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

NCT ID: NCT00931463

Last Updated: 2019-09-04

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

558 participants

Study Classification

INTERVENTIONAL

Study Start Date

2009-09-30

Study Completion Date

2013-08-31

Brief Summary

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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.

Detailed Description

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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.

Conditions

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HIV Infections

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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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.

Group Type ACTIVE_COMPARATOR

2N(t)RTI

Intervention Type DRUG

2N(t)RTIs as prescribed

Ritonavir-boosted lopinavir

Intervention Type DRUG

2 heat-stable tablets of ritonavir-boosted lopinavir taken every 12 hours

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.

Group Type EXPERIMENTAL

raltegravir

Intervention Type DRUG

400 mg raltegravir tablet taken every 12 hours

Ritonavir-boosted lopinavir

Intervention Type DRUG

2 heat-stable tablets of ritonavir-boosted lopinavir taken every 12 hours

Interventions

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raltegravir

400 mg raltegravir tablet taken every 12 hours

Intervention Type DRUG

2N(t)RTI

2N(t)RTIs as prescribed

Intervention Type DRUG

Ritonavir-boosted lopinavir

2 heat-stable tablets of ritonavir-boosted lopinavir taken every 12 hours

Intervention Type DRUG

Other Intervention Names

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Isentress nucleosides, nucleotides, nuncleoside backbone Aluvia, Kaletra

Eligibility Criteria

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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
Minimum Eligible Age

16 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role collaborator

Abbott

INDUSTRY

Sponsor Role collaborator

amfAR, The Foundation for AIDS Research

OTHER

Sponsor Role collaborator

Kirby Institute

OTHER_GOV

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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David A Cooper, MD

Role: STUDY_CHAIR

Kirby Institute

Brian Gazzard, MD

Role: STUDY_CHAIR

St. Stephen's Trust

Locations

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Hospital Interzonal General de Agudos, Oscar Alende

Buenos Aires, Mar Del Plata Provincia, Argentina

Site Status

CAICI

Buenos Aires, Rosario Provincia de Sante Fe, Argentina

Site Status

Hospital General de Agudos 'Teodoro Alvarez'

Buenos Aires, , Argentina

Site Status

FUNCEI

Buenos Aires, , Argentina

Site Status

Hospital de Infecciosas FJ Muniz

Buenos Aires, , Argentina

Site Status

Hospital Italiano

Buenos Aires, , Argentina

Site Status

Hospital J.M. Ramos Mejia

Buenos Aires, , Argentina

Site Status

Hospital Prof. Alejandro Posadas

Buenos Aires, , Argentina

Site Status

Hospital Rawson

Córdoba, , Argentina

Site Status

Hospital Central

Mendoza, , Argentina

Site Status

Liverpool Hospital

Liverpool, New South Wales, Australia

Site Status

Albion Street Centre

Sydney, New South Wales, Australia

Site Status

St Vincent's Hospital

Sydney, New South Wales, Australia

Site Status

The Alfred Hospital

Melbourne, Victoria, Australia

Site Status

Centre Clinic

Melbourne, Victoria, Australia

Site Status

Hospital de la Universidad Catolica Pontificia

Santiago, , Chile

Site Status

Hospital San Borja-Arriaran

Santiago, , Chile

Site Status

Hopital Saint-Louis

Paris, , France

Site Status

Medical Group Practice

Berlin, , Germany

Site Status

J W Goethe Universitat

Frankfurt, , Germany

Site Status

Queen Elizabeth Hospital

Hong Kong, Kowloon, Hong Kong

Site Status

YRG Care

Chennai, , India

Site Status

Institute of Infectious Diseases

Pune, , India

Site Status

Mater Misericordiae-Dublin

Dublin, , Ireland

Site Status

Hospital Pelau Pinang

Kuala Lumpur, , Malaysia

Site Status

Hospital Sungai Buloh

Kuala Lumpur, , Malaysia

Site Status

University of Malaysia

Kuala Lumpur, , Malaysia

Site Status

Hospital General de Guadalajara

Guadalajara, , Mexico

Site Status

Hospital General de Leon

León, , Mexico

Site Status

Instituto Nacional de Ciencias Medicas y Nutricion "Salvado Zubiran"

Mexico City, , Mexico

Site Status

Auckland Hospital

Grafton, Auckland, New Zealand

Site Status

Evangel Hospital (ECWA)

Jos, Plateau State, Nigeria

Site Status

Jos University Teaching Hospital (JUTH)

Jos, Plateau State, Nigeria

Site Status

Plateau State Specialist Hospital

Jos, Plateau State, Nigeria

Site Status

Hospital Almenara

Lima, , Peru

Site Status

IMPACTA/Hospital Dos de Mayo

Lima, , Peru

Site Status

Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia

Lima, , Peru

Site Status

Via Libre

Lima, , Peru

Site Status

Tan Tock Seng Hospital

Singapore, , Singapore

Site Status

Josha Research

Bloemfontein, , South Africa

Site Status

Desmond Tutu HIV Foundation

Cape Town, , South Africa

Site Status

Chris Hani Baragwanath Hospital

Soweto, , South Africa

Site Status

National Taiwan University Hospital

Taipei, , Taiwan

Site Status

Chelsea and Westminster Hospital

Fulham, London, United Kingdom

Site Status

Countries

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Argentina Australia Chile France Germany Hong Kong India Ireland Malaysia Mexico New Zealand Nigeria Peru Singapore South Africa Taiwan United Kingdom

References

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Henry RT, Jiamsakul A, Law M, Losso M, Kamarulzaman A, Phanuphak P, Kumarasamy N, Foulkes S, Mohapi L, Nwizu C, Wood R, Kelleher A, Polizzotto M; SECOND-LINE Study Group. Factors Associated With and Characteristic of HIV/Tuberculosis Co-Infection: A Retrospective Analysis of SECOND-LINE Clinical Trial Participants. J Acquir Immune Defic Syndr. 2021 May 1;87(1):720-729. doi: 10.1097/QAI.0000000000002619.

Reference Type DERIVED
PMID: 33399309 (View on PubMed)

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.

Reference Type DERIVED
PMID: 25723472 (View on PubMed)

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.

Reference Type DERIVED
PMID: 24204757 (View on PubMed)

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.

Reference Type DERIVED
PMID: 23769235 (View on PubMed)

Other Identifiers

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SECOND-LINE

Identifier Type: -

Identifier Source: org_study_id

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