Colchicine for COVID-19 in the community (PRINCIPLE): a randomised, controlled, adaptive platform trial

  1. Jienchi Dorward
  2. Ly-Mee Yu
  3. Gail Hayward
  4. Benjamin R Saville
  5. Oghenekome Gbinigie
  6. Oliver Van Hecke
  7. Emma Ogburn
  8. Philip H Evans
  9. Nicholas PB Thomas
  10. Mahendra G Patel
  11. Duncan Richards
  12. Nicholas Berry
  13. Michelle A Detry
  14. Christina Saunders
  15. Mark Fitzgerald
  16. Victoria Harris
  17. Milensu Shanyinde
  18. Simon de Lusignan
  19. Monique I Andersson
  20. Christopher C Butler
  21. FD Richard Hobbs

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Abstract

Colchicine has been proposed as a COVID-19 treatment.

Aim

To determine whether colchicine reduces time to recovery and COVID-19-related admissions to hospital and/or deaths among people in the community.

Design and setting

Prospective, multicentre, open-label, multi-arm, randomised, controlled, adaptive platform trial (PRINCIPLE).

Method

Adults aged ≥65 years or ≥18 years with comorbidities or shortness of breath, and unwell for ≤14 days with suspected COVID-19 in the community, were randomised to usual care, usual care plus colchicine (500 µg daily for 14 days), or usual care plus other interventions. The co-primary endpoints were time to first self-reported recovery and admission to hospital/death related to COVID-19, within 28 days, analysed using Bayesian models.

Results

The trial opened on 2 April 2020. Randomisation to colchicine started on 4 March 2021 and stopped on 26 May 2021 because the prespecified time to recovery futility criterion was met. The primary analysis model included 2755 participants who were SARS-CoV-2 positive, randomised to colchicine ( n = 156), usual care ( n = 1145), and other treatments ( n = 1454). Time to first self-reported recovery was similar in the colchicine group compared with usual care with an estimated hazard ratio of 0.92 (95% credible interval (CrI) = 0.72 to 1.16) and an estimated increase of 1.4 days in median time to self-reported recovery for colchicine versus usual care. The probability of meaningful benefit in time to recovery was very low at 1.8%. COVID-19-related admissions to hospital/deaths were similar in the colchicine group versus usual care, with an estimated odds ratio of 0.76 (95% CrI = 0.28 to 1.89) and an estimated difference of −0.4% (95% CrI = −2.7 to 2.4).

Conclusion

Colchicine did not improve time to recovery in people at higher risk of complications with COVID-19 in the community.

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  1. Version published to 10.3399/bjgp.2022.0083
  2. ScreenIT

    SciScore for 10.1101/2021.09.20.21263828: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: The UK Medicines and Healthcare products Regulatory Agency and the South Central-Berkshire Research Ethics Committee (Ref: 20/SC/0158) approved the trial protocol.
    Consent: Online consent was obtained from all participants.
    Sex as a biological variablePatient and public involvement: We convened a patient and public involvement group of five women and two men who input into the patient-facing materials, choice of trial outcomes, and delivery plans.
    RandomizationPeople were ineligible to be randomised to colchicine if they were already taking colchicine or if colchicine was contraindicated according to the British National Formulary.
    BlindingThe trial team was blinded to randomisation probabilities.
    Power AnalysisStatistical analysis: Sample size calculation and statistical analysis are detailed in the Adaptive Design Report (appendix pp 130-230) and the Master Statistical Analysis Plan (appendix pp 81-129).

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    of the Master Statistical Analysis Plan, appendix pp 102-109
    Master Statistical Analysis Plan
    suggested: None

    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:
    Strengths and weaknesses: Strengths include the pragmatic design of the PRINCIPLE trial which allowed for efficient evaluation of the effectiveness of colchicine as an early, standalone intervention as it might be used in the community. We focused on patients at increased risk of complications and used routine electronic health records to confirm hospitalisation/death, and obtained primary outcome data on over 95% of participants. Although our primary analysis was restricted to SARS-CoV-2 positive patients, we conducted secondary analyses of the co-primary outcomes among patients with suspected COVID-19 but without PCR confirmed SARS-CoV-2 infection, as limited SARS-CoV-2 testing may necessitate early empirical treatment in low resource settings. Furthermore, variation in PCR testing sensitivity, particularly if self-administered, means some participants will have had false negative tests.28 Time to recovery estimates were similar in the SARS-CoV-2 positive population, all participants irrespective of SARS-CoV-2 status, as well as the concurrent randomisation SARS-CoV-2 positive population (the latter populations are most analogous to those in traditional two arm trials). Although the sample size of the colchicine group in PRINCIPLE was relatively small, the Bayesian primary analysis model leverages previous enrolments in the usual care arm to increase the precision of estimates, which allow us to declare futility with high precision due to very low probability of a meaningfu...

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

    IdentifierStatusTitle
    ISRCTN86534580NANA

    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.

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  3. Version published to 10.1101/2021.09.20.21263828v1 on medRxiv