Clinical Trial Results:
Early administration of Vitamin C in patients with sepsis or septic shock in emergency departments: a multicentre, double blinded, randomized controlled trial: the C-EASIE trial.
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Summary
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EudraCT number |
2020-001862-12 |
Trial protocol |
BE |
Global end of trial date |
15 Nov 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Nov 2024
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First version publication date |
30 Nov 2024
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Other versions |
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Summary report(s) |
Article |
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 |
s63213
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04747795 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
KCE Trials: INV19-1237, CTR Pilot: 389 | ||
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Sponsors
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Sponsor organisation name |
UZ Leuven
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Sponsor organisation address |
Herestraat 49, Leuven, Belgium, 3000
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Public contact |
Emergency Department
Didier Desruelles
C-EASIE Trial Team, UZ Leuven, +32 16343952, ceasie@uzleuven.be
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Scientific contact |
Stefanie Vandervelden
ZAS Augustinus, Antwerp, UZ Leuven, +32 498221142, stefanie.vandervelden@zas.be
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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 |
26 Jan 2024
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
15 Nov 2023
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Global end of trial reached? |
Yes
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Global end of trial date |
15 Nov 2023
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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 |
The objective of the trial was to evaluate the efficacy of early administration of Vitamin C in addition to the standard of care in patients with sepsis or septic shock.
This was done by determining the average post-baseline patient SOFA score (on day 1-5 after patient inclusion). The SOFA score is widely employed in daily monitoring of acute morbidity and is an acceptable surrogate marker of efficacy in exploratory trials of novel therapeutic agents in sepsis.
We aimed to proof that through early admission of Vitamin C, patients who present at an early stage of the disease course will get less sick, resulting in a lower max SOFA score. However, administration of Vitamin C in our sickest population might not necessarily reflect in a lower max SOFA score, but rather in faster recovery (higher delta SOFA between 2 points in time). To capture both phenomena, we looked at the average post-baseline SOFA score as primary outcome supported by a maximum SOFA score as secondary outcome.
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Protection of trial subjects |
- Peer review was conducted by expert referees to the professional and scientific standards expected for clinical studies. The final protocol was reviewed by 2 independent experts and the principal investigators (PIs) of participating sites.
- Exclusion criteria protected participation without (delayed) informed consent, antibiotics as single dose, prophylactic treatment or without accompaning body fluid culture according to the timeframe, 'do no intubate’ or ‘comfort measures only’ status, failure to randomize within 6 hours after ED presentation, weight < 45 kg, pregnant or breastfeeding, known allergy for vitamin C, oxalate nephropathy or hyperoxaluria, glucose-6-phosphate dehydrogenase deficiency, chronic iron overload due to iron storage and other diseases, being already on IV steroids for a reason other than septic shock, proven active COVID-19 infection and participation in an interventional trial with an investigational medicinal product or device.
- Due to the illness of the patient, also the Legally Authorized Representative was able to give informed consent.
- Participants could voluntarily discontinue trial treatment and/or prematurely end their participation in the trial for any reason at any time.
- The Trial Steering Committee included 2 sepsis survivors. This way we combined experts in the field of sepsis, emergency medicine and research as well as patient representatives.
- During the trial 2x an Annual Progress Report has been send to the EC/FAMH, the third year the Clinical Study Report. These reports contained all occurred AE's, trial (recruitment) issues and advices from the DSMB / TSC / Audits.
- The Data and Safety Monitoring Board reviewed the results after a planned blinded interim analysis for sample size recalculation (after 203 patients had completed follow-up for the primary outcome). The power level was at least 80% with the observed values, resulting in an unaltered sample size.
- Monitoring and audit were performed regulary
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Background therapy |
Looking at all previous vitamin C studies reporting a study drug administration time frame, the average time to treatment varied between 3.3 and 18 hours (or <24hrs) after ICU admission. The C-EASIE trail aimed a 1st study drug administration within 6 hours after ED presentation, making it the only trial recruiting patients in the ED and investigating a true early administration effect. The large variety in study set-ups, mixed outcomes, and the inconsistency in the reported results, have made it difficult to estimate the optimal dose and timing of vitamin C administration. As a result of increased metabolism due to enhanced inflammatory response, high doses of vitamin C, up to 3 to 6 gram daily, are needed to normalize the vitamin C plasma level. Based on published clinical data and the pharmacokinetics of vitamin C most studies decided to administer 6g of vitamin C per day divided in four equal doses i.e. every 6 hours. We adopted the same regimen in our protocol. Since this was a pragmatic trial, we did not measure the baseline levels of vitamin C in patients. We deemed this appropriate since a recent prospective pharmacokinetic study on the patients in treatment group of the VITAMINS trial showed that the 6-hourly doses regimen of 1.5g should sufficient to achieve and maintain normal to supranormal vitamin C plasma levels. Treatment with vitamin C was deemed effective when a difference of 1 in average post-baseline patient SOFA score (calculated over day 2-5) between both groups, based on a constrained longitudinal data analysis (cLDA) model with α set at 0.0525 with at least 80% power could be detected. The power was calculated using the approach presented by Stroup. Based on study level data aggregated in a systematic review, Delta fixed-day SOFA scores appeared to be most responsively and consistently associated with mortality. | ||
Evidence for comparator |
We opted for a high dose IV vitamin C only adjuvant therapy, in order to investigate the benefit of mono therapy. All other aspects of care, including the administration of glucocorticoids were performed at the discretion of the treating teams. During the feasibility visits, we inquired about the treatment regimens used regarding sepsis at the participating sites. It was ensured that these were in accordance with current practice guidelines and that they were similar between the different participating hospitals (e.g., corticosteroid dosing and timing). Next, to standardize as much as possible the management of sepsis patients, a sepsis protocol was made. This protocol includes suggested treatment options in regard to antimicrobial therapy, fluid resuscitation, hemodynamic support and RRT, according to international guidelines. Where applicable recommended therapy regimens were mentioned as they were standardized for the C-EASIE-trial protocol. Unless otherwise mentioned, local policy was not allowed to replace treatment strategy for participating patients. For treatment compliance the IMP administration was documented in the electronic patient file and on a Drug Accountability Log. Together with the counted left over ampoules from the treatment kits it was possible to create transparency about the (in)correct IMP administration to obtain the Per Protocol Set for the statistical analysis. Next to the Health Questionnaires all medical trial details were obtained from the electronic patient files. Next to the procalcitonin samples they were all part of the standard of care. During the data cleaning process questions about the recorded trial data could easily be checked with the corresponding medical file. | ||
Actual start date of recruitment |
04 Jun 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 |
Belgium: 292
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Worldwide total number of subjects |
292
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EEA total number of subjects |
292
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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) |
110
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From 65 to 84 years |
167
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85 years and over |
15
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Recruitment
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Recruitment details |
Patients ≥18 yr admitted to the ED with suspected infection and NEWS ≥ 5 were eligible. (Suspected infection: combination of antibiotic administration + body fluid cultures <first 6 hours after ED presentation). Exclusion criteria: contraindications to vitamin C, or a ‘do do no intubate’ or ‘comfort measures only’ status. | |||||||||
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Pre-assignment
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Screening details |
0 | |||||||||
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Period 1
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Period 1 title |
overall trial (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, Monitor, Data analyst, Carer, Assessor | |||||||||
Blinding implementation details |
The digital platform Randomize.net randomly assigned in 1:1 allocation ratio stratified by site with block size 4. A pre-made treatment kit with 52 blinded IV ampoules for the entire treatment period was allocated to the patient. The vitamin C and Normal Saline ampoules had identical sizes, were blinded by a cap and sticker and were both colourless and odourless. Bedside administration was identical (dilute 3 ampoules in 50ml of Normal Saline)
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Vitamin C | |||||||||
Arm description |
Patients in the intervention group received 1,5 g intravenous vitamin C (3 ampoules of vitamin C 500mg/5ml) diluted in 50ml of Normal Saline, administered over 15 minutes, every 6 hours for 4 days (4 times a day in total 16 administrations). A maximum of 8 hours was allowed between 2 doses and only one dose could be missed. Parameters were obtained as part of routine clinical care. On day 1 and 4 a targeted blood sample was collected for procalcitonin determination. Baseline data were obtained as close as possible to the time of randomization. The EQ-5D-5L health questionnaire was obtained on admission, day 5, day 28 and 3 months. ABG analysis was part of routine clinical care in ICU. If the patient was discharged to the ward before day 5, ABG sampling was not considered standard of care. To be able to calculate the SOFA score in this population, we used the SpO2/FiO2 ratio to impute for PaO2/FiO2 ratio in the respiratory component. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Vitamin C
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Infusion
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Dosage and administration details |
1,5 g intravenous vitamin C (3 ampoules of vitamin C 500mg/5ml) diluted in 50ml of Normal Saline, administered over 15 minutes, every 6 hours for 4 days (4 times a day in total 16 administrations).
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Arm title
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Placebo | |||||||||
Arm description |
Patients in the placebo group received a matching placebo with Normal Saline. The administration was identical to the vitamin C treatment: 3 ampoules of Noral Saline 5ml diluted in 50ml of Normal Saline, administered over 15 minutes, every 6 hours for 4 days (4 times a day in total 16 administrations). A maximum of 8 hours was allowed between 2 doses and only one dose could be missed. The obtained parameters, blood samples and health questionnaires and the routine clinical care were identical to the Vitamin C arm. Ardena Gent NV, a Drug Product Development & Manufacturing firm blinded, packaged, relabelled the IMP kits, and provided randomization: 1st batch: number 21C22, expiry date September 2022, 2nd batch: number 22I01, expiry date October 2023. | |||||||||
Arm type |
Placebo | |||||||||
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 |
Solution for injection/infusion
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Routes of administration |
Infusion
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Dosage and administration details |
3 ampoules of 5ml Normal Saline diluted in 50ml of Normal Saline, administered over 15 minutes, every 6 hours for 4 days (4 times a day in total 16 administrations).
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Baseline characteristics reporting groups
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Reporting group title |
overall trial
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Reporting group description |
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Subject analysis sets
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Subject analysis set title |
Per Protocol Set
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Patients from the FAS with substantial protocol deviations (7 hours or more between hospital admission and first administration of study medication, 2 or more successive doses missed, all planned doses missing on the first day) were excluded from the per protocol set (PPS). Both FAS and PPS were used for the evaluation of all efficacy endpoints. Only the FAS was used for the evaluation the safety endpoints.
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Subject analysis set title |
Subgroup Analysis FAS SOFA <6
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
For the baseline SOFA score, subgroups were predefined (SOFA <6 vs >=6). Subgroup analyses were only performed for the FAS.
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Subject analysis set title |
Subgroup Analysis FAS SOFA ≥6
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
For the baseline SOFA score, subgroups were predefined (SOFA <6 vs >=6). Subgroup analyses were only performed for the FAS.
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End points reporting groups
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Reporting group title |
Vitamin C
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Reporting group description |
Patients in the intervention group received 1,5 g intravenous vitamin C (3 ampoules of vitamin C 500mg/5ml) diluted in 50ml of Normal Saline, administered over 15 minutes, every 6 hours for 4 days (4 times a day in total 16 administrations). A maximum of 8 hours was allowed between 2 doses and only one dose could be missed. Parameters were obtained as part of routine clinical care. On day 1 and 4 a targeted blood sample was collected for procalcitonin determination. Baseline data were obtained as close as possible to the time of randomization. The EQ-5D-5L health questionnaire was obtained on admission, day 5, day 28 and 3 months. ABG analysis was part of routine clinical care in ICU. If the patient was discharged to the ward before day 5, ABG sampling was not considered standard of care. To be able to calculate the SOFA score in this population, we used the SpO2/FiO2 ratio to impute for PaO2/FiO2 ratio in the respiratory component. | ||
Reporting group title |
Placebo
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Reporting group description |
Patients in the placebo group received a matching placebo with Normal Saline. The administration was identical to the vitamin C treatment: 3 ampoules of Noral Saline 5ml diluted in 50ml of Normal Saline, administered over 15 minutes, every 6 hours for 4 days (4 times a day in total 16 administrations). A maximum of 8 hours was allowed between 2 doses and only one dose could be missed. The obtained parameters, blood samples and health questionnaires and the routine clinical care were identical to the Vitamin C arm. Ardena Gent NV, a Drug Product Development & Manufacturing firm blinded, packaged, relabelled the IMP kits, and provided randomization: 1st batch: number 21C22, expiry date September 2022, 2nd batch: number 22I01, expiry date October 2023. | ||
Subject analysis set title |
Per Protocol Set
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Patients from the FAS with substantial protocol deviations (7 hours or more between hospital admission and first administration of study medication, 2 or more successive doses missed, all planned doses missing on the first day) were excluded from the per protocol set (PPS). Both FAS and PPS were used for the evaluation of all efficacy endpoints. Only the FAS was used for the evaluation the safety endpoints.
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Subject analysis set title |
Subgroup Analysis FAS SOFA <6
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
For the baseline SOFA score, subgroups were predefined (SOFA <6 vs >=6). Subgroup analyses were only performed for the FAS.
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Subject analysis set title |
Subgroup Analysis FAS SOFA ≥6
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
For the baseline SOFA score, subgroups were predefined (SOFA <6 vs >=6). Subgroup analyses were only performed for the FAS.
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End point title |
Primary: Average post-baseline SOFA score | ||||||||||||||||||||||||
End point description |
The primary outcome was the average post-baseline SOFA score (on day 2-5 after patient inclusion).
Following analyses were performed:
Primary Outcome:
• Calculated SOFA scores for day 1-5 FAS and PPS
• Primary outcome: Average post-baseline SOFA score FAS and PPS
Subgroup analysis:
• Subgroup analysis SOFA <6 FAS
• Subgroup analysis SOFA ≥6 FAS
Interaction models:
• Interaction model baseline SOFA <6 and ≥6 FAS
• Interaction model continuous baseline SOFA FAS and PPS
• Interaction model baseline NEWS FAS and PPS
Maximal SOFA: descriptives FAS and PPS and their comparison.
We used a constrained' longitudinal data analysis (cLDA) model, which constrains means of baseline to be equal between arms. The average SOFA scores (d2-d5) was compared, after correction for baseline SOFA (=primary outcome).
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End point type |
Primary
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End point timeframe |
SOFA scores for day 1-5
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Attachments |
Screening Failures and Post-Random. Exclusions Subject Disposition and Follow-Up FAS Subject Disposition and Follow-Up PPS Subject Disposition Numbers for Patients with FU Subject Flow Number of Days with Follow-Up Missed Doses Definition of Septic Shock Baseline Characteristics FAS Baseline Characteristics PPS Reasons for Exclusions Primary Outcome SOFA Score FAS Primary Outcome SOFA Score FAS Primary Outcome SOFA Score FAS Primary Outcome SOFA Score PPS Primary Outcome SOFA Score PPS Primary Outcome SOFA Score PPS SOFA Score Subgroup Analysis FAS SOFA under 6 SOFA Score Subgroup Analysis FAS SOFA under 6 SOFA Score Subgroup Analysis FAS SOFA under 6 SOFA Score Subgroup Analysis FAS SOFA 6 or above SOFA Score Subgroup Analysis FAS SOFA 6 or above SOFA Score Subgroup Analysis FAS SOFA 6 or above SOFA Score Interaction Model for Baseline SOFA FAS Interaction Model for Continuous Baseline SOFA FAS Interaction Model for Continuous Baseline SOFA FAS Interaction Model for Continuous Baseline SOFA PPS Interaction Model for Continuous Baseline SOFA PPS Interaction Model for Continuous Baseline NEWS FAS Interaction Model for baseline NEWS (FAS) Interaction Model for Continuous Baseline NEWS PPS Interaction Model for Baseline NEWS (PPS) Descriptives Maximal SOFA Score |
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Statistical analysis title |
Calculated SOFA score for day 1-5 | ||||||||||||||||||||||||
Statistical analysis description |
Observed SOFA scores for day 1-5 for the FAS and PPS, also displayed in boxplots. A maximal score of 24 was imputed for deceased patients.
See charts 'Primary Endpoint'.
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Comparison groups |
Vitamin C v Placebo
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Number of subjects included in analysis |
292
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||||||||||||||
P-value |
= 0.272 [2] | ||||||||||||||||||||||||
Method |
t-test, 2-sided | ||||||||||||||||||||||||
Confidence interval |
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| Notes [1] - From the cLDA model used for the primary endpoint, mean values at d2, d3, d4 and d4 will be compared with two-sided tests and 95% confidence intervals will be reported. [2] - day 2 p=0.272 day 3 p= 0.7431 day 4 p= 0.3215 day 5 p= 0.2258 |
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Statistical analysis title |
Average post-baseline SOFA score (day 2-5) | ||||||||||||||||||||||||
Statistical analysis description |
The average post-baseline score compared between Vitamin C and Placeb with a two-sided test derived from cLDA model using a likelihood approach with α=0.05, Kenward-Roger degrees of freedom and the covariance structure based on the Aikake criterion. Site was added as a fixed factor. The cLDA analysis was valid under the MAR and assumes that the probability that an observation is missing depends only on observed values of the individual, but not on the missing ones.
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Comparison groups |
Vitamin C v Placebo
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Number of subjects included in analysis |
292
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||||||||||||||
P-value |
= 0.2955 | ||||||||||||||||||||||||
Method |
cLDA | ||||||||||||||||||||||||
Confidence interval |
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| Notes [3] - An inverse hyperbolic sign transformation was applied to handle the (right-)skewed distribution of the SOFA scores. Results were presented after back-transformation to the original scale. As such, the estimate for the treatment effect referred to a ratio instead of to a difference. Results on untransformed SOFA scores were reported as sensitivity analyses. A maximal score of 24 was imputed for deceased patients. See charts 'Primary Endpoint'. |
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Statistical analysis title |
Interaction model for baseline SOFA <6 and ≥6 FAS | ||||||||||||||||||||||||
Statistical analysis description |
The interaction between the subgroups and treatment effect were tested to assess whether the treatment effect differs according to subgroup: the SOFA <6 and SOFA ≥6 data compared for the Vitamin C and Placebo group with interaction.
See charts 'Primary Endpoint'.
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Comparison groups |
Placebo v Vitamin C
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Number of subjects included in analysis |
292
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Analysis specification |
Pre-specified
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Analysis type |
superiority [4] | ||||||||||||||||||||||||
P-value |
= 0.1513 [5] | ||||||||||||||||||||||||
Method |
interaction model | ||||||||||||||||||||||||
Confidence interval |
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| Notes [4] - Estimates of SOFA (95%CI) obtained from the cLDA model fitted on inverse hyperbolic sign transformed data. Means and 95% confidence intervals are obtained after backtransformation to the original scale. Due to the transformation, the comparison of both groups refers to a ratio. Interactions are allowed with the categorised baseline SOFA score (<6 versus >=6). Focus of interest is the comparison of the intervention effects (at each day separately and the average) between subjects with SOFA<6 and [5] - baseline SOFA score <6: 0.8010 baseline SOFA score >=6: 0.0419 P-interaction 0.1513 |
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Statistical analysis title |
Interaction model for continuous baseline SOFA | ||||||||||||||||||||||||
Statistical analysis description |
It was also verified if the treatment effect depends on the baseline variables baseline SOFA, both FAS and PPS. Comparisons of Vitamin C with placebo obtained from a LDA model fitted on inverse hyperbolic sign transformed data, allowing the effect of Vitamin C to depend on baseline SOFA score (an interaction between the effect of Vitamin C and baseline SOFA is allowed). Due to the transformation of the SOFA score (as outcome variable), the comarison of both groups refers to a ratio (and 95%Cl).
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Comparison groups |
Vitamin C v Placebo
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Number of subjects included in analysis |
292
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Analysis specification |
Pre-specified
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Analysis type |
other [6] | ||||||||||||||||||||||||
P-value |
= 0.3346 [7] | ||||||||||||||||||||||||
Method |
Interaction model | ||||||||||||||||||||||||
Confidence interval |
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| Notes [6] - The effect to the effect averaged over d2-5. Results from 2 versions of this interaction model are presented: 1: assuming linearity for the effect of the baseline SOFA score and for the interaction effect 2: allowing non-linearity in the interaction between the baseline SOFA score and for the interaction effect To this purpose, restricted cubic splines with 4 knots were used. See charts 'Primary Endpoint'. [7] - 1: P-value for interaction: 0.3346 for FAS and 0.3487 for PPS 2: P-value for interaction: 0.2846 for FAS and 0.3661 for PPS The model fitted on the values from d2-d5, hence not including day 1 as outcome variable (model is not a cLDA, but a LDA) |
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Statistical analysis title |
Interaction model for continuous baseline NEWS | ||||||||||||||||||||||||
Statistical analysis description |
It was also verified if the treatment effect depends on the baseline variable baseline NEWS score, both for FAS and PPS. Comparisons of Vitamin C with placebo obtained from the cLDA model fitted on inverse hyperbolic sign transformed data, allowing the effect of Vitamin C to depend on baseline NEWS score (i.e. an interaction between the effect of vitamin C and baseline NEWS is allowed). Due to the transformation of the SOFA score, the comparison of both groups refers to a ratio (and 95%Cl).
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Comparison groups |
Vitamin C v Placebo
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Number of subjects included in analysis |
292
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Analysis specification |
Pre-specified
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Analysis type |
other [8] | ||||||||||||||||||||||||
P-value |
= 0.3852 [9] | ||||||||||||||||||||||||
Method |
interaction model | ||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
| Notes [8] - The effect refers to the effect averaged over d2-5. Results from 2 versions of this interaction model: 1: assuming linearity for the effect of the baseline NEWS score and for the interaction effect 2: allowing non-linearity in the effect of the baseline NEWS score and the interaction with vitamin C. To this purpose, restricted cubix splines with 4 knts were used. See charts 'Primary Endpoint'. [9] - 1: P-value for interaction for the FAS: 0.3852, for the PPS: 0.3343 2: P-value for interaction for the FAS: 0.3377, for the PPS: 0.3551 |
|||||||||||||||||||||||||
Statistical analysis title |
Maximal SOFA | ||||||||||||||||||||||||
Statistical analysis description |
Descriptives for the maximal SOFA score and estimates of mean maximal SOFA for the FAS and PPS and their comparison.
Note that by definition the maximal value over all 20 imputations is at least as high as the observed value.
See charts 'Primary Endpoint'.
|
||||||||||||||||||||||||
Comparison groups |
Vitamin C v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
292
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority [10] | ||||||||||||||||||||||||
P-value |
= 0.4421 | ||||||||||||||||||||||||
Method |
t-test, 2-sided | ||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
| Notes [10] - The maximal SOFA score will be compared using a two-sided unpaired t-test after inverse hyperbolic sign transformation. Estimates of the mean maximal SOFA (95%Cl), obtained from a linear model correcting for study site on transformed (inverse hyperbolic sign transformation) as well as on untransformed data. in the transformed case, the means and 95%Cl) were obtained after backtransformation and the comparison between both groups refers to a ratio. |
|||||||||||||||||||||||||
Statistical analysis title |
Subgroup Analysis SOFA <6 | ||||||||||||||||||||||||
Statistical analysis description |
Subgroup Analysis SOFA <6 FAS and PPS, observed information and estimates of SOFA.
Estimates of SOFA (95%Cl) obtained from the cLDA model fitted on inverse hyperbolic sign transformed data. Means and 95% confidence intervals are obtained after backtransformation to the original scale. Due to the transformation, the comparison of both groups refers to a ratio.
See charts 'Primary Endpoint'.
|
||||||||||||||||||||||||
Comparison groups |
Placebo v Vitamin C
|
||||||||||||||||||||||||
Number of subjects included in analysis |
292
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority [11] | ||||||||||||||||||||||||
P-value |
= 0.801 | ||||||||||||||||||||||||
Method |
cLDA | ||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
| Notes [11] - Estimates of SOFA (95%CI) obtained from the cLDA model fitted on inverse hyperbolic sign transformed data. Means and 95% confidence intervals are obtained after backtransformation to the original scale. Due to the transformation, the comparison of both groups refers to a ratio. |
|||||||||||||||||||||||||
Statistical analysis title |
Subgroup Analysis SOFA ≥6 | ||||||||||||||||||||||||
Statistical analysis description |
Subgroup Analysis SOFA ≥6, observed information SOFA score and estimates.
Estimates of SOFA (95%Cl) obtained from the cLDA model fitted on inverse hyperbolic sign transformed data. Means and 95% confidence intervals are obtained after backtransformation to the original scale. Due to the transformation, the comparison of both groups refers to a ratio.
See charts 'Primary Endpoint'.
|
||||||||||||||||||||||||
Comparison groups |
Vitamin C v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
292
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority [12] | ||||||||||||||||||||||||
P-value |
= 0.0419 | ||||||||||||||||||||||||
Method |
cLDA | ||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
| Notes [12] - Estimates of SOFA (95%CI) obtained from the cLDA model fitted on inverse hyperbolic sign transformed data. Means and 95% confidence intervals are obtained after backtransformation to the original scale. Due to the transformation, the comparison of both groups refers to a ratio. |
|||||||||||||||||||||||||
|
|||||||||||||
End point title |
Secondary: 28d Mortality | ||||||||||||
End point description |
Analysed for both FAS and PPS
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Death at day 28 after inclusion
|
||||||||||||
|
|||||||||||||
Attachments |
28d Mortality Descriptives FAS 28d Mortality FAS 28d Mortality Descriptives PPS 28d Mortality PPS |
||||||||||||
Statistical analysis title |
Secondary: 28d Mortality | ||||||||||||
Statistical analysis description |
28-day mortality was compared using a stratified χ² test (study site as stratum). 95% confidence intervals were reported for the percentage mortality in each treatment group and for the odds ratio. However, when there were subjects lost to follow-up before 28 days, 28-day estimates were derived from the Kaplan-Meier curve and compared using a Z-test (on the complementary log-log scale).
|
||||||||||||
Comparison groups |
Vitamin C v Placebo
|
||||||||||||
Number of subjects included in analysis |
292
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [13] | ||||||||||||
P-value |
= 0.3516 | ||||||||||||
Method |
Z-test after log transformation | ||||||||||||
Confidence interval |
|||||||||||||
| Notes [13] - Event rates were estimated using Kaplan-Meier methodology. Confidence intervals were calculated using a log(-log)-transformation. The comparison at 28 days (secondary outcome) is based on a Z-test after log-log transformation of the survival estimates. The difference (95% Cl) in survival at 28 days equals 4.0% (-3.0%; 11.0%) for FAS and 4.5% (-2.9%; 11.9%) for PPS. An effect size has been added in the table, i.e. the difference in percentage survival at 28 days with a 95% confidence interval. |
|||||||||||||
|
|||||||||||||
End point title |
Secondary: Length of Hospital Stay | ||||||||||||
End point description |
Death during hospital stay was treated as a competing risk
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Between inclusion and discharge
|
||||||||||||
|
|||||||||||||
Attachments |
Length of Hospital Stay Descriptives FAS Length of Hospital Stay FAS Length of Hospital Stay Descriptives PPS Length of Hospital Stay PPS |
||||||||||||
Statistical analysis title |
Secondary: Length of Hospital Stay | ||||||||||||
Statistical analysis description |
To evaluate differences in length of hospital stay, death during hospital stay was treated as a competing risk, using a stratified Gray’s test for the comparison of both groups. Patients not yet discharged were censored. The same approach is used for the secondary outcome Length of ICU Stay.
|
||||||||||||
Comparison groups |
Vitamin C v Placebo
|
||||||||||||
Number of subjects included in analysis |
292
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [14] | ||||||||||||
P-value |
= 0.7063 | ||||||||||||
Method |
Stratified Grays test | ||||||||||||
Confidence interval |
|||||||||||||
| Notes [14] - Event rates were estimated as cumulative incidence funtions (CIF), taking into account the competing ristk of in-hospital death (competing risk). Confidence intervals were calculated using a log(-log)-transformation. The hazard ratio (95%Cl) from a Fine&Gray model equals 0.971 (0.765, 1.233) for the FAS and 0.955 (0.743, 1.228) for the PPS. An effect size has been added in the legend of the table, i.e. hazard ratio from a Fine&Gray model with 95% confidence interval. |
|||||||||||||
|
|||||||||||||||||
End point title |
Secondary: Length of ICU Stay | ||||||||||||||||
End point description |
Analysed for both FAS and PPS.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Between admission to the ICU and discharge from ICU.
|
||||||||||||||||
|
|||||||||||||||||
Attachments |
Length of ICU Stay FAS Length of ICU Stay FAS Length of ICU Stay PPS Length of ICU Stay PPS |
||||||||||||||||
Statistical analysis title |
Secondary: Length of ICU Stay | ||||||||||||||||
Statistical analysis description |
To evaluate differences in length of ICU Stay, death during ICU stay was treated as a competing risk, using a stratified Gray’s test for the comparison of both groups. Patients not yet discharged were censored. The analysis was restricted to patients admitted in ICU. Note however that the time starts at the moment of ICU admission and not at the moment of randomisation (this to handle the possibility that patients need to go the ICU at a later moment during the follow-up).
|
||||||||||||||||
Comparison groups |
Vitamin C v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
292
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [15] | ||||||||||||||||
P-value |
= 0.6336 | ||||||||||||||||
Method |
Grays test | ||||||||||||||||
Confidence interval |
|||||||||||||||||
| Notes [15] - Event rates at specific timepoints were estimated as cumulative incidence functions (CIF), taking into account the competing risk of in-ICU death (competing risk). Confidence intervals were calculated using a log(-log)-transformation. 3 patients were randomised the day after admission to the ICU. For these patients the ICU admission day is set at day 1. The hazard ratio (95%Cl) from a Fine%Gray model equals 1.041 (0.739, 1.467) for the FAS and 1.045 (0.732, 1.491) for the PPS. |
|||||||||||||||||
|
|||||||||||||||||
End point title |
Secondary: Mechanical Ventilation | ||||||||||||||||
End point description |
Mechanical Ventilation needed on day 1-5. Is put on zero when patient is discharged. When a subject is deceased, the value is considered missing from that day on (in case MV information was available on the day of death, the information is considered missing from the day after death on).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Day 1-5
|
||||||||||||||||
|
|||||||||||||||||
Attachments |
Mechanical Ventilation FAS Mechanical Ventilation PPS |
||||||||||||||||
Statistical analysis title |
Secondary: Mechanical Ventilation | ||||||||||||||||
Statistical analysis description |
The probability of MV was compared using a generalised linear mixed model (i.e. a logistic regression model with a random effect of patient). Odds ratio was reported for the comparison of the ‘mean probability’ over d2-d5, and for day-specific odcomparisons. Note that the model was fit on daily information from d1-d5 and the mean duration of MV (i.e. in the period d2-d5) could derived directly from this model as the sum of the daily probabilities.
|
||||||||||||||||
Comparison groups |
Vitamin C v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
292
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [16] | ||||||||||||||||
P-value |
= 0.6958 | ||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||
Confidence interval |
|||||||||||||||||
| Notes [16] - Observed information on mechanical ventilation and predicted probability. Predicted probability (and 95%Cl) of mechanical ventilation is obtained from a generalised linear mixed model (logistic regression with a random effect of patient) with group and time as fixed effects and correcting for study site (as fixed effect). Note that the estimates refer to the predicted probability and the predicted effect for the average patient. |
|||||||||||||||||
|
|||||||||||||||||
End point title |
Secondary: Vasopressor Requirement | ||||||||||||||||
End point description |
Day 1-5 Vasopressor Requirement: Observed Information on vaso-active agents and Comparison of the Probability: the Dose of vasoactive agent, the Probability of receiving vaso-active agents, the Probability of receiving at least Dopamine >5, Epinephrine = 0.1 or Norepinephrine = 0.1 and the Probability of receiving Dopamine >15, Epinephrine >0.1 or Norepinephrine >0.1, for both the FAS and PPS. Note that the option Dopamine ≤5 or Dobutamine (any dose) was never chosen. Vasopressor requirement was an ordinal scale (4 levels starting with ‘no’) and results were reported from separate models using the three possible cut points (for example ‘no’ versus ‘yes’).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
day 1-5. VR put on zero when patient is discharged. When a subject is deceased, the value is considered missing from that day on (in case information was available on the day of death, the information is considered missing from the day after death on).
|
||||||||||||||||
|
|||||||||||||||||
Attachments |
Vasopressor Requirement FAS Vasopressor Requirement PPS |
||||||||||||||||
Statistical analysis title |
Secondary: Vasopressor Requirement | ||||||||||||||||
Statistical analysis description |
The vasopressor requirement was compared using a generalised linear mixed model (i.e. a logistic regression model with a random effect of patient). An odds ratio was reported comparing the use over d2-d5, as well as the timepoint specific use. Study site was added in the model. Note that the model was fit on information from d1-d5. Note that the mean duration of vasopressor requirement (i.e. in the period d2-d5) could be derived directly from this model as the sum of the daily probabilities.
|
||||||||||||||||
Comparison groups |
Vitamin C v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
292
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [17] | ||||||||||||||||
P-value |
= 0.5303 | ||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||
Confidence interval |
|||||||||||||||||
| Notes [17] - Comparison: Note that multiplying the average predicted probability over d2-d5 yields the mean number of days with vasopressor requirement. Estimates (95%Cl) obtained from a generalised lineair mixed model (logistic regression with a random effect of patient) with group and time as fixed effects and correcting for study site (as fixed effect). Note that the estimates refer to the predicted probability and the predicted effect for the average patient. |
|||||||||||||||||
|
|||||||||||||||||
End point title |
Secondary: Renal Replacement Therapy | ||||||||||||||||
End point description |
The probability of RRT was compared using a generalised linear mixed model (i.e. a logistic regression model with a random effect of patient). An odds ratio was reported comparing the ‘mean probability’ over d2-d5. Given the expected low number of events, for the timepoint specific RRT only descriptives were reported. RRT was put on zero when the patient was discharged. When a subject was deceased, the value was considered missing from that day on (in case RRT information was available on the day of death, the information was considered missing from the day after death on). Note that the model was fit on daily information from d1-d5 and that the mean duration of RRT (i.e. in the period d2-d5) could be derived directly from this model as the sum of the daily probabilities.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Number of days with RRT need during day 1-5
|
||||||||||||||||
|
|||||||||||||||||
Attachments |
Renal Replacement Therapy FAS Renal Replacement Therapy PPS |
||||||||||||||||
Statistical analysis title |
Secondary: Renal Replacement Therapy | ||||||||||||||||
Statistical analysis description |
Observed Information and Predicted Probability. Predicted probability (and 95%Cl) of renal replacement therapy obtained from a generalised linear mixed model (logistic regression with a random effect of patient) with group and time as fixed effects. Given the low number of events no correction has been made for study site and daily-specific comparisons where not tested. Note that the estimates refer to the predicted probability and the predicted efect for the average patient.
|
||||||||||||||||
Comparison groups |
Vitamin C v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
292
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [18] | ||||||||||||||||
P-value |
= 0.258 | ||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||
Confidence interval |
|||||||||||||||||
| Notes [18] - Renal replacement therapy is put on zero when patient is discharged. When subject is deceased, the value is missing. The probability of renal replacement therapy (RRT) will be compared using a generalized linear mixed model (i.e. a logistic regression model with a random effect of patient). An odds ratio will be reported comparing the ‘mean probability’ over d2-d5 |
|||||||||||||||||
|
|||||||||||||||||
End point title |
Secondary: Need of Steroids | ||||||||||||||||
End point description |
The daily dose of steroids given was compared between both groups using a multivariate normal model for longitudinal measurements, with the Aikake criterion to select the covariance matrix. The mean dosage over d2-d5 was compared, as well as the timepoint specific dosages. Study site was added in the model. Note that the model fitted on information from all patients in the period d1-d5. For discharged, lost-to-Follow Up and deceased patients, the dose was put on missing.
The need of steroids was compared using a generalised linear mixed model (i.e. a logistic regression model with a random effect of patient) with site added as a fixed effect. An odds ratio was reported for the comparison of the ‘mean probability’ over d2-d5, and for the day-specific comparisons.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Days of steroids needed during day 1-5
|
||||||||||||||||
|
|||||||||||||||||
Attachments |
Need of Steroids FAS Need of Steroids PPS |
||||||||||||||||
Statistical analysis title |
Secondary: Need of Steroids | ||||||||||||||||
Statistical analysis description |
Observed Information and Predicted Probability. Predicted probability (and 95%Cl) of steroid use obtained from a generalised linear mixed model (logistic regression with a random effect of patient) with group and time as fixed effects and correcting for study site (as fixed effect). Note that the estimates refer to the predicted probability and the predicted effect for the average patient. Use of steroids is put on zero when patient is discharged. When subject is deceased, the value is missing.
|
||||||||||||||||
Comparison groups |
Vitamin C v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
292
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [19] | ||||||||||||||||
P-value |
= 0.43 | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Confidence interval |
|||||||||||||||||
| Notes [19] - The need of steroids (MV) will be compared using a generalized linear mixed model (i.e. a logistic regression model with a random effect of patient) with site added as a fixed effect. An odds ratio will be reported for the comparison of the ‘mean probability’ over d2-d5, and for the day-specific comparisons. |
|||||||||||||||||
|
|||||||||||||||||
End point title |
Secondary: Dose of Steroids | ||||||||||||||||
End point description |
The daily dose of steroids given was compared between both groups using a multivariate normal model for longitudinal measurements, with the Aikake criterion to select the covariance matrix. The mean dosage over d2-d5 was compared, as well as the timepoint specific dosages. Study site was added in the model. Note that the model fitted on information from all patients in the period d1-d5. For discharged, lost-to-Follow Up and deceased patients, the dose was put on missing.
The need of steroids was compared using a generalised linear mixed model (i.e. a logistic regression model with a random effect of patient) with site added as a fixed effect. An odds ratio was reported for the comparison of the ‘mean probability’ over d2-d5, and for the day-specific comparisons.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Dose of Corticosteroids needed during day 1-5
|
||||||||||||||||
|
|||||||||||||||||
Attachments |
Dose of Steroids FAS Dose of Steroids PPS |
||||||||||||||||
Statistical analysis title |
Secondary: Dose of Steroids | ||||||||||||||||
Statistical analysis description |
Descriptive information including patients who do not take steroids and descriptive information excluding patients who do nt take steroids and estimates of steroid dose. For discharged, lost-to-FU and deceased patients, the dose was put on missing (unless there was information on the day of discharge or the day of death.)
|
||||||||||||||||
Comparison groups |
Vitamin C v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
292
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [20] | ||||||||||||||||
P-value |
= 0.3564 | ||||||||||||||||
Method |
multivariate normal model | ||||||||||||||||
Confidence interval |
|||||||||||||||||
| Notes [20] - The daily dose of steroids given will be compared between both groups using a multivariate normal model for longitudinal measurements, with the Aikake criterion to select the covariance matrix Estimates of steroid dose (95%Cl) obtained from a linear model for longitudinal measurements fitted on inverse hyperbolic sign transformed data. Means and 95% confidence intervals are obtained after backtransformation to the original scale. Due to the transformation, the comparison of both groups refers t |
|||||||||||||||||
|
|||||||||||||||||
End point title |
Secondary: IV Fluid Balance | ||||||||||||||||
End point description |
Within the group of patients admitted in the ICU the daily fluid balance (ml) was compared between both groups using a multivariate normal model for longitudinal measurements, with the Aikake criterion to select the covariance matrix. The mean over d2-d5 was compared, as well as the timepoint specific value. Study site was added in the model. Note that the model fitted on information from d1-d5, but restricted to the days the patient was in the ICU. For patients who died during ICU, the balance was put on missing.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
IV Fluid balance during day 1-5
|
||||||||||||||||
|
|||||||||||||||||
Attachments |
IV Fluid Balance FAS IV Fluid Balance PPS |
||||||||||||||||
Statistical analysis title |
Secondary: IV Fluid Balance | ||||||||||||||||
Statistical analysis description |
Descriptive information, only including patients in ICUs. For patients deceased in ICU, the fluid balance was put on missing (unless there was information on the day of death). Estimates of mean fluid balance (95%Cl) obtained from a linear model for longitudinal measurements correcting for study site.
|
||||||||||||||||
Comparison groups |
Vitamin C v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
292
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [21] | ||||||||||||||||
P-value |
= 0.5284 | ||||||||||||||||
Method |
multivariate normal model | ||||||||||||||||
Confidence interval |
|||||||||||||||||
| Notes [21] - Within the group of patients admitted in the ICU the daily fluid balance (ml) will be compared between both groups using a multivariate normal model for longitudinal measurements, with the Aikake criterion to select the covariance matrix. The mean over d2-d5 will be compared, as well as the timepoint specific value. Study site will be added in the model |
|||||||||||||||||
|
|||||||||||||||||
End point title |
Secondary: Quality of Life | ||||||||||||||||
End point description |
The EQ-5D-5L questionnaire consists of two parts. The first part is a descriptive system that contains five dimensions; it can be used to estimate the utility index (EQ index). An index of 1 equals perfect health, 0 for death. The second part is the EuroQol visual analogue scale (EQ-VAS), which is a 0–100 scale where respondents indicate their overall health status.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
The EQ-5D-5L questionnaires were obtained on day 1, day 5, day 28 and after 3 months.
|
||||||||||||||||
|
|||||||||||||||||
Attachments |
EQ Index FAS EQ-VAS FAS EQ Index PPS 44 EQ-VAS PPS |
||||||||||||||||
Statistical analysis title |
Secondary: Quality of life - EQ VAS | ||||||||||||||||
Statistical analysis description |
The EQ-5D VAS score. For patients deceased, discharged or lost-to follow the value was put on missing. If the patient was discharged before 5 days, the value refers to the day of discharge. Estimates of mean EQ-D VAS (95%Cl) obtained from a linear model for longitudinal measurements correcting for study site.
|
||||||||||||||||
Comparison groups |
Vitamin C v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
292
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [22] | ||||||||||||||||
P-value |
= 0.8255 [23] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Confidence interval |
|||||||||||||||||
| Notes [22] - Estimates of mean EQ-5D VAS (95%CI) obtained from a linear model for longitudinal measurements correcting for study site. [23] - Day 5 = 0.8255 Day 28 = 0.7213 Month 3 = 0.9997 |
|||||||||||||||||
Statistical analysis title |
Secondary: Quality of life - EQ index | ||||||||||||||||
Statistical analysis description |
The total scores were compared between both groups using a multivariate normal model for longitudinal measurements, with the Aikake criterion to select the covariance matrix. Study site was added in the model. Note that the model fitted on information from baseline – day 5 (or day of discharge if discharge before day 5), day 28 and month 3. For lost-to-Follow Up and deceased patients, the score were put on missing. Comparisons referred to the three specific timepoints after baseline.
|
||||||||||||||||
Comparison groups |
Vitamin C v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
292
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [24] | ||||||||||||||||
P-value |
= 0.6547 [25] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Confidence interval |
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| Notes [24] - EQ-5D index calculated using the Belgian EQ-5D-5L value set (Bouckaert et al. PharmacoEconomics - Open (2022) 6:823-836). For patients deceased, discharged or lost-to follow the value was put on missing. If the patient was discharged before 5 days, the value refers to the day of discharge. Estimates of mean EQ-5D indec (95%Cl) obtained from a linear model for longitudinal measurements correcting for study site. [25] - Day 5 = 0.6547 Day 28 = 0.3119 Month 3 = 0.9505 |
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End point title |
Secondary: Return to Work or Daily Activities | ||||||||||||||||
End point description |
For patients who were at work before inclusion in the study, the time until return to work was compared. Patients lost-to-Follow Up and patients not returned to work (at three months) were censored. Deceased patients were treated as a competing risk. The comparison was based on a stratified Gray’s test.
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End point type |
Secondary
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End point timeframe |
The EQ-5D-5L questionnaires were obtained on day 1, day 5, day 28 and after 3 months.
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Attachments |
Return to Work or Daily Activities FAS Return to Work or Daily Activities FAS Return to Work or Daily Activities PPS Return to Work or Daily Activities PPS |
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Statistical analysis title |
Secondary: Return to Work or Daily Activities | ||||||||||||||||
Statistical analysis description |
The EQ-5D-5L questionnaires were obtained on day 1, day 5, day 28 and after 3 months.
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Comparison groups |
Vitamin C v Placebo
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Number of subjects included in analysis |
292
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Analysis specification |
Pre-specified
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Analysis type |
superiority [26] | ||||||||||||||||
P-value |
= 0.7416 | ||||||||||||||||
Method |
Grays test | ||||||||||||||||
Confidence interval |
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| Notes [26] - Event rates were estimated as cumulative incidence functions (CIF), taking into account the competing risk of death (competing risk). Confidence intervals were calculated using a log(-log)-transformation. It is assumed that deceased subjects with missing information on return, did not return to normal activities. The hazard ratio (95%Cl) from a Fine&Gray model equals 0.936 (0.623,1.407) for the FAS and 0.931 (0.607,1.426) for the PPS. |
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Adverse events information
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Timeframe for reporting adverse events |
From inclusion date till last visit at 3 months. First inclusion June 4th, 2021, last patient last visit November 15th, 2023.
Only adverse events (AEs) that were not expected in the disease progression needed to be recorded.
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Adverse event reporting additional description |
In total 45 AEs in 40 patients, 5 patients had 2 events reported.
In total 44 deaths of which 31 expected and unrecorded (18 Vit C, 13 Placebo)
Unexpected deaths/SAEs: Vit C: 5 deaths and 2 deaths as fatal outcome, Placebo 1 death and 5 deaths as fatal outcome
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
0
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Reporting groups
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Reporting group title |
Vitamin C
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Reporting group description |
Patients in the intervention group received 1,5 g intravenous vitamin C (3 ampoules of vitamin C 500mg/5ml) diluted in 50ml of Normal Saline, administered over 15 minutes, every 6 hours for 4 days (4 times a day in total 16 administrations). A maximum of 8 hours was allowed between 2 doses and only one dose could be missed. Parameters were obtained as part of routine clinical care. On day 1+4 a targeted blood sample was collected for procalcitonin determination. Baseline data were obtained as close as possible to the time of randomization. The EQ-5D-5L health questionnaire was obtained on admission, day 5, d28 and 3 months. ABG analysis was part of routine clinical care in ICU. If the patient was discharged to the ward before day 5, ABG sampling was not considered standard of care. To be able to calculate the SOFA score in this population, we used the SpO2/FiO2 ratio to impute for PaO2/FiO2 ratio in the respiratory component. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Patients in the placebo group received a matching placebo with Normal Saline. The administration was identical to the vitamin C treatment: 3 ampoules of Noral Saline 5ml diluted in 50ml of Normal Saline, administered over 15 minutes, every 6 hours for 4 days (4 times a day in total 16 administrations). A maximum of 8 hours was allowed between 2 doses and only one dose could be missed. The obtained parameters, blood samples and health questionnaires and the routine clinical care were identical to the Vitamin C arm. Ardena Gent NV, a Drug Product Development & Manufacturing firm blinded, packaged, relabelled the IMP kits, and provided randomization: 1st batch: number 21C22, expiry date September 2022 2nd batch: number 22I01, expiry date October 2023 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? No | |||
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. | |||
| - optimal dose and timing of vitamin C administration not known - no measurement of baseline vitamin C levels - one hospital included about 40% of the patients | |||
