Effect of a Multiple-dose Oral Administration of CG5503 PR on the Electrical Activity of the Heart in 48 Healthy Men and Women

Grünenthal GmbH48 enrolled

Overview

The 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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Eligibility

Sex: ALLMin age: 45 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

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);

Outcomes

Primary Outcomes

The mean of corrected QT interval (QTc) differences on Day 3 at 3 to 7 hours to matched time points on Day 0 of the respective treatment period

On Day 0 drug-free baseline 12-lead ECGs were recorded (in supine position after at least 10 minutes of rest) at time points corresponding to those on Day 3. On Day 3, 12-lead ECGs were recorded prior to and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 24 hours after dosing. A regression analysis was applied for each participant to obtain an individual correction.

Time frame: Baseline (Day 0) to Day 3

Secondary Outcomes

The differences of the QTc at each time point on Day 3 to the time matched QTc on Day 0 of each period

In addition to the corrected QT by regression as described for the primary endpoint, QTc was calculated by the following formulas: Fridericia, Framingham, and Bazett.

Time frame: Baseline (Day 0) to Day 3

Incidence of treatment emergent adverse events

Number of adverse events and number of participants with adverse events.

Time frame: Day 1 to Day 5

Withdrawal symptoms: 5 categories of COWS scale, sum of scores (of 11 items) and changes to placebo in sum of scores

The clinical opiate withdrawal scale (COWS) assessment consisted of 11 questions which rated the severity of opiate withdrawal symptoms, including resting pulse rate, gastrointestinal upset, sweating, restlessness, pupil size, tremor, anxiety or irritability, bone or joint aches, gooseflesh skin, yawning, and runny nose or tearing. Each symptom was rated on a scale from 0 (not present) to 4 or 5 (most severe). The total score was calculated by summing the 11 individual scores. Scores from 0 to 4 are considered "no withdrawal", from 5 to 12 "mild withdrawal", from 13 to 24 "moderate withdrawal", 25 to 36 "moderately severe withdrawal" and above 36 "severe withdrawal".

Time frame: Day 4 and Day 5

Pharmacokinetic parameter: Cmax(4-6h) of CG5503 base after the first dose

Maximum serum concentration in the observed time interval between 4 and 6 hours \[Cmax(4-6h)\]. Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration. Concentrations of CG5503 base in serum were determined by using validated High Performance Liquid Chromatography (HPLC) methods with fluorometric detection.

Time frame: Day 1 to Day 5

Pharmacokinetic parameter: tmax(4-6h) of CG5503 base after the first dose

Time to reach maximum serum concentration in the observed time interval between 4 and 6 hours \[tmax(4-6h)\]. Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration.

Time frame: Day 1 to Day 5

Pharmacokinetic parameter: AUCss of CG5503 base after the last dose

Area under the concentration vs. time curve in dosing interval τ at steady state (AUCss). Blood samples for the determination of serum concentrations were taken at pre-dose and at up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration.

Time frame: Day 1 to Day 5

Pharmacokinetic parameter: AUC of CG5503 base after the last dose

Area under the concentration vs. time curve (AUC) after the last dose. Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration.

Time frame: Day 1 to Day 5

Pharmacokinetic parameter: AUCextr of CG5503 base after the last dose

Extrapolated part to infinity of AUC (AUCextr) after the last dose. Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration.

Time frame: Day 1 to Day 5

Pharmacokinetic parameter: AUC%extr of CG5503 base after the last dose

Extrapolated part to infinity of AUC in percent (AUC%extr) after the last dose.

Time frame: Day 1 to Day 5

Pharmacokinetic parameter: Css,min of CG5503 base after the last dose

Minimum observed serum concentration during dosing interval τ at steady state (Css,min). Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration.

Time frame: Day 1 to Day 5

Pharmacokinetic parameter: Css,max of CG5503 base after the last dose

Maximum observed serum concentration during dosing interval τ at steady state (Css,max). Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration.

Time frame: Day 1 to Day 5

Pharmacokinetic parameter: Css,ave of CG5503 base after the last dose

Average serum concentration during dosing interval τ at steady state (Css,ave). Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration.

Time frame: Day 1 to Day 5

Pharmacokinetic parameter: tss,max of CG5503 base after the last dose

Time to reach maximum serum concentration during dosing interval τ at steady state (tss,max). Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration.

Time frame: Day 1 to Day 5

Pharmacokinetic parameter: λz of CG5503 base after the last dose

Apparent terminal elimination rate constant (λz) after the last dose. Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration.

Time frame: Day 1 to Day 5

Pharmacokinetic parameter: t½,z of CG5503 base after the last dose

Apparent terminal half-life (t½,z) after the last dose. Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration.

Time frame: Day 1 to Day 5

Pharmacokinetic parameter: CL/f of CG5503 base after the last dose

Apparent oral clearance at steady state (CL/f). Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration.

Time frame: Day 1 to Day 5

Pharmacokinetic parameter: PTF (%) of CG5503 base after the last dose

Peak-trough fluctuation at steady state (PTF). Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration.

Time frame: Day 1 to Day 5

Pharmacokinetic parameter: RA(Cmax) of CG5503 base after the last dose

Accumulation ratio (RA) calculated from Css,max at steady state and Cmax(4-6 hours) after single dosing. Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration.

Time frame: Day 1 to Day 5

Effect of a Multiple-dose Oral Administration of CG5503 PR on the Electrical Activity of the Heart in 48 Healthy Men and Women

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes