Clinical Trial Results:
An Adaptive Phase 2/3, Randomised, Open-Label Study Assessing Efficacy and Safety of Hydroxychloroquine for Hospitalised Patients with Moderate to Severe COVID-19
Summary
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EudraCT number |
2020-001270-29 |
Trial protocol |
DK CZ DE GB FR |
Global end of trial date |
25 Jun 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
24 Oct 2020
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First version publication date |
24 Oct 2020
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
EFC16858
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
U1111-1249-6096 | ||
Sponsors
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Sponsor organisation name |
Sanofi-aventis Recherche & Développement
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Sponsor organisation address |
1, Avenue Pierre Brossolette, Chilly Mazarin, France, 91385
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Public contact |
Trial Transparency Team, Sanofi-aventis recherche & développement, Contact-US@sanofi.com
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Scientific contact |
Trial Transparency Team, Sanofi-aventis recherche & développement, Contact-US@sanofi.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
09 Jul 2020
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
25 Jun 2020
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To evaluate the effect of hydroxychloroquine (HCQ) in addition to standard of care as compared to standard of care only on oxygen saturation/fraction of inspired oxygen (SpO2/FiO2) ratio in adult subjects hospitalised with moderate to severe coronavirus disease 2019 (COVID-19).
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Protection of trial subjects |
Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject was participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
15 Apr 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 1
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Country: Number of subjects enrolled |
Czech Republic: 7
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Country: Number of subjects enrolled |
Denmark: 3
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Country: Number of subjects enrolled |
France: 3
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Worldwide total number of subjects |
14
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EEA total number of subjects |
14
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
9
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From 65 to 84 years |
4
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85 years and over |
1
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Recruitment
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Recruitment details |
The study was conducted at 20 study centers in 5 countries between 15 April 2020 and 25 June 2020. | ||||||||||||||||||
Pre-assignment
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Screening details |
A total of 14 subjects were randomised and treated in 4 countries. | ||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Hydroxychloroquine + Standard of care | ||||||||||||||||||
Arm description |
Subjects received a loading dose of HCQ orally on Day 1 followed by a maintenance dose for 9 days (Days 2 to 10) plus standard of care. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Hydroxychloroquine
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Investigational medicinal product code |
SAR321068
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Other name |
Plaquenil®, Quensyl®
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received loading dose of HCQ (i.e., 800 milligram (mg) on Day 1, then 400 mg 6 hours later) orally on Day 1 along with meals, followed by maintenance doses of 200 mg three times daily (TID) orally for 9 days (Days 2 to 10).
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Arm title
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Standard of care | ||||||||||||||||||
Arm description |
Subjects received standard of care only i.e., the usual care provided to COVID-19 subjects in the country/investigational site. | ||||||||||||||||||
Arm type |
Standard of care | ||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Baseline characteristics reporting groups
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Reporting group title |
Hydroxychloroquine + Standard of care
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Reporting group description |
Subjects received a loading dose of HCQ orally on Day 1 followed by a maintenance dose for 9 days (Days 2 to 10) plus standard of care. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Standard of care
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Reporting group description |
Subjects received standard of care only i.e., the usual care provided to COVID-19 subjects in the country/investigational site. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Hydroxychloroquine + Standard of care
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Reporting group description |
Subjects received a loading dose of HCQ orally on Day 1 followed by a maintenance dose for 9 days (Days 2 to 10) plus standard of care. | ||
Reporting group title |
Standard of care
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Reporting group description |
Subjects received standard of care only i.e., the usual care provided to COVID-19 subjects in the country/investigational site. |
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End point title |
Change From Baseline in Oxygen Saturation/Fraction of Inspired Oxygen Ratio at Day 15 [1] | ||||||||||||
End point description |
SpO2/FiO2 ratio determined oxygenation status of the subjects. The higher the SpO2/FiO2 ratio is, the better it is for the subject. Intent-to-treat (ITT) population included all randomised subjects. Here, ‘number of subjects analysed’ = subjects with available data at Day 15 for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline, Day 15
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to limited data available following study termination, no statistical analysis was performed. Only descriptive summary. |
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Notes [2] - No data available at specified time point. |
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Oxygen Saturation/Fraction of Inspired Oxygen Ratio at Day 30 | ||||||||||||
End point description |
SpO2/FiO2 ratio determined oxygenation status of the subjects. The higher the SpO2/FiO2 ratio is, the better it is for the subject. ITT population included all randomised subjects. Here, ‘number of subjects analysed’ = subjects with available data at Day 30 for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 30
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Notes [3] - No data available at specified time point. |
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Mean Body Temperature at Day 15 | ||||||||||||
End point description |
Baseline body temperature was defined as the highest temperature recorded prior to the 1st HCQ dosing for HCQ + Standard of care group and recorded on randomisation date for Standard of care only group. ITT population included all randomised subjects. Here, ‘number analysed’ = subjects with available data at Day 15 for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 15
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No statistical analyses for this end point |
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End point title |
Number of Subjects Reporting Each Severity Rating on the 7-Point Ordinal Scale | ||||||||||||||||||||||||||||||
End point description |
Clinical status of the subjects as per 7-point ordinal scale was described as: Category 1. Death; Category 2. Hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); Category 3. Hospitalised, on non-invasive ventilation or high flow oxygen devices; Category 4. Hospitalised, requiring supplemental oxygen; Category 5. Hospitalised, not requiring supplemental oxygen-requiring ongoing medical care (COVID-19 related or otherwise); Category 6. Hospitalised, not requiring supplemental oxygen-no longer requires ongoing medical care and Category 7. Not hospitalised; where higher score indicates better outcomes. Only those scale categories in which at least 1 subject had data were reported. ITT population included all randomised subjects. Here, "n" = subjects with 7-point ordinal scale data available at the specified timepoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 15
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No statistical analyses for this end point |
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End point title |
Number of Subjects Reporting Quantitative Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Virus Load in the Nasopharyngeal (NP) Sample at Days 1, 2, 5, 10 and 15 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Quantitative SARS-CoV-2 virus in NP samples were evaluated by reverse transcription polymerase chain reaction (RT-PCR). The results were categorized as positive, negative or missing data. A positive result means SARS-COV2 detected; where as a negative result means SARS-COV2 not detected, with virus load highly probable less than 509 copies per milliliter. ITT population included all randomised subjects. Here, "n"= subjects with SARS-Cov-2 data available at the specified timepoint.
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End point type |
Secondary
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End point timeframe |
Days 1, 2, 5, 10 and 15
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No statistical analyses for this end point |
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End point title |
Number of Subjects With Severe Adverse Events and Adverse Events Leading to Treatment or Study Discontinuation | ||||||||||||||||||
End point description |
An AEs was any untoward medical occurrence in a patient or clinical study subject, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Severe AEs were defined as an event that prevents normal everyday activities. TEAEs were defined as AEs that developed, worsened or became serious during the treatment-emergent period (defined as the day from randomisation to the end of study i.e., Day 30). Safety population included all subjects who were randomized to standard of care alone group, and all subjects who were randomized to HCQ + standard of care group with at least one dose of HCQ use. Analysed by treatment as actually received.
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End point type |
Secondary
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End point timeframe |
From Baseline to Day 30
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
AEs were collected from time of first dose of study drug up to end of study (Day 30) regardless of seriousness or relationship to investigational product. SAEs, severe AEs and AEs leading to treatment or study discontinuation were collected as AE data.
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Adverse event reporting additional description |
Reported AEs and deaths are TEAEs that developed/worsened during ‘treatment period’ (defined as the day from randomisation to the end of study i.e., Day 30). Analysis was performed on safety population.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.0
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Reporting groups
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Reporting group title |
Hydroxychloroquine + Standard of care
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Reporting group description |
Subjects received a loading dose of HCQ orally on Day 1 followed by a maintenance dose for 9 days (Days 2 to 10) plus standard of care. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Standard of Care
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Reporting group description |
Subjects received standard of care only i.e., the usual care provided to COVID-19 subjects in the country/investigational site. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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02 Apr 2020 |
Following main changes were made: Electrocardiogram (ECG) assessments were added; following exclusion criteria were added: use of antiarythmic medications, subjects with the following ECG findings at screening: QTcF >470 milliseconds (msec) for women or >450 msec for men or heart rate <50 beats/minute, subjects with known G6PD deficiency; pregnant or breastfeeding women. Requirement for contraceptive methods in women of childbearing potential and contraceptive guidance was added in inclusion criteria; clarifications on standard of care, discharge from hospital, schedule of activities SAE reporting. Details of nasopharyngeal swab analysis were added. |
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16 Apr 2020 |
Following main changes were made: update on inclusion criteria: onset of symptoms was changed from within <= 5 days to within two weeks of randomisation. List of contraindicated medications and medications with precautions for use was updated. Clarification on discharge and schedule of activities. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
Due to premature discontinuation, only descriptive analysis were performed. |