A Phase IIIb, Randomized, Multicenter, Active-controlled, Parallel-group, Non-inferiority, Open-label Study Evaluating the Efficacy, Safety, and Tolerability of Switching to Long-acting Cabotegravir Plus Long-acting Rilpivirine Administered Every Two Months From a Bictegravir/Emtricitabine/Tenofovir Alafenamide Single Tablet Regimen in HIV-1 Infected Adults Who Are Virologically Suppressed
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 687
- 试验地点
- 1
- 主要终点
- Percentage of Participants With Plasma Human Immunodeficiency Viruses (HIV)-1 Ribonucleic Acid (RNA) Greater Than or Equal to (>=) 50 Copies Per Milliliter (c/mL) at Month 12/11 - ITT-E Population
研究概览
简要总结
This study is designed to assess the antiviral activity and safety of a two-drug regimen of CAB LA + RPV LA compared with maintenance of BIK. BIKTARVY is a registered trademark of Gilead Sciences.
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
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants aged 18 years or older (or >=19 where required by local regulatory agencies), at the time of signing the informed consent.
- •A female participant is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotropin (hCG) test at screen and a negative urine hCG test at Randomization), not lactating, and at least one of the following conditions applies.
- •Non-reproductive potential defined as:
- •Pre-menopausal females with one of the following:
- •Documented tubal ligation.
- •Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion.
- •Hysterectomy.
- •Documented Bilateral Oophorectomy
- •Postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone [FSH] and estradiol levels consistent with menopause). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment.
- •Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study medication, throughout the study, for at least 30 days after discontinuation of all oral study medications, and for at least 52 weeks after discontinuation of CAB LA and RPV LA.
- •Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the consent form and in this protocol. Eligible participants or their legal guardians (and next of kin when locally required), must sign a written Informed Consent Form before any protocol-specified assessments are conducted. Enrollment of participants who are unable to provide direct informed consent is optional and will be based on local legal/regulatory requirements and site feasibility to conduct protocol procedures.
- •Participants enrolled in France must be affiliated to, or a beneficiary of, a social security category.
- •Must be on the uninterrupted current regimen of BIK for at least 6 months prior to Screening with an undetectable HIV-1 viral load for at least 6 months prior to Screening. BIK must be the participant's first or second regimen. If BIK is the second regimen, the first regimen must be an integrase inhibitor (INI) regimen. Only a single prior Integrase inhibitor (INI) regimen is allowed if BIK is a second line regimen >=6 months prior to screening. Any history of non-integrase strand transfer inhibitor regimens (that is. non-nucleoside reverse transcriptase inhibitor, protease inhibitor, C-C chemokine receptor 5 and other entry inhibitors) are not permitted. Any prior change in regimen, defined as a change of a single drug or multiple drugs simultaneously, must have occurred due to tolerability/safety, access to medications, or convenience/simplification, and must not have been done for treatment failure (HIV-1 RNA >=400 c/mL).
- •The following are limited exceptions:
- •A change from Tenofovir disoproxil fumarate (TDF) to TAF will not be considered a regimen change.
- •Historical perinatal use of Nucleoside reverse transcriptase inhibitor (NRTI) when given in addition to an ongoing Highly active antiretroviral therapy (HAART) will not be considered a change in ART therapy regimen.
- •The past use of ARVs in the context of Post Exposure Prophylaxis (PEP) or Pre-Exposure Prophylaxis (PrEP) while the participant was HIV negative will be allowed. Such cases will be evaluated on a case by case basis with the Medical Monitor, and may require documentation of HIV negative serology during time of PEP or PrEP.
- •A change in dosing scheme of the same drug from twice daily to once daily will not be considered a change in ART regimen if data support similar exposures and efficacy.
- •A change in formulation from multiple class regimens to single treatment regimens (of the same medications) would not be considered a change in ART regimen.
- •Documented evidence of plasma HIV-1 RNA measurements <50 c/mL in the 6 months prior to Screening.
- •Plasma HIV-1 RNA <50 c/mL at Screening.
排除标准
- •Within 6 months prior to Screening, any plasma HIV-1 RNA measurement >=50 c/mL.
- •Within the 6 to 12-month window prior to Screening, documented evidence of any plasma HIV-1 RNA measurement greater than (>)200 c/mL, or 2 or more plasma HIV-1 RNA measurements >=50 c/mL.
- •History of prior treatment failure to any Department of Health and Human Services (DHHS) recommended ART regimen.
- •History of drug holiday >1 month for any reason prior to Screening visit, except where all ART was stopped due to tolerability and/or safety concerns.
- •Any change to a second line regimen, defined as change of a single drug or multiple drugs simultaneously, due to virologic failure to therapy (defined as a confirmed plasma HIV 1 RNA measurement >=200 c/mL after initial suppression to <50 c/mL while on first line HIV therapy regimen).
- •Participants who are currently participating in or anticipate being selected for any other interventional study.
- •Women who are pregnant, breastfeeding or plan to become pregnant or breastfeed during the study.
- •Any evidence of a current Center for Disease Control and Prevention (CDC) Stage 3 disease except cutaneous Kaposi's sarcoma not requiring systemic therapy, and CD4+ counts <200 cells/microliter are not exclusionary.
- •Participants with moderate to severe hepatic impairment.
- •Any pre-existing physical or mental condition (including substance use disorder) 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 determined by the Investigator to have a high risk of seizures, including participants with an unstable or poorly controlled seizure disorder. A participant with a prior history of seizure may be considered for enrollment if the Investigator believes the risk of seizure recurrence is low. All cases of prior seizure history should be discussed with the Medical Monitor prior to enrollment.
- •All participants will be screened for syphilis.
- •Participants with untreated secondary (late latent) or tertiary syphilis infection, defined as a positive rapid plasma reagin (RPR) and a positive treponemal test without clear documentation of treatment, are excluded.
- •Participants with a false positive RPR (with negative treponemal test) or serofast RPR result (persistence of a reactive nontreponemal syphilis test despite history of adequate therapy and no evidence of re-exposure) may enroll after consultation with the Medical Monitor.
- •Participants with primary syphilis or early latent secondary syphilis (acquired within the preceding year) who have a positive RPR test and have not been treated may be treated during the screening period and if completion of antibiotic treatment occurs during the screening period, may be allowed entry after consultation with the Medical Monitor. If antibiotic treatment cannot be completed before the screening window ends, participants may be rescreened once following completion of antibiotic therapy for primary or early latent secondary syphilis.
- •Participants who, in the investigator's judgment, pose a significant suicide risk. Participant's recent history of suicidal behavior and/or suicidal ideation should be considered when evaluating for suicide risk.
- •The participant has a tattoo, gluteal implant/enhancements or other dermatological condition overlying the gluteus region which may interfere with interpretation of injection site reactions.
- •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 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), whether negative or positive for HBV DNA, are excluded.
- •Asymptomatic individuals with chronic hepatitis C virus (HCV) infection will not be excluded, however Investigators must carefully assess if therapy specific for HCV infection is required; participants who require or qualify for immediate HCV treatment are excluded for those co-infected participants who post entry into Switch Onto Long Acting Regimen (SOLAR) decide treatment for HCV infection is warranted or desired either by the participant or by the treating physician.
- •Participants with HCV co-infection will be allowed entry into this study if:
- •Liver enzymes meet entry criteria
- •HCV Disease has undergone appropriate work-up, and is not advanced, and will not require treatment prior to the Month 14 visit. Additional information (where available) on participants with HCV co-infection at screening should include results from any liver biopsy, Fibroscan, ultrasound, or other fibrosis evaluation, history of cirrhosis or other decompensated liver disease, prior treatment, and timing/plan for HCV treatment.
- •In the event that recent biopsy or imaging data is not available or inconclusive, the fibrosis (Fib)-4 score will be used to verify eligibility
- •i. Fib-4 score >3.25 is exclusionary ii. Fib-4 scores 1.45-3.25 requires Medical Monitor consultation Fibrosis 4 Score Formula: d. Age x aspartate aminotransferase (AST)/ Platelets x (square [Alanine aminotransferase {ALT}]).
- •Unstable liver disease (as defined by any of the following: presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice or cirrhosis, or decompensated cirrhosis [for example {e.g.} ascites, encephalopathy, or variceal bleeding]), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment).
- •History of liver cirrhosis with or without hepatitis viral co-infection.
- •Ongoing or clinically relevant pancreatitis
- •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.
- •Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial neoplasia; other localized malignancies require agreement between the investigator and the Study medical monitor for inclusion of the participant prior to randomization.
- •Any condition which, in the opinion of the Investigator, may interfere with the absorption, distribution, metabolism or excretion of the study drugs or render the participant unable to receive study medication.
- •History or presence of allergy or intolerance to the study drugs or their components or drugs of their class. In addition, if heparin is used during pharmacokinetic (PK) sampling, participants with a history of sensitivity to heparin or heparin-induced thrombocytopenia must not be enrolled.
- •Current or anticipated need for chronic anti-coagulation with the exception of the use of low dose acetylsalicylic acid (less than or equal to [<=]325 milligram) or hereditary coagulation and platelet disorders such as hemophilia or Von Willebrand Disease.
- •Corrected QT interval (QTc [Bazett]) >450 milliseconds (msec) or QTc (Bazett) >480 msec for participants with bundle branch block.
- •Known or suspected active Coronavirus Disease-2019 (COVID-19) infection or has had contact with an individual with known COVID-19, within 14 days of study enrollment.
- •Known or suspected presence of resistance mutations as defined by the International Antiviral Society-United States of America (IAS-USA) resistance guidelines to the individual components of BIK (BIC, FTC, TAF), RPV, and CAB by any historical resistance test result.
- •Any verified Grade 4 laboratory abnormality. A single repeat test is allowed during the Screening phase to verify a result.
- •Any acute laboratory abnormality at Screening, which, in the opinion of the investigator, would preclude the participant's participation in the study of an investigational compound.
- •Participant has estimated creatine clearance <30mL/minute per 1.73 meter square (m^2) via Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) Method.
- •ALT >=3 times upper limit of normal (ULN).
- •Exposure to an experimental drug or experimental vaccine within either 30 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 Day 1 of this study.
- •Treatment with any of the following agents within 28 days of Screening:
- •radiation therapy;
- •cytotoxic chemotherapeutic agents;
- •tuberculosis therapy with the exception of isoniazid (isonicotinylhydrazid/INH);
- •anti-coagulation agents;
- •Immunomodulators that alter immune responses such as chronic systemic corticosteroids, interleukins, or interferons.
- •Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening.
- •Treatment with any agent, except recognized ART as allowed above, with documented activity against HIV-1 within 28 days of study Day
- 另有 3 项未显示
研究组 & 干预措施
Biktarvy (BIK)
Participants with HIV-1 received BIK tablet orally until month 12. BIK was a fixed dose combination of 50 mg Bictegravir (BIC) + 200 mg Emtricitabine (FTC) + 25 mg Tenofovir alafenamide (TAF).
干预措施: BIKTARVY Tablets (BIK) (Drug)
Oral lead-in phase (OLI)
Participants with human immunodeficiency viruses (HIV)-1 who chose oral lead in (OLI) received oral 30 milligram (mg) Cabotegravir (CAB) tablet + 25 mg Rilpivirine (RPV) tablet once daily (QD) for one month. At the month 1 visit, the last dose of oral CAB + RPV was given, followed by the first 600 mg CAB long-acting (LA) + 900 mg RPV LA intramuscular injection (IM), and second injection of CAB LA 600 mg + RPV LA 900 mg at month 2, and then subsequent injections once every 2 months (Q2M) until Month 12 (Maintenance Phase). The participants had the option to continue the regimen in the Extension Phase
干预措施: Cabotegravir Tablets (Drug)
Oral lead-in phase (OLI)
Participants with human immunodeficiency viruses (HIV)-1 who chose oral lead in (OLI) received oral 30 milligram (mg) Cabotegravir (CAB) tablet + 25 mg Rilpivirine (RPV) tablet once daily (QD) for one month. At the month 1 visit, the last dose of oral CAB + RPV was given, followed by the first 600 mg CAB long-acting (LA) + 900 mg RPV LA intramuscular injection (IM), and second injection of CAB LA 600 mg + RPV LA 900 mg at month 2, and then subsequent injections once every 2 months (Q2M) until Month 12 (Maintenance Phase). The participants had the option to continue the regimen in the Extension Phase
干预措施: Rilpivirine Tablets (Drug)
Direct to injections (D2I)
Participants with HIV-1 who chose direct to injections (D2I) received the first injections of 600 mg CAB LA + 900 mg RPV LA, IM as initial loading doses at Day 1 one month, followed by second and third subsequent injections (CAB LA 600 mg + RPV LA 900 mg) at month 1 and month 3 followed by Q2M until Month 11. The participants had the option to continue the regimen in the Extension Phase.
干预措施: Cabotegravir Injectable Suspension (CAB LA) (Drug)
Direct to injections (D2I)
Participants with HIV-1 who chose direct to injections (D2I) received the first injections of 600 mg CAB LA + 900 mg RPV LA, IM as initial loading doses at Day 1 one month, followed by second and third subsequent injections (CAB LA 600 mg + RPV LA 900 mg) at month 1 and month 3 followed by Q2M until Month 11. The participants had the option to continue the regimen in the Extension Phase.
干预措施: Rilpivirine Injectable Suspension (RPV LA) (Drug)
Switch Q2M Group
Eligible participants with HIV-1 who received BIK tablet orally switched treatment after month 12 (Extension Phase) to CAB LA 600 mg + RPV LA 900 mg regimen, administered once every 2 months.
干预措施: Cabotegravir Injectable Suspension (CAB LA) (Drug)
Switch Q2M Group
Eligible participants with HIV-1 who received BIK tablet orally switched treatment after month 12 (Extension Phase) to CAB LA 600 mg + RPV LA 900 mg regimen, administered once every 2 months.
干预措施: Rilpivirine Injectable Suspension (RPV LA) (Drug)
结局指标
主要结局
Percentage of Participants With Plasma Human Immunodeficiency Viruses (HIV)-1 Ribonucleic Acid (RNA) Greater Than or Equal to (>=) 50 Copies Per Milliliter (c/mL) at Month 12/11 - ITT-E Population
时间窗: At month 12/11
Percentage of participants with plasma HIV 1 RNA \>= 50 c/mL at month 12 was assessed using the food and drug administration (FDA) snapshot algorithm. For the Q2M arm, data from the Q2M OLI participants at Month 12 visit and Q2M D2I participants at Month 11 visit were combined as the study objective was to demonstrate the non-inferior antiviral activity of (Q2M) (OLI+ D2I combined) compared to BIK. For BIK arm, data was collected at month 12 visit. Month 12/11 refers to the Month 12 (OLI and BIK) visit/Month 11 (DTI) visit. The FDA snapshot algorithm defines a participant's virologic response status using only the viral load at the predefined time point within a window of time (HIV-RNA equal to or above 50 copies/mL and HIV-RNA below 50 copies/mL), along with study drug discontinuation status. The third category of the FDA snapshot ("No virologic data") is not pre-defined as an endpoint and therefore not reported separately.
Percentage of Participants With Plasma HIV-1 RNA Greater >=50 Copies Per Milliliter (c/mL) at Month 12/11 - mITT-E Population
时间窗: At month 12/11
Percentage of participants with plasma HIV 1 RNA \>= 50 c/mL at month 12 was assessed using the food and drug administration (FDA) snapshot algorithm. For the Q2M arm, data from the Q2M OLI participants at Month 12 visit and Q2M D2I participants at Month 11 visit were combined as the study objective was to demonstrate the non-inferior antiviral activity of (Q2M) (OLI+ D2I combined) compared to BIK. For BIK arm, data was collected at month 12 visit. Month 12/11 refers to the Month 12 (OLI and BIK) visit/Month 11 (DTI) visit. The FDA snapshot algorithm defines a participant's virologic response status using only the viral load at the predefined time point within a window of time (HIV-RNA equal to or above 50 copies/mL and HIV-RNA below 50 copies/mL), along with study drug discontinuation status. The third category of the FDA snapshot ("No virologic data") is not pre-defined as an endpoint and therefore not reported separately.
次要结局
- Number of Participants With Treatment-emergent Genotypic Resistance Through Month 12/11(Up to Month 12/11)
- Percentage of Participants With Plasma HIV-1 RNA Less Than (<)50 c/mL at Month 12/11 - ITT-E Population(At month 12/11)
- Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Month 6/5 - ITT-E Population(At month 6/5)
- Absolute Values of Cluster of Differentiation 4 Plus (CD4+) Cell Count(Baseline (Day 1) and up to Month 12)
- Change From Baseline in Renal Biomarkers: Urine Phosphate (Millimoles Per Liter (mmol/L))(Baseline (Day 1) and up to Month 12)
- Change From Baseline in Percentage of Participants With Metabolic Syndrome at Month 12/11(Baseline (Day 1) and at Month 12/11)
- Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Month 6/5 - mITT-E Population(At month 6/5)
- Percentage of Participants With Plasma HIV-1 RNA Greater Than or Equal to (>=) 50 c/mL at Month 6/5(At month 6/5)
- Change From Baseline in CD4+ Cell Count(Baseline (Day 1) and up to Month 12)
- Number of Participants With Treatment-emergent Phenotypic Resistance Through Month 12/11(Up to Month 12/11)
- Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Month 12/11 -mITT-E Population(At month 12/11)
- Change From Baseline in HIV Viral Load(Baseline (Day 1) and up to Month 12)
- Number of Participants With Treatment-emergent Genotypic Resistance Through Month 6/5(Up to Month 6/5)
- Change From Baseline in Bone Biomarkers: Specific Alkaline Phosphatase, Procollagen Type 1 N-Terminal Propeptide, Type 1 Collagen Cross-linked C-telopeptide, Osteocalcin (Micrograms Per Liter (ug/L))(Baseline (Day 1) and up to Month 12)
- Change From Baseline in Bone Biomarkers: Serum 25-hydroxyvitamin D (Nanomoles Per Liter (Nmol/L))(Baseline (Day 1) and up to Month 12)
- Change From Baseline in Renal Biomarkers: Specific Serum Beta-2 Microglobulin, Cystatin c, Retinol Binding Protein, Urine Beta-2 Microglobulin (Milligrams Per Liter [mg/L])(Baseline (Day 1) and up to Month 12)
- Change From Baseline in Renal Biomarker: Urine Retinol Binding Protein 4 (Microgram Per Liter (ug/L))(Baseline (Day 1) and up to Month 12)
- Number of Participants With Protocol-defined Confirmed Virologic Failure (CVF) Through Month 6/5 and 12/11(Up to month 12)
- Absolute Values of HIV Viral Load(Baseline (Day 1) and up to Month 12)
- Number of Participants With Treatment-emergent Phenotypic Resistance Through Month 6/5(Up to Month 6/5)
- Change From Baseline in Renal Biomarker: Urine Retinol Binding Protein/Creatinine (Milligram Per Mole (mg/Mol))(Baseline (Day 1) and up to Month 12)
- Change From Baseline in Homeostasis Model of Assessment-insulin Resistance (HOMA-IR)(Baseline (Day 1) and up to Month 12)
- Percentage of Participants With Treatment Preference as Assessed Using Preference Questionnaire at Month 12/11 - Q2M(Up to month 12/11)
- Change From Baseline in Renal Biomarker: Urine Beta-2 Microglobulin/ Creatinine (Grams Per Mole (g/Mol))(Baseline (Day 1) and up to Month 12)
- Individual Item Scores of HIVTSQc at Month 12/11(At Month 12/11)
- Change From Baseline in Percentage of Participants With Metabolic Syndrome at Month 6/5(Baseline (Day 1) and at month 6/5)
- HIV Treatment Satisfaction Change Questionnaire (HIVTSQc) Total Score at Month 12/11(At Month 12/11)
- Change From Baseline in Total Treatment Satisfaction Score Using HIV Treatment Satisfaction Status Questionnaire (HIVTSQs)(Baseline (Day 1) and up to Month 12)
- Change From Baseline in Individual Item Scores Using HIVTSQs(Baseline (Day 1) and up to Month 12)
- Change From Month 2/1 in Dimension Scores Using Perception of Injection (PIN) Questionnaire - Q2M(From Month 2/1 up to Month 12)
- Change From Month 2/1 in Individual Item Scores Using PIN Questionnaire- Q2M(From Month 2/1 up to Month 12)