Honey and Nigella Sativa in the Prophylaxis of COVID-19; A Randomized Controlled Trial

Considering the therapeutic potential of honey and Nigella sativa (HNS) in coronavirus disease 2019 (COVID-19) patients, the objective of the study is dened to evaluate the prophylactic role of HNS. 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, ecacy, and futility of the trial.


Abstract Objectives
Considering the therapeutic potential of honey and Nigella sativa (HNS) in coronavirus disease 2019  patients, the objective of the study is de ned 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, e cacy, 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 con rmed case. Non-pregnant adults with signi cant exposure level will be enrolled in the study

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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 certi ed 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 14 th day of randomization.

Randomisation
Participants will be randomized into experimental and control groups (1:1 allocation ratio) via the lottery method. There will be strati cation 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 con ict 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

Full Protocol
The full protocol is attached as an additional le, accessible from the Trials website (Additional le 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.

Declarations
Ethics approval and consent to participate The trial was approved by institutional ethical review board of Shaikh Zayed Post-Graduate Medical Complex (IRB ID # SZMC/IRB/Internal/273/2021) on February 15, 2021. Authors certify that the study has received ethical approval from the appropriate ethical committee as stated above. Before enrolment, all partakers will be fully informed of the study and asked to sign the consent form to be eligible for randomization and participation.