Irritable Bowel Syndrome
Conditions
Keywords
Healthy volunteer, Safety, Pharmacokinetics, Dose escalation, GSK3179106, Rearranged during Transfection, Irritable Bowel Syndrome, Adults
Brief summary
GSK3179106 is a potent and relatively selective inhibitor of RET kinase which has been designed to be a safe and effective therapy for irritable bowel syndrome (IBS) patients . This is a randomized, double-blind (sponsor unblind), placebo-controlled, dose escalating, four period, single-dose crossover, first time in human study to assess the safety, tolerability and pharmacokinetics of GSK3179106 in normal healthy subjects. The study will be composed of 2 cohorts, each having screening (21 days prior to first dose of study drug), Treatment, and follow-up periods (7-10 days after their last dose \[Day 1 of dosing period 4\]). The Treatment period will include 4 dosing periods. Subjects will participate in either Cohort 1 or Cohort 2. The total duration of the study for each subject will be approximately 10 weeks. A sufficient number of healthy subjects will be screened to enrol 16 subjects who complete the planned study procedures. Each dosing period will be staggered so that only 2 of the 8 subjects will be administered study drug initially. Once 24 hours (h) have elapsed, and provided there are no safety concerns, the remainder of subjects scheduled for that dosing period may be dosed. A review of safety and tolerability will occur prior to administration of the next dose level. This same procedure will be followed for each escalating dosing period. Subjects assigned to Cohort 1 will participate in 1 placebo and 3 dose escalating periods. Subjects assigned to Cohort 2 will participate in up to 4 dosing periods which include up to 2 escalating doses and placebo in Periods 1 and 2, and a pilot food effect in Periods 3 and 4. Within each cohort, subjects will return for their next scheduled dosing period approximately 14 days after administration of the study drug during the prior dosing period. Cohort 2 will proceed after completion of the treatment periods in Cohort 1. Each subject will be enrolled in only one cohort. The planned dose range is 10 milligram (mg) to 200 mg in Cohort 1. The actual doses to be administered may be adjusted based on safety, tolerability, and pharmacokinetic data at previous dose levels; these dose adjustments may involve either an increase or a decrease in the planned dose for both Cohorts 1 and 2. There are no formal hypotheses being tested in this study.
Interventions
DRUGGSK3179106
GSK3179106 will be provided as white to slightly colored round or oblong tablet for oral administration with unit dose strength of 5 mg, 25 mg and 100 mg
DRUGPlacebo
Placebo will be provided as white to slightly colored round or oblong tablet for oral administration with unit dose strength to match actives across all strengths
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Between 18 and 55 years of age inclusive, at the time of signing the informed consent. * Healthy as determined by the investigator based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or
Exclusion criteria
, outside the reference range for the population being studied may be included only if the investigator, in consultation with the medical monitor, agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. * History of regular bowel habits. * Male or Female Males: Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication until at least five half-lives of study medication after the last dose of study medication. 1. Vasectomy with documentation of azoospermia. 2. Male condom plus partner use of one of the contraceptive options below: Contraceptive subdermal implant, Intrauterine device or intrauterine system, Oral Contraceptive, either combined or progestogen alone Injectable progestogen, Contraceptive vaginal ring. This is an all-inclusive list of those methods that meet the following GlaxoSmithKline (GSK) definition of highly effective: having a failure rate of less than 1 percentage (%) per year when used consistently and correctly and, when applicable, in accordance with the product label. For non-product methods (e.g., male sterility), the investigator determines what is consistent and correct use. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. Females: A female subject is eligible to participate if she is of non-reproductive potential defined as: Pre-menopausal females with one of the following: Documented tubal ligation Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion Hysterectomy Documented Bilateral Oophorectomy Postmenopausal defined as 12 months of spontaneous amenorrhea in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. * Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of subjects with adverse events (AE) and clinical observations as a measure of safety | Up to 10 weeks in each cohort | An AE is any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. |
| Assessment of physical examination findings as a measure of safety | Screening, Day-1 and at follow-up (up to 10 weeks) in each cohort | Physical examination will include the assessment of the cardiovascular, respiratory, gastrointestinal and neurological systems. A brief physical examination will be conducted at follow-up visit which include, at a minimum assessments of the lungs, cardiovascular system, and abdomen (liver and spleen). Height and weight will also be measured and recorded (height will only be recorded at screening assessment). |
| Safety as assessed by 12-lead electrocardiogram (ECG) | Up to 10 weeks in each cohort | Triplicate 12-lead ECGs will be obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT interval (QTc). |
| Safety as assessed by systolic and diastolic blood pressure measurements | Up to 10 weeks in each cohort | Three readings of systolic and diastolic pressure will be taken at each time point and the average will be calculated electronically |
| Safety as assessed by temperature measurements | Up to 10 weeks in each cohort | Temperature measurements will be taken at Screening, Day-1 and pre-dose in each treatment period. For all other vital sign time points if clinically indicated |
| Safety as assessed by pulse rate measurements | Up to 10 weeks in each cohort | Three readings of systolic and diastolic pressure will be taken at each time point and the average will be calculated electronically |
| Composite of clinical laboratory assessments as a measure of safety includes hematology, clinical chemistry and urinalysis | Up to 10 weeks in each cohort | Clinical safety laboratory assessments include hematology, clinical chemistry, urinalysis and additional parameters |
| Bristol Stool Form Scale | Up to Day 4 in each cohort | The Bristol Stool Form Scale describes 7 types of stool and will be used by the subject to monitor the changes in defecation pattern during the study |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absorption rate constant (Ka) of GSK3179106 administered under fasting condition | Day 1 Pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h and 72 h post-dose in each treatment period of cohort 1 | PK parameters under fasting conditions |
| Area under the plasma concentration-time curve (AUC) from zero to time t (AUC [0-t]) of GSK3179106 administered under fasting and fed condition | Day 1 Pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h and 72 h post-dose in each treatment period of cohort 2 | PK parameters under fasting and fed conditions |
| AUC from zero to infinity (AUC [0-infinity]) of GSK3179106 administered under fasting condition fasting and fed condition | Day 1 Pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h and 72 h post-dose in each treatment period of cohort 2 | PK parameters under fasting and fed conditions |
| AUC from zero to 24 h (AUC [0-24 h]) of GSK3179106 administered under fasting condition fasting and fed condition | Day 1 Pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h and 72 h post-dose in each treatment period of cohort 2 | PK parameters under fasting and fed conditions |
| Maximum observed plasma concentration (Cmax) of escalating single oral doses of GSK3179106 administered under fasting and fed condition | Day 1 Pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h and 72 h post-dose in each treatment period of cohort 2 | PK parameters under fasting and fed conditions |
| Area under the plasma concentration-time curve (AUC) from zero to time t (AUC [0-t]) of GSK3179106 administered under fasting condition | Day 1 Pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h and 72 h postdose in each treatment period of cohort 1 | PK parameters under fasting conditions |
| Apparent terminal phase half-life (t1/2) of GSK3179106 administered under fasting and fed condition | Day 1 Pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h and 72 h post-dose in each treatment period of cohort 2 | PK parameters under fasting and fed conditions |
| Clearance (CL/F) of GSK3179106 administered under fasting and fed condition | Day 1 Pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h and 72 h post-dose in each treatment period of cohort 2 | PK parameters under fasting and fed conditions |
| Volume of distribution (V/F) of GSK3179106 administered under fasting and fed condition | Day 1 Pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h and 72 h post-dose in each treatment period of cohort 2 | PK parameters under fasting and fed conditions |
| Absorption rate constant (Ka) of GSK3179106 administered under fasting and fed condition | Day 1 Pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h and 72 h post-dose in each treatment period of cohort 2 | PK parameters under fasting and fed conditions |
| Time to maximum observed plasma concentration (tmax) of GSK3179106 administered under fasting and fed condition | Day 1 Pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h and 72 h post-dose in each treatment period of cohort 2 | PK parameters under fasting and fed conditions |
| AUC from zero to infinity (AUC [0-infinity]) of GSK3179106 administered under fasting condition | Day 1 Pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h and 72 h post-dose in each treatment period of cohort 1 | PK parameters under fasting conditions |
| AUC from zero to 24 h (AUC [0-24 h]) of GSK3179106 administered under fasting condition | Day 1 Pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h and 72 h post-dose in each treatment period of cohort 1 | PK parameters under fasting conditions |
| Maximum observed plasma concentration (Cmax) of escalating single oral doses of GSK3179106 administered under fasting conditions | Day 1 Pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h and 72 h post-dose in each treatment period of cohort 1 | PK parameters under fasting conditions |
| Time to maximum observed plasma concentration (tmax) of GSK3179106 administered under fasting condition | Day 1 Pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h and 72 h post-dose in each treatment period of cohort 1 | PK parameters under fasting conditions |
| Apparent terminal phase half-life (t1/2) of GSK3179106 administered under fasting condition | Day 1 Pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h and 72 h post-dose in each treatment period of cohort 1 | PK parameters under fasting conditions |
| Clearance (CL/F) of GSK3179106 administered under fasting condition | Day 1 Pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h and 72 h post-dose in each treatment period of cohort 1 | PK parameters under fasting conditions |
| Volume of distribution (V/F) of GSK3179106 administered under fasting condition | Day 1 Pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h and 72 h post-dose in each treatment period of cohort 1 | PK parameters under fasting conditions |
Countries
Australia
Outcome results
None listed