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OpenTrials
Completed

NCT Number: NCT01641367

A5288/MULTI-OCTAVE: Management Using Latest Technologies to Optimize Combination Therapy After Viral Failure

The study was done to:

* test a strategy of using a resistance test to choose anti-HIV drugs * see how well combinations of new anti-HIV drugs work to lower HIV infection * see if taking new anti-HIV drugs together is safe and tolerable * see if text messages improve people's anti-HIV drug-taking behavior (only at sites participating in the adherence study) * in people taking certain combinations of anti-HIV drugs with an anti-TB drug, compare how these drugs act in the body * to see how people do after they stop having frequent clinic visits as part of a research study

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Key information

Conditions

HIV-1 Infection

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Hospital Nossa Senhora da Conceicao CRS (12201), Porto Alegre, Rio Grande do Sul, Brazil

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About this study

A5288 was an open-label phase IV, prospective interventional, strategy study in resource-limited settings (RLS) for HIV-1 infected participants with triple-class experience or resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs), and protease inhibitors (PIs) and who were failing their current regimen. The use of novel agents and contemporary clinical decision management tools that include standard genotyping and plasma HIV viral load (VL) monitoring were evaluated. The screening genotype results and antiretroviral (ARV) history were used to allocate potential participants to one of four Cohorts (A, B, C or D) and to select an associated ARV regimen based on the Cohort assignment. In brief, individuals assigned to Cohort A continued on the same PI as in their second-line regimen, with the ability to modify NRTIs. Those assigned to Cohort B who were negative for hepatitis B were randomized to receive RAL and DRV/RTV with either the best available NRTIs (Cohort B1) or ETR (Cohort B2). If they were positive for hepatitis B they were assigned to Cohort B3 and received RAL, DRV/RTV and either FTC/TDF or 3TC/TDF. Individuals assigned to Cohort C received RAL and DRV/RTV with the best available NRTIs. Those ineligible for Cohorts A, B or C were assigned to Cohort D and received the best available regimen that included study provided drugs and any locally provided drugs.

At sites where feasible and relevant, the study evaluated an adherence support intervention. This involved a randomized comparison of a cell phone-based adherence support intervention plus local standard-of-care adherence support procedures (CPI+SOC) versus the SOC adherence support procedures.

Participants enrolled to the study in Step 1. If a participant experienced a confirmed virologic failure (defined as two consecutive HIV-1 RNA measures >= 1000 copies/mL) at/after 22 weeks on their Step 1 regimen, they had another genotype test performed and cohort/regimen selected for Step 2. With the exception of one additional visit 4 weeks after enrollment to Step 2, the visit schedule for Step 2 followed the participant's original Step 1 schedule throughout the remainder of follow up.

Participants were followed in Steps 1 and 2 until 48 weeks after the last participant was enrolled to Step 1. During the first 48 weeks after Step 1 enrollment, clinic visits occurred at weeks 4, 12, 24, 36 and 48. After week 48, visits occurred every 12 weeks for adherence, safety and efficacy measures.

Participants had a final step 1/2 visit between November 22, 2016 and February 13, 2017. At the final step 1/2 visit, participants taking RAL, ETR, or DRV who were unable to obtain these drugs locally (e.g., through local treatment programs), and were otherwise eligible, entered Step 3 and continued to receive these drugs through the study for up to 96 additional weeks. Step 3 participants were dispensed ARVs every 12 weeks and had clinical assessments every 24 weeks. The purpose of Step 3 was to assist participants with the transition back to local care.

The primary analysis specified in the protocol and in the Statistical Analysis Plan was to estimate the proportion of participants in the overall study population who were virologically suppressed (HIV-1 RNA ≤200 copies/mL) at week 48 with a 95% confidence interval.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

for Step 1:

  • 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 VL.
  • Any previous combination of ARV treatment at any time with at least one regimen that contained one NNRTI and two NRTIs which was replaced with a PI-based regimen because of virologic, immunologic, or clinical treatment failure, or because of toxicity.

NOTE: All potential participants with prior RAL exposure were assigned to either Cohort A or Cohort D.

  • At screening, receipt of a PI-based regimen with no regimen change for a minimum of 24 weeks prior to screening.
  • Confirmation of VF of current second-line PI-based ART. NOTE A: Failure of the current second-line regimen was defined as two consecutive measurements of plasma HIV-1 RNA ≥1000 copies/mL obtained at least 1 day apart while on the current PI-based regimen. "Current PI-based regimen" and "current regimen" were understood to be the regimen described (ie, the regimen that the candidate was taking when the first VF sample was drawn plus only those modifications allowed).
  • CD4+ T-cell count result from a specimen drawn within 103 days prior to study entry
  • Laboratory values obtained within 30 days prior to study entry:
  • Absolute neutrophil count (ANC) ≥ 500/mm^3
  • Hemoglobin ≥7.5 g/dL
  • Platelet count ≥40,000/mm^3
  • Creatinine ≤2 X upper limit of normal (ULN)
  • Aspartate aminotransferase (AST), serum glutamic oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT), serum glutamic pyruvic transaminase (SGPT), and alkaline phosphatase ≤5 x ULN
  • Total bilirubin ≤2.5 x ULN
  • Creatinine clearance (CrCl) >30 mL/min, either measured or estimated by Cockcroft-Gault equation
  • Hepatitis B panel that includes HbsAB, HBcAB, and HBsAG or only HBsAG, with plasma stored for later anti-HBs and anti-HBc.

NOTE A: Candidates who were eligible for cohort B and who were positive for active hepatitis B infection were assigned to sub-cohort B3 at registration/randomization.

NOTE B: Candidates with CrCl <60 mL/min who were also positive for active hepatitis B infection were not eligible.

  • Females of reproductive potential (women who have not been post-menopausal for at least 24 consecutive months, ie, who have had menses within the preceding 24 months, or women who have not undergone surgical sterilization, hysterectomy or bilateral salpingectomy or bilateral oophorectomy or tubal ligation) must have had a negative serum or urine pregnancy test prior to the submission of the screening genotype testing sample and again within 48 hours prior to randomization or registration.
  • Female participants of reproductive potential must have agreed not to participate in the conception process (ie, active attempt to become pregnant, in vitro fertilization), and if participating in sexual activity that could lead to pregnancy, the female participant must have used at least one reliable form of contraceptive. Female participants must have continued to use contraceptives while receiving study treatment and for 6 weeks after stopping study treatment.

Acceptable forms of contraceptives included:

  • Condoms (male or female) with or without a spermicidal agent
  • Diaphragm or cervical cap with spermicide
  • Intrauterine device (IUD)
  • Hormonal contraception

Female participants who were not of reproductive potential or whose male partner(s) had documented azoospermia) were not required to use contraceptives. Any statement of self-reported sterility or that of her partner's must have been entered in the source documents.

NOTE: Acceptable documentation of lack of reproductive potential was oral or written documentation from the participant.

  • Karnofsky performance score >/= 70 within 30 days prior to study entry.
  • Ability and willingness of potential participant to provide informed consent.
  • Willingness of potential participant to adhere to protocol requirements, especially with respect to treatment assignment and ability to obtain non-study provided ART, if needed.
  • Ability to take oral study medications.
  • No intention of permanent relocation that would preclude attending Step 1 and 2 study follow-up visits.
  • Availability of a successful, interpretable resistance genotype report from a DAIDS-approved regional genotyping facility from testing performed on a plasma sample that was collected during screening (ie, at or after the date that a sample is collected to confirm HIV-1 virologic failure) and which was shipped to a regional resistance testing laboratory once documentation of two screening plasma HIV-1 RNA values ≥1000 copies/mL were available.
  • Identification of a cohort assignment and ARV regimen for use on study, selected from the recommended options provided by the site investigator, and reviewed and approved by the A5288 Clinical Management Committee (CMC).

Exclusion criteria

for Step 1:

  • Pregnancy or breast-feeding.
  • Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation.
  • Active drug or alcohol use or dependence that, in the opinion of the site investigator, would have interfered with adherence to study requirements.
  • Serious illness requiring systemic treatment and/or hospitalization until candidate either completes therapy or was clinically stable on therapy, in the opinion of the site investigator, for at least 7 days prior to study entry.
  • Concurrent illness or condition that would compromise the ability to take study medication, follow the protocol, or that would make participation not in the best interest of the participant, per the site investigator.
  • Requirement for taking any of the prohibited medications with the selected ARV study regimen, or within 14 days prior to study entry.

NOTE: Study candidates should not have discontinued any component of their ART during screening. The 14-day restriction on prohibited medications did not apply to ARVs.

  • Active tuberculosis (TB) or rifampin exposure less than 2 weeks prior to study entry.
  • Any exposure to darunavir or etravirine.

Treatment and study plan

Darunavir

Drug

Participants were administered darunavir orally as one 600 mg tablet twice a day (1200 mg per day) with food (taken with Ritonavir 100 mg twice a day [200 mg per day])

Other names: DRV, Prezista

Etravirine

Drug

Patients were administered Etravirine orally as two 100 mg tablets or one 200 mg tablet twice a day (400 mg per day) following a meal.

Other names: ETR, Intelence

Emtricitabine/Tenofovir disoproxil fumarate

Drug

Patients were administered FTC/TDF orally as one fixed dose combination tablet (FTC 200 mg/TDF 300 mg) once daily, with or without food.

Other names: FTC/TDF, Truvada

raltegravir

Drug

Participants were administered Raltegravir orally as one 400 mg tablet twice daily (800 mg per day), with or without food

Other names: RAL, Isentress

Second line ART regimens - based on a boosted protease inhibitor (bPI) plus two nucleoside analogues (NRTIs)

Drug

LPV/r and ATV/r were the preferred bPIs for second-line ART. TDF + (3TC or FTC) or AZT + 3TC were the most frequent NRTI backbones. Cohort A did not include any of the new drugs; therefore, it is distinct from Cohorts B, C, and D.

Study provided drugs according to patient resistance profile (DRV, ETR, RTV, FTC/TDF) + any in country available drug as applicable & available

Drug

For Cohort D, in many situations a participant received the same regimen that patients are getting in Cohorts B and C if that was the best combination that can be obtained according to his/her resistance profile and drug availability (as for many countries there were no further drug options beyond the available study drugs).

SOC adherence versus SOC+CPI adherence

Other
  • not participating in the adherence randomization; OR
  • randomized to SOC adherence; OR
  • randomized to SOC+CPI adherence.

Primary outcomes

  1. Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 48 Weeks

    Time frame: 48 weeks after the date of entry

    The measurement closest to exactly 48 weeks (ie, 7x48=336 days) after the date of entry, within the window of 48 weeks ± 6 weeks (specifically 295 to 378 days after randomization, inclusive).

    The analysis in the protocol and in the Stat. Analysis Plan involved estimating the proportion of participants in the overall study population with HIV-1 RNA ≤200 copies/mL at week 48 with a 95% confidence interval calculated via a Wald approach. Death or lost to follow-up before week 48 was considered as HIV-1 RNA>200 copies/mL at week 48. Missing results at week 48 were considered as HIV-1 RNA >200 copies/mL at week 48 unless the immediately preceding and succeeding HIV-1 RNA measurements were ≤200 copies/mL. Since the primary analysis was on the total study population, overall results were also submitted. All participants in B3 had HIV-1 RNA ≤200 copies/mL at week 48. Therefore, Wald confidence interval could not be computed for B3 and Clopper-Pearson Exact confidence interval is provided.

Secondary outcomes

  1. Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 24 Weeks

    Time frame: 24 weeks after the date of entry

    The measurement closest to exactly 24 weeks (ie, 7x24=168 days) after the date of entry, within the window of 24 weeks ± 6 weeks (specifically 127 to 210 days after randomization, inclusive).

    The analysis in the protocol and in the Stat. Analysis Plan involved estimating the proportion of participants in the overall study population with HIV-1 RNA ≤200 copies/mL at week 24 with a 95% confidence interval calculated via a Wald approach. Death or lost to follow-up before week 24 was considered as HIV-1 RNA>200 copies/mL at week 24. Missing results at week 24 were considered as HIV-1 RNA >200 copies/mL at week 24 unless the immediately preceding and succeeding HIV-1 RNA measurements were ≤200 copies/mL. Since the primary analysis was on the total study population, overall results were also submitted. All participants in B3 had HIV-1 RNA ≤200 copies/mL at week 24. Therefore, Wald confidence interval could not be computed for B3 and Clopper-Pearson Exact confidence interval is provided.

  2. Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 72 Weeks

    Time frame: 72 weeks after the date of entry

    The measurement closest to exactly 72 weeks (ie, 7x72=504 days) after the date of entry, within the window of 72 weeks ± 6 weeks (specifically 463 to 546 days, inclusive).

    The analysis in the protocol and in the Analysis Plan involved estimating the proportion of participants in the overall study population with HIV-1 RNA ≤200 copies/mL at week 72 with a 95% confidence interval calculated via a Wald approach. Death or lost to follow-up before week 72 was considered as HIV-1 RNA>200 copies/mL at week 72. If a result was expected, missing results at week 72 were considered as HIV-1 RNA >200 copies/mL at week 72 unless the immediately preceding and succeeding HIV-1 RNA measurements were ≤200 copies/mL. Since the primary analysis was on the total study population, overall results were also submitted. All participants in B3 had HIV-1 RNA ≤200 copies/mL at week 72. Therefore, Wald confidence interval could not be computed for B3 and Clopper-Pearson Exact confidence interval is provided.

  3. Number of Weeks of Follow-up

    Time frame: From study entry through Step 1/2 follow-up

    All participants were followed on step 1/2 until 48 weeks after the last participant was enrolled to step 1 regardless of virologic status or treatment switches. Length of follow-up varied by Cohort.

  4. Time to Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study

    Time frame: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure [specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry (to allow for 14 day window for scheduling the visit). HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement, allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure. Event times were the scheduled week of the initial failing measurement (RNA scheduled at week 0, 12, 24, 48 and every 24 weeks after). Censoring times were the scheduled week of the last RNA result. Length of follow-up varied by Cohort.

  5. Number of Participants With Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study

    Time frame: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure [specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry (to allow for 14 day window for scheduling the visit). HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement, allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure. Length of follow-up varied by Cohort.

  6. Percent of Participants With Confirmed Virologic Failure by Week 48

    Time frame: From week 24 to Week 48

    Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure [specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry(to allow for 14 day window for scheduling the visit). HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement,allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure. Event times were the scheduled week of the initial failing measurement (RNA scheduled at week 0, 12, 24, 48 and every 24 weeks after). Censoring times were the scheduled week of the last RNA result. Length of follow-up varied by Cohort.

  7. Time to Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study, With a New Resistance-associated Mutation Detected in Population-based Sequencing

    Time frame: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure [specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry (to allow for 14 day window for scheduling the visit). HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement, allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure. Event times were the scheduled week of the initial failing measurement (RNA scheduled at week 0, 12, 24, 48 and every 24 weeks after). Censoring times were the scheduled week of the last RNA result. Length of follow-up varied by Cohort. A new resistance-associated mutation is defined as one not present in the genotype prior to entry.

  8. Number of Participants With Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study, With a New Resistance-associated Mutation Detected in Population-based Sequencing

    Time frame: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure[specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry (to allow for 14 day window for scheduling the visit).HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement, allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure. Length of follow-up varied by Cohort. A new resistance-associated mutation is defined as one not present in the genotype prior to entry.

  9. Percent of Participants With Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study, With a New Resistance-associated Mutation Detected in Population-based Sequencing, by Week 48

    Time frame: From week 24 to Week 48

    Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure[specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry(to allow for 14 day window for scheduling the visit).HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement,allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure.Event times were the scheduled week of the initial failing measurement(RNA scheduled at week 0, 12, 24, 48 and every 24 weeks after).Censoring times were the scheduled week of the last RNA result.Length of follow-up varied by Cohort.A new resistance-associated mutation is defined as one not present in the genotype prior to entry.

  10. Time From Study Entry/Randomization to Death

    Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Event time was the exact week of death. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. Length of follow-up varied by Cohort.

  11. Percent of Participants Experiencing Death by Week 48

    Time frame: From study entry to Week 48

    Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Event time was the exact week of death. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit.

  12. Time From Study Entry/Randomization to the First of Death, an AIDS-defining Event or a Non-AIDS-defining Event

    Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Event time was the exact week of death, AIDS-defining event or non-AIDS defining event. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. Only new events were considered, an event that was also reported at or prior to study entry was not included. If a participant experienced multiple events, then the time of the first event was used in the analysis. AIDS defining events included parasitic, fungal, bacterial, and viral infections as well as neoplastic diseases, and neurological disorders. Non-AIDS defining events included malignancies, diabetes, neuropathies, cardiac and renal events. Length of follow-up varied by Cohort.

  13. Percent of Participants Experiencing Death, AIDS-defining Event or a Non-AIDS-defining Event by Week 48

    Time frame: From study entry to Week 48

    Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Event time was the exact week of death, AIDS-defining event or non-AIDS defining event. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. Only new events were considered, an event that was also reported at or prior to study entry was not included. If a participant experienced multiple events, then the time of the first event was used in the analysis. AIDS defining events included parasitic, fungal, bacterial, and viral infections as well as neoplastic diseases, and neurological disorders. Non-AIDS defining events included malignancies, diabetes, neuropathies, cardiac and renal events.

  14. Time From Study Entry/Randomization to the First of Death or Hospitalization.

    Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Event time was the exact week of death or hospitalization. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. If a participant experienced multiple events, then the time of the first event was used in the analysis. Length of follow-up varied by Cohort.

  15. Percent of Participants With Death or Hospitalization by Week 48

    Time frame: From study entry to Week 48

    Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Event time was the exact week of death or hospitalization. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. If a participant experienced multiple events, then the time of the first event was used in the analysis.

  16. Time From Study Entry/Randomization to Treatment Modification or Discontinuation.

    Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Treatment modification is defined as the first occurrence of a substitution or subtraction of one or more drugs in the study regimen, a temporary hold lasting 7 days or longer, or the addition of a new drug to the regimen. This would not include splitting any fixed dose combination medications if the participant continues on the active drugs of the combination. Event time was the exact week of the modification or discontinuation. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. Length of follow-up varied by Cohort.

  17. Percent of Participants With Treatment Modification or Discontinuation by Week 48

    Time frame: From study entry to Week 48

    Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Treatment modification is defined as the first occurrence of a substitution or subtraction of one or more drugs in the study regimen, a temporary hold lasting 7 days or longer, or the addition of a new drug to the regimen. This would not include splitting any fixed dose combination medications if the participant continues on the active drugs of the combination. Event time was the exact week of the modification or discontinuation. Censoring time was the earliest time point between last dose week and the week of the last step 1/2 visit.

  18. Time From Study Entry/Randomization to Treatment Modification or Discontinuation Due to Toxicity

    Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Treatment modification is defined as the first occurrence of a substitution or subtraction of one or more drugs in the study regimen, a temporary hold lasting 7 days or longer, or the addition of a new drug to the regimen, due to an adverse event. This would not include splitting any fixed dose combination medications if the participant continues on the active drugs of the combination. Event time was the exact week of the modification or discontinuation. Censoring time was the earliest time point between last dose week and the week of the last step 1/2 visit. Length of follow-up varied by Cohort. DAIDS AE Grading Table, Version 1.0 was used.

  19. Percent of Participants With Treatment Modification or Discontinuation Due to Toxicity by Week 48

    Time frame: From study entry to Week 48

    Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Treatment modification is defined as the first occurrence of a substitution or subtraction of one or more drugs in the study regimen, a temporary hold lasting 7 days or longer, or the addition of a new drug to the regimen, due to an adverse event. This would not include splitting any fixed dose combination medications if the participant continues on the active drugs of the combination. Event time was the exact week of the modification or discontinuation. Censoring time was the earliest time point between last dose week and the week of the last step 1/2 visit. DAIDS AE Grading Table, Version 1.0 was used.

  20. Time From Study Entry/Randomization to the Development of Immune Reconstitution Inflammatory Syndrome (IRIS)

    Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Event time was the exact week of the diagnosis. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. Length of follow-up varied by Cohort.

  21. Percent of Participants That Developed Immune Reconstitution Inflammatory Syndrome (IRIS) by Week 48

    Time frame: From study entry to week 48

    Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Event time was the exact week of the diagnosis. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit.

  22. Time to First Dose Modification Due to Grade 3 or 4 Toxicity

    Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Event time was the exact week of the modification. Censoring time was the earliest time point between last dose week and the week of the last step 1/2 visit. Length of follow-up varied by Cohort. DAIDS AE Grading Table, Version 1.0 was used.

  23. Percent of Participants With a Dose Modification Due to Grade 3 or 4 Toxicity by Week 48

    Time frame: From study entry to week 48

    Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Event time was the exact week of the modification. Censoring time was the earliest time point between last dose week and the week of the last step 1/2 visit. DAIDS AE Grading Table, Version 1.0 was used.

  24. Change From Baseline in CD4+ T-cell Count

    Time frame: Baseline, week 24, 48, and 72

    Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen (this second date applies only to Cohorts B, C and D as there is no change of regimen for patients in Cohort A)

  25. Change From Baseline in Fasting Values of Total Cholesterol

    Time frame: Baseline, week 24, 48 and 72

    Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen (this second date applies only to Cohorts B, C and D as there is no change of regimen for patients in Cohort A)

  26. Change From Baseline in Fasting Values of High-density Lipoprotein Cholesterol

    Time frame: Baseline, week 24, 48 and 72

    Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen (this second date applies only to Cohorts B, C and D as there is no change of regimen for patients in Cohort A)]

  27. Change From Baseline in Fasting Values of Calculated Low-density Lipoprotein Cholesterol

    Time frame: Baseline, week 24, 48 and 72

    Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen (this second date applies only to Cohorts B, C and D as there is no change of regimen for patients in Cohort A)

  28. Change From Baseline in Fasting Values of Triglycerides

    Time frame: Baseline, week 24, 48 and 72

    Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen (this second date applies only to Cohorts B, C and D as there is no change of regimen for patients in Cohort A)

  29. Change From Baseline in Fasting Values of Glucose

    Time frame: Baseline, week 24, 48 and 72

    Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen (this second date applies only to Cohorts B, C and D as there is no change of regimen for patients in Cohort A)

  30. Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 48 Weeks [CPI+SOC v SOC]

    Time frame: 48 weeks after the date of entry

    The measurement closest to exactly 48 weeks (ie, 7x48=336 days) after the date of entry, within the window of 48 weeks ± 6 weeks (specifically 295 to 378 days after randomization, inclusive).

    The analysis in the protocol and in the Stat. Analysis Plan involved estimating the proportion of participants in the overall study population with HIV-1 RNA ≤200 copies/mL at week 48 with a 95% confidence interval calculated via a Wald approach. Death or lost to follow-up before week 48 was considered as HIV-1 RNA>200 copies/mL at week 48. Missing results at week 48 were considered as HIV-1 RNA >200 copies/mL at week 48 unless the immediately preceding and succeeding HIV-1 RNA measurements were ≤200 copies/mL.

  31. Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 24 Weeks [CPI+SOC v SOC]

    Time frame: 24 weeks after the date of entry

    The measurement closest to exactly 24 weeks (ie, 7x24=168 days) after the date of entry, within the window of 24 weeks ± 6 weeks (specifically 127 to 210 days after randomization, inclusive).

    The analysis in the protocol and in the Stat. Analysis Plan involved estimating the proportion of participants in the overall study population with HIV-1 RNA ≤200 copies/mL at week 24 with a 95% confidence interval calculated via a Wald approach. Death or lost to follow-up before week 24 was considered as HIV-1 RNA>200 copies/mL at week 24. Missing results at week 24 were considered as HIV-1 RNA >200 copies/mL at week 24 unless the immediately preceding and succeeding HIV-1 RNA measurements were ≤200 copies/mL.

  32. Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 72 Weeks [CPI+SOC v SOC]

    Time frame: 72 weeks after the date of entry

    The measurement closest to exactly 72 weeks (ie, 7x72=504 days) after the date of entry, within the window of 72 weeks ± 6 weeks (specifically 463 to 546 days, inclusive).

    The analysis in the protocol and in the Analysis Plan involved estimating the proportion of participants in the overall study population with HIV-1 RNA ≤200 copies/mL at week 72 with a 95% confidence interval calculated via a Wald approach. Death or lost to follow-up before week 72 was considered as HIV-1 RNA>200 copies/mL at week 72. If a result was expected, missing results at week 72 were considered as HIV-1 RNA >200 copies/mL at week 72 unless the immediately preceding and succeeding HIV-1 RNA measurements were ≤200 copies/mL.

  33. Number of Weeks of Follow-up [CPI+SOC v SOC]

    Time frame: From study entry through Step 1/2 follow-up

    All participants were followed on step 1/2 until 48 weeks after the last participant was enrolled to step 1 regardless of virologic status or treatment switches.

  34. Time to Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study [CPI+SOC v SOC]

    Time frame: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure [specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry (to allow for 14 day window for scheduling the visit). HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement, allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure. Event times were the scheduled week of the initial failing measurement (RNA scheduled at week 0, 12, 24, 48 and every 24 weeks after). Censoring times were the scheduled week of the last RNA result.

  35. Number of Participants With Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study [CPI+SOC v SOC]

    Time frame: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure [specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry (to allow for 14 day window for scheduling the visit). HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement, allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure.

  36. Percent of Participants With Confirmed Virologic Failure by Week 48 [CPI+SOC v SOC]

    Time frame: From week 24 to Week 48

    Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure [specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry(to allow for 14 day window for scheduling the visit). HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement,allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure. Event times were the scheduled week of the initial failing measurement (RNA scheduled at week 0, 12, 24, 48 and every 24 weeks after). Censoring times were the scheduled week of the last RNA result.

  37. Time to Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study, With a New Resistance-associated Mutation Detected in Population-based Sequencing [CPI+SOC v SOC]

    Time frame: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure [specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry (to allow for 14 day window for scheduling the visit). HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement, allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure. Event times were the scheduled week of the initial failing measurement (RNA scheduled at week 0, 12, 24, 48 and every 24 weeks after). Censoring times were the scheduled week of the last RNA result. A new resistance-associated mutation is defined as one not present in the genotype prior to entry.

  38. Number of Participants With Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study, With a New Resistance-associated Mutation Detected in Population-based Sequencing [CPI+SOC v SOC]

    Time frame: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure[specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry (to allow for 14 day window for scheduling the visit).HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement, allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure. A new resistance-associated mutation is defined as one not present in the genotype prior to entry.

  39. Percent of Participants With Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study, With a New Resistance-associated Mutation Detected in Population-based Sequencing, by Week 48 [CPI+SOC v SOC]

    Time frame: From week 24 to Week 48

    Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure[specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry(to allow for 14 day window for scheduling the visit).HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement,allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure.Event times were the scheduled week of the initial failing measurement(RNA scheduled at week 0, 12, 24, 48 and every 24 weeks after).Censoring times were the scheduled week of the last RNA result.A new resistance-associated mutation is defined as one not present in the genotype prior to entry.

  40. Time From Study Entry/Randomization to Death [CPI+SOC v SOC]

    Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Event time was the exact week of death. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit.

  41. Percent of Participants Experiencing Death by Week 48 [CPI+SOC v SOC]

    Time frame: From study entry to Week 48

    Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Event time was the exact week of death. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit.

  42. Time From Study Entry/Randomization to the First of Death, an AIDS-defining Event or a Non-AIDS-defining Event [CPI+SOC v SOC]

    Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Event time was the exact week of death, AIDS-defining event or non-AIDS defining event. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. Only new events were considered, an event that was also reported at or prior to study entry was not included. If a participant experienced multiple events, then the time of the first event was used in the analysis. AIDS defining events included parasitic, fungal, bacterial, and viral infections as well as neoplastic diseases, and neurological disorders. Non-AIDS defining events included malignancies, diabetes, neuropathies, cardiac and renal events.

  43. Percent of Participants Experiencing Death, AIDS-defining Event or a Non-AIDS-defining Event by Week 48 [CPI+SOC v SOC]

    Time frame: From study entry to Week 48

    Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Event time was the exact week of death, AIDS-defining event or non-AIDS defining event. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. Only new events were considered, an event that was also reported at or prior to study entry was not included. If a participant experienced multiple events, then the time of the first event was used in the analysis. AIDS defining events included parasitic, fungal, bacterial, and viral infections as well as neoplastic diseases, and neurological disorders. Non-AIDS defining events included malignancies, diabetes, neuropathies, cardiac and renal events.

  44. Time From Study Entry/Randomization to the First of Death or Hospitalization [CPI+SOC v SOC]

    Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Event time was the exact week of death or hospitalization. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. If a participant experienced multiple events, then the time of the first event was used in the analysis.

  45. Percent of Participants With Death or Hospitalization by Week 48 [CPI+SOC v SOC]

    Time frame: From study entry to Week 48

    Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Event time was the exact week of death or hospitalization. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. If a participant experienced multiple events, then the time of the first event was used in the analysis.

  46. Time From Study Entry/Randomization to Treatment Modification or Discontinuation [CPI+SOC v SOC]

    Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Treatment modification is defined as the first occurrence of a substitution or subtraction of one or more drugs in the study regimen, a temporary hold lasting 7 days or longer, or the addition of a new drug to the regimen. This would not include splitting any fixed dose combination medications if the participant continues on the active drugs of the combination. Event time was the exact week of the modification or discontinuation. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit.

  47. Percent of Participants With Treatment Modification or Discontinuation by Week 48 [CPI+SOC v SOC]

    Time frame: From study entry to Week 48

    Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Treatment modification is defined as the first occurrence of a substitution or subtraction of one or more drugs in the study regimen, a temporary hold lasting 7 days or longer, or the addition of a new drug to the regimen. This would not include splitting any fixed dose combination medications if the participant continues on the active drugs of the combination. Event time was the exact week of the modification or discontinuation. Censoring time was the earliest time point between last dose week and the week of the last step 1/2 visit.

  48. Time From Study Entry/Randomization to Treatment Modification or Discontinuation Due to Toxicity [CPI+SOC v SOC]

    Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Treatment modification is defined as the first occurrence of a substitution or subtraction of one or more drugs in the study regimen, a temporary hold lasting 7 days or longer, or the addition of a new drug to the regimen, due to an adverse event. This would not include splitting any fixed dose combination medications if the participant continues on the active drugs of the combination. Event time was the exact week of the modification or discontinuation. Censoring time was the earliest time point between last dose week and the week of the last step 1/2 visit. DAIDS AE Grading Table, Version 1.0 was used.

  49. Percent of Participants With Treatment Modification or Discontinuation Due to Toxicity by Week 48 [CPI+SOC v SOC]

    Time frame: From study entry to Week 48

    Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Treatment modification is defined as the first occurrence of a substitution or subtraction of one or more drugs in the study regimen, a temporary hold lasting 7 days or longer, or the addition of a new drug to the regimen, due to an adverse event. This would not include splitting any fixed dose combination medications if the participant continues on the active drugs of the combination. Event time was the exact week of the modification or discontinuation. Censoring time was the earliest time point between last dose week and the week of the last step 1/2 visit. DAIDS AE Grading Table, Version 1.0 was used.

  50. Time From Study Entry/Randomization to the Development of Immune Reconstitution Inflammatory Syndrome (IRIS) [CPI+SOC v SOC]

    Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Event time was the exact week of the diagnosis. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit.

  51. Percent of Participants That Developed Immune Reconstitution Inflammatory Syndrome (IRIS) by Week 48 [CPI+SOC v SOC]

    Time frame: From study entry to Week 48

    Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Event time was the exact week of the diagnosis. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit.

  52. Time to First Dose Modification Due to Grade 3 or 4 Toxicity [CPI+SOC v SOC]

    Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks

    Event time was the exact week of the modification. Censoring time was the earliest time point between last dose week and the week of the last step 1/2 visit. DAIDS AE Grading Table, Version 1.0 was used.

  53. Percent of Participants With a Dose Modification Due to Grade 3 or 4 Toxicity by Week 48 [CPI+SOC v SOC]

    Time frame: From study entry to Week 48

    Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Event time was the exact week of the modification. Censoring time was the earliest time point between last dose week and the week of the last step 1/2 visit. DAIDS AE Grading Table, Version 1.0 was used.

  54. Change From Baseline in CD4+ T-cell Count [CPI+SOC v SOC]

    Time frame: Baseline, week 24, 48, and 72

    Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen.

  55. Change From Baseline in Fasting Values of Total Cholesterol [CPI+SOC v SOC]

    Time frame: Baseline, week 24, 48, and 72

    Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen.

  56. Change From Baseline in Fasting Values of High-density Lipoprotein Cholesterol [CPI+SOC v SOC]

    Time frame: Baseline, week 24, 48, and 72

    Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen.

  57. Change From Baseline in Fasting Values of Calculated Low-density Lipoprotein Cholesterol [CPI+SOC v SOC]

    Time frame: Baseline, week 24, 48, and 72

    Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen.

  58. Change From Baseline in Fasting Values of Triglycerides [CPI+SOC v SOC]

    Time frame: Baseline, week 24, 48, and 72

    Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen.

  59. Change From Baseline in Fasting Values of Glucose [CPI+SOC v SOC]

    Time frame: Baseline, week 24, 48, and 72

    Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen.

Sponsors and collaborators

Lead sponsor

Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections

Network

Collaborators

  • AbbVie
  • Dimagi Inc.
  • Gilead Sciences
  • Janssen Pharmaceuticals
  • Merck Sharp & Dohme LLC
  • National Institute of Allergy and Infectious Diseases (NIAID)

Registry information

Official study title

Management Using the Latest Technologies in Resource-limited Settings to Optimize Combination Therapy After Viral Failure (MULTI-OCTAVE)

Acronym: MULTI-OCTAVE

Important dates

Study start
2013
Primary completion
2016
Study completion
2018
First posted
Jul 16, 2012
Registry last updated
Mar 15, 2019

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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