Ad-hoc COVID-19 Clinical Pharmacology Task Group: Statement on remdesivir
Clinical Pharmacology Task Group (CPTG) meeting date: June 12, 2020
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- Policy question
- Clinical evidence of efficacy to date
- Clinical evidence of safety to date
- Authorization/licensure status worldwide
The Public Health Agency of Canada (PHAC) asked the ad-hoc COVID-19 Clinical Pharmacology Task Group (CPTG) for advice on whether known and potential benefits of remdesivir outweigh known and potential risks in the treatment of patients hospitalized with COVID-19.
The CPTG recommends that remdesivir should only be administered as part of a randomized controlled trial to monitor whether potential benefits of remdesivir outweigh known and potential risks in the treatment of patients hospitalized with COVID-19.
The group will review emerging evidence as provided by PHAC on an ongoing basis in order to make evidence-informed recommendations in a timely manner.
This statement was approved by the Clinical Pharmacology Task Group on June 29, 2020.
As of June 17, 2020, 24 clinical trials were registered worldwide to investigate remdesivir as a treatment for COVID-19, with 2 trials in Canada. These include CATCO (Canadian Treatments for COVID-19), the Canadian-led arm of WHO’s multinational Solidarity treatment trial (Sunnybrook Research Institute) and a Gilead-led expanded access open-label trial. A series of developments have brought into question the benefit-risk of remdesivir.
On June 12, 2020, the ad-hoc COVID-19 CPTG met, and part of the discussions included a benefit-risk profile of Remdesivir to be included in the pandemic response. The Task Group discussed recent global changes in evidence and clinical practice and were provided an evidence summary prepared by the Canadian Agency for Drugs and Technologies in Health (CADTH)Footnote 1.
Clinical evidence of efficacy to date
- On April 29, 2020, Wang et al. published clinical findings from a Gilead-led phase 3 randomized controlled trials (RCT), sponsored by the National Key Research and Development of China, testing remdesivir in hospitalized adults with severe COVID-19 (n=237 patients enrolled and randomized; China). The authors reported a numerical reduction in time to clinical improvement (21.0 vs. 23.0 days), median duration of invasive mechanical ventilation (7.0 vs. 15.5 days), and median duration of oxygen support (19.0 vs. 21.0 days), in response to treatment. However, the trial was underpowered to show efficacy due to premature termination from insufficient enrolment and therefore all reported differences are statistically insignificant. The study reported similar rates of the percentage of patients with undetectable viral load at day 28, mortality at day 28, and the median number of days in hospital, for patients treated with remdesivir compared to those treated with placeboFootnote 2.
- On May 22, 2020, Beigel et al. published preliminary results from a National Institute of Allergy and Infectious Diseases (NIAID) -led phase 3 RCT testing remdesivir in hospitalized adults with severe COVID-19 (n=1,063 patients enrolled and randomized; multinational). The authors reported a statistically significant reduction in time to clinical recovery compared to placebo (11 vs. 15 days; p<0.001). In addition, the odds of improvement in clinical status at day 15 was statistically higher with remdesivir than with placebo (OR 1.50; p=0.001). Patients who underwent randomization during the first 10 days after the onset of symptoms had a lower rate ratio for recovery compared to patients who underwent randomization more than 10 days after symptom onset (1.28 vs. 1.38). The study reports that patients with severe disease had a higher ratio for recovery than patients with mild-to-moderate disease (1.37 vs. 1.09). However, only 11% of patients had mild to moderate disease, therefore this subgroup analysis is not controlled for type I error. At day 14, mortality rates (Kaplan-Meier estimate) were 7.1% in patients who received remdesivir vs. 11.9% in patients receiving placebo (HR=0.70; 95% CI, 0.47 to 1.04). Note: 28% of patients included in the trial had not reached the 28-day follow-up point at time of publicationFootnote 3.
- On May 27, 2020, Goldman et al. published clinical findings from a Gilead-led randomized, open-label non-controlled phase 3 trial comparing a 5-day vs. a 10-day treatment course of remdesivir in hospitalized patients (≥ 12 years old) with severe COVID-19 not requiring mechanical ventilation (n=397, multinational). The study reported no significant difference between the 5-day and the 10-day course of treatment after adjustment for baseline clinical status, with respect to distribution of clinical status at day 14 (p=0.14), median duration of hospitalization among patients discharged on or before day 14 (7 days vs. 8 days, respectively), clinical improvement at 14 days (64% vs. 54% of patients, respectively), time to clinical improvement for 50% of patients (10 days vs. 11 days, respectively), and mortality at 14 days (8% vs. 11%, respectively). Notably, 1) patients randomly assigned to the 10-day treatment course had a significantly worse clinical status at baseline than patients assigned to the 5-day treatment course (p=0.02), and 2) fewer patients completed their treatment course in the 10-day treatment arm than in the 5-day treatment arm (43% of patients vs. 85% of patients)Footnote 4.
- On June 1, 2020, Gilead released a media statement reporting preliminary findings from their ongoing randomized open-label phase 3 trial comparing a 5-day vs. a 10-day treatment course of remdesivir to standard of care, to treat hospitalized patient (≥ 12 years old) with moderate COVID-19 (n=584 at time of press release). Preliminary evidence suggested remdesivir treatment was associated with clinical benefit compared to standard of care where a 5-day but not a 10-day treatment significantly increased likelihood of clinical improvement on day 11 (p=0.026)Footnote 5.
Clinical evidence of safety to date
- Phase 1 safety data arising from administration to healthy volunteers included evidence of elevated transaminase levels (Grade 1-Grade 2) when administered using the same dosing strategy as that used for COVID-19, for both a 5- and 10-day treatment duration (Study GS-US-399-5505; 200 mg followed by 100 mg dosing for 5–10 days) as well as using a higher dosing regimen (Study GS-US-399-1954; 150 mg daily for 7 or 14 days). Levels normalized after discontinuation of remdesivirFootnote 6.
- All above studies in COVID-19 patients reported on safety and no study reported serious safety signals.
- Wang et al. reported a similar percentage of patients reporting adverse events (AEs) between remdesivir-treatment and placebo; however, more patients in the remdesivir group discontinued treatment due to AEs (12% vs. 5%)Footnote 2.
- In Beigel et al., less patients reported a serious AE (SAE) in the remdesivir treated group compared to standard of care (21.1% vs. 27%); this trend was consistent with reporting of grade 3 or 4 AEs (28.8% of patients in the remdesivir arm vs. 33% of patients in the standard of care arm). There was similar incidence of treatment discontinuation due to AE reportingFootnote 3.
- Goldman et al. noted more SAEs and discontinuations due to AEs in the 10-day treatment course compared to the 5-day treatment course with remdesivirFootnote 4.
- Preliminary safety data from the ongoing Gilead-led randomized open-label phase 3 trial comparing a 5-day vs. a 10-day treatment course of remdesivir to standard of care, reported no increased incidence of AE reporting or SAE reporting associated with 5- or 10-day treatment with remdesivirFootnote 5.
- Post hoc statement added on October 9:
On October 2, 2020, the European Medicines Agency Safety Committee initiated a review to assess reports of acute kidney injury in patients taking remdesivir for COVID-19. In response, Health Canada initiated a priority safety review to investigate safety outcomes following treatment of patients with remdesivir in Canada.
Post hoc statement on authorization/licensure status worldwide (last updated 5 October 2020)
- Remdesivir (brand name Veklury) was authorized with conditions in Canada on July 27, 2020 for the treatment of patients with severe symptoms of COVID-19, who have pneumonia and require supplemental oxygen. It is the first drug authorized in Canada for the treatment of COVID-19. Remdesivir has also been granted emergency or conditional authorization in the U.S., Europe, Japan, Singapore, Switzerland and Australia.
- There is currently limited evidence on the efficacy of remdesivir for COVID-19.
- Reported safety signals following the use of remdesivir in healthy or COVID-19 patient populations include potential impact on liver function.
- Current clinical data on remdesivir as a treatment for COVID-19 is limited to intravenous administration in hospitalized patients with severe COVID-19.
- Therefore, the risk-to-benefit ratio of remdesivir as a treatment for COVID-19 warrants critical evaluation, especially in severe COVID-19 patients requiring mechanical ventilation in the intensive care unit, and in patients with renal injury / failure.
- Strict criteria should be defined to determine the patient population suitable for Remdesivir treatment where those who are least likely to experience adverse effects and most likely to benefit from the drug are prioritized for treatment based on the evidence as it emerges, and based on availability of data for different demographic subgroups such as sex and age.
- The CPTG will re-evaluate the risk-benefit profile of remdesivir for use as treatment of COVID-19 following knowledge of cost of treatment, availability of doses for Canada, and as additional results from RCT are disseminated for publication.
This statement was prepared by: N Forbes, M Patel, M Rieder, and M Salvadori, on behalf of the Clinical Pharmacology Task Group (CPTG).
CPTG Members: M Salvadori (Co-Chair), M Rieder (Co-chair),M Lordkipanidze, R Hall, M Piquette-Miller, A Collier and S Murthy.
CPTG gratefully acknowledges the contribution of: N Abraham, A House, M Tunis, A Killikelly, Y Chung, J Courtemanche, A Coady, B Mitchelmore, E Chong, and R Goddard.
CPTG also gratefully acknowledges the contribution from the Canadian Agency for Drugs and Technologies in Health.
- Footnote 1
CADTH, Remdesivir: Evidence Review and Appraisal. 2020: Ottawa.
- Footnote 2
Wang, Y., et al., Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet, 2020. 395(10236): p. 1569-1578.
- Footnote 3
Beigel, J.H., et al., Remdesivir for the Treatment of Covid-19 - Preliminary Report. N Engl J Med, 2020.
- Footnote 4
Goldman, J.D., et al., Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. N Engl J Med, 2020.
- Footnote 5
Gilead Announces Results From Phase 3 Trial of Remdesivir in Patients With Moderate COVID-19. 2020, www.businesswire.com
- Footnote 6
FDA, FACT SHEET FOR HEALTH CARE PROVIDERS EMERGENCY USE AUTHORIZATION (EUA) OF REMDESIVIR (GS-5734™), FDA, Editor. 2020.
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