Clinical Trial Results:
Oxygen therapy for cluster headache. A mask comparison trial. A single-blinded, placebo-controlled, crossover study.
Summary
|
|
EudraCT number |
2011-006182-18 |
Trial protocol |
DK |
Global end of trial date |
06 Feb 2016
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
12 Aug 2016
|
First version publication date |
12 Aug 2016
|
Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
Trial identification
|
|||
Sponsor protocol code |
15.12.12
|
||
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT01589588 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
|
|||
Sponsor organisation name |
Danish Headache Center
|
||
Sponsor organisation address |
nordre ringvej 57, glostrup, Denmark, 2600
|
||
Public contact |
Mads Barloese, Danish Headache Center, 45 38632062, GLO-hovedpine@regionh.dk
|
||
Scientific contact |
Mads Barloese, Danish Headache Center, 45 38632062, GLO-hovedpine@regionh.dk
|
||
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
06 Feb 2016
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
06 Feb 2016
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
06 Feb 2016
|
||
Was the trial ended prematurely? |
Yes
|
||
General information about the trial
|
|||
Main objective of the trial |
This study will investigate the possible difference in treatment effect between three different oxygen delivery systems in the acute treatment of cluster headaches
|
||
Protection of trial subjects |
All adverse events throughout the study will be recorded. All adverse events will be categorized as serious or non-serious, expected or not expected and the relationship with masks and treatment and placebo given. In assessing whether an adverse reaction expected or not expected we will use the product resume of Airapy and Oxygen AGA.
The experiment is reported to the GCP-unit Region capital as follows with announced and unannounced visits. The trial is blind. A key so that it can always be seen what treatment the patient has received when. If the patient experiences unpleasant side-effects of one of the masks he can use his usual attack treatment after 15 minutes. The trial takes place in a hospital where there is immediate access to medical expertise. It is possible to immediately unblinding of the study using randomiseringsnøglen located at trial site.
Conducted a clinical report form (CRF) for each patient throughout the study. This is designed according GCP unit guidelines
|
||
Background therapy |
preventive medication was stable one week pror to inclusion and during the trial. Patients were allowed rescue medication after 15 minutes of trial theraphy, | ||
Evidence for comparator |
High flow oxygen is known to relief patients within 15 minutes (cohen 2009) and a small open label study showed that DVO migth be more efficiant than high flow oxygen, rozen 2011 | ||
Actual start date of recruitment |
01 Feb 2012
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
No
|
||
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Denmark: 57
|
||
Worldwide total number of subjects |
57
|
||
EEA total number of subjects |
57
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
57
|
||
From 65 to 84 years |
0
|
||
85 years and over |
0
|
|
||||||||||||||||
Recruitment
|
||||||||||||||||
Recruitment details |
We included 57 CH patients from the Danish Headache Center, a tertiary headache center, between June 2012 and December 2014. Hereof, 31 CH patients also participated in an inpatient sleep study (Project ID: H-2-2012-016). Twenty-six CH-patients participated only in the mask comparison trial. | |||||||||||||||
Pre-assignment
|
||||||||||||||||
Screening details |
The inclusion criteria were age between 18 and 65 years; CH diagnosis according to International Classification of Headache Disorders, second edition (ICHD-II) criteria ; regular attack and cluster frequency for at least two years; average attack frequency of two to eight attacks per day prior to inclusion; cluster duration of more than two weeks; | |||||||||||||||
Pre-assignment period milestones
|
||||||||||||||||
Number of subjects started |
57 | |||||||||||||||
Number of subjects completed |
10 [1] | |||||||||||||||
Pre-assignment subject non-completion reasons
|
||||||||||||||||
Reason: Number of subjects |
not enough attacks: 45 | |||||||||||||||
Reason: Number of subjects |
latex allergy: 1 | |||||||||||||||
Reason: Number of subjects |
Protocol deviation: 1 | |||||||||||||||
Notes [1] - The number of subjects reported to be in the pre-assignment period is not consistent with the number starting period 1. It is expected that the number completing the pre-assignment period are also present in the arms in period 1. Justification: 57 patients were enrolled. 42 patients had attacks. The trial is 4 way cross over. |
||||||||||||||||
Period 1
|
||||||||||||||||
Period 1 title |
baseline (overall period)
|
|||||||||||||||
Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
|
|||||||||||||||
Blinding used |
Single blind | |||||||||||||||
Roles blinded |
Subject | |||||||||||||||
Blinding implementation details |
Patinets were blinded for gastype and not masktype. Author MB generated the random sequence with the Microsoft Excel SLUMP function. The list was kept in the trial master file during the trial. Blinding of the mask type currently used was deemed impossible but patients were blinded to the contents of the gas cylinders. The gas cylinders were exactly the same size and covered with black plastic wrapping during the trial. A sticker with the numbers 1–4 distinguished the cylinders
|
|||||||||||||||
Arms
|
||||||||||||||||
Are arms mutually exclusive |
No
|
|||||||||||||||
Arm title
|
DVO Demand valve oxygen | |||||||||||||||
Arm description |
Demand Valve oxygen | |||||||||||||||
Arm type |
Active comparator | |||||||||||||||
Investigational medicinal product name |
Conoxia,
|
|||||||||||||||
Investigational medicinal product code |
||||||||||||||||
Other name |
Oxygen, 100%
|
|||||||||||||||
Pharmaceutical forms |
Gas and solvent for dispersion for injection/infusion
|
|||||||||||||||
Routes of administration |
Inhalation use
|
|||||||||||||||
Dosage and administration details |
accodring to RR and TV
|
|||||||||||||||
Arm title
|
Optimask | |||||||||||||||
Arm description |
Optimask | |||||||||||||||
Arm type |
Active comparator | |||||||||||||||
Investigational medicinal product name |
Conoxia,
|
|||||||||||||||
Investigational medicinal product code |
||||||||||||||||
Other name |
Oxygen, 100%
|
|||||||||||||||
Pharmaceutical forms |
Gas and solvent for dispersion for injection/infusion
|
|||||||||||||||
Routes of administration |
Inhalation use
|
|||||||||||||||
Dosage and administration details |
15 L/min
|
|||||||||||||||
Arm title
|
Simple Mask | |||||||||||||||
Arm description |
Simple mask | |||||||||||||||
Arm type |
Active comparator | |||||||||||||||
Investigational medicinal product name |
Conoxia,
|
|||||||||||||||
Investigational medicinal product code |
||||||||||||||||
Other name |
Oxygen, 100%
|
|||||||||||||||
Pharmaceutical forms |
Gas and solvent for dispersion for injection/infusion
|
|||||||||||||||
Routes of administration |
Inhalation use
|
|||||||||||||||
Dosage and administration details |
15 L/min
|
|||||||||||||||
Arm title
|
Placebo | |||||||||||||||
Arm description |
Place with DVO | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
AIRAPY
|
|||||||||||||||
Investigational medicinal product code |
||||||||||||||||
Other name |
eq air
|
|||||||||||||||
Pharmaceutical forms |
Gas and solvent for dispersion for injection/infusion
|
|||||||||||||||
Routes of administration |
Inhalation use
|
|||||||||||||||
Dosage and administration details |
Accodring to RR and TV
|
|||||||||||||||
|
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
baseline
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
57 patients included in trial | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
End points reporting groups
|
|||
Reporting group title |
DVO Demand valve oxygen
|
||
Reporting group description |
Demand Valve oxygen | ||
Reporting group title |
Optimask
|
||
Reporting group description |
Optimask | ||
Reporting group title |
Simple Mask
|
||
Reporting group description |
Simple mask | ||
Reporting group title |
Placebo
|
||
Reporting group description |
Place with DVO |
|
||||||||||||||||||||||||||
End point title |
Two-point reduction on a five-point rating scale | |||||||||||||||||||||||||
End point description |
The primary endpoint was a two-point reduction on a five-point rating scale within 15 minutes (min).
|
|||||||||||||||||||||||||
End point type |
Primary
|
|||||||||||||||||||||||||
End point timeframe |
15 minutes
|
|||||||||||||||||||||||||
|
||||||||||||||||||||||||||
Attachments |
Untitled (Filename: FIGUR 4.xlsx) |
|||||||||||||||||||||||||
Statistical analysis title |
logistic reg | |||||||||||||||||||||||||
Comparison groups |
Optimask v Simple Mask v DVO Demand valve oxygen v Placebo
|
|||||||||||||||||||||||||
Number of subjects included in analysis |
102
|
|||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||
Analysis type |
other [1] | |||||||||||||||||||||||||
P-value |
= 0.411 [2] | |||||||||||||||||||||||||
Method |
Regression, Logistic | |||||||||||||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||
Notes [1] - After 15 min of therapy, the percentage of patients that were either pain free or had a two-point decrease on the five-point rating scale was 40%, 44% and 52% on the SM, OM and DVO, respectively (Figure 4). We completed a logistic analysis of all attacks for the primary outcome regarding pain relief within 15 min of oxygen therapy, but could not show any significant differences (p = 0.411). [2] - non sig |
|
|||||||||||||||||
End point title |
Mask preference [3] | ||||||||||||||||
End point description |
Only patients who tried all three mask types.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
no time frame
|
||||||||||||||||
Notes [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: We only included patient in this analysis who had tried all three mask types |
|||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
patient preference | ||||||||||||||||
Comparison groups |
Simple Mask v Optimask v DVO Demand valve oxygen
|
||||||||||||||||
Number of subjects included in analysis |
63
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other [4] | ||||||||||||||||
P-value |
< 0.001 [5] | ||||||||||||||||
Method |
Chi-squared | ||||||||||||||||
Confidence interval |
|||||||||||||||||
Notes [4] - The majority of the CH patients preferred DVO (62%) and only 5% preferred the SM (p < 0.001). The remaining 33% favored the OM (p = 0.061, compared to DVO) (Table 3). Only patients who tried all three mask types were included in this analysis (n = 21). [5] - significant |
|
|||||||||||||||||||||
End point title |
First attack Analysis [6] | ||||||||||||||||||||
End point description |
We tested for informative drop-out by means of a logistic regression model for the risk of more than one attack with respect to the mask used during the first attack. In addition, we tested the association between the mask used during the first attack and completion of the crossover study by logistic regression.
To eliminate the possible carry-over effect, we conducted a post hoc comparative cross-sectional analysis, where only the first treated attack was included. Since this was the first attack, the randomization was intact and the risk of bias was minimized.
|
||||||||||||||||||||
End point type |
Post-hoc
|
||||||||||||||||||||
End point timeframe |
15 min
|
||||||||||||||||||||
Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: we only included the first attack, not the second, third or fouth. This was due to risk of unequal distribution and to short a wash out period. |
|||||||||||||||||||||
|
|||||||||||||||||||||
Statistical analysis title |
first attack | ||||||||||||||||||||
Statistical analysis description |
The analysis of the first attack contains 42 CH attacks (Figure 3). The DVO was significantly better than the OM at treating the CH attacks on the five-point rating scale at 15 min with an OR of 5.5 (p = 0.042). The DVO was borderline better than the SM with an OR of 5.0 (p = 0.056). There was no difference between SM and OM (p = 0.918). Pooling the data and comparing the DVO to both SM and OM, the DVO is significantly better (p = 0.018).
|
||||||||||||||||||||
Comparison groups |
DVO Demand valve oxygen v Optimask v Simple Mask
|
||||||||||||||||||||
Number of subjects included in analysis |
42
|
||||||||||||||||||||
Analysis specification |
Post-hoc
|
||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||
P-value |
= 0.018 | ||||||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||||||
Confidence interval |
|
|||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
14 days
|
||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Four adverse events happened after the trial, including one serious, but all were assessed to be unrelated to oxygen therapy.
|
||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||
Dictionary name |
gcp manual | ||||||||||||||||||||||||||||||
Dictionary version |
1.0
|
||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||
Reporting group title |
total population
|
||||||||||||||||||||||||||||||
Reporting group description |
only 42 patients received trial therapy. | ||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
12 Nov 2013 |
Inclusion of more patients and extension of trial period. |
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
patients did not suffer from four attacks and therefor the cross over is not complete and a peer protocol analysis is not possible. |