| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045242 |
| E.1.2 | Term | Type II diabetes mellitus |
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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 in this study is to compare the HbA1c-lowering efficacy of JNJ-28431754 100 mg and JNJ-28431754 300 mg with glimepiride after 52 weeks of treatment.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives in this study are:
From Baseline to Week 52
• To compare the change in body weight from baseline in each JNJ-28431754 group with the glimepiride group
• To compare the incidence of hypoglycemia in each JNJ-28431754 group with the glimepiride group
• To compare the change in systolic and diastolic blood pressure from baseline in each JNJ-28431754 group with the glimepiride group
• To compare the change in fasting plasma glucose (FPG) from baseline in each JNJ-28431754 group with the glimepiride group
• To assess the overall safety and tolerability of JNJ-28431754 compared with glimepiride
At Week 104:
• To compare the durability of HbA1c-lowering efficacy in each JNJ-28431754 group with the glimepiride group from Week 26 to Week 104
• To assess the overall safety and tolerability from baseline of JNJ-28431754 compared with glimepiride in subjects with T2DM throughout the study
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Potential subjects must satisfy all of the following criteria to be eligible to participate in the study:
Inclusion Criteria for Prescreening and Screening
• Man or woman with T2DM between 18 and 80 years of age, inclusive,
– On metformin monotherapy at a stable protocol specified dose* for at least 12 weeks before screening and has an HbA1c of > or =7.0% and < or =9.5% at screening; or
– On metformin monotherapy at a dose <2,000 mg/day with an HbA1c of > or =7.5% and < or =10.0% at screening and has a Week -2 visit HbA1c of > or =7.0% and < or =9.5%, after at least 10 weeks on a stable protocol-specified dose* of metformin; or
– On metformin at a stable protocol specified dose in combination with an one other oral non-thiazolidinedione (TZD) AHA with an HbA1c of > or =6.5% and < or =9.0% at screening and has a Week -2 visit HbA1c of > or =7.0% and , or =9.5%, after discontinuing the AHA and on a stable protocol-specified dose* of metformin at least 10 weeks; or
– On metformin at a dose <2,000 mg/day in combination with an one other oral non-thiazolidinedione (TZD) AHA with an HbA1c of > or =6.5% and o r=9.0% at screening and has a Week -2 visit HbA1c of > or =7.0% and < or =9.5%, after discontinuing the AHA and on a stable protocol-specified dose* of metformin at least 10 weeks (*Protocol-specified dose of metformin: > or =2,000 mg/day [or > or =1,500 mg/day, if unable to tolerate a higher dose].)
• Body mass index (BMI) > or =22 to < or =45 kg/m2, at screening
• Women must be:
– postmenopausal, defined as
>45 years of age with amenorrhea for at least 18 months, or
>45 years of age with amenorrhea for 6 to < 18 months and a serum follicle stimulating hormone (FSH) level >40 IU/mL.
– surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), or
– abstinent (at the discretion of the investigator/per local regulations), or
– if sexually active, be practicing a highly effective method of birth control such as hormonal prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double-barrier method (eg, condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), male partner sterilization before subject randomization and must agree to continue to use a highly effective method of birth control throughout the study, as local regulations permit.
• Women of childbearing potential must have a negative urine Beta human chorionic gonadotropin (Beta hCG) pregnancy test at screening and baseline (predose, Day 1).
• Willing/able to adhere to the prohibitions and restrictions specified in this protocol
• Subjects must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.
• To participate in the optional pharmacogenomic component of this study, subjects must have signed the informed consent form for pharmacogenomic research indicating willingness to participate in the pharmacogenomic component of the study (where local regulations permit). Refusal to give consent for this component does not exclude a subject from participation in the clinical study.
Inclusion Criteria for Randomization
• Subjects must have a HbA1c between (> or =7.0% and (< or =9.5% at Week 2
• Subjects must have a FPG < or =270 mg/dL (15 mmol/L) at Week-2 (At the investigator’s discretion, based upon review of recent SMBG values, subjects not meeting the Week -2 criteria may return to the investigational site within 7 days for a one-time repeat FPG and continue in the study if the subject’s repeat FPG meets the criteria.)
• Fingerstick glucose of >110 mg/dL (6 mmol/L) and <270 mg/dL (15 mmol/L) on Day 1 (At the investigator’s discretion, based upon review of recent SMBG values, subjects not meeting the Day 1 criteria may return to the investigational site within 7 days for a one-time repeat fingerstick glucose and continue in the study if the subject’s repeat fingerstick glucose meets the criteria.)
Note: The site should complete the fingerstick glucose determinations at Day 1 before conducting other visit procedures.
• Subjects must have completed at least 50% or more of their SMBG measurements and diary entries to be considered eligible for randomization.
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| E.4 | Principal exclusion criteria |
Potential subjects who meet any of the following criteria will be excluded from participating in the study:
Metabolic
• History of diabetic ketoacidosis, type 1 diabetes mellitus, pancreas or beta cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy
• History of proliferative diabetic retinopathy for which further evaluation or treatment is planned during the course of the study
• History of >1 severe hypoglycemic episodes, defined as an episode that requires the help of another person, within 6 months before screening. Refer to Attachment 2, Hypoglycemia: Definitions, Symptoms, and Treatment for a definition of severe hypoglycemia.
• History of hereditary glucose-galactose malabsorption or primary renal glucosuria
• Ongoing, uncontrolled, untreated thyroid disorder (ie, the subject has a known thyroid stimulating hormone [TSH] value that is undetectable or >10 mIU/L). Subjects taking a thyroxine supplementation for thyroid disorder should be on a stable dose for (> or =3 months
• History of an ongoing eating disorder or significant weight loss or weight gain, defined as an increase or decrease of 5% in body weight (based on subject report) within 3 months before screening
Renal/Cardiovascular
• Renal disease requiring treatment with immunosuppressive therapy within the past 12 months before screening or a history of dialysis or renal transplant
• History of myocardial infarction, unstable angina, or cerebrovascular accident within 3 months before screening, or history of New York Heart Association (NYHA) Class III-IV cardiac disease; Refer to Attachment 3, New York Heart Association Classification of Cardiac Disease, for a description of the classes
Gastrointestinal
• Ongoing clinically relevant liver disease (eg, hepatitis B or hepatitis C)
• History of prior bariatric surgical procedures
Laboratory
• Serum creatinine (> or =1.4 mg/dL (124 micromol/L) for men and (> or =1.3 mg/dL (115 micromol/L) for women; or estimated glomerular filtration rate (eGFR) <60 mL/min. Note: a one-time repeat measurement of creatinine may be performed, at the discretion of the investigator.
• Serum triglycerides (> or =600 mg/dL (6.74 mmol/L) at screening. A one-time repeat of the serum triglycerides is allowed, at the discretion of the investigator.
• Alanine aminotransferase (ALT) >2.0 times the upper limit of normal (ULN) or total bilirubin >1.5 xULN, at screening, unless in the opinion of the investigator and as agreed upon by the sponsor’s medical officer, the findings are consistent with Gilbert’s disease. A one-time repeat is allowed, at the discretion of the investigator.
Other conditions
• History of malignancy within 5 years before screening (except squamous and basal cell carcinomas and cervical carcinomas in situ)
• History of human immunodeficiency virus (HIV) infection
• Any condition that in the opinion of the investigator would compromise the well-being of the subject or the study or prevent the subject from meeting or performing study requirements (eg., planned inpatient surgery or procedures)
Medications/Therapies
• Current use of a disallowed therapy (refer to Attachment 4, List of Disallowed Therapies for a complete listing of excluded medications and therapies). Known allergies, hypersensitivity, or intolerance to JNJ-28431754 or its excipients (refer to Section 14.1, Physical Description of Study Drug(s)
• Contraindication to the use of glimepiride or metformin, as per the local prescribing information, or suspected hypersensitivity to either medication
• Have taken TZD therapy in the past 16 weeks before screening
• Received an active investigational drug (including vaccines) or used an investigational medical device within 3 months before the planned start of treatment or received at least one dose of JNJ-28431754 in a prior study
General
• History of illicit drug or alcohol abuse within 12 months before screening
• Pregnant or breast-feeding or planning to become pregnant or breast-feed during the study
• Employees of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint will be the change in HbA1c from baseline through Week 52. |
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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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| 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 | 47 |
| 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 | Information not present in EudraCT |
| 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 |
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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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| The end of the trial is 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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