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Effect of GSK3640254 on the Pharmacokinetics of a Combination Oral Contraceptive

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ClinicalTrials.gov Identifier: NCT03984825
Recruitment Status : Completed
First Posted : June 13, 2019
Results First Posted : August 27, 2020
Last Update Posted : August 27, 2020
Sponsor:
Information provided by (Responsible Party):
ViiV Healthcare

Brief Summary:
This is an open-label, single-sequence, 1-way drug-drug interaction study to investigate the effect of GSK3640254 on the pharmacokinetics of a combination oral contraceptive containing ethinyl estradiol (EE) and levonorgestrel (LNG). Effective contraception for women infected with human immunodeficiency virus (HIV) is important in the prevention of unplanned pregnancies. The study will consist of a screening period of 28 days, check-in (Day -4), a run-in period and a treatment period. During the run-in period, subjects will be administered Portia® (0.03 milligrams [mg] EE/0.15 mg LNG) once daily on Days -3 to -1. Subjects will then be administered Portia once daily on Days 1 to 10 of treatment period A followed by administration of Portia once daily along with GSK3640254 200 mg on Days 11 to 21 of treatment period B. The duration of the study is approximately 8 weeks, including Screening and Run-in. Portia is a registered trademark of Teva Pharmaceuticals USA.

Condition or disease Intervention/treatment Phase
HIV Infections Drug: GSK3640254 Drug: Portia Phase 1

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Effect of Coadministration of GSK3640254 on the Pharmacokinetics of a Combined Oral Contraceptive Containing Ethinyl Estradiol and Levonorgestrel in Healthy Female Subjects
Actual Study Start Date : June 13, 2019
Actual Primary Completion Date : August 16, 2019
Actual Study Completion Date : August 16, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Portia followed by Portia co-administered with GSK3640254
Subjects will be administered Portia (0.03 mg EE/0.15 mg LNG) once daily on Days -3 to -1 during run-in period and on Days 1 to 10 in treatment period A. Subjects will then receive Portia (0.03 mg EE/0.15 mg LNG) co-administered with GSK3640254 200 mg once daily on Days 11 to 21 in treatment period B.
Drug: GSK3640254
GSK3640254 will be available as a 100 mg capsule. Subjects will be administered 200 mg GSK3640254 once daily via the oral route on Days 11 to 21.

Drug: Portia
Portia will be available in the form of tablets containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel.




Primary Outcome Measures :
  1. Period 1: Area Under the Plasma Concentration-time Curve From Time 0 to the End of the Dosing Interval at Steady State (AUC [0-tau]) of EE [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of AUC (0-tau) of EE. PK parameters were calculated by standard non-compartmental analysis. The PK population included all participants who underwent plasma PK sampling and had evaluable PK parameters estimated.

  2. Period 2: AUC (0-tau) of EE [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 and 24 hours post dose ]
    Blood samples were collected at indicated time points for the analysis of AUC (0-tau) of EE. PK parameters were calculated by standard non-compartmental analysis.

  3. Period 1:AUC (0-tau) of LNG [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of AUC (0-tau) of LNG. PK parameters were calculated by standard non-compartmental analysis.

  4. Period 2: AUC (0-tau) of LNG [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 and 24 hours post dose ]
    Blood samples were collected at indicated time points for the analysis of AUC (0-tau) of LNG. PK parameters were calculated by standard non-compartmental analysis.

  5. Period 1: Maximum Observed Concentration (Cmax) and Plasma Concentration at the End of the Dosing Interval (Ctau) of EE [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of Cmax and Ctau of EE. PK parameters were calculated by standard non-compartmental analysis.

  6. Period 2: Cmax and Ctau of EE [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 and 24 hours ]
    Blood samples were collected at indicated time points for the analysis of Cmax and Ctau of EE. PK parameters were calculated by standard non-compartmental analysis.

  7. Period 1:Cmax and Ctau of LNG [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of Cmax and Ctau of LNG. PK parameters were calculated by standard non-compartmental analysis.

  8. Period 2: Cmax and Ctau of LNG [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 and 24 hours post dose ]
    Blood samples were collected at indicated time points for the analysis of Cmax and Ctau of LNG. PK parameters were calculated by standard non-compartmental analysis.


Secondary Outcome Measures :
  1. Period 1: Effect of GSK3640254 on PD of EE/LNG- Serum Progesterone Level [ Time Frame: At Day 1 and Day 10 ]
    Serum samples were collected for the analysis of progesterone concentration levels when GSK3640254 is co-administered with EE/LNG. PD concentration Population comprised of all participants who underwent plasma PD sampling and had evaluable PD assay results.

  2. Period 2: Effect of GSK3640254 on PD of EE/LNG- Serum Progesterone Level [ Time Frame: At Days 11, 21 and 22 ]
    Serum samples were collected for the analysis progesterone concentration levels when GSK3640254 is co-administered with EE/LNG.

  3. Period 1: Absolute Values of Effect of GSK3640254 on Luteinizing Hormone (LH) and Follicle-stimulating Hormone (FSH) [ Time Frame: At Day 1 and Day 10 ]
    Serum samples were collected for the analysis of effect of GSK3640254 on LH and FSH.

  4. Period 2: Absolute Values of Effect of GSK3640254 on LH and FSH [ Time Frame: At Days 11, 21 and 22 ]
    Serum samples were collected for the analysis of effect of GSK3640254 on LH and FSH.

  5. Period 2: AUC (0-tau) of GSK3640254 [ Time Frame: Day 21: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8 and 12 and 24 hours post dose ]
    Blood samples were collected at indicated time points for the analysis of AUC (0-tau) of GSK3640254. PK parameters were calculated by standard non-compartmental analysis.

  6. Period 2: Cmax and Ctau of GSK3640254 [ Time Frame: Day 21: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8 and 12 and 24 hours post dose ]
    Blood samples were collected at indicated time points for the analysis of Cmax and Ctau of GSK3640254. PK parameters were calculated by standard non-compartmental analysis.

  7. Period 2: Apparent Terminal Phase Half-life (t1/2) of GSK3640254 [ Time Frame: Day 21: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8 and 12 hours; Day 22: 24 hours; Day 23: 48 hours; Day 24: 72 hours and Day 25: 96 hours ]
    Blood samples were collected at indicated time points for the analysis of t1/2 of GSK3640254. PK parameters were calculated by standard non-compartmental analysis.

  8. Period 2: Time of Maximum Observed Concentration (Tmax) of GSK3640254 [ Time Frame: Day 21: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8 and 12 and 24 hours post dose ]
    Blood samples were collected at indicated time points for the analysis of Tmax of GSK3640254. PK parameters were calculated by standard non-compartmental analysis.

  9. Period 1: t1/2 of EE [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of t1/2 of EE. PK parameters were calculated by standard non-compartmental analysis.

  10. Period 2: t1/2 of EE [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 22: 24 hours; Day 23: 48 hours and Day 24: 72 hours ]
    Blood samples were collected at indicated time points for the analysis of t1/2 of EE. PK parameters were calculated by standard non-compartmental analysis.

  11. Period 1: Tmax of EE [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of Tmax of EE. PK parameters were calculated by standard non-compartmental analysis.

  12. Period 2: Tmax of EE [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 22: 24 hours; Day 23: 48 hours and Day 24: 72 hours ]
    Blood samples were collected at indicated time points for the analysis of Tmax of EE. PK parameters were calculated by standard non-compartmental analysis.

  13. Period 1: t1/2 of LNG [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of t1/2 of LNG. PK parameters were calculated by standard non-compartmental analysis.

  14. Period 2: t1/2 of LNG [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours; Day 22: 24 hours; Day 23: 48 hours and Day 24: 72 hours ]
    Blood samples were collected at indicated time points for the analysis of t1/2 of LNG. PK parameters were calculated by standard non-compartmental analysis.

  15. Period 1: Tmax of LNG [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of Tmax of LNG. PK parameters were calculated by standard non-compartmental analysis.

  16. Period 2: Tmax of LNG [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours; Day 22: 24 hours; Day 23: 48 hours and Day 24: 72 hours ]
    Blood samples were collected at indicated time points for the analysis of Tmax of LNG. PK parameters were calculated by standard non-compartmental analysis.

  17. Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAE) (Treatment Period) [ Time Frame: Up to Day 25 ]
    An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; other important medical events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed before. Safety Population comprised of all participants who received at least one dose of study medication.

  18. Number of Participants With Non-SAEs and SAE (Run-in Period) [ Time Frame: From Day -3 to Day -1 ]
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; other important medical events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed before.

  19. Period 1: Change From Baseline in Clinical Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium and Blood Urea Nitrogen (BUN) [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Glucose, cholesterol, triglycerides, anion gap, calcium, carbon dioxide, chloride, phosphate, potassium, sodium and BUN. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  20. Period 2: Change From Baseline in Clinical Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium and BUN [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Glucose, cholesterol, triglycerides, anion gap, calcium, carbon dioxide, chloride, phosphate, potassium, sodium and BUN. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  21. Period 1: Change From Baseline in Clinical Chemistry Parameters: Plasma Albumin, Globulin and Protein [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma albumin, globulin and protein. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  22. Period 2: Change From Baseline in Clinical Chemistry Parameters: Plasma Albumin, Globulin and Protein [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma albumin, globulin and protein. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  23. Period 1: Change From Baseline in Clinical Chemistry Parameters: Plasma Amylase and Lipase [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma amylase and lipase. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  24. Period 2: Change From Baseline in Clinical Chemistry Parameters: Plasma Amylase and Lipase [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma amylase and lipase. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  25. Period 1: Change From Baseline in Clinical Chemistry Parameters: Plasma Creatine Kinase, Lactate Dehydrogenase, Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma creatine kinase, lactate dehydrogenase, ALT, ALP, AST and GGT. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  26. Period 2: Change From Baseline in Clinical Chemistry Parameters: Plasma Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST and GGT [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma creatine kinase, lactate dehydrogenase, ALT, ALP, AST and GGT. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  27. Period 1: Change From Baseline in Clinical Chemistry Parameters: Plasma Urate, Creatinine, Total Bilirubin and Direct Bilirubin [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma urate, creatinine, total bilirubin and direct bilirubin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  28. Period 2: Change From Baseline in Clinical Chemistry Parameters: Plasma Urate, Creatinine, Total Bilirubin and Direct Bilirubin [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma urate, creatinine, total bilirubin and direct bilirubin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  29. Period 1: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelets [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameters including Basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils and platelets. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  30. Period 2: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelets [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameters including Basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils and platelets. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  31. Period 1: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  32. Period 2: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  33. Period 1: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular volume. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  34. Period 2: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular volume. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  35. Period 1: Change From Baseline in Hematology Parameter: Erythrocytes [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  36. Period 2: Change From Baseline in Hematology Parameter: Erythrocytes [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  37. Period 1: Change From Baseline in Hematology Parameter: Hematocrit [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hematocrit. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  38. Period 2: Change From Baseline in Hematology Parameter: Hematocrit [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hematocrit. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  39. Period 1: Change From Baseline in Hematology Parameter: Hemoglobin [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  40. Period 2: Change From Baseline in Hematology Parameter: Hemoglobin [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  41. Period 1: Change From Baseline in Urine Concentration: Urine Specific Gravity [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Urine samples were collected at indicated time points for the assessment of specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The concentration of the excreted molecules determines the urine's specific gravity. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  42. Period 2: Change From Baseline in Urine Concentration: Urine Specific Gravity [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Urine samples were collected at indicated time points for the assessment of specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The concentration of the excreted molecules determines the urine's specific gravity. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  43. Period 1: Change From Baseline in Urine Concentration: Urine Urobilinogen [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Urine samples were collected at indicated time points for the assessment of urine urobilinogen. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  44. Period 2: Change From Baseline in Urine Concentration: Urine Urobilinogen [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Urine samples were collected at indicated time points for the assessment of urine urobilinogen. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  45. Period 1: Change From Baseline in Urine Concentration: Urine Potential of Hydrogen (pH) [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Urine samples were collected at indicated time points for the assessment of Urinary pH. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  46. Period 2: Change From Baseline in Urine Concentration: Urine pH [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Urine samples were collected at indicated time points for the assessment of Urinary pH. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  47. Period 1: Change From Baseline in Electrocardiogram (ECG) Mean Heart Rate [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure heart rate. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  48. Period 2: Change From Baseline in ECG Mean Heart Rate [ Time Frame: Baseline (Day 11, Pre-dose) and at Day 11: 2, 4, 6 hours, Day 15: 2, 4, 6 hours, Day 21 and 24 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure heart rate. Baseline is defined as the average of the triplicate predose assessments on Day 11. Change from Baseline was defined as post-dose visit value minus Baseline value.

  49. Period 1: Change From Baseline in ECG Parameters: PR Interval, QRS Duration, QT Interval, Fridericia QT Correction Formula (QTcF) Interval, and Bazett QT Correction Formula (QTcB) Interval [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure PR interval, QRS duration, QT Interval, QTcF Interval and QTcB interval. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  50. Period 2: Change From Baseline in ECG Parameters: PR Interval, QRS Duration, QT Interval, QTcF and QTcB Interval [ Time Frame: Baseline (Day 11, Pre-dose) and at Day 11: 2, 4, 6 hours, Day 15: 2, 4, 6 hours, Day 21 and 24 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure heart rate. Baseline is defined as the average of the triplicate predose assessments on Day 11. Change from Baseline was defined as post-dose visit value minus Baseline value.

  51. Period 1: Change From Baseline in Vital Signs: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    SBP and DBP were assessed in the semi-recumbent position with a completely automated device at indicated time-points. Baseline is defined as the average of the triplicate pre-dose assessments. Change from Baseline was defined as post-dose visit value minus Baseline value.

  52. Period 2: Change From Baseline in Vital Signs: SBP and DBP [ Time Frame: Baseline (Day 11, Pre-dose) and at Days 15, 21 and 24 ]
    SBP and DBP were assessed in the semi-recumbent position with a completely automated device at indicated time-points. Baseline is defined as as the average of the triplicate pre-dose assessments. Change from Baseline was defined as post-dose visit value minus Baseline value.

  53. Period 1: Change From Baseline in Pulse Rate [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Pulse rate was assessed in the semi-recumbent position with a completely automated device at indicated time-points. Baseline is defined as the average of the triplicate predose assessments. Change from Baseline was defined as post-dose visit value minus Baseline value.

  54. Period 2: Change From Baseline in Pulse Rate [ Time Frame: Baseline (Day 11, Pre-dose) and at Days 15, 21 and 24 ]
    Pulse rate was assessed in the semi-recumbent position with a completely automated device at indicated time-points. Baseline is defined as the average of the triplicate predose assessments. Change from Baseline was defined as post-dose visit value minus Baseline value.

  55. Period 1: Change From Baseline in Respiratory Rate [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Respiratory rate was assessed at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  56. Period 2: Change From Baseline in Respiratory Rate [ Time Frame: Baseline (Day 11, Pre-dose) and at Days 15, 21 and 24 ]
    Respiratory rate was assessed at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  57. Period 1: Change From Baseline in Temperature [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Temperature was assessed at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  58. Period 2: Change From Baseline in Temperature [ Time Frame: Baseline (Day 11, Pre-dose) and at Days 15, 21 and 24 ]
    Temperature was assessed at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  59. Period 1: Absolute Values of Clinical Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium and BUN [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Glucose, cholesterol, triglycerides, anion gap, calcium, carbon dioxide, chloride, phosphate, potassium, sodium and BUN. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  60. Period 2: Absolute Values of Clinical Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium and BUN [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Glucose, cholesterol, triglycerides, anion gap, calcium, carbon dioxide, chloride, phosphate, potassium, sodium and BUN. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  61. Period 1: Absolute Values of Clinical Chemistry Parameters: Plasma Albumin, Globulin and Protein [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma albumin, globulin and protein. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  62. Period 2: Absolute Values of Clinical Chemistry Parameters: Plasma Albumin, Globulin and Protein [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma albumin, globulin and protein. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  63. Period 1: Absolute Values of Clinical Chemistry Parameters: Plasma Amylase and Lipase [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma amylase and lipase. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  64. Period 2: Absolute Values of Clinical Chemistry Parameters: Plasma Amylase and Lipase [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma amylase and lipase. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  65. Period 1: Absolute Values of Clinical Chemistry Parameters: Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST and GGT [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including creatine kinase, lactate dehydrogenase, ALT, ALP, AST and GGT. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  66. Period 2: Absolute Values of Clinical Chemistry Parameters: Plasma Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST and GGT [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma creatine kinase, lactate dehydrogenase, ALT, ALP, AST and GGT. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  67. Period 1: Absolute Values of Clinical Chemistry Parameters: Urate, Creatinine, Total Bilirubin and Direct Bilirubin [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma urate, creatinine, total bilirubin and direct bilirubin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  68. Period 2: Absolute Values of Clinical Chemistry Parameters: Plasma Urate, Creatinine, Total Bilirubin and Direct Bilirubin [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma urate, creatinine, total bilirubin and direct bilirubin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  69. Period 1: Absolute Values of Hematology Parameters: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelets [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameters including Basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils and platelets. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  70. Period 2: Absolute Values of Hematology Parameters: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelets [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameters including Basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils and platelets. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  71. Period 1: Absolute Values of Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  72. Period 2: Absolute Values of Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  73. Period 1: Absolute Values of Hematology Parameter: Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular volume. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  74. Period 2: Absolute Values of Hematology Parameter: Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular volume. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  75. Period 1: Absolute Values of Hematology Parameter: Erythrocytes [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  76. Period 2: Absolute Values of Hematology Parameter: Erythrocytes [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  77. Period 1: Absolute Values of Hematology Parameter: Hematocrit [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hematocrit. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  78. Period 2: Absolute Values of Hematology Parameter: Hematocrit [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hematocrit. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  79. Period 1: Absolute Values of Hematology Parameter: Hemoglobin [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  80. Period 2: Absolute Values of Hematology Parameter: Hemoglobin [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  81. Period 1: Absolute Values of Urine Concentration: Urine Specific Gravity [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Urine samples were collected at indicated time points for the assessment of specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The concentration of the excreted molecules determines the urine's specific gravity. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  82. Period 2: Absolute Values of Urine Concentration: Urine Specific Gravity [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Urine samples were collected at indicated time points for the assessment of specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The concentration of the excreted molecules determines the urine's specific gravity. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  83. Period 1: Absolute Values of Urine Concentration: Urine Urobilinogen [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Urine samples were collected at indicated time points for the assessment of urine urobilinogen. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  84. Period 2: Absolute Values of Urine Concentration: Urine Urobilinogen [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Urine samples were collected at indicated time points for the assessment of urine urobilinogen. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  85. Period 1: Absolute Values of Urine Concentration: Urine pH [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Urine samples were collected at indicated time points for the assessment of Urinary pH. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  86. Period 2: Absolute Values of Urine Concentration: Urine pH [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Urine samples were collected at indicated time points for the assessment of Urinary pH. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  87. Period 1: Number of Participants With Abnormal Urinalysis Parameters Using Dipstick Method. [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    The dipstick test gives results in a semi-quantitative manner and results for urinalysis parameters (ketones, glucose, bilirubin, occult blood, nitrite and blood protein) can be read as positive, trace, 1+, 2+, 3+ and 4+ indicating proportional concentrations in the urine sample. Only participants with abnormal findings for urinalysis at any visit has been presented.

  88. Period 2: Number of Participants With Abnormal Urinalysis Parameters Using Dipstick Method. [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    The dipstick test gives results in a semi-quantitative manner and results for urinalysis parameters (ketones, glucose, bilirubin, occult blood, nitrite and blood protein) can be read as positive, trace, 1+, 2+, 3+ and 4+ indicating proportional concentrations in the urine sample. Only participants with abnormal findings for urinalysis at any visit has been presented.

  89. Period 1: Absolute Values of ECG Mean Heart Rate [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure heart rate. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  90. Period 2: Absolute Values of ECG Mean Heart Rate [ Time Frame: Baseline (Day 11, Pre-dose) and at Day 11: 2, 4, 6 hours, Day 15: 2, 4, 6 hours, Day 21 and 24 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure heart rate. Baseline is defined as the average of the triplicate predose assessments on Day 11.

  91. Period 1: Absolute Values of ECG Parameters: PR Interval, QRS Duration, QT Interval, QTcF Interval, and QTcB Interval [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure PR interval, QRS duration, QT Interval, QTcF Interval and QTcB interval. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  92. Period 2: Absolute Values of ECG Parameters: PR Interval, QRS Duration, QT Interval, QTcF and QTcB Interval [ Time Frame: Baseline (Day 11, Pre-dose) and at Day 11- 2, 4, 6 hours, Day 15- 2, 4, 6 hours, Day 21 and 24 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure PR Interval, QRS Duration, QT Interval, QTcF and QTcB Interval. Baseline is defined as the average of the triplicate predose assessments on Day 11.

  93. Period 1: Absolute Values of Vital Signs: SBP and DBP [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    SBP and DBP were assessed in the semi-recumbent position with a completely automated device at indicated time-points. Baseline is defined as the average of the triplicate predose assessments on Day 11.

  94. Period 2: Absolute Values of Vital Signs: SBP and DBP [ Time Frame: Baseline (Day 11, Pre-dose) and at Days 15, 21 and 24 ]
    SBP and DBP were assessed in the semi-recumbent position with a completely automated device at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  95. Period 1: Absolute Values of Pulse Rate [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Pulse rate was assessed in the semi-recumbent position with a completely automated device at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  96. Period 2: Absolute Values of Pulse Rate [ Time Frame: Baseline (Day 11, Pre-dose) and at Days 15, 21 and 24 ]
    Pulse rate was assessed in the semi-recumbent position with a completely automated device at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  97. Period 1: Absolute Values of Respiratory Rate [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Respiratory rate was assessed indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  98. Period 2: Absolute Values of Respiratory Rate [ Time Frame: Baseline (Day 11, Pre-dose) and at Days 15, 21 and 24 ]
    Respiratory rate was assessed indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  99. Period 1: Absolute Values of Temperature [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Temperature was assessed at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  100. Period 2: Absolute Values of Temperature [ Time Frame: Baseline (Day 11, Pre-dose) and at Days 15, 21 and 24 ]
    Temperature was assessed at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Subject must be 18 to 50 years of age inclusive, at the time of signing the informed consent.
  • Subjects who are 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 (history and ECG).
  • Body weight >=45.0 kilograms (kg) (99 pounds [lbs]) and body mass index (BMI) within the range 18.5 to 31.0 kilograms per meter square (kg/m^2) (inclusive).
  • Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
  • Female subjects will be included.
  • Subject must not be pregnant or breastfeeding.
  • Subject is a woman of childbearing potential (WOCBP) with intact ovarian function, as determined by medical history. Subjects must use Portia for the duration of the run-in and treatment periods.
  • WOCBP must have been on an acceptable form of contraceptive for at least 28 days prior to start of study intervention. Acceptable forms of contraception prior to study intervention include the following: Intrauterine device or intrauterine system; Combined estrogen and progestogen oral contraceptive; Contraceptive vaginal ring; Percutaneous contraceptive patches (if used, the patch must be removed during study participation); Bilateral tubal occlusion; Male partner sterilization with documentation of azoospermia prior to the female subject's entry into the study, and this male is the sole partner for that subject. The documentation on male sterility can come from the site personnel's review of subject's medical records, medical examination and/or semen analysis, or medical history interview provided by her or her partner.; Sexual abstinence.
  • Subjects who have been on a stable regimen of an oral contraceptive for at least 3 consecutive months must be without evidence of breakthrough bleeding or spotting.
  • Subjects who have been taking oral contraceptives should continue their current regimen until check-in to the clinic for the run-in period. Subjects not currently taking an oral contraceptive are eligible, provided all other eligibility criteria are met.
  • Subjects may proceed to the treatment period provided the toxicity profile during the run-in period with Portia is acceptable in the opinion of the investigator.
  • Subjects must agree to use an additional method of contraception from the following list of contraceptive methods for the run-in period, treatment period, and for 28 days after the last dose of study intervention: Non hormonal Intrauterine device; Bilateral tubal occlusion; Male partner sterilization with documentation of azoospermia prior to the female subject's entry into the study, and this male is the sole partner for that subject. The documentation on male sterility can come from the site personnel's review of subject's medical records, medical examination and/or semen analysis, or medical history interview provided by her or her partner.; Sexual abstinence. For the 28 days after study exit, women may resume oral contraceptives but double barrier methods (a combination of male condom with either cervical cap, diaphragm, or sponge with spermicide) must be used in addition.
  • Women of childbearing potential must have a negative highly sensitive serum pregnancy test on Day -4 and Day -1.
  • Additional requirements for pregnancy testing during and after study intervention as outlined in protocol.
  • Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form and protocol.

Exclusion Criteria:

  • History of jaundice associated with taking oral contraceptives or with pregnancy.
  • History of clinically significant irregular bleeding while taking oral contraceptives.
  • History of past deep venous thrombosis, pulmonary embolism, stroke, transient ischemic attack, phlebitis, or migraine headaches with prolonged aura.
  • History of cerebrovascular or coronary artery disease.
  • History of retinal vascular lesions.
  • History of carcinoma of the breast, endometrium, or other known estrogen-dependent neoplasia.
  • Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • A pre-existing condition interfering with normal gastrointestinal (GI) anatomy or motility (e.g., gastroesophageal reflux disease, gastric ulcers, gastritis), hepatic and/or renal function, that could interfere with the absorption, metabolism, and/or excretion of the study drugs or render the subject unable to take oral study intervention.
  • Any history of significant underlying psychiatric disorder, including, but not limited to, schizophrenia, bipolar disorder with or without psychotic symptoms, other psychotic disorders, or schizotypal (personality) disorder.
  • Any history of major depressive disorder with or without suicidal features, or anxiety disorders that required medical intervention (pharmacologic or not) such as hospitalization or other inpatient treatment and/or chronic (>6 months) outpatient treatment. Subjects with other conditions such as adjustment disorder or dysthymia that have required shorter term medical therapy (<6 months) without inpatient treatment and are currently well-controlled clinically or resolved may be considered for entry after discussion and agreement with the ViiV Healthcare/GlaxoSmithKline (GSK) Medical Monitor.
  • Any pre-existing physical or other psychiatric condition (including alcohol or drug abuse), which, in the opinion of the investigator (with or without psychiatric evaluation), could interfere with the subject's ability to comply with the dosing schedule and protocol evaluations or which might compromise the safety of the subject.
  • Medical history of cardiac arrhythmias, prior myocardial infarction in the past 3 months, or cardiac disease or a family or personal history of long QT syndrome.
  • Presence of hepatitis B surface antigen at Screening or within 3 months prior to starting study intervention.
  • Positive hepatitis C antibody test result at Screening or within 3 months prior to starting study intervention AND positive on reflex to hepatitis C ribonucleic acid (RNA).
  • Positive HIV-1 and -2 antigen/antibody immunoassay at Screening.
  • ALT >1.5 times upper limit of normal (ULN). A single repeat of ALT is allowed within a single screening period to determine eligibility.
  • Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  • Any acute laboratory abnormality at Screening which, in the opinion of the investigator, should preclude participation in the study of an investigational compound.
  • Any Grade 2 to 4 laboratory abnormality at Screening, with the exception of creatine phosphokinase (CPK) and lipid abnormalities (e.g., total cholesterol, triglycerides, etc), and ALT (described above), will exclude a subject from the study unless the investigator can provide a compelling explanation for the laboratory result(s) and has the assent of the sponsor. A single repeat of any laboratory abnormality is allowed within a single screening period to determine eligibility.
  • A positive test result for drugs of abuse (including marijuana), alcohol, or cotinine (indicating active current smoking) at Screening or before the first dose of study intervention.
  • Unable to refrain from the use of prescription or nonprescription 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 intervention and for the duration of the study (acetaminophen/paracetamol at doses of <=2 grams/day and hydrocortisone cream 1% are permitted for use any time during the study).
  • Treatment with any vaccine within 30 days prior to receiving study intervention.
  • Unwillingness to abstain from excessive consumption of any food or drink containing grapefruit and grapefruit juice, Seville oranges, blood oranges, or pomelos or their fruit juices within 7 days prior to the first dose of study intervention(s) until the end of the study.
  • Participation in another concurrent clinical study or prior clinical study (with the exception of imaging trials) 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).
  • Where participation in the study would result in donation of blood or blood products in excess of 500 milliliters (mL) within 56 days.
  • Any positive (abnormal) response confirmed by the investigator on a screening clinician- or qualified designee-administered Columbia Suicide Severity Rating Scale (C-SSRS).
  • Any significant arrhythmia or ECG finding (e.g., symptomatic bradycardia, non-sustained or sustained atrial arrhythmias, non-sustained or sustained ventricular tachycardia, second-degree atrioventricular block Mobitz Type II, or third-degree atrioventricular block) which, in the opinion of the investigator or ViiV Healthcare/GSK Medical Monitor, will interfere with the safety for the individual subject.
  • Exclusion criteria for screening ECG (a single repeat is allowed for eligibility determination): heart rate-<50 or >100 beats per minute and QTcF->450 milliseconds.
  • History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of >14 units. One unit is equivalent to 8 g of alcohol: a half-pint (equivalent to 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
  • Unable to refrain from tobacco- or nicotine-containing within 3 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03984825


Locations
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United States, Texas
GSK Investigational Site
Austin, Texas, United States, 78744
Sponsors and Collaborators
ViiV Healthcare
Investigators
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Study Director: GSK Clinical Trials ViiV Healthcare
  Study Documents (Full-Text)

Documents provided by ViiV Healthcare:
Study Protocol  [PDF] May 10, 2019
Statistical Analysis Plan  [PDF] January 19, 2020

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Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT03984825    
Other Study ID Numbers: 208135
First Posted: June 13, 2019    Key Record Dates
Results First Posted: August 27, 2020
Last Update Posted: August 27, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
URL: http://clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by ViiV Healthcare:
GSK3640254
ethinyl estradiol
levonorgestrel
oral contraceptive
drug-drug interaction
Additional relevant MeSH terms:
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HIV Infections
Blood-Borne Infections
Communicable Diseases
Infections
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Immunologic Deficiency Syndromes
Immune System Diseases