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

NCT01641367 | Completed Phase 4 Results DMC

• 2 other identifiers: ACTG A52881U01AI068636
• Study Type: interventional
• Target: 545
• Locations: 10 countries
• Sites: 19

Brief 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

Conditions

HIV-1 Infection

Outcome Measures

Primary Outcomes (1)

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

  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.

  48 weeks after the date of entry

Secondary Outcomes (59)

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

  24 weeks after the date of entry

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

  72 weeks after the date of entry

• Number of Weeks of Follow-up

  From study entry through Step 1/2 follow-up

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

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

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

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

Study Arms (6)

Cohort A

EXPERIMENTAL

Under Protocol version 1.0: No resistance to NRTIs, PIs, or NNRTI • Continue current second-line regimen; NRTIs could be modified Changed under LOA#2 to: No LPV/RTV resistance and susceptible to at least one NRTI, regardless of NNRTI resistance or prior RAL exposure • Continue second-line regimen which may include LPV/RTV; NRTIs could be modified Changed under LOA#3 to: No LPV/RTV resistance and susceptible to at least one NRTI, regardless of NNRTI resistance or prior RAL exposure • Continue PI backbone; NRTIs could be modified. If on a RAL-containing regimen, RAL must be discontinued.

Drug: Second line ART regimens - based on a boosted protease inhibitor (bPI) plus two nucleoside analogues (NRTIs); Other: SOC adherence versus SOC+CPI adherence

Sub-cohort B1

EXPERIMENTAL

Under Protocol version 1.0: Susceptible to DRV/RTV and ETR with or without resistance to NRTIs (and may have resistance to other PIs) and without active hepatitis B infection at screening • Best available NRTIs, RAL, \& DRV/RTV Changed under LOA#2 to: Resistance to LPV/RTV but susceptible to DRV/RTV and ETR and with no prior RAL exposure and regardless of NRTI resistance (and without active hepatitis B infection at screening) OR Resistance to all NRTIs (i.e. susceptible to none) but susceptible to DRV/RTV and ETR and with no prior RAL exposure (and without active hepatitis B infection at screening) • Best available NRTIs, RAL, \& DRV/RTV

Drug: Darunavir; Drug: Raltegravir; Other: SOC adherence versus SOC+CPI adherence

Sub-cohort B2

EXPERIMENTAL

Under Protocol version 1.0: Susceptible to DRV/RTV and ETR with or without resistance to NRTIs (and may have resistance to other PIs) and without active hepatitis B infection at screening • ETR, RAL, and DRV/RTV Changed under LOA#2 to: Resistance to LPV/RTV but susceptible to DRV/RTV and ETR and with no prior RAL exposure and regardless of NRTI resistance (and without active hepatitis B infection at screening) OR Resistance to all NRTIs (i.e. susceptible to none) but susceptible to DRV/RTV and ETR and with no prior RAL exposure (and without active hepatitis B infection at screening) • ETR, RAL, and DRV/RTV

Drug: Darunavir; Drug: Etravirine; Drug: Raltegravir; Other: SOC adherence versus SOC+CPI adherence

Sub-cohort B3

EXPERIMENTAL

Under Protocol version 1.0: Susceptible to DRV/RTV and ETR with or without resistance to NRTIs (and may have resistance to other PIs) and with active hepatitis B infection at screening • RAL, DRV/RTV, and FTC/TDF or TDF+3TC Changed under LOA#2 to: Resistance to LPV/RTV but susceptible to DRV/RTV and ETR and with no prior RAL exposure and regardless of NRTI resistance (with active hepatitis B infection at screening) OR Resistance to all NRTIs (i.e. susceptible to none) but susceptible to DRV/RTV and ETR and with no prior RAL exposure (with active hepatitis B infection at screening) • RAL, DRV/RTV, and FTC/TDF or TDF+3TC

Drug: Darunavir; Drug: Emtricitabine/tenofovir disoproxil fumarate; Drug: Raltegravir; Other: SOC adherence versus SOC+CPI adherence

Cohort C

EXPERIMENTAL

Under Protocol version 1.0: Resistance to NRTIs and ETR or resistance to ETR alone (and may have resistance to PIs other than DRV) • Best available NRTIs, RAL, and DRV/RTV Changed under LOA#2: Resistance to LPV/RTV and ETR but susceptible to DRV/RTV and with no prior RAL exposure and regardless of NRTI resistance OR Resistance to ETR and to all NRTIs (i.e. susceptible to none) but susceptible to DRV/RTV and with no prior RAL exposure • Best available NRTIs, RAL, and DRV/RTV

Drug: Darunavir; Drug: Raltegravir; Other: SOC adherence versus SOC+CPI adherence

Cohort D

EXPERIMENTAL

Under Protocol version 1.0: Multiple NRTI resistance and/or DRV/RTV resistance or prior RAL exposure: • Best available regimen, including study-provided and any locally available drugs Changed under LOA#2: Not eligible for Cohort A, B, or C: • Best available regimen, including study-provided and any locally available drugs Updated under protocol v2.0: • Best available ART regimen, including study-provided and any locally available non-experimental drugs

Drug: Study provided drugs according to patient resistance profile (DRV, ETR, RTV, FTC/TDF) + any in country available drug as applicable & available; Other: SOC adherence versus SOC+CPI adherence

Interventions

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 \[200 mg per day\])

Also known as: DRV, Prezista

Cohort C; Sub-cohort B1; Sub-cohort B2; Sub-cohort B3

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.

Also known as: ETR, Intelence

Sub-cohort B2

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.

Also known as: FTC/TDF, Truvada

Sub-cohort B3

Raltegravir DRUG

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

Also known as: RAL, Isentress

Cohort C; Sub-cohort B1; Sub-cohort B2; Sub-cohort B3

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.

Cohort A

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).

Cohort D

SOC adherence versus SOC+CPI adherence OTHER

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

Cohort A; Cohort C; Cohort D; Sub-cohort B1; Sub-cohort B2; Sub-cohort B3

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• AbbVie: collaborator
• Gilead Sciences: collaborator
• Janssen Pharmaceuticals: collaborator
• Merck Sharp & Dohme LLC: collaborator
• Dimagi Inc.: collaborator

Study Sites (19)

Hospital Nossa Senhora da Conceicao CRS (12201)

Porto Alegre, Rio Grande do Sul, 9043010, Brazil

Location

Instituto de Pesquisa Clinica Evandro Chagas (12101)

Rio de Janeiro, 21045, Brazil

Location

Les Centres GHESKIO CRS (30022)

Port-au-Prince, Bicentaire, HT-6110, Haiti

Location

GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS

Port-au-Prince, Haiti

Location

BJ Medical College CRS (31441)

Pune, Maharashtra, 411001, India

Location

Chennai Antiviral Research and Treatment (CART) CRS (11701)

Chennai, Taramani, 600113, India

Location

AMPATH at Moi Univ. Teaching Hosp. Eldoret CRS (12601)

Eldoret, 30100, Kenya

Location

Kenya Medical Research Institute/Center for Disease Control (KEMRI/CDC) CRS (31460)

Kisumu, 40100, Kenya

Location

Malawi CRS (12001)

Lilongwe, Malawi

Location

San Miguel CRS (11302)

San Miguel, Lima region, Peru

Location

Barranco CRS (11301)

Lima, 18 PE, Peru

Location

University of the Witwatersrand Helen Joseph (WITS HJH) CRS (11101)

Johannesburg, Gauteng, 2193, South Africa

Location

Family Clinical Research Unit (FAM-CUR) CRS (8950)

Cape Town, West Cape, 7505, South Africa

Location

Durban Adult HIV CRS (11201)

Durban, 4013 SF, South Africa

Location

Soweto ACTG CRS (12301)

Johannesburg, South Africa

Location

31802 Thai Red Cross AIDS Research Centre (TRC-ARC) CRS

Bangkok, Patumwan, 10330, Thailand

Location

31784 Chiang Mai University HIV Treatment CRS

Chiang Mai, 50200, Thailand

Location

JCRC CRS

Kampala, Uganda

Location

UZ-Parirenyatwa CRS (30313)

Harare, Zimbabwe

Location

Related Publications (4)

• Avihingsanon A, Hughes MD, Salata R, Godfrey C, McCarthy C, Mugyenyi P, Hogg E, Gross R, Cardoso SW, Bukuru A, Makanga M, Badal-Aesen S, Mave V, Ndege BW, Fontain SN, Samaneka W, Secours R, Van Schalkwyk M, Mngqibisa R, Mohapi L, Valencia J, Sugandhavesa P, Montalban E, Munyanga C, Chagomerana M, Santos BR, Kumarasamy N, Kanyama C, Schooley RT, Mellors JW, Wallis CL, Collier AC, Grinsztejn B; A5288 Study team. Third-line antiretroviral therapy, including raltegravir (RAL), darunavir (DRV/r) and/or etravirine (ETR), is well tolerated and achieves durable virologic suppression over 144 weeks in resource-limited settings: ACTG A5288 strategy trial. J Int AIDS Soc. 2022 Jun;25(6):e25905. doi: 10.1002/jia2.25905.

  PMID: 36039892 DERIVED

• Godfrey C, Hughes MD, Ritz J, Coelho L, Gross R, Salata R, Mngqibisa R, Wallis CL, Mumbi ME, Matoga M, Poongulali S, Van Schalkwyk M, Hogg E, Fletcher CV, Grinsztejn B, Collier AC; A5288 team. Brief Report: Sex Differences in Outcomes for Individuals Presenting for Third-Line Antiretroviral Therapy. J Acquir Immune Defic Syndr. 2020 Jun 1;84(2):203-207. doi: 10.1097/QAI.0000000000002324.

  PMID: 32049773 DERIVED

• Gross R, Ritz J, Hughes MD, Salata R, Mugyenyi P, Hogg E, Wieclaw L, Godfrey C, Wallis CL, Mellors JW, Mudhune VO, Badal-Faesen S, Grinsztejn B, Collier AC. Two-way mobile phone intervention compared with standard-of-care adherence support after second-line antiretroviral therapy failure: a multinational, randomised controlled trial. Lancet Digit Health. 2019 May;1(1):e26-e34. doi: 10.1016/S2589-7500(19)30006-8. Epub 2019 May 6.

  PMID: 31528850 DERIVED

• Grinsztejn B, Hughes MD, Ritz J, Salata R, Mugyenyi P, Hogg E, Wieclaw L, Gross R, Godfrey C, Cardoso SW, Bukuru A, Makanga M, Faesen S, Mave V, Wangari Ndege B, Nerette Fontain S, Samaneka W, Secours R, van Schalkwyk M, Mngqibisa R, Mohapi L, Valencia J, Sugandhavesa P, Montalban E, Avihingsanon A, Santos BR, Kumarasamy N, Kanyama C, Schooley RT, Mellors JW, Wallis CL, Collier AC; A5288 Team. Third-line antiretroviral therapy in low-income and middle-income countries (ACTG A5288): a prospective strategy study. Lancet HIV. 2019 Sep;6(9):e588-e600. doi: 10.1016/S2352-3018(19)30146-8. Epub 2019 Jul 29.

  PMID: 31371262 DERIVED

Related Links

• DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004; Clarification, August 2009
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

MeSH Terms

Interventions

Darunavir; etravirine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Raltegravir Potassium; bactericidal permeability increasing protein; Ritonavir

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Carbamates; Acids, Acyclic; Carboxylic Acids; Sulfones; Sulfur Compounds; Furans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Tenofovir; Organophosphonates; Organophosphorus Compounds; Emtricitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Drug Combinations; Pharmaceutical Preparations; Pyrrolidinones; Pyrrolidines; Thiazoles; Azoles

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, Inc.

ACTGCT.Gov@s-3.com

(301) 628-3313

Study Officials

• Beatriz Grinsztejn, MD, PhD

  Instituto de Pesquisa Clinica Evandro Chagas-Fiocruz

  STUDY CHAIR

• Peter Mugyenyi, MB ChB, FRCP, DSc

  Joint Clinical Research Center

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 28, 2012
• First Posted: July 16, 2012
• Study Start: February 22, 2013
• Primary Completion: November 23, 2016
• Study Completion: December 31, 2018
• Last Updated: March 15, 2019
• Results First Posted: February 20, 2018

Record last verified: 2019-03

Locations

ZI (1); HA (2); IN (2); KE (2); PE (2); BR (2); ZA (4); UG (1); MA (1); TH (2)