Trial NCT04362085; NCT04444700
Publication RAPID - Sholzberg M, BMJ (2021) (published paper)
Dates: 2020-05-29 to 2021-04-12
Funding: Public/non profit (Task 54, Department of National Defence; St. Michael’s Hospital Foundation; St. Joseph’s Health Centre Foundation; 2020 TD Community Health Solutions Fund – COVID-19 Research Grant; Michael Garron Hospital; The Ottawa Hospital Foundation COVID-19 Emergency Response Fund; INVENT Kickstarter Award; Science Foundation Ireland, Enterprise Ireland, IDA Ireland COVID-19 Rapid Response Funding; SEAMO COVID-19 Innovation Fund; National Institute of General Medical Sciences, NIH; University of Vermont Medical Center Fund Grant; King Saud University)
Conflict of interest: No

Methods
RCT
Blinding: Unblinded
Location : Multicenter / Brazil, Canada, Ireland, Saudi Arabia, UAE, USA
Follow-up duration (days): 28
Inclusion criteria
  • Patients moderately ill
  • admitted to hospital wards for covid-19 with laboratory confirmed SARS-CoV-2 infection
  • Increased D-dimer levels within the first five days of admission (D-dimer levels were required to be above the upper limit of normal of the local hospital)
  • Not already mechanically ventilated, and not imminently requiring mechanical ventilation or critical care
  • Presence of an oxygen saturation ≤93% on room air, or ≥2 times the upper limit of normal irrespective of oxygen saturation.
Exclusion criteria
  • Participants with substantial bleeding risks
  • An absolute indication for or any contraindication to heparin anticoagulation based on care team judgment
  • Pregnant
  • Already experienced, or would imminently experience any component of the primary outcome (all cause death, non-invasive or invasive mechanical ventilation, or ICU admission).
Interventions
Treatment
Therapeutic Heparin
Creatinine clearance ≥30 + BMI <40:
- Enoxaparin 1 mg/kg SC every 12 hours OR 1.5 SC mg/kg every 24 hours;
- Dalteparin 200 units/kg SC every 24 hours OR 100 IU/kg SC every 12 hours;
- Tinzaparin 75 U/kg SC every 24 hours;
- unfractionated heparin IV bolus, with continuous infusion to titrate to institution specific anti-Xa or aPTT values.

Creatinine clearance ≥30 + BMI ≥40:
- Enoxaparin 1 mg/kg every 12 hours;
- Dalteparin 100 units/kg SC every 12 hours;
- Tinzaparin 175 U/kg SC daily;
- unfractionated heparin IV bolus, with continuous infusion to titrate to institution specific anti-Xa or aPTT values.

Creatinine clearance <30:
- UFH IV bolus, with continuous infusion to titrate to institution specific anti-Xa or aPTT values or LMWH per hospital protocol.

Administered until hospital discharge, death, day 28 or study withdrawal.
Control
Prophylactic Heparin
Creatinine clearance ≥30 + BMI <40:
- Enoxaparin 40 mg SC every 24 hours;
- Dalteparin 5000 units SC q24h;
- Tinzaparin 4500 U SC every 24 hours;
- Fondaparinux 2.5 mg SC every 24 hours;
- Unfractionated Heparin 5000 units SC every 8-12 hours.

Creatinine clearance ≥30 + BMI ≥40:
- Enoxaparin 40 mg SC every 24 hours;
- Dalteparin 5000 units SC every 12 hours;
- Tinzaparin 9000 (+/- 1000) U SC every 24 hours;
- Unfractionated Heparin 7000 units SC every 8 hours.

Creatinine clearance <30 + BMI <40:
- UFH 5000 units SC every 8-12 hours or LMWH per hospital protocol.

Creatinine clearance <30 + BMI ≥40:
- UFH 7500 units SC every 8 hours or LMWH per hospital protocol.

Administered until hospital discharge, death, day 28 or study withdrawal.

Participants
Randomized
participants :
Therapeutic Heparin=228
Prophylactic Heparin=237
Characteristics of participants
N= 465
Mean age : NR
264 males
Severity : Mild: n=* / Moderate: n=* / Severe: n=* Critical: n=0
Number of vaccinated participants: NR
Primary outcome
In the register
Composite outcome of ICU admission (yes/no), non-invasive positive pressure ventilation (yes/no), invasive mechanical ventilation (yes/no), or all-cause death (yes/no) up to 28 days. [ Time Frame: up to 28 days ]
In the report
Composite of ICU admission, non-invasive (bilevel or continuous positive airway pressure) or invasive mechanical ventilation, or death up to 28 days
Documents
available

Protocol

Yes. In English

Statistical plan

Yes

Data-sharing willing stated in the publication:

Yes
Risk of bias
Overall
The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review
Some concerns
General comment In addition to the published article, the pre-print, study registries, protocol, supplementary appendix and data gained from contact with authors were used in data extraction and risk of bias assessment. There is no change from the trial registration in the intervention and control treatments. The registry primary outcome reflects the reported primary outcome.
Quote: "RAPID had an adaptive design. The protocol prespecified that the sample size would be increased if the conditional power at 75% of the original sample size was between 60 and 80%.21 However, the conditional power was below 60%, therefore the sample size was not increased, thus RAPID remained underpowered."
The study was updated on the November 24th, 2021 after the published article.
The study was updated on the April 25th, 2022 after contact with the authors.