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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)

Primary Purpose

HIV Infections

Status
Completed
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
raltegravir
2N(t)RTI
Ritonavir-boosted lopinavir
Sponsored by
Kirby Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HIV Infections focused on measuring second line therapy, combination antiretroviral therapy, first-line failure, AIDS, treatment experienced

Eligibility Criteria

16 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Hospital Interzonal General de Agudos, Oscar Alende
  • CAICI
  • Hospital General de Agudos 'Teodoro Alvarez'
  • FUNCEI
  • Hospital de Infecciosas FJ Muniz
  • Hospital Italiano
  • Hospital J.M. Ramos Mejia
  • Hospital Prof. Alejandro Posadas
  • Hospital Rawson
  • Hospital Central
  • Liverpool Hospital
  • Albion Street Centre
  • St Vincent's Hospital
  • The Alfred Hospital
  • Centre Clinic
  • Hospital de la Universidad Catolica Pontificia
  • Hospital San Borja-Arriaran
  • Hopital Saint-Louis
  • Medical Group Practice
  • J W Goethe Universitat
  • Queen Elizabeth Hospital
  • YRG Care
  • Institute of Infectious Diseases
  • Mater Misericordiae-Dublin
  • Hospital Pelau Pinang
  • Hospital Sungai Buloh
  • University of Malaysia
  • Hospital General de Guadalajara
  • Hospital General de Leon
  • Instituto Nacional de Ciencias Medicas y Nutricion "Salvado Zubiran"
  • Auckland Hospital
  • Evangel Hospital (ECWA)
  • Jos University Teaching Hospital (JUTH)
  • Plateau State Specialist Hospital
  • Hospital Almenara
  • IMPACTA/Hospital Dos de Mayo
  • Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia
  • Via Libre
  • Tan Tock Seng Hospital
  • Josha Research
  • Desmond Tutu HIV Foundation
  • Chris Hani Baragwanath Hospital
  • National Taiwan University Hospital
  • Chelsea and Westminster Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Ritonavir-boosted lopinavir and 2N(t)RTI

Ritonavir-boosted lopinavir and raltegravir

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization

Secondary Outcome Measures

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

Full Information

First Posted
July 1, 2009
Last Updated
August 25, 2019
Sponsor
Kirby Institute
Collaborators
Merck Sharp & Dohme LLC, Abbott, amfAR, The Foundation for AIDS Research
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1. Study Identification

Unique Protocol Identification Number
NCT00931463
Brief Title
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
Acronym
SECOND-LINE
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

2. Study Status

Record Verification Date
August 2019
Overall Recruitment Status
Completed
Study Start Date
September 2009 (undefined)
Primary Completion Date
September 2012 (Actual)
Study Completion Date
August 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Kirby Institute
Collaborators
Merck Sharp & Dohme LLC, Abbott, amfAR, The Foundation for AIDS Research

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV Infections
Keywords
second line therapy, combination antiretroviral therapy, first-line failure, AIDS, treatment experienced

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
558 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ritonavir-boosted lopinavir and 2N(t)RTI
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Ritonavir-boosted lopinavir and raltegravir
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
raltegravir
Other Intervention Name(s)
Isentress
Intervention Description
400 mg raltegravir tablet taken every 12 hours
Intervention Type
Drug
Intervention Name(s)
2N(t)RTI
Other Intervention Name(s)
nucleosides, nucleotides, nuncleoside backbone
Intervention Description
2N(t)RTIs as prescribed
Intervention Type
Drug
Intervention Name(s)
Ritonavir-boosted lopinavir
Other Intervention Name(s)
Aluvia, Kaletra
Intervention Description
2 heat-stable tablets of ritonavir-boosted lopinavir taken every 12 hours
Primary Outcome Measure Information:
Title
Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization
Time Frame
48 weeks following randomization
Secondary Outcome Measure Information:
Title
Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population
Description
The per- protocol population includes those participants who fulfil the protocol in the terms of the eligibility, interventions, and outcome assessment
Time Frame
48 weeks
Title
Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population, Non-completer Classed as Failure
Description
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
Time Frame
48 weeks
Title
Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population, Baseline VL >100,000 Copies Per mL
Description
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
Time Frame
48 weeks
Title
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
Description
The per- protocol population includes those participants who fulfil the protocol in the terms of the eligibility, interventions, and outcome assessment
Time Frame
48 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David A Cooper, MD
Organizational Affiliation
Kirby Institute
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Brian Gazzard, MD
Organizational Affiliation
St. Stephen's Trust
Official's Role
Study Chair
Facility Information:
Facility Name
Hospital Interzonal General de Agudos, Oscar Alende
City
Buenos Aires
State/Province
Mar Del Plata Provincia
ZIP/Postal Code
1900
Country
Argentina
Facility Name
CAICI
City
Buenos Aires
State/Province
Rosario Provincia De Sante Fe
ZIP/Postal Code
2000
Country
Argentina
Facility Name
Hospital General de Agudos 'Teodoro Alvarez'
City
Buenos Aires
ZIP/Postal Code
1406
Country
Argentina
Facility Name
FUNCEI
City
Buenos Aires
Country
Argentina
Facility Name
Hospital de Infecciosas FJ Muniz
City
Buenos Aires
Country
Argentina
Facility Name
Hospital Italiano
City
Buenos Aires
Country
Argentina
Facility Name
Hospital J.M. Ramos Mejia
City
Buenos Aires
Country
Argentina
Facility Name
Hospital Prof. Alejandro Posadas
City
Buenos Aires
Country
Argentina
Facility Name
Hospital Rawson
City
Cordoba
Country
Argentina
Facility Name
Hospital Central
City
Mendoza
ZIP/Postal Code
5500
Country
Argentina
Facility Name
Liverpool Hospital
City
Liverpool
State/Province
New South Wales
ZIP/Postal Code
2170
Country
Australia
Facility Name
Albion Street Centre
City
Sydney
State/Province
New South Wales
ZIP/Postal Code
2010
Country
Australia
Facility Name
St Vincent's Hospital
City
Sydney
State/Province
New South Wales
ZIP/Postal Code
2010
Country
Australia
Facility Name
The Alfred Hospital
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3004
Country
Australia
Facility Name
Centre Clinic
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3182
Country
Australia
Facility Name
Hospital de la Universidad Catolica Pontificia
City
Santiago
Country
Chile
Facility Name
Hospital San Borja-Arriaran
City
Santiago
Country
Chile
Facility Name
Hopital Saint-Louis
City
Paris
Country
France
Facility Name
Medical Group Practice
City
Berlin
Country
Germany
Facility Name
J W Goethe Universitat
City
Frankfurt
Country
Germany
Facility Name
Queen Elizabeth Hospital
City
Hong Kong
State/Province
Kowloon
Country
Hong Kong
Facility Name
YRG Care
City
Chennai
Country
India
Facility Name
Institute of Infectious Diseases
City
Pune
Country
India
Facility Name
Mater Misericordiae-Dublin
City
Dublin
Country
Ireland
Facility Name
Hospital Pelau Pinang
City
Kuala Lumpur
Country
Malaysia
Facility Name
Hospital Sungai Buloh
City
Kuala Lumpur
Country
Malaysia
Facility Name
University of Malaysia
City
Kuala Lumpur
Country
Malaysia
Facility Name
Hospital General de Guadalajara
City
Guadalajara
Country
Mexico
Facility Name
Hospital General de Leon
City
Leon
Country
Mexico
Facility Name
Instituto Nacional de Ciencias Medicas y Nutricion "Salvado Zubiran"
City
Mexico City
Country
Mexico
Facility Name
Auckland Hospital
City
Grafton
State/Province
Auckland
ZIP/Postal Code
1
Country
New Zealand
Facility Name
Evangel Hospital (ECWA)
City
Jos
State/Province
Plateau State
Country
Nigeria
Facility Name
Jos University Teaching Hospital (JUTH)
City
Jos
State/Province
Plateau State
Country
Nigeria
Facility Name
Plateau State Specialist Hospital
City
Jos
State/Province
Plateau State
Country
Nigeria
Facility Name
Hospital Almenara
City
Lima
Country
Peru
Facility Name
IMPACTA/Hospital Dos de Mayo
City
Lima
Country
Peru
Facility Name
Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia
City
Lima
Country
Peru
Facility Name
Via Libre
City
Lima
Country
Peru
Facility Name
Tan Tock Seng Hospital
City
Singapore
ZIP/Postal Code
308433
Country
Singapore
Facility Name
Josha Research
City
Bloemfontein
Country
South Africa
Facility Name
Desmond Tutu HIV Foundation
City
Cape Town
Country
South Africa
Facility Name
Chris Hani Baragwanath Hospital
City
Soweto
Country
South Africa
Facility Name
National Taiwan University Hospital
City
Taipei
Country
Taiwan
Facility Name
Chelsea and Westminster Hospital
City
Fulham
State/Province
London
ZIP/Postal Code
SW10 9NH
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
33399309
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.
Results Reference
derived
PubMed Identifier
25723472
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. Erratum In: PLoS One. 2015;10(10):e0140623.
Results Reference
derived
PubMed Identifier
24204757
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.
Results Reference
derived
PubMed Identifier
23769235
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.
Results Reference
derived

Learn more about this trial

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

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