NCT03635788已完成3 期
A Phase III Study to Evaluate Long-Acting Antiretroviral Therapy in Non-Adherent HIV-Infected Individuals
National Institute of Allergy and Infectious Diseases (NIAID)66 个研究点 分布在 2 个国家目标入组 456 人开始时间: 2019年3月28日最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 456
- 试验地点
- 66
- 主要终点
- Cumulative Probability of Regimen Failure in Step 2 at Any Time Post Randomization and Week 48 Visit
研究概览
简要总结
The purpose of this study was to compare the efficacy, safety, and durability of two different strategies to treat participants with a history of sub-optimal adherence and control of their HIV infection: long-acting (LA) antiretroviral therapy (ART) and all-oral standard of care (SOC).
详细描述
This study compared the efficacy, safety, and durability of two different strategies to treat participants with a history of sub-optimal adherence and control of their HIV infection: long-acting (LA) antiretroviral therapy (ART) with rilpivirine (RPV) LA and cabotegravir (CAB) LA versus all-oral standard of care (SOC).
As the study was originally designed, the study included four steps.
Step 1, Induction
Previously non-adherent individuals were enrolled and underwent a period (up to 24 weeks) of induction SOC ART regimen using conditional economic incentives (CEI). Participants who achieved virologic suppression criteria at or after Step 1, week 4, defined as: a) HIV-1 RNA ≤200 copies/mL or b) HIV-1 RNA of 201-399 copies/mL followed by HIV-1 RNA ≤200 copies/mL by Step 1, week 24, were eligible to enter Step 2.
Step 2, Randomization
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
- •Step 1 Inclusion Criteria
- •HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.
- •NOTE: The term "licensed" referred to an FDA-approved kit, which was required for all IND studies.
- •WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandated that confirmation of the initial test result had to use a test that was different from the one used for the initial assessment. A reactive initial rapid test had to be confirmed by either another type of rapid assay or an E/CIA that was based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.
- •HIV-1 Plasma viral load (VL) greater than 200 copies/mL within 12 months prior to study entry by any US laboratory that had a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent, unless the participant had been lost to clinical follow-up (see protocol for more information) and no viral load result was available within the last 12 months.
- •NOTE: Participants who satisfied non-adherence eligibility due to loss to clinical follow-up might not have had a viral load result available at the time of consideration for eligibility. Those participants could be screened and, regardless of their screening viral load result (either ≤ or >200 copies/mL), they would have been eligible for study entry if they met all other inclusion/
排除标准
- •Evidence of non-adherence to ART according to at least one of the following criteria:
- •Poor virologic response within 18 months prior to study entry (defined as less than 1 log10 decrease in HIV-1 RNA or HIV-1 RNA greater than 200 copies/mL at two time points at least 4 weeks apart) in individuals who had been prescribed ART for at least 6 consecutive months.
- •Lost to clinical follow-up within 18 months prior to study entry with ART non-adherence for greater than or equal to 6 consecutive months.
- •NOTE: Lost to clinical follow-up was defined as either no contact with the provider or missing greater than or equal to 1 appointment in a 6-month period. ART non-adherence was defined as a lapse in ART greater than or equal to 7 days (consecutive or non-consecutive), in the 6-month period where they were lost to clinical follow-up per participant report.
- •No evidence of any clinically relevant RPV or INSTI resistance-associated mutations (see protocol for more information) through commercially available genotypic (or phenotypic, if available) analyses from any laboratory that had a CLIA certification or equivalent within 60 days of study entry (see protocol for more information), nor history of such mutations on review of prior HIV-1 drug resistance tests by the site investigator. For participants in whom a screening HIV-1 conventional genotype could not be resulted by the testing laboratory, review of historical genotypes and treatment history by the IoR could be used to satisfy this criterion as indicated in the protocol.
- •Ability of site clinician, in conjunction with the participant, to construct an oral induction antiretroviral (ARV) regimen that had to include at least three ARVs of which at least two had to be predicted to be fully active. The regimen had to include PI/cobi and/or an INSTI based on screening and/or historic resistance testing.
- •Laboratory values obtained within 60 days prior to study entry by any laboratory that had a CLIA certification or its equivalent:
- •Hemoglobin greater than or equal to 9.0 g/dL
- •Absolute neutrophil count (ANC) greater than or equal to 600/mm^3
- •Alanine aminotransferase (ALT) less than or equal to 3 x upper limit of normal (ULN)
- •Creatinine Clearance (CrCl) greater than or equal to 50 mL/min estimated by Chronic Kidney Disease Epidemiology Collaboration equation (CKD-Epi).
- •For participants of reproductive potential, a negative serum or urine pregnancy test with a sensitivity of less than or equal to 25 mIU/mL at screening. This was repeated again at study entry.
- •NOTE: Participants were considered to be NOT of reproductive potential if: 1) they had had amenorrhea for at least 12 consecutive months prior to study entry (i.e., who had had no menses within 12 months prior to study entry), and had a documented follicle-stimulating hormone (FSH) greater than 40 IU/mL; OR 2) an FSH level was not available, but they had had 24 consecutive months of amenorrhea (in the absence of medications known to induce amenorrhea); OR 3) they reported having undergone surgical sterilization (e.g., hysterectomy, or bilateral oophorectomy, or bilateral tubal ligation/hysteroscopic tubal occlusion).
- •Contraception Requirements
- •Participants of Reproductive Potential: Participants of reproductive potential, who were participating in sexual activity that could lead to pregnancy, had to agree to use at least one of the listed highly effective methods for contraception from 30 days prior to the first dose of study medication, while receiving the study drugs, and for 30 days after stopping oral medications, or the duration specified in the product label if receiving study drugs not supplied by the study, or 52 weeks after stopping RPV-LA or CAB-LA. Acceptable methods of contraception included:
- •Contraceptive subdermal implant
- •Intrauterine device or intrauterine system
- •Combined estrogen and progestogen oral contraceptive
- •Injectable progestogen
- •Contraceptive vaginal ring
- •Percutaneous contraceptive patches
- •Participants Who Were Not of Reproductive Potential: Participants who were not of reproductive potential were eligible to start study drugs without requiring the use of contraceptives. Any statement of self-reported sterility or that of her partner's had to be entered in the source documents.
- •NOTE A: Acceptable documentation of lack of reproductive potential was the participant's self-reported history of surgical sterilization, menopause, or male partner's azoospermia.
- •NOTE B: ALL participants in the study were to be counseled 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 a partner without HIV.
- •Ability and willingness of participant or legal guardian/representative to provide written informed consent.
- •Step 1 Exclusion Criteria
- •Currently pregnant, planning to become pregnant during the study period, or currently breastfeeding.
- •Participants determined by the Site Investigator to have had a high risk of seizures, including participants with an unstable or poorly controlled seizure disorder.
- •NOTE: A participant with a prior history of seizure could have been considered for enrollment if the Investigator believed the risk of seizure recurrence was low. All cases of prior seizure history were to be discussed with the A5359 protocol leadership team (actg.leada5359@fstrf.org) prior to enrollment.
- •Advanced liver disease (as defined by any of the following: presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) OR history of liver cirrhosis.
- •Chronic Hepatitis C (HCV) with planned or anticipated use of anti-HCV therapy prior to the completion of Step
- •History of or current active hepatitis B (HBV) infection defined as a positive HBV surface antigen test or any detectable HBV DNA in participants with isolated HBcAb and HBV DNA as follows:
- •Participants positive for HBsAg were excluded.
- •Participants negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and any detectable HBV DNA were excluded.
- •NOTE: Participants positive for anti-HBc (negative HBsAg status) and positive for anti-HBs (past and/or current evidence) were immune to HBV and were not excluded. If prior documentation of immunity was available, repeat testing at screening was not required.
- •Current or anticipated need for chronic anti-coagulation therapy.
- •Unwilling to receive injections, or unable to receive gluteal injections.
- •Tattoo or other condition over the gluteus region, which could have interfered with the interpretation of injection site reaction.
- •Previous use of CAB.
- •Any acute or serious illness, within 7 days prior to entry, requiring systemic treatment and/or hospitalization that could have rendered the participant unable to receive study medication, in the opinion of the site investigator.
- •QTc greater than 450 ms using either Bazett or Fridericia method within 60 days prior to study entry: Whichever method was used at screening had to be used throughout the study period.
- •Any serious medical or psychiatric condition, which could have rendered the participant unable to receive study medication in the opinion of the site investigator.
- •Known allergy/sensitivity or any hypersensitivity to components of study drug(s) or their formulation.
- •Requirement for any medication that was prohibited with a study medication (refer to protocol-specific web page [PSWP]).
- •Step 2 Inclusion Criteria
- •Meeting virologic suppression criteria at or after Step 1, week 4, defined as:
- •HIV-1 RNA ≤200 copies/mL OR
- •HIV-1 RNA of 201-399 copies/mL followed by HIV-1 RNA ≤200 copies/mL by Step 1, week
- •NOTE: The HIV-1 RNA viral load that was used to determine eligibility for randomization had to have been collected within 4 weeks (28 days) of the Step 2 randomization visit.
- •Step 2 Exclusion Criteria
- 另有 25 项未显示
研究组 & 干预措施
Step 1 SOC
Other
In Step 1, participants received SOC oral ART regimen for up to 24 weeks.
干预措施: Standard of Care (SOC) Oral ART (Drug)
Step 2 Arm A: LA ART
Experimental
In Step 2, participants received oral RPV once daily and oral CAB once daily for 4 weeks (optional), followed by a RPV-LA loading dose and a CAB-LA loading dose, followed in 4 weeks by an RPV-LA maintenance dose and a CAB-LA maintenance dose every 4 weeks for 44 weeks.
干预措施: RPV-LA Loading Dose (Drug)
Step 2 Arm A: LA ART
Experimental
In Step 2, participants received oral RPV once daily and oral CAB once daily for 4 weeks (optional), followed by a RPV-LA loading dose and a CAB-LA loading dose, followed in 4 weeks by an RPV-LA maintenance dose and a CAB-LA maintenance dose every 4 weeks for 44 weeks.
干预措施: CAB-LA Loading Dose (Drug)
Step 2 Arm A: LA ART
Experimental
In Step 2, participants received oral RPV once daily and oral CAB once daily for 4 weeks (optional), followed by a RPV-LA loading dose and a CAB-LA loading dose, followed in 4 weeks by an RPV-LA maintenance dose and a CAB-LA maintenance dose every 4 weeks for 44 weeks.
干预措施: CAB-LA Maintenance Dose (Drug)
Step 2 Arm A: LA ART
Experimental
In Step 2, participants received oral RPV once daily and oral CAB once daily for 4 weeks (optional), followed by a RPV-LA loading dose and a CAB-LA loading dose, followed in 4 weeks by an RPV-LA maintenance dose and a CAB-LA maintenance dose every 4 weeks for 44 weeks.
干预措施: Oral RPV (Drug)
Step 2 Arm A: LA ART
Experimental
In Step 2, participants received oral RPV once daily and oral CAB once daily for 4 weeks (optional), followed by a RPV-LA loading dose and a CAB-LA loading dose, followed in 4 weeks by an RPV-LA maintenance dose and a CAB-LA maintenance dose every 4 weeks for 44 weeks.
干预措施: Oral CAB (Drug)
Step 2 Arm A: LA ART
Experimental
In Step 2, participants received oral RPV once daily and oral CAB once daily for 4 weeks (optional), followed by a RPV-LA loading dose and a CAB-LA loading dose, followed in 4 weeks by an RPV-LA maintenance dose and a CAB-LA maintenance dose every 4 weeks for 44 weeks.
干预措施: RPV-LA Maintenance Dose (Drug)
Step 2 Arm B: SOC
Active Comparator
In Step 2, participants continued SOC oral ART regimen for 52 weeks.
干预措施: Standard of Care (SOC) Oral ART (Drug)
结局指标
主要结局
Cumulative Probability of Regimen Failure in Step 2 at Any Time Post Randomization and Week 48 Visit
时间窗: From Step 2 randomization to Step 2, Week 48 visit (up to 50 weeks)
Regimen failure was defined as the occurrence of the earlier of the following two events * virologic failure (defined as two consecutive HIV-1 RNA \>200 copies/mL after Step 2 randomization * Permanent discontinuation of randomized study treatment prior to or at Week 48 visit Cumulative probability was calculated by Kaplan-Meier method.
次要结局
- Number of Participants With Virologic Non-success (>= 200 Copies/ml)(From Step 2 randomization to Step 2, Week 48 (up to 50 weeks))
- Percentage of Participants With Grade 1 or Higher Injection Site Reactions (ISR) During Step 2(Measured from Step 2 randomization through Step 2, Week 52)
- Cumulative Probability of Virologic Failure in Step 2 at Any Time Post Randomization to Week 48 Visit(From Step 2 randomization to Step 2, Week 48 visit (up to 50 weeks))
- Cumulative Probability of the Treatment-related Failure in Step 2 at Any Time Post Randomization to Week 48 Visit(From after Step 2 randomization to Step 2, Week 48 (up to 50 weeks))
- Number of Participants With Virologic Non-success (>= 50 Copies/ml)(from Step 2 randomization to Step 2, Week 48 (up to 50 weeks))
- Percentage of Participants With Plasma HIV-1 RNA Level Less Than 50 Copies/mL at Scheduled Study Visits on Steps 1(Measured from Step 1 entry through Step 1, Week 20 visit)
- Percentage of Participants With Plasma HIV-1 RNA Level Less Than 200 Copies/mL at Scheduled Study Visits on Steps 1(Measured from Step 1 entry through Step 1, Week 20 visit)
- Percentage of Participants With Plasma HIV-1 RNA Level Less Than 50 Copies/mL at Scheduled Study Visits on Steps 2(Measured from Step 2 entry through Step 2, Week 48 visit)
- Percentage of Participants With Plasma HIV-1 RNA Level Less Than 200 Copies/mL at Scheduled Study Visits on Steps 2(Measured from Step 2 entry through Step 2, Week 48 visit)
- Cumulative Probability of Discontinuation of Randomized Treatment in Step 2(Measured from Step 2 randomization through Step 2, Week 48 (up to 50 weeks))
- Median Summary Score of HIV Treatment Satisfaction Questionnaire (HIVTSQ) in Step 2(HIVTSQ status was collected on both arms at Step 2 entry and Week 24, and also at Week 48 for those randomized to SOC. At Week 48, HIVTSQ change was collected for participants on the LA-ART arm.)
- Number of Participants With Missed or Delayed Injections for Participants Who Received LA ART in Step 2(Measured from Step 2 randomization through Step 2, Week 52)
- Median of Summary Scores of HIV Treatment Adherence Self-Efficacy Scale in Step 1(Step 1 entry, Weeks 12 and 20.)
- Median of Summary Scores of HIV Treatment Adherence Self-Efficacy Scale in Step 2(As Step 2 Week 0, Week 24 and Week 48)
- Number of Participants With New Drug-resistance Mutations in Participants With Virologic Failure in Step 2(Measured at Step 1 screening/entry and at the time of virologic failure in Step 2)
- Percentage of Participants Who Preferred Monthly Injections of Long-Acting HIV Treatment or Daily Oral HIV Treatment at Each Visit(Step 2 week 48, premature treatment visit, and study discontinuation visit)
- Percentage of Participants With Opinions About Conditional Economic Incentive (CEI) Withdrawal(At Step 2 entry and Step 2, Week 8)
- Median of Average Total Score of Step 1 HIV Treatment Adherence Self-Efficacy Scale Score (HIV-ASES)(Step 1 entry, Step 1 Weeks 12, and Step 1 Weeks 20)
- Percentage of Participants With Missed Treatment Doses Among Participants Who Randomized to SOC Arm in Step 2(At Step 2 entry, Step 2 week 4, Step 2 week 8, step 2 week 16, step 2 week 24, step 2 week 36, Step 2 week 48, and Step 2 week 52)
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研究点 (66)
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