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Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial · 10.1016/j.ijantimicag.2020.105949

Name: Verified Rigor Record — Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial · 10.1016/j.ijantimicag.2020.105949
Item: Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial · 10.1016/j.ijantimicag.2020.105949
Rating: 63
Author: Αlpha¹

Paper source

Αlpha¹ Editorial

This rigor review was examined and confirmed by Αlpha¹ Editorial · July 6, 2026

Αlpha¹ Rigor Review

Rigor Reviewed

WARN

Warnings to address · Interventional Study

Eight dimensions — click a segment for details

Critical

High-priority

Model-reported confidence: ModerateReviewer agreement: moderateEngine: 7.5.0Source: full text

Not verified in this report

No data or code availability links were detected to verify.

This Αlpha¹ Rigor Review uses AI Rigor Reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.

6 major claims checked against the paper's own evidence: 4 not fully backed by the presented evidence (unsupported or overstated).

Recomputed 6 tests: 6 consistent, 0 inconsistent, 6 via agent-written checks.

6 integrity concerns flagged (1 high).

Rigor

Eight Dimensions2 pass · 3 warn · 3 fail

6 major claims1 unsupported3 overstated2 partial

Prior research is extensively cited, including in vitro data on chloroquine and hydroxychloroquine against SARS-CoV-2, and early Chinese clinical trials showing chloroquine's effect. The rationale for using hydroxychloroquine over chloroquine (better safety profile, team's experience) is clearly articulated. The study addresses a key limitation of prior research: the urgent need for clinical data on hydroxychloroquine. The limitations of the current study itself are also discussed.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The scientific premise is well-established: prior in vitro and clinical evidence for chloroquine/hydroxychloroquine against SARS-CoV-2 is cited, a logical rationale links this to the study objectives, and limitations of prior work are acknowledged.

Evidence

direct quote[Introduction, paragraphs 3-5]

“A recent paper reported an inhibitor effect of remdesivir (a new antiviral drug) and chloroquine (an old antimalarial drug) on the growth of SARS-CoV-2 in vitro...an early clinical trial conducted in Chinese COVID-19 patients, showed that chloroquine had a significant effect...”

direct quote[Introduction, paragraph 5]

“Hydroxychloroquine (an analogue of chloroquine) has been demonstrated to have an anti-SARS-CoV activity in vitro . Hydroxychloroquine clinical safety profile is better than that of chloroquine (during long-term use) and allows a higher daily dose and has fewer concerns regarding drug-drug interactions.”

direct quote[Discussion, paragraph 8]

“Our study has some limitations including a small sample size, limited long-term outcome follow-up, and dropout of six patients from the study”

PASSReviewer 2· 85% conf

Prior work on chloroquine/hydroxychloroquine is cited and a logical rationale is provided, though limitations of prior research are not discussed.

Evidence

direct quote[Introduction, paragraph 3]

“A recent paper reported an inhibitor effect of remdesivir (a new antiviral drug) and chloroquine (an old antimalarial drug) on the growth of SARS-CoV-2 in vitro, and an early clinical trial conducted in Chinese COVID-19 patients, showed that chloroquine had a significant effect...”

direct quote[Introduction, paragraph 4]

absence[Introduction]

Limitations of prior research are not addressed.

The study explicitly states it is 'open-label non-randomized'. The method of assigning patients to treatment or control is not randomized: treated patients were from one center, controls from another center or those who refused treatment. No blinding of investigators or patients is mentioned or attempted. Although a power analysis is reported, the target sample size of 48 was not reached (only 36 completed). The primary analysis is per-protocol, excluding 6 hydroxychloroquine-treated patients who dropped out, which can introduce bias. No pre-specified inclusion/exclusion criteria for the control group are provided beyond not receiving treatment. Outliers are not discussed. The dependent replication of the key finding is not reported.

Sub-criteria

controlsINADEQUATE

power analysisADEQUATE

blinding levelsNOT REPORTED

outlier handlingNOT REPORTED

randomization unitNOT REPORTED

inclusion exclusionINADEQUATE

randomization methodNOT REPORTED

replicate distinctionN/A

independent replicationNOT REPORTED

Per reviewer (2) — the votes behind the verdict

FAILReviewer 1· 95% conf

The study design is a non-randomized, open-label trial with major methodological flaws: no randomization, no blinding, no placebo control, and a per-protocol analysis that excludes dropouts, leading to a high risk of bias.

Evidence

direct quote[Title]

“Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial”

direct quote[Abstract and Methods, section 2.4]

“Untreated patients from another center and cases refusing the protocol were included as negative controls.”

paraphrase[Results, section 3.1]

“The paper reports results for 20 hydroxychloroquine-treated patients, after excluding 6 patients who dropped out, rather than an intention-to-treat analysis.”

WARNReviewer 2· 80% conf

The study is non-randomized and open-label without a rationale for blinding; a power analysis and inclusion/exclusion criteria are reported, but the control group is not comparable and dropouts are handled without ITT.

Evidence

direct quote[Title]

“Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial”

direct quote[Methods, Statistics section]

“Assuming a 50% efficacy of hydroxychloroquine in reducing the viral load at day 7, an 85% power, a type I error rate of 5% and 10% loss to follow-up, we calculated that a total of 48 COVID-19 patients (ie, 24 cases in the hydroxychloroquine group and 24 in the control group) would be required for the analysis.”

direct quote[Results, paragraph 1]

“Six hydroxychloroquine-treated patients were lost during the follow-up of the survey because of early cessation of treatment. ... The results presented here are therefore those of 36 patients (20 hydroxychloroquine-treated patients and 16 control patients).”

Age, sex, and clinical status are reported, and age differed between groups (51.2 vs 37.3 years), but this is noted in a table without adjustment. Health status is categorized as asymptomatic, URTI, or LRTI. No race/ethnicity data are provided. For a human clinical trial, species/strain/source and housing conditions are not applicable.

Sub-criteria

demographicsINADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthINADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 90% conf

Human demographics are partially reported, but age shows a notable imbalance between groups, and health status is only broadly categorized; sex is reported but not justified for the single-sex analysis, and no biological variables beyond humans are applicable.

Evidence

direct quote[Table 1]

“Age (years) Mean ± SD ... Hydroxychloroquine treated patients (N=20) 51.2 ± 18.7 ... Control patients (N=16) 37.3 ± 24.0”

direct quote[Methods, section 2.5 and Table 1]

“Patients were grouped into three categories: asymptomatic, upper respiratory tract infection (URTI)...and lower respiratory tract infections (LRTI)...”

absence[Table 1 and Demographics section]

No race/ethnicity data are reported.

WARNReviewer 2· 75% conf

Sex and age are reported, but weight and race/ethnicity are not; demographics are incomplete.

Evidence

direct quote[Results, paragraph 2]

“Overall, 15 patients were male (41.7%), with a mean age of 45.1 years.”

paraphrase[Results, paragraph 2 and Table 1]

“Mean age is given as 51.2 years for treated and 37.3 for controls, but no weight is reported.”

absence[Results, Table 1]

Race/ethnicity and comorbidities are not reported.

The paper explicitly states the protocol was approved by the French National Agency for Drug Safety (ANSM) and the French Ethic Committee (CPP Ile de France) with provided IDs and dates. Written informed consent was obtained. Compliance with ICH-GCP guidelines and the Declaration of Helsinki is declared. This satisfies all applicable sub-criteria for a human interventional trial.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals are thoroughly documented: a named ethics committee and drug agency approved the protocol with clear ID numbers, consent procedures are described, and regulatory compliance with ICH-GCP and the Declaration of Helsinki is stated.

Evidence

direct quote[Methods, section 2.3]

“The protocol, appendices and any other relevant documentation were submitted to the French National Agency for Drug Safety (ANSM) (2020-000890-25) and to the French Ethic Committee (CPP Ile de France) (20.02.28.99113) for reviewing and were approved on 5 th and 6 th March, 2020, respectively.”

direct quote[Methods, section 2.3]

“Before being included in the study, patients meeting inclusion criteria had to give their consent to participate to the study. Written informed signed consent was obtained from adult participants”

direct quote[Methods, section 2.3]

“The study was conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines of good clinical practice, the Helsinki Declaration, and applicable standard operating procedures.”

PASSReviewer 2· 95% conf

Ethics approval from named committees, informed consent, and regulatory compliance are all adequately reported.

Evidence

direct quote[Methods, Informed consent section]

“Written informed signed consent was obtained from adult participants (≥ 18 years) or from parents or legal guardians for minors (<18 years).”

direct quote[Methods, Informed consent section]

The investigational drugs (hydroxychloroquine and azithromycin) are named with doses but without manufacturer or lot numbers. Vero E6 cells are identified (ATCC CRL-1586) but no authentication (e.g., STR profiling) is reported. Mycoplasma testing is not mentioned. Stata 14.2 is adequately identified. Only 1 of 5 applicable sub-criteria (software_tools_identified) is adequate, resulting in a fail.

Sub-criteria

mycoplasma testingNOT REPORTED

reagents identifiedINADEQUATE

organisms identifiedINADEQUATE

antibodies identifiedN/A

cell line authenticationINADEQUATE

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

The investigational product (hydroxychloroquine) is adequately identified with dosage and regimen, and key software (Stata) is identified with version. Other resources like the PCR assay and culture materials are described in sufficient detail for replication.

Evidence

direct quote[Methods, section 2.4]

“All patients in the Marseille center were proposed oral hydroxychloroquine sulfate 200 mg, three times per day for ten days...Hydroxychloroquine was provided by the National Pharmacy of France on nominative demand.”

direct quote[Methods, section 2.10]

“Analyses were performed in Stata version 14.2.”

direct quote[Methods, section 2.8]

“...wells contained Vero E6 cells (ATCC CRL-1586)...”

FAILReviewer 2· 85% conf

Key resources are inadequately identified: drugs lack manufacturer/source, cell lines are not authenticated, mycoplasma testing is absent, and only software is adequately reported.

Evidence

direct quote[Methods, Procedure section]

“All patients in the Marseille center were proposed oral hydroxychloroquine sulfate 200 mg, three times per day for ten days... Hydroxychloroquine was provided by the National Pharmacy of France on nominative demand.”

direct quote[Methods, Culture section]

“4 wells contained Vero E6 cells (ATCC CRL-1586) in Minimum Essential Medium culture medium...”

absence[Methods, Culture section]

Mycoplasma testing is not reported.

Tests named (Pearson's chi-square, Fisher's exact, Student's t-test), power analysis with parameters is present, and Stata version is named. However, p-values are reported as ranges (p<0.001, p=0.001, p=0.002, etc.) or categorical (p<0.05), not always exact. No effect sizes or confidence intervals are reported for the primary outcome. Data presentation uses percentages without individual data points shown. Mathematical plausibility: The percentages in Table 1 for the control group (25.0% asymptomatic, 62.5% URTI, 12.5% LRTI) sum to 100%, and for treated patients (10.0%, 60.0%, 30.0%) also sum to 100%. However, total patients from Table 3: 16 + 14 + 6 = 36, which matches the total 36. The proportions in Table 2 and 3 are plausible, though no GRIM check is possible as individual data points are not provided.

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciNOT REPORTED

data presentationINADEQUATE

software identifiedADEQUATE

assumptions verifiedNOT REPORTED

mathematical plausibilityPASS

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 90% conf

Statistical tests are named, power analysis is reported, and software is identified. However, exact p-values are not always given (e.g., p<0.05), no effect sizes or confidence intervals are reported, and the mathematical plausibility of reported percentages has minor issues.

Evidence

direct quote[Methods, section 2.10]

“Statistical differences were evaluated by Pearson's chi-square or Fisher's exact tests as categorical variables, as appropriate. Means of quantitative data were compared using Student's t-test.”

absence[Results, section 3.3]

No effect sizes or confidence intervals are reported.

direct quote[Results, section 3.3 and Table 2/3]

“...70% of hydroxychloroquine-treated patients were virologically cured compared to 12.5% in the control group (p= 0.001). ...100% of patients treated with a combination... (p<0.001).”

WARNReviewer 2· 80% conf

Statistical tests are named, exact p-values are reported, and software is identified, but assumptions are not verified, effect sizes and confidence intervals are absent, and data presentation lacks individual points.

Evidence

direct quote[Methods, Statistics section]

“Statistical differences were evaluated by Pearson's chi-square or Fisher's exact tests as categorical variables, as appropriate. Means of quantitative data were compared using Student's t-test.”

direct quote[Results, Table 2 and Table 3]

“At day6 post-inclusion, 70% of hydroxychloroquine-treated patients were virologically cured compared to 12.5% in the control group (p= 0.001).”

absence[Results, Tables 2 and 3]

Effect sizes and confidence intervals are not reported.

The paper does not include a data availability statement. No data are deposited in a repository. No accession numbers are provided. No custom code is shared. All applicable sub-criteria are not reported, resulting in a fail.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositNOT REPORTED

data availability statementNOT REPORTED

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 95% conf

The data availability statement is present but vague ('from the corresponding author on reasonable request'), with no dedicated repository or clear access mechanism. No code sharing is reported.

Evidence

absence[Throughout the paper]

No formal data availability statement is present in the paper.

absence[Throughout the paper]

No code sharing is mentioned.

direct quote[Results, section 3]

“(detailed results are available in supplementary Table 1)”

FAILReviewer 2· 90% conf

No data availability statement, repository deposit, or code sharing is reported; the paper lacks any open science practices.

Evidence

absence[Entire paper]

No data availability statement.

absence[Entire paper]

No repository deposit.

absence[Entire paper]

No code sharing.

The trial is registered (2020-000890-25). Methods are described but not in complete enough detail for full replication (e.g., the exact daily sampling schedule for controls is unclear). No reporting guideline is mentioned. The primary outcome (viral clearance at day 6) is reported, but secondary outcomes like clinical follow-up and side effects are promised in a 'further paper'. Limitations are discussed. Conclusions are proportional in that they state association and recommend further studies, though the final recommendation to treat with the combination is somewhat strong given the study's limitations.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessINADEQUATE

all outcomes reportedINADEQUATE

limitations discussedADEQUATE

conclusions proportionalINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 90% conf

The study is registered, methods are partially described, limitations are discussed, and conclusions are somewhat proportional, but no CONSORT or other reporting checklist is referenced, the analysis plan is not pre-specified, and null results for side effects are deferred to a future paper.

Evidence

direct quote[Methods, section 2.3]

“This trial is registered in EU Clinical Trials Register with number 2020-000890-25.”

absence[Methods]

No reporting guideline is referenced.

direct quote[Results, section 3.1]

“Clinical follow-up and occurrence of side-effects will be described in a further paper at the end of the trial.”

WARNReviewer 2· 75% conf

Methods are detailed, the trial is registered, and limitations are discussed, but a reporting guideline is not referenced, not all secondary outcomes are reported, conclusions may be overstated, and a conflict of interest statement is missing.

Evidence

direct quote[Methods, Informed consent section]

“This trial is registered in EU Clinical Trials Register with number 2020-000890-25.”

direct quote[Results, paragraph 3]

“Clinical follow-up and occurrence of side-effects will be described in a further paper at the end of the trial.”

absence[Declarations section]

No conflict of interest statement.

11 copyedit issues flagged: mostly typo, consistency, clarity.

Checked 20 references: 19 verified — 1 unresolved.

Reproducibility

Registration stated in text, but no registry ID was detected. No reporting guideline cited.

Full text (22,576 chars)Analyzed: Jul 6, 2026

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