Clinical Trials Register

Summary
EudraCT Number:	2017-004318-25
Sponsor's Protocol Code Number:	NL63681.029.18
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-06-08
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2017-004318-25

A.3

Full title of the trial

Early high-dose vitamin C in post-cardiac arrest syndrome.

Vroege hoge dosis intraveneuze vitamine C na reanimatie.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Early high-dose vitamin C to prevent and/or treat organ dysfunction after cardioplumonary resusciation.

Vroege hoge dosis intraveneuze vitamine C na reanimatie.

A.3.2

Name or abbreviated title of the trial where available

Vitamin C post cardiac arrest

Vitamine C na reanimatie

A.4.1

Sponsor's protocol code number

NL63681.029.18

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	VU University Medical Center
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	The Netherlands Organisation for Health Research and Development
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	VU University Medical Center
B.5.2	Functional name of contact point	Dept. of Intensive Care
B.5.3	Address:
B.5.3.1	Street Address	De Boelelaan 1117
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1081 HV
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31204443924

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Ascorbic acid 5 gr/50 ml
D.3.2	Product code	1.5 gr and 5 gr
D.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ascorbic acid
D.3.9.3	Other descriptive name	ASCORBIC ACID PH EUR
D.3.9.4	EV Substance Code	SUB29103
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Ascorbic acid 100 mg/ml
D.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ascorbic acid
D.3.9.3	Other descriptive name	ASCORBIC ACID PH EUR
D.3.9.4	EV Substance Code	SUB29103
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients admitted to the Intensive Care after out-of-hospital cardiac arrest with return of spontaneous circulation, ventricular fibrillation or ventricular tachycardia as first registered cardiac rhythm and EMV-score ≤8

Patiënten opgenomen op de Intensive Care na een reanimatie buiten het ziekenhuis met herstel van spontane circulatie, ventrikel fibrilleren of ventrikel tachycardie als eerste geregistreerde ritme en een EMV-score ≤8

E.1.1.1

Medical condition in easily understood language

Patients admitted to the Intensive Care after after cardiopulmonary resuscitation who remain comatose

Patiënten opgenomen op de Intensive Care na een reanimatie buiten het ziekenhuis die buiten bewustzijn blijven

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10078202
E.1.2	Term	Post cardiac arrest syndrome
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

- To determine whether an early high dose i.v. vitamin C can improve organ function, especially neurological outcome, in patients after cardiac arrest

- Kan een vroeg toegediende, hoge dosis i.v. vitamine C orgaan functie (in het bijzonder neurologische uitkomst), verbeteren in patienten na reanimatie?

E.2.2

Secondary objectives of the trial

- To explore the optimal dosing regimen for high dose i.v. vitamin C
- To investigate in vitro the difference in effect of plasma obtained from post cardiac arrest patients treated with placebo, 3 gr/day or 10 gr/day vitamin C on endothelial cell viability and underlying oxidative pathways.

- Indien vitamine C orgaanfunctie verbetert, werkt 3 gr/dag dan beter dan 10 gr/dag?
- Is er in vitro verschil in effect van het plasma van de studiepatiënten op endotheliale celdood en wat zijn de onderliggende oxidatieve mechanismen?

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients suffering an out-of-hospital cardiac arrest with return of spontaneous circulation, ventricular fibrillation or ventricular tachycardia as first registered cardiac rhythm and EMV-score ≤8 will be included.

Patiënten op de Intensive Care opgenomen na een reanimatie buiten het ziekenhuis met herstel van spontane circulatie, ventrikel fibrilleren of ventrikel tachycardie als eerste geregistreerde ritme en een EMV-score ≤8 zullen worden geincludeerd.

E.4

Principal exclusion criteria

Patients with pre-existent terminal renal insufficiency (i.e. receiving renal replacement therapy (RRT)), known glucose 6-phosphate dehydrogenase deficiency (risk of hemolysis), history of urolithiasis, oxalate nephropathy, hemochromatosis or treatment limitations will be excluded.

Patiënten met in de voorgeschiedenis pre-existente terminale nierinsufficiëntie (d.w.z. het ontvangen van nierfunctie vervangende therapie), glucose 6-phosphate dehydrogenase deficientie (risico op hemolyse), urolithiasis, oxalate nefropathie, hemochromatose of behandel beperkingen zullen worden geexcludeerd.

E.5 End points

E.5.1

Primary end point(s)

We will determine organ failure at 96 hours measured by the delta (Δ) Sequential Organ Failure Assessment (SOFA) score. ΔSOFA score is defined as the difference between SOFA admission and SOFA at 96 hour. Death at 96-hours will be counted as the maximum SOFA score (24 points).

We onderzoeken orgaanfalen na 96 uur gekwantificeerd door de delta (Δ) Sequential Organ Failure Assessment (SOFA) score. ΔSOFA score is gedefinieerd door het verschil tussen SOFA bij opname en SOFA na 96 uur. Overleden na 96 uur zal berekend worden als de maximale SOFA score (24 punten).

E.5.1.1

Timepoint(s) of evaluation of this end point

After 96 hours

Na 96 uur

E.5.2

Secondary end point(s)

As secondary outcomes we will investigate: neurological outcome (Maximal Glasgow Coma Score at 96-h and and the end of ICU-stay; Cerebral Performance Categories scale and Modified Rankin Scale at 30 and 180 days; HUI-3 questionnaire at 180 days; neuron-specific enolase day 1, 2 and 3); clinical parameters (IC- and hospital stay, 30-day and 90-day mortality), organ injury (myocardial injury measured by troponin and CK-MB (maximum day 1), lung injury score, ventilation time, renal function, need of renal replacement therapy, IC-acquired weakness (Medical Research Council score), delirium (CAM-ICU score), mitoPO2, oxidative stress parameters (such as F2-isoprostanes and oxidation reduction potential (ORP)), anti-oxidant capacity (AOC) and vitamin C plasma concentrations.

In vitro experiments:
To determine the different effect of 3 or 10 gram vitamin C or placebo on the underlying oxidative pathways we will investigate how plasma obtained from the trial patients affects cultured human systemic microvascular endothelial cells with regard to endothelial cell viability, ROS production intracellular vitamin C concentrations, NADPH-oxidase expression, p47Phox expression, endothelial barrier function and mitochondrial respiratory chain function.

Als secondaire uitkomstmaten zullen we onderzoeken: neurologische uitkomst (Maximale Glasgow Coma Score na 96 uur en aan het einde van de IC-opname; Cerebral Performance Categories scale en Modified Rankin Scale na 30 en 180 dagen, HUI-3 vragenlijst na 180 dagen; neuron-specific enolase dag 1, 2 en 3); klinische parameters (IC- en ziekenhuis ligduur, 30-dagen en 90-dagen mortaliteit), orgaan schade (myocardiale schade gemeten door troponine en CK-MB (maximum van dag 1), lung injury score, beademingsduur, nierfunctie, noodzaak tot nierfunctie-vervangende therapie, IC-acquired weakness (Medical Research Council score), delier (CAM-ICU score), mitoPO2, oxidatieve stress parameters (zoals F2-isoprostanen en oxidatie reductie potentiaal (ORP)), anti-oxidante capaciteit (AOC) en vitamine C plasma concentraties.

In vitro experimenten: om het verschil in effect te bepalen van 3 gr of 10 gr vitamine C per dag of placebo op de onderliggende oxidatieve mechanismen zullen we het effect onderzoeken van plasma verkregen van de trial patienten op gekweekte humane systemische microvasculaire endotheliale cellen met betrekking tot endotheliale cel overleving, ROS productie, intracellulaire vitamine C concentraties, NADPH-oxidase expressie, p47Phox expressie, endotheliale barriere functie en mitochondriale respiratoire keten functie.

E.5.2.1

Timepoint(s) of evaluation of this end point

After 96 hours and at the end of ICU-stay. Neurological outcome will also be evaluated after 30 days and after 180 days.

Na 96 uur en aan het einde van de IC-opname. Neurologische uitkomst zal ook onderzocht worden na 30 en 180 dagen.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Andere dosis

Other dosage

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

When the last subject has finished his/her follow up of 180 days.

Als de laatste patient gedurende 180 dagen gevolgd is.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

130

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

230

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Comatous patients admitted to the Intensive Care after cardiac arrest.

Comateuze patiënten die opgenomen worden op de intensive Care na reanimatie.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

360

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None.
Extra note with regard to the planned number of subjects to be included:
Eventually, we aim to include in this RCT 270 EVALUABLE patients. To achieve the inclusion of this number of evaluable patients, we expect that we have to randomize 360 patients.

Geen.
Uiteindelijk willen we in deze RCT 270 EVALUEERBARE patiënten hebben. Om dit aantal te bereiken verwachten we ongeveer 360 patiënten te zullen moeten randomiseren.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Tergooiziekenhuizen
G.4.3.4	Network Country	Netherlands
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	Ziekenhuis Gelderse Vallei
G.4.3.4	Network Country	Netherlands
G.4 Investigator Network to be involved in the Trial: 3
G.4.1	Name of Organisation	Sint Franciscus Gasthuis & Vlietland
G.4.3.4	Network Country	Netherlands
G.4 Investigator Network to be involved in the Trial: 4
G.4.1	Name of Organisation	Erasmus Medisch Centrum
G.4.3.4	Network Country	Netherlands
G.4 Investigator Network to be involved in the Trial: 5
G.4.1	Name of Organisation	Noordwest Ziekenhuisgroep
G.4.3.4	Network Country	Netherlands
G.4 Investigator Network to be involved in the Trial: 6
G.4.1	Name of Organisation	Amphia Ziekenhuis
G.4 Investigator Network to be involved in the Trial: 7
G.4.1	Name of Organisation	Maasstad Hospital
G.4.3.4	Network Country	Netherlands
G.4 Investigator Network to be involved in the Trial: 8
G.4.1	Name of Organisation	OLVG Oost
G.4.3.4	Network Country	Netherlands

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-06-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-04-16

P. End of Trial
P.	End of Trial Status	Ongoing

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