Clinical Trial Results:
Randomized open pilot study to evaluate the efficacy of subcutaneous sarilumab in patients with moderate-severe COVID-19 infection.
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Summary
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EudraCT number |
2020-001634-36 |
Trial protocol |
ES |
Global end of trial date |
04 Dec 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
28 Apr 2022
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First version publication date |
28 Apr 2022
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Other versions |
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Summary report(s) |
SARCOVID_Summary Report |
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 |
SARCOVID
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04357808 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Rheumatology Service, Hospital Universitario de la Princesa
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Sponsor organisation address |
Diego de León 62, Madrid, Spain, 28006
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Public contact |
Rosario García de Vicuña, Rosario García de Vicuña, 0034 915202473, mariadelrosario.garcia@salud.madrid.org
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Scientific contact |
Rosario García de Vicuña, Rosario García de Vicuña, 0034 915202473, mariadelrosario.garcia@salud.madrid.org
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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 |
04 Dec 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
04 Dec 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
04 Dec 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
-To evaluate the efficacy of the early administration of sarilumab subcutaneously in patients with moderate-severe COVID-19 infection in early stages compared to the current treatment standard.
-To compare the baseline clinical and biological parameters, including serum IL-6, of the intervention population against historical controls, to search for possible markers that identify candidates for treatment with subcutaneous IL-6 inhibitors and attempt an approximation to the time frame of “window of opportunity”.
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Protection of trial subjects |
The trial was approved by the AEMPS and the Research Ethics Committee of the HUP on April 9th, 2020 (Reference number 4078) and was conducted in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Conference on Harmonization.
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Background therapy |
Sarilumab (SAR) is a human monoclonal antibody that binds membrane-bound and soluble IL-6 receptors to inhibit IL-6 signaling, licensed in a subcutaneous route administration for the treatment of Rheumatoid Arthritis. At a moment where the health system was overrun, especially emergency and intensive care unit (ICU) facilities, with real concern about TCZ shortages, we conceived that subcutaneous administration of SAR could facilitate the administration of an IL-6 inhibitor in all settings, including wards and overloaded emergency rooms. Additionally, the safety and maximum pharmacodynamic effects of a single 200 mg dose of subcutaneous SAR are known through the results of two open randomized controlled trials. Data were similar to those obtained with single doses of 4 and 8 mg/kg intravenous TCZ, with a longer effect of TCZ in the second week. Our hypothesis was that the use of 2 subcutaneous SAR injections and early intervention (window of opportunity) could prevent higher oxygenation requirements through non-invasive (NI) and invasive mechanical ventilation (IMV) and reduce death rate. Thus, we proposed an open pilot pragmatic RCT to evaluate the efficacy and safety of a single 400 mg subcutaneous dose of SAR, in patients with moderate to early severe COVID-19, compared to standard care (SC). | ||
Evidence for comparator |
The pharmacodynamic effect and safety of a single dose of sarilumab s.c (150 and 200 mg) and of tocilizumab i.v. (4 and 8 mg / kg) were evaluated in two open, randomized trials, in Japanese (n = 30) (PDY14191 [NCT02404558]) and non-Japanese (n = 101) (6R88-RA-1309 [NCT02097524]) population of patients with RA. Although there were differences in the baseline pharmacodynamic parameters between both studies, the onset of the effect on the absolute neutrophil count, C-reactive protein (CRP), serum levels of IL-6 and the soluble IL-6 receptor, during the first week after a single dose, it was similar regardless of drug, dose, or route of administration. The maximum effects on neutrophil count nadir and CRP, and on serum peaks of IL-6 and soluble IL-6 receptor were comparable in both studies for sarilumab and tocilizumab. The pharmacodynamic response was longer for i.v. tocilizumab. and there were no substantial differences in safety. | ||
Actual start date of recruitment |
13 Apr 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Spain: 30
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Worldwide total number of subjects |
30
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EEA total number of subjects |
30
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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) |
18
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From 65 to 84 years |
12
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85 years and over |
0
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Recruitment
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Recruitment details |
This study was conducted in the Hospital Universitario de La Princesa in Patients older than 18 attending the emergency room of this hospital in need for hospitalization by COVID-19. All patients or their legal representatives provided oral informed consent according to the AEMPS exceptional measures applicable for COVID19 studies. | |||||||||
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Pre-assignment
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Screening details |
Patients 18 and <80-years attending the emergency room with confirmed pneumonia by COVID-19. at least 2 of the following additional criteria needed to be fulfilled: Fever ≥ 37.8°C; IL-6 in serum ≥ 25 pg/mL or PCR> 5mg/dL; Lymphocytes <600/mm3; Ferritin > 300 μg/L and LDH > 250, or D-dimer > 1 mg/L. | |||||||||
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Period 1
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Period 1 title |
Only 1 period in parallel desing (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||
Blinding implementation details |
This is an open label phase II pragmatic RCT (randomized clinical trial) to evaluate the efficacy and safety of a single 400 mg subcutaneous dose of SAR, in patients with moderate to early severe COVID-19, compared to standard care (SC). This study was open for investigators and patients.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Sarilumab plus Standard of Care | |||||||||
Arm description |
Sarilumab Kevzara 200 mg, 2 sc injections in pre-filled syringe or pen, 400 mg single dose. The patients of this arm also received drugs, including corticosteroids, or full supportive care according to the best SC updated in the local protocol for COVID-19. Sarilumab (ATC code L04AC14) is a fully human anti-IL-6R monoclonal IgG1 antibody that binds to both membrane bound and soluble interleukin 6 (IL-6) receptor forms, thus blocking the cis- and trans-inflammatory signalling cascades of IL-6. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Sarilumab
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Investigational medicinal product code |
SAR153191
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Other name |
Kevzaras
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
The pharmacodynamic and safety characteristics of a single dose of 150 and 200 mg sarilumab s.c. are known, which do not differ significantly from those obtained with single doses of 4 and 8 mg / kg of tocilizumab i.v. The administration of 2 injections s.c. of sarilumab and in earlier stages (moderate COVID-19 pneumonia or early severe disease), it was expected that it could increase the initial concentration peak and compensate for the somewhat shorter duration of its pharmacodynamic effects, described for a single 200 mg dose.
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Arm title
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Standard Care | |||||||||
Arm description |
Patients in standard care (SC) will received drugs, including corticosteroids, or full supportive care according to the best SC updated in the local protocol for COVID-19. Patients in the standard care (SC) were given the option to receive intravenous Tocilizumab (TCZ) after randomization if they worsened at investigator discretion, as this agent had become the SC in our centre when the protocol was designed. | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
Standard Care
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Investigational medicinal product code |
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Other name |
Could use tozilizumab
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Pharmaceutical forms |
Solution for injection in pre-filled pen
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Routes of administration |
Intravenous use
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Dosage and administration details |
Patients in the standard care (SC) were given the option to receive intravenous TCZ after randomization if they worsened at investigator discretion, as this agent had become the SC in our centre when the protocol was designed
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Baseline characteristics reporting groups
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Reporting group title |
Sarilumab plus Standard of Care
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Reporting group description |
Sarilumab Kevzara 200 mg, 2 sc injections in pre-filled syringe or pen, 400 mg single dose. The patients of this arm also received drugs, including corticosteroids, or full supportive care according to the best SC updated in the local protocol for COVID-19. Sarilumab (ATC code L04AC14) is a fully human anti-IL-6R monoclonal IgG1 antibody that binds to both membrane bound and soluble interleukin 6 (IL-6) receptor forms, thus blocking the cis- and trans-inflammatory signalling cascades of IL-6. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Standard Care
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Reporting group description |
Patients in standard care (SC) will received drugs, including corticosteroids, or full supportive care according to the best SC updated in the local protocol for COVID-19. Patients in the standard care (SC) were given the option to receive intravenous Tocilizumab (TCZ) after randomization if they worsened at investigator discretion, as this agent had become the SC in our centre when the protocol was designed. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Sarilumab plus Standard of Care
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Reporting group description |
Sarilumab Kevzara 200 mg, 2 sc injections in pre-filled syringe or pen, 400 mg single dose. The patients of this arm also received drugs, including corticosteroids, or full supportive care according to the best SC updated in the local protocol for COVID-19. Sarilumab (ATC code L04AC14) is a fully human anti-IL-6R monoclonal IgG1 antibody that binds to both membrane bound and soluble interleukin 6 (IL-6) receptor forms, thus blocking the cis- and trans-inflammatory signalling cascades of IL-6. | ||
Reporting group title |
Standard Care
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Reporting group description |
Patients in standard care (SC) will received drugs, including corticosteroids, or full supportive care according to the best SC updated in the local protocol for COVID-19. Patients in the standard care (SC) were given the option to receive intravenous Tocilizumab (TCZ) after randomization if they worsened at investigator discretion, as this agent had become the SC in our centre when the protocol was designed. | ||
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End point title |
Change in Clinical Status Assessment | ||||||||||||
End point description |
Score ranges 1-7
1. Death;
2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO);
3. Hospitalized, requiring 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
No significant differences were seen in the median change [IQR] in clinical status on the 7-category ordinal scale at day 7 between SAR and SC (2 [0-3] vs 3 [0-3], p 0.32)
Chart: Evolution of clinical status in COVID-19 patients from baseline to day 14 according to the 7-category ordinal scale. Data are shown as the percentage of patients at each ordinal point in the sarilumab + standard care (SAR; n=20) and standard care (SC; n=10) groups, displayed as boxes with the different hues ranging
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End point type |
Primary
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End point timeframe |
Day 7 After Randomisation
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Attachments |
Evolution of clinical status in COVID-19 patients |
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Statistical analysis title |
Statistical Methods Change in clinical status 7 d | ||||||||||||
Comparison groups |
Sarilumab plus Standard of Care v Standard Care
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Number of subjects included in analysis |
30
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||
P-value |
= 0.05 | ||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||
Parameter type |
Log hazard ratio | ||||||||||||
Confidence interval |
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End point title |
Duration of Hospitalisation | ||||||||||||
End point description |
Median days to discharge on SAR and SC were similar (HR 0.65, SD 0.26; p 0.27)
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End point type |
Primary
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End point timeframe |
30 days form enrolment
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Statistical analysis title |
Statistical Methods Duration of hospitalization | ||||||||||||
Comparison groups |
Sarilumab plus Standard of Care v Standard Care
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Number of subjects included in analysis |
30
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||
P-value |
= 0.05 | ||||||||||||
Method |
Kruskal-wallis | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Confidence interval |
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End point title |
Death (30-day mortality) | |||||||||
End point description |
Regarding 30-day mortality, 2/20 (10%) patients died in the SAR arm while no events (0/10) were found in SC. Those results were identical for in hospital mortality. Two deaths occurred in patients with previous grade III chronic kidney disease (CKD) and NIMV at randomization.
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End point type |
Primary
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End point timeframe |
30 days from enrolment
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Statistical analysis title |
Death Statistical Analysis Death | |||||||||
Comparison groups |
Standard Care v Sarilumab plus Standard of Care
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Number of subjects included in analysis |
30
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | |||||||||
P-value |
= 0.05 | |||||||||
Method |
Wilcoxon (Mann-Whitney) | |||||||||
Parameter type |
Log hazard ratio | |||||||||
Confidence interval |
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End point title |
Time to Become Afebrile | ||||||||||||
End point description |
Time to become afebrile for a minimum period of 48 hours, without antipyretics
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End point type |
Secondary
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End point timeframe |
30 days from enrolment
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Progresion to Mechanical Ventilation | |||||||||||||||
End point description |
In SAR, 4/20 (20%) and 3/20 (15%) patients required No-Invasive Mechanical Ventilation (NIMV) and Invasive Mechanical Ventilation (IMV) respectively vs none in the SC. Notably, 2/3 patients progressing to IMV were not receiving corticosteroids at randomization. The median time to oxygen withdrawal was similar between groups
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End point type |
Secondary
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End point timeframe |
30 days from enrolment
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Time to Independence From Supplementary Oxygen Therapy | ||||||||||||
End point description |
Days from enrolment to supplementary oxygen therapy withdrawal. Evolution of partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) throughout study visits (Chart, panel A) showed no significant differences between both allocated interventions at day 1, 2, and 7 after randomization, nor at discharge.
Chart: Evolution of partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) throughout study visits. Patients are grouped depending on: A) allocated interventions: standard care (SC) or sarilumab (SAR) and B) level of serum interleukin-6 (IL-6) at randomization (cut-off for high levels ≥ 30 pg/ml). Two patients died and their last observed value was carried forward. IL-6 levels at randomization were available only in 24 patients; high IL-6 levels were observed in 3 patients from the SAR group and 1 patient from the SC group. Data are shown as interquartile ranges (p75 upper edge of box, p25 lower edge, p50 midline) as well as the p95 & P5.
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End point type |
Secondary
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End point timeframe |
30 days from enrolment
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Attachments |
Evolution of PaO2/FiO2 |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Evolution of laboratory parameters | |||||||||
End point description |
Regarding surrogate inflammatory markers and laboratory parameters, no significant differences were observed between arms at baseline nor along the study, except for significant reductions of LDH levels after day 2 from randomization (Chart) in patients allocated to SC. The time plot decline of median CRP levels was consistent with previously reported data for sarilumab after a single 200 mg subcutaneous injection with a maximum decrease in day 7, but we did not observe a steeper decrease with 400 mg SAR on days 1,2, 4-5 after randomization compared to the control group (Chart, panel A)
Chart: Evolution of laboratory parameters throughout study visits. Patients from standard care (SC; white boxes) and sarilumab (SAR; gray boxes). Only values available at each time-point are shown and results are displayed as interquartile range (p75 upper edge of box, p25 lower edge, p50 midline) as well as the p95 (line above box) and p5 (line below). Dots represent outliers.
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End point type |
Secondary
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End point timeframe |
30 days from enrolment-
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Attachments |
Evolution of laboratory parameters |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Change in Clinical Status Assessment (14 days) | ||||||||||||
End point description |
Scale ranges 1-7:
1. Death
2. Hospitalized, with mechanical ventilation or extracorporeal membrane oxygenation (ECMO).
3. Hospitalized, with non-invasive mechanical ventilation, a mask with a reservoir or oxygen with high flow nasal goggles.
4. Hospitalized with oxygen supplement
5. Hospitalized, without oxygen supplement, but in need of continued medical care (related or not with COVID)
6. Hospitalized, without oxygen supplement and without the need for continued medical care
7 Not hospitalized
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End point type |
Secondary
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End point timeframe |
14 days from enrolment
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Discontinuation Due to Adverse Reactions | |||||||||
End point description |
Number of adverse reactions that requires discontinuation of any drug in the study
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End point type |
Secondary
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End point timeframe |
30 days after enrolment
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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 |
14 days post hospital discharge
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Adverse event reporting additional description |
At the beginning of each visit, the patients were asked about the possible appearance of any adverse effect. The adverse events described spontaneously by the patients were also reported. Each adverse event was described temporarily. Adverse Events were defined as Definite, Probable, Posible, Unlikely or Conditional and Unrelated acoording to the c
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24
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Reporting groups
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Reporting group title |
Sarilumab plus Standard of Care
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Reporting group description |
Sarilumab Kevzara 200 mg, 2 sc injections in pre-filled syringe or pen, 400 mg single dose. The patients of this arm also received drugs, including corticosteroids, or full supportive care according to the best SC updated in the local protocol for COVID-19. Sarilumab (ATC code L04AC14) is a fully human anti-IL-6R monoclonal IgG1 antibody that binds to both membrane bound and soluble interleukin 6 (IL-6) receptor forms, thus blocking the cis- and trans-inflammatory signalling cascades of IL-6. | |||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Standard Care
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Reporting group description |
Patients in standard care (SC) will received drugs, including corticosteroids, or full supportive care according to the best SC updated in the local protocol for COVID-19. Patients in the standard care (SC) were given the option to receive intravenous Tocilizumab (TCZ) after randomization if they worsened at investigator discretion, as this agent had become the SC in our centre when the protocol was designed. | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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06 Apr 2020 |
Positive serology (IgG/gM by ICT or IgM/IgA by ELISA) is included in the detection of Covid-19, in addition to the PCR already included in the original protocol.
Study treatment defined, Kevzara 200 mg, 2 sc injections in prefilled syringe or autoinjector, 400 mg single dose. The original protocol established 400 mg or 300 mg based on the number of neutrophils. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
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. | |||
| This is a pilot study and the small sample size is the main limitation of the study. A full analysis of the limitations of the study is included in the publication in Frontiers of medicine doi: 10.3389/fmed.2022.819621. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/32907638 http://www.ncbi.nlm.nih.gov/pubmed/34228774 http://www.ncbi.nlm.nih.gov/pubmed/35280907 |
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