A Study to Investigate the Pharmacokinetics of a Combined Oral Contraceptive When Given Alone and in Combination With GSK3036656 in Female Participants of Non-childbearing Potential Aged 18 to 65 Years of Age

Phase 1

Completed

Conditions: Tuberculosis

Interventions: Drug: Microgynon
Drug: GSK3036656

Registration Number: NCT06354257

Lead Sponsor: GlaxoSmithKline

Brief Summary: The purpose of this study is to provide data showing if there are any effects of GSK3036656 on a combined oral contraceptive containing Ethinyl Estradiol (EE) and Levonorgestrel (LNG), which will help inform future studies on suitable contraceptive measures to be used.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 20

Inclusion Criteria

Age:

Participant was 18 to 65 years of age, inclusive, at the time of signing the informed consent.

Type of Participant and Disease Characteristics:
Participants were healthy or compensated, as determined by the investigator or medically qualified designee, based on a medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring (history and ECG).
Creatinine clearance was >= 75 mL/min.
Echocardiogram was normal or showed normal left ventricular function; at most trace to mild valvular regurgitation was allowed, with no valvular stenosis.

Weight:
Body weight was >= 45.0 kg (99 lbs), and body mass index was within the range 18.5 to 31.0 kg/m² (inclusive).

Sex:
Female participants were of Nonchildbearing Potential (WONCBP).

Women in the following categories were considered WONCBP:

Permanently sterile due to one of the following procedures:
1. Documented hysterectomy.
2. Documented bilateral salpingectomy.
3. Documented bilateral oophorectomy.
Postmenopausal females. A postmenopausal state was defined as no menses for 12 months without an alternative medical cause.
- A high follicle-stimulating hormone (FSH) level in the postmenopausal range could have been used to confirm a postmenopausal state in women not using hormonal contraception or hormone replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with >1 FSH measurement was required within the screening period.
- Females on HRT and whose menopausal status was in doubt discontinued HRT >= 30 days prior to the start of Treatment Period 1 to allow confirmation of postmenopausal status before study enrolment.
Informed Consent:
Participant was capable of giving signed informed consent, which included compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol.

Exclusion Criteria

Medical History:

History of known cardiac valve abnormalities.

Laboratory Assessments:
Presence of hepatitis B surface antigen at Screening or within 3 months prior to starting study treatment.
Positive hepatitis C antibody test result at Screening or within 3 months prior to starting study treatment, and positive on reflex to hepatitis C RNA.
Positive HIV-1 and -2 antigen/antibody immunoassay at Screening.
Alanine aminotransferase (ALT) > 1.5×ULN. A single repeat of ALT was allowed within a single screening period to determine eligibility.
Bilirubin > 1.5×ULN (isolated bilirubin > 1.5×ULN was acceptable if bilirubin was fractionated and direct bilirubin was < 35%).
Any acute laboratory abnormality at Screening which, in the opinion of the investigator, should have precluded participation in the study of an investigational compound.
Participants with haemoglobin < 8.0 g/dL.
Any Grade 2 to 4 laboratory abnormality at Screening-except creatine phosphokinase, lipid abnormalities, and ALT (as above)-excluded a participant unless the investigator provided a compelling explanation and had sponsor assent. A single repeat of any laboratory abnormality was allowed within a single screening period.
Positive test result for drugs of abuse (including marijuana), alcohol, or cotinine at Screening or before the first study dose.

Prior/Concomitant Therapy:
Participants were unable to refrain from using prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's wort), within 7 days prior to the first dose and throughout the study.

Levothyroxine and omeprazole were allowed if participants had been on a stable dose for >= 1 month prior to Treatment Period 1 and maintained the same dose. Microgynon was administered >= 1 hour after levothyroxine or omeprazole. Other medications were allowed on a case-by-case basis with medical monitor and GSK ganfeborole team approval.
Participants received any vaccine within 30 days prior to study treatment.
Participants were unwilling to abstain from excessive consumption of caffeine, grapefruit, grapefruit juice, Seville oranges, blood oranges, pomelos, or their juices within 7 days prior to first dose through study end.
Participants who had undergone IVF or assisted reproductive techniques within 9 months prior to screening, were currently participating, or planned such procedures during the following year were excluded.

Prior/Concurrent Clinical Study Experience:
Participants had taken part in another clinical study within 30 days, 5 half-lives + 10 days, or 2× duration of the investigational product's biological effect (whichever was longer).
Study participation resulted in donation of blood or blood products > 500 mL within 56 days.

Diagnostic Assessments:
Significant arrhythmia or ECG findings, in the opinion of the investigator or GSK Medical Monitor, would have interfered with participant safety.
Exclusion criteria for screening ECG:

Heart rate < 50 or > 100 bpm

QTcF interval > 450 ms

Other Exclusion Criteria:
Participants with vitiligo.
Participants with hypertension or Type 2 diabetes that could not be controlled with diet and exercise alone.
History of regular alcohol consumption within 6 months of the study, defined as an average weekly intake > 14 units.
Use of tobacco- or nicotine-containing products within 3 months prior to Screening.
History of sensitivity to any study medications or components, or any allergy that, in the investigator's or medical monitor's opinion, contraindicated participation.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Combined Participants Group	Microgynon	Participants received a dose of Microgynon \[0.03 mg Ethinyl Estradiol (EE)/0.15 mg Levonorgestrel (LNG)\] on Day 1 of Treatment Period 1. In Treatment Period 2, they received GSK3036656 40 mg on Day 4 followed by GSK3036656 20 mg once daily from Day 5 to Day 14. In Treatment Period 3, participants received Microgynon (EE/LNG) along with GSK3036656 20 mg on Day 15, followed by GSK3036656 20 mg once daily from Day 16 to Day 17.
Combined Participants Group	GSK3036656	Participants received a dose of Microgynon \[0.03 mg Ethinyl Estradiol (EE)/0.15 mg Levonorgestrel (LNG)\] on Day 1 of Treatment Period 1. In Treatment Period 2, they received GSK3036656 40 mg on Day 4 followed by GSK3036656 20 mg once daily from Day 5 to Day 14. In Treatment Period 3, participants received Microgynon (EE/LNG) along with GSK3036656 20 mg on Day 15, followed by GSK3036656 20 mg once daily from Day 16 to Day 17.

Primary Outcome Measures

Name	Time	Method
Area Under the Plasma Drug Concentration (AUC) From Time Zero Extrapolated to Infinity (AUC[0-inf]) After a Single Dose of EE and LNG	At Day 1 for the Treatment Period 1: Microgynon Group and at Day 15 for the Treatment Period 3: Microgynon + GSK3036656 Group	AUC(0-inf) is defined as the area under the concentration-time curve from time 0 extrapolated to infinity and was calculated by using a non-compartmental analysis.
Maximum Observed Plasma Concentration (Cmax) After a Single Dose of EE and LNG	At Day 1 for the Treatment Period 1: Microgynon Group and at Day 15 for the Treatment Period 3: Microgynon + GSK3036656 Group	Cmax is defined as the maximum observed plasma concentration determined directly from the concentration-time data and was calculated by using a non-compartmental analysis.

Secondary Outcome Measures

Name	Time	Method
AUC Versus Time Curve From Time Zero During a Dosage Interval of Time at Steady State [AUC(0-tau)] of GSK3036656 With EE/LNG	At Day 15	AUC(0-tau) is defined as the area under the concentration-time curve over a dosing interval and was calculated by using a non-compartmental analysis.
Cmax at Steady State of GSK3036656 With EE/LNG	At Day 15	Cmax is defined as the maximum observed plasma concentration determined directly from the concentration-time data and was calculated by using a non-compartmental analysis.
Trough Plasma Concentration (Ctau) at Steady State of GSK3036656 With EE/LNG and GSK3036656 Alone	At Day 8, 10, 12, 15 and 16	Ctau is defined as the concentration reached by the drug immediately before the next dose is administered.
Time to Maximum Observed Plasma Drug Concentration (Tmax) at Steady State of GSK3036656 With EE/LNG	At Day 15	Tmax is defined as a measure of the time required to reach the maximum concentration of the drug, determined directly from the concentration-time data.
AUC Versus Time Curve (AUC[0-t]) of EE and LNG Alone and With GSK3036656	At Day 1 for the Treatment Period 1: Microgynon Group and at Day 15 for the Treatment Period 3: Microgynon + GSK3036656 Group	AUC(0-t) is defined as area under the plasma drug concentration versus time curve from time zero (pre-dose) to last time of quantifiable concentration and was calculated by using a non-compartmental analysis.
Tmax of EE and LNG Alone and With GSK3036656	At Day 1 for the Treatment Period 1: Microgynon Group and at Day 15 for the Treatment Period 3: Microgynon + GSK3036656 Group	Tmax is defined as a measure of the time required to reach the maximum concentration of the drug, determined directly from the concentration-time data.
Apparent Terminal Half-life (t1/2) of EE and LNG Alone and With GSK3036656	At Day 1 for the Treatment Period 1: Microgynon Group and at Day 15 for the Treatment Period 3: Microgynon + GSK3036656 Group	t1/2 is defined as the time required by the plasma concentration to decline by 50% and was calculated by using a non-compartmental analysis.
Number of Participants With Serious Adverse Events (SAEs)	From the signing of the informed consent form (a period starting up to 14 days before the first dose on Day 1) up to Day 18	A SAE is defined as any untoward medical occurrence that, at any dose: resulted in death, was life threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment.
Number of Participants With Grade 3 or Higher Severity Adverse Events (AEs)	From Day 1 up to Day 18	The intensity of AEs was assessed using the Division of Acquired Immunodeficiency Syndrome (DAIDS) criteria Version 2.1 where grades are defined based on numeric criteria as follows Grade 3: severe or medically significant; Grade 4: potentially life-threatening; Grade 5: death. A higher grade indicates greater severity.
Number of Participants With Drug-related AEs Following Administration of Microgynon and Following the Administration of GSK3036656	From Day 1 up to Day 18	The drug-related AEs were assessed by the investigator to be possibly, probably or definitely related to the study interventions.
Number of Participants Withdrawn From the Treatment Due to AEs	From Day 1 up to Day 18	Adverse events resulting in withholding of study intervention administration were included in this outcome measure.
Number of Participants Withdrawn From the Study Due to AEs	From Day 1 up to Day 18
Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Importance (PCI)	From Day 1 up to Day 18	PCI ECG values are defined as any ECG findings which, in the opinion of the investigator or medical monitor would interfere with the safety of the individual participant. The ECG measurements analyzed are PR Interval, QRS Duration, and QTcF Interval. A value was reported as "high" for a period if it shifted from "low" or "within range" (W/in) at the start of the treatment period but was "high" during or at the end of the same treatment period. A value was reported as "low" for a period if it shifted from "high" or "W/in" at the start of the treatment period but was "low" during or at the end of the same treatment period. A value was reported as "No Change" if it remained unchanged (e.g. High to High), or as "To W/in Range" if it was within range.
Number of Participants With Clinical Chemistry Laboratory Values of PCI	From Day 1 up to Day 18	The chemistry parameters analyzed are homocysteine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin, bilirubin, calcium, creatine kinase, potassium, protein, sodium, urea, and glucose. A value was reported as "high" for a period if it shifted from "low" or "within range" (W/in) at the start of the treatment period but was "high" during or at the end of the same treatment period. A value was reported as "low" for a period if it shifted from "high" or "W/in" at the start of the treatment period but was "low" during or at the end of the same treatment period. A value was reported as "No Change" if it remained unchanged (e.g. High to High), or as "To W/in Range" if it was within range.
Number of Participants With Haematology Laboratory Values of PCI	From Day 1 up to Day 18	The analyzed hematology parameters are reticulocytes/erythrocytes, monocytes/leukocytes, erythrocytes, basophils/leukocytes, eosinophils/leukocytes, mean corpuscular hemoglobin, hematocrit, hemoglobin, lymphocytes, neutrophils, and platelets. A value was reported as "high" for a period if it shifted from "low" or "within range" (W/in) at the start of the treatment period but was "high" during or at the end of the same treatment period. A value was reported as "low" for a period if it shifted from "high" or "W/in" at the start of the treatment period but was "low" during or at the end of the same treatment period. A value was reported as "No Change" if it remained unchanged (e.g. High to High), or as "To W/in Range" if it was within range.
Number of Participants With Vital Signs Parameters of PCI	From Day 1 up to Day 18	The analyzed vital signs are systolic blood pressure, diastolic blood pressure, heart rate, body temperature, and respiration rate. A value was reported as "high" for a period if it shifted from "low" or "within range" (W/in) at the start of the treatment period but was "high" during or at the end of the same treatment period. A value was reported as "low" for a period if it shifted from "high" or "W/in" at the start of the treatment period but was "low" during or at the end of the same treatment period. A value was reported as "No Change" if it remained unchanged (e.g. High to High), or as "To W/in Range" if it was within range.