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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by AIDS Clinical Trials Group
Sponsor:
Collaborator:
Information provided by (Responsible Party):
AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT01641367
First received: June 28, 2012
Last updated: June 5, 2014
Last verified: June 2014
  Purpose

The study is being done to:

  • test a strategy of using a resistance test to choose anti-HIV drugs. Resistance tests look at the HIV in your blood to see which drugs might work best to lower your HIV infection.
  • 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 doing 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
  • in Step 3, to see how people do after they stop having frequent clinic visits as part of a research study

Condition Intervention Phase
HIV-1 Infection
Drug: Darunavir
Drug: Etravirine
Drug: Emtricitabine/tenofovir disoproxil fumarate
Drug: Raltegravir
Drug: Second line ART regimens are usually 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
Other: SOC adherence versus SOC+CPI adherence
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Management Using the Latest Technologies in Resource-limited Settings to Optimize Combination Therapy After Viral Failure (MULTI-OCTAVE)

Resource links provided by NLM:


Further study details as provided by AIDS Clinical Trials Group:

Primary Outcome Measures:
  • Suppression rate of plasma HIV-1 RNA to ≤200 copies/mL at 48 weeks [ Time Frame: 48 weeks after the date of randomization ] [ Designated as safety issue: No ]
    The measurement closest to exactly 48 weeks (ie, 7x48=336 days) after the date of randomization, within the window of 48 weeks ± 6 weeks (specifically 295 to 378 days after randomization, inclusive).


Secondary Outcome Measures:
  • Suppression rate of plasma HIV-1 RNA to ≤200 copies/mL at week 24 and 72 [ Time Frame: Baseline to week 24 and 72 ] [ Designated as safety issue: No ]
  • Time to confirmed VF defined as first HIV-1 RNA >200 copies/mL at or after 24 weeks. [ Time Frame: Throughout study; participants are expected to be followed for an average of 84 weeks ] [ Designated as safety issue: No ]
    The VF has to be confirmed by the next HIV-1 RNA measurement also being >200 copies/mL (irrespective of the time between the initial and confirmatory measurements provided that they are obtained on different days, and irrespective of ART being received at the times of these measurements). For the purposes of this outcome measure, a week 24 measurement includes any HIV-1 RNA measurement obtained at ≥7*22=154 days after randomization (to allow for the protocol-defined 14 day window for scheduling the week 24 visit)

  • Time to confirmed VF defined as first HIV-1 RNA >200 copies/mL at or after 24 weeks with a new resistance-associated mutation detected in population-based sequencing. [ Time Frame: Throughout study; participants are expected to be followed for an average of 84 weeks ] [ Designated as safety issue: No ]
    The new resistance-associated mutation is defined as one not present in the last population-based sequence obtained prior to randomization

  • Change in CD4+ T-cell count from baseline at week 24, 48, and 72. [ Time Frame: Baseline to week 24, 48, and 72 ] [ Designated as safety issue: No ]
    Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of 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)

  • Time from randomization to death. [ Time Frame: Throughout study; participants are expected to be followed for an average of 84 weeks ] [ Designated as safety issue: No ]
  • Time from randomization to the first of death, an AIDS-defining event or a non-AIDS-defining event. [ Time Frame: Throughout study; participants are expected to be followed for an average of 84 weeks ] [ Designated as safety issue: No ]
  • Time from randomization to the first of death or hospitalization. [ Time Frame: Throughout study; participants are expected to be followed for an average of 84 weeks ] [ Designated as safety issue: No ]
  • Time from randomization to treatment modification or discontinuation. [ Time Frame: Throughout study; participants are expected to be followed for an average of 84 weeks ] [ Designated as safety issue: No ]
    Treatment modification is defined as the first occurrence of a substitution or subtraction of one or more drugs in the study regimen or of the addition of a new drug. This would not include splitting any fixed dose combination medications if the participant continues on the active drugs of the combination.

  • Time from randomization to treatment modification or discontinuation due to toxicity. [ Time Frame: Throughout study; participants are expected to be followed for an average of 84 weeks ] [ Designated as safety issue: No ]
  • Change from baseline in fasting values of total cholesterol at week 24, 48 and 72. [ Time Frame: Baseline to week 24, 48 and 72 ] [ Designated as safety issue: No ]
    Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of 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)

  • Change from baseline in fasting values of HDL-C at week 24, 48 and 72. [ Time Frame: Baseline to week 24, 48 and 72 ] [ Designated as safety issue: No ]
    Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of 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)]

  • Change from baseline in fasting values of calculated LDL-C at week 24, 48 and 72. [ Time Frame: Baseline to week 24, 48 and 72 ] [ Designated as safety issue: No ]
    Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of 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)

  • Change from baseline in fasting values of triglycerides at week 24, 48 and 72. [ Time Frame: Baseline to week 24, 48 and 72 ] [ Designated as safety issue: No ]
    Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of 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)

  • Change from baseline in fasting values of glucose at week 24, 48 and 72. [ Time Frame: Baseline to week 24, 48 and 72 ] [ Designated as safety issue: No ]
    Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of 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)

  • Time from randomization to the development of IRIS. [ Time Frame: Throughout study; participants are expected to be followed for an average of 84 weeks ] [ Designated as safety issue: No ]
  • Time to first dose modification due to Grade 3 or 4 toxicity. [ Time Frame: Throughout study; participants are expected to be followed for an average of 84 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 500
Study Start Date: October 2012
Estimated Study Completion Date: April 2018
Estimated Primary Completion Date: April 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort A: No resistance to NRTIs, PIs, or NNRTI Drug: Second line ART regimens are usually based on a boosted protease inhibitor (bPI) plus two nucleoside analogues (NRTIs)
LPV/r and ATV/r are the preferred bPIs for second-line ART. TDF + (3TC or FTC) or AZT + 3TC are the most frequent NRTI backbones. Cohort A will not include any of the new drugs; therefore, it is distinct from Cohorts B, C, and D.
Other: SOC adherence versus SOC+CPI adherence
  • not participating in the adherence randomization; OR
  • randomized to SOC adherence; OR
  • randomized to SOC+CPI adherence.
Experimental: Sub-cohort B1: Best available NRTIs, RAL, & DRV/RTV
Participants susceptible to DRV/RTV and ETR with or without resistance to NRTIs (and may have resistance to other PIs). Participants without active hepatitis B infection at screening will be randomized 1:1 to sub-cohort B1 or B2
Drug: Darunavir
Participants will be administered darunavir orally as one 600 mg tablet twice a day (1200 mg per day) with food (must be taken with Ritonavir 100 mg twice a day [200 mg per day])
Other Names:
  • DRV
  • Prezista
Drug: Raltegravir
Participants will be administered Raltegravir orally as one 400 mg tablet twice daily (800 mg per day), with or without food
Other Names:
  • RAL
  • Isentress
Other: SOC adherence versus SOC+CPI adherence
  • not participating in the adherence randomization; OR
  • randomized to SOC adherence; OR
  • randomized to SOC+CPI adherence.
Experimental: Sub-cohort B2: ETR, RAL, and DRV/RTV
Susceptible to DRV/RTV and ETR with or without resistance to NRTIs (and may have resistance to other PIs). Participants without active hepatitis B infection at screening will be randomized 1:1 to sub-cohort B1 or B2.
Drug: Darunavir
Participants will be administered darunavir orally as one 600 mg tablet twice a day (1200 mg per day) with food (must be taken with Ritonavir 100 mg twice a day [200 mg per day])
Other Names:
  • DRV
  • Prezista
Drug: Etravirine
Patients will be 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
Drug: Raltegravir
Participants will be administered Raltegravir orally as one 400 mg tablet twice daily (800 mg per day), with or without food
Other Names:
  • RAL
  • Isentress
Other: SOC adherence versus SOC+CPI adherence
  • not participating in the adherence randomization; OR
  • randomized to SOC adherence; OR
  • randomized to SOC+CPI adherence.
Experimental: Sub-cohort B3: RAL, DRV/RTV & FTC/TDF or TDF + 3TC
Participants with active hepatitis B infection at screening will be assigned to sub-cohort B3
Drug: Darunavir
Participants will be administered darunavir orally as one 600 mg tablet twice a day (1200 mg per day) with food (must be taken with Ritonavir 100 mg twice a day [200 mg per day])
Other Names:
  • DRV
  • Prezista
Drug: Emtricitabine/tenofovir disoproxil fumarate
Patients will be 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
Drug: Raltegravir
Participants will be administered Raltegravir orally as one 400 mg tablet twice daily (800 mg per day), with or without food
Other Names:
  • RAL
  • Isentress
Other: SOC adherence versus SOC+CPI adherence
  • not participating in the adherence randomization; OR
  • randomized to SOC adherence; OR
  • randomized to SOC+CPI adherence.
Experimental: Cohort C: NRTI & ETR Resistance or ETR Resistance Alone
May have resistance to PIs other than DRV
Drug: Darunavir
Participants will be administered darunavir orally as one 600 mg tablet twice a day (1200 mg per day) with food (must be taken with Ritonavir 100 mg twice a day [200 mg per day])
Other Names:
  • DRV
  • Prezista
Drug: Raltegravir
Participants will be administered Raltegravir orally as one 400 mg tablet twice daily (800 mg per day), with or without food
Other Names:
  • RAL
  • Isentress
Other: SOC adherence versus SOC+CPI adherence
  • not participating in the adherence randomization; OR
  • randomized to SOC adherence; OR
  • randomized to SOC+CPI adherence.
Active Comparator: Cohort D: NRTI and/or DRV/RTV resistance or prior RAL exposure Drug: Study provided drugs according to patient resistance profile (DRV, ETR, RTV, FTC/TDF) + any in country available drug as applicable & available
For Cohort D, in many situations a patient will indeed receive the same regimen that patients are getting in Cohorts B and C if that is the best combination that can be obtained according to his/her resistance profile and drug availability (as for many countries there will be no further drug options beyond the available study drugs).
Other: SOC adherence versus SOC+CPI adherence
  • not participating in the adherence randomization; OR
  • randomized to SOC adherence; OR
  • randomized to SOC+CPI adherence.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria for Step 1:

  • HIV-1 infection
  • 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 will be assigned to Cohort D.

  • Current receipt of a PI-based regimen with no regimen change for a minimum of 24 weeks prior to screening.

NOTE A: Within the 30 days prior to collection of the confirmatory VF sample, alteration in dose, dose frequency, or any within-class substitution(s) for intolerance is permitted, as are drug interruptions for fewer than 7 cumulative days.

NOTE B: There can be no changes and no drug interruptions within the 3 days immediately prior to the collection of the confirmatory VF sample.

  • Confirmation of VF of current second-line PI-based ART. NOTE A: Failure of the current second-line regimen is 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.

NOTE B: The first measurement of plasma HIV-1 RNA ≥1000 copies/mL must have been obtained after at least 24 weeks of being on the current PI-based regimen and within 240 days prior to study entry. This measurement may be obtained from any local laboratory or from medical records regardless of the laboratory that performed the test.

NOTE C: The second measurement of plasma HIV-1 RNA ≥1000 copies/mL must be obtained within 103 days prior to study entry and must be performed in a DAIDS-approved laboratory.

  • CD4+ T-cell count result from a specimen drawn within 103 days prior to study entry; the date of specimen draw and CD4+ T-cell count must be recorded.
  • Certain laboratory values obtained within 30 days prior to study entry.
  • 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 a negative serum or urine pregnancy test within 48 hours prior to randomization or registration.
  • Female participants of reproductive potential must agree 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 use at least one reliable form of contraceptive. Potential female participants must continue to use contraceptives while receiving study treatment and for 6 weeks after stopping study treatment.
  • Female participants who are not of reproductive potential or whose male partner(s) has documented azoospermia) are not required to use contraceptives. Any statement of self-reported sterility or that of her partner's must be entered in the source documents.

NOTE: Acceptable documentation of lack of reproductive potential is 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 was available.

NOTE: A repeat test of the original sample is acceptable if the initial genotype results are not available due to technical reasons.

  • 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 CMC.

NOTE: The final CMC-approved cohort (A, B, C, or D) and planned ARV regimen must be entered into the enrollment system, the ACS, and kept in hardcopy as source documentation at the site.

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 interfere with adherence to study requirements.
  • Serious illness requiring systemic treatment and/or hospitalization until candidate either completes therapy or is 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.
  • Active tuberculosis (TB) or rifampin exposure less than 2 weeks prior to study entry.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01641367

Locations
South Africa
Univ. of Witwatersrand CRS (11101) Recruiting
Johannesburg, South Africa
Contact: Pauline C Vunandlala, BS    27 11 717 2810    idsyndicate@witshealth.co.za   
Principal Investigator: Prudence Ive, FCP         
Sponsors and Collaborators
AIDS Clinical Trials Group
Investigators
Study Chair: Beatriz Grinsztejn, MD, PhD Instituto de Pesquisa Clinica Evandro Chagas-Fiocruz
Study Chair: Peter Mugyenyi, MB ChB, FRCP, DSc Joint Clinical Research Center
  More Information

No publications provided

Responsible Party: AIDS Clinical Trials Group
ClinicalTrials.gov Identifier: NCT01641367     History of Changes
Other Study ID Numbers: ACTG A5288, 1U01AI068636
Study First Received: June 28, 2012
Last Updated: June 5, 2014
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Protease Inhibitors
Darunavir
HIV Protease Inhibitors
Tenofovir
Tenofovir disoproxil
Etravirine
Emtricitabine
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on August 18, 2014