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. |
|
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. |
|
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 | 18.1 |
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 metformin ≥1500 mg/day, after 26 weeks:
1. To assess the A1C-lowering efficacy of the addition of ertugliflozin 15 mg q.d. plus sitagliptin 100 mg q.d. compared with the addition of sitagliptin 100 mg q.d. alone.
2. To assess the A1C-lowering efficacy of the addition of ertugliflozin 15
mg q.d. plus sitagliptin 100 mg q.d. compared with the addition of ertugliflozin 15 mg q.d. alone.
3. To assess the A1C-lowering efficacy of the addition of ertugliflozin 5 mg
q.d. plus sitagliptin 100 mg q.d. compared with the addition of sitagliptin 100 mg q.d. alone.
4. To assess the A1C-lowering efficacy of the addition of ertugliflozin 5 mg
q.d. plus sitagliptin 100 mg q.d. compared with the addition of ertugliflozin 5 mg q.d. alone.
5. To assess the safety and tolerability of the addition of ertugliflozin plus
sitagliptin 100 mg q.d., ertugliflozin alone, and sitagliptin 100 mg q.d. alone. |
|
E.2.2 | Secondary objectives of the trial |
In subjects with T2DM and inadequate glycemic control on metformin ≥1500 mg/day, after 26 weeks:
1. To assess the body weight-lowering efficacy of the addition of ertugliflozin plus sitagliptin 100 mg q.d. compared with the addition of sitagliptin 100 mg q.d. alone.
2. To assess the fasting plasma glucose (FPG) -lowering efficacy of the addition of ertugliflozin plus sitagliptin 100 mg q.d. compared with the addition of ertugliflozin alone and sitagliptin 100 mg q.d. alone.
3. To assess the change from baseline in systolic and diastolic blood pressure with the addition of ertugliflozin plus sitagliptin 100 mg q.d. compared with the addition of sitagliptin 100 mg q.d. alone.
4. To assess the proportion of subjects at target A1C control [A1C <7% (<53 mmol/mol)] with the addition of ertugliflozin plus sitagliptin 100 mg q.d. compared with the addition of ertugliflozin alone and sitagliptin 100 mg q.d. alone.
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 [15] and be ≥18 years of age on the day of signing the ICF.
2. Meet one of the following criteria:
* On metformin monotherapy (≥1500 mg/day) for ≥8 weeks with a Visit 1/Screening A1C ≥7.5% and ≤11.0% (≥58 mmol/mol and ≤97 mmol/mol)
* On metformin monotherapy (≥1500 mg/day) for <8 weeks with a Visit 1/Screening A1C ≥7.5% and ≤11.0% (≥58 mmol/mol and ≤97 mmol/mol)
OR
* On metformin monotherapy <1500 mg/day with a Visit 1/Screening A1C ≥8.0%
and ≤11.5% (≥64 mmol/mol and ≤102 mmol/mol)
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).
† 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, post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception.
At Visit 3/Week -2
7. Be on metformin monotherapy (≥1500 mg/day) for ≥8 weeks with a Visit 3/Week -2 A1C ≥7.5% and ≤11.0% (≥58 mmol/mol and ≤97 mmol/mol).
Note: Subjects who are already on metformin at ≥1500 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 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 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
* Alpha glucosidase inhibitors or meglitinides
* Dipeptidyl-peptidase 4 inhibitor (DPP-4 inhibitor)
* Sulfonylureas (SUs)
* 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., antipsychotic 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.
15. Has an exclusionary laboratory value as listed in protocol Table 3 (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 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 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.
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.
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, 3-10, Rescue, Discontinuation
2) Visits 1, 3-10, Rescue, Discontinuation
3) Visits 3-5, 8, Rescue
4) Visits, 3, 8, 10, Rescue, Discontinuation
5) Visits, 3, 8, 10, Discontinuation
6) Visits 3-10, Rescue, Discontinuation
7) Throughout the study |
|
E.5.2 | Secondary end point(s) |
Laboratory Assessments
8) FPG
9) A1C
10) Fasting C-peptide
11) Lipid Panel
12) Chemistry Panel
13) Hematology
14) Urine Collection (Urinalysis and Urine Albumin/Creatinine Ratio)
15) Urine Pregnancy Test (women of childbearing potential only)
16) MMTT at selected sites: Blood samples at -30, 0, 15, 30, 60, 90, 120, and 180 minute samples, relative to the start of the meal, for glucose, insulin, and C-peptide
17) PK Sample for Ertugliflozin: Pre-Dose
18) PK Sample for Ertugliflozin as Part of MMTT: 0, 60 and 120 minutes Post Dose
19) 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 4, 8, 10, Rescue, Discontinuation
12) Visits 1, 3-10, Rescue, Discontinuation
13) Visits 1, 3, 4, 6, 8, 10, Rescue, Discontinuation
14) Visits 2, 4, 8, 10, Rescue, Discontinuation
15)Visits 1, 4-10, Rescue, Discontinuation
16) Visits 4, 8, Rescue, Discontinuation
17) Visits 5, 6, 8
18) Visit 8
19) Visits 4, 8, 10, 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 | 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 | 5 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 104 |
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 |
Canada |
Chile |
Colombia |
Czech Republic |
Finland |
Germany |
Hungary |
Israel |
Italy |
Malaysia |
Mexico |
New Zealand |
Peru |
Philippines |
Poland |
Romania |
Russian Federation |
Slovakia |
Spain |
Thailand |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |