Clinical Trial Results:
Carbon Dioxide for the Treatment of Febrile Seizures
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Summary
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EudraCT number |
2011-001403-12 |
Trial protocol |
DE |
Global end of trial date |
30 Jun 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
05 May 2022
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First version publication date |
05 May 2022
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Other versions |
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Summary report(s) |
pre-ended-statement_CARDIF |
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 |
CARDIF
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01370044 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Charité - Universitätsmedizin Berlin
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Sponsor organisation address |
Charitéplatz 1, Berlin, Germany, 10117
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Public contact |
Universitaetsmedizin Berlin, Charite Universitaetsmedizin Berlin, +49 304505566112, markus.schuelke@charite.de
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Scientific contact |
Universitaetsmedizin Berlin, Charité - Universitaetsmedizin Berlin, +49 304505566112, markus.schuelke@charite.de
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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 |
Interim
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Date of interim/final analysis |
30 Jun 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
30 Jun 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Jun 2015
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To evaluate the efficacy of a carbogen-inhalation in patients with febrile
seizures compared to a placebo-inhalation
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Protection of trial subjects |
The safety of the therapy with carbogen-inhalation in patients with febrile seizures assessed by physical examination, vital signs, and evaluation of adverse events. Furthermore, the patients were monitored for spontaneous complaints after treatments.
The study will be performed in accordance with the Good Clinical Practice (GCP) guidelines, the Declaration of Helsinki, the German Medical Drug Law and Data Protection Laws in their current or effective versions. An extensive GCP monitoring will be conducted. Additionally, we put strategies in place to maximize data quality, such as intensive training of the study team, nursing personal and parents. Adverse event management will be done according to standard regulations.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
16 Jul 2012
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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 |
Germany: 20
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Worldwide total number of subjects |
20
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EEA total number of subjects |
20
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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) |
12
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Children (2-11 years) |
8
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients will be recruited from the Children’s University Hospital of the Charité in Berlin. Parents or custodians of potential participants will be thoroughly informed about the study rationale, procedures, potential risks and benefits. | |||||||||
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Pre-assignment
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Screening details |
Assessed for eligibility: 97; Excluded: 3; 94 were randomized. | |||||||||
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Period 1
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Period 1 title |
Treatment (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 | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Verum Group | |||||||||
Arm description |
Carbogen is a gas mixture composed of 5% CO2 and 95% O2, which is stored in compressed gas cylinders. the application of CO2-enriched air or of medical carbogen (5% CO2 plus 95% O2), which ensures that the blood pCO2 does not increase and the pO2 does not drop beyond certain limits. The added oxygen even improves oxygenation and prevents hypoxia. As febrile seizures usually occur at home, where no blood gas monitoring is possible, we opted for carbogen to be used in our clinical trial. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Carbogengas
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Investigational medicinal product code |
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Other name |
CO2
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Pharmaceutical forms |
Inhalation vapour
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Routes of administration |
Respiratory use
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Dosage and administration details |
CO2 (5%) with O2(95%) inhalation of 6 liters carbogen over 3 minutes once the seizure occur
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Arm title
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Placebo Group | |||||||||
Arm description |
- | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
100% O2
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Pharmaceutical forms |
Inhalation vapour
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Routes of administration |
Respiratory use
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Dosage and administration details |
100% O2 (Low-pressure can containing 6 liter of Oxygen). Administration once the seizure has started over 3min.
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Baseline characteristics reporting groups
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Reporting group title |
Verum Group
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Reporting group description |
Carbogen is a gas mixture composed of 5% CO2 and 95% O2, which is stored in compressed gas cylinders. the application of CO2-enriched air or of medical carbogen (5% CO2 plus 95% O2), which ensures that the blood pCO2 does not increase and the pO2 does not drop beyond certain limits. The added oxygen even improves oxygenation and prevents hypoxia. As febrile seizures usually occur at home, where no blood gas monitoring is possible, we opted for carbogen to be used in our clinical trial. | ||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo Group
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Crossover patients
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
After the first seizure recurrence a crossover occurs. With this, regardless of the result of the first treatment, patients who received placebo for the first seizure recurrence receive verum for the second one or vice versa. From the third seizure recurrence onwards, all patients receive open label verum. Since it is anticipated that only a minority of patients will suffer from a second seizure recurrence and thus enter the crossover arm, the study is not a true crossover study. Data from the “crossover” and the open label extension phase will thus only be considered for secondary analyses. The primary analysis will only include the first seizure recurrence, while the secondary analyses consider all seizure recurrences per patient.
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End points reporting groups
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Reporting group title |
Verum Group
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Reporting group description |
Carbogen is a gas mixture composed of 5% CO2 and 95% O2, which is stored in compressed gas cylinders. the application of CO2-enriched air or of medical carbogen (5% CO2 plus 95% O2), which ensures that the blood pCO2 does not increase and the pO2 does not drop beyond certain limits. The added oxygen even improves oxygenation and prevents hypoxia. As febrile seizures usually occur at home, where no blood gas monitoring is possible, we opted for carbogen to be used in our clinical trial. | ||
Reporting group title |
Placebo Group
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Reporting group description |
- | ||
Subject analysis set title |
Crossover patients
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
After the first seizure recurrence a crossover occurs. With this, regardless of the result of the first treatment, patients who received placebo for the first seizure recurrence receive verum for the second one or vice versa. From the third seizure recurrence onwards, all patients receive open label verum. Since it is anticipated that only a minority of patients will suffer from a second seizure recurrence and thus enter the crossover arm, the study is not a true crossover study. Data from the “crossover” and the open label extension phase will thus only be considered for secondary analyses. The primary analysis will only include the first seizure recurrence, while the secondary analyses consider all seizure recurrences per patient.
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End point title |
Efficacy of a Carbogen inhalation | |||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
24 months study period
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Statistical analysis title |
Determation of the success rate | |||||||||||||||
Statistical analysis description |
Statistical planning is based on the modified intention-to-treat principle, i.e. only patients suffering from a febrile seizure recurrence during the study period of 24 months will be assigned to the intention-to-treat population.
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Comparison groups |
Verum Group v Placebo Group
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Number of subjects included in analysis |
20
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | |||||||||||||||
P-value |
> 0.3 [2] | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Confidence interval |
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| Notes [1] - The aim of the study is the proof of the superiority of the experimental intervention (carbogen) versus control (oxygen) to suppress a seizure recurrence within 3 minutes. Success rates under intervention and control being p_i and p_K, the statistical null hypothesis is pI = pK, and the alternative hypothesis pI ≠ pK. The analyses will be carried out according to Bauer & Köhne with α = 0.025, cα= 0.00380 and α0 = 0.5 (in each case one-sided). [2] - the p-value of the exact Fischer test was p = 0.07 and for the one sided fischer exact test was p=0.035 in favor of Placebo. Hence the formal criteria was p_0 > 0.3 |
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End point title |
Crossover confirmation | ||||||||||
End point description |
After the first seizure recurrence a crossover occurs. With this, regardless of the result of the first treatment, patients who received placebo for the first seizure recurrence receive verum for the second one or vice versa. From the third seizure recurrence onwards, all patients receive open label verum. Since it is anticipated that only a minority of patients will suffer from a second seizure recurrence and thus enter the crossover arm, the study is not a true crossover study. Data from the “crossover” and the open label extension phase will thus only be considered for secondary analyses. The primary analysis will only include the first seizure recurrence, while the secondary analyses consider all seizure recurrences per patient.
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End point type |
Secondary
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End point timeframe |
within the study duration: 24months
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| No statistical analyses for this end point | |||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
24 months study period
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
own | ||||||||||||||||||||||||||||||||||||||||
Dictionary version |
1
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Reporting groups
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Reporting group title |
Verum Group
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo Group
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Medication not taken
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: No non-serious adverse events were reported |
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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06 Jul 2012 |
late registration PI |
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28 Dec 2012 |
LKP-Change: EK-Vote |
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01 Jan 2013 |
Bfarm-Vote; new protocol verion 1.2 (13th of Dec, 2012) |
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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. | |||
| The study was prematurely ended due to futility. In the interim analysis of the CARDIF study results were unexpectedly found in favor of an inferiority of the verum compound. For this reason the study had to be aborted ("stopping for futility"). Si | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/23806032 |
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