| 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 | 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 |
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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 |
1. To compare the addition of ertugliflozin with the addition of placebo on the change from baseline in hemoglobin A1C (A1C) at 24 weeks
2. To assess the safety and tolerability of ertugliflozin over 24 weeks and 54 weeks
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| E.2.2 | Secondary objectives of the trial |
1. To compare the addition of ertugliflozin, with dosing optimized according to A1C response, to the addition of placebo on the change from baseline in A1C at 24 weeks.
2. To compare the addition of ertugliflozin 5 mg with the addition of placebo on the change from baseline in A1C at 24 weeks.
3. To compare the effect of the addition of ertugliflozin to the addition of placebo on the change from baseline in fasting plasma glucose (FPG) at 24 weeks
4. To assess the within-group (ertugliflozin and placebo) changes from baseline at 54 weeks for A1C and FPG |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have T2DM as indicated by “yes” answers to all of the following:
i. Participant has diabetes diagnosed by one of the following American Diabetes Association (ADA) criteria, eg:
a) Laboratory determinations of FPG ≥126 mg/dL (7.0 mmol/L), OR
b) Random plasma glucose ≥200 mg/dL (11.1 mmol/L), OR
c) 2-hour oral glucose tolerance test (OGTT) plasma glucose ≥200 mg/dL (11.1 mmol/L), OR
d) A1C ≥6.5% (48 mmol/mol) test performed using a method that is National Glycohemoglobin Standardization Program (NGSP) certified and standardized to the Diabetes Control and Complications Trial (DCCT) assay
ii. Participant has BMI ≥85th percentile at screening OR
participant has a history of being overweight or obese at time of diagnosis of T2DM
2. Have:
i. T2DM for ≥2 years, OR
ii. T2DM for <2 years and a fasting C-peptide value >0.6 ng/mL at Screening Visit/Visit 1
3. Be:
i. On stable metformin monotherapy (≥1500 mg/day, for ≥8 weeks prior to Screening Visit/Visit 1), OR
ii. On a stable metformin dose (≥1500 mg/day, for ≥8 weeks prior to Screening Visit/Visit 1) and a stable dose of insulin (of any type, variance in dose to be ≤15% of total daily dose for ≥8 weeks prior to Screening Visit/ Visit 1)
4. Have an A1C ≥6.5% and ≤10.0% (48 mmol/mol and 86 mmol/mol) at Screening Visit/Visit 1 if on metformin monotherapy, OR an A1C ≥7.0% and ≤10.0% (53 mmol/mol and 86 mmol/mol) at Screening Visit/Visit 1 if on metformin + insulin
5. Be male or female, ≥10 years and ≤17 years of age, when the informed consent is signed by the legally acceptable representative, and randomization (Visit 3/Day 1/Randomization) will occur prior to the participant’s 18th birthday
6. Contraceptive use by male participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
7. Contraceptive use by female participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
8. Be a female participant who is unlikely to conceive as indicated by at least 1 “yes” response to the following which will remain consistent for the projected duration of the study and for 14 days after the last dose of study treatment:
i. Participant is a non-sterilized female who is currently not sexually active and agrees to follow statement “iii” if heterosexual activity is initiated, OR
ii. Participant is a non-sterilized female who agrees to abstain from heterosexual activity
iii. Participant is a non-sterilized female who agrees to start contraception prior to initiating sexual activity and who agrees to use an adequate method of contraception
9. Have a legally acceptable representative who understands the study procedures,alternative treatments available and risks involved with the study, and voluntarily agrees to the child's participation by giving informed written consent, and the participant has an age-appropriate understanding of the same by giving informed written assent. In addition, the legally acceptable representative may also consent to have the child participate in Future Biomedical Research (FBR) by signing a separate consent. Otherwise eligible participants will be able to participate in the main study even if they opt to not participate in FBR
10. Have a family member or adult who, along with the participant, will be closely involved in the participant’s daily activities (in the opinion of the investigator) and in the participant's treatment and study procedures (ie, available for telephone calls, study visits and administration of study medication as needed)
11. Have ≥80% compliance with placebo treatment during the single-blind run-in as measured by site-performed tablet count |
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| E.4 | Principal exclusion criteria |
At Screening Visit/Visit 1
1. Is or has an immediate family member who is investigational site or Sponsor staff directly involved with this study
2. Has known type 1 diabetes mellitus or documented evidence of positive diabetes autoantibodies performed when participant was diagnosed with diabetes
3. Has known monogenic diabetes, or secondary diabetes
4. Has symptomatic hyperglycemia and/or moderate to large ketonuria requiring immediate initiation of another antihyperglycemic agent, including insulin
5. Has active, obstructive uropathy or indwelling urinary catheter
6. Has history of malignancy ≤5 years prior to signing informed consent, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer
7. Has a known hypersensitivity or intolerance to any SGLT2 inhibitor
8. Has active liver disease (other than non-alcoholic hepatic steatosis) by history, including chronic active hepatitis B or C, primary biliary cirrhosis, or symptomatic gallbladder disease
9. Has active nephropathy or abnormalities of genitourinary tract that predispose to recurrent urinary tract infections
10. Meets any of the following criteria:
i. Participant is on a weight-loss program and is not weight-stable
ii. Participant is on a weight-loss or weight changes medications and is not weight-stable
iii. Participant had bariatric surgery at any time in the past
11. Has been previously diagnosed with disorders of growth or bone metabolism
12. Has a clinically significant hematological disorder (such as aplastic anemia, thrombocytopenia, myeloproliferative or myelodysplastic syndrome)
13. Is pregnant, or breast feeding or is expecting to conceive or donate eggs during the study, including 14 days following the last dose of study medication
14. Has been treated with a sulfonylurea, metiglinide, alpha glucosidase inhibitor, DPP-4 inhibitor, or incretin-based agent in the 8 weeks prior to Screening Visit/Visit 1
15. Has been treated with a thiazolidinedione in the 16 weeks prior to Screening Visit/Visit 1
16. Is taking blood pressure medication(s) and will not be on a stable dose for at least 4 weeks prior to Visit 3/Day 1/Randomization.
17. Is currently being treated for hyperthyroidism
18. Is on, or likely to require treatment with, ≥14 consecutive days or repeated courses of pharmacologic doses of corticosteroids
19. Has previously taken an SGLT2 inhibitor (such as canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin) or was enrolled in a study for these agents
20. Has a Screening Visit/Visit 1 SBP or diastolic blood pressure (DBP) ≥95th percentile for age, height percentile, and gender and is not considered likely to have values <95th percentile for age, height percentile and gender by Visit 3/Day 1/Randomization even with appropriate antihypertensive therapy
21. Has fasting serum triglyceride >500 mg/dL (5.65 mmol/L) at Screening Visit /Visit 1, confirmed by a single repeat if deemed necessary
22. Has an eGFR <45 mL/min/1.73m2 at Screening Visit/ Visit 1
23. Has an aspartate transaminase (AST) or alanine transaminase (ALT) >2.5X the upper limit of normal (ULN) at Screening Visit/ Visit 1, or a total bilirubin >1.5X the ULN unless the participant has a history of Gilbert syndrome
24. Has hemoglobin levels below normal range for age and sex at Screening Visit/Visit 1
25. Has thyroid-stimulating hormone (TSH) levels outside normal range at Screening Visit/ Visit 1
26. Has a history of idiopathic acute pancreatitis or chronic pancreatitis
27. Has a history of severe hypoglycemia while on insulin
At Visit 2/Week -1
28. Has symptomatic hyperglycemia or ketonuria
29. Has a clinically significant ECG abnormality that requires further diagnostic evaluation or intervention which, in the opinion of the investigator, exposes the participant to risk by enrolling in the study. Or participant has a prolonged QTc interval for age
30. Requires initiation of concomitant medications listed in the protocol
At Visit 3/Day 1/Randomization
31. Has symptomatic hyperglycemia, and/or ketonuria, requiring immediate change to his/her antihyperglycemic therapy
32. Has developed a new medical condition, suffered a change in status of an established medical condition, developed a laboratory abnormality, or required a new treatment or medication during the run-in which meets any previously described study exclusion criterion
33. Is female with a positive pregnancy test
34. Has a site fasting fingerstick glucose (FFSG) >240 mg/dL (13.3 mmol/L)
35. Has a FFSG <130 mg/dL (7.2 mmol/L) if on insulin
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Change from Baseline in A1C at 24 weeks (pooled ertugliflozin 5 mg and 15 mg versus placebo)
2. Number of Participants Who Experience an Adverse Event (AE)
3. Number of Participants Who Experience an AE
4. Number of Participants Who Discontinue Study Treatment Due to an AE
5. Number of Participants Who Discontinue Study Treatment Due to an AE |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Baseline and 24 weeks
2. Up to 24 weeks
3. Up to 54 weeks
4. Up to 24 weeks
5. Up to 54 weeks |
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| E.5.2 | Secondary end point(s) |
1. Change from Baseline in A1C at week 24 (dose-optimized ertugliflozin versus placebo)
2. Change from Baseline in A1C at week 24 (ertugliflozin 5 mg versus placebo)
3. Change from Baseline in FPG at 24 weeks
4. Change from Baseline in A1C at 54 weeks
5. Change from Baseline in FPG at 54 weeks |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Baseline and 24 weeks
2. Baseline and 24 weeks
3. Baseline and 24 weeks
4. Baseline and 54 weeks
5. Baseline and 54 weeks |
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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 | Yes |
| 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 | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| Canada |
| Colombia |
| Costa Rica |
| Dominican Republic |
| Guatemala |
| Israel |
| Malaysia |
| Mauritius |
| Mexico |
| Philippines |
| Russian Federation |
| Saudi Arabia |
| Turkey |
| Ukraine |
| United Arab Emirates |
| United States |
| Belgium |
| France |
| Hungary |
| Italy |
| Poland |
| United Kingdom |
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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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| End of study will be declared after (1) all participants in the study have completed Week 54 or have discontinued from study prior to Week 54, (2) the database has been locked (after medical and scientific reviews of the data have been completed), and (3) the data have been unblinded. |
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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 | 6 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
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