Clinical trial NCT03951402: Effect of a Multiple-dose Oral Administration of CG5503 PR on the Electrical Activity of the Heart in 48 Healthy Men and Women
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Prolonged QTc Interval
Pharmacokinetic
Keywords: QT/QTc Interval
Lead sponsor: Grünenthal GmbH
Sponsor class: INDUSTRY
First posted: 2019-05-15
Enrollment: 48
Sex: ALL
Minimum age (years): 45
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This study was a randomized, double-blind, double-dummy, placebo- and moxifloxacin-controlled, 4-way cross-over study. The randomization was in the ratio 1:1:1:1. In all treatments the amount of administered tablets and capsules were the same. At the lower dose step the amount of tablets/capsules was adjusted with matching placebos. All study procedures were the same, irrespective of whether active compound, positive control or placebo was administered.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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);

Primary outcomes:
measure: 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
timeFrame: Baseline (Day 0) to Day 3
Secondary outcomes:
measure: The differences of the QTc at each time point on Day 3 to the time matched QTc on Day 0 of each period
timeFrame: Baseline (Day 0) to Day 3
measure: Incidence of treatment emergent adverse events
timeFrame: Day 1 to Day 5
measure: Withdrawal symptoms: 5 categories of COWS scale, sum of scores (of 11 items) and changes to placebo in sum of scores
timeFrame: Day 4 and Day 5
measure: Pharmacokinetic parameter: Cmax(4-6h) of CG5503 base after the first dose
timeFrame: Day 1 to Day 5
measure: Pharmacokinetic parameter: tmax(4-6h) of CG5503 base after the first dose
timeFrame: Day 1 to Day 5
measure: Pharmacokinetic parameter: AUCss of CG5503 base after the last dose
timeFrame: Day 1 to Day 5
measure: Pharmacokinetic parameter: AUC of CG5503 base after the last dose
timeFrame: Day 1 to Day 5
measure: Pharmacokinetic parameter: AUCextr of CG5503 base after the last dose
timeFrame: Day 1 to Day 5
measure: Pharmacokinetic parameter: AUC%extr of CG5503 base after the last dose
timeFrame: Day 1 to Day 5
measure: Pharmacokinetic parameter: Css,min of CG5503 base after the last dose
timeFrame: Day 1 to Day 5
measure: Pharmacokinetic parameter: Css,max of CG5503 base after the last dose
timeFrame: Day 1 to Day 5
measure: Pharmacokinetic parameter: Css,ave of CG5503 base after the last dose
timeFrame: Day 1 to Day 5
measure: Pharmacokinetic parameter: tss,max of CG5503 base after the last dose
timeFrame: Day 1 to Day 5
measure: Pharmacokinetic parameter: λz of CG5503 base after the last dose
timeFrame: Day 1 to Day 5
measure: Pharmacokinetic parameter: t½,z of CG5503 base after the last dose
timeFrame: Day 1 to Day 5
measure: Pharmacokinetic parameter: CL/f of CG5503 base after the last dose
timeFrame: Day 1 to Day 5
measure: Pharmacokinetic parameter: PTF (%) of CG5503 base after the last dose
timeFrame: Day 1 to Day 5
measure: Pharmacokinetic parameter: RA(Cmax) of CG5503 base after the last dose
timeFrame: Day 1 to Day 5
Other outcomes:
Locations:
city: Neuss
country: Germany
facility: DE001 - Contract research organisation
Study officials:
affiliation: Grünenthal GmbH
name: Grünenthal Study Director
role: STUDY_DIRECTOR
References: