Human Immunodeficiency VirusPhase 4ARROWNCT02028676
Efficacy Study of Different Laboratory Management Strategies and Drug Regimens in HIV-infected Children in Africa
A Phase 4 study testing Clinically Driven Monitoring (CDM), Laboratory plus Clinical Monitoring (LCM) and Arm A: ABC+3TC+NNRTI in people with Human Immunodeficiency Virus, run by Medical Research Council at 4 sites in 2 countries.
Trial summary
The two original objectives were to determine in HIV-infected children initiating antiretroviral therapy (ART): 1. Whether clinically driven monitoring (CDM) will have a similar outcome in terms of disease progression or death as routine laboratory and clinical monitoring (LCM) for toxicity (haematology/biochemistry)… Read more about this study
- Who is it for?
- Ages 3 months to 17 years
- Conditions the study is for
- Human Immunodeficiency Virus
- What is being tested?
- Clinically Driven Monitoring (CDM), Laboratory plus Clinical Monitoring (LCM) and Arm A: ABC+3TC+NNRTI
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1,206 participants
- Where
- 4 sitesin 2 countries
- Study dates
- Mar 2007to Jun 2012
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 3 months to 17 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Children should have an adult carer in the household who is either:
- participating in the DART trial OR
- being treated with ART OR
- HIV positive but not yet needing treatment but with access to a treatment programme when ART is required OR
- HIV negative. Children of DART participants should have first priority on any available remaining slots to enter ARROW.
- Parents or guardians, and children where appropriate according to age and knowledge of HIV status, must be willing and able to give informed consent for randomisation to CDM or LCM and to first-line ART strategy.
Show all 21Show fewer
- Participants must have a confirmed documented diagnosis of HIV-1 infection:
- For children aged under 18 months: two separate peripheral blood specimens from different days, both results being positive with HIV-DNA polymerase chain reaction (PCR).
- For children aged 18 months or over: antibody positive serology by ELISA test (confirmed by licensed second ELISA or Western Blot) or WHO approved rapid test (performed in series) both on the same sample. Any child previously tested at another clinic should have a repeat test at an ARROW screening laboratory to confirm their status.
- Age 3 months to 17 years (13-17 years to be capped at 10%)
- ART naïve (except for exposure to perinatal ART for the prevention of mother-to-child HIV transmission).
- Meeting criteria for requiring ART according to WHO stage and CD4 percent or count:
- WHO paediatric clinical stage IV disease: treat regardless of CD4 percent or count
- WHO paediatric clinical stage III disease:
- <12 months: treat all
- >12 months: treat all children irrespective of the CD4 percent or count; however, in children aged > 12 months with tuberculosis, lymphocytic interstitial pneumonia (LIP), oral hairy leukoplakia (OHP) or thrombocytopenia (low platelet count treat) be guided by CD4 cell assays (see below).
- WHO paediatric clinical stage II or I disease: treat guided by CD4 percent or count
- CD4%<25% for infants <12 months;
- CD4%<20% for children 1-<3 years;
- CD4% <15% for children 3-<5years;
- CD4% <15% for children > 5years (consideration should also be taken of the CD4 count. A CD4 count <200 cells/mm3 can be used to guide starting ART and CD4 should generally be <350 cells/mm3.)
Who cannot join
- Cannot, or unlikely to attend regularly (e.g. usual residence too far from study centre)
- Likelihood of poor adherence
- Presence of acute infection (e.g. malaria, helminthiasis, acute hepatitis, acute pneumonia, septicaemia, meningitis). Children may be admitted after recovery of an acute infection. Children with chronic lung disease, including recurrent respiratory infections, are eligible. Children with tuberculosis (TB) will not be enrolled while on the intensive phase of anti-tuberculosis therapy, but should be re-evaluated after the intensive phase and a decision made then about starting ART (see 4 below)
- In receipt of medication contraindicated by ART
- children under three years of age receiving anti-tuberculosis therapy should not be enrolled (as they will have to receive nevirapine).
- on chemotherapy for malignancy
Show all 24Show fewer
- Laboratory abnormalities which are a contra-indication for the child to start ART (haemoglobin <8.5g/dL; neutrophils <0.50x109/L; aspartate transaminase (AST) or alanine transaminase (ALT) >5 x the upper limit of normal (ULN); grade 3 renal dysfunction - creatinine >1.9 x ULN).
- N.B. causes of anaemia, such as concurrent bacterial infection, malaria, helminthiasis and/or malnutrition should be investigated, and treatment for anaemia and its causes commenced prior to re-screening for eligibility.
- Being pregnant or breast-feeding an infant
- Perinatal exposure to nevirapine (either through prevention of mother-to-child transmission (pMTCT) or breastfeeding) for children aged 3 - 6 months only
- Eligibility criteria for the secondary randomisation to once vs twice daily lamivudine+abacavir Inclusion criteria
- Participating in ARROW
- On ART for at least 36 weeks
- Currently taking lamivudine+abacavir twice daily as part of their ART regimen and expected to stay on these two drugs for at least the next 12 weeks
- Parents or guardians, and children where appropriate according to age and knowledge of HIV status, must be willing and able to give informed consent for randomisation to once or twice daily lamivudine+abacavir
- Likely to switch to second-line therapy in the next 12 weeks
- Eligibility criteria for the secondary randomisation to stop or continue cotrimoxazole prophylaxis randomisation Inclusion criteria
- Participating in ARROW
- Aged at least 3 years
- Initiated ART at least 96 weeks previously, and received at least 96 weeks of ART allowing for any interruptions in ART
- Currently prescribed daily cotrimoxazole as primary prophylaxis
- Parents or guardians, and children where appropriate according to age and knowledge of HIV status, must be willing and able to give informed consent for randomisation to stop or continue daily cotrimoxazole prophylaxis
- If living in a malaria endemic area, has an insecticide treated bednet and prepared to use this for the child.
- Previous diagnosis of Pneumocystis jiroveci pneumonia (cotrimoxazole is secondary prophylaxis and should not be discontinued)
Trial locations and contacts
4 sites in 2 countries.
4 sites in 2 countries
Uganda3 sites
MRC /UVRI Uganda Research Unit on AIDS
Entebbe
Joint Clinical Research Centre
Kampala
Baylor College of Medicine Children's Foundation
Mulago
About this study
Official title: A Randomised Trial of Monitoring Practice and Induction Maintenance Drug Regimens in the Management of Antiretroviral Therapy in Children With HIV Infection in Africa
The two original objectives were to determine in HIV-infected children initiating antiretroviral therapy (ART):
- Whether clinically driven monitoring (CDM) will have a similar outcome in terms of disease progression or death as routine laboratory and clinical monitoring (LCM) for toxicity (haematology/biochemistry) and efficacy (CD4)?
- Whether induction with four drugs from two ART classes followed by maintenance with three drugs after 36 weeks be more effective than a continuous non-nucleoside reverse transcriptase inhibitors (NNRTI)-based triple drug regimen in terms of CD4 and clinical outcome? Two secondary objectives were to determine
- Whether changing from twice daily lamivudine+abacavir to once daily lamivudine+abacavir after 48 weeks on ART will have a similar outcome in terms of virological suppression and will result in improvements in adherence to ART?
- Whether stopping daily cotrimoxazole prophylaxis in children over 3 years of age who have been on ART for at least 96 weeks has a similar outcome in terms of hospitalisation or death as continuing daily cotrimoxazole?
Read the detailed description
The ARROW (AntiRetroviral Research fOr Watoto) protocol describes an open-label randomised trial primarily evaluating two strategic approaches for management of antiretroviral therapy (ART) in 1200 symptomatic HIV-infected infants and children initiating ART following WHO guidelines in Uganda and Zimbabwe. The first strategy compares clinically driven monitoring (CDM) with laboratory plus clinical monitoring (LCM). In both groups, tests for toxicity (standard haematology and biochemistry panels) and efficacy (lymphocyte subsets including CD4 count) will be done every 12 weeks. In LCM, all results will be returned for patient management. In CDM, physicians may request results from routine haematology/biochemistry panels if needed for clinical management, but results will not be returned routinely, and lymphocyte subsets will never be returned. Extra laboratory tests may be requested outside of the scheduled visits at any time in either group (except for lymphocyte subsets in CDM). The second strategy compares a continuous WHO-recommended first-line ART three-drug two-class regimen, comprising two Nucleoside Reverse Transcriptase Inhibitors (NRTIs) plus one Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), with induction with four drugs (two classes) for 36 weeks followed by maintenance with three drugs. After at least 36 and 96 weeks on ART respectively, two further randomisations will assess simplification strategies which could improve long-term ART adherence (i) once versus twice daily lamivudine+abacavir NRTI drugs (ii) stopping versus continuing daily cotrimoxazole prophylaxis.
- Conditions
- Human Immunodeficiency Virus
- Being tested
- Clinically Driven Monitoring (CDM), Laboratory plus Clinical Monitoring (LCM), Arm A: ABC+3TC+NNRTI, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC maintenance
- Keywords
- HIV, Africa, children, antiretroviral therapy, laboratory monitoring, toxicity, CD4, induction maintenance, cotrimoxazole, prophylaxis, abacavir, lamivudine, once daily
- Medical subject headings
- Acquired Immunodeficiency Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Clinically Driven Monitoring (CDM)Other
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 at and after randomisation 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)Other
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: ABC+3TC+NNRTIDrug
Also called ABC: abacavir: Ziagen, 3TC: lamivudine: Epivir, ABC+3TC co-formulated: Kivexa, NVP: nevirapine, Viramune
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 maintenanceDrug
Also called ZDV: zidovudine, azidothymidine, Retrovir, ABC: abacavir: Ziagen, 3TC: lamivudine: Epivir, ZDV+3TC co-formulated: Combivir
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 maintenanceDrug
Also called ZDV: zidovudine, azidothymidine, Retrovir, ABC: abacavir: Ziagen, 3TC: lamivudine: Epivir, ZDV+3TC co-formulated: Combivir
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+3TCDrug
Also called ABC: abacavir: Ziagen, 3TC: lamivudine: Epivir, ABC+3TC co-formulated: Kivexa
Twice-daily ABC+3TCDrug
Also called ABC: abacavir: Ziagen, 3TC: lamivudine: Epivir, ABC+3TC co-formulated: Kivexa
Continued cotrimoxazole prophylaxisDrug
Also called trimethoprim+sulfamethoxazole
Stopped cotrimoxazole prophylaxisOther
| Study group | Role | What they receive |
|---|---|---|
| Clinically Driven Monitoring (CDM) | Experimental | Not described Receives: Other: Clinically Driven Monitoring (CDM) |
| Laboratory plus Clinical Monitoring (LCM) | Active comparator | Not described Receives: Other: Laboratory plus Clinical Monitoring (LCM) |
| Arm A: abacavir (ABC)+lamivudine (3TC)+NNRTI | Active comparator | 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. Receives: Drug: Arm A: ABC+3TC+NNRTI |
| Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenance | Experimental | 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. Receives: Drug: Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenance |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC maintenance | Experimental | 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. Receives: Drug: Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC maintenance |
| Once-daily ABC+3TC | Experimental | 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 Receives: Drug: Once-daily ABC+3TC |
| Twice-daily ABC+3TC | Active comparator | 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 Receives: Drug: Twice-daily ABC+3TC |
| Continued cotrimoxazole prophylaxis | Active comparator | 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 Receives: Drug: Continued cotrimoxazole prophylaxis |
| Stopped cotrimoxazole prophylaxis | Experimental | Children had been taking once-daily cotrimoxazole prophylaxis since at least ART initiation. Children randomised to this experimental arm stopped taking cotrimoxazole prophylaxis. Receives: Other: Stopped cotrimoxazole prophylaxis |
What is being measured
The primary outcome is the main question the study is designed to answer.
LCM vs CDM: Disease Progression to a New WHO Stage 4 Event or Death
Number of participants with disease progression to a new WHO stage 4 event or death, to be analysed using time-to-event methods
Measured: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
LCM vs CDM: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV
Number of participants with a new Grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods
Measured: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
Induction ART: Change From Baseline in CD4% 72 Weeks After ART Initiation
Measured: Baseline, 72 weeks
Induction ART: Change From Baseline in CD4% to 144 Weeks From ART Initiation
Measured: Baseline, 144 weeks
Induction ART: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV
Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods
Measured: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
Once Versus Twice Daily Abacavir+Lamivudine: Suppressed HIV RNA Viral Load 48 Weeks After Randomisation
Number of participants with HIV RNA viral load <80 copies/ml at 48 weeks. Measured retrospectively on stored plasma specimens: due to low stored volumes from some children, samples had to be diluted and therefore a threshold of <80 copies/ml was used to indicate suppression.
Measured: 48 weeks
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
Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, judged definitely/probably or uncertain whether related to lamivudine or abacavir, to be analysed using time-to-event methods
Measured: Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
Cotrimoxazole: New Hospitalisation or Death
Number of participants with a new hospitalisation or death, to be analysed using time-to-event methods
Measured: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
Cotrimoxazole: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV
Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods
Measured: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
Secondary outcomes (49)
LCM vs CDM, Induction ART: All-cause Mortality
Number of participants who died from any cause, to be analysed using time-to-event methods
Measured: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
Induction ART: New WHO Stage 4 Event or Death
Number of participants with a new WHO stage 4 event or death, to be analysed using time-to-event methods
Measured: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
LCM vs CDM, Induction ART: New WHO Stage 3 or 4 Event or Death
Number of participants with a new WHO stage 3 or 4 event or death, to be analysed using time-to-event methods
Measured: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
LCM vs CDM, Induction ART: New or Recurrent WHO Stage 3 or 4 Event or Death
Number of participants with a new or recurrent WHO stage 3 or 4 event or death, to be analysed using time-to-event methods
Measured: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
LCM vs CDM, Induction ART: Weight-for-age Z-score
Age-adjusted change in weight-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Measured: Baseline and a median of 4 years (maximum 5 years)
LCM vs CDM, Induction ART: Height-for-age Z-score
Age-adjusted change in weight-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Measured: Baseline and a median of 4 years (maximum 5 years)
LCM vs CDM, Induction ART: Body Mass Index-for-age Z-score
Age-adjusted change in body mass index-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Measured: Baseline and a median of 4 years (maximum 5 years)
LCM vs CDM: Change From Baseline in CD4% to Week 72
Measured: Baseline, week 72
LCM vs CDM: Change From Baseline in CD4% to Week 144
Measured: Baseline, week 144
LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 72
Estimated in those >5 years at enrolment, in whom absolute CD4 is meaningful. (In uninfected children, CD4 decreases with age during early childhood.)
Measured: Baseline, week 72
LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 144
Estimated in those >5 years at enrolment, in whom absolute CD4 is meaningful. (In uninfected children, CD4 decreases with age during early childhood.)
Measured: Baseline, week 144
CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 72 Weeks After Baseline
Number of participants with HIV RNA viral load <80 copies/ml 72 weeks after baseline. Threshold for suppression <80 copies/ml as samples had to be diluted due to low volumes.
Measured: 72 weeks
CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 144 Weeks After Baseline
Number of participants with HIV RNA viral load <80 copies/ml 144 weeks after baseline. Threshold for suppression <80 copies/ml as samples had to be diluted due to low volumes.
Measured: 144 weeks
LCM vs CDM, Induction ART: Cessation of First-line Regimen for Clinical/Immunological Failure
Number of participants stopping their first-line regimen for clinical/immunological failure, to be analysed using time-to-event methods
Measured: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
LCM vs CDM, Induction ART: New Grade 3 or 4 Adverse Event Definitely/Probably or Uncertainly Related to ART
Number of participants with a new grade 3 or 4 adverse event definitely/probably or uncertainly related to ART, to be analysed using time-to-event methods
Measured: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
LCM vs CDM, Induction ART: New Serious Adverse Events Not Solely Related to HIV
Number of participants with a new serious adverse events not solely related to HIV, to be analysed using time-to-event methods
Measured: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
LCM vs CDM, Induction ART: New ART-modifying Adverse Event
Number of participants with a new ART-modifying adverse event, to be analysed using time-to-event methods
Measured: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
LCM vs CDM, Induction ART: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks)
Binary outcome measure: missed any doses of ART in the last 4 weeks by self-report. Mean calculated across all 12-weekly visits attended over the whole follow-up (no specific timepoint prespecified), giving the percentage of visits attended where the carer/participant reported missing any pills in the last 4 weeks.
Measured: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
Once Versus Twice Daily Abacavir+Lamivudine: Suppression of HIV RNA Viral Load 96 Weeks After Randomisation
Number of participants with HIV RNA viral load <80 copies/ml at 96 weeks. Threshold for suppression <80 copies/ml as samples had to be diluted due to low volumes.
Measured: 96 weeks
Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 48
Measured: Randomisation to once vs twice daily, week 48
Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 72
Measured: Baseline, week 72
Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 96
Measured: Randomisation to once vs twice daily, week 96
Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 48
Estimated in those >5 years at enrolment, in whom absolute CD4 is meaningful. (In uninfected children, CD4 decreases with age during early childhood.)
Measured: Randomisation to once vs twice daily, week 48
Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 72
All participants aged >5 years at randomization to once versus twice daily alive in follow-up with CD4 measured
Measured: Baseline, week 72
Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 96
All participants aged >5 years at randomization to once versus twice daily alive in follow-up with CD4 measured
Measured: Randomisation to once vs twice daily, week 96
Once Versus Twice Daily Abacavir+Lamivudine: All-cause Mortality
Number of participants who died, to be analysed using time-to-event methods
Measured: Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)
Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 4 Event or Death
Number of participants with a new WHO stage 4 event or death, to be analysed using time-to-event methods
Measured: Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)
Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 3 or 4 Event or Death
Number of participants with a new WHO stage 3 or 4 event or death, to be analysed using time-to-event methods
Measured: Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)
Once Versus Twice Daily Abacavir+Lamivudine: Height-for-age Z-score
Age-adjusted change in height-for-age Z-score over all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Measured: Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
Once Versus Twice Daily Abacavir+Lamivudine: Weight-for-age Z-score
Age-adjusted change in weight-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Measured: Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
Once Versus Twice Daily Abacavir+Lamivudine: Body Mass Index-for-age Z-score
Age-adjusted change in body mass index-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Measured: Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
Once Versus Twice Daily Abacavir+Lamivudine: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV
Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods
Measured: Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
Once Versus Twice Daily Abacavir+Lamivudine: New Serious Adverse Events Not Solely Related to HIV
Number of participants with a new serious adverse event not solely related to HIV, to be analysed using time-to-event methods
Measured: Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
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
Number of participants reporting missing any doses of ART in the last 4 weeks by self-report at 48 weeks.
Measured: 48 weeks after randomization to once- versus twice-daily
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
Number of participants reporting missing any doses of ART in the last 4 weeks by self-report at 96 weeks.
Measured: 96 weeks after randomization to once- versus twice-daily
Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks)
Binary outcome measure: missed any doses of ART in the last 4 weeks by self-report. Mean calculated across all 12-weekly visits attended over the whole follow-up (no specific timepoint prespecified), giving the percentage of visits attended where the carer/participant reported missing any pills in the last 4 weeks.
Measured: Mean over median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
Cotrimoxazole: New Clinical and Diagnostic Positive Malaria
Number of participants with a new clinical and diagnostic positive malaria, to be analysed using time-to-event methods. Diagnostic positive by either microscopy (thick film) or rapid diagnostic test (RDT)
Measured: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
Cotrimoxazole: New Severe Pneumonia
Number of participants with a new severe pneumonia, to be analysed using time-to-event methods
Measured: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
Cotrimoxazole: New WHO Stage 3 or 4 Event or Death
Number of participants with a new WHO stage 3 or 4 event or death, to be analysed using time-to-event methods
Measured: Median 2 years (from randomization to 16 March 2012; maximum 2.5 years)
Cotrimoxazole: New WHO Stage 3 Severe Recurrent Pneumonia or Diarrhoea
Number of participants with a new WHO stage 3 severe recurrent pneumonia or diarrhoea, to be analysed using time-to-event methods
Measured: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
Cotrimoxazole: New WHO Stage 4 Event or Death
Number of participants with a new WHO stage 4 event or death, to be analysed using time-to-event methods
Measured: Median 2 years (from randomization to 16 March 2012; maximum 2.5 years)
Cotrimoxazole: All-cause Mortality
Number of participants who died, to be analysed using time-to-event methods
Measured: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
Cotrimoxazole: Weight-for-age Z-score
Age-adjusted change in weight-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Measured: Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
Cotrimoxazole: Height-for-age Z-score
Age-adjusted change in height-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Measured: Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
Cotrimoxazole: Body Mass Index-for-age Z-score
Age-adjusted change in body mass index-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Measured: Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
Cotrimoxazole: Change From Baseline in CD4% to Week 72
Measured: Baseline, week 72
Cotrimoxazole: Change From Baseline in Absolute CD4 to Week 72
Estimated in those >5 years at randomization to stop vs continue, in whom absolute CD4 is meaningful. (In uninfected children, CD4 decreases with age during early childhood.)
Measured: Baseline, week 72
Cotrimoxazole: New Serious Adverse Events Not Solely Related to HIV
Number of participants with a new serious adverse event not solely related to HIV, to be analysed using time-to-event methods
Measured: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
Cotrimoxazole: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks)
Binary outcome measure: missed any doses of ART in the last 4 weeks by self-report. Mean calculated across all 12-weekly visits attended over the whole follow-up (no specific timepoint prespecified), giving the percentage of visits attended where the carer/participant reported missing any pills in the last 4 weeks.
Measured: Mean over median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Jan 2014 (estimated)
- Study startMar 2007
- Primary completionMar 2012
- Study completionJun 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Human Immunodeficiency VirusStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Enrolment
- 1,206 participants (actual)
Sponsor and investigators
- Lead sponsor
- Medical Research Council
- Sponsor type
- Other government
- Collaborators
- Department for International Development, United Kingdom, ViiV Healthcare, GlaxoSmithKline
- Responsible party
- Principal investigator, Diana M Gibb, Medical Research Council
- Investigators
- Diana M Gibb, MD, Principal investigator, Medical Research CouncilPeter Mugyenyi, PhD, Principal investigator, Joint Clinical Research Centre, Kampala, UgandaKusum Nathoo, PhD, Principal investigator, University of Zimbabwe, Harare, ZimbabweAdeodata Kekitiinwa, MD, Principal investigator, Baylor College of Medicine Children's Foundation, Mulago, UgandaPaula Munderi, MBChB, Principal investigator, MRC /UVRI Uganda Research Unit on AIDS, Entebbe, UgandaVictor Musiime, PhD, Principal investigator, Joint Clinical Research Centre, Kampala, UgandaMutsa F Bwakura-Dangarembizi, MBChB, Principal investigator, University of Zimbabwe, Harare, ZimbabwePhilippa Musoke, PhD, Principal investigator, Baylor College of Medicine Children's Foundation, Mulago, Uganda
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02028676
- Sponsor's protocol ID
- G0300400
- Other IDs
- 24791884, G0300400
- Acronym
- ARROW
- Status last verified
- Jun 2014
- First submitted
- 31 Dec 2013
- Last updated
- 6 Jun 2014
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
ARROW Trial team. Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in African children with HIV (ARROW): a 5-year open-label randomised factorial trial. Lancet. 2013 Apr 20;381(9875):1391-1403. doi: 10.1016/S0140-6736(12)62198-9. Epub 2013 Mar 7.
PubMed 23473847Bwakura-Dangarembizi M, Kendall L, Bakeera-Kitaka S, Nahirya-Ntege P, Keishanyu R, Nathoo K, Spyer MJ, Kekitiinwa A, Lutaakome J, Mhute T, Kasirye P, Munderi P, Musiime V, Gibb DM, Walker AS, Prendergast AJ. A randomized trial of prolonged co-trimoxazole in HIV-infected children in Africa. N Engl J Med. 2014 Jan 2;370(1):41-53. doi: 10.1056/NEJMoa1214901.
PubMed 24382064Musiime V, Kasirye P, Naidoo-James B, Nahirya-Ntege P, Mhute T, Cook A, Mugarura L, Munjoma M, Thoofer NK, Ndashimye E, Nankya I, Spyer MJ, Thomason MJ, Snowden W, Gibb DM, Walker AS; ARROW Trial Team. Once vs twice-daily abacavir and lamivudine in African children. AIDS. 2016 Jul 17;30(11):1761-70. doi: 10.1097/QAD.0000000000001116.
PubMed 27064996
Study at a glance
From the registry record, last updated by the sponsor on 6 Jun 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomised Trial of Monitoring Practice and Induction Maintenance Drug Regimens in the Management of Antiretroviral Therapy in Children With HIV Infection in Africa
- ClinicalTrials.gov ID
- NCT02028676
- Acronym / sponsor ID
- ARROW / G0300400
- Conditions
- Human Immunodeficiency Virus
- Keywords
- HIV, Africa, children, antiretroviral therapy, laboratory monitoring, toxicity, CD4, induction maintenance
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1,206 participants (actual)
- Lead sponsor
- Medical Research CouncilOther government
- Collaborators
- Department for International Development, United Kingdom, ViiV Healthcare, GlaxoSmithKline
- Study start
- Mar 2007
- Primary completion
- Mar 2012 (actual)
- Study completion
- Jun 2012 (actual)
- First posted
- 7 Jan 2014 (estimated)
- Results
- Posted 6 Jun 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The two original objectives were to determine in HIV-infected children initiating antiretroviral therapy (ART):
- Whether clinically driven monitoring (CDM) will have a similar outcome in terms of disease progression or death as routine laboratory and clinical monitoring (LCM) for toxicity (haematology/biochemistry) and efficacy (CD4)?
- Whether induction with four drugs from two ART classes followed by maintenance with three drugs after 36 weeks be more effective than a continuous non-nucleoside reverse transcriptase inhibitors (NNRTI)-based triple drug regimen in terms of CD4 and clinical outcome? Two secondary objectives were to determine
- Whether changing from twice daily lamivudine+abacavir to once daily lamivudine+abacavir after 48 weeks on ART will have a similar outcome in terms of virological suppression and will result in improvements in adherence to ART?
- Whether stopping daily cotrimoxazole prophylaxis in children over 3 years of age who have been on ART for at least 96 weeks has a similar outcome in terms of hospitalisation or death as continuing daily cotrimoxazole?
Detailed description
The ARROW (AntiRetroviral Research fOr Watoto) protocol describes an open-label randomised trial primarily evaluating two strategic approaches for management of antiretroviral therapy (ART) in 1200 symptomatic HIV-infected infants and children initiating ART following WHO guidelines in Uganda and Zimbabwe. The first strategy compares clinically driven monitoring (CDM) with laboratory plus clinical monitoring (LCM). In both groups, tests for toxicity (standard haematology and biochemistry panels) and efficacy (lymphocyte subsets including CD4 count) will be done every 12 weeks. In LCM, all results will be returned for patient management. In CDM, physicians may request results from routine haematology/biochemistry panels if needed for clinical management, but results will not be returned routinely, and lymphocyte subsets will never be returned. Extra laboratory tests may be requested outside of the scheduled visits at any time in either group (except for lymphocyte subsets in CDM). The second strategy compares a continuous WHO-recommended first-line ART three-drug two-class regimen, comprising two Nucleoside Reverse Transcriptase Inhibitors (NRTIs) plus one Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), with induction with four drugs (two classes) for 36 weeks followed by maintenance with three drugs. After at least 36 and 96 weeks on ART respectively, two further randomisations will assess simplification strategies which could improve long-term ART adherence (i) once versus twice daily lamivudine+abacavir NRTI drugs (ii) stopping versus continuing daily cotrimoxazole prophylaxis.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Number of arms
- 9
| Arm | Type | Receives |
|---|---|---|
| Clinically Driven Monitoring (CDM) | Experimental | Other: Clinically Driven Monitoring (CDM) |
| Laboratory plus Clinical Monitoring (LCM) | Active comparator | Other: Laboratory plus Clinical Monitoring (LCM) |
| Arm A: abacavir (ABC)+lamivudine (3TC)+NNRTI | Active comparator | Drug: Arm A: ABC+3TC+NNRTIABC [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 B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenance | Experimental | Drug: Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenanceZDV [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 | Experimental | Drug: Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC maintenanceZDV [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. |
| Once-daily ABC+3TC | Experimental | Drug: Once-daily ABC+3TCABC [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 |
| Twice-daily ABC+3TC | Active comparator | Drug: Twice-daily ABC+3TCABC [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 |
| Continued cotrimoxazole prophylaxis | Active comparator | Drug: Continued cotrimoxazole prophylaxisOnce-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 |
| Stopped cotrimoxazole prophylaxis | Experimental | Other: Stopped cotrimoxazole prophylaxisChildren had been taking once-daily cotrimoxazole prophylaxis since at least ART initiation. Children randomised to this experimental arm stopped taking cotrimoxazole prophylaxis. |
Who may qualify
- Ages
- 3 months to 17 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (21 listed)
- Children should have an adult carer in the household who is either:
- Parents or guardians, and children where appropriate according to age and knowledge of HIV status, must be willing and able to give informed consent for randomisation to CDM or LCM and to first-line ART strategy.
- Participants must have a confirmed documented diagnosis of HIV-1 infection:
- Age 3 months to 17 years (13-17 years to be capped at 10%)
- ART naïve (except for exposure to perinatal ART for the prevention of mother-to-child HIV transmission).
Key exclusion criteria (24 listed)
- Cannot, or unlikely to attend regularly (e.g. usual residence too far from study centre)
- Likelihood of poor adherence
- Presence of acute infection (e.g. malaria, helminthiasis, acute hepatitis, acute pneumonia, septicaemia, meningitis). Children may be admitted after recovery of an acute infection. Children with chronic lung disease, including recurrent respiratory infections, are eligible. Children with tuberculosis (TB) will not be enrolled while on the intensive phase of anti-tuberculosis therapy, but should be re-evaluated after the intensive phase and a decision made then about starting ART (see 4 below)
- In receipt of medication contraindicated by ART
- Laboratory abnormalities which are a contra-indication for the child to start ART (haemoglobin <8.5g/dL; neutrophils <0.50x109/L; aspartate transaminase (AST) or alanine transaminase (ALT) >5 x the upper limit of normal (ULN); grade 3 renal dysfunction - creatinine >1.9 x ULN).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 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 at and after randomisation 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. | Other | Clinically Driven Monitoring (CDM) |
| 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. | Other | Laboratory plus Clinical Monitoring (LCM) |
| Arm A: ABC+3TC+NNRTIAlso: ABC: abacavir: Ziagen, 3TC: lamivudine: Epivir, ABC+3TC co-formulated: Kivexa, NVP: nevirapine, ViramuneChildren 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. | Drug | Arm A: abacavir (ABC)+lamivudine (3TC)+NNRTI |
| Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenanceAlso: ZDV: zidovudine, azidothymidine, Retrovir, ABC: abacavir: Ziagen, 3TC: lamivudine: Epivir, ZDV+3TC co-formulated: CombivirChildren 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. | Drug | Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenance |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC maintenanceAlso: ZDV: zidovudine, azidothymidine, Retrovir, ABC: abacavir: Ziagen, 3TC: lamivudine: Epivir, ZDV+3TC co-formulated: CombivirChildren 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. | Drug | Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC maintenance |
| Once-daily ABC+3TCAlso: ABC: abacavir: Ziagen, 3TC: lamivudine: Epivir, ABC+3TC co-formulated: Kivexa | Drug | Once-daily ABC+3TC |
| Twice-daily ABC+3TCAlso: ABC: abacavir: Ziagen, 3TC: lamivudine: Epivir, ABC+3TC co-formulated: Kivexa | Drug | Twice-daily ABC+3TC |
| Continued cotrimoxazole prophylaxisAlso: trimethoprim+sulfamethoxazole | Drug | Continued cotrimoxazole prophylaxis |
| Stopped cotrimoxazole prophylaxis | Other | Stopped cotrimoxazole prophylaxis |
Primary outcome
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)
Number of participants with disease progression to a new WHO stage 4 event or death, to be analysed using time-to-event methods
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)
Number of participants with a new Grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods
Induction ART: Change From Baseline in CD4% 72 Weeks After ART Initiation
Time frame: Baseline, 72 weeks
Induction ART: Change From Baseline in CD4% to 144 Weeks From ART Initiation
Time frame: Baseline, 144 weeks
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)
Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods
Once Versus Twice Daily Abacavir+Lamivudine: Suppressed HIV RNA Viral Load 48 Weeks After Randomisation
Time frame: 48 weeks
Number of participants with HIV RNA viral load <80 copies/ml at 48 weeks. Measured retrospectively on stored plasma specimens: due to low stored volumes from some children, samples had to be diluted and therefore a threshold of <80 copies/ml was used to indicate suppression.
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)
Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, judged definitely/probably or uncertain whether related to lamivudine or abacavir, to be analysed using time-to-event methods
Cotrimoxazole: New Hospitalisation or Death
Time frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
Number of participants with a new hospitalisation or death, to be analysed using time-to-event methods
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)
Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods
49 secondary outcomes
LCM vs CDM, Induction ART: All-cause Mortality
Time frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
Induction ART: New WHO Stage 4 Event or Death
Time frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
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)
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)
LCM vs CDM, Induction ART: Weight-for-age Z-score
Time frame: Baseline and a median of 4 years (maximum 5 years)
LCM vs CDM, Induction ART: Height-for-age Z-score
Time frame: Baseline and a median of 4 years (maximum 5 years)
LCM vs CDM, Induction ART: Body Mass Index-for-age Z-score
Time frame: Baseline and a median of 4 years (maximum 5 years)
LCM vs CDM: Change From Baseline in CD4% to Week 72
Time frame: Baseline, week 72
LCM vs CDM: Change From Baseline in CD4% to Week 144
Time frame: Baseline, week 144
LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 72
Time frame: Baseline, week 72
LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 144
Time frame: Baseline, week 144
CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 72 Weeks After Baseline
Time frame: 72 weeks
CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 144 Weeks After Baseline
Time frame: 144 weeks
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)
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)
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)
LCM vs CDM, Induction ART: New ART-modifying Adverse Event
Time frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
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)
Once Versus Twice Daily Abacavir+Lamivudine: Suppression of HIV RNA Viral Load 96 Weeks After Randomisation
Time frame: 96 weeks
Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 48
Time frame: Randomisation to once vs twice daily, week 48
Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 72
Time frame: Baseline, week 72
Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 96
Time frame: Randomisation to once vs twice daily, week 96
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
Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 72
Time frame: Baseline, week 72
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
Once Versus Twice Daily Abacavir+Lamivudine: All-cause Mortality
Time frame: Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)
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)
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)
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)
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)
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)
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)
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)
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
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
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)
Cotrimoxazole: New Clinical and Diagnostic Positive Malaria
Time frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
Cotrimoxazole: New Severe Pneumonia
Time frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
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)
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)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Jun 2014.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 23473847ARROW Trial team. Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in African children with HIV (ARROW): a 5-year open-label randomised factorial trial. Lancet. 2013 Apr 20;381(9875):1391-1403. doi: 10.1016/S0140-6736(12)62198-9. Epub 2013 Mar 7.
- Results publication: PubMed 24382064Bwakura-Dangarembizi M, Kendall L, Bakeera-Kitaka S, Nahirya-Ntege P, Keishanyu R, Nathoo K, Spyer MJ, Kekitiinwa A, Lutaakome J, Mhute T, Kasirye P, Munderi P, Musiime V, Gibb DM, Walker AS, Prendergast AJ. A randomized trial of prolonged co-trimoxazole in HIV-infected children in Africa. N Engl J Med. 2014 Jan 2;370(1):41-53. doi: 10.1056/NEJMoa1214901.
- Derived from this study: PubMed 27064996Musiime V, Kasirye P, Naidoo-James B, Nahirya-Ntege P, Mhute T, Cook A, Mugarura L, Munjoma M, Thoofer NK, Ndashimye E, Nankya I, Spyer MJ, Thomason MJ, Snowden W, Gibb DM, Walker AS; ARROW Trial Team. Once vs twice-daily abacavir and lamivudine in African children. AIDS. 2016 Jul 17;30(11):1761-70. doi: 10.1097/QAD.0000000000001116.
- main ARROW trial webpageLink provided by the sponsor.
Related trials for Human Immunodeficiency Virus
Not yet recruiting
HealthMpowerment Korea: Pilot Testing the Cultural Adaptation of a Digital HIV Intervention for Men Who Have Sex With Men in South Korea
HIV Infections, HIV Prevention and Care
Not yet recruiting
Prescribe to Prevent HIV: A Hybrid Trial Helping Addiction Clinics Prevent HIV & Infections Through Safer Drug Use Support
People Who Use Opioids/People With Opioid Use Disorder (OUD)
Recruiting
Evaluating the Impact of Using the B-OK Bottles for HIV and ART Literacy in South Africa
HIV, HIV Treatment
Recruiting
Trial Phase: Syndemic Adapted Medly Uganda
Mental Health
RecruitingObservational study
Olfactory Function and Model-Based Behavior in People Living With HIV and SUD
HIV, Substance Use Disorder
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Diana M Gibb, MD principal investigator
Medical Research Council
Peter Mugyenyi, PhD principal investigator
Joint Clinical Research Centre, Kampala, Uganda
Kusum Nathoo, PhD principal investigator
University of Zimbabwe, Harare, Zimbabwe
4 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Clinically Driven Monitoring (CDM), Laboratory plus Clinical Monitoring (LCM) and Arm A: ABC+3TC+NNRTI in people with Human Immunodeficiency Virus, run by Medical Research Council at 4 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 21 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Jun 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in Uganda, Zimbabwe. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 6 Jun 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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)). The study lists 9 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02028676, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Jun 2014.