Fourteen-days Evolution of COVID-19 Symptoms During the Third Wave in Non-vaccinated Subjects and Effects of Hesperidin Therapy: A randomized, double-blinded, placebo-controlled study

  1. Jocelyn Dupuis
  2. Pierre Laurin
  3. Jean-Claude Tardif
  4. Leslie Hausermann
  5. Camille Rosa
  6. Marie-Claude Guertin
  7. Karen Thibaudeau
  8. Lyne Gagnon
  9. Frank Cesari
  10. Martin Robitaille
  11. John E. Moran

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Abstract

COVID-19 symptoms can cause substantial disability, yet no therapy can currently reduce their frequency or duration. We conducted a double-blind placebo-controlled trial of hesperidin 1000 mg once-daily for 14 days in 216 symptomatic non-vaccinated COVID-19 subjects. Thirteen symptoms were recorded after 3, 7, 10 and 14 days. The primary endpoint was the proportion of subjects with any of four cardinal (group A) symptoms: fever, cough, shortness of breath or anosmia. At baseline, symptoms in decreasing frequency were: cough (53.2%), weakness (44.9%), headache (42.6%), pain (35.2%), sore throat (28.7%), runny nose (26.9%), chills (22.7%), shortness of breath (22.2%), anosmia (18.5%), fever (16.2%), diarrhea (6.9%), nausea/vomiting (6.5%) and irritability/confusion (3.2%). Group A symptoms in the placebo vs hesperidin group was 88.8% vs 88.5% (day 1) and reduced to 58.5 vs 49.4 % at day 14 (OR 0.69, 95% CI 0.38–1.27, p = 0.23). At day 14, 15 subjects in the placebo group and 28 in the hesperidin group failed to report their symptoms. In an attrition bias analysis imputing “no symptoms” to missing values, the hesperidin group shows reduction of 14.5 % of group A symptoms from 50.9% to 36.4% (OR: 0.55, 0.32–0.96, p = 0.03). Anosmia, the most frequent persisting symptom (29.3%), was lowered by 7.3% at 25.3 % in the hesperidin group vs 32.6% in the placebo group (p = 0.29). Mean number of symptoms in placebo and hesperidin was 5.10 ± 2.26 vs 5.48 ± 2.35 (day 1) and 1.40 ± 1.65 vs 1.38 ± 1.76 (day 14) (p = 0.92). In conclusion, most non-vaccinated COVID-19 infected subjects remain symptomatic after 14 days with anosmia being the most frequently persisting symptom. Hesperidin 1g daily may help reduce group A symptoms. Earlier treatment of longer duration and/or higher dosage should be tested.

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    SciScore for 10.1101/2021.10.04.21264483: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Health Canada gave its authorization to conduct the study, which was also reviewed and approved by the Montreal Heart Institute Research and Ethics Committees (2021-2841).
    Consent: All randomized subjects signed an electronic informed consent form using the DocuSign online service.
    Sex as a biological variableNon-hospitalized male and female subjects of at least 18 years of age with a positive diagnosis of COVID-19 confirmed by polymerase chain reaction (PCR) testing within the last 48 hours and with at least one COVID-19 symptom were included.
    RandomizationParticipants: This was a phase 2, randomized, double-blind, placebo-controlled study conducted at the Montreal Heart Institute (MHI) and comparing the effects of hesperidin (1000 mg once daily) and matching placebo (ratio 1:1) on COVID-19 symptoms during 14 days in participants infected with COVID-19 (detailed protocol is presented in S1 Protocol).
    BlindingAllocation was performed through a randomization list generated by the MHICC (blocks sequence was fixed with block size of 4) and provided to the MHI pharmacists who dispensed the medication (hesperidin or placebo) according to the list after randomization of the participants by the study coordinators, keeping participants, investigators and staff blinded to drug assignment for the whole study duration.
    Power AnalysisStatistical analyses: Sample size was based on the proportion of subjects with any of the following group A COVID-19 symptoms: fever, cough, shortness of breath or anosmia at day 7.

    Table 2: Resources

    No key resources detected.

    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:
    Besides the attrition bias discussed above, there are several limitations that need to be considered in the planning of future phase 3 studies: delay of treatment, dosing, and duration of treatment and follow-up. The mean delay of 3.83 ± 1.84 days before enrollment into the trial may certainly mitigate the benefits of therapy as it has been largely reported that viral load peaks at symptoms onset and for the few following days, which is concordant with the infectiousness profile of COVID-19 [21]. The optimal therapeutic dosage of hesperidin has not previously been reported in human subjects. Participants were asked to take 2 capsules of 500 mg each once daily, the maximal allowable daily dose by the Non-Prescription and Natural Health Products Directorate (NNHPD) of Canada. Higher dosage more than once a day may be necessary to obtain optimal therapeutic effects. Finally, the duration of therapy and of follow-up may need to be longer to provide maximal benefit and better detect improvement of persisting symptoms, especially anosmia. Our study showed good safety of hesperidin with no evidence for greater drug-related AE compared to placebo and no drug-related SAE. This concords with previous pre-clinical observations in Sprague Dawley rats, with low observed adverse effects at a dosage of 1000 mg/kg in a sub-chronic oral toxicity study [22]. As well, human studies showed a safe profile of hesperidin at a dosage ranging from 500 mg daily for 3 weeks [23] to 800 mg daily for up ...

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

    IdentifierStatusTitle
    NCT04715932CompletedStudy of Hesperidin Therapy on COVID-19 Symptoms (HESPERIDIN…

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    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.

    Results from scite Reference Check: We found no unreliable references.

    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.

  2. Version published to 10.1101/2021.10.04.21264483 on medRxiv