Phase 4
N=545
A5288/MULTI-OCTAVE: Management Using Latest Technologies to Optimize Combination Therapy After Viral Failure
HIV-1 Infection
Bottom Line
View on ClinicalTrials.gov: NCT01641367 ↗Enrolled (actual)
545
Serious AEs
18.0%
Results posted
Feb 2018
Primary outcome: Primary: Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 48 Weeks — 0.64; 0.44; 0.88; 0.88 proportion of participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 4
- Interventions
- Darunavir (Drug); Etravirine (Drug); Emtricitabine/tenofovir disoproxil fumarate (Drug); Raltegravir (Drug); Second line ART regimens - based on a boosted protease inhibitor (bPI) plus two nucleoside analogues (NRTIs) (Drug); Study provided drugs according to patient resistance profile (DRV, ETR, RTV, FTC/TDF) + any in country available drug as applicable & available (Drug); SOC adherence versus SOC+CPI adherence (Other)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
- Primary completion
- Nov 2016
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 48 Weeks |
0.64; 0.44; 0.88; 0.88; 1.00; 0.90 | — |
| SECONDARY Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 24 Weeks |
0.64; 0.43; 0.89; 0.88; 1.00; 0.90 | — |
| SECONDARY Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 72 Weeks |
0.64; 0.44; 0.92; 0.87; 1.00; 0.85 | — |
| SECONDARY Number of Weeks of Follow-up |
72; 96; 84; 96; 72; 96 | — |
| SECONDARY Time to Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study |
24; 24; 24; NA; 24; 24 | — |
| SECONDARY Number of Participants With Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study |
145; 6; 4; 0; 5; 6 | — |
| SECONDARY Percent of Participants With Confirmed Virologic Failure by Week 48 |
48.9; 8.2; 2.9; 0; 5.8; 18.6 | — |
| SECONDARY 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 |
24; 24; 24; NA; 48; 24 | — |
| SECONDARY 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 |
48; 1; 2; 0; 1; 5 | — |
| SECONDARY 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 |
16.6; 1.4; 1.4; 0; 1.5; 15.4 | — |
| SECONDARY Time From Study Entry/Randomization to Death |
11.3; 3.1; 44.6; NA; 77.9; 2.4 | — |
| SECONDARY Percent of Participants Experiencing Death by Week 48 |
3.9; 1.4; 1.4; 0; 0; 2.9 | — |
| SECONDARY Time From Study Entry/Randomization to the First of Death, an AIDS-defining Event or a Non-AIDS-defining Event |
4.0; 3.1; 16.3; NA; 3.3; 2.4 | — |
| SECONDARY Percent of Participants Experiencing Death, AIDS-defining Event or a Non-AIDS-defining Event by Week 48 |
8.8; 5.4; 4.2; 0; 5.8; 5.9 | — |
| SECONDARY Time From Study Entry/Randomization to the First of Death or Hospitalization. |
2.4; 2.3; 3.0; 16.4; 2.0; 2.3 | — |
| SECONDARY Percent of Participants With Death or Hospitalization by Week 48 |
12.3; 8.1; 9.7; 12.5; 5.7; 5.9 | — |
| SECONDARY Time From Study Entry/Randomization to Treatment Modification or Discontinuation. |
1.0; 3.1; 4.4; 4.4; 0.1; 2.4 | — |
| SECONDARY Percent of Participants With Treatment Modification or Discontinuation by Week 48 |
19.9; 6.8; 19.4; 12.5; 14.3; 11.8 | — |
| SECONDARY Time From Study Entry/Randomization to Treatment Modification or Discontinuation Due to Toxicity |
2.1; 15.0; 6.4; NA; 0.1; NA | — |
| SECONDARY Percent of Participants With Treatment Modification or Discontinuation Due to Toxicity by Week 48 |
3.2; 2.7; 1.4; 0; 4.3; 0 | — |
| SECONDARY Time From Study Entry/Randomization to the Development of Immune Reconstitution Inflammatory Syndrome (IRIS) |
NA; NA; 25.0; NA; NA; 13.0 | — |
| SECONDARY Percent of Participants That Developed Immune Reconstitution Inflammatory Syndrome (IRIS) by Week 48 |
0.7; 0; 1.4; 0; 0; 3.0 | — |
| SECONDARY Time to First Dose Modification Due to Grade 3 or 4 Toxicity |
45.7; 63.3; NA; NA; NA; NA | — |
| SECONDARY Percent of Participants With a Dose Modification Due to Grade 3 or 4 Toxicity by Week 48 |
1.0; 0; 0; 0; 0; 0 | — |
| SECONDARY Change From Baseline in CD4+ T-cell Count |
39; 109; 116; 142; 100; 90 | — |
| SECONDARY Change From Baseline in Fasting Values of Total Cholesterol |
5.7; 16.7; 32.5; 12.4; 16.5; 7.9 | — |
| SECONDARY Change From Baseline in Fasting Values of High-density Lipoprotein Cholesterol |
2.8; 3.2; 11.4; 2.1; 1.0; -2.2 | — |
| SECONDARY Change From Baseline in Fasting Values of Calculated Low-density Lipoprotein Cholesterol |
1.3; 13.3; 21.5; -0.5; 12.2; 9.9 | — |
| SECONDARY Change From Baseline in Fasting Values of Triglycerides |
15.4; -3.6; 27.6; 36.0; 15.4; 28.9 | — |
| SECONDARY Change From Baseline in Fasting Values of Glucose |
1.9; 8.8; 6.1; 6.6; 2.1; 3.2 | — |
| SECONDARY Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 48 Weeks [CPI+SOC v SOC] |
0.66; 0.62 | — |
| SECONDARY Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 24 Weeks [CPI+SOC v SOC] |
0.68; 0.61 | — |
| SECONDARY Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 72 Weeks [CPI+SOC v SOC] |
0.69; 0.62 | — |
| SECONDARY Number of Weeks of Follow-up [CPI+SOC v SOC] |
72; 72 | — |
| SECONDARY 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] |
24; 24; 24; 24; 24; 24 | — |
| SECONDARY 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] |
66; 89 | — |
| SECONDARY Percent of Participants With Confirmed Virologic Failure by Week 48 [CPI+SOC v SOC] |
24.9; 32.2 | — |
| SECONDARY 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] |
24; 24; 24; 24; NA; 48 | — |
| SECONDARY 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] |
20; 32 | — |
| SECONDARY 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] |
7.8; 12.1 | — |
| SECONDARY Time From Study Entry/Randomization to Death [CPI+SOC v SOC] |
11.3; 15.9; NA; 82.1; NA; NA | — |
| SECONDARY Percent of Participants Experiencing Death by Week 48 [CPI+SOC v SOC] |
3.9; 1.5 | — |
| SECONDARY Time From Study Entry/Randomization to the First of Death, an AIDS-defining Event or a Non-AIDS-defining Event [CPI+SOC v SOC] |
4.0; 4.0; 27.6; 42.3; 60.6; 77.9 | — |
| SECONDARY Percent of Participants Experiencing Death, AIDS-defining Event or a Non-AIDS-defining Event by Week 48 [CPI+SOC v SOC] |
8.2; 6.5 | — |
| SECONDARY Time From Study Entry/Randomization to the First of Death or Hospitalization [CPI+SOC v SOC] |
2.3; 2.3; 11.3; 20.3; 44.6; 45.3 | — |
| SECONDARY Percent of Participants With Death or Hospitalization by Week 48 [CPI+SOC v SOC] |
10.6; 10.6 | — |
| SECONDARY Time From Study Entry/Randomization to Treatment Modification or Discontinuation [CPI+SOC v SOC] |
1.0; 2.4; 5.1; 22.3; 23.6; 38.9 | — |
| SECONDARY Percent of Participants With Treatment Modification or Discontinuation by Week 48 [CPI+SOC v SOC] |
19.1; 13.6 | — |
| SECONDARY Time From Study Entry/Randomization to Treatment Modification or Discontinuation Due to Toxicity [CPI+SOC v SOC] |
3.1; 9.0; NA; NA | — |
| SECONDARY Percent of Participants With Treatment Modification or Discontinuation Due to Toxicity by Week 48 [CPI+SOC v SOC] |
2.8; 2.3 | — |
| SECONDARY Time From Study Entry/Randomization to the Development of Immune Reconstitution Inflammatory Syndrome (IRIS) [CPI+SOC v SOC] |
NA; 25.0; NA; NA | — |
| SECONDARY Percent of Participants That Developed Immune Reconstitution Inflammatory Syndrome (IRIS) by Week 48 [CPI+SOC v SOC] |
0.4; 1.1 | — |
| SECONDARY Time to First Dose Modification Due to Grade 3 or 4 Toxicity [CPI+SOC v SOC] |
45.7; NA; NA; NA | — |
| SECONDARY Percent of Participants With a Dose Modification Due to Grade 3 or 4 Toxicity by Week 48 [CPI+SOC v SOC] |
1.2; 0 | — |
| SECONDARY Change From Baseline in CD4+ T-cell Count [CPI+SOC v SOC] |
72; 74; 112; 107; 145; 134 | — |
| SECONDARY Change From Baseline in Fasting Values of Total Cholesterol [CPI+SOC v SOC] |
10.1; 14.4; 15.1; 14.1; 17.4; 18.7 | — |
| SECONDARY Change From Baseline in Fasting Values of High-density Lipoprotein Cholesterol [CPI+SOC v SOC] |
2.9; 3.6; 5.6; 3.7; 6.0; 6.6 | — |
| SECONDARY Change From Baseline in Fasting Values of Calculated Low-density Lipoprotein Cholesterol [CPI+SOC v SOC] |
5.5; 9.5; 12.0; 10.1; 11.9; 12.8 | — |
| SECONDARY Change From Baseline in Fasting Values of Triglycerides [CPI+SOC v SOC] |
15.3; 18.7; 2.2; 19.6; 13.7; 7.1 | — |
| SECONDARY Change From Baseline in Fasting Values of Glucose [CPI+SOC v SOC] |
3.7; 3.7; 3.6; 5.1; 3.6; 1.5 | — |
Summary
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
Eligibility Criteria
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 /= 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
Data sourced from ClinicalTrials.gov (NCT01641367). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.