What is the treatment effect of two different dose regimes of LNS against placebo in reducing the incidence of dengue patients who progress into critical phase and related complication?

Study setting: The study will be conducted at the National Institute of Infectious Diseases (NIID), Angoda. Patients who visit the OPD of the NIID and diagnosed with dengue, confirmed by a positive NS1 antigen, will be invited to participate in the study. A leaflet containing a brief introduction about the study will be distributed among the patients. Volunteer participants who fulfill the inclusion criteria will be recruited to the study.

Randomization: Simple randomization method using computer-generated random numbers

Blinding: Neither participants, nor investigators, nor data collectors nor the study team nor data analysts will be aware of treatment assignments prior to the final breaking of codes of data base. The code of database will be opened after completion of data analysis and conclusion of the study.

Intervention: Two doses of treatment and placebo tablets will be packed into identical white HDPE (High Density Polyethylene) plastic bottles numbered from 1 to 240 by a senior R&D Scientist (Pharmacist) at Link Natural Products (Pvt.) Ltd. according to the list of computer-generated random numbers provided by the statistician. The label of each bottle will indicate only the patient’s random number and the directions for taking the tablets. Each bottle will contain 60 tablets needed for the whole duration of treatment of 10 days. The patients will be treated according to the current Dengue guidelines published by the Ministry of Health, Sri Lanka. The patients who fulfil the admission criteria will be admitted to the ward while other patients who do not need admission will be managed as OPD patients following National Dengue Management Guideline. Patients in three groups (two test doses and placebo) will be instructed to take a dose of two tablets of LNS or placebo three times a day before meals orally starting on the day of recruitment until day 10 after onset of fever, in addition to the standard treatment as per national guidelines. 2 tablets of LNS high dose (750 mg) or 2 tablets of LNS low dose (550 mg) or 2 tablets of placebo to be given three times a day orally before meals for 10 days from the onset of fever.

Dosage form of LNS and placebo is a tablet.

Link Natural Sudarshana Tablet comprises 49 herbal ingredients [Ingredients found in Bhaisajya Ratnavali, Sharangadhara Samhitha, Ayurveda Pharmacopoeia of Sri Lanka and Ayurveda Formulary of India] The placebo tablet comprises, microcrystalline cellulose BP., maize starch BP., sodium starch glycolate BP., carboxymethyl cellulose BP., Aerosil 200 Pharma., and magnesium stearate BP [All excipients in the investigational medicine other than the active ingredient is included].

• Laboratory evidence of Dengue: All Patients with confirmed dengue infection by a positive dengue NS1 antigen detection test and confirmed by PCR test. The dengue NS1 antigen will be done by rapid immunochromatographic assays (rapid strip tests at the OPD). Those who provides informed written consent and who fulfil all of the following criteria will be recruited. • Age: between 18-70 * Both male and female • Duration of illness: Equal or less than 48 hours of the onset of fever

Those who already have evidence of fluid leakage. • Fever for more than 48 hours • Pregnant women • Those who have known allergies to ingredients of LNS. • Those who are unable to take the drugs orally. • Those who have known hepatic impairment defined as following: All of the 3 following criteria should be present. • Presence of any previously known liver disease • A prolonged prothrombin time of 4-6 seconds or more • An INR of >1.5 • Those with known renal impairment. They will be defined as those who fulfil either of the following criteria regardless of age, hypertension and diabetes. Patients will be inquired regarding presence of diabetes and hypertension and any pre-existing renal disease . They would have renal impairment if they have any of the following. - Predicted GFR <60 ml/min per 1.73 m2 - Hereditary kidney disease - Recurrent or extensive nephrolithiasis (renal calculi)