| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type 2 Diabetes Mellitus with Stage 3 Chronic Kidney Disease Who Have Inadequate Glycemic Control on Background Antihyperglycemic Therapy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Type 2 Diabetes with Stage 3 Chronic Kidney Disease Whose Sugar Levels are NOT Well Controlled by Their Current Treatment |
|
| 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 | 20.0 |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045250 |
| E.1.2 | Term | Type II diabetes mellitus with renal manifestations |
| E.1.2 | System Organ Class | 100000004857 |
|
| 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 standard diabetes therapy with a Visit 3/Week -2 eGFR of ≥30 to <60 mL/min/1.73m2, after 26 weeks:
1. To assess the A1C-lowering efficacy of the addition of ertugliflozin 15 mg q.d. compared to the addition of placebo.
2. To assess the A1C-lowering efficacy of the addition of ertugliflozin 5 mg q.d. compared to the addition of placebo.
3. To assess the safety and tolerability of ertugliflozin. |
|
| E.2.2 | Secondary objectives of the trial |
1. To assess the A1C-lowering efficacy of the addition of ertugliflozin 15 mg q.d. compared to the addition of placebo.
2. To assess the A1C-lowering efficacy of the addition of ertugliflozin 5 mg q.d. compared to the addition of placebo.
3. To assess the effect of the addition of ertugliflozin 15 mg q.d. compared with the addition of placebo on the change from baseline in body weight.
4. To assess the effect of the addition of ertugliflozin 15 mg q.d. compared with the addition of placebo on the change from baseline in systolic blood pressure.
5. To assess the effect of the addition of ertugliflozin 5 mg q.d. compared with the addition of placebo on the change from baseline in body weight.
6. To assess the effect of the addition of ertugliflozin 5 mg q.d. compared with the addition of placebo on the change from baseline in systolic blood pressure.
Please 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 [1] and be ≥25 years of age on the day of signing the informed consent form.
2. Meet one of the following criteria:
a) Subject is not on metformin: Subject is on stable diabetes therapy (diet/exercise therapy alone or AHA monotherapy or combination therapy) for ≥6 weeks prior to Visit 1/Screening with a Visit 1/Screening A1C of 7.0%-10.5% (53-91 mmol/mol), inclusive.
Note: Allowable AHAs include injectable and oral agents except metformin, rosiglitazone, and other SGLT2 inhibitors (see Section 5.5 for excluded medications).
or
b) Subjects is on metformin: Subject is on metformin (with or without diet/exercise therapy or other AHA therapy) with a Visit 1/Screening A1C of 6.5%-10.0% (48-86 mmol/mol), inclusive, and is willing to undergo a 10-week metformin wash-off period.
Note: Subjects who wash-off metformin can have their AHAs adjusted (i.e., dose
change of current AHA(s) or initiation of new AHA) with the exception of pioglitazone. Subjects on pioglitazone should remain on the same dose and pioglitazone must not be initiated in subjects who are not already on pioglitazone.
3. Have an eGFR of ≥30 to <60 mL/min/1.73m2 (calculated using the MDRD formula).
Note: Subjects who do not meet the eGFR entry criterion may have one repeat determination performed if the investigator considers the Visit 1/Screening result to be inconsistent with prior determinations.
4. Have a Body Mass Index (BMI) >18.0 kg/m2.
5. Have personally signed and dated informed consent document 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.
6. Be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
7. 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 (if this form of birth control is accepted by local regulatory agencies and ethics review committees as the sole method of birth control for subjects participating in clinical trials), or
(2) agrees to use (or have her partner use) acceptable contraception to prevent
pregnancy while receiving investigational product and for 14 days after the last dose of 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
8. Have an A1C of 7.0%-10.5% (53-91 mmol/mol), inclusive, in subjects who have undergone metformin wash-off.
9. Have an eGFR of ≥30 to <60 mL/min/1.73m2 (calculated using the MDRD formula) with <10 mL/min/1.73m2 change in eGFR from Visit 1 to Visit 3.
Note: If the Visit 1/Screening eGFR is repeated to determine eligibility, the repeat eGFR value should be used to determine the change in eGFR, and the measurements must be at least 4 weeks apart.
At Visit 4/ Randomization (Day 1)
10. 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, Renal-related Medical History, and Prior Therapy Criteria
1. Has a history of type 1 diabetes mellitus or a history of ketoacidosis.
2. Has a history of other secondary causes of diabetes (e.g., genetic syndromes, secondary pancreatic diabetes, diabetes due to endocrinopathies, drug- or chemical-induced, and post-organ transplant).
3. Has a history of nephrotic range proteinuria (>3000 mg/day) with hypoalbuminemia and edema.
4. Has a history of rapidly progressive glomerulonephritis, lupus nephritis, renal or systemic vasculitis, renal artery stenosis with renovascular hypertension, or ischemic nephropathy.
5. Has a history of familial renal glucosuria.
6. Has a history of renal dialysis or renal transplant or renal disease requiring treatment with any immunosuppressive agent.
7. Has a known hypersensitivity or intolerance to any SGLT2 inhibitor.
8. 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 >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.
9. Has been treated with any of the following agents (not permitted within 12 weeks of Visit 1/Screening or during the pre-randomization period):
Rosiglitazone
Other SGLT2 inhibitors
10. Has active, obstructive uropathy or indwelling urinary catheter.
Concomitant Disease of Organs and Systems
11. 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.
12. Has a 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.
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 any history of melanoma, leukemia, lymphoma, or renal cell carcinoma is excluded.
13. Has human immunodeficiency virus (HIV) as assessed by medical history.
14. Has
Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells, or
Any other clinically significant hematological disorder (such as aplastic anemia, myeloproliferative or myelodysplastic syndromes, thrombocytopenia)
15. 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.
16. Has any clinically significant malabsorption condition.
17. Is currently being treated for hyperthyroidism.
18. Has not been on a stable dose of thyroid replacement therapy for at least 6 weeks prior to Visit 1. Subjects who meet this criterion may be re-screened after being on a stable dose of thyroid replacement therapy for at least 6 weeks.
19. Has an exclusionary laboratory value as listed in Table 2 (see protocol page 27)
Other Criteria
20. Has been previously randomized in a study with ertugliflozin.
21. Has participated in other studies involving investigational drug(s) (Phase I-IV) within 30 days prior to Visit 1/Screening and/or during trial participation.
22. Has undergone a surgical procedure within 6 weeks prior to signing informed consent 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.
23. Has a positive urine pregnancy test.
24. Is pregnant or breast-feeding, or is planning to conceive during the trial, including 14 days following the last dose of blinded investigational product.
25. 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 critieria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Body weight
2. Vital Signs (pulse rate and blood pressure)
3. Post Ural blood pressure and pulse rate
4. 12-lead ECG
5. Fasting fingerstick glucose (in clinic)
6. Review of SMBG Measurements and HAL
7. Adverse event monitoring |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Each visit
2. Each visit
3. Visits 3, 4, 5, 8, rescue
4. Visits 3, 4, 8, 11, rescue, discontinuation
5. Visit 4
6. Visits 3-11, rescue, discontinuation
7. Throughout the study
|
|
| E.5.2 | Secondary end point(s) |
Laboratory Procedures/ Assessments
8. FPG
9. A1C
10. Lipid Panel
11. Chemistry Panel
12. Hematology
13. Urine Collection/Urinalysis and Urine Albumin: Creatinine Ratio
14. Urine Pregnancy Test (women of childbearing potential only)
15. Bone Biomarkers, PTH and Vitamin D levels
16. PK Sample for ertugliflozin: pre-dose
17. PK Sample for ertugliflozin: 1h post
dose
18. Plasma and serum for Future Biomedical Research
19. Blood (DNA) for Future Biomedical
Research |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
8. Visits 1, 4-11, rescue, discontinuation
9. Visits 1, 3-11, rescue, discontinuation
10. Visits 4, 8, 11, rescue, discontinuation
11. Visits 1, 3-11, rescue, discontinuation, follow-up
12. Visits 1, 3, 4, 5, 7-11, rescue, discontinuation, follow-up
13. Visits 2, 4, 8, 11, rescue, discontinuation
14. Visits 1, 3-11, rescue, discontinuation
15. Visits 4, 8, 11, discontinuation
16. Visits 5-7
17. Visit 6
18. Visits 4, 8, 11, discontinuation
19. Visit 4
|
|
| 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 | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 90 |
| 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 |
| Canada |
| Colombia |
| Germany |
| Hungary |
| Israel |
| Mexico |
| Peru |
| Philippines |
| Poland |
| Romania |
| Russian Federation |
| South Africa |
| Spain |
| 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 | 3 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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