COVID-19 Ring-based Prevention Trial With Lopinavir/Ritonavir (CORIPREV-LR)

COVID-19 has rapidly evolved into a generalized global pandemic. Post-exposure prophylaxis (PEP) against on COVID-19 was identified as an urgent research priority by the WHO, and lopinavir/ritonavir (LPV/r) is a promising candidate for both COVID-19 treatment and PEP, with a good safety profile and global availability. This is a cluster randomized controlled trial (RCT) of oral LPV/r as PEP against COVID-19, that will address the immediate need for preventive interventions, generate key data on COVID-19 transmission, and serve as a research platform for future vaccines and preventive agents.

Study Overview

• Status: Active, not recruiting
• Conditions: Coronavirus Infections; Post-exposure Prophylaxis
• Intervention / Treatment: Drug: Lopinavir/ritonavir

• Study Type: Interventional
• Enrollment (Actual): 123
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • St. Paul's Hospital
  • Ontario
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital
    • Toronto, Ontario, Canada, M5G 2N2
      • Toronto General Hospital
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. High risk close contact with a confirmed COVID-19 case during their symptomatic period, including one day before symptom onset, within the past 1-7 days. High risk close contact is defined as any of the following exposures without the consistent appropriate use of recommended personal protective equipment:

   1. Provided direct care for the index case
   2. Had close physical contact with the index case
   3. Lived with the index case
   4. Had close contact (within 2 metres), without direct physical contact, for a prolonged period of time
   5. Had direct contact with infectious body fluids, including oral secretions, respiratory secretions, or stool.
2. Successfully contacted by the study team within 24 hours of study team notification of the relevant index COVID-19 case. This time window is necessary because the efficacy of PEP may be dependent on the timing of its initiation, and because randomization of a ring cannot be delayed while awaiting response from contacts that cannot be rapidly reached.
3. Age ≥6 months, since the safety and pharmacokinetic profiles of LPV/r in pediatric patients below the age of 6 months have not been established.
4. Ability to communicate with study staff in English

Exclusion Criteria:

1. Known hypersensitivity/allergy to lopinavir or ritonavir.
2. Current use of LPV/r for the treatment or prevention of HIV infection.
3. Receipt of LPV/r in the context of this trial or any other trial of COVID-19 PEP within 2 days or less prior to the last known contact with the index COVID-19 case. The two day time window is intended to ensure that exposure would not have occurred in the presence of clinically relevant drug levels (five times the elimination half-life of LPV/r, which is estimated at 4-6 hours with prolonged use).
4. Baseline respiratory tract specimen positive for COVID-19. Randomized participants whose baseline samples subsequently show COVID-19 will have study drug discontinued but still remain under observation.
5. Current breastfeeding, due to potential for serious adverse reactions in nursing infants exposed to LPV/r

6. Concomitant medications with prohibited drug interactions with LPV/r that cannot be temporarily suspended/replaced, including but not restricted to: 37

   • alfuzosin (e.g. Xatral®)
   • amiodarone (e.g. Cordarone™)
   • apalutamide (e.g. Erleada™)
   • astemizole*, terfenadine*
   • cisapride*
   • colchicine, when used in patients with renal and/or hepatic impairment
   • dronedarone (e.g., Multaq®)
   • elbasvir/grazoprevir (e.g., ZepatierTM)
   • ergotamine* (e.g. Cafergot®*), dihydroergotamine (e.g. Migranal®), ergonovine, methylergonovine*
   • fusidic acid (e.g., Fucidin®), systemic*
   • lurasidone (e.g., Latuda®), pimozide (e.g., Orap®*)
   • neratinib (e.g., Nerlynx®)
   • sildenafil (e.g., Revatio®)
   • triazolam (e.g. Halcion®), midazolam oral*
   • rifampin (e.g. Rimactane®*, Rifadin®, Rifater®*, Rifamate®*)
   • St. John's Wort
   • Tadalafil (e.g. Adcirca®)
   • venetoclax (e.g. Venclexta®)
   • lovastatin (e.g., Mevacor®*), lomitapide (e.g., JuxtapidTM) or simvastatin (e.g., Zocor®)
   • vardenafil (e.g., Levitra® or Staxyn®)

   • salmeterol (e.g., Advair® or Serevent®)

     • denotes products not marketed in Canada

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Lopinavir/ritonavir; This arm will receive oral lopinavir/ritonavir 400/100 mg (or equivalent weight-based dosing) twice daily for 14 days.	Drug: Lopinavir/ritonavir; The intervention is a 14-day course of LPV/r 400/100 mg orally twice daily, or equivalent weight-based dosing, to be initiated as soon as possible (within 1-7 days) after the last exposure.; Other Names: Kaletra; Aluvia
NO_INTERVENTION: Control; This arm will receive no intervention.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiologic evidence of infection	The primary outcome is microbiologically confirmed COVID-19 infection, ie. detection of viral RNA in a respiratory specimen (mid-turbinate swab, nasopharyngeal swab, sputum specimen, saliva specimen, oral swab, endotracheal aspirate, bronchoalveolar lavage specimen) by day 14 of the study.	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	a) Adverse events: as defined using the DAIDS Table for Grading the Severity of Adverse Events, at 7, 14, 28 & 90 days	90 days
Symptomatic COVID-19 disease	fever, cough or other respiratory/ systemic symptoms (including but not limited to fatigue, myalgias, arthralgias, shortness of breath, sore throat, headache, chills, coryza, nausea, vomiting, diarrhea) by day 14 in a patient with laboratory confirmed infection, combined with microbiologic confirmation of COVID-19 infection in the participant.	14 days
Seropositivity	Reactive serology to SARS-CoV-2	28 days
Days of hospitalization attributable to COVID-19 disease	The number of days (or partial days) spent admitted to an acute care hospital will be tabulated both at day 28 and day 90	90 days
Respiratory failure requiring ventilatory support attributable to COVID-19 disease	The number of days (or partial days) requiring i) non-invasive and ii) endotracheal intubation with ventilation will be tabulated both at day 28 and day 90.	90 days
Mortality	Death attributable to COVID-19 disease and all-cause mortality	90 days
Short-term psychological impact of exposure to COVID-19 disease	Short-term psychological distress will be measured using the K10, with a standard cutoff score of ≥16.	28 days
Long-term psychological impact of exposure to COVID-19 disease	Long-term impact will be measured at day 90 using the Impact of Event Scale, a validated measure of traumatic stress response, using a standard cutoff score of ≥26	90 days
Health-related quality of life	Health-related quality of life will be measured using the EQ-5D-5L (EuroQol-5D). The EQ-5D consists of two pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The tool will be administered to participants at 1, 14, 28 and 90 days.	90 days

Collaborators and Investigators

• Sponsor: Unity Health Toronto

Publications and helpful links

General Publications

• Sultana J, Crisafulli S, Gabbay F, Lynn E, Shakir S, Trifiro G. Challenges for Drug Repurposing in the COVID-19 Pandemic Era. Front Pharmacol. 2020 Nov 6;11:588654. doi: 10.3389/fphar.2020.588654. eCollection 2020.
• Akhtar S, Das JK, Ismail T, Wahid M, Saeed W, Bhutta ZA. Nutritional perspectives for the prevention and mitigation of COVID-19. Nutr Rev. 2021 Feb 11;79(3):289-300. doi: 10.1093/nutrit/nuaa063.
• Tan DHS, Chan AK, Juni P, Tomlinson G, Daneman N, Walmsley S, Muller M, Fowler R, Murthy S, Press N, Cooper C, Lee T, Mazzulli T, McGeer A. Post-exposure prophylaxis against SARS-CoV-2 in close contacts of confirmed COVID-19 cases (CORIPREV): study protocol for a cluster-randomized trial. Trials. 2021 Mar 22;22(1):224. doi: 10.1186/s13063-021-05134-7.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 17, 2020
• Primary Completion (ACTUAL): August 27, 2021
• Study Completion (ANTICIPATED): March 31, 2022

Study Registration Dates

• First Submitted: March 18, 2020
• First Submitted That Met QC Criteria: March 23, 2020
• First Posted (ACTUAL): March 25, 2020

Study Record Updates

• Last Update Posted (ACTUAL): December 14, 2021
• Last Update Submitted That Met QC Criteria: November 29, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Coronavirus Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Lopinavir
• Other Study ID Numbers: CORIPREV-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: TBA

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes