Efficacy Study of Different Laboratory Management Strategies and Drug Regimens in HIV-infected Children in Africa (ARROW)

This study has been completed.
Sponsor:
Collaborators:
Department for International Development, United Kingdom
ViiV Healthcare
GlaxoSmithKline
Information provided by (Responsible Party):
Diana M Gibb, Medical Research Council
ClinicalTrials.gov Identifier:
NCT02028676
First received: December 31, 2013
Last updated: June 4, 2014
Last verified: June 2014
Results First Received: January 15, 2014  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Factorial Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Human Immunodeficiency Virus
Interventions: Other: Clinically Driven Monitoring (CDM)
Other: Laboratory plus Clinical Monitoring (LCM)
Drug: Arm A: ABC+3TC+NNRTI
Drug: Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenance
Drug: Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC maintenance
Drug: Once-daily ABC+3TC
Drug: Twice-daily ABC+3TC
Drug: Continued cotrimoxazole prophylaxis
Other: Stopped cotrimoxazole prophylaxis

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
All recruited children (n=1206) were randomly assigned to CDM vs LCM and the three different induction ART strategies at enrolment (3/2007-11/2008). This was a factorial randomisation meaning that the children were effectively randomized into 6 parallel groups. Baseline characteristics are presented below separately for each initial randomization.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
There were two additional nested substudy randomizations after initial trial enrolment (see inclusion/exclusion criteria for eligibility). From 8/2009 to 6/2010, eligible children were randomized to once vs twice daily abacavir+lamivudine. From 9/2009 to 2/2011, eligible children were randomized to stop vs continue cotrimoxazole prophylaxis.

Reporting Groups
  Description
Clinically Driven Monitoring (CDM) Clinically Driven Monitoring (CDM): Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.
Laboratory Plus Clinical Monitoring (LCM) Laboratory plus Clinical Monitoring (LCM): Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.
Arm A: Abacavir (ABC)+Lamivudine (3TC)+NNRTI

ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO non-nucleoside reverse transcriptase inhibitor (NNRTI): either nevirapine or efavirenz based on availability (provided by national ART programmes in Uganda/Zimbabwe). Nevirapine syrup or tablet dosed twice-daily according to weight-bands following WHO. Efavirenz tablets dosed once-daily according to weight-bands following WHO.

Arm A: ABC+3TC+NNRTI: Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.

Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance

ZDV [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO NNRTI: either nevirapine or efavirenz based on availability (provided by national ART programmes in Uganda/Zimbabwe). Nevirapine syrup or tablet dosed twice-daily according to weight-bands following WHO. Efavirenz tablets dosed once-daily according to weight-bands following WHO.

Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenance: Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.

Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance

ZDV [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO NNRTI: either nevirapine or efavirenz based on availability (provided by national ART programmes in Uganda/Zimbabwe). Nevirapine syrup or tablet dosed twice-daily according to weight-bands following WHO. Efavirenz tablets dosed once-daily according to weight-bands following WHO.

Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC maintenance: Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.

Once-daily ABC+3TC

ABC [abacavir]: syrup or tablet, dosed once-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed once-daily according to weight-bands following WHO

Once-daily ABC+3TC

Twice-daily ABC+3TC

ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO

Twice-daily ABC+3TC

Continued Cotrimoxazole Prophylaxis

Once-daily doses 5-<15 kg: 200 mg of trimethoprim + 40 mg sulfamethoxazole 15-<30 kg: 400 mg trimethoprim + 80 mg sulfamethoxazole >=30 kg: 800 mg trimethoprim + 160 mg sulfamethoxazole

Continued cotrimoxazole prophylaxis

Stopped Cotrimoxazole Prophylaxis

Children had been taking once-daily cotrimoxazole prophylaxis since at least ART initiation. Children randomised to this experimental arm stopped taking cotrimoxazole prophylaxis.

Stopped cotrimoxazole prophylaxis


Participant Flow for 4 periods

Period 1:   Initial Enrolment: CDM vs LCM
    Clinically Driven Monitoring (CDM)     Laboratory Plus Clinical Monitoring (LCM)     Arm A: Abacavir (ABC)+Lamivudine (3TC)+NNRTI     Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance     Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance     Once-daily ABC+3TC     Twice-daily ABC+3TC     Continued Cotrimoxazole Prophylaxis     Stopped Cotrimoxazole Prophylaxis  
STARTED     606 [1]   600 [1]   0 [1]   0 [1]   0 [1]   0 [2]   0 [2]   0 [2]   0 [2]
COMPLETED     606     600     0     0     0     0     0     0     0  
NOT COMPLETED     0     0     0     0     0     0     0     0     0  
[1] Factorial randomization at enrolment: Number of eligible children randomized to this group in ARROW
[2] Secondary partial factorial randomization: Only a subset of ARROW children were eligible

Period 2:   Initial Enrolment: Induction ART
    Clinically Driven Monitoring (CDM)     Laboratory Plus Clinical Monitoring (LCM)     Arm A: Abacavir (ABC)+Lamivudine (3TC)+NNRTI     Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance     Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance     Once-daily ABC+3TC     Twice-daily ABC+3TC     Continued Cotrimoxazole Prophylaxis     Stopped Cotrimoxazole Prophylaxis  
STARTED     0     0     397     404     405     0     0     0     0  
COMPLETED     0     0     397     404     405     0     0     0     0  
NOT COMPLETED     0     0     0     0     0     0     0     0     0  

Period 3:   Subsequent Once vs Twice Daily ABC+3TC
    Clinically Driven Monitoring (CDM)     Laboratory Plus Clinical Monitoring (LCM)     Arm A: Abacavir (ABC)+Lamivudine (3TC)+NNRTI     Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance     Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance     Once-daily ABC+3TC     Twice-daily ABC+3TC     Continued Cotrimoxazole Prophylaxis     Stopped Cotrimoxazole Prophylaxis  
STARTED     0     0     0     0     0     336     333     0     0  
COMPLETED     0     0     0     0     0     336     333     0     0  
NOT COMPLETED     0     0     0     0     0     0     0     0     0  

Period 4:   Subsequent Cotrimoxazole Randomization
    Clinically Driven Monitoring (CDM)     Laboratory Plus Clinical Monitoring (LCM)     Arm A: Abacavir (ABC)+Lamivudine (3TC)+NNRTI     Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance     Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance     Once-daily ABC+3TC     Twice-daily ABC+3TC     Continued Cotrimoxazole Prophylaxis     Stopped Cotrimoxazole Prophylaxis  
STARTED     0     0     0     0     0     0     0     376     382  
COMPLETED     0     0     0     0     0     0     0     376     382  
NOT COMPLETED     0     0     0     0     0     0     0     0     0  



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who were randomized were included except those who were randomised in error (main enrollment: 1 child HIV-uninfected, 2 on main phase of tuberculosis treatment; cotrimoxazole secondary randomization: 2 children receiving dapsone prophylaxis not cotrimoxazole).

Reporting Groups
  Description
Clinically Driven Monitoring (CDM) Clinically Driven Monitoring (CDM): Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.
Laboratory Plus Clinical Monitoring (LCM) Laboratory plus Clinical Monitoring (LCM): Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.
Arm A: Abacavir (ABC)+Lamivudine (3TC)+NNRTI

ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO non-nucleoside reverse transcriptase inhibitor (NNRTI): either nevirapine or efavirenz based on availability (provided by national ART programmes in Uganda/Zimbabwe). Nevirapine syrup or tablet dosed twice-daily according to weight-bands following WHO. Efavirenz tablets dosed once-daily according to weight-bands following WHO.

Arm A: ABC+3TC+NNRTI: Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.

Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance

ZDV [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO NNRTI: either nevirapine or efavirenz based on availability (provided by national ART programmes in Uganda/Zimbabwe). Nevirapine syrup or tablet dosed twice-daily according to weight-bands following WHO. Efavirenz tablets dosed once-daily according to weight-bands following WHO.

Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenance: Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.

Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance

ZDV [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO NNRTI: either nevirapine or efavirenz based on availability (provided by national ART programmes in Uganda/Zimbabwe). Nevirapine syrup or tablet dosed twice-daily according to weight-bands following WHO. Efavirenz tablets dosed once-daily according to weight-bands following WHO.

Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC maintenance: Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.

Once-daily ABC+3TC

ABC [abacavir]: syrup or tablet, dosed once-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed once-daily according to weight-bands following WHO

Once-daily ABC+3TC

Twice-daily ABC+3TC

ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO

Twice-daily ABC+3TC

Continued Cotrimoxazole Prophylaxis

Once-daily doses 5-<15 kg: 200 mg of trimethoprim + 40 mg sulfamethoxazole 15-<30 kg: 400 mg trimethoprim + 80 mg sulfamethoxazole >=30 kg: 800 mg trimethoprim + 160 mg sulfamethoxazole

Continued cotrimoxazole prophylaxis

Stopped Cotrimoxazole Prophylaxis

Children had been taking once-daily cotrimoxazole prophylaxis since at least ART initiation. Children randomised to this experimental arm stopped taking cotrimoxazole prophylaxis.

Stopped cotrimoxazole prophylaxis

Total Total of all reporting groups

Baseline Measures
    Clinically Driven Monitoring (CDM)     Laboratory Plus Clinical Monitoring (LCM)     Arm A: Abacavir (ABC)+Lamivudine (3TC)+NNRTI     Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance     Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance     Once-daily ABC+3TC     Twice-daily ABC+3TC     Continued Cotrimoxazole Prophylaxis     Stopped Cotrimoxazole Prophylaxis     Total  
Number of Participants  
[units: participants]
  606     600     397     404     405     336     333     376     382     3839  
Age [1]
[units: years]
Median ( Inter-Quartile Range )
  5.9  
  ( 2.2 to 9.2 )  
  6.0  
  ( 2.6 to 9.4 )  
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  6.0  
  ( 2.4 to 9.3 )  
Age, Customized [1]
[units: participants]
                   
< 3 years     197     173     NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [3]
3 years or older     409     427     NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [3]
Gender  
[units: participants]
                   
Female     308     302     NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [3]
Male     298     298     NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [3]
Region of Enrollment [4]
[units: participants]
                   
Uganda     405     401     NA [2]   NA [2]   NA [2]   NA [5]   NA [2]   NA [2]   NA [2]   NA [3]
Zimbabwe     201     199     NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [3]
Age, continuous: Period 2 (trial enrollment, induction ART) [1]
[units: years]
Median ( Inter-Quartile Range )
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  6.1  
  ( 2.4 to 9.3 )  
  6.2  
  ( 2.5 to 9.4 )  
  5.7  
  ( 2.3 to 9.3 )  
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  6.0  
  ( 2.4 to 9.4 )  
Age, continuous: Period 3 (randomization to once vs twice daily ABC+3TC) [6]
[units: years]
Median ( Inter-Quartile Range )
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  5.9  
  ( 3.8 to 8.6 )  
  5.1  
  ( 3.6 to 8.3 )  
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  5.5  
  ( 3.7 to 8.5 )  
Age, continuous: Period 4 (randomization to stop versus continue cotrimoxazole) [7]
[units: years]
Median ( Inter-Quartile Range )
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  7.5  
  ( 4.6 to 11.1 )  
  8.3  
  ( 4.5 to 11.0 )  
  7.9  
  ( 4.6 to 11.1 )  
Age, categorical: Period 2 (trial enrollment, induction ART)  
[units: participants]
                   
<3 years     NA [2]   NA [2]   121     117     132     NA [2]   NA [2]   NA [2]   NA [2]   NA [3]
3 years or older     NA [2]   NA [2]   276     287     273     NA [2]   NA [2]   NA [2]   NA [2]   NA [3]
Age, categorical: Period 3 (randomization to once vs twice daily ABC+3TC)  
[units: participants]
                   
<3 years     NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   36     38     NA [2]   NA [2]   NA [3]
3 years and older     NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   300     295     NA [2]   NA [2]   NA [3]
Age, categorical: Period 4 (randomization to stop versus continue cotrimoxazole)  
[units: participants]
                   
<3 years     NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   0     0     NA [3]
3 years and older     NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   376     382     NA [3]
Gender, Male/Female: Period 2 (trial enrollment, induction ART)  
[units: participants]
                   
Female     NA [2]   NA [2]   204     197     209     NA [2]   NA [2]   NA [2]   NA [2]   NA [3]
Male     NA [2]   NA [2]   193     207     196     NA [2]   NA [2]   NA [2]   NA [2]   NA [3]
Gender, Male/Female: Period 3 (randomization to once vs twice daily ABC+3TC)  
[units: participants]
                   
Female     NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   173     172     NA [2]   NA [2]   NA [3]
Male     NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   163     161     NA [2]   NA [2]   NA [3]
Gender, Male/Female: Period 4 (randomization to stop versus continue cotrimoxazole)  
[units: participants]
                   
Female     NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   195     203     NA [3]
Male     NA [2]   NA [2]   NA [2]   NA [2]   NA [5]   NA [2]   NA [2]   181     179     NA [3]
Region of Enrollment: Period 2 (trial enrollment, induction ART)  
[units: participants]
                   
Uganda     NA [2]   NA [2]   266     268     272     NA [2]   NA [2]   NA [2]   NA [5]   NA [3]
Zimbabwe     NA [2]   NA [2]   131     136     133     NA [2]   NA [2]   NA [2]   NA [2]   NA [3]
Region of Enrollment: Period 3 (randomization to once vs twice daily ABC+3TC)  
[units: participants]
                   
Uganda     NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   249     246     NA [2]   NA [2]   NA [3]
Zimbabwe     NA [2]   NA [2]   NA [5]   NA [2]   NA [2]   87     87     NA [2]   NA [2]   NA [3]
Region of Enrollment: Period 4 (randomization to stop versus continue cotrimoxazole)  
[units: participants]
                   
Uganda     NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   283     286     NA [3]
Zimbabwe     NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   NA [2]   93     96     NA [3]
CD4 T cell percentage [8]
[units: percentage of total lymphocytes]
Median ( Inter-Quartile Range )
  12.5  
  ( 7.5 to 17.3 )  
  12.0  
  ( 7.0 to 17.0 )  
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  12.0  
  ( 7.3 to 17.1 )  
CD4 T cell percentage: Period 2 (trial enrollment, induction ART) [8]
[units: percentage of total lymphocytes]
Median ( Inter-Quartile Range )
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  11.7  
  ( 6.9 to 17.5 )  
  12.0  
  ( 7.1 to 17.0 )  
  12.5  
  ( 8.0 to 17.0 )  
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  12.0  
  ( 7.3 to 17.1 )  
CD4 T cell percentage: Period 3 (randomization to once vs twice daily ABC+3TC) [9]
[units: percentage of total lymphocytes]
Median ( Inter-Quartile Range )
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  33.0  
  ( 28.0 to 39.0 )  
  33.0  
  ( 27.0 to 39.0 )  
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  33.0  
  ( 28.0 to 39.0 )  
CD4 T cell percentage: Period 4 (randomization to stop versus continue cotrimoxazole) [10]
[units: percentage of total lymphocytes]
Median ( Inter-Quartile Range )
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  33.0  
  ( 26.0 to 39.0 )  
  32.0  
  ( 26.0 to 39.0 )  
  33.0  
  ( 26.0 to 39.0 )  
Duration of antiretroviral therapy: Period 3 (randomization to once vs twice daily ABC+3TC) [11]
[units: years]
Median ( Full Range )
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  1.8  
  ( 0.9 to 3.0 )  
  1.8  
  ( 0.9 to 3.0 )  
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  1.8  
  ( 0.9 to 3.0 )  
Duration of antiretroviral therapy: Period 4 (randomization to stop versus continue cotrimoxazole) [12]
[units: years]
Median ( Full Range )
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  2.1  
  ( 1.6 to 3.2 )  
  2.1  
  ( 1.8 to 3.2 )  
  2.1  
  ( 1.6 to 3.2 )  
Weight-for-age Z-score: Period 1 (trial enrollment, CDM vs LCM) [13]
[units: Z-score]
Median ( Inter-Quartile Range )
  -2.3  
  ( -3.4 to -1.3 )  
  -2.2  
  ( -3.3 to -1.3 )  
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  -2.2  
  ( -3.3 to -1.3 )  
Weight-for-age Z-score: Period 2 (trial enrollment, induction ART) [13]
[units: Z-score]
Median ( Inter-Quartile Range )
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  -2.3  
  ( -3.5 to -1.3 )  
  -2.2  
  ( -3.2 to -1.4 )  
  -2.2  
  ( -3.4 to -1.3 )  
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  -2.2  
  ( -3.3 to -1.3 )  
Weight-for-age Z-score: Period 3 (randomization to once vs twice daily ABC+3TC) [14]
[units: Z-score]
Median ( Inter-Quartile Range )
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [5]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  -1.4  
  ( -2.0 to -0.7 )  
  -1.3  
  ( -2.0 to -0.6 )  
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  -1.4  
  ( -2.0 to -0.7 )  
Weight-for-age Z-score: Period 4 (randomization to stop versus continue cotrimoxazole) [15]
[units: Z-score]
Median ( Inter-Quartile Range )
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  NA  
  ( NA to NA ) [2]
  -1.3  
  ( -1.9 to -0.6 )  
  -1.3  
  ( -1.9 to -0.7 )  
  -1.3  
  ( -1.9 to -0.6 )  
[1] Age at trial enrollment (antiretroviral therapy initiation).
[2] Different randomized comparison
[3] Total not calculated because data are not available (NA) in one or more arms.
[4] Region of enrollment at trial enrollment (antiretroviral therapy initiation).
[5] Different randomized comparisonDifferent randomized comparison
[6] Age at the time of the secondary randomization to once versus twice daily abacavir+lamivudine (in those children eligible and randomized).
[7] Age at the time of the secondary randomization to stop versus continue cotrimoxazole prophylaxis (in those children eligible and randomized).
[8] CD4 T cell percentage at trial enrollment (antiretroviral therapy initiation).
[9] CD4 T cell percentage at the time of the secondary randomization to once versus twice daily abacavir+lamivudine (in those children eligible and randomized).
[10] CD4 T cell percentage at the time of the secondary randomization to stop versus continue cotrimoxazole prophylaxis (in those children eligible and randomized).
[11] Years on antiretroviral therapy at the time of the secondary randomization to once versus twice daily abacavir+lamivudine (in those children eligible and randomized).
[12] Years on antiretroviral therapy at the time of the secondary randomization to stop versus continue cotrimoxazole prophylaxis (in those children eligible and randomized).
[13] Weight-for-age Z-score at trial enrollment (antiretroviral therapy initiation).
[14] Weight-for-age Z-score at the time of the secondary randomization to once versus twice daily abacavir+lamivudine (in those children eligible and randomized).
[15] Weight-for-age Z-score at the time of the secondary randomization to stop versus continue cotrimoxazole prophylaxis (in those children eligible and randomized).



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   LCM vs CDM: Disease Progression to a New WHO Stage 4 Event or Death   [ Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years) ]

2.  Primary:   LCM vs CDM: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV   [ Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years) ]

3.  Primary:   Induction ART: Change From Baseline in CD4% 72 Weeks After ART Initiation   [ Time Frame: Baseline, 72 weeks ]

4.  Primary:   Induction ART: Change From Baseline in CD4% to 144 Weeks From ART Initiation   [ Time Frame: Baseline, 144 weeks ]

5.  Primary:   Induction ART: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV   [ Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years) ]

6.  Primary:   Once Versus Twice Daily Abacavir+Lamivudine: Suppressed HIV RNA Viral Load 48 Weeks After Randomisation   [ Time Frame: 48 weeks ]

7.  Primary:   Once Versus Twice Daily Abacavir+Lamivudine: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV, Judged Definitely/Probably or Uncertain Whether Related to Lamivudine or Abacavir   [ Time Frame: Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years) ]

8.  Primary:   Cotrimoxazole: New Hospitalisation or Death   [ Time Frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) ]

9.  Primary:   Cotrimoxazole: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV   [ Time Frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) ]

10.  Secondary:   LCM vs CDM, Induction ART: All-cause Mortality   [ Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years) ]

11.  Secondary:   Induction ART: New WHO Stage 4 Event or Death   [ Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years) ]

12.  Secondary:   LCM vs CDM, Induction ART: New WHO Stage 3 or 4 Event or Death   [ Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years) ]

13.  Secondary:   LCM vs CDM, Induction ART: New or Recurrent WHO Stage 3 or 4 Event or Death   [ Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years) ]

14.  Secondary:   LCM vs CDM, Induction ART: Weight-for-age Z-score   [ Time Frame: Baseline and a median of 4 years (maximum 5 years) ]

15.  Secondary:   LCM vs CDM, Induction ART: Height-for-age Z-score   [ Time Frame: Baseline and a median of 4 years (maximum 5 years) ]

16.  Secondary:   LCM vs CDM, Induction ART: Body Mass Index-for-age Z-score   [ Time Frame: Baseline and a median of 4 years (maximum 5 years) ]

17.  Secondary:   LCM vs CDM: Change From Baseline in CD4% to Week 72   [ Time Frame: Baseline, week 72 ]

18.  Secondary:   LCM vs CDM: Change From Baseline in CD4% to Week 144   [ Time Frame: Baseline, week 144 ]

19.  Secondary:   LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 72   [ Time Frame: Baseline, week 72 ]

20.  Secondary:   LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 144   [ Time Frame: Baseline, week 144 ]

21.  Secondary:   CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 72 Weeks After Baseline   [ Time Frame: 72 weeks ]

22.  Secondary:   CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 144 Weeks After Baseline   [ Time Frame: 144 weeks ]

23.  Secondary:   LCM vs CDM, Induction ART: Cessation of First-line Regimen for Clinical/Immunological Failure   [ Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years) ]

24.  Secondary:   LCM vs CDM, Induction ART: New Grade 3 or 4 Adverse Event Definitely/Probably or Uncertainly Related to ART   [ Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years) ]

25.  Secondary:   LCM vs CDM, Induction ART: New Serious Adverse Events Not Solely Related to HIV   [ Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years) ]

26.  Secondary:   LCM vs CDM, Induction ART: New ART-modifying Adverse Event   [ Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years) ]

27.  Secondary:   LCM vs CDM, Induction ART: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks)   [ Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years) ]

28.  Secondary:   Once Versus Twice Daily Abacavir+Lamivudine: Suppression of HIV RNA Viral Load 96 Weeks After Randomisation   [ Time Frame: 96 weeks ]

29.  Secondary:   Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 48   [ Time Frame: Randomisation to once vs twice daily, week 48 ]

30.  Secondary:   Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 72   [ Time Frame: Baseline, week 72 ]

31.  Secondary:   Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 96   [ Time Frame: Randomisation to once vs twice daily, week 96 ]

32.  Secondary:   Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 48   [ Time Frame: Randomisation to once vs twice daily, week 48 ]

33.  Secondary:   Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 72   [ Time Frame: Baseline, week 72 ]

34.  Secondary:   Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 96   [ Time Frame: Randomisation to once vs twice daily, week 96 ]

35.  Secondary:   Once Versus Twice Daily Abacavir+Lamivudine: All-cause Mortality   [ Time Frame: Median 2 years (from randomization to 16 March 2012; maximum 2.6 years) ]

36.  Secondary:   Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 4 Event or Death   [ Time Frame: Median 2 years (from randomization to 16 March 2012; maximum 2.6 years) ]

37.  Secondary:   Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 3 or 4 Event or Death   [ Time Frame: Median 2 years (from randomization to 16 March 2012; maximum 2.6 years) ]

38.  Secondary:   Once Versus Twice Daily Abacavir+Lamivudine: Height-for-age Z-score   [ Time Frame: Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years) ]

39.  Secondary:   Once Versus Twice Daily Abacavir+Lamivudine: Weight-for-age Z-score   [ Time Frame: Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years) ]

40.  Secondary:   Once Versus Twice Daily Abacavir+Lamivudine: Body Mass Index-for-age Z-score   [ Time Frame: Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years) ]

41.  Secondary:   Once Versus Twice Daily Abacavir+Lamivudine: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV   [ Time Frame: Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years) ]

42.  Secondary:   Once Versus Twice Daily Abacavir+Lamivudine: New Serious Adverse Events Not Solely Related to HIV   [ Time Frame: Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years) ]

43.  Secondary:   Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) at 48 Weeks   [ Time Frame: 48 weeks after randomization to once- versus twice-daily ]

44.  Secondary:   Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) at 96 Weeks   [ Time Frame: 96 weeks after randomization to once- versus twice-daily ]

45.  Secondary:   Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks)   [ Time Frame: Mean over median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years) ]

46.  Secondary:   Cotrimoxazole: New Clinical and Diagnostic Positive Malaria   [ Time Frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) ]

47.  Secondary:   Cotrimoxazole: New Severe Pneumonia   [ Time Frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) ]

48.  Secondary:   Cotrimoxazole: New WHO Stage 3 or 4 Event or Death   [ Time Frame: Median 2 years (from randomization to 16 March 2012; maximum 2.5 years) ]

49.  Secondary:   Cotrimoxazole: New WHO Stage 3 Severe Recurrent Pneumonia or Diarrhoea   [ Time Frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) ]

50.  Secondary:   Cotrimoxazole: New WHO Stage 4 Event or Death   [ Time Frame: Median 2 years (from randomization to 16 March 2012; maximum 2.5 years) ]

51.  Secondary:   Cotrimoxazole: All-cause Mortality   [ Time Frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) ]

52.  Secondary:   Cotrimoxazole: Weight-for-age Z-score   [ Time Frame: Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) ]

53.  Secondary:   Cotrimoxazole: Height-for-age Z-score   [ Time Frame: Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) ]

54.  Secondary:   Cotrimoxazole: Body Mass Index-for-age Z-score   [ Time Frame: Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) ]

55.  Secondary:   Cotrimoxazole: Change From Baseline in CD4% to Week 72   [ Time Frame: Baseline, week 72 ]

56.  Secondary:   Cotrimoxazole: Change From Baseline in Absolute CD4 to Week 72   [ Time Frame: Baseline, week 72 ]

57.  Secondary:   Cotrimoxazole: New Serious Adverse Events Not Solely Related to HIV   [ Time Frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) ]

58.  Secondary:   Cotrimoxazole: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks)   [ Time Frame: Mean over median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.


Results Point of Contact:  
Name/Title: Professor Ann Sarah Walker
Organization: Medical Research Council
phone: +44 20 7670 4726
e-mail: rmjlasw@ucl.ac.uk


Publications of Results:

Responsible Party: Diana M Gibb, Medical Research Council
ClinicalTrials.gov Identifier: NCT02028676     History of Changes
Other Study ID Numbers: G0300400, 24791884, G0300400
Study First Received: December 31, 2013
Results First Received: January 15, 2014
Last Updated: June 4, 2014
Health Authority: Uganda: National Council for Science and Technology
Uganda: National Drug Authority
Zimbabwe: Medical Research Council