COVID-19 Ring-based Prevention Trial With Lopinavir/Ritonavir

Study Overview
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Brief Summary
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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.

Official Title
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COVID-19 Ring-based Prevention Trial With Lopinavir/Ritonavir

Conditions
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Coronavirus Infections, Post-exposure Prophylaxis

Intervention / Treatment
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* Drug: Lopinavir/ritonavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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: Provided direct care for the index case Had close physical contact with the index case Lived with the index case Had close contact (within 2 metres), without direct physical contact, for a prolonged period of time Had direct contact with infectious body fluids, including oral secretions, respiratory secretions, or stool. 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. 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. Ability to communicate with study staff in English Exclusion Criteria: Known hypersensitivity/allergy to lopinavir or ritonavir. Current use of LPV/r for the treatment or prevention of HIV infection. 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). 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. Current breastfeeding, due to potential for serious adverse reactions in nursing infants exposed to LPV/r 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

Ages Eligible for Study
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Minimum Age: 18 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lopinavir/ritonavir<br>This arm will receive oral lopinavir/ritonavir 400/100 mg (or equivalent weight-based dosing) twice daily for 14 days. | Drug: Lopinavir/ritonavir<br>* 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.<br>* Other names: Aluvia;|
| No Intervention: Control<br>This arm will receive no intervention. | |

What is the study measuring?
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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 |