A Phase 2a Multicentre, Randomized, Open-Label, Two-Part Adaptive Design Study to Evaluate the Antiviral Effect, Safety and Tolerability of GSK3810109A, an HIV-1 Specific Broadly Neutralizing Human Monoclonal Antibody in Antiretroviral-naïve HIV-1-Infected Adults
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 62
- 试验地点
- 1
- 主要终点
- Maximum Decline From Baseline in Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) Levels - Monotherapy Phase
研究概览
简要总结
This study is to evaluate antiviral activity, efficacy, safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of GSK3810109A in HIV-1 infected treatment naive adults. Participants will receive a single dose of GSK3810109A administered either intravenously (IV) or subcutaneously (SC). The study includes a screening phase, a randomized monotherapy phase and a standard of care follow-up phase.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
盲法说明
This is an open-label study
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
- •Participant must be 18 to 65 years of age inclusive, at the time of signing the informed consent.
- •Participants must have HIV-1 infection within 45 days of the Screening Visit: Plasma HIV-1 RNA greater than or equal to (>=) 5000 copies/mL (c/mL).
- •Confirmed screening CD4+ T-cell count >= 350 cells per cubic millimeter (cells/mm3).
- •Antiretroviral naïve: No Antiretroviral therapy (ARTs) (in combination or monotherapy) received after the diagnosis of HIV-1 infection.
- •Body weight >= 50 kg to less than or equal to (<=) 115 kg.
- •Male and/or female. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. All participants participating in the study should be counselled on safer sexual practices including the use and benefit/risk of effective barrier methods (e.g. male condom) and on the risk of HIV transmission to an uninfected partner; a. Participants who are female at birth are eligible to participate if at least one of the following conditions applies: Not Pregnant or breastfeeding and at least one of the following conditions applies: Is not a participant of childbearing potential (POCBP). OR Is a POCBP and using an acceptable contraceptive method during the intervention period (at a minimum until after the last dose of study intervention). The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention. A POCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) on Day 1, prior to the first dose of study intervention. If a urine test cannot be confirmed as negative (example [e.g.], an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
- •Corrected QT interval (QTc) Interval <= 450 milliseconds (msec)
- •Capable of giving signed informed consent.
排除标准
- •Participants with primary HIV infection, evidenced by acute retroviral syndrome (e.g., fever, malaise, fatigue, etc) and/or evidence of recent (within 3 months) documented viremia without antibody production and/or evidence of recent (within 3 months) documented seroconversion.
- •Participants who are pregnant, breastfeeding, plan to become pregnant or breastfeed during the study.
- •The participant has an underlying skin disease or disorder (example i.e. infection, inflammation, dermatitis, eczema, drug rash, drug allergy, psoriasis, food allergy, urticaria) that would interfere with assessment of injection sites.
- •Known history of cirrhosis with or without viral hepatitis co-infection.
- •History of clinically relevant hepatitis within last 6 months.
- •Evidence of Hepatitis B virus (HBV) infection based on the results of testing at screening for Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (anti-HBc), Hepatitis B surface antigen antibody (anti-HBs) and HBV Deoxyribonucleic acid (DNA) as follows: Participants positive for HBsAg are excluded; Participants negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and positive for HBV DNA are excluded. Participants negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and negative for HBV DNA are not excluded.
- •Participants with Hepatitis C co-infection.
- •Untreated syphilis infection (positive rapid plasma reagin [RPR] at screening) without documentation of treatment. Participants who are one month post completed treatment are eligible if recruitment is open.
- •Rescreening is allowed after treatment.
- •Prior receipt of licensed or investigational monoclonal antibody.
- •Any evidence of an active Centers for Disease Control and Prevention (CDC) Stage 3 disease except cutaneous Kaposi's sarcoma not requiring systemic therapy.
- •Known or suspected moderate or severe hepatic impairment (Class C as determined by Child-Pugh Classification) coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
- •Clinically significant cardiovascular disease, as defined by history/evidence of congestive heart failure, symptomatic arrhythmia, angina/ischemia, coronary artery bypass grafting (CABG) surgery or percutaneous transluminal coronary angioplasty (PTCA) or any clinically significant cardiac disease at the discretion of the investigator.
- •Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal or penile intraepithelial neoplasia; other localized malignancies require agreement between the investigator and the study medical monitor for inclusion of the participant prior to randomization.
- •Any pre-existing physical or mental condition which, in the opinion of the investigator, may interfere with the participant's ability to comply with the dosing schedule and/or protocol evaluations, or which may compromise the safety of the participant.
- •Participants with substance abuse disorders or social restraints that the investigator considers to be possible deterrents to successful completion of the study.
- •Participants who in the investigator's judgment, pose a significant suicidality risk. Participants' history of suicidal behavior and/or suicidal ideation should be considered when evaluating for suicide risk.
- •History of sensitivity to any of the study medications or their components or drugs of their class, or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
- •Any condition which, in the opinion of the investigator, may interfere with the absorption, distribution, metabolism or excretion of the study drugs, combination ART or render the participant unable to take oral medication.
- •Participants with a positive Corona Virus Disease 2019 (COVID-19) test at Screening. Participants with known COVID-19 positive contacts within the past 14 days, or with symptoms suggestive of active COVID-19 (fever, cough, myalgias, shortness of breath, loss of taste or smell), should be excluded. Participants who remain symptom-free for at least 14 days after a COVID-19 exposure are allowed.
- •Has received any HIV-1 immunotherapeutic vaccine or prophylactic vaccine.
- •Treatment with any of the following agents within 28 days of screening: radiation therapy; cytotoxic chemotherapeutic agents; any systemic immune suppressant;
- •Exposure to an experimental drug or experimental vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to the first dose of IP.
- •Participants receiving any prohibited medication and who are unwilling or unable to switch to an alternate medication.
- •Participant enrolled in a prior or concurrent clinical study that includes a drug intervention within the last 30 days.
- •Any acute laboratory abnormality at Screening, which, in the opinion of the investigator, would preclude the participant's inclusion in the study of an investigational compound.
- •Any verified Grade 4 laboratory abnormality. A single repeat test is allowed during the Screening period to verify a result.
- •ALT >= 3 times the upper limit of normal (ULN).
- •Creatinine clearance of <50 mL/minute/1.73 meter^2) via Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method.
- •The participant has a tattoo or other dermatological condition overlying potential injection sites which may interfere with interpretation of injection site reactions or administration of GSK3810109A.
研究组 & 干预措施
Part 1:GSK3810109A 40milligram(mg)/kilogram intravenously (IV)
Participants with human immunodeficiency viruses-1 (HIV-1) received GSK3810109A as a single intravenous (IV) infusion of 40 milligrams per kilogram (mg/kg) dose based on individual bodyweight on Day 1 in part 1.
干预措施: GSK3810109A (Biological)
Part 1: GSK3810109A 280 mg IV
Participants with HIV-1 received GSK3810109A as a single IV infusion of 280 mg dose on Day 1 in part 1.
干预措施: GSK3810109A (Biological)
Part 2: GSK3810109A 700 mg IV
Participants with HIV-1 received GSK3810109A as a single IV infusion of 700 mg dose on Day 1 in part 2. This included dose level determined based on the data of part 1.
干预措施: GSK3810109A (Biological)
Part 2: GSK3810109A 70 mg IV
Participants with HIV-1 received GSK3810109A as a single IV infusion of 70 mg dose on Day 1 in part 2. This included dose level determined based on the data of part 1.
干预措施: GSK3810109A (Biological)
Part 2: GSK3810109A 700 mg subcutaneously (SC)
Participants with HIV-1 received GSK3810109A as a subcutaneous (SC) injection of total 700 mg dose administered as three equally divided SC injections of 2.33 mL each (approximately 7 mL) in quick succession at same time on Day 1 in part 2. This included dose level determined based on the data of part 1.
干预措施: GSK3810109A (Biological)
Standard of care (SOC) - GSK3810109A 40mg/kg IV
Participants who completed the monotherapy phase of treatment of GSK3810109A 40mg/kg IV entered SOC phase to receive dolutegravir + lamivudine regimen as a SOC treatment on SOC Day 1 if deemed appropriate by the investigator and consistent with local guidelines.
干预措施: Dolutegravir+lamivudine SOC regimen (Biological)
SOC - GSK3810109A 280 mg IV
Participants who completed the monotherapy phase of treatment of GSK3810109A 280 mg IV entered SOC phase to receive dolutegravir + lamivudine regimen as a SOC treatment on SOC Day 1 if deemed appropriate by the investigator and consistent with local guidelines.
干预措施: Dolutegravir+lamivudine SOC regimen (Biological)
SOC - GSK3810109A 700 mg IV
Participants who completed the monotherapy phase of treatment of GSK3810109A 700 mg IV entered SOC phase to receive dolutegravir + lamivudine regimen as a SOC treatment on SOC Day 1 if deemed appropriate by the investigator and consistent with local guidelines.
干预措施: Dolutegravir+lamivudine SOC regimen (Biological)
SOC - GSK3810109A 70 mg IV
Participants who completed the monotherapy phase of treatment of GSK3810109A 70 mg IV entered SOC phase to receive dolutegravir + lamivudine regimen as a SOC treatment on SOC Day 1 if deemed appropriate by the investigator and consistent with local guidelines.
干预措施: Dolutegravir+lamivudine SOC regimen (Biological)
SOC - GSK3810109A 700 mg SC
Participants who completed the monotherapy phase of treatment of GSK3810109A 700 mg SC entered SOC phase to receive dolutegravir + lamivudine regimen as a SOC treatment on SOC Day 1 if deemed appropriate by the investigator and consistent with local guidelines.
干预措施: Dolutegravir+lamivudine SOC regimen (Biological)
结局指标
主要结局
Maximum Decline From Baseline in Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) Levels - Monotherapy Phase
时间窗: Baseline (Day 1) and up to Day 84 or end of Monotherapy Phase
Plasma samples were collected for quantitative analysis of plasma HIV-1 RNA. Maximum decline from baseline in plasma HIV-1 RNA were measured in participants. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. End of Monotherapy Phase is defined as the timepoint when a participant had reached the monotherapy endpoint criteria or a maximum of 84 days follow-up, whichever occurred first.
Number of Participants With Adverse Events (AEs) - Monotherapy Phase
时间窗: Up to Day 84 or end of Monotherapy Phase
An adverse event (AE) is defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. End of Monotherapy Phase is defined as the timepoint when a participant had reached the monotherapy endpoint criteria or a maximum of 84 days follow-up, whichever occurred first.
Number of Participants With Worst-case Maximum Grade 2-4 Increase in Post-baseline Values of Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) Compared to the Baseline Values - Monotherapy Phase
时间窗: Baseline (Day 1) and up to Day 84 or end of Monotherapy Phase
Blood samples were collected for the analysis of ALT and AST parameters. The parameters ALT and AST were graded using the Division of Acquired Immunodeficiency Syndrome (DAIDS) criteria Version 2.1 where grades were defined based on numeric criteria as follows Grade 0: participants with missing baseline values; Grade 1: Mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Higher grade indicates greater severity. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Data of number of participants with 2-4 grade increase at worst-case post-baseline (maximum grade increase post-baseline) is presented. End of Monotherapy Phase is defined as the timepoint when a participant had reached the monotherapy endpoint criteria or a maximum of 84 days follow-up, whichever occurred first.
Number of Participants With Treatment-emergent Abnormal Electrocardiogram (ECG) Findings - Monotherapy Phase
时间窗: Up to Day 84 or end of Monotherapy Phase
A 12-lead ECG were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and QT interval corrected using Fridericia's formula (QTcF) intervals. ECG findings were categorized as normal, abnormal clinically significant (CS) and abnormal not clinically significant (NCS). Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Number of participants with abnormal (CS and NCS) ECG findings are presented. End of Monotherapy Phase is defined as the timepoint when a participant had reached the monotherapy endpoint criteria or a maximum of 84 days follow-up, whichever occurred first.
Number of Participants With Grade 2-4 Injection Site Reactions (ISR) - Monotherapy Phase
时间窗: Up to Day 84 or end of Monotherapy Phase
Number of participants with grade 2-4 injection site reactions are presented. The ISR were graded using the Division of Acquired immunodeficiency syndrome (DAIDS) criteria Version 2.1 where grades were defined based on numeric criteria as follows Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Higher grade indicates more severe condition. End of Monotherapy Phase is defined as the timepoint when a participant had reached the monotherapy endpoint criteria or a maximum of 84 days follow-up, whichever occurred first.
次要结局
- Area Under the Plasma Concentration-time Curve From Time Zero to the Day 14 (AUC [0-14]) of GSK3810109A - Monotherapy Phase(Pre-dose (Day 1), 3 and 24 hours post-dose on day 1, days 3, 6, 9, 11, and 14)
- Maximum Observed Plasma Concentration (Cmax) of GSK3810109A - Monotherapy Phase(Pre-dose (Day 1), 3 and 24 hours post-dose on day 1, days 3, 6, 9, 11, and 14)
- Time to Reach Maximum Observed Plasma Concentration (Tmax) of GSK3810109A - Monotherapy Phase(Pre-dose (Day 1), 3 and 24 hours post-dose on day 1, days 3, 6, 9, 11, and 14)
- Plasma Concentration at Day 14 (C14) of GSK3810109A - Monotherapy Phase(At Day 14)
- Change From Baseline in Log10 Plasma HIV-1 RNA Relative to Cmax - Monotherapy Phase(Baseline (Day 1) and up to Day 84 or end of Monotherapy Phase)
- Absolute Values of Cluster of Differentiation 4 Plus (CD4+) and CD8+ T Cell Counts - Monotherapy Phase(From Day 1 (Baseline) and up to Day 84 or end of Monotherapy Phase)
- Absolute Values of CD4+ and CD8+ T Cell Counts - SOC Phase(Up to Week 48 (SOC Phase))
- Change From Baseline in CD4+ and CD8+ T Cell Counts - Monotherapy Phase(Up to Day 84 or end of Monotherapy Phase (compared with baseline [Day 1]))
- Change From Baseline in CD4+ and CD8+ T Cell Counts - SOC Phase(Up to Week 48 (SOC Phase))
- Number of Participants With Positive Anti-drug Antibodies (ADAs) Against GSK3810109A - Monotherapy Phase(At Day 1 and Day 84 or end of Monotherapy Phase)
- Number of Participants With Positive ADAs Against GSK3810109A - SOC Phase(At Week 48 (SOC Phase))
- Titers of Positive ADAs Against GSK3810109A - Monotherapy Phase(At Day 84 or end of Monotherapy Phase)
- Titers of Positive ADAs Against GSK3810109A - SOC Phase(At Week 48 (SOC Phase))