METHODS: An electronic data search in Web of Science, SCOPUS, and PubMed for relevant papers; those written in English; those reporting quantitative data; and those including more than one hundred patients who received just chemotherapy were included. Studies involving participants that received other kinds of anti-neoplastic therapies were excluded.

RESULTS: A total of 35 papers published between January 2000 and December 2021 were retrieved from the search databases of which (11612 patients) met the inclusion criteria. Findings showed that fatigue negatively affected QOL with a pooled prevalence of 49% (95% CI; 25.00-74.00) and the significant heterogeneity between articles was (I²=98%, P <0.001). Further, breast cancer contributed to the majority of selected articles with about 55 % (95%CI; 9:00- 94:00), followed by cancer (unspecified) 44% (95%CI; 5:00 - 92:00). Most studies (71%) (95%CI; 4:00 - 99:00) used the brief fatigue inventory (BFI) tool to assess severity of fatigue and 39% (95%CI; 17:00 -68:00) employed the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire to evaluate QOL among cancer survivors.

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 .