E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diabetes Mellitus, Type 2 |
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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 | 17.1 |
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 |
The primary objective of this study is to show superiority of the addition of once weekly dulaglutide 1.5 mg compared to the addition of once weekly placebo to titrated basal insulin glargine, with or without metformin, on change from baseline in HbA1c after 28 weeks of treatment in patients with Type 2 Diabetes Mellitus. |
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E.2.2 | Secondary objectives of the trial |
Secondary Efficacy Objectives:
Compare 2 groups at 28 weeks on:
• % of patients at HbA1c <7.0% or ≤6.5%
• % of patients at HbA1c <7.0% & without weight gain (<0.1 kg) at 28 weeks & without documented symptomatic hypoglycemia during maintenance period;
• % of patients at HbA1c <7.0% at 28 weeks & without documented symptomatic hypoglycemia during maintenance period;
• % of patients at HbA1 <7.0% & without weight gain (<0.1 kg);
• Changes from baseline in: fasting serum glucose, plasma glucose from daily self-monitored plasma glucose profiles, body weight, daily mean glargine doses.
Secondary Safety Objectives:
Compare 2 groups at 28 weeks on incidence of:
• Adjudicated deaths & nonfatal major CV events;
• Self-reported hypoglycemic events & of patients discontinuing study due to severe, persistent hyperglycemia;
• Pancreatitis confirmed by adjudication;
• Thyroid neoplasms;
• Dulaglutide anti-drug antibodies & of allergic & hypersensitivity reactions.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Where local regulations and ERBs allow, a blood sample will be collected for pharmacogenetic and biomarker analysis. |
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E.3 | Principal inclusion criteria |
Male or female patients are eligible to be included in the study only if they meet all of the following criteria:
[1] are men or non-pregnant women aged ≥18 years at screening
[2] have type 2 diabetes (based on the World Health Organization’s [WHO] diagnostic criteria);
[3] have been treated with basal insulin glargine once daily with or without metformin for at least 3 months prior to screening
[4] doses of once daily insulin glargine and metformin (if taken) must be stable during the 3-month period prior to screening. Insulin glargine dose is considered stable when all doses during this period are within the range defined by ±10% of the most commonly used insulin glargine dose during this same period if that dose is ≥40 IU; if the most commonly used insulin glargine dose is <40 IU, then all doses for that period must be within the ±4 IU range of the most commonly used dose. Doses of metformin are considered stable if all prescribed doses during this period are in the range between the minimum required dose (≥1500 mg/day) and the maximum approved dose per the locally-approved label;
[5] have an HbA1c value ≥7.0% and ≤10.5% as assessed by the central laboratory at screening;
[6] require further insulin glargine dose increase at randomisation per the TTT algorithm based on the SMPG data collected during the prior week;
[7] have stable weight (±5%) ≥3 months prior to screening;
[8] have body mass index (BMI) ≤45 kg/m2 at screening;
[9] are able and willing to administer once weekly randomized therapy;
[10] in the investigator’s opinion, are well motivated, capable, and willing to:
[a] perform fingerstick PG monitoring, including scheduled PG profile with up to 7 measurements in 1 day;
[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;
[11] Are females of childbearing potential (a woman will be considered of childbearing potential if she is not surgically sterilized or if she is between menarche and 1-year postmenopausal [2-years postmenopausal if <50 years of age]) who must:
[a] Test negative for pregnancy at screening, based on a serum pregnancy test;
[b] Agree to use a reliable method of birth control (eg, 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 if consistent with lifestyle) during the study and for 1 month following the last dose of study drug; and
[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;
[13] Have a sufficient understanding of the primary language of the country such that they will be able to complete the patient questionnaires.
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E.4 | Principal exclusion criteria |
Patients excluded from study if meet following criteria at screening, or when indicated below for specific criteria, at randomization/baseline, or any time during screening & lead-in periods:
• have type 1 diabetes mellitus
• treated with ANY other antihyperglycemia regimen, other than basal insulin glargine once daily with/without metformin, within 3 months prior to screening or during lead-in period
• per TTT algorithm, do not require insulin glargine dose increase at randomisation based on SMPG data collected during prior week
• history of ≥1 episode of ketoacidosis or hyperosmolar state/coma
• history of hypoglycemia unawareness within 6 months prior to screening
• treated with drugs promoting weight loss within 3 months prior to screening or during lead in period
• receiving chronic (>14 days) systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, intra-articular, or inhaled preparations) or have received such therapy within 4 weeks prior to screening or during lead in period
• had any of following CV conditions within 2 months prior to screening: acute myocardial infarction , New York Heart Association Class III or IV heart failure, or cerebrovascular accident
• have known clinically significant gastric emptying abnormality (eg, severe diabetic gastroparesis or gastric outlet obstruction) or have undergone gastric bypass (bariatric) surgery or restrictive bariatric surgery
• have acute or chronic hepatitis, signs & symptoms of any other liver disease, or alanine aminotransferase (ALT) level >2.5 times upper limit of reference range, determined by central laboratory (patients with nonalcoholic fatty liver disease eligible)
• history of chronic pancreatitis or acute idiopathic pancreatitis, or diagnosed with any type of acute pancreatitis within 3 months prior to screening
• estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, calculated by Chronic Kidney Disease-Epidemiology (CKD-EPI) equation, as determined by central laboratory; for patients on metformin, have renal disease or renal dysfunction (eg. a serum creatinine ≥1.5 mg/dL [male] or ≥1.4 mg/dL [female] or eGFR [CKD-EPI] <60 mL/min/1.73 m2) (metformin SPC, 2008; Glucophage® USPI, 2009)
• have evidence of significant, uncontrolled endocrine abnormality (eg, thyrotoxicosis, adrenal crisis), in opinion of investigator
• any self or family history of type 2A or type 2B multiple endocrine neoplasia (MEN 2A or 2B) in absence of known C-cell hyperplasia (exclusion includes patients with family history of MEN 2A or 2B, whose family history for the syndrome is rearranged during transfection [RET]-negative; only exception for this exclusion will be for patients whose family members with MEN 2A or 2B have known RET mutation & potential patient for study is negative for RET mutation)
• any self or family history of medullary C-cell hyperplasia, focal hyperplasia, or carcinoma (including sporadic, familial, or part of MEN 2A or 2B syndrome)
• serum calcitonin ≥20 pg/mL, determined by central laboratory
• evidence of significant, active autoimmune abnormality
• any other condition not listed in this section that is contraindication for use of insulin glargine, or, for patients using metformin, have a condition that is contraindication for use of metformin & would require metformin discontinuation per label
• history of transplanted organ (corneal transplants [keratoplasty] are allowed)
• history of active or untreated malignancy, or are in remission from clinically significant malignancy (other than basal or squamous cell skin cancer, in situ carcinomas of cervix, or in situ prostate cancer) during 5 years prior to screening
• history of any other condition (eg, known drug or alcohol abuse or psychiatric disorder), which, in opinion of investigator, may preclude patient from following & completing protocol
• any hematologic condition that may interfere with HbA1c measurement (eg, hemolytic anemias, sickle-cell disease)
• investigator site personnel directly affiliated with this study and/or their immediate families (immediate family is defined as spouse, parent, child, or sibling, whether biological or legally adopted)
• Lilly employees
• currently enrolled in or discontinued within 30 days prior to screening from a clinical trial involving an off-label use of an investigational drug or device (other than study drug/device used in this study), or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. If previous investigational product has a long half-life, 3 months or 5 half-lives (whichever is longer) should have passed
• previously screen failed, withdrawn, discontinued from, or completed this study or been randomized in any clinical trial of dulaglutide
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in HbA1c |
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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) |
Compare 2 groups at 28 weeks on:
• Percentage of patients at HbA1c <7.0% or ≤6.5%
• Percentage of patients at HbA1c <7.0% & without weight gain (<0.1 kg) at 28 weeks & without documented symptomatic hypoglycemia during maintenance period;
• Percentage of patients at HbA1c <7.0% at 28 weeks & without documented symptomatic hypoglycemia during maintenance period
• Percentage of patients at HbA1 <7.0% & without weight gain (<0.1 kg)
• Changes from baseline in: fasting serum glucose, plasma glucose from daily self-monitored plasma glucose profiles, body weight, daily mean glargine doses
• Confirmed by adjudication:
a. Deaths
b. Non-fatal major cardiovascular events
c. Confirmed pancreatitis cases
d. Presence of thyroid neoplasms
• Incidence of dulaglutide anti-drug antibodies & of allergic & hypersensitivity reactions.
• Incidence of self-reported hypoglycemic events & of patients discontinuing study due to severe, persistent hyperglycemia.
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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 | 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 | 2 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
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 |
Czech Republic |
Hungary |
Italy |
Spain |
United Kingdom |
United States |
United States Minor Outlying Islands |
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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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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 | 4 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 15 |