Honey and Nigella sativa against COVID-19 in Pakistan (HNS-COVID-PK): A multicenter placebo-controlled randomized clinical trial.

Until now, no specific and effective treatment exists for coronavirus disease 2019 (COVID-19). Since honey and Nigella sativa (HNS) have established antiviral, antibacterial, antiinflammatory, antioxidant, and immunomodulatory properties, we tested their efficacy for this disease in a multicenter, placebo-controlled, and randomized clinical trial at four medical care facilities in Pakistan. RT-PCR confirmed COVID-19 adults showing moderate or severe disease were enrolled in the trial. Patients were randomly assigned in a 1:1 ratio to receive either honey (1 g kg-1 day-1 ) and Nigella sativa seeds (80 mg kg-1 day-1 ) or a placebo for up to 13 days along with standard care. The outcomes included symptoms' alleviation, viral clearance, and 30-day mortality in the intention-to-treat population. Three hundred and thirteen patients, 210 with moderate and 103 with severe disease, underwent randomization from April 30 to July 29, 2020. Among the moderate cases, 107 were assigned to HNS, whereas 103 were assigned to the placebo group. Among the severe cases, 50 were given HNS, and 53 were given the placebo. HNS resulted in ~50% reduction in time taken to alleviate symptoms as compared to placebo (moderate cases: 4 vs. 7 days, Hazard Ratio [HR]: 6.11; 95% Confidence Interval [CI]: 4.23-8.84, p < 0.0001 and for severe cases: 6 vs. 13 days, HR: 4.04; 95% CI: 2.46-6.64; p < 0.0001). HNS also cleared the virus earlier than placebo in both moderate cases (6 vs. 10 days, HR: 5.53; 95% CI: 3.76-8.14, p < 0.0001) and severe cases (8.5 vs. 12 days, HR: 4.32; 95% CI: 2.62-7.13, p < 0.0001). HNS further led to a better clinical score on day 6 with normal activity resumption in 63.6% vs. 10.9% among moderate cases (OR: 0.07; 95% CI: 0.03-0.13, p < 0.0001) and hospital discharge in 50% versus 2.8% in severe cases (OR: 0.03; 95% CI: 0.01-0.09, p < 0.0001). In severe cases, the mortality rate was less than 1/4th in the HNS group than in placebo (4% vs. 18.87%, OR: 0.18; 95% CI: 0.02-0.92, p = 0.029). No HNS-related adverse effects were observed. HNS, compared with placebo, significantly improved symptoms, expedited viral load clearance, and reduced mortality in COVID-19 patients. This trial was registered on April 15, 2020 with ClinicalTrials.gov Identifier: NCT04347382.

A quadruple blinded placebo controlled randomised trial to evaluate the effectiveness of an Iodine complex for patients with mild to moderate COVID-19 in Pakistan (I-COVID-PK): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The objective of the study is to measure the efficacy of ionic-iodine polymer complex [1] for clinical and radiological improvement in coronavirus disease 2019 (COVID-19) patients. TRIAL DESIGN: The trial will be closed label, randomized and placebo-controlled with a 1:1:1:1 allocation ratio and superiority framework. PARTICIPANTS: All PCR confirmed COVID-19 adult patients including non-pregnant females, with mild to moderate disease, will be enrolled from Shaikh Zayed Post-Graduate Medical Complex, Ali Clinic and Doctors Lounge in Lahore (Pakistan). Patients with any pre-existing chronic illness will be excluded from the study. INTERVENTION AND COMPARATOR: In this multi-armed study ionic-iodine polymer complex with 200 mg of elemental iodine will be given using three formulations to evaluate efficacy. Patients will be receiving either encapsulated iodine complex of 200 mg (arm A), iodine complex syrup form 40 ml (arm B), iodine complex throat spray of 2 puffs (arm C) or empty capsule (arm D) as placebo; all three times a day. All the 4 arms will be receiving standard care as per version 3.0 of the clinical management guidelines for COVID-19 established by the Ministry of National Health Services of Pakistan. MAIN OUTCOMES: Primary outcomes will be viral clearance with radiological and clinical improvement. SARS-CoV-2 RT-PCR and HRCT chest scans will be done on the admission day and then after every fourth day for 12 days or till the symptoms are resolved. RT-PCR will only be shown as positive or negative while HRCT chest scoring will be done depending on the area and severity of lung involvement [2]. Time taken for the alleviation of symptoms will be calculated by the number of days the patient remained symptomatic. 30-day mortality will be considered as a secondary outcome. RANDOMISATION: Stratification for initial COVID-19 status (or days from initial symptoms as a proxy), age groups, gender, baseline severity of symptoms and co-morbidities will be used to ensure that the study arms remain balanced in size for the 1:1:1:1 allocation ratio. Randomization will be done using the lottery method. As patients are being admitted at different times, they will be recruited after obtaining their voluntary written informed consent following all standard protocols of the infection, control and disinfection. BLINDING (MASKING): This is a quadruple (participants, care providers, investigators and outcomes assessors) blinded study where only the study's Primary Investigator will have information about the arms and their interventions. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 200 patients will be randomized into four groups with three experimental and one placebo arm. TRIAL STATUS: Protocol Version Number is 2.3 and it is approved from IRB Shaikh Zayed Hospital with ID SZMC/IRB/Internal0056/2020 on July 14th, 2020. The recruitment is in progress. It was started on July 30, 2020, and the estimated end date for the trial is August 15, 2021. TRIAL REGISTRATION: Clinical Trial has been retrospectively registered on www.clinicaltrials.gov with registration ID NCT04473261 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.

Clinical efficacy of iodine complex in SARS-CoV-2-infected patients with mild to moderate symptoms: study protocol for a randomized controlled trial.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by the novel coronavirus-infected millions globally. Despite a wide range of advised options for the treatment of COVID-19, a single strategy to tackle this pandemic remains elusive, thus far. That is why we are conducting a clinical trial to find out the efficacy of iodine complex to clear a viral load of severe respiratory syndrome coronavirus-2 (SARS-CoV-2) along with a reduction in time taken to alleviate symptoms. METHOD: The proposed study is a placebo-controlled, add-on, randomized trial using parallel group designs. This is a closed-label and adaptive with sample size reassessment, multi-centered design with a 1:1:1:1 allocation ratio and superiority framework. It will be conducted in Shaikh Zayed Post-Graduate Medical Complex, Ali Clinic, and Doctors Lounge, Lahore, Pakistan. This study will have three arms of mild to moderately symptomatic COVID-19 patients (50 patients in each) which will receive ionic-iodine polymer complex with 200 mg of elemental iodine: interventional arm A will have encapsulated, arm B will receive suspension syrup form, arm C will get throat spray, while arm X will be standard care with placebo. Data will be collected on self-constructed, close-ended questionnaires after obtaining written consent. Data will be analyzed using SAS version 9.4. COVID-19 patients will be monitored by RT-PCR and HRCT (high-resolution computed tomography) chest. In addition to these, the duration of the symptomatic phase and mortality benefits will be analyzed in both groups. DISCUSSION: The study is designed to measure the superior efficacy of the iodine complex as an add-on in treating COVID-19-positive patients with mild to moderate symptoms. This combination is hypothesized to improve various parameters like rapid viral load reduction, clinical and radiological improvement, lower mortality, and reduction in hospitalization. The trial will aid in devising a better strategy to cope with COVID-19 in a relatively inexpensive and accessible way. The implications are global, and this could prove itself to be the most manageable intervention against COVID-19 especially for patients from limited-resource countries with deprived socioeconomic status. TRIAL REGISTRATION: ClinicalTrials.gov NCT04473261 . Registered on July 16, 2020.

Prophylactic potential of honey and Nigella sativa L. against hospital and community-based SARS-CoV-2 spread: a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Considering the therapeutic potential of honey and Nigella sativa (HNS) in coronavirus disease 2019 (COVID-19) patients, the objective of the study is defined to evaluate the prophylactic role of HNS. TRIAL DESIGN: The study is a randomized, placebo-controlled, adaptive clinical trial with parallel group design, superiority framework with an allocation ratio of 1:1 among experimental (HNS) and placebo group. An interim analysis will be done when half of the patients have been recruited to evaluate the need to adapt sample size, efficacy, and futility of the trial. PARTICIPANTS: All asymptomatic patients with hospital or community based COVID-19 exposure will be screened if they have had 4 days exposure to a confirmed case. Non-pregnant adults with significant exposure level will be enrolled in the study High-risk exposure (<6 feet distance for >10min without face protection) Moderate exposure (<6 feet distance for >10min with face protection) Subjects with acute or chronic infection, COVID-19 vaccinated, and allergy to HNS will be excluded from the study. Recruitment will be done at Shaikh Zayed Post-Graduate Medical Institute, Ali Clinic and Doctors Lounge in Lahore (Pakistan). INTERVENTION AND COMPARATOR: In this clinical study, patients will receive either raw natural honey (0.5 g) and encapsulated organic Nigella sativa seeds (40 mg) per kg body weight per day or empty capsule with and 30 ml of 5% dextrose water as a placebo for 14 days. Both the natural products will be certified for standardization by Government College University (Botany department). Furthermore, each patient will be given standard care therapy according to version 3.0 of the COVID-19 clinical management guidelines by the Ministry of National Health Services of Pakistan. MAIN OUTCOMES: Primary outcome will be Incidence of COVID-19 cases within 14 days of randomisation. Secondary endpoints include incidence of COVID-19-related symptoms, hospitalizations, and deaths along with the severity of COVID-19-related symptoms till 14th day of randomization. RANDOMISATION: Participants will be randomized into experimental and control groups (1:1 allocation ratio) via the lottery method. There will be stratification based on high risk and moderate risk exposure. BLINDING (MASKING): Quadruple blinding will be ensured for the participants, care providers and outcome accessors. Data analysts will also be blinded to avoid conflict of interest. Site principal investigator will be responsible for ensuring masking. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 1000 participants will be enrolled in the study with 1:1 allocation. TRIAL STATUS: The final protocol version 1.4 was approved by institutional review board of Shaikh Zayed Post-Graduate Medical Complex on February 15, 2021. The trial recruitment was started on March 05, 2021, with a trial completion date of February 15, 2022. TRIAL REGISTRATION: Clinical trial was registered on February 23, 2021, www.clinicaltrials.gov with registration ID NCT04767087 . 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.

Anti-COVID property of subcutaneous ivermectin in synergy with zinc among midlife moderately symptomatic patients: a structured summary of a study protocol for a randomised controlled trial.

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.