylureas and glinides.
NOTE: “low dose” defined as ≤50% of maximum labeled dose of an AHA.
3. Have a body mass index (BMI) ≥18.0 kg/m2.
4. Have personally signed and dated the ICF indicating that he/she has been informed of all pertinent aspects of the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
5. Be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
6. Meet one of the following criteria:
a. Subject is a male
b. Subject is a female not of reproductive potential defined as one who:
(1) is postmenopausal (defined as at least 12 months with no menses in women ≥45 years of age) or
(2) has had a hysterectomy and/or bilateral oophorectomy, or had bilateral tubal ligation or occlusion at least 6 weeks prior to Visit 1/Screening
c. Subject is a female of reproductive potential and:
(1) agrees to remain abstinent from heterosexual activity or
(2) agrees to use (or have their partner use) acceptable contraception to prevent pregnancy within the projected duration of the trial and for 14 days after the last dose of blinded investigational product. Two methods of contraception will be used to avoid pregnancy. Acceptable combinations of methods include:
• Use of one of the following double-barrier methods: diaphragm with spermicide and a condom; cervical cap and a condom; or a contraceptive sponge and condom.
• Use of hormonal contraception (any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent [including oral, subcutaneous, intrauterine and intramuscular agents, and cutaneous patch]) with one of the following: diaphragm with spermicide; cervical cap; contraceptive sponge; condom; vasectomy; or IUD.
• Use of an IUD with one of the following: condom; diaphragm with spermicide; contraceptive sponge; vasectomy; or hormonal contraception (see above).
• Vasectomy with one of the following: diaphragm with spermicide; cervical cap; contraceptive sponge; condom; IUD; or hormonal contraception (see above).
At Visit 3/Week -2
7. A1C ≥8.0% and ≤10.5% (≥64 mmol/mol and ≤91 mmol/mol).
Note: Subjects who are not on an AHA for ≥8 weeks at Visit 1/Screening, going directly to a combined Visit 2/3 at Week 2, will have the Visit 1/Screening A1C determination used to assess this inclusion criterion if the Visit 1/Screening A1C was obtained within 2 weeks of the combined Visit 2/3.
At Visit 4/Day 1
8. Be ≥80% compliant with the placebo run-in medication (as determined by site-performed pill count). |
|
E.4 | Principal exclusion criteria |
Diabetes Diagnosis and Prior Therapy Criteria
1. Has a history of type 1 diabetes mellitus or a history of ketoacidosis or subject assessed by the investigator as possibly having type 1 diabetes mellitus confirmed with a C-peptide <0.7 ng/mL (0.23 nmol/L).
Note: Only subjects assessed by the investigator as possibly having type 1 diabetes should have C-peptide measured at Visit 1/Screening.
2. Has a history of other specific types of diabetes (e.g., genetic syndromes, secondary pancreatic diabetes, diabetes due to endocrinopathies, drug- or chemical-induced, and post-organ transplant).
3. Has a known hypersensitivity or intolerance to any SGLT2 inhibitor or sitagliptin.
4. Has been treated with any of the following agents within 12 weeks of Visit 1/Screening or during the pre-randomization period:
• Insulin of any type (except for short-term use [i.e., ≤7 days] during concomitant illness or other stress)
• Other injectable anti-hyperglycemic agents (e.g., pramlintide, exenatide, liraglutide)
• Pioglitazone or rosiglitazone
• Other SGLT2 inhibitors
• Dipeptidyl-peptidase 4 inhibitors (DPP-4 inhibitor)
• Bromocriptine (Cycloset™)
• Colesevelam (Welchol™)
• Any other AHA with the exception of the protocol-approved agents
5. Meets the following criteria:
• Subject is on weight loss program and is not weight-stable.
• Subject is on a weight-loss medication (e.g., orlistat, phentermine/topiramate, lorcaserin) and is not weight-stable.
• Subject is on other medications associated with weight changes (e.g., anti-psychotic agents) and is not weight-stable.
• Subject has undergone bariatric surgery >12 months prior to Visit 1/Screening and is not weight-stable.
• Subject has undergone bariatric surgery within 12 months of Visit 1/Screening.
Note: Weight-stable is defined as <5% change in body weight in the last 6 months.
Concomitant Disease of Organs and Systems
6. Has a history of myocardial infarction, unstable angina, arterial revascularization, stroke, transient ischemic attack, or NYHA functional class III-IV heart failure within 3 months of Visit 1/Screening.
7. Has active, obstructive uropathy or indwelling urinary catheter
8. Has a history of malignancy ≤5 years prior to signing the ICF, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer:
Note (1) A subject with a history of malignancy ≥5 years prior to signing informed consent should have no evidence of residual or recurrent disease.
Note (2) A subject with a history of melanoma, leukemia, lymphoma, or renal carcinoma is excluded.
9. Has human immunodeficiency virus (HIV) as assessed by medical history.
10. Has
• A blood dyscrasia or any disorder causing hemolysis or unstable red blood cells, or
• A clinically important hematological disorder (such as aplastic anemia, myeloproliferative or myelodysplastic syndromes, thrombocytopenia).
11. Has a medical history of active liver disease (other than non-alcoholic hepatic steatosis), including chronic active hepatitis B or C (assessed by medical history), primary biliary cirrhosis, or symptomatic gallbladder disease.
12. Has any clinically significant malabsorption condition.
13. Is currently being treated for hyperthyroidism
14. Is on thyroid replacement therapy and has not been on a stable dose for at least 6 weeks prior to Visit 1/Screening.
Note: Subjects who meet this criterion may be re-screened after being on a stable dose of thyroid replacement therapy for at least 6 weeks.
Exclusion Criteria Based on Laboratory Abnormalities
15. Has an exclusionary laboratory value as listed in Table 3 of the protocol (page 30):
Other Criteria
16. Has been previously randomized in a study with ertugliflozin.
17. Has participated in other studies involving investigational drug(s) (Phase 1-4) within 30 days prior to Visit 1/Screening or during the pre-randomization period.
18. Has undergone a surgical procedure within 6 weeks prior to signing the ICF or has major surgery planned during the trial.
Note: A subject who has undergone minor surgery within the 6 weeks prior to Visit 1/Screening and is fully recovered or a subject who has planned minor surgery may participate. Minor surgery is defined as a surgical procedure involving local anesthesia.
19. Has a positive urine pregnancy test.
20. Is pregnant or breast-feeding, or is planning to conceive during the trial, including 14 days following the last dose of blinded investigational product.
Please see protocol section 5.1.3 for the full list of exclusion criteria |
|
E.5 End points |
E.5.1 | Primary end point(s) |
1) Body weight
2) Vital Signs (pulse rate and blood pressure)
3) Postural blood pressure and pulse rate
4) Physical Examination
5) 12-lead ECG
6) Review of SMBG Measurements and HAL
7) Adverse event monitoring |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) Visits 1, 3-8, Rescue, Discontinuation
2) Visits 1, 3-8, Rescue, Discontinuation
3) Visits 3-5, 8, Rescue, Discontinuation
4) Visits, 3, 8, Rescue, Discontinuation
5) Visits, 3, 8, Rescue, Discontinuation
6) Visits 3-8, Rescue, Discontinuation
7) Throughout the study |
|
E.5.2 | Secondary end point(s) |
Laboratory Assessments
8) FPG
9) A1C
10) Mixed Meal Tolerance Test
11) Fasting C-peptide
12) Lipid Panel
13) Chemistry Panel
14) Hematology |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
8) Visits 1, 3-8, Rescue, Discontinuation
9) Visits 1, 3-8, Rescue, Discontinuation
10) Visits 4, 8, Rescue, Discontinuation
11) Visit 1
12) Visits 4, 8, Rescue, Discontinuation
13) Visits 1, 3-8, Rescue, Discontinuation
14) Visits 1, 3, 4, 6, 8, Rescue, Discontinuation |
|
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 | No |
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) | 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 | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 36 |
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 |
Bulgaria |
Croatia |
Czech Republic |
Estonia |
Hungary |
Israel |
Italy |
Serbia |
Ukraine |
United Kingdom |
United States |
|
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
|
|
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 | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |