NCT04335552

Pragmatic Factorial Trial of Hydroxychloroquine, Azithromycin, or Both for Treatment of Severe SARS-CoV-2 Infection

Terminated Phase 2 Results posted Last updated 17 May 2021

What this trial tests

Phase 2 trial testing Standard of care in SARS-CoV-2 in 11 participants. Terminated before completion.

Timeline

17 April 2020

Primary endpoint
17 June 2020

26 June 2020

Quick facts

Lead sponsor	Duke University
Phase	Phase 2
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	factorial
Masking	none
Primary purpose	treatment
Enrollment	11
Start date	17 April 2020
Primary completion	17 June 2020
Estimated completion	26 June 2020
Sites	4 locations across United States

Drugs / interventions tested

• Standard of care
• Hydroxychloroquine (HYDROXYCHLOROQUINE) — full drug profile →
• Azithromycin (azithromycin) — full drug profile →

Conditions studied

• SARS-CoV-2 — all drugs for SARS-CoV-2 →

Sponsor

Duke University

Who can join

12 and older, any sex, with SARS-CoV-2. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

World Health Organization (WHO) Ordinal Scale Measured at 14 Days After Enrollment Primary · Day 14

The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitati

Group	Value	95% CI
Standard of Care	1	± NA
Standard of Care Plus Hydroxychloroquine	2.5	± 3
Standard of Care Plus Azithromycin	5.3	± 3.8
Standard of Care Plus Hydroxychloroquine Plus Azithromycin	4.5	± 5.0

Number of Participants Who Died During the Index Hospitalization Secondary · Index hospitalization, up to 46 days

Group	Value	95% CI
Standard of Care	0
Standard of Care Plus Hydroxychloroquine	1
Standard of Care Plus Azithromycin	2
Standard of Care Plus Hydroxychloroquine Plus Azithromycin	1

Number of Days on Mechanical Ventilation Secondary · Baseline

Group	Value	95% CI
Standard of Care	0	± NA
Standard of Care Plus Hydroxychloroquine	5.5	± 11
Standard of Care Plus Azithromycin	8.67	± 15
Standard of Care Plus Hydroxychloroquine Plus Azithromycin	0	± 0

Number of Patients Not Receiving Mechanical Ventilation at Baseline Who Progress to Requiring Mechanical Ventilation During the Index Hospitalization Secondary · Index hospitalization, up to 46 days

Group	Value	95% CI
Standard of Care	0
Standard of Care Plus Hydroxychloroquine	1
Standard of Care Plus Azithromycin	1
Standard of Care Plus Hydroxychloroquine Plus Azithromycin	0

WHO Ordinal Scale Measured at 28 Days After Enrollment Secondary · Day 28

The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitati

Group	Value	95% CI
Standard of Care	1	± NA
Standard of Care Plus Hydroxychloroquine	2.8	± 3.5
Standard of Care Plus Azithromycin	5.3	± 3.8
Standard of Care Plus Hydroxychloroquine Plus Azithromycin	4.5	± 5.0

Hospital Length of Stay in Days for the Index Hospitalization Secondary · Index hospitalization, up to 46 days

Group	Value	95% CI
Standard of Care	6	± NA
Standard of Care Plus Hydroxychloroquine	9	± 11
Standard of Care Plus Azithromycin	14.7	± 14.6
Standard of Care Plus Hydroxychloroquine Plus Azithromycin	2.5	± 0.7

Number of Participants With All-cause Study Medication Discontinuation Secondary · Index hospitalization, up to 46 days

Number of participants who discontinued study medication for any reason

Group	Value	95% CI
Standard of Care	0
Standard of Care Plus Hydroxychloroquine	0
Standard of Care Plus Azithromycin	0
Standard of Care Plus Hydroxychloroquine Plus Azithromycin	0

Number of Participants With Severe Adverse Events Secondary · Day 14

Group	Value	95% CI
Standard of Care	0
Standard of Care Plus Hydroxychloroquine	1
Standard of Care Plus Azithromycin	1
Standard of Care Plus Hydroxychloroquine Plus Azithromycin	0

Adverse events — posted to ClinicalTrials.gov

Time frame: 2 months. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Standard of Care

Serious: 0/1 (0%)

Deaths: 0/1

Standard of Care Plus Hydroxychloroquine

Serious: 1/4 (25%)

Deaths: 1/4

Standard of Care Plus Azithromycin

Serious: 1/3 (33%)

Deaths: 2/3

Standard of Care Plus Hydroxychloroquine Plus Azithromycin

Serious: 0/2 (0%)

Deaths: 1/2

Serious adverse events (2 terms)

Reaction	System	Standard of Care	Standard of Care Plus Hydr…	Standard of Care Plus Azit…	Standard of Care Plus Hydr…
Acute renal failure	Renal and urinary disorders	—	—	—	—
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—	—	—

Most-reported serious reactions: Acute renal failure, Acute respiratory failure.

Data from ClinicalTrials.gov NCT04335552 adverse events section.

Sponsor's own description

This is a pragmatic, randomized, open-label, incomplete factorial with nested randomization clinical trial evaluating the efficacy and safety of two potential treatments for hospitalized patients with confirmed SARS-CoV-2 infection. Participants who are hospitalized and have a positive nucleic acid amplification test for SARS-CoV-2 will undergo an initial randomization in a 1:1 ratio to one of the following regimens:

Arm 1: Standard of care alone

Arm 2: Standard of care plus hydroxychloroquine

Participants who meet eligibility criteria to receive azithromycin will undergo a second randomization in a 1:1 ratio to receive additional concurrent therapy. This will effectively result in four treatment groups:

1. Standard of care alone
2. Standard of care plus hydroxychloroquine
3. Standard of care plus azithromycin
4. Standard of care plus hydroxychloroquine plus azithromycin

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials.
   Axfors C, Schmitt AM, Janiaud P, Van't Hooft J, et al · · 2021 · cited 217× · PMID 33859192 · DOI 10.1038/s41467-021-22446-z
2. COVID-19 and Cancer: a Comprehensive Review.
   Gosain R, Abdou Y, Singh A, Rana N, et al · · 2020 · cited 187× · PMID 32385672 · DOI 10.1007/s11912-020-00934-7
3. An update on drugs with therapeutic potential for SARS-CoV-2 (COVID-19) treatment.
   Drożdżal S, Rosik J, Lechowicz K, Machaj F, et al · · 2021 · cited 186× · PMID 34991982 · DOI 10.1016/j.drup.2021.100794
4. FDA approved drugs with pharmacotherapeutic potential for SARS-CoV-2 (COVID-19) therapy.
   Drożdżal S, Rosik J, Lechowicz K, Machaj F, et al · · 2020 · cited 105× · PMID 32717568 · DOI 10.1016/j.drup.2020.100719
5. Multicenter Initial Guidance on Use of Antivirals for Children With Coronavirus Disease 2019/Severe Acute Respiratory Syndrome Coronavirus 2.
   Chiotos K, Hayes M, Kimberlin DW, Jones SB, et al · · 2020 · cited 91× · PMID 32318706 · DOI 10.1093/jpids/piaa045
6. Transcriptional landscape of SARS-CoV-2 infection dismantles pathogenic pathways activated by the virus, proposes unique sex-specific differences and predicts tailored therapeutic strategies.
   Fagone P, Ciurleo R, Lombardo SD, Iacobello C, et al · · 2020 · cited 90× · PMID 32376402 · DOI 10.1016/j.autrev.2020.102571
7. COVID-19: Progress in diagnostics, therapy and vaccination.
   Liu X, Liu C, Liu G, Luo W, et al · · 2020 · cited 85× · PMID 32685022 · DOI 10.7150/thno.47987
8. Therapeutic use of chloroquine and hydroxychloroquine in COVID-19 and other viral infections: A narrative review.
   Hashem AM, Alghamdi BS, Algaissi AA, Alshehri FS, et al · · 2020 · cited 85× · PMID 32387694 · DOI 10.1016/j.tmaid.2020.101735