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Trial Details
indicate updates made to monitored data item(s) since trial registration. These data item(s) are monitored to ensure they comply with the WHO / journal editors standards.
 
Request Number: 320665
ACTR Number: ACTRN12609000881235
Trial Status: Registered
Date Submitted: 2/10/2009
Date Registered: 9/10/2009

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Public title: A randomised open-label study comparing the safety and efficacy of ritonavir boosted lopinavir and 2-3 nucleoside reverse transcriptase inhibitors (NRTI) backbone versus ritonavir boosted lopinavir and raltegravir in participants virologically failing first-line non-nucleoside reverse transcriptase inhibitors (NNRTI)/2 NRTI therapy (the SECOND-LINE study). This study is for Human Immunodeficiency Virus (HIV) infection.
ANZCTR registration title: A randomised open-label study comparing the safety and efficacy of ritonavir boosted lopinavir and 2-3 nucleoside reverse transcriptase inhibitors (NRTI) backbone versus ritonavir boosted lopinavir and raltegravir in participants virologically failing first-line non-nucleoside reverse transcriptase inhibitors (NNRTI)/2 NRTI therapy (the SECOND-LINE study). This study is for Human Immunodeficiency Virus (HIV) infection.
Secondary ID 1:National Centre in HIV Epidemiology and Clinical Research (NCHECR) SECOND-LINE study 
Secondary ID 2:ClinicalTrials.gov number: NCT00931463 
UTN:
Trial acronym: SECOND-LINE Study

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Health condition(s) or problem(s) studied:
Human Immunodeficiency Virus (HIV) -1 infection 
Condition category: Condition code:
Infection Acquired immune deficiency syndrome (AIDS / HIV) 

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Description of intervention(s) / exposure: This study is a Phase IIIB/IV, randomised, open label comparison of two independent regimens of combination antiretrovirals as second-line therapy following confirmed virological failure of a first-line non-nucleoside and two nucleoside reverse transcriptase inhibitors (NNRTI/2N(t)RTI) combination antiretroviral (ART) regimen. Eligible participants will be randomly allocated to receive one of the two study regimens.

I. ritonavir boosted lopinavir (LPV/r) 200mg/50mg 4 tablets once daily or 2 tabs twice daily + 2-3N(t)RTIs
II. ritonavir boosted lopinavir (LPV/r) 200mg/50mg 4 tablets once daily or 2 tabs twice daily + raltegravir 400 mg 1 tablet twice daily.

All treatments will be adminstered orally.
The dose of 2-3N(t)RTIs given will be at the treating physician's discretion, according to the local guidelines and the patient's condition.
Intervention code:Treatment: drugs 
Comparator / control treatment: ritonavir boosted lopinavir (LPV/r) 200mg/50mg 4 tablets once daily or 2 tabs twice daily + 2-3N(t)RTIs The overall duration of treatment is at the physician's discretion.
Control group: Active

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Primary outcome:To compare the virological efficacy of the two regimens as measured by the proportion of participants with HIV ribonucleic acid (RNA) <200 copies/mL 48-weeks and 96 weeks after randomisation in the intention-to-treat (ITT) population. 
Timepoint:The primary analysis will summarise study variables when the last patient randomised has completed 48 weeks of follow-up. 
Secondary outcome 1:Virological endpoints - an analysis of the time to loss of virological response (TLOVR) - proportions of participants with <50 and <400 HIV RNA copies /mL - time to plasma HIV RNA <200 copies/mL - time to treatment failure (>200 copies/mL) 
Timepoint:A number of secondary endpoints will be examined at week 48 and 96 in this protocol by randomised treatment arm. 
Secondary outcome 2:Immunological endpoints - mean change in CD4+ cell count from baseline. Blood tests will be conducted to assess this outcome. 
Timepoint:A number of secondary endpoints will be examined at week 48 and 96 in this protocol by randomised treatment arm. 
Secondary outcome 3:Safety - total number of participants with any serious adverse events (SAEs), and the cumulative incidence of SAEs - total number of participants with any adverse event(s) (AEs) and the cumulative incidence of all AEs - total number of participants with any adverse event (AE), and cumulative incidence of all AEs associated with cessation of randomly assigned therapy SAEs include those defined in the International Conference on Harmonisation, Good Clinical Practice (ICH-GCP) guidelines. 
Timepoint:A number of secondary endpoints will be examined at week 48 and 96 in this protocol by randomised treatment arm. 
Secondary outcome 4:Antiretroviral treatment - analyses in which participants who change ART for any reason are classified as having failed randomised treatment - time to change in randomly assigned therapy (all reasons individually and on aggregate) 
Timepoint:A number of secondary endpoints will be examined at week 48 and 96 in this protocol by randomised treatment arm. 

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Key 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 = 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 (=7 days apart) HIV RNA results of >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
Minimum Age: 16 Years
Maximum Age: No limit
Gender: Both males and females
Healthy volunteers? No
Key exclusion criteria: 1. The following laboratory variables a) absolute neutrophil count (ANC) <500 cells/microlitres. b) hemoglobin <7.0 g/dL c) platelet count <50,000 cells/microlitres d) Alanine transaminase (ALT) >5 x upper limit normal (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, St. John’s wort) 6. Intercurrent illness requiring hospitalisation 7. Active opportunistic disease not under adequate control in the opinion of the investigator 8. Participants with current alcohol or illicit substance abuse that in the opinion of the investigator might adversely affect participation in the study 9. Participants deemed by the investigator unlikely to be able to remain in follow-up for the protocol defined period

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Study type: Interventional
Purpose of the study: Treatment
Allocation to intervention: Randomised controlled trial
Describe the procedure for enrolling a subject and allocating the treatment (allocation concealment procedures): Participants will undergo screening procedures as described in the protocol. All data will be entered onto a web-based electronic case report form (eCRF). Once all screening data has been entered and verified as correct and meeting the eligibility criteria, participants will be randomized immediately via the web-based system. Randomisation will be stratified for the following variables: - clinical site - plasma HIV-1 RNA viral load < or = 100,000 copies/mL
Describe the methods used to generate the sequence in which subjects will be randomised (sequence generation): Stratification was by baseline plasma HIV-1 RNA viral load < or =100,000 copies/mL. A computerised random number generator with a blocking factor of four was used to produce a random number list, which was then built into the eCRF to maintain blinding of physician and participant until randomisation occurred.
Masking / blinding: Open (masking not used)
Assignment: Parallel
Other design features (specify):
Type of endpoint(s): Safety/efficacy

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Phase Phase 4
Anticipated or actual date of first participant enrolement: 1/11/2009
Target sample size: 550
Recruitment status: Open to recruitment

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Funding source 1:University 
Name:University of New South Wales/National Centre in HIV Epidemiology and Clinical Research 
Address:Level 2, 376 Victoria Street Darlinghurst NSW 2010 
Country:Australia 
Funding source 2:Commercial sector/Industry 
Name:Abbott 
Address:32-34 Lord Street BOTANY NSW 2019 AUSTRALIA 
Country:Australia 
Funding source 3:Commercial sector/Industry 
Name:Merck Sharpe & Dohme 
Address:54/68 Ferndell St South Granville NSW 2142 
Country:Australia 
Primary sponsor: University
Name: University of New South Wales/National Centre in HIV Epidemiology and Clinical Research
Address: Level 2, 376 Victoria Street Darlinghurst NSW 2010
Country: Australia
Secondary sponsor:None 
Name: 
Address: 
Country: 
Other collaborator: 

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Has the study received approval from at least one ethics committee? Yes
Ethics Committee name:St Vincent's Hospital Human Research Ethcis Committee (HREC) 
Address:Victoria Street Darlinghurst NSW 2010 
Country:Australia 
Date of approval:8/09/2009 
HREC Number:HREC/09/SVH/89 
Countries of recruitment:Australia 
Postcode:2010, 2170, 3071, 3181 
Outside Australia 
New Zealand - Auckland 
Argentina - Buenos Aires 
Argentina - Mendoza 
Argentina - Cordoba 
Chile - Santiago 
Peru - Lima 
Peru - San Martin de Porres 
Mexico - Mexico D.F. 
Mexico - Estado de Jalisco 
United Kingdom - London 
Ireland - Dublin 
France - Paris 
Germany - Frankfurt 
Germany - Berlin 
Israel - Haifa 
Malaysia - Kuala Lumpur 
Malaysia - Pulau Pinang 
Malaysia - Selangor 
Hong Kong - Kowloon 
Taiwan, Province Of China - Taipei 
Singapore 
Thailand - Bangkok 
Thailand - Khon Kaen 
Viet Nam - Ho Chi Minh City 
India - Chennai 
South Africa - Bloemfontein 
South Africa - Soweto 
Nigeria - Plateau State 
China - Beijing 
China - Shanghai 
China - Guangzhou 
Brief summary: Research Hypothesis:
In HIV-infected subjects who have virologically failed first-line antiretroviral therapy comprising 2NRTI + 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 2-3NRTIs.

Study Design:
This is a Phase IIIb/IV, international, randomised, open label study comparing two regimens of combination antiretroviral therapy in people living with HIV with confirmed virological failure of first-line NNRTI/2 NRTI regimens. The study will run for 96-weeks but the primary analysis will take place at the week 48 time point.
Eligible participants will be randomised in equal proportions to one of two regimens of combination ART as follows:
I. ritonavir boosted lopinavir (LPV/r) + 2-3NRTIs
II. ritonavir boosted lopinavir (LPV/r) + raltegravir

Number of Subjects per Group:
Approximately 275 eligible subjects will be randomly allocated to each of the two treatment arms giving a study total of 550 participants.
Trial website:
Presentations / publication list:

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Contact person for public queries
Name: Dr Mark Boyd
Address: National Centre in HIV Epidemiology and Clinical Research (NCHECR)
376 Victoria Street
Darlinghurst NSW 2010
Country: Australia
Tel: +61 2 9385 0900
Fax:
Email: mboyd@nchecr.unsw.edu.au

Contact person for scientific queries
Name: Dr Mark Boyd
Address: National Centre in HIV Epidemiology and Clinical Research (NCHECR)
376 Victoria Street
Darlinghurst NSW 2010
Country: Australia
Tel: +61 2 9385 0900
Fax:
Email: mboyd@nchecr.unsw.edu.au

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