Reduction of Early mortaLITY in HIV-infected African adults and children starting antiretroviral therapy: REALITY trial

Lead Research Organisation: MRC Clinical Trials Unit

Abstract

The risk of dying AFTER starting treatment with antiretrovirals(ARVs) is about 7 times higher among HIV-infected adults and children in Africa than in developed countries, particularly if immunity is poor (low CD4 cell counts), because such people often harbour infections like tuberculosis and bacterial infections which show themselves when ARVs are started and immunity improves. The question about how to reduce high early death rates when people start ARVs has been identified by doctors and the African HIV community as being very important. In the REALITY trial, we will test 3 different ways to reduce high early death rates in 1200 adults and 600 children aged 5-12 years starting ARVs with CD4 cell counts less than 100 from 4 African countries (Uganda, Kenya, Zimbabwe, Malawi). Each approach will be compared with a standard approach (like doing 3 trials in one) and we will also be able to see if all approaches can provide additional benefits if used together in a package. The questions are whether any of the following reduce the risk of early death after starting ARVs:(1)using stronger ARVs(4 instead of 3 ARVs)for the first 3 months;(2)giving preventative treatment(prophylaxis)against life-threatening infections (e.g.tuberculosis, bacterial infections, cryptococcal meningitis) for 3 months after starting ARVs; (3) giving extra food to everyone (not just those with malnutrition) for 3 months; this might also help people take their ARVs as we know many get very hungry after starting ARVs. Adults and children over 5 years will be invited to join REALITY, and if they consent, at the time of starting ARVs, they will be given either the new approach or standard of care for each of the 3 questions. This will be done at random, like tossing a coin, but by a computer. All participants will be followed for at least one year to see how well they do, as well as to find out how acceptable these extra approaches are and whether there are any side effects. We will also measure whether these new approaches are cost effective to be rolled out in Africa. Adults and children are treated together in ARV clinics across Africa and have similar HIV progression and early death rates on ARVs: including adults and children aged over 5 years in the same integrated research study will provide the most relevant answers to improve the care of future patients.

Technical Summary

REALITY is an open-label randomised trial of 1800 adults, adolescents and children (600 aged 5-12 years) with low CD4 counts (!U100 cells/mm3) initiating antiretroviral therapy(ART), to be enrolled over 18 months and followed for 48 weeks in centres in 4 African countries (Uganda, Kenya, Zimbabwe, Malawi). The trial will simultaneously evaluate three potential interventions to reduce early mortality following ART initiation using a 2X2X2 factorial design: (i) increasing ART potency with 12-weeks induction using 4 antiretroviral drugs from 3 classes; (ii) augmented early prophylaxis against opportunistic and bacterial infections and helminths (5 days azithromycin, plus fluconazole, antihelminthic and isoniazid prophylaxis at ART initiation in addition to cotrimoxazole (for all); (iii) macronutrient intervention using ready-to-use food for 12 weeks to all (rather than only to those with malnutrition). Randomisation will be open for logistical reasons and because a key objective is to identify the acceptability of enhanced interventions around ART initiation which would not be possible using placebo pills. Use of an objective endpoint (mortality) will minimise potential bias. A major reason for including all three approaches in the same trial is efficiency: each targets a different mechanism and therefore running one large trial addressing all three questions rather than three large trials separately is more efficient. Furthermore, by using a factorial design in a large trial, interactions between interventions can be identified and the relative contribution of each explored; this has been allowed for in the sample size calculations. The design is pragmatic, aiming to recruit those as typical as possible of future late presenting patients, and treat them with practical interventions which could be implemented in ART rollout programs in Africa. Inclusion criteria are therefore broad, and prophylaxis and nutritional control groups are based on standard of care in national guidelines. We justify inclusion of children !Y5 years because the criteria for starting ART and risk factors for progression are the same as for young adults (in contrast to younger children) and early mortality following ART initiation and spectrum of causes of death overlap considerably (data from joint analysis of DART and ARROW trials); toxicity and tolerability can be addressed with inclusion of 600 children. The inclusion of children also adds to the efficiency and value for money of the trial as well as promoting family-based approaches to care and treatment. Key further areas will include economics and social science, as well as separately funded pharmacokinetic and diagnostic substudies.

Publications

10 25 50
 
Description Clinical Care Options use REALITY figures in CME educational activity
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
 
Guideline Title Guidelines for the diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children: Supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection
Description WHO Cryptococcal disease guidelines 2018 cite REALITY
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
URL http://apps.who.int/iris/bitstream/10665/260399/1/9789241550277-eng.pdf
 
Description Reduction of Early mortaLITY in HIV-infected African adults and children starting antiretroviral therapy: REALITY trial
Amount £3,986,746 (GBP)
Funding ID MC_EX_G1100693 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2012 
End 03/2018
 
Title Development of Open Clinica for multisite trial 
Description Open Clinica an open source database software that was specifically adapted for use in this trial by our programmer/data manager 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact Wider appreciation that open source software can be used as a platform for GCP trial and is compliant with FDA standards 
URL http://www.ncbi.nlm.nih.gov/pubmed/21453454
 
Title Pragmatic Deferred Consent Proceedure for research in emergency medicine 
Description FEAST is the largest Phase III paediatric fluid resuscitation trial ever undertaken. To ensure an ethical and humane process to approaching parents- we developed a novel strategy for deferred consent. We were uncomfortable with full consent waiver since this may mean that parents may never get to know that their child was involved in a research study - which if they had known at the time of admission they could have exercised their right to refuse. For the sickest children we opted for, and have ethical approval for, parental verbal assent, where parents understood that their child would be involved in a clinical trial, but the details would be given after recruitment - during informed consent- once their child was stablised. We plan substudies to evaluate this with social sciences groups specializing in research ethics. Our methodology has been written up and recently submitted for publication. 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact The ethical landscape has changed so vastly such that any pragmatic consenting process giving the key sensitivities to parents so they can weigh up risks and benefits contextually is now a rare phenomenon. Having presented the FEAST trial at international paediatric critical care conferences and more recently in a meningitis meeting - our consent process was welcomed as practical and helpful example by paediatricians who are struggling with European ICH GCP legislation. There have been two important regulatory developments in recent years. Firstly, in January 2007 EU paediatric medicine regulation (Regulation (EC) No 1901/2006) requiring all new license applications to include paediatric data. Followed by the December 2006 amendment to the EU trials directive that was intended to enable research in emergencies. Recent reports suggest this is not working in practice. The new requirement for research in children is compounded by the lack of guidance for conducting studies in this setting. FEAST trial consent process therefore sets a benchmark for future paediatric trials. 
URL http://www.ncbi.nlm.nih.gov/pubmed/23408950
 
Description Joint Clinical Research Centre, Kampala, Uganda 
Organisation Joint Clinical Research Center, Kampala
Country Uganda 
Sector Academic/University 
PI Contribution Multicentre clinical trial collaboration on DART, ARROW, CHAPAS 3, PENTA 16 (BREATHER) and REALITY Trials and substudies Partner on the Lablite Project and on PENTA 17 (SMILE) and PENTA 20 (ODYSSEY) trials
Collaborator Contribution Clinical trials site and coordination of satelite sites. Laboratory substudies e.g HIV virology and immunology
Impact Trial results and substudies DART, ARROW, CHAPAS 2, CHAPAS 3, BREATHER and REALITY trials including virology, social science and economic substudies DART trial Fim Young lives project from ARROW trial Outputs from the Lablite Project
Start Year 2006
 
Description Kemri Wellcome Trust, Kilifi Kenya 
Organisation Wellcome Trust
Department KEMRI-Wellcome Trust Research Programme
Country Kenya 
Sector Multiple 
PI Contribution Scientific leadership designing the TRACT and FEAST trials in collaboration with Professor Kath Maitland (Imperial College and KEMRI Wellcome Trust). Analysis and writing up of the FEAST trial; oversight of trial management and mentoring the trial team in Kilifi. Chair of Trial Steering Committe of Cotrimoxizole trial for Jay Berkley.
Collaborator Contribution the CTU lead network of trial monitoring in East Africa. The FEAST trial monitors also monitored the VITA trials in Tanzania. Trial sites for REALITY Trial
Impact The FEAST trial paper in NEJM, follow up papers ongoing. BMJ paper of the year 2012.
Start Year 2009
 
Description Mbale Clinical Research Institute, Mbale, Uganda 
Organisation Mbale Clinical Research Institute
Country Uganda 
Sector Hospitals 
PI Contribution The Wellcome Trust has funded MCRI as part of the Major Overseas Award to Oxford-Kemri Wellcome Trust Programme. The collaboration is led by Programme members working with the Director of the Mbale Clinical Research Unit. We have established a strong relationship with MCRI having supported his PhD studies and his transition from a clinical and managerial career to a research career.
Collaborator Contribution Over the last 3 years Mbale has established a track record of clinical trials, receiving subcontracts for £996k and £812k in the last 3 years (subcontracted from the £3.2M and £2.4M awards for the TRACT and COAST trials) and recent award from MRC for a Phase II study of antibiotic treatment targeting non-typhoidal salmonellae (TABS).
Impact Award of a subcontract from the KEMRI Wellcome Trust Programme for £1.5 Million in 2016. The building of a new research laboratory to strengthen diagnostic and molecular research. The will enable the centre to expand its research portfolio in future.
Start Year 2016
 
Description Medical Research Council Clinical Trials Unit 
Organisation Imperial College London
Department Department of Paediatrics
Country United Kingdom 
Sector Academic/University 
PI Contribution Work leading up the trials, identification of partners, trial sites and design and execution of clinical trials
Collaborator Contribution Design of clinical trials, trial governance and data management, statatistical expertise Multidisciplinary clinical trialists, infectious disease speacialists, health economists and specialists in health policy
Impact FEAST trial Publications Alexander Fleming Award TRACT trial
Start Year 2008
 
Description Medical Research Council Clinical Trials Unit 
Organisation Wellcome Trust
Department KEMRI-Wellcome Trust Research Programme
Country Kenya 
Sector Multiple 
PI Contribution Work leading up the trials, identification of partners, trial sites and design and execution of clinical trials
Collaborator Contribution Design of clinical trials, trial governance and data management, statatistical expertise Multidisciplinary clinical trialists, infectious disease speacialists, health economists and specialists in health policy
Impact FEAST trial Publications Alexander Fleming Award TRACT trial
Start Year 2008
 
Description POST and COAST trials 
Organisation The Prince Charles Hospital
Department Social Work Department
Country Australia 
Sector Hospitals 
PI Contribution Development and conduct a pilot study (POST) for the main COAST trial
Collaborator Contribution Development of the pilot study (POST) and partnership with Fischer and Paykel
Impact none realised yet
Start Year 2012
 
Description SMAART consortium 
Organisation Wellcome Trust
Department Mahidol University-Oxford Tropical Medicine Research Programme
Country Thailand 
Sector Academic/University 
PI Contribution The main aim of SMAART is to conduct better research studies faster, to improve outcomes from severe malaria. SMAART will act as the operational platform by which future research is planned in a coordinated and reciprocal manner to continuously update disease definitions and treatment guidelines for severe malaria.
Collaborator Contribution To overcome the barriers to achieving this goal, SMAART brings together applicants and co-investigators from three Wellcome Trust major overseas programmes (KEMRI Wellcome Trust Programme, Kenya, Malawi-Liverpool-Wellcome Trust Unit, Malawi (Prof David Lalloo) and Mahidol Oxford Research Unit, Thailand together with African scientists from existing or new collaborations and specialists in clinical trials ( MRC CTU at UCL) and ultimately national and international stakeholders. All are necessary to ensure that the most important questions are identified and combined optimally in the most efficient trial design which is acceptable and relevant to parents, healthcare professionals, ethical review boards and ministries of health. The network is thus a multi-disciplinary team providing complementary expertise and added value including links to other networks. The SMAART consortium encompasses decades of clinical and academic experience, track records of successful high quality research in low-income settings, and significant impact as evidenced by publication citation, grant funding and policy change.
Impact none yet; meeting planned for June 2016 to plan the grant submission to UK funder collaborative award
Start Year 2015
 
Description SMAART consortium 
Organisation Wellcome Trust
Department Malawi-Liverpool Wellcome Trust Clinical Research Programme
Country Malawi 
Sector Charity/Non Profit 
PI Contribution The main aim of SMAART is to conduct better research studies faster, to improve outcomes from severe malaria. SMAART will act as the operational platform by which future research is planned in a coordinated and reciprocal manner to continuously update disease definitions and treatment guidelines for severe malaria.
Collaborator Contribution To overcome the barriers to achieving this goal, SMAART brings together applicants and co-investigators from three Wellcome Trust major overseas programmes (KEMRI Wellcome Trust Programme, Kenya, Malawi-Liverpool-Wellcome Trust Unit, Malawi (Prof David Lalloo) and Mahidol Oxford Research Unit, Thailand together with African scientists from existing or new collaborations and specialists in clinical trials ( MRC CTU at UCL) and ultimately national and international stakeholders. All are necessary to ensure that the most important questions are identified and combined optimally in the most efficient trial design which is acceptable and relevant to parents, healthcare professionals, ethical review boards and ministries of health. The network is thus a multi-disciplinary team providing complementary expertise and added value including links to other networks. The SMAART consortium encompasses decades of clinical and academic experience, track records of successful high quality research in low-income settings, and significant impact as evidenced by publication citation, grant funding and policy change.
Impact none yet; meeting planned for June 2016 to plan the grant submission to UK funder collaborative award
Start Year 2015
 
Description THE COLLEGE OF MEDICINE University of Malawi 
Organisation University of Malawi
Department College of Medicine
Country Malawi 
Sector Academic/University 
PI Contribution TRACT and REALITY Trials Lablite Project (funded by DFid)
Collaborator Contribution Clinical sites for TRACT and REALITY Trials Dignitas International are an IMplementation partner in the Lablite Project
Impact publications from the Lablite Project REALITY TRial and TRACT trial ongoing
Start Year 2012
 
Description Uganda Blood Transfusion 
Organisation Imperial College London
Department Department of Paediatrics
Country United Kingdom 
Sector Academic/University 
PI Contribution For the purposes of the FEAST and TRACT trial developed new network of clinical trial sites
Collaborator Contribution Blood transfusion services will be critical in this collaboration for the successful conduct of the transfusion componant of the TRACT trial
Impact TRACT trial protocol approval in Uganda Trial started enrolment in Sept 2013
Start Year 2013
 
Description Uganda Blood Transfusion 
Organisation Medical Research Council (MRC)
Department MRC Clinical Trials Unit
Country United Kingdom 
Sector Public 
PI Contribution For the purposes of the FEAST and TRACT trial developed new network of clinical trial sites
Collaborator Contribution Blood transfusion services will be critical in this collaboration for the successful conduct of the transfusion componant of the TRACT trial
Impact TRACT trial protocol approval in Uganda Trial started enrolment in Sept 2013
Start Year 2013
 
Description Uganda Blood Transfusion 
Organisation Wellcome Trust
Department KEMRI-Wellcome Trust Research Programme
Country Kenya 
Sector Multiple 
PI Contribution For the purposes of the FEAST and TRACT trial developed new network of clinical trial sites
Collaborator Contribution Blood transfusion services will be critical in this collaboration for the successful conduct of the transfusion componant of the TRACT trial
Impact TRACT trial protocol approval in Uganda Trial started enrolment in Sept 2013
Start Year 2013
 
Description Uganda Blood Transfusion 
Organisation Wellcome Trust
Department KEMRI-Wellcome Trust Research Programme
Country Kenya 
Sector Multiple 
PI Contribution For the purposes of the FEAST and TRACT trial developed new network of clinical trial sites
Collaborator Contribution Blood transfusion services will be critical in this collaboration for the successful conduct of the transfusion componant of the TRACT trial
Impact TRACT trial protocol approval in Uganda Trial started enrolment in Sept 2013
Start Year 2013
 
Description University of Zimbabwe 
Organisation University of Zimbabwe
Country Zimbabwe 
Sector Academic/University 
PI Contribution DART, ARROW, REALITY Trials funding and coordination by MRC CTU LAblite Project on enabling rollout of antiretroviral therapy.
Collaborator Contribution Clinical sites for DART, ARROW, REALITY, PENTA 20(ODYSSEY) Trials Staff are partners in all aspects of reserach from design through to enrolling patients and writing results papers
Impact DART and ARROW trials and substudy outcomes and implementation impact; ARROW young lives study and economic substudies REALITY trial ongoing LAblite Project outputs
Start Year 2006
 
Title REALITY trial - CTX/INH 
Description Fixed dose combination of cotrimoxazole, isoniazid and pyridoxine. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2012
Development Status Under active development/distribution
Clinical Trial? Yes
Impact N/A 
URL http://www.controlled-trials.com/ISRCTN43622374
 
Description ICASA 2015 - Intenational Conference on AIDS and STIs in Africa. Oral presentation. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Oral presentation; abstract Title: Sulfamethoxazole/Trimethoprim/Isoniazid/Pyridoxine scored tablets are bioequivalent to individual products and are acceptable to patients with advanced HIV infection in the REALITY trial

Authors: Bwakura-Dangarembizi M2, Gibb DM1, Abhyankar D9, Agutu C3, Lugemwa A4, Abongomera G5, Miranda S6, Musiime V7, Mallewa J8, Siika A11, Baleeta K12, Mehta V9, Malhotra G9, Griffiths A1, Kityo C10, Maitland K3, Chidziva E2, Chepkorir P11, Szubert AJ1, Gogtay J9, Hakim J2 and the REALITY Trial Team

Background Patients initiating ART with low CD4 counts benefit from isoniazid and cotrimoxazole prophylaxis, but these increase pill burden; stockouts of single formulations are also common.
Methods: Sulfamethoxazole/Trimethoprim/Isoniazid/Pyridoxine (800/160/300/25mg) fixed-dose-combination (FDC) scored tablets (Cipla , India) were compared with Septrin®Forte (sulfamethoxazole-800mg/trimethoprim-160mg (GlaxoWellcome)) and Isoniazid-300mg (Sandoz) separate tablets in 28 healthy volunteers (18male; 10female) in an open-label, randomized, single-dose, two-treatment, two-period, 26-sample crossover pharmacokinetic bioequivalent study. Acceptability and adherence questionnaire data were collected in the ongoing, 2x2x2 factorial, REALITY randomised trial evaluating enhanced OI prophylaxis, 4-drug ART and enhanced nutrition for 12 weeks after ART initiation, in 1805 African adults/children(=5years) with CD4 <100cells/mm3. Within-individual data on FDC (weeks 12-24) vs cotrimoxazole alone (weeks 0-12) were compared in 319 patients; and in weeks 0-12 among those receiving FDC+fluconazole (for prophylaxis against cryptococcal disease) (n=543) vs cotrimoxazole (n=604).
Results: Geometric mean test-to-reference ratios for sulfamethoxazole (AUC: 99.8% (90% CI 96.2%-103.5%) and Cmax: 103.2%(99.5%-107.0%)), trimethoprim (97.2%(93.7-100.9)%; 98.2%(93.4-103.3)%) and isoniazid 103.8%(99.5-108.3); 104.3%(95.1-114.4)) were well within required 80-125% range. In REALITY, acceptability was similar between FDC (12-24 weeks) and cotrimoxazole (0-12 weeks): 99.7% vs 99.4% reported none/not much daily-life interference; 95.6% vs 96.6% reported drugs were very easy/easy to take. Comparing groups (0-12 weeks) gave similar results: 500/543(92.1%) vs 565/604(93.5%),(p=0.8) reported taking medication was very easy/easy; 4.0% vs 3.9% reported missing =1 dose.
Conclusions: Sulfamethoxazole/Trimethoprim/Isoniazid/Pyridoxine FDC tablets are bioequivalent to individual drugs (data submitted for WHO prequalification). They are acceptable, reduce pill burden and could improve adherence, in addition to simplifying drug distribution for programmes.
Year(s) Of Engagement Activity 2015
URL http://icasa2015zimbabwe.org/
 
Description MRC Festival Workshop on Getting Results Faster for Patients 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact As part of the Medical Research Council (MRC) Festival of Medical Research, the MRC Clinical Trials Unit at University College London (MRC CTU at UCL) held a half-day workshop exploring how the Unit is working to get faster results and impact from clinical trials. We invited patient representatives involved in our studies, and patient groups who are interested in clinical trials. 30 people from 20 patient groups and various trials attended the workshop, along with around 20 members of MRC CTU at UCL staff.
Year(s) Of Engagement Activity 2016
URL http://www.ctu.mrc.ac.uk/news/2016/getting_results_faster_workshop_report_010816
 
Description REALITY RUSF animated infographic 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Animated version of the infographic summarising key messages from the REALITY trial results around supplementary feeding.
Year(s) Of Engagement Activity 2018
URL https://vimeo.com/263871783
 
Description REALITY RUSF briefing paper 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Briefing paper summarising the REALITY findings on supplementary feeding for policymakers.
Year(s) Of Engagement Activity 2018
 
Description REALITY animation 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Animated version of the REALITY infographic
Year(s) Of Engagement Activity 2017
URL https://vimeo.com/226262006
 
Description REALITY briefing paper 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Briefing paper describing the enhanced prophylaxis results from the REALITY trial.
Year(s) Of Engagement Activity 2017
URL http://www.ctu.mrc.ac.uk/13706/13710/reality_prophylaxis_briefing_paper_2017
 
Description REALITY film 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact One in five people starting HIV treatment in low and middle income countries have a low CD4 count (a measure of the strength of their immune system). This puts them at high risk of dying in the first few weeks of treatment. The REALITY trial tested giving people starting treatment with a low CD4 count an enhanced package of drugs to prevent infections. It found this package was highly effective at preventing deaths and illnesses. This film explores those results.
Year(s) Of Engagement Activity 2017
URL https://vimeo.com/225532382
 
Description REALITY infographic 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact An infographic summarising the results of the REALITY trial
Year(s) Of Engagement Activity 2017
URL http://www.ctu.mrc.ac.uk/12602/13005/REALITYinfographic140717.png
 
Description The 46th Union World Conference on Lung Health, Cape Town, 2-6 December 2015. Oral Presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Abstract Title: Sulfamethoxazole/Trimethoprim/Isoniazid/Pyridoxine scored tablets are bioequivalent to individual products and are acceptable to patients with advanced HIV infection in the REALITY trial
Authors: Gibb DM1, Bwakura-Dangarembizi M2, Abhyankar D9, Szubert AJ1, Agutu C3, Lugemwa A4, Abach J5, Kemigisa M6, Mallewa J8, Siika A10, Mukuye A11, Mehta V9, Malhotra G9, Nambi E10, Thomason M1, Pett S1, Berkley J3, Meli B10, Kityo C7, Nathoo K2, Musiime V7, Walker AS1, Gogtay J9 and the REALITY Trial Team
Affiliations: 1MRC Clinical Trials Unit at UCL, London, UK; 2University of Zimbabwe, Harare, Zimbabwe; 3KEMRI Wellcome Trust Research Programme, Kilifi, Kenya; 4Joint Clinical Research Centre, Mbarara, Uganda; 5Joint Clinical Research Centre, Gulu, Uganda; 6Joint Clinical Research Centre, Fort Portal, Uganda; 7Joint Clinical Research Centre, Kampala, Uganda and Makerere University College of Health Sciences, Kampala, Uganda; 8University of Malawi, Blantyre, Malawi; 9Cipla Ltd., Mumbai, India; 10 Moi University Clinical Research Centre, Eldoret, Kenya, 11Joint Clinical Research Centre, Mbale, Uganda
Background: HIV-infected patients initiating antiretroviral therapy (ART) with low CD4 counts particularly benefit from OI and anti-tuberculosis prophylaxis. However, individual drug formulations of isoniazid and cotrimoxazole add to the pill burden of ART and adherence difficulties early in treatment when mortality is highest; stockouts are also frequent in low-resource settings.
Methods: Sulfamethoxazole/Trimethoprim/Isoniazid/Pyridoxine (800/160/300/25mg) fixed-dose-combination (FDC) scored tablets, made by Cipla, India, were evaluated for bioequivalence vs separate tablets of Septrin®Forte (sulfamethoxazole-800mg/trimethoprim-160mg (GlaxoWellcome)) and Isoniazid-300mg (Sandoz) in an open-label, randomized, single-dose, two-treatment, two-period, 26-sample crossover pharmacokinetic study. Acceptability and adherence questionnaire data were collected in the ongoing, 2x2x2 factorial, REALITY randomised trial evaluating 12-week enhanced OI prophylaxis, 4-drug ART and enhanced nutrition in 1805 African adults/children (=5years) with CD4 <100cells/mm3. Within-individual data on FDC (weeks 12-24) vs cotrimoxazole alone (weeks 0-12) were compared in 319 patients; and in weeks 0-12 among those receiving FDC+fluconazole (for prophylaxis against cryptococcal disease) (n=543) vs cotrimoxazole (n=604).
Results: Among 28 fasting healthy subjects (18 male; 10 female; Mean(range) age 31(18-45)years; BMI 25.1+2.9), geometric mean test-to-reference ratios for sulfamethoxazole (AUC: 99.8% (90% CI 96.2%-103.5%) and Cmax: 103.2%(99.5%-107.0%)), trimethoprim (97.2%(93.7-100.9)%; 98.2%(93.4-103.3)%) and isoniazid 103.8%(99.5-108.3); 104.3%(95.1-114.4)) were well within required 80-125% range. In REALITY, no within-individual differences in acceptability were reported between FDC (12-24 weeks) vs cotrimoxazole (0-12 weeks): 99.7% vs 99.4% reported none/not much interference with everyday life and 95.6% vs 96.6% reported drugs were very easy/easy to take. Comparing groups over 0-12 weeks gave similar results: 500/543(92.1%) vs 565/604(93.5%) (p=0.8) reported taking medication was very easy/easy; 4.0% vs 3.9% reported missing =1 dose.
Conclusions: Sulfamethoxazole/Trimethoprim/Isoniazid/Pyridoxine scored FDC tablets are bioequivalent to individual drugs; data have been submitted for WHO prequalification. They are acceptable, reduce pill burden and could improve adherence for adults/children =5 years, in addition to simplifying drug distribution for HIV programmes.
Year(s) Of Engagement Activity 2015
URL http://capetown.worldlunghealth.org/
 
Description Youth Trial Board meeting with MRC CTU 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact We held a meeting with the UK Youth Trial Board to share our research and get their feedback.
Year(s) Of Engagement Activity 2017