A randomised trial of monitoring practice and pulse antiretroviral therapy in African children with HIV infection

Lead Research Organisation: MRC Clinical Trials Unit

Abstract

In industrialised countries, triple-drug Anti-Retroviral Therapy (ART) has transformed AIDS from a fatal to a chronic disease where the main issues are the effects of long-term side-effects to these drugs. ART is becoming increasingly available in resource-poor countries, following dramatic price reductions and donor commitments to provide drugs, such as the global fund for Malaria, TB and AIDS. However, ART remains out of reach for many patients in the African countries worst affected by AIDS. This is also because of the additional need for infrastructure to do blood tests for monitoring immunity levels and side-effects of drugs. These test are routinely done in industrialised countries but are expensive, require special machines and trained personnel and may not always be necessary. The DART trial is finding out whether ART can be given safely and effectively to adults with HIV by health agencies with limited ability to do monitoring. DART is also investigating whether intermittent therapy (in regular on-off cycles), which might reduce long-term side-effects as well as drug costs, is as safe and effective as continuous ART at fighting HIV/AIDS. The results are expected in 2008. So far 2000 of the 3000 adults needed for the trial have been enrolled during 2003. In an anonymous survey, we found out that around 40% DART trial participants are caring for a sick child with symptoms suggestive of HIV in the same household. Therefore for ethical as well as scientific and practical reasons (to avoid pill-sharing), we are planning a similar trial to DART for children. Junior DART will enrol 1200 children and adolescents of DART families and address similar questions as adult DART. Growth could be an important additional way to monitor how well children are responding to ART, making clinical monitoring even more viable than in adults. In addition, children have more active immune systems, which may recover better and more quickly when ART is restarted after a period off therapy. Therefore it is quite possible that the results from the adult DART trial cannot just be assumed to be the same for children DART and Junior DART will be done in the same centres in Uganda and Zimbabwe and will form the basis of developing family-based care for HIV infection in Africa.

Technical Summary

Junior DART is a randomised open-label trial enrolling 1200 African HIV-infected children, aged 6 months to 18 years, with an adult carer in the DART (Development of AntiRetroviral Therapy) trial which has enrolled 2000 of 3000 adults in Uganda (2 sites) and Zimbabwe (1 site). Junior DART will take place in the same sites and the 2 trial teams will work closely together. Junior DART will have two major randomisations: to clinical monitoring only (CMO) versus laboratory and clinical monitoring (LCM); and to intermittent (planned treatment interruptions, PTI) versus continuous ART. In a further randomised substudy, 3 regimen strategies for initiating ART will be compared in terms of HIV RNA viral load response.
Eligible children should have paediatric WHO Stage 2 or 3 disease, and CD4 percent 20% for children 2 years, 15% for children 2-11 years, or CD4 count 200 cells/mm3 for those aged 12-18 years. It is expected that at least 750 children randomised to CMO versus LCM will be 2 years and have achieved a sufficient increase in CD4 (CD4 ?20% for 2-11 years and CD4 250 cells/mm3 for 12-18 years) by 48 or 72 weeks to be eligible for the second randomisation to PTI versus continuous ART. This will only open after a non-randomised pilot study of PTIs in 100 children satisfying these threshold criteria has been completed (with all children having monthly CD4 measurements) and the DSMC and Trial Steering Committee have assessed the safety of the proposed PTI strategy.
Recruitment into the trial will take place over one year with minimum follow-up of 4 years. First and second-line ART will be available for all children (for up to five years). The decision to change to second-line ART will be based on clinical criteria alone for the CMO arm and on clinical plus laboratory criteria for the LCM arm. Issues of after-trial ART are being negotiated with governments in the same way as for adult DART.
The primary efficacy endpoint will be progression to a new paediatric WHO stage 3 (AIDS) event or death in children under 13 years, or adult WHO stage 4 disease for those 13 years and older. The primary outcome for the randomised substudy will be change in HIV RNA from baseline to 48 weeks, performed retrospectively on stored plasma samples.

Publications

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Bwakura-Dangarembizi M (2014) A randomized trial of prolonged co-trimoxazole in HIV-infected children in Africa. in The New England journal of medicine

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Fillekes Q (2011) Pediatric underdosing of efavirenz: a pharmacokinetic study in Uganda. in Journal of acquired immune deficiency syndromes (1999)

 
Guideline Title GUIDELINE ON WHEN TO START ANTIRETROVIRAL THERAPY AND ON PRE-EXPOSURE PROPHYLAXIS FOR HIV
Description ARROW influence on WHO Guidelines on When to Start ART (2015)
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact The new WHO guidelines cite the ARROW results, saying "Expanding ART services for children will require strategies to improve retention in care and to support adherence. Careful clinical monitoring remains essential to assess the risk of treatment failure, but lack of laboratory monitoring should not be a barrier to initiating ART." ARROW showed that children on ART had excellent outcomes with clinical monitoring, and that routine laboratory monitoring was not cost-effective in most circumstances. It is important that this is acknowledged in the WHO guidelines, as there is a move towards requiring routine viral load monitoring, which could act as a barrier to access for children in rural areas in low-income countries.
URL http://apps.who.int/iris/bitstream/10665/186275/1/9789241509565_eng.pdf?ua=1
 
Description Antiretroviral Therapy of HIV Infection in infants and Children in Resource-Limited Setttings: Towards Universal Access. Recommendations for a public health approach
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
 
Guideline Title WHO Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach
Description Influence on WHO ART guidelines 2013
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
 
Description Member of WHO Maternal and Child Health Guideline Development Group
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
 
Description Post marketing data for EMA for scored adult tablets for children (antiretroviral therapy)
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact The data provided from ARROW was submitted to EMA for scored adult tablets for children, along with evidence of acceptability, required post-licensing. THese products now widely used for children worldwide. (antiretroviral therapy)
 
Description WHO advisory group on formulations of antiretroviral medicines for HIV infected children
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
Impact Data from ARROW has provided evidence on pharmacokinetics and acceptability of weightband tables for scored tablet formulations in HIV-infected children.
 
Description ARROW: A randomised trial of monitoring practice in the management of antiretroviral therapy in children with HIV infection in Africa/Medical Research Council (MRC) and Department for International Development (DFID)
Amount £1,651,128 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2006 
End 06/2012
 
Description ARROW: A randomised trial of monitoring practice in the management of antiretroviral therapy in children with HIV infection in Africa/Medical Research Council (MRC) and Department for International Development (DFID)
Amount £1,651,128 (GBP)
Organisation Government of the UK 
Department Department for International Development (DfID)
Sector Public
Country United Kingdom
Start 06/2006 
End 06/2012
 
Description The Causes and Consequences of Residual Immune Activation in HIV-Infected Children on ART in Resource-Limited Settings
Amount £654,391 (GBP)
Funding ID G1001190 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 05/2011 
End 04/2016
 
Description Young Lives: the Social Contexts of Paediatric Anti-Retroviral Therapy. A DFID Social Science programme in Uganda and Zimbabwe
Amount £788,800 (GBP)
Organisation Government of the UK 
Department Department for International Development (DfID)
Sector Public
Country United Kingdom
Start 01/2011 
End 01/2015
 
Title ARROW Pharmacy Database 
Description Prior to ARROW the sites in Uganda and Zimbabwe had used paper based methods for recording for all drug processes in the pharmacy. ARROW has created an ACCESS pharmacy database which allows for ease of tracking and accountability of drugs in the trial. 
Type Of Material Database/Collection of Data/Biological Samples 
Provided To Others? No  
Impact The creation of the ARROW Pharmacy database resulted in capacity development for local staff from Uganda, who were instrumental in the development of the database along with members of the ARROW team at MRC. This has also resulted the person being involved in on-going database maintenance work and other data services work with the MRC. 
 
Description DFID (Department for International Development) 
Organisation Government of the UK
Department Department for International Development (DfID)
Country United Kingdom 
Sector Public 
PI Contribution The research team at the MRC co-ordinates the ARROW trial and the Lablite Project. The Young Lives project team (LSHTM) work across ARROW and PENTA 16 trials in Uganda.
Collaborator Contribution DFID fund Lablite and co-funded ARROW and the Young Lives. They attend all Trial Steering Committees and we have an ongoing active communication and collaboration.
Impact DFID co-funds ARROW and provides funding for the Young lives social science study. Without the co-funding from DFID ARROW would not be possible
Start Year 2006
 
Description GlaxoSmithKline 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution The research team at the MRC co-ordinates the overall ARROW trial and reports regularly to GSK on drug consumption and any reported events that may be related to GSK drugs. Protocols for GSK funded sub-studies were written and implemented through the MRC and results are shared with GSK before being publicly disseminated.
Collaborator Contribution GSK provide first line ART drugs for the trial.GSK will compensate ARROW up to a total amount of $212,700.00 (not £) for the work on Virology.
Impact GSK donates ARROW first-line drugs and provides funding for sub-studies (Pharmacokinetic of syrups and tablets; Acceptability/Adherence of these formulations; virology) Data from part of the Virology sub-study has been submitted to FDA for once daily dosing of Abacavir+lamivudine for children; in 2014 these data contributed to approval also of once daily dosing of fixed dose combination tablet from a generic company
Start Year 2006
 
Description GlaxoSmithKline 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution The research team at the MRC co-ordinates the overall ARROW trial and reports regularly to GSK on drug consumption and any reported events that may be related to GSK drugs. Protocols for GSK funded sub-studies were written and implemented through the MRC and results are shared with GSK before being publicly disseminated.
Collaborator Contribution GSK provide first line ART drugs for the trial.GSK will compensate ARROW up to a total amount of $212,700.00 (not £) for the work on Virology.
Impact GSK donates ARROW first-line drugs and provides funding for sub-studies (Pharmacokinetic of syrups and tablets; Acceptability/Adherence of these formulations; virology) Data from part of the Virology sub-study has been submitted to FDA for once daily dosing of Abacavir+lamivudine for children; in 2014 these data contributed to approval also of once daily dosing of fixed dose combination tablet from a generic company
Start Year 2006
 
Description Institute of Child Health 
Organisation University College London
Department Institute of Child Health
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaborators on an MRC Immunology substudy within ARROW, delegating activities as described under an agreement with ICH, and we take responsibility for the project in accordance with the provisions of the Funder; application for NIHR funding for PENTA 16 immunology substudy
Collaborator Contribution Training, laboratory capacity building, teaching on PENTA Courses in East and West Europe and across Africa; sharing supervision of PhD Wellcome Trust studentships (Prof. Nigel Klein). Working together on EuroCoord, EPPICC, PENTA and Hepatitis C activities (Dr Claire Thorne). Collaborators and grant holders on NIHR PENTA 16 main study and biomarker substudy
Impact MRC grant secured in 2010. Work ongoing with baseline data presented at international conferences. Involves collaboration, training and capacity building between clinical, laboratory and trial management personnel at Ugandan and Zimbabwean sites and MRC CTU and Institute of Child Health. Site laboratory trained in four colour Immunophenotyping, nucleic acid extraction protocols and quantitative and real time PCRs (on HIV, CMV and EBV), and ELISA assays. Further training will be done on other techniques, in year 2 of the study. Training was done by personnel from both CTU and ICH.
Start Year 2010
 
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 Monument Trust 
Organisation The Sainsbury Family Charitable Trusts
Department Monument Trust
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution MRC CTU co-ordinates the CHAPAS-2 trial and the AALPHI study
Collaborator Contribution funding. The Monument Trust also contribute to I-Base publications which CTU staff have input in to.
Impact The Monument Trust funds the pharmacokinetic teams at 2 of the Ugandan trial centres for ARROW and CHAPAS trials. Some second-line children from ARROW are co-enroled in CHAPAS-2. AALPHI study started recruiting in Q3 2012.
Start Year 2010
 
Description Radboud University Nijmegen Medical Centre, the Netherlands 
Organisation Radboud University Nijmegen Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution The research team at the MRC co-ordinates the ARROW, CHAPAS-1,2,3 and PENTA trials and provides scientific input and analysis of EDCTP funded VITA 1 and 2 trials.
Collaborator Contribution Long standing nesting of key pharmacokinetic studies within larger trial programmes. Contributed to several PhD studentships (all Dutch), PK data resulted in licensing of new appropriate antiretroviral formulations for children in resource limited settings.
Impact Radbound University has been involved in the analysis and writing up of the pharmacokinetics data from ARROW, PENTA 18 and the CHAPAS trials which has resulted in presentations at international conferences, peer review publications, FDA and EMA approval of drugs and Clinton Foundation and UNITAID dissemination in Africa.
Start Year 2007
 
Description The London School of Hygiene and Tropical Medicine 
Organisation London School of Hygiene and Tropical Medicine (LSHTM)
Department Faculty of Public Health and Policy
Country United Kingdom 
Sector Academic/University 
PI Contribution coordination and facilitation of the Young Lives substudy in the ARROW trial, qualatative substudy of PENTA 16 (UK, Uganda and US) and input in to AALPHI.
Collaborator Contribution intensive training in areas of social science adding to collaborations in the African centres (ARROW and PENTA 16). provision of a forum for young people in the ARROW trial to contribute to knowledge about living with HIV infection in Africa
Impact 3 Social Scientists trained in Africa; publications and presentations at major conferences on qualitative work in ARROW and BREATHER (PENTA 11)
Start Year 2011
 
Description University of Zambia 
Organisation University of Zambia
Country Zambia 
Sector Academic/University 
PI Contribution Contribution to CHAP, CHAPAS 1 & 3 trials
Collaborator Contribution enrolled patients into CHAP, CHAPAS 1 & 3 trials Project lead of EDCTP project Contribution to all aspects of reserach including outputs and implementation (CHAP Trial of cotimroxazole prophylaxis)
Impact Trial results and substudies and implementation and impact of CHAP & CHAPAS 1 and 3 trials, including economic analyses CHAPAS 3 trial just completed and papers ongoing
Start Year 2006
 
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 ARROW Trial 
Description 4 randomisations, 1) monitoring for efficacy and toxicity of ART in children. 2) induction maintenance ART strategies versus standard of care. 3) stoping cotrimoxazole prophylaxis 4) once versus twice daily lamivudine plus abacavir. 
Type Management of Diseases and Conditions
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2012
Development Status Closed
Clinical Trial? Yes
Impact influenced WHO ART 2013 Guidelines (monitoring management, ART for TB co-infection, cotrimoxazole prophylaxis 
URL http://www.controlled-trials.com/ISRCTN24791884
 
Title ARROW Trial scored formulations of lamivudine, abacavir, combivir made by GlaxoSmithKline 
Description GSK provided funding for the PK and acceptability substudies which were undertaken in ARROW clinical sites 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2011
Development Status Closed
Clinical Trial? Yes
Impact greater choice of appropriate drug formulations for children worldwide 
URL http://www.arrowtrial.org/
 
Description ARROW Cotrimoxazole film 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Film about the ARROW cotrimoxazole results released on YouTube.

161 views so far from the YouTube website. Unsure how many views from the MRC CTU website.
Year(s) Of Engagement Activity 2014
URL https://www.youtube.com/watch?v=D1n_We7x8Do
 
Description ARROW Cotrimoxazole policy brief 
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 The policybrief was distributed to policymakers in the Ministry of Health in Uganda and Zimbabwe (where the trial took place). It has also been more widely distributed at meetings, and is available on the MRC CTU website.

Feedback from policymakers at the Ministry of Health was very positive about the policy brief.
Year(s) Of Engagement Activity 2014
URL http://www.ctu.mrc.ac.uk/12602/13009/children_on_art_in_africa_need_to_continue_cotrimoxazole_prophy...
 
Description ARROW Induction-maintenance policy brief (2013) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact The policy brief was circulated to policymakers at the Ministry of Health in Zimbabwe and Uganda. It was also distributed at the CROI conference in 2013 when the results of ARROW were presented. It has been distributed to members of staff at the UK Department for International Development. It has also been distributed via the MRC CTU, Lablite and ARROW websites.

The 2013 Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection included a recommendation that a triple NRTI regimen could be used for children while on TB treatment. (See Influence on Policy section).
Year(s) Of Engagement Activity 2013
URL http://www.ctu.mrc.ac.uk/PDF/ARROWInductionMaintenancepolicybrief.pdf
 
Description ARROW case studies 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Primary Audience Public/other audiences
Results and Impact Three policy briefs on different aspects within ARROW (Tablets are more acceptable and give fewer problems than syrups among young HIV-infected children in resource-limited settings in the ARROW trial; improving children's access to research participation in poorly resourced communities; Use of scored tablets of first line antiretroviral drugs in HIV-infected children in resource limited settings: Experiences from the ARROW Clinical trial

The case studies were well received in both Uganda and Zimbabwe with copies of the documents being handed out at the National Ugandan Paediatric conference and at the MRC stand for BHIVA.
Year(s) Of Engagement Activity 2010
 
Description ARROW immune reconstitution press release (2013) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact A press release based on the ARROW immune reconsistution paper was issued.

This story was covered by Medical Xpress.
Year(s) Of Engagement Activity 2013
URL http://www.mrc.ac.uk/Newspublications/News/MRC009540
 
Description ARROW monitoring film 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact We made a short film about the monitoring results of the ARROW trial. It has been made available on the Lancet website, as well as YouTube, the MRC CTU website, ARROW website and Lablite website. It has also been screened at the BHIVA conference. It has had 121 views on YouTube, but we do not have statistics on views via the other websites.

The results regarding toxicity monitoring have fed into the WHO Consolidated Guidelines (see Influence on Policy Section).
Year(s) Of Engagement Activity 2013
URL http://www.youtube.com/watch?v=vhCBXmxE7DQ&feature=c4-overview&list=UUxUK9Zn4Es5SxMbAYeTSO2g
 
Description ARROW monitoring policy brief (2013) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact The policy brief was circulated to policymakers at the Ministry of Health in Zimbabwe and Uganda. It was also distributed at the CROI conference in 2013 when the results of ARROW were presented. It has been distributed to members of staff at the UK Department for International Development. It has also been distributed via the MRC CTU, Lablite and ARROW websites.

The results regarding toxicity monitoring providing no benefit discussed in this policy brief have influenced WHO guidelines (see entry in Influence on Policy, Practice, Patients & the Public section).
Year(s) Of Engagement Activity 2013
URL http://www.ctu.mrc.ac.uk/PDF/ARROWmonitoringstrategypolicybrief.pdf
 
Description ARROW monitoring press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact A press release was issued to tie-in with the publication of the ARROW monitoring and induction-maintenance results. A press conference was also held at CROI.

The story was covered by HIVandHepatits.com and AIDSMap in their conference reporting.
Year(s) Of Engagement Activity 2013
URL http://www.mrc.ac.uk/Newspublications/News/MRC009041
 
Description Graphic novels on growing up with HIV (based on ARROW Young Lives research) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact We produced a series of 3 graphic novels to communicate the findings of the ARROW Young Lives social science sub-study. These novels explore what it is like to grow up with HIV in Uganda. The novels are available in English and Luganda.
The novels were distributed to study participants at a results meeting, and to clinic waiting rooms. They are also available online, and are being translated into different languages for use in other countries.
Year(s) Of Engagement Activity 2015
URL http://www.ctu.mrc.ac.uk/resources/multimedia/arrow_graphic_novels/
 
Description Series of training videos for managing children on antiretroviral therapy 
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 We have produced a set of interactive training videos to teach paediatric HIV care. The videos were filmed mostly in a district hospital in Malawi and follow the management of children with HIV over time. They are designed to force students to make the kinds of clinical decisions they will face in their work. Topics include early infant diagnosis, ART initiation, common opportunistic infections, drug reactions and assessing possible treatment failure.

The videos have frequent stop points with questions which can be used to generate discussion. They are accompanied by detailed notes for teachers and trainers which can easily be adapted to different settings and guidelines. At present the videos are being used in PENTA (Paediatric European Network for the Treatment of AIDS) courses which are held around the world.

The films are available to watch and download for free on our Vimeo Channel, where the notes and scripts can also be downloaded. They vary in length from 3 minutes to 16 in length. At present 12 videos are complete. There will be an additional 8 videos uploaded in coming months.
Year(s) Of Engagement Activity 2014,2015,2016
URL http://www.ctu.mrc.ac.uk/resources/multimedia/arrow_videos_and_teaching_scripts/