| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of type 2 diabetes mellitus (T2DM) and inadequate glycemic control on treatment with metformin and sitagliptin. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Type 2 Diabetes Whose Sugar Levels are NOT Well Controlled by Their Current Treatment with Metformin and Sitagliptin. |
|
| 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 | 19.0 |
| 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 |
After 26 weeks, in subjects with T2DM and inadequate glycemic control on treatment with
metformin ≥1500 mg/day and sitagliptin 100 mg q.d.:
1) To assess the A1C-lowering efficacy of the addition of ertugliflozin 15 mg q.d. relative to the addition of placebo.
2) To assess the A1C-lowering efficacy of the addition of ertugliflozin 5 mg q.d. relative to the addition of placebo.
3) To assess the safety and tolerability of the addition of ertugliflozin. |
|
| E.2.2 | Secondary objectives of the trial |
After 26 weeks, in subjects with T2DM and inadequate glycemic control on treatment with
metformin≥1500 mg/day and sitagliptin 100 mg q.d.:
1) To assess the fasting plasma glucose (FPG)-lowering efficacy of the addition of ertugliflozin 15 mg q.d. relative to the addition of placebo.
2) To assess the FPG-lowering efficacy of the addition of ertugliflozin 5 mg q.d. relative to the addition of placebo.
3) To assess the effect of the addition of ertugliflozin 15 mg q.d. relative to the addition of placebo on body weight.
4) To assess the effect of the addition of ertugliflozin 5 mg q.d. relative to the addition of placebo on body weight.
5) To assess the effect of the addition of ertugliflozin 5 mg q.d. relative to the addition of placebo on the proportion of subjects with an A1C<7.0% (53 mmol/mol).
6) To assess the effect of the addition of ertugliflozin 15 mg q.d. relative to the addition of placebo on systolic blood pressure.
See protocol section 3.2 for all 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 [1] and be ≥18 years of age on the day of signing the informed consent form (ICF).
2. Meet one of the following criteria:
* On metformin ≥1500 mg/day and sitagliptin 100 mg/day for ≥8 weeks with an A1C ≥7.0% and ≤10.5% (≥53 mmol/mol and ≤91 mmol/mol)
OR
* On metformin ≥1500 mg/day and sitagliptin 100 mg/day for <8 weeks with an A1C ≥7.0% and ≤10.5% (≥53 mmol/mol and ≤91 mmol/mol)
OR
* On metformin ≥1500 mg/day and a DPP-4 inhibitor (other than sitagliptin) with an A1C ≥7.0% and ≤10.5% (≥53 mmol/mol and ≤91 mmol/mol)
OR
* On metformin ≥1500 mg/day and an SU with an A1C ≥7.0% and ≤10.5% (≥53 mmol/mol and ≤91 mmol/mol)
OR
* On metformin <1500 mg/day and any DPP-4 inhibitor with an A1C ≥7.5% and ≤11.0% (≥58 mmol/mol and ≤97 mmol/mol)
Note: Subjects on an FDC with metformin and a DPP-4 inhibitor at Visit 1/Screening will switch to co-administration treatment with metformin (titrated to ≥1500 mg/day as needed) and sitagliptin 100 mg q.d. at Visit 2 or Combined Visit 2/3 (as appropriate).
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.
c) Subject is a female of reproductive potential and:
1) agrees to remain abstinent from heterosexual activity
2) agrees to use (or have her partner use) acceptable contraception to prevent pregnancy while receiving blinded investigational product 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).
Abstinence can be used as the sole method of contraception if it is in line with the subject’s
preferred and usual lifestyle and if considered acceptable by local regulatory agencies and
ethics committees. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, postovulation methods, etc.) and withdrawal are not acceptable methods of contraception.
At Visit 3/Week -2
7. Be on metformin (≥1500 mg/day) and sitagliptin (100 mg/day) for ≥8 weeks and have an A1C ≥7.0% and ≤10.5% (≥53 mmol/mol and ≤91 mmol/mol).
Note: Subjects who are already on metformin ≥1500 mg/day and sitagliptin 100 mg/day 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 single-blind placebo run-in medication (as determined by site performed pill count). |
|
| E.4 | Principal exclusion criteria |
At Visit 1/Screening
Diabetes Diagnosis and Prior Therapy Criteria
1. Has a history of type 1 diabetes mellitus or a history of ketoacidosis, or subject is 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 any DPP-4 inhibitor.
4. Meets any of the following criteria:
* Subject is on a 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., antipsychotic agents) and is not weight-stable.
* Subject has undergone bariatric surgery within 12 months of Visit 1/Screening.
* Subject has undergone bariatric surgery >12 months prior to Visit 1/Screening and is not weight stable.
Note: Weight-stable is defined as <5% change in body weight in the last 6 months.
5. Has been treated with any of the following agents within 12 weeks of Visit 1/Screening:
* Insulin of any type (except for short-term use [i.e., ≤7 days] during concomitant illness or other stress)
* Other injectable AHAs (e.g., pramlintide, exenatide, liraglutide)
* Pioglitazone or rosiglitazone
* Other SGLT2 inhibitors
* Alpha glucosidase inhibitors or meglitinides
* Bromocriptine (Cycloset™)
* Colesevelam (Welchol™)
* Any other AHA with the exception of the protocol-approved agents
Concomitant Disease of Organs and Systems
6. Has active, obstructive uropathy or indwelling urinary catheter.
7. 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.
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 the ICF should have no evidence of residual or recurrent disease.
Note (2): A subject with any history of melanoma, leukemia, lymphoma, or renal cell carcinoma is excluded.
9. Has human immunodeficiency virus (HIV) as assessed by medical history.
10. Has
* Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells, or
* Clinically important hematological disorders (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 active 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 (pg 30)
Other Criteria
16. Has been previously randomized in a study with ertugliflozin.
17. Has participated in other studies involving investigational drug(s) (Phase I-IV) within 30 days prior to Visit 1/Screening.
18. Has undergone a surgical procedure within 6 weeks prior to signing the ICF or has planned major surgery 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.
21. Is planning to undergo hormonal therapy in preparation to donate eggs during the trial, including 14 days following the last dose of blinded investigational product.
For the full list of exclusion criteria see protocol section 5.1.3. |
|
| 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) EQ-5D-3L Assessment
6) 12-lead ECG
7) Review of SMBG Measurements and HAL
8) Adverse event monitoring |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) Visits 1, 3-10, Rescue, Discontinuation
2) Visits 1, 3-10, Rescue, Discontinuation
3) Visits 3-5, 8, Rescue
4) Visits, 3, 8, 10, Rescue, Discontinuation
5) Visits 4, 8, 10
6) Visits, 3, 8, 10, Discontinuation
7) Visits 3-10, Rescue, Discontinuation
8) Throughout the study |
|
| E.5.2 | Secondary end point(s) |
Laboratory Assessments
9) FPG
10) A1C
11) Fasting C-peptide
12) Lipid Panel
13) Chemistry Panel
14) Hematology
15) Urine Collection for Urinalysis
16) Urine Pregnancy Test (women of childbearing potential only)
17) Plasma and serum for Future Biomedical Research |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
9) Visits 1, 3-10, Rescue, Discontinuation
10) Visits 1, 3-10, Rescue, Discontinuation
11) Visits 1, 4, 8, 10, Rescue, Discontinuation
12) Visits 4, 8, 10, Rescue, Discontinuation
13) Visits 1, 3-10, Rescue, Discontinuation
14) Visits 1, 3, 4, 6, 8, 10, Rescue, Discontinuation
15) Visits 4, 8, 10, Rescue, Discontinuation
16) Visits 1, 4-10, Rescue, Discontinuation
17) Visits 4, 8, 10, 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 | Yes |
| 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 | 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 | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
| Bulgaria |
| Colombia |
| Czech Republic |
| Finland |
| Hungary |
| Israel |
| Italy |
| Korea, Republic of |
| Romania |
| 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 | 1 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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