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

NCT02727283 | Completed Phase 1

• 1 other identifier: 204729
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

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.

Conditions

Irritable Bowel Syndrome

Keywords

Healthy volunteer; Safety; Pharmacokinetics; Dose escalation; GSK3179106; Rearranged during Transfection; Irritable Bowel Syndrome; Adults

Outcome Measures

Primary Outcomes (8)

• 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.

  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).

  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).

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

Study Arms (2)

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

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

Drug: GSK3179106; Drug: Placebo

Interventions

GSK3179106 DRUG

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

Cohort 1; Cohort 2

Placebo DRUG

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

Cohort 1; Cohort 2

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Between 18 and 55 years of age inclusive, at the time of signing the informed consent.

You may not qualify if:

• 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:
• 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.
• 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

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Adelaide, South Australia, 5000, Australia

Location

Related Publications (1)

• 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.

  PMID: 30277655 DERIVED

Related Links

• Results for study 204729 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Irritable Bowel Syndrome; Multiple Endocrine Neoplasia Type 2a

Condition Hierarchy (Ancestors)

Colonic Diseases, Functional; Colonic Diseases; Intestinal Diseases; Gastrointestinal Diseases; Digestive System Diseases; Multiple Endocrine Neoplasia; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Neoplasms, Multiple Primary; Neoplastic Syndromes, Hereditary; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Endocrine System Diseases

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 14, 2015
• First Posted: April 4, 2016
• Study Start: November 26, 2015
• Primary Completion: March 18, 2016
• Study Completion: March 18, 2016
• Last Updated: May 8, 2017

Record last verified: 2017-05

Locations

AU (1)