A Trial of 2 Options for Second Line Combination Antiretroviral Therapy Following Virological Failure of a Standard Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI)+2N(t)RTI First Line Regimen (SECOND-LINE)

This study has been completed.
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
Abbott
amfAR, The Foundation for AIDS Research
Information provided by (Responsible Party):
Kirby Institute
ClinicalTrials.gov Identifier:
NCT00931463
First received: July 1, 2009
Last updated: February 12, 2014
Last verified: February 2014
  Purpose

The investigators hypothesize that following virological failure of a standard NNRTI+2N(T)RTI regimen second-line antiretroviral therapy consisting of ritonavir-boosted lopinavir and 2N(T)RTIs will offer comparable efficacy to that provided by ritonavir-boosted lopinavir and raltegravir.

The study will be conducted for 96-weeks with the primary endpoint analyzed after 48-weeks.

The primary endpoint is virological: a comparison of virological suppression in plasma < 200 copies/mL between the randomized arms after 48 weeks.

Secondary and exploratory endpoints include virological, immunological, safety, clinical, metabolic, drug adherence, drug resistance and quality of life.


Condition Intervention Phase
HIV Infections
Drug: raltegravir
Drug: 2N(t)RTI
Drug: Ritonavir-boosted lopinavir
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: A Randomised Open-label Study Comparing the Safety and Efficacy of Ritonavir Boosted Lopinavir and 2-3N(t)RTI Backbone Versus Ritonavir Boosted Lopinavir and Raltegravir in Participants Virologically Failing First-line NNRTI/2N(t)RTI Therapy

Resource links provided by NLM:


Further study details as provided by Kirby Institute:

Primary Outcome Measures:
  • Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization [ Time Frame: 48 weeks following randomization ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    The per- protocol population includes those participants who fulfil the protocol in the terms of the eligibility, interventions, and outcome assessment

  • Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population, Non-completer Classed as Failure [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]

    The non-completer classed as failure analysis will include all randomised participants; participants who meet the following criteria will be defined as failures:

    i. week 48 HIV RNA being above each threshold ii. has missing HIV-1 RNA data for any reason iii. stops randomly assigned therapy


  • Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population, Baseline VL >100,000 Copies Per mL [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    The difference between treatment arms in proportion of participants with plasma HIV RNA < 200 copies/mL 48 weeks after randomization, per-protocol population: stratified analysis by baseline plasma viral load (less than or equal to 100,000 copies per mL or >100,000 copies per mL) on those participants who fulfil the protocol in the terms of the eligibility, interventions, and outcome assessment

  • Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population, VL Less Than or Equal to 100,000 Copies Per mL [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    The per- protocol population includes those participants who fulfil the protocol in the terms of the eligibility, interventions, and outcome assessment


Enrollment: 558
Study Start Date: September 2009
Study Completion Date: August 2013
Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Ritonavir-boosted lopinavir and 2N(t)RTI
This is the current standard of care for second line therapy following failure of standard first-line NNRTI+2N(t)RTIs according to WHO guidelines.
Drug: 2N(t)RTI
2N(t)RTIs as prescribed
Other Name: nucleosides, nucleotides, nuncleoside backbone
Drug: Ritonavir-boosted lopinavir
2 heat-stable tablets of ritonavir-boosted lopinavir taken every 12 hours
Other Name: Aluvia, Kaletra
Experimental: Ritonavir-boosted lopinavir and raltegravir
This is an experimental arm which is likely to be fully active in the presence of N(t)RTI mutations and which preliminary evidence suggests should be potent and durable.
Drug: raltegravir
400 mg raltegravir tablet taken every 12 hours
Other Name: Isentress
Drug: Ritonavir-boosted lopinavir
2 heat-stable tablets of ritonavir-boosted lopinavir taken every 12 hours
Other Name: Aluvia, Kaletra

Detailed Description:

In HIV-infected subjects who have virologically failed first-line antiretroviral therapy comprising 2N(t)RTI + NNRTI a regimen of second-line therapy incorporating ritonavir-boosted lopinavir and raltegravir provides comparable (i.e., non-inferior) antiretroviral efficacy over 48 weeks to a regimen containing ritonavir-boosted lopinavir and 2-3N(t)RTIs.

Eligible patients will be randomised to one of two arms:

I. ritonavir boosted lopinavir (LPV/r) 200mg/50mg 4 tabs once daily or 2 tabs twice daily + 2-3N(t)RTIs

II. ritonavir boosted lopinavir (LPV/r) 200mg/50mg 4 tabs once daily or 2 tabs twice daily + raltegravir 400 mg twice daily

The primary objective of this study is to compare the virological efficacy of the two strategies as measured by the proportion of participants with HIV RNA < 200 copies/mL 48 weeks after randomisation.

Secondary objectives include virological, immunological, safety and antiretroviral therapy endpoints.

Exploratory endpoints include clinical, metabolic, drug resistance, medication adherence and quality of life endpoints.

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. HIV-1 positive by licensed diagnostic test
  2. Aged 16 years or older (or minimum age as determined by local regulations or as legal requirements dictate)
  3. Have received first antiretroviral regimen consisting of an NNRTI plus 2N(t)RTIs for at least 24 weeks
  4. No change in antiretroviral therapy within 12 weeks prior to screening
  5. Failed first-line NNRTI + 2N(t)RTI combination therapy according to virological criteria defined by two consecutive (at least 7 days apart) HIV RNA results of greater then 500 copies/mL
  6. No prior or current exposure to HIV protease inhibitors and/or HIV integrase inhibitors
  7. Able to provide written informed consent

Exclusion Criteria:

  1. The following laboratory variables:

    • absolute neutrophil count (ANC) < 500 cells/microlitres
    • hemoglobin < 7.0 g/decilitres
    • platelet count < 50,000 cells/microlitres
    • ALT great than 5 x ULN
  2. Pregnant or nursing mothers
  3. Participants with active viral hepatitis B infection defined by the presence in serum of hepatitis B surface antigen
  4. Use of immunomodulators within 30 days prior to screening
  5. Use of any prohibited medications (rifampicin, midazolam, triazolam, cisapride, pimozide, amiodarone, dihydroergotamine, ergotamine, ergonovine, methylergonovine, astemizole, terfenadine, vardenafil, and St. John's wort)
  6. Intercurrent illness requiring hospitalization
  7. Active opportunistic disease not under adequate control in the opinion of the site Principal Investigator
  8. Participants with current alcohol or illicit substance abuse that in the opinion of the site Principal Investigator might adversely affect participation in the study
  9. Participants deemed by the site Principal Investigator unlikely to be able to remain in follow-up for the protocol-defined period
  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: NCT00931463

  Show 44 Study Locations
Sponsors and Collaborators
Kirby Institute
Merck Sharp & Dohme Corp.
Abbott
amfAR, The Foundation for AIDS Research
Investigators
Study Chair: David A Cooper, MD Kirby Institute
Study Chair: Brian Gazzard, MD St. Stephen's Trust
  More Information

No publications provided by Kirby Institute

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Kirby Institute
ClinicalTrials.gov Identifier: NCT00931463     History of Changes
Other Study ID Numbers: SECOND-LINE
Study First Received: July 1, 2009
Results First Received: October 14, 2013
Last Updated: February 12, 2014
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration
European Union: European Medicines Agency
Malaysia: Ministry of Health
Nigeria: The National Agency for Food and Drug Administration and Control
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Argentina: Human Research Bioethics Committee
Argentina: Ministry of Health
Chile: Comisión Nacional de Investigación Científica y Tecnológica
Chile: Instituto de Salud Pública de Chile
Mexico: Ethics Committee
Mexico: Federal Commission for Protection Against Health Risks
Peru: Ethics Committee
Peru: Ministry of Health

Keywords provided by Kirby Institute:
second line therapy
combination antiretroviral therapy
first-line failure
AIDS
treatment experienced

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

ClinicalTrials.gov processed this record on September 14, 2014