Title
Effect of a Multiple-dose Oral Administration of CG5503 PR on the Electrical Activity of the Heart in 48 Healthy Men and Women
Investigation of the Effect on the QT/QTc Interval After Multiple Dose Oral Administration (100 and 200 mg Bid) of CG5503 PR in a Randomised, Double-blind, Double-dummy Placebo- and Moxifloxacin-controlled 4- Way Cross-over Phase I Study in 48 Healthy Male and Female Volunteers
Phase
Phase 1Lead Sponsor
GrunenthalStudy Type
InterventionalStatus
Completed No Results PostedIndication/Condition
Prolonged QTc Interval PharmacokineticIntervention/Treatment
100 mg CG5503 (tapentadol hydrochloride) PR tablet 400 mg Moxifloxacin tablet (overencapsulated) ...Study Participants
48The effect of multiple oral administration of two doses of CG5503 PR (prolonged release) compared to placebo on the electrical activity of the heart were investigated. The rationale to perform this study was to exclude any effect of CG5503 on the heart rhythm. This study was a randomised, double-blind, double-dummy, placebo- and moxifloxacin-controlled, 4-way cross-over study. Participants were given a combination of either CG5503 PR and placebo (medication with inactive ingredients which looks like the study drug) or moxifloxacin and placebo. Moxifloxacin was used as a positive control. It has consistently shown that it has an effect on the heart rhythm.
Within 14 days prior to the first dosing, participants had a physical examination, a 12-lead electrocardiogram (ECG) was recorded and haematological, serological, biochemical, and urine analyses took place. A blood sample for optional genotyping of genes responsible for long QT syndrome was taken. During each dosing session, the participants were confined in the evening before baseline assessments were performed and stayed in the clinic until 48 hours after the last dosing. Study medication was administered on Day 1 and 2 in the morning (0.5 hours after breakfast) and in the evening (1.5 hours after dinner), and on Day 3 in the morning (0.5 hours after breakfast). Dosing was separated by at least 7 days between the last dosing of each period and the first dosing of next period. Interim analysis of ECG-data were performed after completion of 24 participants (group 1) with possible subsequent adjustment of sample size for group 2.
100 mg CG5503 (tapentadol hydrochloride) PR tablet.
Matching placebo tablet to CG5503 PR tablet.
Matching placebo capsule to moxifloxacin capsule.
Overencapsulated 400 mg Moxifloxacin tablet.
Each participant received a morning and an evening dose of 100 mg CG5503 PR on days 1 and 2 and a morning dose on Day 3 (each dose: 1 tablet CG5503 PR and 1 placebo-tablet, matching CG5503 PR); additionally at each dosing each participant received 2 placebo-capsules, matching moxifloxacin 400 mg. The participants received 2 tablets and 2 capsules at each dosing with approximately 150 ml water.
Each participant received a morning and an evening dose of 200 mg CG5503 PR on days 1 and 2 and a morning dose on Day 3 (each dose: 2 tablets CG5503 PR); additionally at each dosing each participant received 2 placebo-capsules, matching moxifloxacin. The participants received 2 tablets and 2 capsules at each dosing with approximately 150 ml water.
Each participant received a morning and an evening dose of placebo to CG5503 PR on days 1 and 2 and a morning dose on Day 3 (each dose: 2 tablets placebo, matching CG5503 PR); additionally at each dosing each participant received 2 placebo-capsules, matching moxifloxacin. The participants received 2 tablets and 2 capsules at each dosing with approximately 150 ml water.
Each participant received a morning and an evening dose of placebo to CG5503 PR on days 1 and 2 and a morning dose on Day 3 (each dose: 2 tablets placebo, matching CG5503 PR); and 2 placebo-capsules, matching moxifloxacin on days 1 and 2; In the morning of Day 3, each participant received additionally 2 capsules each containing 1 tablet moxifloxacin. The participants received 2 tablets and 2 capsules at each dosing with approximately 150 ml water.
Inclusion Criteria: Male or female Caucasian participants aged 45-65 years; Body mass index (BMI) between 19 and 27 kilograms/square meter inclusive; Participants must be in good health as determined by medical history, physical examination, 12-lead electrocardiogram , vital signs, and clinical laboratory parameters (serum/urine biochemistry, serology and haematology). Electrocardiogram (ECG) parameters and vitals signs must be in the ranges given in exclusion criteria 3-8 and 11-14, respectively) Minor deviations of laboratory values from the normal range may be accepted (except potassium and magnesium), if judged by the investigator to have no clinical relevance and if not considered to interfere with the study objectives. Negative human immunodeficiency virus (HIV) 1/2 -antibodies, hepatitis B surface (HBs)-antigen, hepatitis B core (HBc)-antibodies and hepatitis C virus (HCV)-antibodies at the prestudy medical examination; Negative blood beta-human chorionic gonadotropine (HCG)-test for women of child bearing potential; Participants giving written consent to participate within this study; Participants giving written consent for blood sampling to be genotyped for genes responsible for long QT syndrome (KCNQ1, human ether-a-go-go-related gene (HERG), SCN5A, KCNE1, KCNE2, KCNJ2). Exclusion Criteria: Regular use of any medication within four weeks prior to commencement of the study (self-medication or prescription except for hormonal contraception and HRT); Smoker more than 5 cigarettes per day; No regular sinus rhythm; ECG interval: QRS complex above 100 millisecond; ECG interval: PQ above 200 milliseconds; ECG interval: RR above 1333 milliseconds; QT/QTc intervals above 450 milliseconds; Known family history of sudden cardiac death and arrhythmias; Diseases and functional disorders of the gastrointestinal tract, liver, cardiovascular system or kidneys; Malignancy; History of orthostatic hypotension; Resting pulse rate below 45 beats/min or above 90 beats per minute; Systolic blood pressure above 160 mmHg or below 100 mmHg; Diastolic blood pressure above 95 mmHg or below 50 mmHg; History of drug allergy; Bronchial asthma; Participation in another clinical trial within the last three months before starting this study (exception: characterisation of metaboliser status); Blood donation (more than 100 milliliters) in the last three months before the start of the study; History or evidence of alcohol or drug abuse; Positive drug abuse screening test; Extremely unbalanced diet (in the opinion of the investigator); Excessive consumption of food or beverages containing caffeine (more than 1000 milliliters of coffee per day or other equivalent amounts of caffeine); Known or suspected of not being able to comply with the study protocol; Not able to communicate meaningfully with the investigator and staff; Neurotic personality, psychiatric illness, or suicide risk; History of seizures; Known hypersensitivity to opioids or quinolones; Pregnancy (for female participants);
