Phase 1
Completed N=80
Safety, Tolerability and Preliminary Pharmacokinetics (PK) and Pharmacodynamics (PD) of Single and Repeat Oral Doses of GSK3008356 in Healthy and Obese Subjects
Healthy Volunteers
Source: ClinicalTrials.gov NCT02742766 ↗
Enrolled (actual)
80
Serious AEs
0.0%
Results posted
Jan 2019
Primary outcomePrimary: Part 1: Number of Participants With Abnormal Findings in Physical Examinations — 2; 1; 0; 1 Participants
Summary
This study is a phase I, randomized, placebo-controlled, double-blind (sponsor unblind), three part study. The primary objective of the study is to characterize the safety, and tolerability of GSK3008356 single dose, 14 daily repeat doses in healthy subjects and 28 daily repeat doses in obese subjects. The study has three parts. Part 1, will be a single and multiple-dose, dose-rising study in healthy subjects. Part 2, will be a 14-day, repeat-dose, dose-rising study in healthy subjects, and part 3 will be a 28-day, repeat-dose study in obese subjects. For Parts 1 and 2, data from prior doses cohorts will be available prior to escalation decisions. Data from Parts 1 and 2 will be available prior to initiation of the three parallel cohorts in Part 3. A dose escalation meeting will be held to review these data and document the decision to proceed as planned or make any alterations in dosing, if indicated. Part 1, Part 2 and Part 3 study will have approximately 88, 24 and 30 subjects, respectively.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Part 1: Number of Participants With Abnormal Findings in Physical Examinations |
2; 1; 0; 1; 0; 0 | — |
| PRIMARY Part 1: Number of Participants With Vital Signs of Potential Clinical Concern |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Part 1: Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern |
4; 3; 3; 2; 3; 0 | — |
| PRIMARY Part 1: Number of Participants With Clinically Significant Findings During Cardiac Monitoring |
0; 0; 1; 0; 0; 0 | — |
| PRIMARY Part 1: Number of Participants With Laboratory Values of Potential Clinical Concern |
1; 1; 0; 0; 1; 0 | — |
| PRIMARY Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) |
5; 2; 1; 1; 3; 4 | — |
| PRIMARY Part 2: Number of Participants With Abnormal Findings in Physical Examination |
2; 2; 3; 4 | — |
| PRIMARY Part 2: Number of Participants With Vital Signs of Potential Clinical Concern |
1; 0; 0; 1 | — |
| PRIMARY Part 2: Number of Participants With 12-lead ECG Values of Potential Clinical Concern |
1; 1; 0; 2 | — |
| PRIMARY Part 2: Number of Participants With Clinically Significant Findings During Cardiac Monitoring |
0; 0; 0; 0 | — |
| PRIMARY Part 2: Number of Participants With Laboratory Values of Potential Clinical Concern |
0; 1; 0; 0 | — |
| PRIMARY Part 2: Number of Participants With AE and SAE |
3; 5; 6; 5; 0; 0 | — |
| PRIMARY Part 3: Number of Participants With Abnormal Findings in Physical Examination |
— | — |
| PRIMARY Part 3: Number of Participants With Vital Signs of Potential Clinical Concern |
— | — |
| PRIMARY Part 3: Number of Participants With 12-lead ECG Values of Potential Clinical Concern |
— | — |
| PRIMARY Part 3: Number of Participants With Clinically Significant Findings During Cardiac Monitoring |
— | — |
| PRIMARY Part 3: Number of Participants With Laboratory Values of Potential Clinical Concern |
— | — |
| PRIMARY Part 3: Number of Participants With AE and SAE |
— | — |
| SECONDARY Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) |
190.004; 313.349; 840.806; 1960.374; 5493.574; 4042.579 | — |
| SECONDARY Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3008356 |
92.417; 190.655; 458.496; 890.913; 1865.337; 1568.035 | — |
| SECONDARY Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 |
0.833; 0.542; 0.750; 0.756; 0.917; 0.917 | — |
| SECONDARY Part 1: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of GSK3008356 |
7.958; 8.699; 22.738; 62.332; 169.051; 106.273 | — |
| SECONDARY Part 1: Renal Clearance of Drug From Plasma (CLr) of GSK3008356 |
4115.667; 2752.580; 2659.878; 3214.711; 3091.822; 2751.679 | — |
| SECONDARY Part 1: Dose Proportionality of GSK3008356 for Dose 5 mg Versus (vs.) 200 mg After Single Dose Administration and Multiple Dose Administration (100 mg t0, t4 and 100 mg t0, t16) Based on AUC |
0.92; 0.78; 0.94; 0.91; 0.78; 0.94 | — |
| SECONDARY Part 1: Dose Proportionality of GSK3008356 for Dose 5 mg vs. 200 mg After Single Dose Administration Based on Cmax |
0.81 | — |
| SECONDARY Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 |
0.925; 0.900; 0.800; 0.767; 0.742; 1.008 | — |
| SECONDARY Part 2: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to the End of Dosing Interval (AUC[0 to Tau]) of GSK3008356 on Day 1 and Day 14 |
279.222; 31.959; 107.191; 37.429; 101.151 | — |
| SECONDARY Part 2: Cmax of GSK3008356 on Day 1 and Day 14 |
187.032; 17.638; 77.326; 16.424; 46.736 | — |
| SECONDARY Part 2: t1/2 and Tmax of GSK3008356 on Day 1 and Day 14 |
1.319; 1.312; 1.443; 1.406; 2.115; 0.517 | — |
| SECONDARY Part 2: Ae of GSK3008356 on Day 14 |
— | — |
| SECONDARY Part 2: CLr of GSK3008356 on Day 14 |
— | — |
| SECONDARY Part 2: Dose Proportionality of GSK3008356 for Dose 1 mg BID vs 10 mg BID and 3 mg BID After Repeat Dose Administration Based on AUC |
0.94; 1.10; 0.90; 0.94; 1.10 | — |
| SECONDARY Part 2: Dose Proportionality of GSK3008356 for Dose 1 mg BID vs 10 mg BID and 3 mg BID After Repeat Dose Administration Based on Cmax |
1.03; 1.35; 0.95 | — |
| SECONDARY Part 2: Observed Accumulation Ratio of GSK3008356 |
1.171; 1.010; 0.931; 0.606 | — |
| SECONDARY Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing |
11.953; 2.595; 4.025; 11.528; 1.362; 1.940 | — |
| SECONDARY Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 |
0.867; 0.950; 1.217; 0.800; 0.783; 0.950 | — |
| SECONDARY Part 3: AUC (0-tau) of GSK3008356 on Day 1 and Day 28 |
— | — |
| SECONDARY Part 3: Cmax of GSK3008356 on Day 1 and Day 28 |
— | — |
| SECONDARY Part 3: Tmax of GSK3008356 on Day 1 and Day 28 |
— | — |
| SECONDARY Part 3: t1/2 of GSK3008356 on Day 28 |
— | — |
| SECONDARY Part 3: Ae of GSK3008356 on Day 28 |
— | — |
| SECONDARY Part 3: CLr of GSK3008356 on Day 28 |
— | — |
| SECONDARY Part 3: Dose Proportionality of GSK3008356 |
— | — |
| SECONDARY Part 3: Observed Accumulation Ratio of GSK3008356 |
— | — |
| SECONDARY Part 3: Ctrough to Assess Steady State of GSK3008356 Following 28-day Repeat Dosing |
— | — |
| SECONDARY Part 3: Postprandial Triglyceride Levels Following 28-day Repeat Dosing of GSK3008356 in Obese Participants |
— | — |
Eligibility Criteria
Inclusion Criteria
- Between 18 and 65 years of age inclusive, at the time of signing the informed consent.
- For Part 1 and Part 2: Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
- For Part 3: Obese subjects may have chronic disease not specifically excluded and not requiring chronic medication for treatment and are otherwise healthy as determined by the investigator or medically qualified designee 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.
- Body weight >=50 kilograms (kg)
- For Part 1 and Part 2 body mass index (BMI) 19-25 kilogram per meter square (inclusive)
- For Part 3 BMI >=30 kilogram per meter square
- Males or Females of non-childbearing potential as follows: 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 following contraceptive options: Contraceptive subdermal implant; Intrauterine device or intrauterine system; Oral Contraceptive, either combined or progestogen alone; Injectable progestogen; Contraceptive vaginal ring; Percutaneous contraceptive patches
- Males or Females of non-childbearing potential as follows: A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin [hCG] test), not lactating, and the following condition applies:
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) > 40 milli-international units per milliliter (MlU/ml) and estradiol 1.5 times upper limit of normal (isolated bilirubin >1.5 times upper limit of normal is acceptable if bilirubin is fractionated and direct bilirubin 450 millisecond (msec)
- Current or chronic history of gastrointestinal illness or conditions interfering with normal gastrointestinal anatomy or motility. Examples include gastrointestinal bypass surgery, cholecystectomy, partial or total gastrectomy, small bowel resection, vagotomy, malabsorption, Crohn's disease, ulcerative colitis, irritable bowel syndrome (IBS), or celiac sprue.
- 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 drug, unless in the opinion of the Investigator and GlaxoSmithKline (GSK) Medical Monitor the medication will not interfere with the study procedures or compromise subject safety. By exception, subject may take acetaminophen ( 14 standard drinks. One standard drink is equivalent to 10 grams of alcohol: 285 milliliter (mL) of beer, 100 mL of wine or 30 mL of 40% alcohol by volume distilled spirits.
- For Part 1 and Part 2, urinary cotinine levels indicative of smoking or history or regular use of tobacco-
Data sourced from ClinicalTrials.gov (NCT02742766). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.