Clinical trial NCT00931463: 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
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV Infections
Keywords: second line therapy
combination antiretroviral therapy
first-line failure
AIDS
treatment experienced
Lead sponsor: Kirby Institute
Sponsor class: OTHER_GOV
Collaborators: name: Merck Sharp & Dohme LLC
name: Abbott
name: amfAR, The Foundation for AIDS Research
First posted: 2009-07-02
Enrollment: 558
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 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

Primary outcomes:
measure: Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization
timeFrame: 48 weeks following randomization
Secondary outcomes:
measure: Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population
timeFrame: 48 weeks
measure: Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population, Non-completer Classed as Failure
timeFrame: 48 weeks
measure: Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population, Baseline VL >100,000 Copies Per mL
timeFrame: 48 weeks
measure: 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
timeFrame: 48 weeks
Other outcomes:
Locations:
city: Buenos Aires
country: Argentina
facility: Hospital Interzonal General de Agudos, Oscar Alende
state: Mar Del Plata Provincia
city: Buenos Aires
country: Argentina
facility: CAICI
state: Rosario Provincia De Sante Fe
city: Buenos Aires
country: Argentina
facility: Hospital General de Agudos 'Teodoro Alvarez'
city: Buenos Aires
country: Argentina
facility: FUNCEI
city: Buenos Aires
country: Argentina
facility: Hospital de Infecciosas FJ Muniz
city: Buenos Aires
country: Argentina
facility: Hospital Italiano
city: Buenos Aires
country: Argentina
facility: Hospital J.M. Ramos Mejia
city: Buenos Aires
country: Argentina
facility: Hospital Prof. Alejandro Posadas
city: Cordoba
country: Argentina
facility: Hospital Rawson
city: Mendoza
country: Argentina
facility: Hospital Central
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Albion Street Centre
state: New South Wales
city: Sydney
country: Australia
facility: St Vincent's Hospital
state: New South Wales
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Centre Clinic
state: Victoria
city: Santiago
country: Chile
facility: Hospital de la Universidad Catolica Pontificia
city: Santiago
country: Chile
facility: Hospital San Borja-Arriaran
city: Paris
country: France
facility: Hopital Saint-Louis
city: Berlin
country: Germany
facility: Medical Group Practice
city: Frankfurt
country: Germany
facility: J W Goethe Universitat
city: Hong Kong
country: Hong Kong
facility: Queen Elizabeth Hospital
state: Kowloon
city: Chennai
country: India
facility: YRG Care
city: Pune
country: India
facility: Institute of Infectious Diseases
city: Dublin
country: Ireland
facility: Mater Misericordiae-Dublin
city: Kuala Lumpur
country: Malaysia
facility: Hospital Pelau Pinang
city: Kuala Lumpur
country: Malaysia
facility: Hospital Sungai Buloh
city: Kuala Lumpur
country: Malaysia
facility: University of Malaysia
city: Guadalajara
country: Mexico
facility: Hospital General de Guadalajara
city: Leon
country: Mexico
facility: Hospital General de Leon
city: Mexico City
country: Mexico
facility: Instituto Nacional de Ciencias Medicas y Nutricion "Salvado Zubiran"
city: Grafton
country: New Zealand
facility: Auckland Hospital
state: Auckland
city: Jos
country: Nigeria
facility: Evangel Hospital (ECWA)
state: Plateau State
city: Jos
country: Nigeria
facility: Jos University Teaching Hospital (JUTH)
state: Plateau State
city: Jos
country: Nigeria
facility: Plateau State Specialist Hospital
state: Plateau State
city: Lima
country: Peru
facility: Hospital Almenara
city: Lima
country: Peru
facility: IMPACTA/Hospital Dos de Mayo
city: Lima
country: Peru
facility: Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia
city: Lima
country: Peru
facility: Via Libre
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital
city: Bloemfontein
country: South Africa
facility: Josha Research
city: Cape Town
country: South Africa
facility: Desmond Tutu HIV Foundation
city: Soweto
country: South Africa
facility: Chris Hani Baragwanath Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Fulham
country: United Kingdom
facility: Chelsea and Westminster Hospital
state: London
Study officials:
affiliation: Kirby Institute
name: David A Cooper, MD
role: STUDY_CHAIR
affiliation: St. Stephen's Trust
name: Brian Gazzard, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.