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Trial registered on ANZCTR


Registration number
ACTRN12609000881235
Ethics application status
Approved
Date submitted
2/10/2009
Date registered
9/10/2009
Date last updated
25/09/2012
Type of registration
Prospectively registered

Titles & IDs
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.
Scientific 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] 1109 0
Kirby Institute
Secondary ID [2] 1112 0
ClinicalTrials.gov number: NCT00931463
Universal Trial Number (UTN)
Trial acronym
SECOND-LINE Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Human Immunodeficiency Virus (HIV) -1 infection 251943 0
Condition category
Condition code
Infection 252128 252128 0 0
Acquired immune deficiency syndrome (AIDS / HIV)

Intervention/exposure
Study type
Interventional
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 [1] 241362 0
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

Outcomes
Primary outcome [1] 253007 0
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 [1] 253007 0
The primary analysis will summarise study variables when the last patient randomised has completed 48 weeks of follow-up.
Secondary outcome [1] 257780 0
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 [1] 257780 0
A number of secondary endpoints will be examined at week 48 and 96 in this protocol by randomised treatment arm.
Secondary outcome [2] 257781 0
Immunological endpoints
- mean change in CD4+ cell count from baseline. Blood tests will be conducted to assess this outcome.
Timepoint [2] 257781 0
A number of secondary endpoints will be examined at week 48 and 96 in this protocol by randomised treatment arm.
Secondary outcome [3] 257782 0
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 [3] 257782 0
A number of secondary endpoints will be examined at week 48 and 96 in this protocol by randomised treatment arm.
Secondary outcome [4] 257783 0
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 [4] 257783 0
A number of secondary endpoints will be examined at week 48 and 96 in this protocol by randomised treatment arm.

Eligibility
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
Sex
Both males and females
Can healthy volunteers participate?
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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
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
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)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
1/11/2009
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
550
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment postcode(s) [1] 2146 0
2010
Recruitment postcode(s) [2] 2147 0
2170
Recruitment postcode(s) [3] 2148 0
3071
Recruitment postcode(s) [4] 2149 0
3181
Recruitment outside Australia
Country [1] 2163 0
New Zealand
State/province [1] 2163 0
Auckland
Country [2] 2164 0
Argentina
State/province [2] 2164 0
Buenos Aires
Country [3] 2165 0
Argentina
State/province [3] 2165 0
Mendoza
Country [4] 2166 0
Argentina
State/province [4] 2166 0
Cordoba
Country [5] 2167 0
Chile
State/province [5] 2167 0
Santiago
Country [6] 2168 0
Peru
State/province [6] 2168 0
Lima
Country [7] 2169 0
Peru
State/province [7] 2169 0
San Martin de Porres
Country [8] 2170 0
Mexico
State/province [8] 2170 0
Mexico D.F.
Country [9] 2171 0
Mexico
State/province [9] 2171 0
Estado de Jalisco
Country [10] 2172 0
United Kingdom
State/province [10] 2172 0
London
Country [11] 2173 0
Ireland
State/province [11] 2173 0
Dublin
Country [12] 2174 0
France
State/province [12] 2174 0
Paris
Country [13] 2175 0
Germany
State/province [13] 2175 0
Frankfurt
Country [14] 2176 0
Germany
State/province [14] 2176 0
Berlin
Country [15] 2177 0
Israel
State/province [15] 2177 0
Haifa
Country [16] 2178 0
Malaysia
State/province [16] 2178 0
Kuala Lumpur
Country [17] 2179 0
Malaysia
State/province [17] 2179 0
Pulau Pinang
Country [18] 2180 0
Malaysia
State/province [18] 2180 0
Selangor
Country [19] 2181 0
Hong Kong
State/province [19] 2181 0
Kowloon
Country [20] 2182 0
Taiwan, Province Of China
State/province [20] 2182 0
Taipei
Country [21] 2183 0
Singapore
State/province [21] 2183 0
Country [22] 2184 0
Thailand
State/province [22] 2184 0
Bangkok
Country [23] 2185 0
Thailand
State/province [23] 2185 0
Khon Kaen
Country [24] 2186 0
Viet Nam
State/province [24] 2186 0
Ho Chi Minh City
Country [25] 2187 0
India
State/province [25] 2187 0
Chennai
Country [26] 2188 0
South Africa
State/province [26] 2188 0
Bloemfontein
Country [27] 2189 0
South Africa
State/province [27] 2189 0
Soweto
Country [28] 2190 0
Nigeria
State/province [28] 2190 0
Plateau State
Country [29] 2191 0
China
State/province [29] 2191 0
Beijing
Country [30] 2192 0
China
State/province [30] 2192 0
Shanghai
Country [31] 2193 0
China
State/province [31] 2193 0
Guangzhou

Funding & Sponsors
Funding source category [1] 243823 0
University
Name [1] 243823 0
University of New South Wales/Kirby Institute
Country [1] 243823 0
Australia
Funding source category [2] 243824 0
Commercial sector/Industry
Name [2] 243824 0
Abbott
Country [2] 243824 0
Australia
Funding source category [3] 243825 0
Commercial sector/Industry
Name [3] 243825 0
Merck Sharpe & Dohme
Country [3] 243825 0
Australia
Funding source category [4] 269756 0
Charities/Societies/Foundations
Name [4] 269756 0
amfAR
Country [4] 269756 0
United States of America
Primary sponsor type
University
Name
University of New South Wales/Kirby Institute
Address
45 Beach St, Coogee NSW 2034
Country
Australia
Secondary sponsor category [1] 237173 0
None
Name [1] 237173 0
Address [1] 237173 0
Country [1] 237173 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 243952 0
St Vincent's Hospital Human Research Ethcis Committee (HREC)
Ethics committee address [1] 243952 0
Victoria Street
Darlinghurst NSW 2010
Ethics committee country [1] 243952 0
Australia
Date submitted for ethics approval [1] 243952 0
06/07/2009
Approval date [1] 243952 0
08/09/2009
Ethics approval number [1] 243952 0
HREC/09/SVH/89

Summary
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
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 30344 0
Address 30344 0
Country 30344 0
Phone 30344 0
Fax 30344 0
Email 30344 0
Contact person for public queries
Name 13591 0
Dr Mark Boyd
Address 13591 0
University of New South Wales/Kirby Institute
Country 13591 0
Australia
Phone 13591 0
+61 2 9385 0900
Fax 13591 0
Email 13591 0
[email protected]
Contact person for scientific queries
Name 4519 0
Dr Mark Boyd
Address 4519 0
University of New South Wales/Kirby Institute
Country 4519 0
Australia
Phone 4519 0
+61 2 9385 0900
Fax 4519 0
Email 4519 0
[email protected]

No information has been provided regarding IPD availability


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No Supporting Document Provided



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