A Phase 2a Study to Compare Antiviral Effect, Safety, Tolerability and Pharmacokinetics of GSK1265744 Monotherapy Versus Placebo in HIV-1 Infected Adults (ITZ112929)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 9
- 试验地点
- 1
- 主要终点
- Change From Baseline in Plasma Human Immunodeficiency Virus (HIV-1) Ribonucleic Acid (RNA) to Day 11
研究概览
简要总结
The purpose of this randomized, double-blinded study is to test the safety of GSK1265744 and how well it works on reducing the amount of HIV in the blood. It will also look at how people react to and how a human body uses GSK1265744. This study will compare the effects of GSK1265744 and placebo.
The study will consist of 1 or 2 parts to look at doses of GSK1265744. About 8 people will take part in Part 1 of the study receiving dose A. If additional dosing information is needed after Part 1, about 6 people will take part in Part 2 of the study receiving dose B.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •A subject will be eligible for inclusion in this study only if all of the following criteria apply:
- •Male or female between 18 and 65 years of age inclusive, at the time of signing the informed consent.
- •A female subject is eligible to participate if she is of non-childbearing potential, defined as:
- •Pre-menopausal females with a documented bilateral oophorectomy, tubal ligation or hysterectomy; or
- •Postmenopausal defined as 12 months of spontaneous amenorrhea. A follicle stimulating hormone level will be performed to confirm post-menopausal status. For this study, FSH levels > 40 MlU/ml and estradiol < 40 pg/ml (<140 pmol/L) is confirmatory.
- •Male subjects must agree to use one of the contraception methods listed in Section 8.
- •This criterion must be followed from the time of the first dose of study medication until 14 days after the last dose of study medication.
- •CD4+ cell count greater than or equal to 200 cells/mm3 and plasma HIV-1 RNA greater than or equal to 5000 copies/mL at Screening.
- •No current antiretroviral therapy and have not received any in the 12 weeks prior to first dose.
- •For subjects who have received antiretroviral treatment in the past, adequate treatment options to construct HAART therapy with at least 3 active antiretrovirals for Optimized Therapy, as selected by the Investigator.
- •Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
- •Exclusion Criteria
- •A subject will not be eligible for inclusion in this study if any of the following criteria apply:
- •A positive screening Hepatitis B surface antigen; positive screening hepatitis C virus (HCV) antibody and detectable HCV ribonucleic acid (RNA) on subsequent testing. If the hepatitis C antibody is positive but the HCV RNA is undetectable, the subject may be included in the study.
- •AST and ALT > 3ULN at Screening. A single repeat is allowed for eligibility determination.
- •Inadequate renal function at Screening, defined as either a serum creatinine >1.5 mg/dL or a calculated creatinine clearance (CrCl) ≤ 50 mL/min. A single repeat serum creatinine is allowed to determine eligibility.
- •Any acute laboratory abnormality at screening which, in the opinion of the investigator, should preclude the subject's participation in the study of an investigational compound. Any grade 4 laboratory abnormality at screening, with the exception of CPK, will exclude a subject from study participation unless the investigator can provide a compelling explanation for the laboratory result(s) and has the assent of the sponsor. A single repeat is allowed for eligibility determination.
- •A positive drug screen at screening and baseline. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine or PCP.
- •History of regular alcohol consumption, defined as an average weekly intake of >14 drinks for males or >7 drinks for females, within 6 months of Screening.
- •Note: One drink is equivalent to 12 g of alcohol: 12 ounces (360 ml) of beer, 5 ounces (150 ml) of wine or 1.5 ounces (45 ml) of 80 proof distilled spirits.
- •Any condition (including alcohol or drug abuse) which, in the opinion of the investigator, 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.
- •Prior treatment with an integrase inhibitor (greater than or equal to 1 dose).
- •Treatment with radiation therapy or cytotoxic chemotherapeutic agents within 30 days of study drug administration or anticipated need for such treatment within the study.
- •Treatment with immunomodulating agents (such as systemic corticosteroids, interleukins, interferons) or any agent with known anti-HIV activity (such as hydroxyurea or foscarnet) within 30 days of study drug administration.
- •Treatment with any vaccine within 30 days prior to receiving study medication.
- •An active Center for Disease Control and Prevention (CDC) Category C disease, except cutaneous Kaposi's sarcoma not requiring systemic therapy during the trial.
- •Pregnant females as determined by positive serum or urine hCG test at screening or prior to dosing.
- •Lactating females.
- •Use of multivitamins or antacids within 24 hours prior to the first dose of investigational product.
- •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 GSK Medical Monitor, contraindicates their participation. In addition, if heparin is used during PK sampling, subjects with a history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled.
- •Note: Study medications refer to GSK1265744 or placebo.
- •The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
- •Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
- •History of clinically relevant pancreatitis or hepatitis within the previous 6 months.
- •Subjects with a pre-existing condition interfering with normal gastrointestinal anatomy or motility, hepatic and/or renal function, that could interfere with the absorption, metabolism, and/or excretion of the study drugs.
- •Exclusion Criteria for Screening ECG (A single repeat is allowed for eligibility determination):
- •Exclusion Criteria for Screening ECG:
- •Males Females Heart rate <45 and >100 bpm <50 and >100 bpm QRS duration >120 msec >120 msec QTc interval (Bazett) > 450 msec > 450 msec Non-sustained (≥ 3 consecutive beats) or sustained ventricular tachycardia. Sinus Pauses >3 seconds. 2nd degree (Type II) or higher AV block. Evidence of previous myocardial infarction (pathologic Q waves, S-T segment changes (except early repolarization)).
排除标准
- 未提供
研究组 & 干预措施
GSK1265744 30 mg
GSK1265744 30 mg
干预措施: GSK1265744 30mg (Drug)
Placebo
Placebo to match GSK1265744
干预措施: Placebo (Drug)
GSK1265744 5 mg
GSK1265744 5 mg
干预措施: GSK1265744 5mg (Drug)
结局指标
主要结局
Change From Baseline in Plasma Human Immunodeficiency Virus (HIV-1) Ribonucleic Acid (RNA) to Day 11
时间窗: Baseline (Day 1) and Day 11
Plasma for quantitative HIV-1 RNA was collected on Day 1, 2, 3, 4, 7, 8, 9, 10 and 11. On Days 1, 10 and 11, two samples for HIV-1 RNA was collected between 5-20 minutes apart to reduce sample variability. An HIV-1 RNA PCR assay with a lower limit of detection (LLOD) of 50 copies/milliliter (mL) (ultrasensitive assay) was used for post-baseline assessments. An HIV-1 RNA PCR assay with a LLOD of 400 copies/mL (standard assay) was used for screening and Baseline assessments and included a re-test with and ultrasensitive assay for all Baseline values below the LLOD. Baseline was defined at Day 1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.
GSK1265744 Pharmacokinetic (PK) Parameters Following Dose Administration on Day 1: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration Within a Participant Across All Treatments(AUC[0-24])
时间窗: Day 1 (Pre-dose [within 15 minutes prior to dosing] and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose)
Blood samples for PK analysis of AUC(0-24) of GSK1265744 was collected on Day 1 (Pre-dose \[within 15 minutes prior to dosing\] and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose). Samples were collected at nominal times relative to the proposed time of GSK1265744 dosing. The actual date and time of each blood sample collection was recorded. AUC was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations.
GSK1265744 PK Parameters Following Dose Administration on Day 1: Concentration at 24 Hours Post Dose (C24)
时间窗: Day 1 (Pre-dose [within 15 minutes prior to dosing] and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose)
Blood samples for PK analysis of C24 of GSK1265744 was collected on Day 1 (Pre-dose \[within 15 minutes prior to dosing\] and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose). Samples were collected at nominal times relative to the proposed time of GSK1265744 dosing. The actual date and time of each blood sample collection was recorded.
GSK1265744 PK Parameters Following Dose Administration on Day 10: Area Under the Concentration-time Curve Over the Dosing Interval (AUC[0-tau])
时间窗: Day 10 (Pre-dose [within 15 minutes prior to dosing] and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose)
Blood samples for PK analysis of C24 of GSK1265744 was collected on Day 10 (Pre-dose \[within 15 minutes prior to dosing\] and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose). Samples were collected at nominal times relative to the proposed time of GSK1265744 dosing. The actual date and time of each blood sample collection was recorded. AUC was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations.
GSK1265744 PK Parameters Following Dose Administration on Day 10: Predose Concentration (C0), Concentration at End of Dosing Interval (Ctau), Minimum Observed Concentration During One Dosing Interval (Cmin)
时间窗: Day 10 (Pre-dose [within 15 minutes prior to dosing] and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose)
Blood samples for PK analysis of C0, Ctau and Cmin of GSK1265744 was collected on Day 10 (Pre-dose \[within 15 minutes prior to dosing\] and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose). Samples were collected at nominal times relative to the proposed time of GSK1265744 dosing. The actual date and time of each blood sample collection was recorded.
GSK1265744 PK Parameters Following Dose Administration on Day 1 and Day 10: Maximum Observed Concentration (Cmax)
时间窗: Pre-dose (within 15 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose on Days 1 and 10
Blood samples for PK analysis of Cmax of GSK1265744 was collected at pre-dose (within 15 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose on Days 1 and 10. Samples were collected at nominal times relative to the proposed time of GSK1265744 dosing. The actual date and time of each blood sample collection was recorded.
GSK1265744 PK Parameters Following Dose Administration on Day 1 and Day 10: Time to Cmax (Tmax)
时间窗: Pre-dose (within 15 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose on Days 1 and 10
Blood samples for PK analysis of tmax of GSK1265744 was collected at pre-dose (within 15 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose on Days 1 and 10. Samples were collected at nominal times relative to the proposed time of GSK1265744 dosing. The actual date and time of each blood sample collection was recorded.
GSK1265744 PK Parameters Following Dose Administration on Day 1 and Day 10: Terminal Half-life (t1/2) and Absorption Lag Time (Tlag)
时间窗: Day 1 and Day 10
PK sampling was planned to be collected up to 24 hours only on Day 1 and Day 10. The data for this outcome measure was however not collected.
GSK1265744 PK Parameters Following Last Repeat Administration on Day 10: Apparent Clearance Following Oral Dosing (CL/F)
时间窗: Day 10 (Pre-dose [within 15 minutes prior to dosing] and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose)
Blood samples for PK analysis of CL/F of GSK1265744 was collected on Day 10 (Pre-dose \[within 15 minutes prior to dosing\] and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose). Samples were collected at nominal times relative to the proposed time of GSK1265744 dosing. The actual date and time of each blood sample collection was recorded.
Number of Participants With Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: Day 1 to Day 11
An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, medically significant or is associated with liver injury and impaired liver function.
Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (ANC- Absolute Neutrophil Count), White Blood Cell Count
时间窗: Baseline (Day 1) and Day 3, 7, 10
Blood samples for assessment of hematology parameters of basophils, eosinophils, lymphocytes, monocytes, total neutrophils (ANC- absolute neutrophil count) and white blood cell count was collected at Baseline, Day 3, 7 and 10. Baseline was defined at Day 1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.
Change From Baseline in Hematology Parameters: Hemoglobin
时间窗: Baseline (Day 1) and Day 3, 7, 10
Blood samples for assessment of hematology parameter of hemoglobin was collected at Baseline, Day 3, 7 and 10. Baseline was defined at Day 1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.
Change From Baseline in Hematology Parameters: Mean Corpuscle Hemoglobin
时间窗: Baseline (Day 1) and Day 3, 7, 10
Blood samples for assessment of hematology parameter of mean corpuscle hemoglobin was collected at Baseline, Day 3, 7 and 10. Baseline was defined at Day 1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.
Change From Baseline in Hematology Parameters: Mean Corpuscle Volume
时间窗: Baseline (Day 1) and Day 3, 7, 10
Blood samples for assessment of hematology parameter of mean corpuscle volume was collected at Baseline, Day 3, 7 and 10. Baseline was defined at Day 1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.
Change From Baseline in Hematology Parameters: Platelet Count
时间窗: Baseline (Day 1) and Day 3, 7, 10
Blood samples for assessment of hematology parameter of platelet count was collected at Baseline, Day 3, 7 and 10. Baseline was defined at Day 1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.
Change From Baseline in Hematology Parameters: Red Blood Cell Count
时间窗: Baseline (Day 1) and Day 3, 7, 10
Blood samples for assessment of hematology parameter of red blood cell count was collected at Baseline, Day 3, 7 and 10. Baseline was defined at Day 1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.
Change From Baseline in Hematology Parameters: Reticulocytes
时间窗: Baseline (Day 1) and Day 3, 7, 10
Blood samples for assessment of hematology parameter of reticulocytes was collected at Baseline, Day 3, 7 and 10. Baseline was defined at Day 1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.
Change From Baseline in Clinical Chemistry Data: Albumin, Total Protein
时间窗: Baseline (Day 1) and Day 3, 7, 10
Blood samples for assessment of clinical chemistry parameters of albumin and total protein was collected at Baseline, Day 3, 7 and 10. Baseline was defined at Day 1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.
Change From Baseline in Clinical Chemistry Data: Alkaline Phosphatase, Alanine Amino Transferase, Aspartate Amino Transferase, Creatine Kinase, Lipase
时间窗: Baseline (Day 1) and Day 3, 7, 10
Blood samples for assessment of clinical chemistry parameters of alkaline phosphatase, alanine amino transferase, aspartate amino transferase, creatine kinase and lipase was collected at Baseline, Day 3, 7 and 10. Baseline was defined at Day 1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.
Change From Baseline in Direct Bilirubin, Total Bilirubin, Calcium, Cholesterol, Creatinine, Glucose, High Density Lipoprotein (HDL) Cholesterol Direct, Low Density Lipoprotein (LDL) Cholesterol Calculation, Triglycerides, Urea/Blood Urea Nitrogen
时间窗: Baseline (Day 1) and Day 3, 7, 10
Blood samples for assessment of clinical chemistry parameters of direct bilirubin, total bilirubin, calcium, cholesterol, creatinine, glucose, HDL cholesterol direct, LDL cholesterol calculation, triglycerides,Urea/BUN was collected at Baseline, Day 3, 7 and 10. Baseline was defined at Day 1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.
Change From Baseline in Clinical Chemistry Data: Chloride, Carbon Dioxide Content/Bicarbonate, Magnesium, Sodium, Potassium
时间窗: Baseline (Day 1) and Day 3, 7, 10
Blood samples for assessment of clinical chemistry parameters of chloride, carbon dioxide content/bicarbonate, magnesium, sodium and potassium was collected at Baseline, Day 3, 7 and 10. Baseline was defined at Day 1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.
Number of Participants With Urinalysis Data
时间窗: Day 1 to Day 10
Samples for urinalysis assessment was collected on Day 1, Day 3 and Day 10. Urinalysis parameters included urine bilirubin, urine occult blood, urine glucose, urine ketones, urine nitrite, urine pH, urine protein, urine specific gravity and urine leukocyte esterase test for detecting white blood cell.
Change From Baseline in Vital Sign: Systolic and Diastolic Blood Pressure
时间窗: Baseline (Day 1, pre-dose) and Day 1 (2 hours post dose), 4, 7, 10
Systolic and diastolic blood pressure was measured at Baseline (Day 1 pre-dose), 2 hour post dose on Day 1, pre-dose on Day 4, 7, 10 and 2 hours post dose on Day 10. Baseline was defined at Day 1 pre-dose. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.
Change From Baseline in Vital Sign: Heart Rate
时间窗: Baseline (Day 1, pre-dose) and Day 1 (2 hours post dose), 4, 7, 10
Heart rate was measured at Baseline (Day 1 pre-dose), 2 hour post dose on Day 1, pre-dose on Day 4, 7, 10 and 2 hours post dose on Day 10. Baseline was defined at Day 1 pre-dose. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.
Change From Baseline in Electrocardiogram (ECG) Parameters
时间窗: Baseline (Day 1, pre-dose) and Day 1 (2 hours post dose), 4, 7, 10
All ECGs were obtained after a minimum 10 minute rest in a semi-supine position. The 12-lead ECGs were obtained at Baseline (Day 1 pre-dose), 2 hour post dose on Day 1, pre-dose on Day 4, 7, 10 and 2 hours post dose on Day 10 using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and Bazett's correction (QTcB) and Fridericia correction (QTcF) intervals. Baseline was defined at Day 1 pre-dose. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.
次要结局
- Change From Baseline in Plasma HIV-1 RNA(Baseline (Day 1 pre-dose) and Day 1 (post dose), 2, 3, 4, 7, 8, 9, 10)
- Change From Baseline in Plasma HIV-1 RNA to Nadir Over 11 Days(Baseline (Day 1) and Day 11)
- Plasma HIV-1 RNA Rate of Decline (Slope) Over 11 Days(Up to Day 10)
- Number of Participants With HIV-1 RNA<400 Copies/mL(Up to Day 11)
- Number of Participants With HIV-1 RNA<50 Copies/mL(Up to Day 11)
- Change From Baseline in CD4+ Cell Count to Day 11(Baseline (Day 1) and Day 11)
- Pre-morning Dose Concentrations (C0) on Day 2 Through 10 to Assess the Achievement of Steady State of GSK1265744 Following Repeat Administration(Day 1 24 hours (Day 2), Pre-dose on Days 3, 4, 7, 8, 9 and 10)
- Accumulation Ratios for AUC, Cmax, and Ctau(Days 1 and 10)
- Day 1 AUC(0-24) at Different Doses for the Assessment of Dose Proportionality Using Power Model(Day 1)
- Day 1 Cmax and C24 at Different Doses for the Assessment of Dose Proportionality Using Power Model(Day 1)
- Day 10 AUC(0-tau) at Different Doses for the Assessment of Dose Proportionality Using Power Model(Day 10)
- Day 10 Cmax, C0 and Ctau at Different Doses for the Assessment of Dose Proportionality Using Power Model(Day 10)