OBJECTIVES: The study objective is to quantify the effectiveness of ivermectin (subcutaneous/oral IVM) in the presence or absence of zinc (Zn) for clinical and radiological improvement in coronavirus disease 2019 (COVID-19) patients with moderate severity. TRIAL DESIGN: This quadruple-blinded, placebo-controlled randomized clinical trial will be a multiarmed multi-centered study with superiority framework. PARTICIPANTS: Quinquagenarian and sexagenarian patients with moderate COVID-19 symptoms and positive severe respiratory syndrome coronavirus -2 (SARS-CoV-2) PCR will be included. Participants with co-morbidities and pregnant women will be excluded. Patient recruitment will be done in Shaikh Zayed Medical Complex, Doctors Lounge and Ali Clinic in Lahore (Pakistan). INTERVENTION AND COMPARATOR: The registered patients will be allocated in 6 groups (30 participants each). Patients will be taking subcutaneous IVM at 200 µg/kg/48 h (Arm A) or subcutaneous IVM at 200 µg/kg/48 h and oral Zn 20mg/8 h (Arm B) or oral IVM at 0.2 mg/kg/day (Arm C) or oral IVM at 0.2 mg/kg/day and oral Zn 20mg/8 h (Arm D) or alone oral Zn 20mg/8 h (Arm E) or placebo alone (Arm X). Patients in all arms will receive standard care and respective placebo (empty capsule 8 hourly and/or subcutaneous normal saline 2ml/48 h). MAIN OUTCOMES: Primary endpoints will be duration of symptomatic phase and SARS-CoV-2 clearance along with high resolution CT (HRCT) chest score and clinical grade scale (CGS) on day 6. 30-day mortality will be documented as a secondary endpoint. SARS-CoV-2 clearance will be calculated by second PCR on day 7. HRCT chest score will be measured by the percentage and lung lobes involvement on day 6 with a maximum score of 25. CGS will be recorded on a seven-point scale; grade 1 (not hospitalized, no evidence of infection and resumption of normal activities), grade 2 (not hospitalized, but unable to resume normal activities), grade 3 (hospitalized, not requiring supplemental oxygen), grade 4 (hospitalized, requiring supplemental oxygen), grade 5 (hospitalized, requiring nasal high-flow oxygen therapy and/or noninvasive mechanical ventilation), grade 6 (hospitalized, requiring ECMO and/or invasive mechanical ventilation) and grade 7 (death). RANDOMISATION: A simple lottery method will be used to randomly allocate scrutinized patients in 1:1:1:1:1:1 ratio in 6 groups. BLINDING (MASKING): Patients, primary care physicians, outcome assessors and the data collection team will be blinded. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 180 participants will be randomized into six arms with five investigational and one placebo group. TRIAL STATUS: Institutional Review Board Shaikh Zayed Post-Graduate Medical Complex, Lahore, Pakistan has approved the protocol (version 2.3) with ID SZMC/IRB/Internal0056/2020. The trial was approved on July 14, 2020, and enrolment started on July 30, 2020. The estimated completion date is October 30, 2021. TRIAL REGISTRATION: Clinical Trial has been retrospectively registered on www.clinicaltrials.gov with registration ID NCT04472585 dated July 16, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). With the intention of expediting dissemination of this trial, the conventional 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 Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines.
Subject(s)COVID-19 , Ivermectin , Female , Humans , Ivermectin/adverse effects , Multicenter Studies as Topic , Pregnancy , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome , Zinc/adverse effects
Subject(s)COVID-19 Drug Treatment , Zinc/administration & dosage , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/pathology , Female , Humans , Male , Middle Aged , Outpatients , Retrospective Studies , SARS-CoV-2/isolation & purification , Treatment Outcome , Young Adult , Zinc/adverse effects
INTRODUCTION: SARS-CoV-2 (COVID-19) has caused an international pandemic of respiratory illness, resulting in significant healthcare and economic turmoil. To date, no robust vaccine or treatment has been identified. Elemental zinc has previously been demonstrated to have beneficial effects on coronaviruses and other viral respiratory infections due to its effect on RNA polymerase. Additionally, zinc has well-demonstrated protective effects against hypoxic injury-a clear mechanism of end-organ injury in respiratory distress syndrome. We aimed to assess the effect of high-dose intravenous zinc (HDIVZn) on SARS-CoV-2 infection. The end of study analyses will evaluate the reduction of impact of oxygen saturations or requirement of oxygen supplementation. METHODS AND ANALYSIS: We designed a double-blind randomised controlled trial of daily HDIVZn (0.5 mg/kg) versus placebo. Primary outcome measures are lowest oxygen saturation (or greatest level of supplemental oxygenation) for non-ventilated patients and worst PaO2/FiO2 for ventilated patients. Following power calculations, 60 hospitalised patients and 100 ventilated patients will be recruited to demonstrate a 20% difference. The duration of follow-up is up to the point of discharge. ETHICS AND DISSEMINATION: Ethical approval was obtained through the independent Human Research Ethics Committee. Participant recruitment will commence in May 2020. Results will be published in peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: ACTRN126200000454976.
Subject(s)COVID-19 Drug Treatment , Zinc/administration & dosage , Administration, Intravenous , Adult , Clinical Trials, Phase II as Topic , Double-Blind Method , Female , Humans , Hypoxia/prevention & control , Male , Oxygen/blood , Pandemics , Randomized Controlled Trials as Topic , SARS-CoV-2 , Zinc/adverse effects
OBJECTIVES: The primary objectives of this study are to determine efficacy of Siddha medicine, Kabasura kudineer in reduction of SARS-CoV-2 viral load and reducing the onset of symptoms in asymptomatic COVID-19 when compared to Vitamin C and Zinc (CZ) supplementation. In addition, the trial will examine the changes in the immunological markers of the Siddha medicine against control. The secondary objectives of the trial are to evaluate the safety of the Siddha medicine and to document clinical profile of asymptomatic COVID-19 as per principles of Siddha system of Medicine. TRIAL DESIGN: A single centre, open-label, parallel group (1:1 allocation ratio), exploratory randomized controlled trial. PARTICIPANTS: Cases admitted at non-hospital settings designated as COVID Care Centre and managed by the State Government Stanley Medical College, Chennai, Tamil Nadu, India will be recruited. Eligible participants will be those tested positive for COVID-19 by Reverse Transcriptase Polymerase Chain reaction (RT-PCR) aged 18 to 55 years without any symptoms and co-morbidities like diabetes mellitus, hypertension and bronchial asthma. Those pregnant or lactating, with severe respiratory disease, already participating in COVID trials and with severe illness like malignancy will be excluded. INTERVENTION AND COMPARATOR: Adopting traditional methods, decoction of Kabasura kudineer will be prepared by boiling 5g of KSK powder in 240 ml water and reduced to one-fourth (60ml) and filtered. The KSK group will receive a dose of 60ml decoction, orally in the morning and evening after food for 14 days. The control group will receive Vitamin C (60000 IU) and Zinc tablets (100mg) orally in the morning and evening respectively for 14 days. MAIN OUTCOMES: The primary outcomes are the reduction in the SARS-CoV-2 load [as measured by cyclic threshold (CT) value of RT-PCR] from the baseline to that of seventh day of the treatment, prevention of progression of asymptomatic to symptomatic state (clinical symptoms like fever, cough and breathlessness) and changes in the immunity markers [Interleukins (IL) 6, IL10, IL2, Interferon gamma (IFNÎ³) and Tumor Necrosis Factor (TNF) alpha]. Clinical assessment of COVID-19 as per standard Siddha system of medicine principles and the occurrence of adverse effects will be documented as secondary outcomes. RANDOMISATION: The assignment to the study or control group will be allocated in equal numbers through randomization using random number generation in Microsoft Excel by a statistician who is not involved in the trial. The allocation scheme will be made by an independent statistician using a sealed envelope. The participants will be allocated immediately after the eligibility assessment and informed consent procedures. BLINDING (MASKING): This study is unblinded. The investigators will be blinded to data analysis, which will be carried out by a statistician who is not involved in the trial. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Sample size could not be calculated, as there is no prior trial on KSK. This trial will be a pilot trial. Hence, we intend to recruit 60 participants in total using a 1:1 allocation ratio, with 30 participants randomised into each arm. TRIAL STATUS: Protocol version 2.0 dated 16th May 2020. Recruitment is completed. The trial started recruitment on the 25th May 2020. We anticipate study including data analysis will finish on November 2020. We also stated that protocol was submitted before the end of data collection TRIAL REGISTRATION: The study protocol was registered with clinical trial registry of India (CTRI) with CTRI/2020/05/025215 on 16 May 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 Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
Subject(s)Ascorbic Acid , Betacoronavirus , Coronavirus Infections , Medicine, Ayurvedic/methods , Pandemics , Pneumonia, Viral , Zinc , Adult , Ascorbic Acid/administration & dosage , Ascorbic Acid/adverse effects , Asymptomatic Infections/therapy , Betacoronavirus/drug effects , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Dietary Supplements , Drug Monitoring/methods , Female , Humans , India , Male , Pneumonia, Viral/diagnosis , Pneumonia, Viral/drug therapy , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome , Viral Load/methods , Zinc/administration & dosage , Zinc/adverse effects
The aim of this study was to describe the outcomes of patients with coronavirus disease 2019 (COVID-19) in the outpatient setting after early treatment with zinc, low-dose hydroxychloroquine and azithromycin (triple therapy) dependent on risk stratification. This was a retrospective case series study in the general practice setting. A total of 141 COVID-19 patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the year 2020 were included. The main outcome measures were risk-stratified treatment decision and rates of hospitalisation and all-cause death. A median of 4 days [interquartile range (IQR) 3-6 days; available for n = 66/141 patients] after the onset of symptoms, 141 patients (median age 58 years, IQR 40-67 years; 73.0% male) received a prescription for triple therapy for 5 days. Independent public reference data from 377 confirmed COVID-19 patients in the same community were used as untreated controls. Of 141 treated patients, 4 (2.8%) were hospitalised, which was significantly fewer (P < 0.001) compared with 58 (15.4%) of 377 untreated patients [odds ratio (OR) = 0.16, 95% confidence interval (CI) 0.06-0.5]. One patient (0.7%) in the treatment group died versus 13 patients (3.4%) in the untreated group (OR = 0.2, 95% CI 0.03-1.5; P = 0.12). No cardiac side effects were observed. Risk stratification-based treatment of COVID-19 outpatients as early as possible after symptom onset using triple therapy, including the combination of zinc with low-dose hydroxychloroquine, was associated with significantly fewer hospitalisations.