E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 2 Diabetes and Moderate or Severe Chronic Kidney Disease |
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E.1.1.1 | Medical condition in easily understood language |
Type 2 Diabetes and Moderate or Severe Chronic Kidney Disease |
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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 | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064848 |
E.1.2 | Term | Chronic kidney disease |
E.1.2 | System Organ Class | 100000004857 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067585 |
E.1.2 | Term | Type 2 diabetes mellitus |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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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 |
The primary objective of this glycemic efficacy study is to demonstrate that the effect on HbA1c (measured as change from baseline) in the treatment of patients with type 2 diabetes and moderate or severe chronic kidney disease (CKD) with once-weekly dulaglutide is at least non-inferior compared with insulin glargine at 26 weeks. |
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E.2.2 | Secondary objectives of the trial |
To demonstrate that the effect of treatment of patients with type 2 diabetes and moderate or severe CKD with once-weekly dulaglutide on HbA1c (measured as change from baseline) is non-inferior compared with insulin glargine at 52 weeks • To assess the proportion of patients whose HbA1c is <7.0% (at 26 and 52 weeks) • To assess the proportion of patients whose HbA1c is <8.0% (at 26 and 52 weeks) • To assess the effects of once-weekly dosing of dulaglutide compared with insulin glargine on glycemic control by measuring: - glucose values from the 8-point self-monitored plasma glucose (SMPG) profiles (change from baseline at 26 and 52 weeks) - fasting glucose (change from baseline at 26 and 52 weeks) • To measure mean daily insulin lispro use based on a 4-week interval prior to 26-week and 52-week visits. • To assess the proportion of patients with estimated average glucose <154 mg/dL from 8-point SMPG (at 26 and 52 weeks) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. - Type 2 diabetes 2. - The HbA1c criterion for study eligibility depends on the patient’s antihyperglycemic regimen at screening, as follows: a) If receiving insulin, plus OAM(s) and/or pramlintide, the patient falls into Group A, and undergoes a Screening/Lead-In Period of 13 weeks: the HbA1c must be ≥7.5% and ≤10.5% at the initial screening visit at Week -13 (Visit 1). At Week -12 (Visit 1A), OAM(s) and/or the pramlintide must be discontinued, and entry insulin regimen optimized, throughout the Lead-In Period. At Week -1 (Visit 2), the repeat HbA1c must be ≥7.5% in order to randomize. b) If receiving ONLY insulin (the regimen, defined as the same formulation(s) of insulin, must be stable and the dose has not been changed by more than 10 % [increase or decrease] over the past 4 weeks), then the patient falls into Group B, and undergoes a Lead-In Period of 3 weeks. The HbA1c obtained at the initial screening visit at Week -3 (Visit 1) must be ≥7.5% and ≤10.5% in order to randomize. The insulin regimen and dose is expected to remain stable throughout the Lead-In Period. c) Patients receiving ONLY OAM(s) and/or pramlintide are not eligible for this study. 3. - Patients with presumed diabetic kidney disease with or without hypertensive nephrosclerosis diagnosed with moderate or severe CKD (Stages 3 and 4, respectively) according to the National Kidney Foundation, Kidney Disease Outcomes Quality Initiative (NKF KDOQI) Guidelines. These stages are collectively defined by an eGFR of ≥15 to <60 mL/min/1.73 m2. 4. - At screening, the patient must have been receiving an ACEI and/or ARB (or the combination of the 2) that is considered the maximal appropriate dose by the PI for treatment of diabetic kidney disease or hypertension (unless the patient has low blood pressure or hypotension) and the dose is unchanged for 1 month prior to screening a) Additionally, no further dose changes should be expected during screening, randomization, and treatment b) Patients who are intolerant to ACEI/ARBs are allowed to enter the study 5. - Doses of blood pressure medications (other than ACEI/ARBs), need to be stable for at least 1 month before screening 6. - Willing to avoid NSAIDs and COX-2 inhibitors in favor of acetaminophen for the duration of the study 7. - Able and willing to perform multiple daily injections, and/or comply with investigator’s recommendation for treating diabetes 8. - Body mass index (BMI) between 23 and 45 kg/m2, inclusive 9. - In the investigator’s opinion, well motivated, capable, and willing to: a) perform SMPG testing b) learn how to self-inject treatment, as required for this protocol (visually impaired persons who are not able to perform the injections must have the assistance of a sighted individual trained to inject the study drug; persons with physical limitations who are not able to perform the injections must have the assistance of an individual trained to inject the study drug) c) maintain a study diary, as required for this protocol 10. - Men and non-pregnant women aged ≥18 years 11. - Women of childbearing potential (not surgically sterilized and between menarche and 1-year postmenopausal [2-years postmenopausal if <50 years of age]) must: a) test negative for pregnancy at screening based on a serum pregnancy test b) agree to use a reliable method of birth control (for example, use of oral contraceptives or Norplant®; a reliable barrier method of birth control [diaphragms with contraceptive jelly, cervical caps with contraceptive jelly, condoms with contraceptive foam, intrauterine devices]; partner with vasectomy; or abstinence) during the study and for 1 month following the last dose of study drug; c) not be breastfeeding 12. - Have given written informed consent to participate in this study in accordance with local regulations and the Ethical Review Board (ERB) governing the study site. |
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E.4 | Principal exclusion criteria |
1. - At any point in the 2 months prior to randomization: Stage 5 CKD or AKI 2. - Rapidly progressing renal dysfunction likely to require renal replacement therapy in the next 26 weeks 3. - History of a transplanted organ, including renal transplantation or currently taking nephrotoxic immunosuppressive agents 4. - Type 1 diabetes mellitus 5. - At the Screening Visit, a systolic blood pressure of ≥150 mmHg or a diastolic blood pressure of ≥90 mmHg with or without antihypertensive medication 6. - Currently taking or have taken (in the last one month prior to screening) prescription or over-the-counter medications to promote weight loss 7. - Receipt of GLP-1 receptor agonists in the last one month prior to screening 8. - Receipt of DPP-IV inhibitors in the last one month prior to screening 9. - Taking a total daily dose of 70 units or more of long-acting insulin 10. - Receiving chronic (>14 days) systemic (that is, oral, intravenous, intramuscular, or intra-articular administration) glucocorticoid therapy or have received such therapy within 1 month immediately prior to Screening Visit 11. - Patients who are likely to require concurrent treatment with systemic steroids in the next 26 weeks 12. - An episode of ketoacidosis or hyperosmolar state/coma in the past 6 months or a history of severe hypoglycemia in the past 3 months prior to the Screening Visit 13. - A known history of untreated proliferative retinopathy 14. - Any of the following cardiovascular (CV) conditions within 12 weeks prior to randomization: acute myocardial infarction, New York Heart Association (NYHA) class III or class IV heart failure, or cerebrovascular accident (stroke) 15. - Known clinically significant gastric emptying abnormality, have undergone gastric bypass, surgery or restrictive bariatric surgery, or chronically take drugs that directly affect GI motility 16. - Acute or chronic hepatitis, signs and symptoms of any other liver disease, or alanine transaminase (ALT) level ≥3 times the upper limit of the normal reference range, as determined by the central laboratory at the Screening Visit 17. - Signs and symptoms of chronic or acute pancreatitis, or were in the past diagnosed with pancreatitis 18. - Evidence of a significant, uncontrolled endocrine abnormality in the opinion of the investigator 19. - Any self or family history of type 2A or type 2B multiple endocrine neoplasia in the absence of known C-cell hyperplasia. 20. - Any self or family history of medullary C-cell hyperplasia, focal hyperplasia, or carcinoma 21. - Serum calcitonin ≥35 pg/mL at Screening Visit 22. - History of an active or untreated malignancy, or in remission from a clinically significant malignancy during the last 5 years before screening 23. - Have any known hematological condition that may interfere with HbA1c measurement 24. - History of any other condition (such as known drug or alcohol abuse or psychiatric disorder) which, in the opinion of the investigator, may preclude the patient from following and completing the protocol 25. - Are investigator site personnel directly affiliated with this study and/or their immediate families. 26. - Are Lilly or CRO employees 27. - Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device 28. - Have previously completed or withdrawn from this study or any clinical study of dulaglutide (LY2189265) after providing informed consent 29. - Any serious medical condition which, in the opinion of the Investigator, would pose a significant risk to the patient or interfere with the interpretation of safety, efficacy, or pharmacodynamic data. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The change from baseline in HbA1c at 26 weeks |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Change from baseline in HbA1c at 52 weeks • Proportion of patients whose HbA1c is <7.0% (at 26 and 52 weeks) • Proportion of patients whose HbA1c is <8.0% (at 26 and 52 weeks) • Glucose values from the 8-point SMPG profiles (change from baseline to 26 and 52 weeks) • Fasting glucose (change from baseline to 26 and 52 weeks) • Mean daily insulin lispro use based on a 4-week interval prior to 26-week and 52-week visits • Proportion of patients with estimated average glucose <154 mg/dL from 8-point SMPG (at 26 and 52 weeks) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | 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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 |
Brazil |
Hungary |
India |
Mexico |
Poland |
Romania |
South Africa |
Spain |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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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The date of the last visit or last scheduled procedure shown in the Study Schedule for the last active patient in the study. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |