Last updated: 07/31/2020 02:30:18
A Single Dose pharmacokinetic (PK) and safety study of GSK2838232 with and without Ritonavir (RTV) conducted in healthy subjects
Clinicaltrials.gov ID
EudraCT ID
Not applicable
EU CT Number
Not applicable
Trial status
Other
Other
Trial overview
Official title: A Double-Blind, Randomized, Placebo-Controlled, Continuation Single Dose Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of GSK2838232 with and without Ritonavir, and to Evaluate Different Formulations of GSK2838232, in Healthy Subjects
Trial description: This study investigates the safety, tolerability and PKs of GSK2838232 with and without Ritonavir, and to evaluate different formulations of GSK2838232 in healthy subjects. This study will evaluate higher single and RTV boosted doses to support continued clinical development of GSK2838232 at clinically relevant doses, and subsequently in those infected with HIV in a dose ranging phase 2 study. The study is conducted in 2 parts: Part A and Part B, study Part A and Part B may be conducted in parallel. Approximately 20 healthy subjects will be enrolled into the study, 8 in Part A and 12 in Part B. Part A is a double-blind, randomized, placebo-controlled, 4-period, single dose escalation design. Subjects will be randomized 3:1 to receive GSK2838232 or placebo. Subjects randomized to placebo will receive placebo in all four periods. Following completion of Period 2 PK assessments at 96hr post-dose, subjects will begin daily dosing of RTV 100mg for a total of 26 days. Part B is a randomized, open-label, unbalanced, 3-period, cross-over design; subjects will be randomized 1:1 to each sequence. The relative bioavailability of single 100mg doses of powder in a bottle (PIB) active pharmaceutical ingredient (API) of GSK2838232 versus PIB spray-dried dispersion (SDD) will be assessed. A single dose of GSK2838232 will co-administered on the 10th day of RTV dosing; RTV dosing will continue for an additional 4 days (total of 14 days). Subjects will have a screening visit within 30 days prior to first dose and a follow-up visit 7-14 days after the last dose.
Primary purpose:
Treatment
Trial design:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Allocation:
Randomized
Primary outcomes:
Adverse events (AEs) assessments
Timeframe: Up to approximately 7 weeks
Safety assessed by laboratory evaluations
Timeframe: Up to approximately 7 weeks
Vital signs assessments
Timeframe: Up to approximately 7 weeks
Electrocardiogram (ECG) parameters assessments
Timeframe: Up to approximately 7 weeks
Composite PK profile of GSK2838232, , with and without RTV for Part A and Part B
Timeframe: During Part A: Day 1 to Day 5 (Period 1 & 2), Day 10-Day 15 (Period 3), Day 8 – Day 13 (Period 4). During Part B: Day 1 to Day 4 (Period 1 & 2), Day 10-Day 14 (Period 3)
Composite PK profile of GSK2838232 to assess the relative bioavailability of the PIB API suspension versus PIB SDD suspension (Part B)
Timeframe: During Part B: Day 1 to Day 4 (Period 1 & 2), Day 10-Day 14 (Period 3)
Composite PK profile of GSK2838232 to assess single dose proportionality of GSK2838232 with and without steady-state RTV (Part A)
Timeframe: During Part A: Day 1 to Day 5 (Period 1 & 2), Day 10-Day 15 (Period 3), Day 8 – Day 13 (Period 4).
Secondary outcomes:
Not applicable
Interventions:
Enrollment:
20
Primary completion date:
2015-10-03
Observational study model:
Not applicable
Time perspective:
Not applicable
Clinical publications:
Johnson, M; Jewell RC; Peppercorn, A; Gould E; Xu, J; Lou, Y; Davies, M; Baldwin, S; Tenorio, A; Burke, M; Jeffrey J and Johns, B .The Safety, Tolerability, and Pharmacokinetic Profile of GSK2838232, a Novel 2nd Generation HIV Maturation Inhibitor, as Assessed in Healthy Subjects .Pharmacol Res Perspect.2018;
DOI: 10.1002/prp2.408
Medical condition
Infection, Human Immunodeficiency Virus
Product
GSK2838232, ritonavir
Collaborators
Not applicable
Study date(s)
November 2014 to March 2015
Type
Interventional
Phase
1
Participation criteria
Sex
Female & Male
Age
18 - 55 years
Accepts healthy volunteers
Yes
- Between 18 and 55 years of age inclusive, at the time of signing the informed consent
- 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.
- Alanine aminotransferase and bilirubin >1.5xupper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
- Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
Inclusion and exclusion criteria
Inclusion criteria:
- Between 18 and 55 years of age inclusive, at the time of signing the informed consent
- 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 if required agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
- A Creatinine clearance (CLcr) >80 millilitre per minute (mL/min) as determined by Cockcroft-Gault equation where age is in years, weight (Wt) is in kg, and serum creatinine (Scr) is in units of milligram / decilitre (mg/dL); CLcr (mL/min) = (140 – age) * Wt / (72 * Scr) (times 0.85 if female).
- Body weight >= 50 kilogram (kg [110 pounds {lbs}]) for men and >= 45 kg (99 lbs) for women and body mass index (BMI) within the range 18.5-31.0 kilogram per meter square kg/m^2 (inclusive)
- Male or Female; Female subject of non-reproductive potential : is eligible to participate if she is not pregnant (as confirmed by a negative serum or urine human chorionic gonadotrophin (hCG) test), not lactating, and at least one of the following conditions applies: 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) must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. 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 one week after the last dose of study medication. a) Vasectomy with documentation of azoospermia, b) Male condom plus partner use of one of the contraceptive options below: Contraceptive subdermal implant that meets the standard operating procedure (SOP) effectiveness criteria including a <1% rate of failure per year, as stated in the product label, Intrauterine device or intrauterine system that meets the SOP effectiveness criteria including a <1% rate of failure per year, as stated in the product label, Oral Contraceptive, either combined or progestogen alone Injectable progestogen, Contraceptive vaginal ring, Percutaneous contraceptive patches. These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
- Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
Exclusion criteria:
- Alanine aminotransferase and bilirubin >1.5xupper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
- Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
- Subjects who have asthma or a history of asthma.
- Medical history of cardiac arrhythmias or cardiac disease or a family and personal history of long QT syndrome.
- 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, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
- History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 ml) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
- Regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
- 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 Medical Monitor, contraindicates their participation.
- Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
- Screening or baseline cardiac troponin I greater than the 99% cutoff (>.045 nanogram/ milliliter [ng/mL] by the Dimension Vista Cardiac troponin assay).
- A positive pre-study drug/alcohol screen.
- A positive test for HIV antibody.
- Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 56 days.
- 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 four new chemical entities within 12 months prior to the first dosing day.
- Exclusion Criteria for 24-Hour Screening Holter: Any symptomatic arrhythmia (except isolated extra systoles), Sustained cardiac arrhythmias (such as atrial fibrillation or flutter, supraventricular tachycardia (>=10 consecutive beats), complete heart block). Non-sustained or sustained ventricular tachycardia (defined as >= 3 consecutive ventricular ectopic beats). Any conduction abnormality (including but not specific to left or right incomplete or complete bundle branch block, atrioventricular (AV) block [2nd degree or higher], Wolff–Parkinson–White [WPW] syndrome etc.). Sinus Pauses > 3 seconds. 300 or more supraventricular ectopic beats in 24 hours. 250 or more ventricular ectopic beats in 24 hours.
- Any clinically significant abnormal echocardiogram finding. Abnormal echocardiogram findings should be discussed with the Medical Monitor prior to enrolment.
- Exclusion criteria for screening ECG (a single repeat is allowed for eligibility determination): Heart rate <45 and >100 beats per minute (bpm) (Males); <50 and >100 bpm (females); For both Males and Females: PR Interval <120 and >220 msec, QRS duration <70 and >120 millisecond (msec); QTc interval (Fridericia’s) >450 msec. Notes: A heart rate from 100 to 110 bpm can be rechecked by ECG or vitals within 30 minutes to verify eligibility. Evidence of previous myocardial infarction (Does not include ST segment changes associated with repolarization). Any conduction abnormality (including but not specific to left or right complete bundle branch block, AV block [2nd degree or higher], WPW syndrome). Sinus Pauses > 3 seconds. Any significant arrhythmia which, in the opinion of the principal investigator or GlaxoSmithKline medical monitor, will interfere with the safety for the individual subject. Non-sustained or sustained ventricular tachycardia (>= 3 consecutive ventricular ectopic beats).
Trial location(s)
Location
GSK Investigational Site
Baltimore, Maryland, United States, 21225
Status
Study Complete
Study documents
Clinical study report
Available language(s): English
Protocol
Available language(s): English
Scientific result summary
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Refer to study documents
Recruitment status
Other
Actual primary completion date
2015-10-03
Actual study completion date
2015-10-03
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
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Additional information
Results for study 200912 can be found on the GSK Clinical Study Register.
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