Irritable Bowel SyndromePhase 1NCT02727283

A Phase 1, Randomized, Placebo-Controlled, Ascending Cohort, Dose Escalation Study in Normal Healthy Volunteers

A Phase 1 study testing GSK3179106 in people with Irritable Bowel Syndrome, run by GlaxoSmithKline at 1 site in Australia.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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… Read more about this study

Who is it for?: Ages 18 to 55 yearsHealthy volunteers can take part
Conditions the study is for: Irritable Bowel Syndrome
What is being tested?: GSK3179106
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 16 participants
Where: 1 siteAustralia
Study dates: 26 Nov 2015to 18 Mar 2016
Phase: Phase 1
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 55 years
All sexes
Healthy volunteers accepted
Adult

Who may be able to join

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.
Vasectomy with documentation of azoospermia.
Male condom plus partner use of one of the contraceptive options below:

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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.

Who cannot join

Alanine Transferase (ALT) and bilirubin >1.5x upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
Previous diagnosis of IBS.
Estimated Glomerular Filtration Rate <60 milliliters per minute 1.73 square meter (mL/min/1.73m^2).
Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
History of gastroesophageal reflux disease (GERD), dyspepsia, gastrointestinal (GI) bleeding, GI surgery that could affect motility
A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.

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A positive pre-study drug/alcohol screen.
A positive test for human immunodeficiency virus (HIV) antibody.
History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of >14 standard drinks. One standard drink is equivalent to 10 grams (g) of alcohol: 285 ml of beer, 100 ml of wine or 30 ml of 40% alcohol by volume distilled spirits.
Current smoker or use of nicotine containing products within the past 3 months or unable to abstain from smoking tobacco or the use of nicotine-containing products while on study.
Unable to refrain from consumption of red wine, seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 1 day prior to the first dose of study drug on Day 1 of each dosing period, until completion of the last PK blood sample time point for that dose period.
Corrected QT interval to Fridericia's formula (QTcF) >450 milliseconds (msec)
History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
Unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication for each dosing period until Day 4 of each dosing period, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety. Paracetamol (<=2 grams per day) is acceptable.
The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
Exposure to more than 4 investigational medicinal products within 12 months prior to the first dosing day
Unwillingness or inability to follow the procedures outlined in the protocol.
Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.

Trial locations and contacts

1 site in 1 country.

Australia1 site

GSK Investigational Site
Adelaide, South Australia, 5000

Other trials in Australia

About this study

Official title: A Phase 1, Randomized, Placebo-Controlled, Double-Blind, Ascending Dose Escalating, 4 Period Crossover Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Food Effect of Single Doses of GSK3179106, a REarranged During Transfection (RET) Growth Factor Receptor Tyrosine Kinase Inhibitor, in Normal Healthy Volunteers

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.

Conditions: Irritable Bowel Syndrome
Being tested: GSK3179106, Placebo
Keywords: Healthy volunteer, Safety, Pharmacokinetics, Dose escalation, GSK3179106, Rearranged during Transfection, Irritable Bowel Syndrome, Adults
Medical subject headings: Irritable Bowel Syndrome, Multiple Endocrine Neoplasia Type 2a

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

GSK3179106Drug
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
PlaceboDrug
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

Study groups in NCT02727283
Study group	Role	What they receive
Cohort 1	Experimental	Subjects will receive 1 placebo and 3 escalating doses in one of the four treatment periods. The planned dose range is 10 mg to 200 mg. A review of safety and tolerability will occur prior to administration of the next dose level and the same procedure will be followed for each escalating dosing period. 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 Receives: Drug: GSK3179106; Drug: Placebo
Cohort 2	Experimental	Cohort 2 will proceed after completion of the treatment periods in Cohort 1. 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. A review of safety and tolerability will occur prior to administration of the next dose level and the same procedure will be followed for each escalating dosing period. 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 Receives: Drug: GSK3179106; Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

Number of subjects with adverse events (AE) and clinical observations as a measure of safety
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.
Measured: Up to 10 weeks in each cohort
Assessment of physical examination findings as a measure of safety
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).
Measured: Screening, Day-1 and at follow-up (up to 10 weeks) in each cohort
Safety as assessed by 12-lead electrocardiogram (ECG)
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).
Measured: Up to 10 weeks in each cohort
Safety as assessed by systolic and diastolic blood pressure measurements
Three readings of systolic and diastolic pressure will be taken at each time point and the average will be calculated electronically
Measured: Up to 10 weeks in each cohort
Safety as assessed by temperature measurements
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
Measured: Up to 10 weeks in each cohort
Safety as assessed by pulse rate measurements
Three readings of systolic and diastolic pressure will be taken at each time point and the average will be calculated electronically
Measured: Up to 10 weeks in each cohort
Composite of clinical laboratory assessments as a measure of safety includes hematology, clinical chemistry and urinalysis
Clinical safety laboratory assessments include hematology, clinical chemistry, urinalysis and additional parameters
Measured: Up to 10 weeks in each cohort
Bristol Stool Form Scale
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
Measured: Up to Day 4 in each cohort

Secondary outcomes (18)

Area under the plasma concentration-time curve (AUC) from zero to time t (AUC [0-t]) of GSK3179106 administered under fasting condition
PK parameters under fasting conditions
Measured: 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
AUC from zero to infinity (AUC [0-infinity]) of GSK3179106 administered under fasting condition
PK parameters under fasting conditions
Measured: 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
AUC from zero to 24 h (AUC [0-24 h]) of GSK3179106 administered under fasting condition
PK parameters under fasting conditions
Measured: 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
Maximum observed plasma concentration (Cmax) of escalating single oral doses of GSK3179106 administered under fasting conditions
PK parameters under fasting conditions
Measured: 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
Time to maximum observed plasma concentration (tmax) of GSK3179106 administered under fasting condition
PK parameters under fasting conditions
Measured: 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
Apparent terminal phase half-life (t1/2) of GSK3179106 administered under fasting condition
PK parameters under fasting conditions
Measured: 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
Clearance (CL/F) of GSK3179106 administered under fasting condition
PK parameters under fasting conditions
Measured: 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
Volume of distribution (V/F) of GSK3179106 administered under fasting condition
PK parameters under fasting conditions
Measured: 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
Absorption rate constant (Ka) of GSK3179106 administered under fasting condition
PK parameters under fasting conditions
Measured: 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
Area under the plasma concentration-time curve (AUC) from zero to time t (AUC [0-t]) of GSK3179106 administered under fasting and fed condition
PK parameters under fasting and fed conditions
Measured: 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
AUC from zero to infinity (AUC [0-infinity]) of GSK3179106 administered under fasting condition fasting and fed condition
PK parameters under fasting and fed conditions
Measured: 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
AUC from zero to 24 h (AUC [0-24 h]) of GSK3179106 administered under fasting condition fasting and fed condition
PK parameters under fasting and fed conditions
Measured: 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
Maximum observed plasma concentration (Cmax) of escalating single oral doses of GSK3179106 administered under fasting and fed condition
PK parameters under fasting and fed conditions
Measured: 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
Time to maximum observed plasma concentration (tmax) of GSK3179106 administered under fasting and fed condition
PK parameters under fasting and fed conditions
Measured: 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
Apparent terminal phase half-life (t1/2) of GSK3179106 administered under fasting and fed condition
PK parameters under fasting and fed conditions
Measured: 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
Clearance (CL/F) of GSK3179106 administered under fasting and fed condition
PK parameters under fasting and fed conditions
Measured: 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
Volume of distribution (V/F) of GSK3179106 administered under fasting and fed condition
PK parameters under fasting and fed conditions
Measured: 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
Absorption rate constant (Ka) of GSK3179106 administered under fasting and fed condition
PK parameters under fasting and fed conditions
Measured: 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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

26 Nov 201518 Mar 2016

First posted4 Apr 2016 (estimated)
Study start26 Nov 2015
Primary completion18 Mar 2016
Study completion18 Mar 2016

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Irritable Bowel SyndromeStudies of the same condition, open and under way.
More trials run by GlaxoSmithKlineThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Double blind
Who is masked: Participant, Investigator
Enrolment: 16 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02727283
Sponsor's protocol ID: 204729
Status last verified: May 2017
First submitted: 14 Dec 2015
Last updated: 8 May 2017
Results posted: No
Data monitoring committee: No

Publications

Cooper M, O'Connor-Semmes R, Reedy BA, Hacquoil K, Gorycki P, Pannullo K, Verticelli A, Shakib S. First-in-Human Studies for a Selective RET Tyrosine Kinase Inhibitor, GSK3179106, to Investigate the Safety, Tolerability, and Pharmacokinetics in Healthy Volunteers. Clin Pharmacol Drug Dev. 2019 Feb;8(2):234-245. doi: 10.1002/cpdd.600. Epub 2018 Sep 13.
PubMed 30277655

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 8 May 2017. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase 1, Randomized, Placebo-Controlled, Double-Blind, Ascending Dose Escalating, 4 Period Crossover Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Food Effect of Single Doses of GSK3179106, a REarranged During Transfection (RET) Growth Factor Receptor Tyrosine Kinase Inhibitor, in Normal Healthy Volunteers
ClinicalTrials.gov ID: NCT02727283
Acronym / sponsor ID: 204729
Conditions: Irritable Bowel Syndrome
Keywords: Healthy volunteer, Safety, Pharmacokinetics, Dose escalation, GSK3179106, Rearranged during Transfection, Irritable Bowel Syndrome, Adults
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 16 participants (actual)
Lead sponsor: GlaxoSmithKlineIndustry (pharma, biotech, devices)
Study start: 26 Nov 2015 (actual)
Primary completion: 18 Mar 2016 (actual)
Study completion: 18 Mar 2016 (actual)
First posted: 4 Apr 2016 (estimated)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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 .

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Double blind (participant, investigator)
Number of arms: 2

Arm	Type	Receives
Cohort 1	Experimental	Drug: GSK3179106, Drug: PlaceboSubjects will receive 1 placebo and 3 escalating doses in one of the four treatment periods. The planned dose range is 10 mg to 200 mg. A review of safety and tolerability will occur prior to administration of the next dose level and the same procedure will be followed for each escalating dosing period. 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
Cohort 2	Experimental	Drug: GSK3179106, Drug: PlaceboCohort 2 will proceed after completion of the treatment periods in Cohort 1. 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. A review of safety and tolerability will occur prior to administration of the next dose level and the same procedure will be followed for each escalating dosing period. 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

Who may qualify

Ages: 18 to 55 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult

Key inclusion criteria (12 listed)

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.
Contraceptive subdermal implant, Intrauterine device or intrauterine system, Oral Contraceptive, either combined or progestogen alone Injectable progestogen, Contraceptive vaginal ring.

Key exclusion criteria (18 listed)

Alanine Transferase (ALT) and bilirubin >1.5x upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
Previous diagnosis of IBS.
Estimated Glomerular Filtration Rate <60 milliliters per minute 1.73 square meter (mL/min/1.73m^2).
Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
History of gastroesophageal reflux disease (GERD), dyspepsia, gastrointestinal (GI) bleeding, GI surgery that could affect motility

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
GSK3179106GSK3179106 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	Drug	Cohort 1, Cohort 2
PlaceboPlacebo 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	Drug	Cohort 1, Cohort 2

Primary outcome

Number of subjects with adverse events (AE) and clinical observations as a measure of safety
Time frame: 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
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Up to 10 weeks in each cohort
Clinical safety laboratory assessments include hematology, clinical chemistry, urinalysis and additional parameters
Bristol Stool Form Scale
Time frame: 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

18 secondary outcomes

Area under the plasma concentration-time curve (AUC) from zero to time t (AUC [0-t]) of GSK3179106 administered under fasting condition
Time frame: 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
AUC from zero to infinity (AUC [0-infinity]) of GSK3179106 administered under fasting condition
Time frame: 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
AUC from zero to 24 h (AUC [0-24 h]) of GSK3179106 administered under fasting condition
Time frame: 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
Maximum observed plasma concentration (Cmax) of escalating single oral doses of GSK3179106 administered under fasting conditions
Time frame: 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
Time to maximum observed plasma concentration (tmax) of GSK3179106 administered under fasting condition
Time frame: 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
Apparent terminal phase half-life (t1/2) of GSK3179106 administered under fasting condition
Time frame: 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
Clearance (CL/F) of GSK3179106 administered under fasting condition
Time frame: 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
Volume of distribution (V/F) of GSK3179106 administered under fasting condition
Time frame: 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
Absorption rate constant (Ka) of GSK3179106 administered under fasting condition
Time frame: 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
Area under the plasma concentration-time curve (AUC) from zero to time t (AUC [0-t]) of GSK3179106 administered under fasting and fed condition
Time frame: 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
AUC from zero to infinity (AUC [0-infinity]) of GSK3179106 administered under fasting condition fasting and fed condition
Time frame: 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
AUC from zero to 24 h (AUC [0-24 h]) of GSK3179106 administered under fasting condition fasting and fed condition
Time frame: 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
Maximum observed plasma concentration (Cmax) of escalating single oral doses of GSK3179106 administered under fasting and fed condition
Time frame: 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
Time to maximum observed plasma concentration (tmax) of GSK3179106 administered under fasting and fed condition
Time frame: 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
Apparent terminal phase half-life (t1/2) of GSK3179106 administered under fasting and fed condition
Time frame: 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
Clearance (CL/F) of GSK3179106 administered under fasting and fed condition
Time frame: 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
Volume of distribution (V/F) of GSK3179106 administered under fasting and fed condition
Time frame: 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
Absorption rate constant (Ka) of GSK3179106 administered under fasting and fed condition
Time frame: 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

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 8 May 2017.
Derived from this study: PubMed 30277655Cooper M, O'Connor-Semmes R, Reedy BA, Hacquoil K, Gorycki P, Pannullo K, Verticelli A, Shakib S. First-in-Human Studies for a Selective RET Tyrosine Kinase Inhibitor, GSK3179106, to Investigate the Safety, Tolerability, and Pharmacokinetics in Healthy Volunteers. Clin Pharmacol Drug Dev. 2019 Feb;8(2):234-245. doi: 10.1002/cpdd.600. Epub 2018 Sep 13.
Results for study 204729 can be found on the GSK Clinical Study Register.Link provided by the sponsor.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

GSK Clinical Trials study director

GlaxoSmithKline

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing GSK3179106 in people with Irritable Bowel Syndrome, run by GlaxoSmithKline at 1 site in Australia.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 12 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 8 May 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of subjects with adverse events (AE) and clinical observations as a measure of safety (time frame: Up to 10 weeks in each cohort). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02727283, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 May 2017.