Clinical trial NCT05760261: Drug Interaction Assessment of GSK3882347 in Healthy Participants Aged 18 to 65 Years
Official title: A Phase 1, Open-Label Study in Healthy Participants Aged 18 to 65 Years to Investigate the CYP3A4 Induction Potential of GSK3882347
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Urinary Tract Infections
Keywords: Drug-drug interaction
Cytochrome P450 3A4 (CYP3A4)
1-hydroxymidazolam
Hormonal contraceptive agent
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2023-03-08
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The objective of this study is to determine the magnitude and clinical relevance of a potential drug-drug interaction of GSK3882347 with midazolam (MDZ) in healthy participants. This study assesses the effect of GSK3882347 as an inducer of Cytochrome P450 3A4 (CYP3A4) using MDZ, a sensitive substrate of hepatic and intestinal CYP3A4. The study will investigate MDZ pharmacokinetic (PK) effect in two dosing periods:

Period 1: A single dose of MDZ Period 2: 14-days of once daily repeat dosing of GSK3882347 followed by single dose of MDZ co-administered with GSK3882347 on Day 15 (14-days has been selected as this duration is required in order to maximize any potential CYP3A4 enzyme induction).


Eligibility criteria: Inclusion criteria:

* Participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring. A participant with a clinical abnormality or laboratory parameter(s) not specifically listed in the exclusion or exclusion criteria that is 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.
* Body weight at least 50.0 kilogram (kg) (110 pound \[lbs.\]) for males and 45.0 kg (99 lbs.) for females; and body mass index (BMI) within the range 18.5 - 32.0 kg per meter square (kg/m\^2) (inclusive).
* Male participants are eligible to participate if they agree to the following during the study intervention Period and for at least 3 days, after the last dose of study intervention:

  * Refrain from donating fresh unwashed semen

Plus, either:

• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent.

OR

• Must agree to use contraception/barrier.

* A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:

  * Is a woman of non-childbearing potential (WONCBP) . OR
  * Is a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective, with a failure rate of lesser than (\<) 1 percent (%).
* A WOCBP must have a negative highly sensitive pregnancy test \[urine or serum\] as required by local regulations) within 24h before the first dose of study intervention.
* The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
* Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF).

Exclusion Criteria:

* History or presence of significant cardiovascular, respiratory, hepatic, renal, urological, gastrointestinal, metabolic, endocrinological, hematological, immunologic, dermatologic, neurological or psychiatric disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data or in the opinion of the investigator places the participants at unacceptable risk or would make adhering to study procedures for the duration of the study difficult. Participants who have had a gastric bypass or a cholecystectomy are excluded from the study.
* Abnormal blood pressure, as determined by the investigator.
* Alanine transferase (ALT) value greater than (\>)1.5 × upper limit of normal (ULN).
* Bilirubin value \>1.5 × ULN (isolated bilirubin \>1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* The participant has a current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* The participant has congenital long QT syndrome or known prolongation of the corrected QT (QTc) interval.
* The participant has any history of heart failure.
* The participant has a family history of QT prolongation or sudden death.
* The participant has any current or previous a history of episodes of symptomatic bradycardia or bradyarrhythmia.
* The participant has a QTc \>450 millisecond (msec). Note: The QTc is the QT interval corrected for heart rate according to Fridericia formula, machine, or manual overread.

  11. The participant has anuria, oliguria, or impairment of renal function (GFR by Modification of diet in renal disease \[MDRD\] \<90 milliliter per minute per 1.73 meter square \[mL/min/1.73m\^2\] or serum creatinine \> ULN or urine albumin-creatinine ratio \[ACR\] of ≥300 milligram per gram \[mg/g\] at screening).
* The participant must agree to and adhere to the concomitant therapy (including nondrug therapies) restrictions from the Screening Visit through to the end of the end of the study (including telephone visit).
* Participation in the study would result in loss of blood or blood products in excess of 500 milliliter (mL) within 56 days.
* Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
* Current enrolment or past participation within the last 30 days or 5 half-lives, whichever is longer, before signing of consent in any other clinical study involving an investigational study intervention or any other type of medical research.
* Current enrolment or past participation in this clinical study.
* Positive human immunodeficiency virus (HIV) antibody test.
* Presence of Hepatitis B surface antigen (HbsAg) at screening or within 3 months prior to first dose of study intervention.
* Hepatitis C antibody test result at screening or within 3 months prior to first dose of study intervention.
* A positive confirmation of Coronavirus disease 2019 (COVID-19) infection, or high clinical index of suspicion for COVID-19.
* The participant, in the judgment of the investigator, would not be able or willing to comply with the protocol or complete the study.
* Regular alcohol consumption within 6 months prior to the study. An average weekly intake of \>14 units for males or females. One unit is equivalent to approximately to 8 g of alcohol: a half-pint (approximately \[\~\]240 mL) of beer, one glass (125 mL) of wine or one (25 mL) measure of spirits.
* Positive smoke breathalyzer indicative of smoking history at screening and each in-house admission to the clinical research unit or regular use of tobacco or nicotine-containing products (i.e., nicotine patches or vaporizing devices) within 3 months prior to screening.
* Regular use of combustible tobacco products, and non-combustible nicotine delivery systems, inclusive of cigarettes, cigars, pipes, and materials used to "vape".
* Any history of substance abuse or a positive urine test for drugs of abuse/ alcohol breath screen at screening or admission.
* Known hypersensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.
* Contraindication for MDZ (i.e., Hypersensitivity to the active substance, benzodiazepines or to any of the excipients, myasthenia gravis, respiratory insufficiency, sleep apnea syndrome, severe hepatic impairment).
* Use of any products intended to treat medical conditions that are not approved by the governing health authority in a given country or region (for example, herbal medicine, health supplements, traditional medicine, homeopathic remedies, etc.).

Primary outcomes:
measure: Period 1: Area under the curve from time zero to 24 hours (AUC [0-24]) for plasma concentration of MDZ
timeFrame: Up to 24 hours
measure: Period 1: AUC (0-24) for plasma concentration of 1-hydroxy-MDZ
timeFrame: Up to 24 hours
measure: Period 2: AUC (0-24) for plasma concentration of MDZ
timeFrame: Up to 24 hours
measure: Period 2: AUC (0-24) for plasma concentration of 1-hydroxy-MDZ
timeFrame: Up to 24 hours
measure: Period 1: AUC from time zero to last time of quantifiable concentration (AUC [0-tau]) for plasma concentration of MDZ
timeFrame: Up to Day 2
measure: Period 1: AUC (0-tau) for plasma concentration of 1-hydroxy-MDZ
timeFrame: Up to Day 2
measure: Period 2: AUC (0-tau) for plasma concentration of MDZ
timeFrame: Up to Day 15
measure: Period 2: AUC (0-tau) for plasma concentration of 1-hydroxy-MDZ
timeFrame: Up to Day 15
measure: Period 1: AUC from time zero extrapolated to infinite time (AUC [0-inf]) for plasma concentration of MDZ
timeFrame: Up to Day 2
measure: Period 1: AUC (0-inf) for plasma concentration of 1-hydroxy-MDZ
timeFrame: Up to Day 2
measure: Period 2: AUC (0-inf) for plasma concentration of MDZ
timeFrame: Up to Day 15
measure: Period 2: AUC (0-inf) for plasma concentration of 1-hydroxy-MDZ
timeFrame: Up to Day 15
measure: Period 1: Maximum plasma concentration (Cmax) of MDZ
timeFrame: Up to Day 2
measure: Period 1: Cmax of 1-hydroxy-MDZ
timeFrame: Up to Day 2
measure: Period 2: Cmax of MDZ
timeFrame: Up to Day 15
measure: Period 2: Cmax of 1-hydroxy-MDZ
timeFrame: Up to Day 15
measure: Period 1: Time to Cmax (Tmax) of MDZ
timeFrame: Up to Day 2
measure: Period 1: Tmax of 1-hydroxy-MDZ
timeFrame: Up to Day 2
measure: Period 2: Tmax of MDZ
timeFrame: Up to Day 15
measure: Period 2: Tmax of 1-hydroxy-MDZ
timeFrame: Up to Day 15
measure: Period 1: Time lag before observation of measurable concentrations (Tlag) of MDZ
timeFrame: Up to Day 2
measure: Period 1: Tlag of 1-hydroxy-MDZ
timeFrame: Up to Day 2
measure: Period 2: Tlag of MDZ
timeFrame: Up to Day 15
measure: Period 2: Tlag of 1-hydroxy-MDZ
timeFrame: Up to Day 15
measure: Period 1: Time to half-life (T1/2) of MDZ
timeFrame: Up to Day 2
measure: Period 1: T1/2 of 1-hydroxy-MDZ
timeFrame: Up to Day 2
measure: Period 2: T1/2 of MDZ
timeFrame: Up to Day 15
measure: Period 2: T1/2 of 1-hydroxy-MDZ
timeFrame: Up to Day 15
Secondary outcomes:
measure: Number of participants with adverse events (AEs) and serious adverse events (SAEs)
timeFrame: Up to Day 15
measure: Number of participants with clinically significant changes in hematology laboratory values
timeFrame: Up to Day 15
measure: Number of participants with clinically significant changes in chemistry laboratory values
timeFrame: Up to Day 15
measure: Number of participants with clinically significant changes in urinalysis laboratory values
timeFrame: Up to Day 15
measure: Number of participants with clinically significant changes in vital sign values
timeFrame: Up to Day 15
measure: Number of participants with clinically significant changes in 12-lead electrocardiogram (ECG) readings
timeFrame: Up to Day 15
measure: AUC (0-24) for plasma concentration of GSK3882347
timeFrame: Up to 24 hours
measure: Plasma concentrations over the dosing interval tau (Ctau) of GSK3882347
timeFrame: Up to Day 15
measure: Oral clearance (CL/F) of GSK3882347
timeFrame: Up to Day 15
measure: Volume of distribution/ Bioavailability (Vd/F) of GSK3882347
timeFrame: Up to Day 15
measure: Mean residence time (MRT) of GSK3882347
timeFrame: Up to Day 15
measure: AUC(0-inf) for single dose of GSK3882347
timeFrame: Up to Day 2
measure: Cmax for single dose of GSK3882347
timeFrame: Up to Day 2
measure: AUC(0-tau) for repeat dose of GSK3882347
timeFrame: Up to Day 15
measure: Cmax for repeat dose of GSK3882347
timeFrame: Up to Day 15
measure: Accumulation ratio (Ro) using AUC (0-tau) for repeat dose of GSK3882347
timeFrame: Up to Day 15
measure: Time invariance using AUC(0-tau) (repeat dose) of GSK3882347
timeFrame: Up to Day 15
measure: Time invariance using AUC(0-inf) (single dose) of GSK3882347
timeFrame: Up to Day 2
measure: Achievement of steady state of GSK3882347
timeFrame: Up to Day 15
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: