A double blinded placebo controlled comparative clinical trial to evaluate the effectiveness of Siddha medicines, Kaba Sura Kudineer (KSK) & Nilavembu Kudineer (NVK) along with standard Allopathy treatment in the management of symptomatic COVID 19 patients - a structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: The primary objectives of the study are to determine the effectiveness of the Kaba Sura Kudineer (KSK) & Nilavembu Kudineer (NVK) along with standard Allopathy Treatment to compared with Placebo (Decaffeinated Tea) with standard Allopathy Treatment in the management of Symptomatic COVID 19 patients and also in reduction of Hospital Stay Time & Changes in Immunological (IL6) and Bio Chemical Markers (Ferritin, CRP, D-Dimer and LDH). The secondary objectives are to evaluate the safety of the trial medicines and their effects in the reduce the risks of the disease. In addition, to document the profile of Symptomatic COVID 19 patients as per Siddha Principles. TRIAL DESIGN: A Double Blinded, Three arm, Single Centre, Placebo Controlled, Exploratory and comparative Randomized Controlled Trial PARTICIPANTS: Patients who were admitted to the COVID Care Centre at Govt. Institute of Medical Sciences. Noida in India will be recruited. These will be patients with Mild and Moderate symptoms with laboratory confirmed COVID 19 (RT - PCR Tested Positive) aged 18-65, willing and consenting to participate. INTERVENTION AND COMPARATOR: Arm I: Decaffeinated Tea (Placebo - similar in taste and appearance to the other Two Decoctions), 60 Ml Morning and Night after Food, along with standard Allopathy Treatment for 10 days. Arm II: Nilavembu Kudineer (The Siddha Medicines which is used as a standard Anti-Viral drug for the past Pandemics by Siddha Physicians) 60 Ml Morning and Night after Food, along with standard Allopathy Treatment for 10 days. Arm III: Kaba Sura Kudineer (The Siddha Medicine which is proposed to be used as a Treatment for COVID 19 based on Siddha Literature) 60 Ml Morning and Night after Food, along with standard Allopathy Treatment for 10 days. The investigational drugs are registered products under the Govt.of India and bought from GMP Certified Manufacturing Units. MAIN OUTCOMES: Primary outcomes: 1. Reduction in Viral load of SARS-CoV-2 at the end of treatment (10 days). 2. Time taken to convert Patient from symptomatic to Asymptomatic based on Reduction in clinical symptoms (10 days). 3. Effect of drugs inflammatory markers (IL6,) at the end of treatment (10 days). 4. Reduction in hospital stay time (20 days follow up). (Based on RT PCR CT Value 3rd, 6th if needed 10th day). (Based on IL 6 Value needed 10th day or IL6 value on turning negative. (entry level/exit level). Secondary outcomes (10 days): 1. Reduction in use of Intensive Supportive Care. 2. Reduction in incidence of complications (Acute Respiratory Distress Syndrome, other systemic complications). 3. MuLBSTA score for viral pneumonia (multinodular infiltration, hypo-lymphocytosis, bacterial co infection, Total Leucocyte Count (TLC ≤ 0.8 x 109/L), smoking history, hyper-tension and age) score. 4. Laboratory markers (Haematological & Biochemical Markers). 5. Adverse events/effects Siddha-based measurements. 6. Siddha Udaliyal assessment by using Yakkai Ilakkanam (YI) Tool to diagnose body condition for covid-19 patients. RANDOMISATION: The assignment of the participants into 3 Groups will be allocated in 1:1:1 Ratio through randomization Blocks in Microsoft Excel by a Statistician who is not involved in the study. The allocation scheme will be made by another statistician by using a closed envelope after the assessment of eligibility and Informed consent procedures. The groups will be balanced for age and sex with 3:1 Ratio in each group for mild: severe COVID-19 symptoms. BLINDING: The Study is Double Blinded. Participants and Investigators were blinded. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Sample size could not be calculated, Since there are no prior trials on KSK and NVK as a comparative trial. In addition, there are no prior trials on KSK and NVK in this region. A total Number of 120 Patients, 40 each in 3 groups will be recruited in 1:1:1 Ratio. TRIAL STATUS: Protocol Number : SCRUND GIMS Noida Study 1,Version: 2.0 Protocol Date : 20.08.2020 The recruitment period is completed for the trial. The Trial started its recruitment on 22.8.2020. We anticipate study including data analysis will finish in January 2021. This is to state that it was a late submission from authors for publication of the protocol to the BMC, after enrolment in the study was over. TRIAL REGISTRATION: The trial protocol was registered with CTRI (Clinical Trial Registry of India) and number is CTRI/2020/08/027286 on 21.08.2020 FULL PROTOCOL: The full Protocol is attached as an additional file, Accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated. This letter serves as a summary of the key elements of the full protocol. The Study protocol has been reported in accordance with the SPIRIT guidelines.

Efficacy of two siddha polyherbal decoctions, Nilavembu Kudineer and Kaba Sura Kudineer, along with standard allopathy treatment in the management of mild to moderate symptomatic COVID-19 patients-a double-blind, placebo-controlled, clinical trial.

BACKGROUND AND AIM: Globally, the ongoing pursuit in exploring an effective drug to combat severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus has not met with significant success to date. Indian traditional medicines, especially polyherbal formulations like Nilavembu Kudineer (NVK) and Kaba Sura Kudineer (KSK) of the Siddha system of medicine, have been used as public health interventions for controlling viral epidemics like dengue and Chikungunya. These traditional therapies have been found safe, effective, and widely accepted. The current study evaluates the comparative efficacy of NVK and KSK as opposed to the placebo, in the management of mild to moderate COVID-19 disease. METHODS: The study was a double-blind, placebo-controlled comparative clinical trial, with the primary objective of determining the efficacy of KSK and NVK. Patients (n=125) diagnosed with mild to moderate COVID-19 symptoms were enrolled in the study over a period of 4 months (Aug 2020-Dec 2020). Participants were randomized into 3 arms; placebo-decaffeinated tea in Arm I, NVK in Arm II, and KSK in Arm III. Each arm received 60 ml of the respective treatment twice a day, post morning and evening meals, along with standard allopathy treatment for a maximum of 10 days. The main outcome measures of the study were the reduction in SARS-CoV-2 viral load, hospital stay, and time taken by the patients to become asymptomatic from symptomatic. Efficacy assessments included clinical symptoms (fever, cough, and breathlessness) each day and real-time reverse transcription-polymerase chain reaction (RT-PCR), liver function test (LFT), renal function test (RFT), and electrolytes and electrocardiogram (ECG) at baseline (day 0) and days 3, 6, and 10. Post-treatment, participants were followed up for 30 days via phone for adverse effects if any. Effects of drugs on inflammatory markers (IL6) at the end of treatment were also recorded. Adverse events (AE) were monitored throughout the study. RESULTS: The results revealed that when compared to patients in the placebo arm, those in NVK and KSK arms showed a statistically significant reduction in hospital stay time, reduction in viral load of SARS-CoV-2, and the time taken to become symptomatic from asymptomatic. Out of 125 COVID-19 patients recruited, 120 completed the study; two from the placebo group developed severe symptoms and were shifted to the intensive care unit (ICU) and three patients from Arms II and III withdrew from the study. The mean age of females (n=60) and males (n=60) enrolled was between 40.2 and 44.3 years, respectively. Results were more promising for all the patients in NVK and KSK arms as all enrolled participants (100%) under this group got discharged by day 6 as compared to only 42.5% (n=17) from the placebo group on that day. The hospital stay time for patients in Arm I was significantly longer (mean [SD]=8.4 [2.0] days) as compared to the Arms II and III (mean [SD]=4.7 [1.5] and 4.2 [1.5] days, respectively (Kruskal-Wallis test, P=0.0001). Patients in the three groups took a significantly different number of days to become asymptomatic. While Arm II and III patients took mean of 2.5 and 1.7 days, respectively, Arm I, patients took a mean of 4.2 days (Kruskal-Wallis test, P=0.0001). In all, two adverse events were recorded, one for vomiting and one for diarrhea lasting a day in Arm I and Arm II, respectively. The mean value of interleukin-6 (IL6) was significantly different in comparison to the placebo-decaffeinated tea arm (NVK=2.6 and KSK=2.2, placebo=4.0, P=0.02). The other blood biochemical parameters like C-reactive protein (CRP), lactate dehydrogenase (LDH), ferritin, and D-dimer that were analyzed at the baseline and at the time of discharge from the hospital, were not significantly different in the three arms. CONCLUSION: NVK and KSK arms showed a statistically significant reduction in hospital stay time, reduction in viral load of SARS-CoV-2, and time taken for patients to become asymptomatic from symptomatic, when compared to the placebo (decaffeinated tea). The primary outcome measures of the KSK arm were significantly better than those in the NVK arm.