The treatment and care process for COVID-19 disease has continually evolved since our knowledge and understanding have been expanded. The main goal of treatment was decreasing the viral replication activities to limit the number of viruses, aiming to reduce the magnitude of clinical symptoms. Multiple techniques, such as vaccines and medication, could achieve this goal. Andrographolide extract was prepared with active ingredients of 180 mg andrographolide for COVID-19 treatment with a regimen of three times a day for five consecutive days. The AG was claimed to be used in-vitro to inhibit SARS-CoV-2 viral replication through the virus life-cycle and also inhibit Spike protein, Angiotensin Converting Enzyme 2 (ACE2), PLpro and 3CLpro. As a result, this study plans to prove AG’s efficacy in COVID-19 treatment in vitro by performing Double-blinded Randomized-Controlled Trial under the robust quality control of quality by Data-Safety Monitoring Board (DSMB), approved by ethical committee from Department of Thai Alternative Medicine, Ministry of Public Health project number 11-2564, RCT registration number was TCTR20211224002 from www.thaiclinicaltrials.org and granted budget by Health System Research Institute (Thailand). This study was conducted in a multicenter health facility throughout the Health Region 4 of Thailand. We enrolled 396 people, of which 201 were assigned to receive standard treatment with a placebo (PB), and the rest received standard therapy with andrographolide (AG) add-on. The general characteristic of samples was males 38%, and the median age of samples was 35 years old, with indifferent vaccine history but significantly different rate of lorazepam taken in the AG group (p=0.038) The efficacy of AG was evaluated with multiple rubrics: 1. The incidence rate of pneumonia was 0.51% with 95%-CI 0.06% to 1.82%; PB was 0.50 % vs. AG 0.52% but no statistical significance. 2. We found an insignificance difference between AG and PB in clinical spectrums: a. Percentage of subjects who self-reported clinical resolved (on Day10 86% vs. 89%, p=0.133) b. Time of detection of low level of blood oxygenation (O2 sat less than 96%) (Kaplan-Meier; Log-rank test = 0.471) 3. We found no difference in terms of the ability to decrease SARS-CoV-2 viral load between PB and AG: a. Viral load decreased from 104 copies/ml baseline to 102 copies/ml on Day 5 and 10 copies/ml on Day 10 in both groups (p=0.624 and p=0.685) b. The percentage of samples that were presented with less than 35 percent of viral load when compared to baseline on Day 5 (PB 85% vs. AG 86%, p=1.000) and Day 10 (PB 91% vs. AG 97%, p=0.175) were found no different. c. The percentage of samples that were presented with no virus found on Day 5 (PB 41% vs. AG 37%, p=0.624) and Day 10 (PB 87% vs. AG 90%, p=0.685) showed insignificant changes after treatment. Moreover, this study aimed to monitor the side effects of AG during the regular COVID-19 routine treatment. We measured some adverse impact on AG treatment: 1. Liver function: a. The AG group showed a significant elevation level of Aspartate transferase (AST) on Day 10 (PB: 19 IU/L vs. AG: 22.5 IU/L, p=<0.001) but not statistically significantly different in case of three times the upper normal limit b. The AG group showed a significant elevation level of Alanine transferase (ALT) on Day 5 (PB: 20 IU/L vs AG 24 IU/L, p=0.041) and Day 10 (PB: 22 IU/L vs AG 27.5 IU/L, p=<0.001). Moreover, we found that enzyme elevation was over three times higher than the upper normal limit significantly (1% vs. 4%, p=0.03) 2. Kidney function by Estimated Glomerular Filtration Rate(eGFR): Due to the accidental finding of significant differences between PB and AG since baseline measurement until day 10; Day 0: 105 cc/min vs. 110 cc/min, p=0.017, Day 5: 110 cc/min vs. 116 cc/min, p=0.002 and Day10: 111 cc/min vs. 117 cc/min, p=0.010. By the way, both groups of samples showed gradual renal function improvement. 3. Potassium levels were found to be insignificant different through the course of treatment: Day 5 (PB: 3.9 mmol/L vs. AG: 3.8 mmol/L, p=0.218 and Day 10 (PB: 3.8 mmol/L vs. AG: 3.8 mmol/L, p=0.895) Based on AG’s adverse event finding versus the fact that no significant drug efficacy was found during the preliminary analysis, the DSMB has decided to discontinue the trial because the risk was higher than the benefit. In conclusion, AG extract was found to have no efficacy on pneumonia prevention, symptom reduction, and decreasing viral replication compared with placebo based on this number of samples but a significant risk of hepatitis. So, we recommend making public communication on these topics: 1. The 180 mg of AG extract daily showed no clinical effectiveness in pneumonia prevention, symptom reduction, and decreasing viral replication activity more than usual based on the limited number of samples. A vaccine was one of the most substantial pieces of evidence to prevent the clinical symptoms and pneumonia prevention. 2. The Department of Thai and Alternative Medicines and the Thai Food and Drug Administration should announce the warning that AG usage can produce significant levels of hepatitis. So, the physician should prescribe this herb with risk concerns, and close monitoring should be recommended. Avoid using this drug with other herbs or medicines metabolized by the liver, such as Warfarin. The following study could be done on three more issues: the Dose-Related effect of AG, contraindication of usage, and other diseases that benefit from AG extracts.