Trial background and governance
GoLBeT was a pragmatic randomized controlled trial of podoconiosis lymphoedema management (ISRCTN67805210). The trial was funded by the UK Joint Global Health Trials initiative in 2013. The protocol, including numbers and dates of all ethical approvals, has been published [10]; in essence, the trial compared patients randomized to the intervention arm (who were trained to self-care using a hygiene and foot care intervention which comprised use of soap, Whitfield ointment, bandages, socks and shoes, exercise and elevation) with patients randomized to the control arm, who were followed quarterly but received no intervention until the trial was completed. The primary outcome was reduction in frequency of ADLA episodes. Patients in both groups filled in a monthly primary outcome diary and Case Report Forms (CRFs) were completed at 3-monthly intervals.
Trial setting and participants
The trial was conducted in Aneded district, East Gojam Zone, Amhara regional state (Fig. 1). There are 19 kebeles (sub-districts) in Aneded district (Fig. 2), which is 18 km from the zonal capital, Debre Markos, where the trial field coordination office was located [11]. Debre Markos is 305 km from Addis Ababa, a drive of approximately six hours which crosses the Blue Nile Gorge. At the time of this trial, no formal government or private treatment for podoconiosis was available within Aneded district. Within the district, there are two health centres, and each kebele has a health post. Reaching these health posts could take up to two hours from the asphalt in the dry season, and longer in the rainy season. We made the decision not to include the most remote kebele (Malgash, 19 in Fig. 2) even though many patients were registered there, because access entailed a 1.5 h drive and then a 1.5 h walk. However, patients in Malgash were given education about podoconiosis and three months’ treatment supplies, at the close of the trial.
Inclusion and exclusion criteria are detailed in the protocol [10], and their application resulted in exclusion of only 19 of 1339 patients screened.
External support and monitoring
The trial coordinator and data manager spent two weeks at the KWTRP Clinical Trials Facility during the preparatory period. They were given hands-on training in several important aspects of trial management including development of Standard Operating Procedures (SOPs), logs, forms and master files; use of GPS; handling of the intervention product; Good Clinical Practice (GCP) training of field staff; management of hard-copy data; OpenClinica and other database development. Trial monitoring site visits were conducted by staff of the KWTRP Clinical Trials Facility and the Nuffield Department of Tropical Medicine, Oxford University. A Trial Preparation Visit was made in April 2013, a Site Initiation Visit in December 2014, Routine Monitoring Visits were made in March 2014 and December 2015, and a Close Out Visit in May 2017. These visits and a series of Skype calls aimed to review protocol fidelity and regulatory compliance.
Development of trial Proformas
Under guidance from the KWTRP Clinical Trials Facility, SOPs were developed by the trial coordinator, the data manager (both based in Ethiopia) and the UK-based trial principal investigator through email exchanges, weekly Skype meetings and quarterly face-to-face meetings. Information gathered through a Rapid Ethical Assessment [12] was used to develop the patient information sheet and informed consent forms. Meetings to explain the trial were held with district Health Office personnel and with larger gatherings (including administrative, education, agriculture and religious leaders and Health Extension Workers from kebeles selected for the study). These aimed to disseminate accurate information about the trial through the district and to garner support of the various departments to ensure the smooth conduct of the trial.
CRFs were prepared for baseline, 3, 6, 9 and 12 months, according to the data collection schedule described in the protocol [10]. These were made easily distinguishable through different coloured covers (white, blue, green, purple and yellow, respectively). In addition, a patient-completed pictorial diary was developed. Patients were trained to complete the diary by inserting a mark in the appropriate column for that day – either one headed by a picture of a person in bed with ADLA or one headed by a person working in the field (both men and women work in the field in this part of rural Ethiopia). The diary was tested for acceptability, feasibility and accuracy using patient interviews and assessment of patient records against health professional diagnoses. The Ethiopian calendar was used for data collection and entry.
Recruitment and training of field staff
Twenty Community Podoconiosis Agents (CPAs), and two CPA supervisors; ten data collectors and two data collector supervisors were recruited and given five days’ training on GCP, screening, informed consent administration and enrollment (all field staff); on data collection, data management and data security procedures (data collectors and their supervisors); and on intervention training, outcome diary checking and adherence monitoring (CPAs). Because of delays in gaining ethical approval, another five days’ refresher training was given immediately before enrollment commenced.
Database development
After consideration of continuity of power supply, internet access, servicing, security and protection from water damage, the server was located in the IOCC office in Addis Ababa rather than in Debre Markos. An OpenClinica template was created and tested prior to data entry. Difficulties exporting data to other programmes were resolved. Two data entry clerks were given three days’ training to enter baseline data from the Case Report Forms. Access to the database from the KWTRP Clinical Trials Facility was tested several times before data entry was commenced.
Ethical and regulatory considerations
Ethical approval required three serial applications. Approval from the School of Public Health was a prerequisite of applying to the Addis Ababa University Institutional Review Board (IRB). Approval from the IRB was necessary before the process could continue with the national regulator and the national ethics review committee in Ethiopia. Regulatory approval elicited questions about the need for purchase approval for the intervention product even though it was already publicly available. Approval at national level was delayed because this committee was disbanded in the week following submission of the GoLBet dossier, and was not reconvened for several months. Another reason for the delay at national level was loss of the study documents submitted for review, necessitating resubmission. Approval was eventually given at the start of the rainy season, so the decision was made to postpone screening until after the rainy season so as to maximise enrollment. A six-month extension to the project was requested and granted by the funding body.