Efficacy, Safety and Dose Response of Vitamin D in Prevention of Dengue Haemorrhagic Fever and Dengue Shock Syndrome- A Phase 2 Open-label Randomized Controlled Trial

Dengue is an arthropod-borne disease, found in tropical and sub-tropical climates worldwide, mostly in urban and semi-urban areas. Unfortunately, there is no intervention available to stop dengue severity. Despite significant efforts into developing vaccine and antiviral drug for dengue fever over the years, numerous challenges remain before an efficient, safe vaccine and antiviral drug. Dengue Haemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS) are a serious form of dengue infection that can escalate in a non-negligible percentage of febrile patients. Factors responsible for this deterioration are weakly understood. The host's genetics and secondary infections from novel dengue serotypes are obvious risk factors. The dietary state of the host has also been emphasized as a potentially important predictor of progression because some nutrients have potent immunomodulatory effects. Vitamin D is particularly important as it has ability to control immunological processes, including the downregulation of pro-inflammatory Th1 activity, which has been linked to the pathophysiology of severe dengue. There is a preliminary study regarding the effectiveness of vitamin D in the prevention of DHF and DSS in human. But a larger study is needed to prove its utility. The objective of the study is to determine the role of Vitamin D in efficacy, safety and dose response in the prevention of DHF and DSS. This will be an open-label Phase-2 Randomized controlled trial (RCT) which will be carried out in Dengue cell, Emergency Department and Outpatient Department (OPD) of Medicine Department in Bangabandhu Sheikh Mujib Medical University, Dhaka. It will be conducted from September 2023 to August 2024 enrolling about 120 patients from Dengue cell, Emergency Department and OPD of Medicine Department BSMMU. The duration of the study will be one year. All the investigations will be done in BSMMU. Patients will be followed up by phone call and physical visit. Those with severe symptoms will be admitted and evaluated accordingly. The study will have three arms namely, Arm 1(receiving standard care), Arm 2(receiving standard care and 2,00,000 IU Vitamin D oral solution) and Arm 3(receiving standard treatment and 4,00,000 IU Vitamin D oral solution). The patients will be enrolled according to inclusion criteria (having age more than 18 to 65years, NS1 positive, fever more than ≥38°C for 3days or less, typical sign symptoms of Dengue fever) and exclusion criteria (>72hours of fever, critically ill patients, pregnancy, known Vitamin D hypersensitivity, high serum calcium level, hypoalbuminaemia, malignancy, known nephrolithiasis and severe renal impairment). Information will be obtained on socio-demographic and clinical characteristics through face to face interview using a structured questionnaire. Clinical data and relevant blood samples will be taken at first appointment then after 4th day and 8th day of enrollment. This study has minimal chance of physical risks. Study purpose will be explained to the participants and informed written consent will be taken before collection of data. Data will be collected with assurance of proper safety and privacy. The interventional drug, vitamin D3 is a widely used agent with rare minimal side effects like, vomiting, abdominal pain, headache, constipation etc. Each participant will be counselled about the outcome of the drug and will be followed up and managed for potential side effects. Participants will be identified by a code number, strict confidentiality and anonymity will be maintained. There will be no loss of work time and no compensation will be available for the participants as this will be a part of standard care. On the other hand, this study would be helpful for both the clinician and the patients in making a rational approach in Group A Dengue fever for the prevention of DHF and DSS. Prior to the commencement of this study, the research protocol will take approval from Research and Training Monitoring Department(RTMD) of BCPS. The analyzed data will be presented in the form of text, tables, and graphs. Finally collected data will be analyzed by graph pad prism. Statistical analysis will be performed by Chi-square test on categorical data and one way ANOVA with Tukey's multiple comparisons test on continuous data. Kaplan-Meier Curve will be used to study the progression into DHF and DSS. This study, for the first time in Bangladesh, will obtain the baseline data regarding the utility of Vitamin D therapy in Dengue uncomplicated cases in preventing further deterioration of clinical severity and mortality. This trial will help clinicians and policy makers to avail a possible repurposing of Vitamin D for prevention of severe dengue. In addition, it will guide designing larger study to generate strong evidence and change the national health response accordingly.