Repurposing Existing Medications for Coronavirus Disease 2019 – Protocol for a Rapid/Living Systematic Review

 

Prepared by: Ben Geisler

Last update: 3/26/2020

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Collaborators

• Benjamin P. Geisler, MD MPH FACEP MRCP (London), Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA

• Lara Zahabi-Bekdash, MD MHSc PhD, McGill University, Montreal, Canada

• Naomi Eastwood, MBBS, Wirral University Teaching Hospital NHS Foundation Trust, Wirral, UK

• Elaine Tennant, MBBS, Royal North Shore Hospital & UTS, Sydney, NSW, Australia; University of New South Wales, Sydney, NSA, Australia

• Ljiljana Lukic, MD MSc PhD, University Hospital for Infectious Disease Zagreb, Zagreb, Coratia

• Elad Sharon, MD MPH, National Cancer Institute, Rockville, MD, USA

• Hai-Hua Chaung, MD, Linkou Chang Gung Memorial Hospital/Chang Gung University, Taoyuan, Taiwan; National Taipei University of Technology, Taipei, Taiwan; Geisinger Clinic, Danville, PA, USA

• Chang Berm, MBA, Proof Biotechnologies

• Knakita Clayton-Johnson, MD, Portmore Hospital Complex, Portmore, Jamaica

• Ahmed Aljaberi, MD, Brigham and Women’s Hospital, Boston, MA, USA

• Haining Yu, MD MPH, University of California San Francisco Medical Center, San Francisco, CA, USA

• Farrin A. Manian, MD MPH FACP FIDSA FSHEA, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA

• Robert Hallowell?

• Rob M. van Dam, National University of Singapore, Singapore

 

Timeline

Anticipated or actual start date: 03/20/2020

Anticipated completion date: early April

 

Review Questions

1. What repurposed existing medications have shown any in vitro or clinical activity against SARS-CoV2, SARS, or MERS,

2. What is the level of evidence and effect size,

3. What are possible harms, and

4. What is therefore the most promising compound?

 

Search Strategy

• PubMed

• Embase

• ClinicalTrials.gov

• Google Scholar

• Preprint servers

  • MedRxiv

  • BioRxiv

  • chemrxiv

  • Preprints.org

  • ChinaXiv

 

Search Dates

PubMed, Embase, andClinicalTrials.gov (search date: March 21, 2020); BioRxiv, MedRxiv, ChemRxiv, and Google Scholar (search date: March 23, 2020), and , ChinaXiv (March 26, 2020); no restrictions

 

Condition or domain being studied

• Coronavirus Disease 2019 (COVID-19)

• Severe Acute Respiratory Syndrome (SARS)

• Middle Eastern Respiratory Syndrome (MERS)

 

Participants/population

Patients with confirmed infection with

1. SARS-CoV2 (the virus that causes Covid-19),

2. SARS-CoV (the virus that causes severe acute respiratory syndrome, SARS), or

3. MERS-CoV (the virus that causes middle eastern respiratory syndrome, MERS)

 

Interventions

• Individual drugs

  • Arbidol (Umifenovir)

  • Atazanavir

  • Azithromycin and combinations

  • Baloxavir marboxil +/- favipiravir

  • Baricitinib

  • Bevacizumab

  • Chloroquine

  • Colchicine

  • Darunavir/cobicistat +/- lopinavir/ritonavir and thymosin α1

  • Emtricitabine/tenofovir

  • Enisamium iodide

  • Favipiravir (T-705 or Avigan)

  • Fingolimod

  • Ganciclovir

  • Hydroxychloroquine

  • Indinavir

  • Lopinavir/ritonavir (Kaletra) +/- interferon +/- ribavirin

  • Mycophenolic acid/mofetil and combinations (e.g. inferteron)

  • Nelfinavir

  • Niclosamide

  • Nitazoxanide

  • Novaferon

  • Oseltamivir

  • Pirfenidone (Esbriet)

  • Quercetin

  • Remdesivir (GS-5734)

  • Ribavirin and combinations

  • Ruxolitinib

  • Sirolimus

  • Sofosbuvir

  • Tocilizumab

  • Thymosin alpha-1

  • Triazavirin

• Groups of drugs

  • Glucocorticosteroids +/- mineralosteroids

  • (peg)Interferonalpha

  • (peg)Interferonalpha2a

  • (peg)Interferonalpha2b

  • (peg)Interferonbeta

  • (peg)Interferonbeta1a

  • (peg)Interferonbeta1b

  • (peg)Interferongamma

  • Interferon combinations (e.g. ribavirin)

  • Statins

• Convalescent plasma/serum

 

Comparators/Controls

Both single-arm studies and controlled studies will be included

 

Types of study to be included

All study types are acceptable, specifically, in vitro studies, animal studies, single-arm studies, and non-randomized and randomized controlled trials, both blinded and open-label trials.

 

Context

To be included in our review, patients have not just have to have symptoms compatible with Coronavirus Disease 2019 (Covid-19) but have a laboratory confirmation of infection of SARS-CoV2, usually via nasopharyngeal/oropharyngeal swab with rt-PCR. We will include all patient cohorts, regardless of setting (inpatient/outpatient), age, gender, and disease stage. In addition to the entire cohort, we will also consider subgroups, for example patients who have been diagnosed with acute respiratory distress syndrome, been admitted to an intensive care unit, been intubated etc.

 

Main Outcome

The pre-specified main outcome will be all-cause mortality. We will consider various follow up time horizons, e.g. in-hospital and 30 days.

 

Measures of effect

For controlled studies, we will calculate a relative risk with a 95% confidence interval via a meta-analysis if more than one study is available for a comparable endpoint.

 

Additional Outcomes

Additional outcomes will consist of

• time to viral clearance;

• total length of stay;

• proportion of intensive care unit (ICU) admission and/or progression to severe sepsis/ARDS

• ICU length of stay;

• proportion intubated;

• days intubated;

• normalization of selected laboratory data, including C-reactive protein, d-dimer, lactate dehydrogenase, ferritin, and lymphocyte count;

• adverse events;

• for outpatients specifically:

  1. hospitalization rate;

  2. days to resolution of symptoms;

  3. time to viral clearance;

  4. normalization of selected laboratory data, including C-reactive protein, d-dimer, lactate dehydrogenase, ferritin, and lymphocyte count;

• for uncontrolled studies, we will report any available data (e.g., pre/post); and

• risk of bias (see below)

 

Data extraction (selection and coding)

We will include all in vitro or clinical studies that test one of more of the candidate compounds, both single arm and controlled studies. We will collate the results of the studies in tables. Data for the endpoints above will be extracted via Covidence.

We will the collected the results in tables and post them online and condense them for a preprint and eventual publication. A quantitative synthesis (in a meta-analysis) is less likely to happen unless there is more than one controlled study per compound.

 

Risk of bias (quality) assessment

Risk of bias will be assessed either by

• Study type and one of the following

  • Cochrane's domains of bias concept

  • via the GRADE system

 

Analysis of subgroups or subsets

In addition to the entire cohort, we will also consider subgroups, for example patients who have been diagnosed with acute respiratory distress syndrome, been admitted to an intensive care unit, been intubated, or by severity of the disease as judged by laboratory analysis and clinical judgement etc.

 

Strategy for data synthesis

If more than one controlled study is available per endpoint and candidate drug, we will meta-analyze the results in random effects models (in either Review Manager or STATA). Otherwise, we will attempt a qualitative synthesis of the results of the included studies in tables by endpoint (see above). These tables will be created in Excel, and our plan is to post them online with an interface where the use can select the results to be displayed, filter, and sort them. Finally, we will create a narrative synthesis by judging the level of available evidence for the effectiveness per drug compound, possible effect sizes (if a quantitative synthesis is possible), the possible harms, and finally a priority list that could be used to select or deselect drugs for further clinical trials, including - if available - possible effect estimate for sample size/power calculations.

 

Search Syntax

PubMed

("COVID-19" [Supplementary Concept] or
"covid-19*"[tiab] or
"covid19*"[tiab] or
"sars-cov2*"[tiab] OR
"2019-nCoV"[tiab] OR
((novel*[tiab] OR 2019[tiab]) AND ("Coronavirus Infections"[Mesh] OR Coronavirus*[tiab] OR "Corona-virus*"[tiab] OR (Corona*[tiab] and virus*[tiab]))) OR
"SARS Virus"[Mesh] OR
"Severe Acute Respiratory Syndrome*"[tiab] OR
"SARS-CoV"[tiab] OR
SARS*[tiab] OR
"Middle East Respiratory Syndrome Coronavirus"[Mesh] OR
"Middle East Respiratory Syndrome"[tiab] OR
"MERS-CoV*"[tiab] OR
MERS*[tiab])

AND

("arbidol" [Supplementary Concept] OR arbidol*[tiab] OR Umifenovir*[tiab] OR
"Azithromycin"[Mesh] OR Azithromycin*[tiab] OR
"baloxavir" [Supplementary Concept] OR baloxavir*[tiab] or
"baricitinib" [Supplementary Concept] OR baricitinib*[tiab] OR
"Bevacizumab"[Mesh] OR Bevacizumab[tiab] OR
"Chloroquine"[Mesh] OR Chloroquine*[tiab] OR
"Darunavir"[Mesh] OR Darunavir*[tiab] OR "Cobicistat"[Mesh] OR Cobicistat*[tiab] OR
"Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination"[Mesh] OR  "Emtricitabine"[Mesh] OR Emtricitabine*[tiab] or Tenofovir*[tiab] OR
"enisamium" [Supplementary Concept] OR enisamium*[tiab] or
"favipiravir" [Supplementary Concept] OR favipiravir[tiab] OR
"Fingolimod Hydrochloride"[Mesh] OR Fingolimod*[tiab] OR
"Ganciclovir"[Mesh] OR Ganciclovir*[tiab] OR
"Hydroxychloroquine"[Mesh] OR Hydroxychloroquine*[tiab] OR " Hydroxy-chloroquine*[tiab]"
"Lopinavir"[Mesh] OR "lopinavir-ritonavir drug combination" [Supplementary Concept] OR Lopinavir*[tiab] OR
"Mycophenolic Acid"[Mesh] OR "Mycophenolic Acid"[tiab] OR "mycophenolate"[tiab] OR (Mycophenol*[tiab] AND Acid [tiab]) OR (Mycophenol*[tiab] AND Mofetil*[tiab]) OR (Mofetil[tiab] and Hydrochlorid*[tiab]) OR
"Nelfinavir"[Mesh] OR Nelfinavir*[tiab] OR
"Niclosamide"[Mesh] OR Niclosamide*[tiab] OR
"nitazoxanide" [Supplementary Concept] OR nitazoxanide*[tiab] OR
"Novaferon" [Supplementary Concept] OR Novaferon*[tiab] OR
"Oseltamivir"[Mesh] OR Oseltamivir*[tiab] OR
"pirfenidone" [Supplementary Concept] OR pirfenidone*[tiab] OR
"Quercetin"[Mesh] OR Quercetin*[tiab] OR
"remdesivir" [Supplementary Concept] OR remdesivir*[tiab] or
"Ribavirin"[Mesh] OR Ribavirin*[tiab] OR
"INCB018424" [Supplementary Concept] OR Ruxolitinib*[tiab] OR
"Sirolimus"[Mesh] OR Sirolimus*[tiab] OR
"Sofosbuvir"[Mesh] OR Sofosbuvir*[tiab] OR
"Thymalfasin"[Mesh] OR  "thymosin alpha(1) (24-28)" [Supplementary Concept] OR Thymalfasin*[tiab] OR
"triazavirin" [Supplementary Concept] OR triazavirin*[tiab] OR
"tocilizumab" [Supplementary Concept] OR tocilizumab*[tiab] OR
"Steroids"[Mesh] or steroid*[tiab] or corticosteroid*[tiab] or "cortico-steroid*"[tiab] or "Hydrocortisone"[Mesh] or Hydrocort*[tiab] OR "Cortisone"[Mesh]  OR Cortis*[Mesh] OR "Prednisone"[Mesh] OR  "prednisone sodium succinate" [Supplementary Concept] OR Prednis*[tiab] OR "Prednisolone"[Mesh] "Methylprednisolone"[Mesh] OR "Methylprednisolone Acetate"[Mesh] OR  "Methylprednisolone Hemisuccinate"[Mesh] OR Methylpred*[tiab] or "Methyl-pred*"[tiab] or "Dexamethasone"[Mesh] OR  "Dexamethasone Isonicotinate"[Mesh] OR dexameth*[tiab] or "Fludrocortisone"[Mesh] OR "fludrocortisone acetate" [Supplementary Concept] OR fludrocort*[tiab] OR
"Interferon-alpha"[Mesh] OR "Interferon alpha-2"[Mesh] OR "Receptor, Interferon alpha-beta"[Mesh] or "interferon-alpha*"[tiab] or (interferon*[tiab] and alpha[tiab]) OR "interferon alfacon-1" [Supplementary Concept] OR (interferon*[tiab] AND ("alfacon-1"[tiab] OR alfacon*[tiab])) OR
"Interferon-beta"[Mesh] OR "Interferon beta-1b"[Mesh] OR  "Interferon beta-1a"[Mesh] OR "interferon-beta*"[tiab] or (interferon*[tiab] and beta[tiab]) OR
"Interferon-gamma"[Mesh] OR "interferon-gamma*"[tiab] or (interferon*[tiab] and gamma[tiab]) OR
"Atorvastatin Calcium"[Mesh] OR "atorvastatin*"[tw] OR "Rosuvastatin Calcium"[Mesh] OR "rosuvastatin*"[tw] OR "Simvastatin"[Mesh] OR "simvastatin acid" [Supplementary Concept] OR "simvastatin*"[tw] OR "Pravastatin"[Mesh] OR  "Pravastatin*"[tw] OR "fluvastatin"[Supplementary Concept] OR "fluvastatin*"[tw] OR "fluindostatin*"[tw] OR
"Lovastatin"[Mesh] OR "Lovastatin*"[tw] OR "mevinolin*"[tw] OR "pitavastatin"[Supplementary Concept] OR "pitavastatin*"[tw] OR "statin*")

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Corrected mistake (bold OR after "Middle East Respiratory Syndrome"[tiab] was missing) on 3/23 and uploaded 278 additional references (367-95)