| 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 | 10029883 |
| E.1.2 | Term | Obesity |
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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 |
| To investigate mean changes in Hepatic Triglyceride Content (HTGC) from baseline to week 6 and 12 by 1H-Magnetic Resonance Spectroscopy (MRS) in obese subjects treated with JNJ-16269110: 10 mg bid, 15 mg bid or placebo. |
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| E.2.2 | Secondary objectives of the trial |
· To investigate time-course, dose-dependency and relationship of changes in HTGC to PK exposure
· To evaluate changes in HTGC versus observed changes in weight of JNJ-16269110 versus placebo
· To explore changes in obesity-associated co-morbidities as assessed by glucose homeostasis, fasting lipid profile, and systolic and diastolic blood pressure
· To explore the effect of JNJ-16269110 on health status using the Impact of Weight on Quality of Life-Lite (IWQOL-Lite) questionnaire
· To explore patient-reported assessment of gastrointestinal (GI) symptoms
· To assess safety and tolerability with specific emphasis on GI adverse events and hepatic function.
· To assess pharmacokinetic (PK) exposure and to explore exposure-response relationships
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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 |
The effect of microsomal triglyceride transferprotein (MTP) inhibitor and weight loss on liver fat content, fat tissue metabolism and morphology, 19 December 2007, version ______
The purpose of the sub-study is to answer the following questions in addition to the questions asked in the JNJ16269110 clinical protocol R256918OBE1008:
- The effect of 12 week treatment with MTP/Placebo on subcutaneous fat tissue morfology and metabolism
- To investigate if the subjects have genetic polymorfisms which influence the regulation of liver fat content |
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| E.3 | Principal inclusion criteria |
· Men or women
· Between 18 and 65 years of age, inclusive
· Women must be:
· postmenopausal, defined as having a last menstrual period at least 1 year before screening with a serum follicle-stimulating hormone (FSH) level consistent with postmenopausal status
· or surgically incapable of childbearing (have had a hysterectomy or bilateral oophorectomy or tubal ligation or otherwise incapable of pregnancy)
· or if sexually active, be practicing an effective method of birth control (such as hormonal contraceptives, intrauterine device (IUD), or having a vasectomized partner
· or sexually abstinent
· Women of childbearing potential must be practicing an effective method of birth control (as previously defined) and have a negative urine pregnancy test at screening as well as at the baseline visit before receiving study drug, which will be followed immediately by a serum beta-human chorionic gonadotropin (b-hCG) test. Subjects may be admitted to the study if the urine pregnancy test is negative, but will be discontinued immediately should the serum results be positive. Only a serum test is necessary at the end of the double-blind treatment phase. During the double-blind phase, a pregnancy test will be performed if pregnancy is suspected. Additional pregnancy tests may be performed at the discretion of the investigator.
· Must be obese, defined as: BMI ³30 kg/m2 and <50 kg/m2
· If subjects are hypertensive, they must be controlled with appropriate drug treatment.
· If subjects are clinically diagnosed with dyslipidemia as a result of screening assessments, they can only continue in the study if in the clinical judgment of the investigator initiation of lipid-lowering therapy is not required either immediately or during the course of the study.
· A stable weight, i.e., increasing or decreasing not more than 5 kg in the 3 months before the screening period.
· Ability to enter the coil of the MRS (60 cm diameter)
· A HTGC between 3% and 15%
· Consumption of breakfast and dinner on a daily basis
· Ability to swallow the intact capsule (17.5 mm in length and 9.1 mm in diameter) with water, as judged by e.g. the subject's history of having no difficulty with swallowing e.g. capsules or intact tablets
· Fasting plasma glucose <7.0 mmol/L (126 mg/dL) at screening; in cases in which there is doubt concerning fasting conditions, a 1-time repeat of the fasting plasma glucose is allowed (fasting is defined as no caloric intake for at least 8 hours before the test)
· Willing 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 (or their legally acceptable representative) must have signed the informed consent for pharmacogenomic research indicating willingness to participate in the pharmacogenomic component of the study (where local regulations permit). Refusal to consent for either component does not exclude a subject from participation in the clinical study.
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| E.4 | Principal exclusion criteria |
· Any metal objects in the body or on the body that cannot be removed (including pacemaker, prostheses, bullets, certain types of tattoos, piercings, metal based IUDs, ferromagnetic surgical clips)
· History of obesity with a known cause (e.g., Cushing’s disease)
· History of anorexia nervosa, bulimia, or binge-eating disorder
· An established diagnosis of diabetes mellitus or treatment with glucose-lowering prescription drugs
· Prior exposure or known contraindication or hypersensitivity to JNJ 16269110
· History of weight-reducing diet or receiving any drugs to treat obesity within the 3 months prior to screening
· Treatment with any investigational drug or device within 1 month before the screening period
· History of HIV or presence of hepatitis C antibodies or positive hepatitis B serology (refer to Attachment 2, Interpretation of Hepatitis B Results for Enrolling Subjects at screening)
· History of clinically significant GI disease (including but not limited to gluten- and non-gluten-induced enteropathy, inflammatory bowel disease, malabsorption syndromes)
· History of major GI surgery other than appendectomy or uncomplicated cholecystectomy.
· Previous gastric restrictive surgery or other surgical procedures to induce weight loss
· Liposuction within the last 3 months before screening
· Pregnant or nursing women, or women who plan to become pregnant during the study
· History of significant cardiovascular disease, including a history of myocardial infarction (MI), unstable angina and cerebrovascular accident (CVA) within 6 months of enrollment.
· History of clinically significant cardiac valvular disease, or congestive heart failure (cardiovascular disability functional Class III-IV according to the New York Heart Association Classification of Cardiac Disease20, refer to Attachment 3)
· 12-lead ECG showing evidence of clinically significant heart rhythm or conduction abnormality at screening or baseline.
· An average of 3 seated readings where diastolic blood pressure ³100 mmHg or a systolic blood pressure ³160 mmHg
· Thyroid-stimulating hormone (TSH) >1.5 times ULN at screening. Subjects on medication for hypothyroidism should have been on a stable dosage for at least 3 months before enrollment.
· A significant change in smoking habits within 3 months of screening subjects planning to alter smoking habits during the course of the study
· Malignancy or a history of a malignancy within 5 years before screening, other than basal cell carcinomas of the skin or in situ cervical carcinoma
· History or evidence of clinically significant abnormal values for hematology, coagulation, or clinical biochemistry.
· Increased LFTs,
· ALT above 1.5 x ULN
· any of the listed parameters: GGT, AST, total/direct bilirubin, alkaline phosphatase, or lactic acid dehydrogenase (LDH) above 2 x ULN
· a concomitant increase of two or more of the above parameters, including:
a. ALT> ULN and/or
b. AST, total/direct bilirubin, alkaline phosphatase or LDH above 1.5 xULN and/or
c. GGT above 2x ULN
In doubtful or borderline cases, an additional retest sampling is allowed.
· Increased creatinine kinase (CK) above ULN in subjects who take lipid lowering agents and CK level above 2 x ULN in subjects who do not take lipid lowering agents
· Fasting triglycerides>6.77 mmol/L (600 mg/dL). A 1 time repeat of the fasting triglycerides is allowed (fasting is defined as no caloric intake for at least 8 hours before the test)
· Evidence of renal impairment (serum creatinine >133 mmol/L (1.5 mg/dL) in men, >124 mmol/L (1.4 mg/dL) in women)
· History of drug or alcohol abuse within the previous 2 years
· Alcohol consumption exceeding 2 units per day; 1 unit is defined as 330 mL beer, 100 mL wine, or 30 mL distilled spirits or the equivalent of this21
· Receiving any excluded medication (refer to Section 8, Concomitant Therapy)
· History of seizures or significant central nervous system-related disorders
· History of significant psychiatric disorder, including, schizophrenia, or psychosis (depressive disorders do not preclude participation in the trial)
· Current use of cannabinoids
· Any condition that in the opinion of the investigator would complicate or compromise the study, or the well being of the subject
· 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) |
HTGC (Hepatic Triglyceride content) measured by MRS
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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 | No |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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.8.3 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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