Study of Options for Second-Line Effective Combination Therapy (SELECT)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT01352715
First received: January 12, 2011
Last updated: January 28, 2014
Last verified: January 2014

January 12, 2011
January 28, 2014
January 2012
October 2014   (final data collection date for primary outcome measure)
Time to virologic failure [ Time Frame: At or after study Week 24 ] [ Designated as safety issue: No ]
The primary endpoint is time to virologic failure. Virologic failure is defined as confirmed viral load >400 copies/mL at or after week 24.
Same as current
Complete list of historical versions of study NCT01352715 on ClinicalTrials.gov Archive Site
  • Change in CD4+ cell count from baseline [ Time Frame: Weeks 48 and 96 ] [ Designated as safety issue: No ]
    CD4+ cell count at baseline, weeks 48, 96 and at virologic failure
  • HIV-1 drug resistance mutations in gag, protease, reverse transcriptase, and integrase in participants with virologic failure at baseline and at time of virologic failure [ Time Frame: Through to week 96 ] [ Designated as safety issue: No ]
  • Time to first Grade 3 or higher Adverse Event (AE) that is at least one grade higher than baseline [ Time Frame: Through to week 96 ] [ Designated as safety issue: Yes ]
  • Time to discontinuation of randomized treatment for toxicity [ Time Frame: Through to week 96 ] [ Designated as safety issue: Yes ]
    Time to discontinuation of randomized treatment for toxicity (including participant decision to discontinue for low grade toxicity); within class NRTI changes are not considered an endpoint.
  • Time to new AIDS-defining events, death and targeted serious non-AIDS-defining events [ Time Frame: Through to week 96 ] [ Designated as safety issue: Yes ]
  • Duration of hospitalizations [ Time Frame: Through to week 96 ] [ Designated as safety issue: No ]
  • Changes in fasting total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and glucose from baseline [ Time Frame: Weeks 48 and 96 ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Study of Options for Second-Line Effective Combination Therapy (SELECT)
Multicenter Study of Options for Second-Line Effective Combination Therapy (SELECT)

The study is being done with people who are taking their first anti-HIV drug regimen (including an Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), a type of anti-HIV drug) but the drugs in this regimen are not doing a good job of fighting their HIV infection.

The main purpose of this study is to compare two other anti-HIV drug regimens to see how well they fight HIV. The study will also see how well participants tolerate the drug regimens and how safe they are.

The study will determine whether taking the combination of lopinavir/ritonavir (LPV/r) plus raltegravir (RAL) works as well as what usually is used for second-line therapy: LPV/r plus the best-available nucleoside (nucleotide) reverse transcriptase inhibitor (NRTI) combination. Testing a regimen that does not include any NRTI is important because NRTIs may no longer work for patients who received them as part of their first treatment regimen.

As more HIV-infected persons start antiretroviral therapy (ART) worldwide, the number needing second-line therapy is increasing. In many settings, an NNRTI-based regimen is the preferred first-line ART, whereas a protease inhibitor (PI)-based regimen is often reserved for second-line ART. Both of these types of regimens usually include two NRTIs.

As with initial ART, second-line regimens ideally should be composed of three fully active drugs that have potent anti-HIV activity to maximize the chances of durable viral suppression. However, such a goal may not be achieved with second-line PI-based regimens containing NRTIs because of resistance mutations from first-line therapy that reduce the activity of the NRTI class. The most significant of these mutations include M184V, thymidine analogue mutations (TAMs), Q151M complex, and K65R. The presence of K65R would result in resistance to most NRTIs (leaving only zidovudine (ZDV) and possibly abacavir (ABC) as active second-line options); the presence of multiple TAMs and/or Q151M alone or in complex with other mutations would also result in resistance to most NRTIs.

Recent data suggest that patients with isolated M184V-related NRTI resistance who subsequently switch to a boosted PI plus lamivudine (3TC)- or emtricitabine (FTC)-based regimen may achieve HIV-1 RNA suppression without the need to switch to more complex regimens [1]. Detection of an isolated M184V NRTI mutation is possible when resources allow for early diagnosis of virologic failure. However, in many resource-limited settings (RLS) early diagnosis of virologic failure is difficult because of infrequent monitoring of viral load or unavailability of viral load testing. This study is intended to provide information that is applicable to the vast majority of RLS where resistance testing is not used routinely for selection of second-line regimens and PIs not needing refrigeration are preferred.

This is a phase III, dual-arm, open-label, randomized, non-inferiority study for participants who are on a failing NNRTI-containing first-line regimen. The study will evaluate the difference in virologic failure rate between two treatment arms:

Arm A: LPV/r plus RAL Arm B: LPV/r plus best available NRTIs

Best available NRTI combinations will be selected by the site investigator prior to randomization from a list of combinations approved by the study or in consultation with the A5273 Clinical Management Committee (CMC). The NRTIs provided by the study are FTC/TDF, ABC/3TC/ZDV, ABC/3TC, 3TC/ZDV, ABC, 3TC, and ZDV.

Participants will take their assigned study therapy until the participant reaches 96 weeks of follow-up. This study plans to enroll 600 participants (300 per study arm). Participants will be assigned with equal probability to one of the two treatment regimens using permuted blocks. Randomization will be stratified by three factors: screening HIV-1 RNA (≥100,000 versus <100,000 copies/mL); screening CD4+ cell count (≥100 versus <100 cells/mm3), and selection of ZDV in the NRTI regimen (yes/no). Furthermore, randomization will be balanced by site.

During the study, participants will be asked to return to the clinic at Weeks 4, 12, 24, and then every 12 weeks until week 96. Visits will last about 30 minutes. At most visits, participants will have a physical exam, have their arm, waist and hip circumference measured, and will answer questions about their medical condition and any medications they are taking. At some visits, participants will complete questionnaires to see how they are feeling, if they have been hospitalized recently, and how well they are taking their anti-HIV drugs, will have their blood drawn and will be asked to give urine samples. Participants will need to fast before the study visits at weeks 24, 48, 72, and 96 visits. If the participant is female and able to become pregnant, a pregnancy test may be given at any visit if pregnancy is suspected.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
HIV-1 Infection
  • Drug: Lopinavir/ritonavir
    Lopinavir 400mg/ritonavir 100mg (given as two LPV 200mg/RTV 50mg fixed-dose combination tablets) orally twice daily, with or without food, until the participant reaches 96 weeks of follow-up.
    Other Names:
    • Aluvia
    • LPV/r
    • Kaletra
  • Drug: Lopinavir/ritonavir
    Lopinavir 400mg/ritonavir 100mg (given as three LPV 133.3 mg/RTV 33.3 mg fixed-dose combination soft gelatin capsules) orally twice daily, with food until the participant reaches 96 weeks of follow-up.
    Other Names:
    • Kaletra
    • LPV/r
  • Drug: Raltegravir
    Raltegravir 400 mg tablet orally twice daily, with or without food, until the participant reaches 96 weeks of follow-up.
    Other Names:
    • Isentress
    • RAL
  • Drug: Emtricitabine/tenofovir disoproxil fumarate
    Emtricitabine 200 mg/tenofovir disoproxil fumarate 300mg fixed-dose combination tablet orally once daily, with or without food, until the participant reaches 96 weeks of follow-up.
    Other Names:
    • Truvada
    • FTC/TDF
  • Drug: Abacavir/lamivudine/zidovudine
    Abacavir 300 mg/lamivudine 150 mg/zidovudine 300 mg fixed-dose combination tablet orally twice daily, with or without food, until the participant reaches 96 weeks of follow-up.
    Other Names:
    • Trizivir
    • ABC/3TC/ZDV
  • Drug: Abacavir/lamivudine
    Abacavir 600 mg/lamivudine 300 mg fixed-dose combination tablet orally once daily, with or without food, until the participant reaches 96 weeks of follow-up.
    Other Names:
    • Epzicom
    • ABC/3TC
  • Drug: Lamivudine/zidovudine
    Lamivudine 150 mg/zidovudine 300 mg fixed-dose combination tablet orally twice daily, with or without food, until the participant reaches 96 weeks of follow-up.
    Other Names:
    • Combivir
    • CBV
    • 3TC/ZDV
  • Drug: Abacavir
    Abacavir 300 mg tablet orally twice daily or 600 mg (given as two 300 mg tablets) once daily, with or without food, until the participant reaches 96 weeks of follow-up.
    Other Names:
    • Ziagen
    • ABC
  • Drug: Zidovudine
    Zidovudine 300 mg tablet orally twice daily, with or without food, until the participant reaches 96 weeks of follow-up.
    Other Names:
    • Retrovir
    • ZDV
  • Drug: Lamivudine
    Lamivudine 150 mg tablet orally twice daily, with or without food, until the participant reaches 96 weeks of follow-up.
    Other Names:
    • Epivir
    • 3TC
  • Experimental: Arm A: LPV/r plus RAL
    Participants will be administered LPV/r plus RAL orally twice daily until the participant reaches 96 weeks of follow-up.
    Intervention: Drug: Lopinavir/ritonavir
  • Experimental: Arm B: LPV/r plus best available NRTIs

    Participants will be administered LPV/r orally twice daily, plus NRTI options provided by the study, to include the best available NRTIs (listed below) until the participant reaches 96 weeks of follow-up-

    • FTC/TDF orally twice daily
    • ABC/3TC/ZDV orally twice daily
    • ABC/3TC orally once daily
    • 3TC/ZDV orally twice daily
    • ABC 300mg orally twice daily or 600 mg once daily
    • 3TC orally twice daily
    • ZDV orally twice daily
    Interventions:
    • Drug: Lopinavir/ritonavir
    • Drug: Raltegravir
    • Drug: Emtricitabine/tenofovir disoproxil fumarate
    • Drug: Abacavir/lamivudine/zidovudine
    • Drug: Abacavir/lamivudine
    • Drug: Lamivudine/zidovudine
    • Drug: Abacavir
    • Drug: Zidovudine
    • Drug: Lamivudine
[1] Hull M, Moore D, Harris M, et al. A lamivudine (3TC)-based backbone in conjunction with a boosted protease inhibitor (PI) is sufficient to achieve virologic suppression in the presence of M184V mutations. Program and abstracts of the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 12-15, 2009; San Francisco, California. Abstract H-916.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
600
November 2015
October 2014   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • HIV-1 infected
  • Confirmation of first-line virologic failure
  • Certain laboratory values obtained within 45 days prior to study entry. More information on this criterion can be found in the study protocol.
  • Negative pregnancy test within 48 hours prior to study entry.
  • Must refrain from participating in a conception process, and, if participating in sexual activity that could lead to pregnancy, must use at least one acceptable type of contraceptive. More information on this criterion can be found in the study protocol.
  • Karnofsky performance score >/= 70 within 45 days prior to study entry.
  • Ability and willingness of participant or legal guardian/representative to provide informed consent.
  • No intention to relocate away from current geographical area of residence for the duration of study participation.

Exclusion Criteria:

  • Use of any immunomodulator, HIV vaccine, or other investigational therapy within 45 days prior to study entry, with the exception of a tapering course of corticosteroids as acute therapy for pneumocystis jiroveci pneumonia (PCP) or acute asthma/chronic obstructive pulmonary disease flare and/or prednisone at a daily dose of <10 mg (physiologic replacement dose).
  • If the potential participant has had resistance testing, evidence of broad NRTI cross-resistance that, in the opinion of the investigator, would not allow selection of an effective NRTI combination if the participant were randomized to the LPV/r + best available NRTIs arm.
  • Prior exposure to a Protease Inhibitor.
  • Known history of congenital long QT syndrome, hypokalemia, or planned use of other drugs that prolong the QT interval.
  • Pregnancy or breast-feeding.
  • Known history of chronic hepatitis B virus (HBV) infection or current HBV infection defined by the presence of hepatitis B surface antigen in serum or plasma.
  • Active tuberculosis (TB) requiring treatment with rifampicin.
  • Previously diagnosed malignancies other than basal cell carcinoma and cutaneous Kaposi sarcoma.
  • Requirement for taking any medications that are prohibited with the study drugs. More information on this criterion can be found in the study protocol, section 5.4.
  • Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation.
  • Active drug or alcohol use or dependence or other condition 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.
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
South Africa,   Malawi
 
NCT01352715
ACTG A5273, 1U01AI068636
Yes
AIDS Clinical Trials Group
AIDS Clinical Trials Group
National Institute of Allergy and Infectious Diseases (NIAID)
Study Chair: Alberto M La Rosa, MD Asociacion Civil Impacta Salud y Educacion - Miraflores, CRS
Study Chair: Ann C Collier, MD Univ. of Washington Clinical HIV Research Program (CHIRP)
AIDS Clinical Trials Group
January 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP