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

  1. Sohaib Ashraf
  2. Shoaib Ashraf
  3. Moneeb Ashraf
  4. Muhammad Ahmad Imran
  5. Larab Kalsoom
  6. Uzma Nasim Siddiqui
  7. Iqra Farooq
  8. Zaighum Habib
  9. Sidra Ashraf
  10. Muhammad Ghufran
  11. Muhammad Kiwan Akram
  12. Nighat Majeed
  13. Zain-ul-Abdin
  14. Rutaba Akmal
  15. Sundas Rafique
  16. Khawar Nawaz
  17. Muhammad Ismail K Yousaf
  18. Sohail Ahmad
  19. Muhammad Sarmad Shahab
  20. Muhammad Faisal Nadeem
  21. Muhammad Azam
  22. Hui Zheng
  23. Amber Malik
  24. Mahmood Ayyaz
  25. Talha Mahmud
  26. Qazi Abdul Saboor
  27. Ali Ahmad
  28. Muhammad Ashraf
  29. Mateen Izhar
  30. for the COALITION COVID-19 Shaikh Zayed
  31. Abubakar Hilal
  32. Arz Muhammad
  33. Zeeshan Shaukat
  34. Ayesha Khaqan
  35. Kanwal Hayat
  36. Shahroze Arshad
  37. Muhammad Hassan
  38. Abeer-bin-Awais
  39. Ammara Ahmad
  40. Tayyab Mughal
  41. Abdur Rehman Virk
  42. Muhammad Umer
  43. Muhammad Suhail
  44. Sibgha Zulfiqar
  45. Saulat Sarfraz
  46. Muhammad Imran Anwar
  47. Ayesha Humayun
  48. R A Khokhar
  49. S Siddique

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Abstract

BACKGROUND

No definitive treatment exists for Coronavirus Disease 2019 (COVID-19). Honey and Nigella sativa (HNS) have established antiviral, antibacterial, anti-inflammatory and immunomodulatory properties. Hence, we investigated efficacy of HNS against COVID-19. wide

METHODS

We conducted a multicenter, placebo-controlled, randomized clinical trial at 4 centers in Pakistan. RT-PCR confirmed COVID-19 adults showing moderate or severe disease were enrolled in the study. Patients presenting with multi-organ failure, ventilator support, and chronic diseases (except diabetes mellitus and hypertension) were excluded. Patients were randomly assigned in 1:1 ratio to receive either honey (1 gm/Kg/day) and Nigella sativa seeds (80 mg/Kg/day) or placebo up-to 13 days along with standard care. The outcomes included symptom alleviation, viral clearance, and a 30-day mortality in intention-to-treat population. This trial was registered with ClinicalTrials.gov, NCT04347382 .

RESULTS

Three hundred and thirteen patients - 210 moderate and 103 severe - underwent randomization from April 30 to July 29, 2020. Among these, 107 were assigned to HNS whereas 103 to placebo for moderate cases. For severe cases, 50 were given HNS and 53 were given placebos. HNS resulted in ∼50% reduction in time taken to alleviate symptoms as compared to placebo (Moderate (4 versus 7 days), Hazard Ratio [HR]: 6.11; 95% Confidence Interval [CI]: 4.23-8.84, P<0.0001 and severe (6 versus 13 days) HR: 4.04; 95% CI, 2.46-6.64, P<0.0001). HNS also cleared the virus 4 days earlier than placebo group in moderate (6 versus 10 days, HR: 5.53; 95% CI: 3.76-8.14, P<0.0001) and severe cases (8.5 versus 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% versus 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, mortality rate was four-fold lower in HNS group than placebo (4% versus 18.87%, OR: 0.18; 95% CI: 0.02-0.92, P=0.029). No HNS-related adverse effects were observed.

CONCLUSION

HNS significantly improved symptoms, viral clearance and mortality in COVID-19 patients. Thus, HNS represents an affordable over the counter therapy and can either be used alone or in combination with other treatments to achieve potentiating effects against COVID-19.

FUNDING

Funded by Smile Welfare Organization, Shaikh Zayed Medical Complex, and Services Institute of Medical Sciences.

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  1. ScreenIT

    SciScore for 10.1101/2020.10.30.20217364: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: The trial was approved by the institutional review boards of Shaikh Zayed Post-Graduate Medical Complex and Services Institute of Medical Sciences and supervised by an independent trial steering committee.
    Consent: Exclusion criteria included having mild to lacking clinical symptoms, inability to give written consent, multi-organ dysfunction, ventilator support or PaO2/FIO2 of less than 100, septic shock, known hypersensitivity to HNS and chronic illness other than hypertension and diabetes mellitus.
    RandomizationSTUDY DESIGN: The study was an investigator-initiated, multicenter placebo controlled randomized trial with superiority framework conducted in four medical care facilities in Pakistan (
    BlindingCare providers and outcome assessors were blinded with site investigators’ help to provide placebo or therapeutic regimen to the participants and masked clinicians to assess the clinical, laboratory and radiological findings.
    Power Analysisnot detected.
    Sex as a biological variableThe virus nucleic acid positive, adult males and non-pregnant females, who presented to seek medical care within 96 h of ailment underwent randomization.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    SAS software version 9.4 (SAS Institute Inc.
    SAS
    suggested: (SASqPCR, RRID:SCR_003056)
    SAS Institute
    suggested: (Statistical Analysis System, RRID:SCR_008567)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    A major limitation of this study was that the honey and NS were not administered as treatments to the patients separately. Patients on ventilator support were not enrolled in this study. A multinational study with a larger sample size is required to investigate potential variations in responses to the treatment in COVID-19 patients from different racial and ethnic origins.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04347382CompletedHoney & Nigella Sativa Trial Against COVID-19

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

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