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)

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ClinicalTrials.gov Identifier: NCT00931463

Recruitment Status : Completed

First Posted : July 2, 2009

Results First Posted : January 17, 2014

Last Update Posted : March 13, 2014

Sponsor:

Collaborators:

Merck Sharp & Dohme Corp.

Abbott

amfAR, The Foundation for AIDS Research

Information provided by (Responsible Party):

Kirby Institute

Study Description

Brief Summary:

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 or disease	Intervention/treatment	Phase
HIV Infections	Drug: raltegravir Drug: 2N(t)RTI Drug: Ritonavir-boosted lopinavir	Phase 4

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.

Study Design


Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	558 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (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
Study Start Date :	September 2009
Actual Primary Completion Date :	September 2012
Actual Study Completion Date :	August 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Drug Information available for: Ritonavir Lopinavir Raltegravir Raltegravir potassium

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
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

Outcome Measures

Primary Outcome Measures :

Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization [ Time Frame: 48 weeks following randomization ]

Secondary Outcome Measures :

Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population [ Time Frame: 48 weeks ]
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 ]
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 ]
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 ]
The per- protocol population includes those participants who fulfil the protocol in the terms of the eligibility, interventions, and outcome assessment

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	16 Years and older (Child, Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

HIV-1 positive by licensed diagnostic test
Aged 16 years or older (or minimum age as determined by local regulations or as legal requirements dictate)
Have received first antiretroviral regimen consisting of an NNRTI plus 2N(t)RTIs for at least 24 weeks
No change in antiretroviral therapy within 12 weeks prior to screening
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
No prior or current exposure to HIV protease inhibitors and/or HIV integrase inhibitors
Able to provide written informed consent

Exclusion Criteria:

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
Pregnant or nursing mothers
Participants with active viral hepatitis B infection defined by the presence in serum of hepatitis B surface antigen
Use of immunomodulators within 30 days prior to screening
Use of any prohibited medications (rifampicin, midazolam, triazolam, cisapride, pimozide, amiodarone, dihydroergotamine, ergotamine, ergonovine, methylergonovine, astemizole, terfenadine, vardenafil, and St. John's wort)
Intercurrent illness requiring hospitalization
Active opportunistic disease not under adequate control in the opinion of the site Principal Investigator
Participants with current alcohol or illicit substance abuse that in the opinion of the site Principal Investigator might adversely affect participation in the study
Participants deemed by the site Principal Investigator unlikely to be able to remain in follow-up for the protocol-defined period

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): 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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Amin J, Boyd MA, Kumarasamy N, Moore CL, Losso MH, Nwizu CA, Mohapi L, Kerr SJ, Sohn AH, Teppler H, Renjifo B, Molina JM, Emery S, Cooper DA. Raltegravir non-inferior to nucleoside based regimens in second-line therapy with lopinavir/ritonavir over 96 weeks: a randomised open label study for the treatment of HIV-1 infection. PLoS One. 2015 Feb 27;10(2):e0118228. doi: 10.1371/journal.pone.0118228. eCollection 2015. Erratum in: PLoS One. 2015;10(10):e0140623.

Martin A, Moore CL, Mallon PW, Hoy JF, Emery S, Belloso WH, Phanuphak P, Ferret S, Cooper DA, Boyd MA; Second-Line Study Team. HIV lipodystrophy in participants randomised to lopinavir/ritonavir (LPV/r) +2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTI) or LPV/r + raltegravir as second-line antiretroviral therapy. PLoS One. 2013 Oct 30;8(10):e77138. doi: 10.1371/journal.pone.0077138. eCollection 2013.

SECOND-LINE Study Group, Boyd MA, Kumarasamy N, Moore CL, Nwizu C, Losso MH, Mohapi L, Martin A, Kerr S, Sohn AH, Teppler H, Van de Steen O, Molina JM, Emery S, Cooper DA. Ritonavir-boosted lopinavir plus nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with virological failure of a standard first-line ART regimen (SECOND-LINE): a randomised, open-label, non-inferiority study. Lancet. 2013 Jun 15;381(9883):2091-9. doi: 10.1016/S0140-6736(13)61164-2.


Responsible Party:	Kirby Institute
ClinicalTrials.gov Identifier:	NCT00931463 History of Changes
Other Study ID Numbers:	SECOND-LINE
First Posted:	July 2, 2009 Key Record Dates
Results First Posted:	January 17, 2014
Last Update Posted:	March 13, 2014
Last Verified:	February 2014

Keywords provided by Kirby Institute:


second line therapy combination antiretroviral therapy first-line failure AIDS treatment experienced

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 Ritonavir Lopinavir Raltegravir Potassium Reverse Transcriptase Inhibitors	HIV Protease Inhibitors Protease Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Anti-HIV Agents Anti-Retroviral Agents Antiviral Agents Anti-Infective Agents Cytochrome P-450 CYP3A Inhibitors Cytochrome P-450 Enzyme Inhibitors HIV Integrase Inhibitors Integrase Inhibitors Nucleic Acid Synthesis Inhibitors

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