Randomised controlled trial of podoconiosis treatment in northern Ethiopia.

Lead Research Organisation: University of Sussex
Department Name: Brighton and Sussex Medical School

Abstract

Podoconiosis is one of the forgotten types of leg swelling (elephantiasis) in the tropics. Unlike the other, better-known types of leg swelling, podoconiosis is not caused by any parasite, virus or bacterium, but by an abnormal reaction to minerals found in the clay soils of some tropical highland areas. Although an estimated 4 million people are affected by podoconiosis across Africa, there is no government health service provision for patients in any endemic country. In Ethiopia, where 1 million people with podoconiosis live, non-government organizations (NGOs) have been responsible for the development of simple treatment methods using low-cost, locally accessible materials. Treatment takes the form of foot hygiene, skin care, bandaging, exercises to improve lymph drainage and use of socks and shoes. Although the NGOs consider the treatment to be effective, no formal test has yet been conducted.
Our main objective is to test whether the 'standard' treatment reduces the number of times a patient experiences 'acute episodes', when the leg become hot, painful and more swollen than usual. These episodes significantly compromise patients' ability to work or carry out normal day-to-day tasks. We will also test whether the effectiveness of 'standard' treatment can be increased by first giving daily lymph drainage massage for two weeks. We will measure the cost-effectiveness of both types of treatment in relation to the costs of living with untreated disease.
The trial will be sited in northern Ethiopia, where 3% of the adult population is affected by podoconiosis. Prior to the trial, an economic context survey will be performed to supply background information on typical work hours and settings, labour and medical costs and productivity losses related to podoconiosis. The trial will also be preceded by rapid ethical assessment to identify optimal methods of conveying information about the trial and the approaches to obtaining informed consent preferred by the community.
We have identified and located at least 2000 patients who need treatment but are not yet receiving it. We plan to randomly allocate 900 of these patients to one of three groups: either to 'standard' treatment, or to 'intensive' treatment or to delayed treatment. Provision of care will be organised through the IOCC Podoconiosis Project, which already has excellent links with the community and local government. The randomisation process, data monitoring and statistical analysis will be overseen by experts at the Clinical Trials Facility in Kilifi, Kenya, who will make twice-yearly visits to the trial site. Data collection will be performed monthly by a team of 10 recruited specifically for the task, and independent of the community project assistants providing care. More detailed examination will be performed at 6 months and 1 year. The Clinical Trials Facility will ensure data quality, will monitor safety reports and will supervise data analysis, building capacity within Ethiopia for future clinical trials through frequent training and monitoring visits.
The results of the trial will be disseminated through a workshop in Addis Ababa to government and non-government organizations affiliated to the Ethiopian National Podoconiosis Action Network; through peer-reviewed publications and Footwork (the new International Podoconiosis Initiative) to stakeholders in other podoconiosis-endemic countries.

Technical Summary

The objective of this trial is to test the effectiveness of lymphoedema management in podoconiosis patients. We plan to achieve this using a pragmatic, single-blind, randomised controlled trial (RCT) with three intervention 'arms' that will compare two models of podoconiosis lymphoedema management in the community with delayed treatment (as control).

'Standard' podoconiosis lymphoedema intervention consists of twice-weekly group meetings with instruction and practical demonstration of foot hygiene by a community project assistant. Management comprises: foot hygiene, use of emollient, bandaging, exercises to improve lymph drainage, elevation of the foot of the bed and use of shoes and socks. 'Intensive' podoconiosis lymphoedema management consists of 'standard' plus additional 5 times per week clinic-based manual lymphatic drainage for one hour for the first two weeks.

900 adult podoconiosis patients located in independent households will be randomised, 300 to each arm. The primary outcome is incidence of acute dermatoadenolymhangitis (ADLA, a common, debilitating complication of untreated podoconiosis). Secondary outcomes include adherence with treatment, clinical stage of disease, lower leg and foot circumference, quality of life, prevalence of entry lesions, duration of ADLA, perceived stigma and economic productivity. The principal analyses will be conducted at 6 and 12 months of follow-up, and will be based on the rate of ADLA events using multivariable Poisson regression.

Results will be disseminated rapidly through the National Podoconiosis Action Network in Ethiopia, and through Footwork, the International Podoconiosis Initiative, to stakeholders in other podoconiosis-endemic countries, as well as through more conventional academic channels such as peer-reviewed articles. The demand for information from potential podoconiosis care-giving organisations is high, and application of results is likely to be swift.

Planned Impact

Who will benefit from this research?
Beneficiaries of our research will include patients, their families and communities; government and non-government health workers who care for patients with podoconiosis; policy makers and governmental health agencies in endemic countries; and the private sector.

How will they benefit?
Patients, their families and communities: Although not usually fatal, podoconiosis reduces the health and wellbeing of about 4 million people globally and constrains economic development in many countries. Patients are highly stigmatised, excluded from social and religious gatherings and marriage, and disabled in their most economically productive years, losing an estimated 45% of working days to the disease. We aim to collect data demonstrating cost-effectiveness of podoconiosis lymphoedema treatment in order to influence government policy to invest scarce resources to relieve suffering and restore productivity among podoconiosis patients. Improved health and wellbeing will lead to economic benefits for patients and their dependents that will benefit the wider community. Within Ethiopia, patients and their families are likely to experience benefits within 5 years of the completion of the trial, since podoconiosis is already included in the National Integrated Management of NTD Strategy.

Public and voluntary sector health workers: the trial results will be used to influence professional practice, benefitting those who treat podoconiosis patients. Until recently, little information on podoconiosis existed in health curricula in endemic countries, and most health professionals were unaware that treatment was possible. In 2011, the PA worked with Open University to develop an in-service training module for Ethiopian Health Extension Workers (http://labspace.open.ac.uk/mod/oucontent/view.php?id=452781), and evidence from the proposed trial will be added to this and to training materials for other government and non-government health professionals in endemic countries. We anticipate the timeline of adaptations of materials to be within one year of completion of the trial.

Transferable professional skills: in addition to academic skills described elsewhere, staff working on the project will develop a range of skills (e.g. in people, project and finance management; leadership; communication and strategy) appropriate to their role in the project which will be transferable to other sectors in future.

Policy makers in endemic countries: The impact of our earlier research is demonstrated by the formal adoption of podoconiosis as a Neglected Tropical Disease (NTD) by WHO and the inclusion of podoconiosis into the Ethiopian Ministry of Health's Integrated Management of NTD Strategy. We will use these channels and Footwork, the International Podoconiosis Initiative, to bring the results of the proposed trial to policy makers in affected tropical countries. As the host country of the first RCT in podoconiosis, Ethiopia's place as a leader in podoconiosis control will be consolidated, which will have beneficial impact on researchers' careers, and potentially, national pride.

Global funding bodies: The trial results will also be important for those prioritizing decisions at major global funding bodies. Clear evidence of treatment effectiveness will be essential to attract substantial funds towards a global podoconiosis control programme.

Private Sector: Should the lymphoedema treatment trialled prove successful, business opportunities to manufacture the consumables required for treatment will open up. Some of these opportunities will be within government-controlled industries (pharmaceuticals), but others will be open to private investment and entrepreneurship (socks, shoes). The estimated 1 million patients within Ethiopia will create a substantial internal market through both government and private procurement.
 
Title Animated video 'Best Foot Forward' 
Description This video was developed by RippleEffect Images, a US-based group of journalists. The PI provided information based in part on the Golbet trial. 
Type Of Art Film/Video/Animation 
Year Produced 2016 
Impact The video is only just out, but has already attracted interest from endemic country policy makers. Our Artist in Residence will be using it in March as part of a workshop for the Octagon Club and Transitions Art Group based at Orleans House, Twickenham. 
URL http://rippleeffectimages.org/films/
 
Title Clay workshop 
Description Two half-day workshops held at Orleans House, Twickenham, to explore ideas of 'exposure' and 'protection' in relation to podoconiosis, soil and shoes. About 20 adults and young people modeled shoes from clay mixed with soil from podoconiosis-endemic areas. 
Type Of Art Artwork 
Year Produced 2016 
Impact The models were displayed in an exhibition (part of 'The Golden Thread' at the Stables Gallery. 
URL http://www.richmond.gov.uk/home/services/arts/the_stables_gallery/stables_previous_exhibitions/2016_...
 
Description Input into Ethiopian National NTD Guideline (2nd edition, 2017)
Geographic Reach National 
Policy Influence Type Participation in a national consultation
URL https://www.infontd.org/resource/second-edition-national-neglected-tropical-diseases-master-plan
 
Description Input to Rwanda National Neglected Tropical Disease and Other Parasitic Disease Guidelines, February 2018
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Input to SKin-NTD guidelines being developed by WHO
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Description Meeting with Minister for Health, Dr Keseteberhan Admassu, February 2015
Geographic Reach National 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
 
Description Meeting with State Minister for Health, Dr Kebede Worku, February 2016
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description Participation in Ethiopian Federal Ministry of Health Annual NTD Review Meeting
Geographic Reach Africa 
Policy Influence Type Participation in a advisory committee
 
Description Submitted evidence to 'Road Map to the Development of a 3rd NTD Masterplan' workshop in Addis Ababa, Ethiopia
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact The Ministry of Health has committed domestic budget (9 million Ethiopian Birr, approx £330,000) to training of health professionals in lymphoedema care for podoconiosis patients in the three most endemic regions of Ethiopia.
 
Description IMPRESS - Improving access to integrated Morbidity management and disability PREvention Services through Stigma reduction for people with lower limb lymphoedema in Ethiopia: Feasibility and quasi-experimental study.
Amount $193,775 (USD)
Organisation Government of the UK 
Department Department for International Development (DfID)
Sector Public
Country United Kingdom
Start 03/2020 
End 02/2021
 
Description NIHR Global Health Research Units
Amount £5,700,000 (GBP)
Funding ID 16/136/29 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 06/2017 
End 03/2021
 
Description Social Sciences for Severe Stigmatising Skin Diseases (the 5-S Foundation).
Amount £3,519,288 (GBP)
Funding ID 200140 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 09/2019 
End 08/2023
 
Description University of Sussex Chancellor's International Scholarship
Amount £48,600 (GBP)
Organisation University of Sussex 
Sector Academic/University
Country United Kingdom
Start 10/2013 
End 09/2016
 
Title Development of ADLA diary 
Description Patients with podoconiosis experience foot swelling which extends up the leg (lymphoedema). The lymphoedema is sometimes accompanied by attacks of fever or rigors and intensified pain and swelling. These episodes are known as attacks of acute dermatolymphangioadenitis (ADLA), which are thought to become more frequent as the disease progresses and worsen the damage caused to the lymphatic vessels with each attack. To date there has been no tool developed to measure occurrence of ADLA. We developed a simple diary in which patients record ADLA attacks. We have demonstrated that completing these diaries is feasible, and the attacks recorded by patients are valid when compared with diagnosis by a local health professional, ie the diaries enable valid recording of ADLA. 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? No  
Impact This tool may in the future be used by other groups investigating conditions in which ADLA occurs, for example, lymphatic filariasis. 
 
Title Rapid Ethical Assessment 
Description Rapid Ethical Assessment is a type of rapid ethnographic assessment conducted before the start of a study among key stakeholders, to guide the research process. We used this during the preparatory phases of the trial to inform the approach to the community and the informed consent process. 
Type Of Material Improvements to research infrastructure 
Year Produced 2013 
Provided To Others? Yes  
Impact Has been used in Cameroon and is being assessed prior to three other projects within Ethiopia. 
 
Title GoLBeT database 
Description The Golbet database is available for use by other interested researchers under the terms of a data sharing policy available via http://www.podo.org/research/current/golbet-trial/ 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact The GoLBeT team has published from this database (see Outputs). As yet no other researcher has applied for access. 
URL http://www.podo.org/research/current/golbet-trial/
 
Description GolBet GlobalHealthTrials partnership 
Organisation Imperial College London
Department School of Public Health
Country United Kingdom 
Sector Academic/University 
PI Contribution Members of our research team have contributed blogs to the website (https://globalhealthtrials.tghn.org/), particularly in the area of Rapid Ethical Assessment.
Collaborator Contribution The online training courses offered by GlobalHealthTrials have been invaluable for GolBet team members and the Local Safety Monitors. An on-site training course on Clinical Trials, which will include faculty of nearby Universities, is planned for Spring 2015.
Impact One output has been setting up a methodology study to run in parallel with the GolBet trial. This is described in the following article: A research methodology study to map the process of initiating and operating a randomised controlled trial of podoconiosis treatment in northern Ethiopia. Lang T, Clarke M, Newport MJ, Enquoselassie F, van Loggerenberg F, Franzen S, Furtado T, Njuguna P, Fegan G, Davey G. Trials 2013; 14:031.
Start Year 2013
 
Description GolBet-MoreTrials collaboration 
Organisation MoreTrials
Country Global 
Sector Charity/Non Profit 
PI Contribution MoreTrials is a campaign for more, better trials. I was asked to co-sign a letter to the European Medicine Agency about the proposed update to GCP-ICH which would have hampered future trials, and to join MoreTrials to ensure a strong collective voice on the issue.
Collaborator Contribution MoreTrials will lead a campaign to renew guidelines on trials so these better reflect current trial practice.
Impact Letter to the European Medicine Agency submitted early February 2016.
Start Year 2016
 
Description Golbet-Kilifi CTF Partnership 
Organisation Kenyan Institute for Medical Research (KEMRI)
Department Clinical Trials Facility
Country Kenya 
Sector Charity/Non Profit 
PI Contribution The Golbet Trial Coordinator and Data Manager attended Kilifi CTF for 2 weeks' training on GCP and OpenClinica in early September 2013.
Collaborator Contribution Kilifi CTF staff hosted the training and provided practical field visits as well as training on SOPs, CRFs and database management.
Impact Not yet, this is part of preparation for the Golbet trial.
Start Year 2013
 
Description Partnership with CDT-Africa 
Organisation Center for innovative Drug Development and Therapeutic Trials for Africa
Country Kenya 
Sector Charity/Non Profit 
PI Contribution Members of the GoLBeT research team supported the launch of the Centre for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa) and have subsequently developed successful funding proposals.
Collaborator Contribution The Center for innovative Drug Development and Therapeutic Trials for Africa is a semi-autonomous, World Bank supported regional center of excellence for education and research. Its vision is to be an Africa-based, world-class center that provides ground-breaking discoveries and inventions of drugs, vaccines, diagnostics and other interventions. Objectives are to support equitable access to interventions (medicines, vaccines, diagnostics and other interventions) and bring about sustainable development in Africa through high quality capacity development for novel therapeutic discoveries supported by clinical trials. The approaches used will Increase human and infrastructure capacity, generate high quality research for therapeutic discovery, develop skils for industrial manufacturing in Africa, and create sustainable impact through medicinal plant conservation, public and policy engagement, and sustainable financing.
Impact NIHR Global Health Research Unit funded in 2018 - multidisciplinary collaboration which includes public health, spatial epidemiology, social science, ethnobotany, pharmacology and engineering.
Start Year 2017
 
Description TAKeOFF consortium - doxycycline in podoconiosis trial 
Organisation University of Bonn
Department Institute of Medical Microbiology, Immunology and Parasitology
Country Germany 
Sector Academic/University 
PI Contribution Advisory role during protocol development and on DSMB for trial.
Collaborator Contribution Secured funding for trial from German Federal Ministry of Education and Research, developed protocol, has responsibility for executing trial in North West Cameroon
Impact Trial is underway
Start Year 2015
 
Title Simple lymphoedema management 
Description The simple lymphoedema management package comprises training in self-care to - i) soak and wash the feet with soap; ii) dry the feet and apply Whitfield ointment; iii) apply short-stretch bandages if appropriate; iv) use socks and shoes; v) perform regular exercises to promote lymph drainage; vi) make adaptations to eg. raise the foot of the bed. Group training sessions are held monthly, and patients advised to practise self-care daily in their own homes. 
Type Management of Diseases and Conditions
Current Stage Of Development Small-scale adoption
Year Development Stage Completed 2017
Development Status Under active development/distribution
Impact The intervention targets a difficult to reach population: patients with podoconiosis in remote rural communities. This is the first trial of this podoconiosis lymphoedema management package. We anticipate having results on its impact on morbidity, economic benefits and quality of life in May 2017. We will report on impact in terms of public health policy subsequent to that. 
URL http://www.podo.org/research/current/golbet-trial/
 
Description Close-out celebration 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact A 'close-out' celebration was held at which carers were presented with certificates of recognition.
Year(s) Of Engagement Activity 2016
 
Description Conference Presentation, 11th International Statistics Days Conference, Bodrum, Turkey 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The study data manager, Dr Meseret Molla, presented the main GoLBeT outcomes to an audience of statisticians and triallists at the International Statistics Conference in Bodrum, Turkey.
Year(s) Of Engagement Activity 2018
URL http://igs2018.mu.edu.tr/en
 
Description Conference Presentation, First International Podoconiosis Conference, Addis Ababa 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact The main outcomes of GoLBeT were presented at the First International Podoconiosis Conference in Addis Ababa on September 23rd, 2018. The conference was attended by about 150 delegates, who included patients, implementers, policy makers and academics.
Year(s) Of Engagement Activity 2018
URL https://podo.org/conference-2018/presentations
 
Description Dissemination workshop in Addis Ababa 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact About 45 people attended the Addis Ababa dissemination workshop on May 24th, 2017. Delegates included podoconiosis care implementers from four regions of Ethiopia, research staff from 7 Universities and FMoH representatives. Members of the GoLBeT research team outlined the background to the trial, explained the methodology and then presented the key results. The participants then discussed how the findings would change policy and practice.
Year(s) Of Engagement Activity 2017
 
Description Dissemination workshop in East Gojjam Zone 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact A regional dissemination workshop was held on Saturday 3rd June for implementers across the district and officials from the Amhara Regional Health Bureau. GoLBeT team members introduced the background to the trial, outlined the methods and explained the results. Discussion on the feasibility of roll out across Aneded district and East Gojjam zone ensued.
Year(s) Of Engagement Activity 2017
 
Description End of fieldwork 'handover' workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Trial team updated woreda (district) health officials on completion of trial fieldwork and handover of patients trained in self-care.
Year(s) Of Engagement Activity 2016
 
Description Regional Faculty for 2015 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact In collaboration with GlobalHealthTrials, a workshop on 'Essential Clinical Research Skills: a skills-sharing workshop' was conducted at Debre Markos University, June 15-17, 2015. 96 teaching staff and postgraduate students participated.
Year(s) Of Engagement Activity 2015
 
Description Woreda refresher sensitisation 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Key district health officials attended a morning workshop to explain the progress of the trial and the plans for its final year. Numbers of participants enrolled by 'kebele' (sub-district) were presented, as were the plans for handover of care to the Faith-Based Organisation working in the zone (International Orthodox Christian Charities). Questions were taken and plans for future dissemination of information made.
Year(s) Of Engagement Activity 2016
 
Description Woreda sensitisation meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact 46 participants (including health extension workers in the selected areas, area chairmen, health center heads, woreda (district) health, education, agriculture and administration officers) attended a meeting at which the scale of the problem of podoconiosis and its impact on socio-economic development were discussed. The options for prevention and treatment were explained, as was the role of GolBet in building evidence for treatment.

The woreda administration pledged cooperation and collaboration for the duration of the trial.
Year(s) Of Engagement Activity 2013
 
Description World Service Global Briefing 
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 Public/other audiences
Results and Impact The PI (Prof. Gail Davey) was interviewed by the BBC World Service Global Briefing team in May 2018, shortly after publication of the main outcome article. The interview was aired twice in the following week, featured in the 'Africa' News section of the main BBC website, and was then available on iPlayer.
A number of listeners subsequently made contact, including patients with lymphoedema, practitioners/implementers and researchers.
Year(s) Of Engagement Activity 2018
URL https://www.bbc.co.uk/programmes/w3cswjkg