Clinical Trial Results:
A Multicenter, Phase III Randomized, Double-Blind, Placebo-Controlled, Outpatient Study to Evaluate the Efficacy, Safety, Antiviral Activity of RO7496998 (AT-527) in Patients With Mild or Moderate COVID-19
Summary
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EudraCT number |
2020-005759-18 |
Trial protocol |
DE BE DK FR PT IT RO |
Global end of trial date |
02 Dec 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Jun 2022
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First version publication date |
15 Jun 2022
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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 |
CV43043
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04889040 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
F. Hoffmann-La Roche AG
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Sponsor organisation address |
Grenzacherstrasse 124, Basel, Switzerland, CH-4070
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Public contact |
F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
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Scientific contact |
F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-002963-PIP01-21 | ||
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 |
31 Mar 2022
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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 |
02 Dec 2021
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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 efficacy of RO7496998 (AT-527) compared with placebo
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Protection of trial subjects |
All study subjects were required to read and sign an Informed Consent Form.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
28 Apr 2021
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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 |
Argentina: 1
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Country: Number of subjects enrolled |
Belgium: 18
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Country: Number of subjects enrolled |
Brazil: 17
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Country: Number of subjects enrolled |
Switzerland: 11
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Country: Number of subjects enrolled |
Germany: 8
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Country: Number of subjects enrolled |
Denmark: 3
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Country: Number of subjects enrolled |
Japan: 39
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Country: Number of subjects enrolled |
Mexico: 32
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Country: Number of subjects enrolled |
Portugal: 2
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Country: Number of subjects enrolled |
Romania: 8
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Country: Number of subjects enrolled |
Turkey: 35
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Country: Number of subjects enrolled |
Ukraine: 42
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Worldwide total number of subjects |
216
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EEA total number of subjects |
39
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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) |
3
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Adults (18-64 years) |
201
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From 65 to 84 years |
11
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85 years and over |
1
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Recruitment
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Recruitment details |
Participants were non-hospitalized, with mild to moderate COVID-19, with or without risk factors for severe disease. | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
216 subjects were enrolled in the study and 212 subjects received either AT-527 or matching placebo. | ||||||||||||||||||||||||
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 |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | ||||||||||||||||||||||||
Arm description |
The dose and regimen of the placebo will match that of AT-527. | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
The dose and regimen of the placebo will match that of AT-527.
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Arm title
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RO7496998 (AT-527) | ||||||||||||||||||||||||
Arm description |
Orally administered, 550 mg twice daily (BID) for 5 days | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
AT-527
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Investigational medicinal product code |
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Other name |
RO7496998
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
550 mg twice daily (BID) for 5 days
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
The dose and regimen of the placebo will match that of AT-527. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
RO7496998 (AT-527)
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Reporting group description |
Orally administered, 550 mg twice daily (BID) for 5 days | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
The dose and regimen of the placebo will match that of AT-527. | ||
Reporting group title |
RO7496998 (AT-527)
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Reporting group description |
Orally administered, 550 mg twice daily (BID) for 5 days |
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End point title |
Time to Alleviation or Improvement of COVID-19 Symptoms (21.5 hours) [1] | ||||||||||||
End point description |
COVID-19 symptoms will be evaluated using the COVID-19 Symptom Diary (questions 1-12). The severity of each COVID-19 symptom will be recorded on a Likert scale (i.e none/mild/moderate/severe).
The time to alleviation or improvement of COVID-19 symptoms is defined as follows: for new symptoms, it is defined as the length of time taken from randomization to the point at which a Score of 0 or 1 has been maintained for a duration of at least 21.5 hours. For preexisting symptoms, it is defined as the time from randomization to when a patient's symptoms have been maintained or improved (requires at least a single category improvement from baseline on the COVID-19 Symptom Diary Likert scale) for a duration of 21.5 hours.
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End point type |
Primary
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End point timeframe |
Up to 29 days
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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 early trial termination, the targeted enrolment numbers were not reached and no meaningful statistical analyses could be performed. |
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No statistical analyses for this end point |
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End point title |
Time to Alleviation or Improvement of COVID-19 Symptoms (43 hours) | ||||||||||||
End point description |
COVID-19 symptoms will be evaluated using the COVID-19 Symptom Diary (questions 1-12). The severity of each COVID-19 symptom will be recorded on a Likert scale (i.e none/mild/moderate/severe).
The time to alleviation or improvement of COVID-19 symptoms is defined as follows: for new symptoms, it is defined as the length of time taken from randomization to the point at which a Score of 0 or 1 has been maintained for a duration of at least 43 hours. For preexisting symptoms, it is defined as the time from randomization to when a patient's symptoms have been maintained or improved (requires at least a single category improvement from baseline on the COVID-19 Symptom Diary Likert scale) for a duration of 43 hours.
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End point type |
Secondary
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End point timeframe |
Up to 29 days
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No statistical analyses for this end point |
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End point title |
Time to Alleviation of COVID-19 Symptoms (21.5 hours) | ||||||||||||
End point description |
Time from randomization to the point at which the following criterion is met and maintained for at least 21.5 hours.
- Score of 0 or 1 on Items 1-12 of the COVID-19 Symptom Diary.
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End point type |
Secondary
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End point timeframe |
Up to 29 days
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No statistical analyses for this end point |
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End point title |
Time to Alleviation of COVID-19 Symptoms (43 hours) | ||||||||||||
End point description |
Time from randomization to the point at which the following criterion is met and maintained for at least 43 hours.
- Score of 0 or 1 on Items 1-12 of the COVID-19 Symptom Diary.
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End point type |
Secondary
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End point timeframe |
Up to 29 days
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No statistical analyses for this end point |
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End point title |
Time to One-Category Improvement of Baseline Presenting COVID-19 Symptoms | ||||||||||||
End point description |
Time from randomization to the point at which symptoms (Items 1-12 of the COVID-19 Symptom Diary) have improved by at least one category from baseline on the COVID-19 Symptom Diary Likert scale, maintained for at least 21.5 hours.
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End point type |
Secondary
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End point timeframe |
Up to 29 days
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No statistical analyses for this end point |
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End point title |
Time to Alleviation of Individual Symptoms | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Time from randomization to the point at which the following criterion is met and maintained (for each individual symptom) for at least 21.5 hours.
- Score of 0 or 1 for Items 1-14 of the COVID-19 Symptom Diary
Here 99999 or 0.99999 represents values that were not evaluable due to an insufficient number of events.
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End point type |
Secondary
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End point timeframe |
Up to 29 days
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No statistical analyses for this end point |
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End point title |
Proportion of Participants Requiring Hospitalization for COVID-19 | ||||||||||||
End point description |
Hospitalizations for COVID-19 are defined as SAEs for which the investigator has cited that the suspected cause was the disease under study and where there is a non-missing hospital admission date.
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End point type |
Secondary
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End point timeframe |
Up to Day 33 visit
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No statistical analyses for this end point |
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End point title |
Proportion of Participants with Greater than or Equal to 1 COVID-19 Related Medically Attended Visit | ||||||||||||
End point description |
Medically attended visit is defined as hospitalization, emergency room (ER) visit, urgent care visit, physician’s office visit, or telemedicine visit, with the primary reason for the visit being COVID-19.
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End point type |
Secondary
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End point timeframe |
Up to Day 33 visit
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No statistical analyses for this end point |
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End point title |
Duration of Fever | ||||||||||||
End point description |
Time to return to an afebrile state (temperature ≤ 37.5°C) maintained for at least 21.5 hours in patients with a fever at baseline.
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End point type |
Secondary
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End point timeframe |
Up to 29 days
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No statistical analyses for this end point |
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End point title |
Frequency of COVID-19 Related Complications | ||||||||||||
End point description |
COVID-related complications are defined as death, hospitalization, pneumonia, sepsis, coagulopathy, pericarditis/myocarditis and cardiac failure.
Pneumonia, acute respiratory failure, sepsis, coagulopathy, pericarditis/myocarditis, and cardiac failure were adjudicated per blinded manual medical review of events by an internal adjudication team before study readout.
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End point type |
Secondary
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End point timeframe |
Up to Day 33 visit
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No statistical analyses for this end point |
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End point title |
Proportion of Participants with any Post-Treatment Infection | ||||||||||||
End point description |
Post-treatment infections were defined as any treatment-emergent adverse event with a primary system organ class of infections and infestations.
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End point type |
Secondary
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End point timeframe |
Up to Day 33 visit
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No statistical analyses for this end point |
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End point title |
Change from Baseline in the Amount of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Virus RNA | |||||||||||||||||||||||||||
End point description |
SARS-CoV-2 virus RNA will be measured by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR)
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End point type |
Secondary
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End point timeframe |
Baseline and on Days 3, 5, 7 and 14
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No statistical analyses for this end point |
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End point title |
Time to Cessation of SARS-CoV-2 Viral Shedding | ||||||||||||
End point description |
Defined as time from randomization to the first time when a negative qualitative virus RNA by RT-PCR test result is obtained.
Here 99999 represents data that were not evaluable.
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End point type |
Secondary
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End point timeframe |
Up to 14 days
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No statistical analyses for this end point |
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End point title |
Proportion of Participants Positive for SARS-CoV-2 Virus RNA at Specified Timepoints | |||||||||||||||||||||||||||
End point description |
Defined as proportion of patients with a positive qualitative virus RNA by RT-PCR.
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End point type |
Secondary
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End point timeframe |
Baseline and on Days 3, 5, 7 and 14
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No statistical analyses for this end point |
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End point title |
Area Under the Curve (AUC) in the Amount of SARS-CoV-2 Virus RNA | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Up to 14 days
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No statistical analyses for this end point |
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End point title |
Percentage of Participants with Adverse Events (AEs) | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Up to Day 33 visit
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No statistical analyses for this end point |
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End point title |
Plasma Concentration of AT-511 at Specified Timepoints [2] | ||||||||||||||||||||||||||||
End point description |
AT-511 is the free base form of RO7496998 (AT-527).
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End point type |
Secondary
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End point timeframe |
Up to 7 days
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Notes [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Plasma concentrations were measured in subjects that received AT-527. Therefore the placebo arm was excluded from this endpoint. |
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No statistical analyses for this end point |
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End point title |
Plasma Concentration of AT-551 at Specified Timepoints [3] | ||||||||||||||||||||||||||||
End point description |
AT-511 is the free base form of RO7496998 (AT-527). Major metabolites are AT-551, AT-229, and AT-273 (a surrogate for the intracellular concentration of the active triphosphate metabolite AT-9010)
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End point type |
Secondary
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End point timeframe |
Up to 7 days
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Notes [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Plasma concentrations were measured in subjects that received AT-527. Therefore the placebo arm was excluded from this endpoint. |
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No statistical analyses for this end point |
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End point title |
Plasma Concentration of AT-229 at Specified Timepoints [4] | ||||||||||||||||||||||||||||
End point description |
AT-511 is the free base form of RO7496998 (AT-527). Major metabolites are AT-551, AT-229, and AT-273 (a surrogate for the intracellular concentration of the active triphosphate metabolite AT-9010)
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End point type |
Secondary
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End point timeframe |
Up to 7 days
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Notes [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Plasma concentrations were measured in subjects that received AT-527. Therefore the placebo arm was excluded from this endpoint. |
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No statistical analyses for this end point |
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End point title |
Plasma Concentration of AT-273 at Specified Timepoints [5] | ||||||||||||||||||||||||||||
End point description |
AT-511 is the free base form of RO7496998 (AT-527). Major metabolites are AT-551, AT-229, and AT-273 (a surrogate for the intracellular concentration of the active triphosphate metabolite AT-9010)
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End point type |
Secondary
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End point timeframe |
Up to 7 days
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Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Plasma concentrations were measured in subjects that received AT-527. Therefore the placebo arm was excluded from this endpoint. |
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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 |
Up to the Day 33 visit
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.1.
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Reporting groups
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Reporting group title |
AT-527
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Reporting group description |
Orally administered, 550 mg twice daily (BID) for 5 days | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
The dose and regimen of the placebo will match that of AT-527. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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08 Apr 2021 |
The purpose of this update was to address the feedback and questions received as part of a multinational clinical trial authorization application process. |
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02 Jun 2021 |
Major updates included Study Rationale and Benefit-Risk Assessment, addition of 2 additional efficacy endpoints, updated number of study sites and eligibility criteria. |
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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. | |||||||
The study was terminated with only 16% of the planned sample size. |