Intracranial Pressure in Experimental Models of Headache

• Sponsor: Bangor University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01288781
• Collaborator: Universita di Verona (Other), North Wales Research Committee, UK (Other)
• Enrollment: 23
• Location: 1
• Arms: 2
• Duration (Months): 1
• Patients Per Site Per Month: 22.6

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether increased pressure in the head is elevated in people who suffer from High Altitude Headache. We hypothesise that head pressure will be elevated in people with High Altitude Headache.

Condition or Disease	Intervention/Treatment	Phase
High Altitude Headache	Drug: Acetazolamide; Drug: Lactose monohydrate	N/A

Detailed Description

High Altitude Headache is the primary symptom of Acute Mountain Sickness. However, at present the reason why some individuals suffer from High Altitude Headache and others do not remains unknown. It is widely believed that elevated pressure within the brain leads to stretching of pain sensitive fibres and thus headache. However, evidence of raised intracranial pressure during High Altitude Headache is currently unavailable. Therefore, this study aims to examine a proxy measure of intracranial pressure (Optic Nerve Sheath Diameter) in persons visiting High Altitude, half of whom have been given the drug acetazolamide that is known to reduce headache symptoms.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Intracranial Pressure in Experimental Models of Headache
• Study Start Date: Jul 1, 2011
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Aug 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Acetazolamide Arm 1: ACETAZOLAMIDE (250mg) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).	Drug: Acetazolamide; During a forty eight hour hypoxic exposure (3777m), subjects will be given either acetazolamide or placebo at hours fifteen, twenty and thirty two.; Other Names: Diamox
Placebo Comparator: Placebo Placebo (LACTOSE MONOHYDRATE) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).	Drug: Lactose monohydrate; During a forty eight hour hypoxic exposure (3777m), subjects will be given either acetazolamide or placebo at hours fifteen, twenty and thirty two.

Outcome Measures

Primary Outcome Measures

1. Change in Optic Nerve Sheath Diameter by Ultrasonography [Optic Nerve Sheath Diameter: baseline, 24 hours.]

   Baseline is defined as the average of the 3 hour and 12 hour normoxia measurement. 24 hours is defined at the 24 hour hypoxia measurement. Optic nerve sheath diameter obtained by ultrasonography of the eye. Increased optic nerve sheath diameter suggests greater intra cranial pressure.

Secondary Outcome Measures

1. Change in High Altitude Headache by Visual Analogue Scale [High Altitude Headache: baseline, 24 hours.]

   Baseline is defined as the average of the 3 hour and 12 hour normoxia measurement. 24 hours is defined at the 24 hour hypoxia measurement. Outcome measured using visual analogue scale, where 0 mm is no headache and 100 mm is maximum headache.

2. Change in Blood Oxygen Saturation [Blood Oxygen Saturation: baseline, 24 hours.]

   Baseline is defined as the average of the 3 hour and 12 hour normoxia measurement. 24 hours is defined at the 24 hour hypoxia measurement.

3. Change in Fluid Balance [Fluid Balance: baseline, 24 hours.]

   Baseline is defined as the average of the 3 hour and 12 hour normoxia measurement. 24 hours is defined at the 24 hour hypoxia measurement. Urine output was recorded by 24 hour urine collection and fluid intake by 24 hour food diaries. Fluid balance was calculated as: (urine output (L) / fluid intake (L) ) * 100.

4. Change in Optic Nerve Sheath Diameter [Optic Nerve Sheath Diameter: baseline, 3 hours.]

   Baseline is defined as the average of the 3 hour 12 hour normoxia measurements. 3 hours is defined at the 3 hour hypoxia measurement.

5. Change in Optic Nerve Sheath Diameter [Optic Nerve Sheath Diameter: baseline, 12 hours.]

   Baseline is defined as the average of the 3 hour 12 hour normoxia measurements. 12 hours is defined at the 12 hour hypoxia measurement.

6. Change in Optic Nerve Sheath Diameter [Optic Nerve Sheath Diameter: baseline, 36 hours.]

   Baseline is defined as the average of the 3 hour and 12 hour normoxia measurements. 36 hours is defined at the 36 hour hypoxia measurement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Member of the Italian High Altitude Research Expeditions

Exclusion Criteria:

• Are under the age of 18years;

• sulfonamide allergy

• Liver or kidney disfunction

• Have any other uncontrolled medical condition

• Or are unable to give consent.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	School of Sport, Health and Exercise Sciences, Bangor University	Bangor	Gwynedd	United Kingdom	LL57 2PZ

Sponsors and Collaborators

• Bangor University
• Universita di Verona
• North Wales Research Committee, UK

Investigators

• Principal Investigator: Justin S Lawley, BSc, Bangor University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bangor University
• ClinicalTrials.gov Identifier: NCT01288781
• Other Study ID Numbers: F002686; 2010-019520-31
• First Posted: Feb 2, 2011
• Last Update Posted: Feb 7, 2012
• Last Verified: Dec 1, 2011

• Keywords provided by Bangor University: High Altitude Headache; intra-cranial pressure; hypoxia
• Additional relevant MeSH terms: Headache; Acetazolamide

Study Results

Participant Flow

Recruitment Details	Participants attending the Antur Ymchwil 2011 Expedition to the European Alps were recruited between 01.07.11 and 01.08.11.
Pre-assignment Detail	Participants completed two trials, including a 12 hour sea level exposure followed by a 36 hour high altitude exposure (3777m). Participants were assigned to one of two groups based on High-altitude headache susceptibility determined by visual analogue score obtained after 12 hours at high altitude. No participants were excluded.

Arm/Group Title	Acetazolamide	Placebo
Arm/Group Description	Arm 1: ACETAZOLAMIDE (250mg) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).	Placebo (LACTOSE MONOHYDRATE) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).
Period Title: Overall Study
STARTED	11	12
COMPLETED	11	12
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Acetazolamide	Placebo	Total
Arm/Group Description	Arm 1: ACETAZOLAMIDE (250mg) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).	Placebo (LACTOSE MONOHYDRATE) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).	Total of all reporting groups
Overall Participants	11	12	23
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	11 100%	12 100%	23 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	24 (6)	20 (1)	21 (3)
Sex: Female, Male (Count of Participants)
Female	2 18.2%	4 33.3%	6 26.1%
Male	9 81.8%	8 66.7%	17 73.9%
Region of Enrollment (participants) [Number]
United Kingdom	11 100%	12 100%	23 100%

Outcome Measures

1. Primary Outcome

Title	Change in Optic Nerve Sheath Diameter by Ultrasonography
Description	Baseline is defined as the average of the 3 hour and 12 hour normoxia measurement. 24 hours is defined at the 24 hour hypoxia measurement. Optic nerve sheath diameter obtained by ultrasonography of the eye. Increased optic nerve sheath diameter suggests greater intra cranial pressure.
Time Frame	Optic Nerve Sheath Diameter: baseline, 24 hours.

Outcome Measure Data

Analysis Population Description

All participants were included. Analysis was intention to treat. There were no missing data.

Arm/Group Title	Acetazolamide	Placebo
Arm/Group Description	Arm 1: ACETAZOLAMIDE (250mg) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).	Placebo (LACTOSE MONOHYDRATE) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).
Measure Participants	11	12
Mean (Standard Deviation) [mm]	0.02 (0.06)	0.02 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acetazolamide, Placebo
	Comments	Omnibus analysis was performed. 2 (drug: Acetazolamide versus placebo) * 2 (susceptibility: high altitude headache resistant versus high altitude headache susceptible) * 6 (time: sea level, 3 & 12; high altitude, 3, 12, 24 & 36 hours) analysis of variance with repeated measures on the third factor. Data presented here are for the drug * time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.98
	Comments	P < 0.05 considered statistically significant.
	Method	ANOVA
	Comments	Adjustments to the degrees of freedom were made when assumptions of sphericity were violated.

2. Secondary Outcome

Title	Change in High Altitude Headache by Visual Analogue Scale
Description	Baseline is defined as the average of the 3 hour and 12 hour normoxia measurement. 24 hours is defined at the 24 hour hypoxia measurement. Outcome measured using visual analogue scale, where 0 mm is no headache and 100 mm is maximum headache.
Time Frame	High Altitude Headache: baseline, 24 hours.

Outcome Measure Data

Analysis Population Description

All participants were included. Analysis was intention to treat. There were no missing data.

Arm/Group Title	Acetazolamide	Placebo
Arm/Group Description	Arm 1: ACETAZOLAMIDE (250mg) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).	Placebo (LACTOSE MONOHYDRATE) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).
Measure Participants	11	12
Mean (Standard Deviation) [mm]	6.4 (10.5)	7.2 (10.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acetazolamide, Placebo
	Comments	Omnibus analysis was performed. 2 (drug: Acetazolamide versus placebo) * 2 (susceptibility: high altitude headache resistant versus high altitude headache susceptible) * 6 (time: sea level, 3 & 12; high altitude, 3, 12, 24 & 36 hours) analysis of variance with repeated measures on the third factor. Data presented here are for the drug * time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.63
	Comments	P < 0.05 considered statistically significant.
	Method	ANOVA
	Comments	Adjustments to the degrees of freedom were made when assumptions of sphericity were violated.

3. Secondary Outcome

Title	Change in Blood Oxygen Saturation
Description	Baseline is defined as the average of the 3 hour and 12 hour normoxia measurement. 24 hours is defined at the 24 hour hypoxia measurement.
Time Frame	Blood Oxygen Saturation: baseline, 24 hours.

Outcome Measure Data

Analysis Population Description

All participants were included. Analysis was intention to treat. There were no missing data.

Arm/Group Title	Acetazolamide	Placebo
Arm/Group Description	Arm 1: ACETAZOLAMIDE (250mg) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).	Placebo (LACTOSE MONOHYDRATE) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).
Measure Participants	11	12
Mean (Standard Deviation) [% oxygen saturation]	10.8 (4.3)	11.1 (4.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acetazolamide, Placebo
	Comments	Omnibus analysis was performed. 2 (drug: Acetazolamide versus placebo) * 2 (susceptibility: high altitude headache resistant versus high altitude headache susceptible) * 6 (time: sea level, 3 & 12; high altitude, 3, 12, 24 & 36 hours) analysis of variance with repeated measures on the third factor. Data presented here are for the drug * time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.20
	Comments	P < 0.05 considered statistically significant.
	Method	ANOVA
	Comments	Adjustments to the degrees of freedom were made when assumptions of sphericity were violated.

4. Secondary Outcome

Title	Change in Fluid Balance
Description	Baseline is defined as the average of the 3 hour and 12 hour normoxia measurement. 24 hours is defined at the 24 hour hypoxia measurement. Urine output was recorded by 24 hour urine collection and fluid intake by 24 hour food diaries. Fluid balance was calculated as: (urine output (L) / fluid intake (L) ) * 100.
Time Frame	Fluid Balance: baseline, 24 hours.

Outcome Measure Data

Analysis Population Description

All participants were included. Analysis was intention to treat. There were no missing data.

Arm/Group Title	Acetazolamide	Placebo
Arm/Group Description	Arm 1: ACETAZOLAMIDE (250mg) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).	Placebo (LACTOSE MONOHYDRATE) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).
Measure Participants	11	12
Mean (Standard Deviation) [% of fluid intake]	342 (109)	147 (85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acetazolamide, Placebo
	Comments	Omnibus analysis was performed. 2 (drug: Acetazolamide versus placebo) * 2 (susceptibility: high altitude headache resistant versus high altitude headache susceptible) * 6 (time: sea level, 3 & 12; high altitude, 3, 12, 24 & 36 hours) analysis of variance with repeated measures on the third factor. Data presented here are for the drug * time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments	P < 0.05 considered statistically significant.
	Method	ANOVA
	Comments	Adjustments to the degrees of freedom were made when assumptions of sphericity were violated.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Acetazolamide, Placebo
	Comments	Post hoc follow up test. T test between acetazolamide and placebo on data at 24 hr time point.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments	Step down Holm Bonferroni correction was applied
	Method	t-test, 2 sided
	Comments

5. Secondary Outcome

Title	Change in Optic Nerve Sheath Diameter
Description	Baseline is defined as the average of the 3 hour 12 hour normoxia measurements. 3 hours is defined at the 3 hour hypoxia measurement.
Time Frame	Optic Nerve Sheath Diameter: baseline, 3 hours.

Outcome Measure Data

Analysis Population Description

All participants were included. Analysis was intention to treat. There were no missing data.

Arm/Group Title	Acetazolamide	Placebo
Arm/Group Description	Arm 1: ACETAZOLAMIDE (250mg) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).	Placebo (LACTOSE MONOHYDRATE) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).
Measure Participants	11	12
Mean (Standard Deviation) [mm]	0.00 (0.06)	-0.01 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acetazolamide, Placebo
	Comments	Omnibus analysis was performed. 2 (drug: Acetazolamide versus placebo) * 2 (susceptibility: high altitude headache resistant versus high altitude headache susceptible) * 6 (time: sea level, 3 & 12; high altitude, 3, 12, 24 & 36 hours) analysis of variance with repeated measures on the third factor. Data presented here are for the drug * time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.98
	Comments	P < 0.05 considered statistically significant.
	Method	ANOVA
	Comments	Adjustments to the degrees of freedom were made when assumptions of sphericity were violated.

6. Secondary Outcome

Title	Change in Optic Nerve Sheath Diameter
Description	Baseline is defined as the average of the 3 hour 12 hour normoxia measurements. 12 hours is defined at the 12 hour hypoxia measurement.
Time Frame	Optic Nerve Sheath Diameter: baseline, 12 hours.

Outcome Measure Data

Analysis Population Description

All participants were included. Analysis was intention to treat. There were no missing data.

Arm/Group Title	Acetazolamide	Placebo
Arm/Group Description	Arm 1: ACETAZOLAMIDE (250mg) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).	Placebo (LACTOSE MONOHYDRATE) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).
Measure Participants	11	12
Mean (Standard Deviation) [mm]	0.01 (0.04)	0.01 (0.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acetazolamide, Placebo
	Comments	Omnibus analysis was performed. 2 (drug: Acetazolamide versus placebo) * 2 (susceptibility: high altitude headache resistant versus high altitude headache susceptible) * 6 (time: sea level, 3 & 12; high altitude, 3, 12, 24 & 36 hours) analysis of variance with repeated measures on the third factor. Data presented here are for the drug * time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.98
	Comments	P < 0.05 considered statistically significant.
	Method	ANOVA
	Comments	Adjustments to the degrees of freedom were made when assumptions of sphericity were violated.

7. Secondary Outcome

Title	Change in Optic Nerve Sheath Diameter
Description	Baseline is defined as the average of the 3 hour and 12 hour normoxia measurements. 36 hours is defined at the 36 hour hypoxia measurement.
Time Frame	Optic Nerve Sheath Diameter: baseline, 36 hours.

Outcome Measure Data

Analysis Population Description

All participants were included. Analysis was intention to treat. There were no missing data.

Arm/Group Title	Acetazolamide	Placebo
Arm/Group Description	Arm 1: ACETAZOLAMIDE (250mg) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).	Placebo (LACTOSE MONOHYDRATE) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).
Measure Participants	11	12
Mean (Standard Deviation) [mm]	0.01 (0.04)	0.00 (0.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acetazolamide, Placebo
	Comments	Omnibus analysis was performed. 2 (drug: Acetazolamide versus placebo) * 2 (susceptibility: high altitude headache resistant versus high altitude headache susceptible) * 6 (time: sea level, 3 & 12; high altitude, 3, 12, 24 & 36 hours) analysis of variance with repeated measures on the third factor. Data presented here are for the drug * time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.98
	Comments	P < 0.05 considered statistically significant.
	Method	ANOVA
	Comments	Adjustments to the degrees of freedom were made when assumptions of sphericity were violated.

Adverse Events

Time Frame	Study data collection period only (baseline and high altitude exposures up to 36 hours).
Adverse Event Reporting Description	Adverse events recorded by study investigators at six hourly interviews.
Arm/Group Title	Acetazolamide		Placebo
Arm/Group Description	Arm 1: ACETAZOLAMIDE (250mg) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).		Placebo (LACTOSE MONOHYDRATE) will be given to subjects at fifteen, twenty and thirty two hours post hypoxic exposure (3777m).
All Cause Mortality
	Acetazolamide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Acetazolamide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Acetazolamide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/12 (0%)

Limitations/Caveats

Acetazolamide did not reduce high altitude headache as expected. Nevertheless the relationship between optic nerve sheath diameter and headache could still be determined by completing other analyses.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.