Setting up a Clinical Trial for a Novel Disease: a Case Study Of

Global Health Action ISSN: 1654-9716 (Print) 1654-9880 (Online) Journal homepage: http://www.tandfonline.com/loi/zgha20 Setting up a clinical trial for a novel disease: a case study of the Doxycycline for the Treatment of Nodding Syndrome Trial – challenges, enablers and lessons learned Ronald Anguzu, Pamela R Akun, Rodney Ogwang, Abdul Rahman Shour, Rogers Sekibira, Albert Ningwa, Phellister Nakamya, Catherine Abbo, Amos D Mwaka, Bernard Opar & Richard Idro To cite this article: Ronald Anguzu, Pamela R Akun, Rodney Ogwang, Abdul Rahman Shour, Rogers Sekibira, Albert Ningwa, Phellister Nakamya, Catherine Abbo, Amos D Mwaka, Bernard Opar & Richard Idro (2018) Setting up a clinical trial for a novel disease: a case study of the Doxycycline for the Treatment of Nodding Syndrome Trial – challenges, enablers and lessons learned, Global Health Action, 11:1, 1431362, DOI: 10.1080/16549716.2018.1431362 To link to this article: https://doi.org/10.1080/16549716.2018.1431362 © 2018 The Author(s). Published by Informa Published online: 31 Jan 2018. UK Limited, trading as Taylor & Francis Group. Submit your article to this journal Article views: 108 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=zgha20 GLOBAL HEALTH ACTION, 2018 VOL. 11, 1431362 https://doi.org/10.1080/16549716.2018.1431362 STUDY DESIGN ARTICLE Setting up a clinical trial for a novel disease: a case study of the Doxycycline for the Treatment of Nodding Syndrome Trial – challenges, enablers and lessons learned Ronald Anguzu a,b,c, Pamela R Akuna,b, Rodney Ogwanga,b, Abdul Rahman Shourc, Rogers Sekibiraa,b, Albert Ningwaa,b, Phellister Nakamyad, Catherine Abboa, Amos D Mwakaa, Bernard Opard and Richard Idroa,b,e aDepartment of Paediatrics and Child Health, Makerere University College of Health Sciences, Uganda; bDepartment of Paediatrics and Child Health, Centre of Tropical Neuroscience, Kitgum Site, Uganda; cInstitute of Health and Equity, MoH, Medical College of Wisconsin, Kampala, USA; dMinistry of Health, Headquarters, Uganda; eNuffield Department of Medicine, University of Oxford, Oxford, UK ABSTRACT ARTICLE HISTORY A large amount of preparation goes into setting up trials. Different challenges and lessons are Received 23 October 2017 experienced. Our trial, testing a treatment for nodding syndrome, an acquired neurological Accepted 8 January 2018 disorder of unknown cause affecting thousands of children in Eastern Africa, provides a RESPONSIBLE EDITOR unique case study. As part of a study to determine the aetiology, understand pathogenesis Stig Wall, Umeå University, and develop specific treatment, we set up a clinical trial in a remote district hospital in Sweden Uganda. This paper describes our experiences and documents supportive structures (enablers), challenges faced and lessons learned during set-up of the trial. Protocol develop- KEYWORDS ment started in September 2015 with phased recruitment of a critical study team. The team Nodding syndrome; spent 12 months preparing trial documents, procurement and training on procedures. randomized clinical trial; doxycycline; Kitgum General Potential recruitment sites were pre-visited, and district and local leaders met as key stake- Hospital holders. Key enablers were supportive local leadership and investment by the district and Ministry of Health. The main challenges were community fears about nodding syndrome, adverse experiences of the community during previous research and political involvement. Other challenges included the number and delays in protocol approvals and lengthy procurement processes. This hard-to-reach area has frequent power and Internet fluctuations, which may affect cold chains for study samples, communication and data management. These concerns decreased with a pilot community engagement programme. Experiences and lessons learnt can reduce the duration of processes involved in trial-site set-up. A programme of community engagement and local leader involvement may be key to the success of a trial and in reducing community opposition towards participation in research. Background inter-institutional factors, which may be protracted and challenging [8]. In Uganda, most clinical trials Randomized clinical trials (RCTs) are considered the have focused on infectious diseases such as malaria, criterion standard to assess the efficacy of interven- HIV/AIDS and tuberculosis. Infrastructural demands, tions or treatment [1]. Conducting RCTs is time- scarcity of trained personnel and lack of funding are consuming and expensive [2,3]. Complexity of trial also common limitations. Other hindrances to setting conduct usually occurs in multiple sites or those up trials such as site identification, methodological focused on poorly understood disorders or in emer- concerns related to study design, ethics and results gencies. Physical access issues such as distant sites interpretation with implications for practice and pol- and community perceptions further complicate site icy are poorly documented. set-up. Trials may experience logistical challenges Planning for clinical trial site initiation typically such as sophisticated equipment and materials, begins before protocol development with the conduct which may be costly or unavailable [4]. of feasibility assessments for their suitability and Experiences from the increasing number of clinical readiness in respective settings [9]. As part of the trials conducted in low-income countries is seldom planning process, investigators need to consider reported [5,6]. The complexity of implementing trials building a qualified implementation team, assessing includes lengthy procedures for study approval, reg- the local environment and complex dynamics of the ulatory processes and community engagement needs, target community, infrastructure needs and the which make trial set-up labour-intensive and costly potential to conduct and complete the trial within [7]. In addition, the process of testing Investigational the proposed timelines. The process of involving Medicinal Products and material procurement such communities in the research process is becoming as equipment or drugs often depends on intra- and CONTACT Ronald Anguzu [email protected] Medical College of Wisconsin, USA © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 2 R. ANGUZU ET AL. increasingly important because this demonstrates monitoring. Similar scheduled follow-up visits will be mutual respect for participants [10]. From a commu- conducted in the 3rd, 6th, 12th and 18th month visits nity perceptive, engagement of the general public in peripheral clinics or KGH. Unscheduled visits, i.e. enables their understanding of ethical concerns such assessments occurring between specified follow-up as a participant vulnerability [11]. visits for unanticipated illnesses, are expected. At Nodding syndrome is a devastating neurological 24 months after the intervention, all participants disorder of unknown cause affecting children in will be assessed for the primary outcome (end- Eastern Africa [12]. Head nodding is the pathognomo- point) in the KGH. The trial primary outcome will nic symptom with onset in children aged 3 to 18 years be the proportion of patients with antibodies to neu- [13]. Subsequent complications include multiple sei- ron surface proteins (leiomodin) in the 24th month. zure types, cognitive decline, behavioural problems, This case study describes the step-by-step activities psychiatric disorders, severe physical disability, malnu- involved in setting up this clinical trial and prepara- trition, and delayed physical growth and sexual devel- tions made to operationalize the trial site. opment [14]. Symptoms, however, improve with symptomatic treatment [15]. Many deaths have been Setting reported often associated with status epilepticus, drowning and severe burns [12]. To date, the only The study area includes the districts of Kitgum, Pader strong aetiologic association is infection by and Lamwo in Northern Uganda with a 2016 mid-year Onchocerca volvulus [16]. More recent pilot studies population projection of 209,600, 183,500 and 137,000 suggest that nodding syndrome may be a neuro- respectively [19]. This community is predominantly inflammatory disorder with antibodies to O. volvulus involved in agricultural activity for subsistence inhab- cross-reacting with host neuron proteins [12,17]. Our ited mainly by people belonging to the Acholi ethnic study, Doxycycline for the Treatment of Nodding group. The population prevalence of nodding syn- Syndrome (ClinicalTrials.gov NCT02850913), is a drome in the affected region is 6.8 (95% CI 5.9–7.7) novel trial [18]withaconcurrentnestedcase–control per 1000 [20]. The region has high poverty levels, study investigating the cause and pathogenesis of nod- psycho-socio problems and neglected tropical diseases, ding syndrome. The trial is examining the efficacy and and until recently, most of the population lived in safety of 100 mg of oral doxycycline or placebo daily internally displaced people’s camps during a pro- for six weeks as treatment for nodding syndrome in tracted two-decade civil war. KGH is a public health Uganda. This paper describes

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