Three New Ideas to Protect Special Forces From the Stress of High Altitude

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT02463357
• Collaborator: Alma College (Other)
• Enrollment: 148
• Location: 1
• Arms: 5
• Actual Duration (Months): 13
• Patients Per Site Per Month: 11.3

Study Details

Study Description

Brief Summary

Acute Mountain Sickness (AMS) is a well-documented syndrome that affects 42% of non-acclimatized individuals traveling to altitudes above 10,000 feet. Decreased barometric pressure, which leads to low blood oxygen levels, is the primary casual factor of AMS. Symptoms of AMS are characterized by headache, nausea, vomiting, dizziness, fatigue and difficultly sleeping. Moreover, when people travel to high altitude, cognitive performance and endurance exercise capacity are impaired. Therefore, the goal of this research is to identify effective pharmacological agents that will help reduce the symptoms of AMS and improve physical and cognitive performance at high altitude.

The investigators will study the efficacy of the dietary supplement, quercetin, the drugs nifedipine (extended release) and methazolamide taken together, the drug metformin, and the drug nitrite in reducing symptoms of AMS and improving cognitive and exercise performance at high altitudes.

Condition or Disease	Intervention/Treatment	Phase
Mountain Sickness	Dietary Supplement: Quercetin; Drug: Nifedipine extended release; Drug: Methazolamide; Drug: Metformin; Drug: Placebo; Drug: Nitrite	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 148 participants
• Allocation: Non-Randomized
• Intervention Model: Factorial Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Three New Ideas to Protect Special Forces From the Stress of High Altitude
• Actual Study Start Date: Aug 1, 2015
• Actual Primary Completion Date: Sep 1, 2016
• Actual Study Completion Date: Sep 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Quercetin Quercetin: 500mg pill, twice daily for 5 days	Dietary Supplement: Quercetin
Experimental: Nifedipine+Methazolamide Nifedipine extended release: 30mg pill, twice daily for 5 days; Methazolamide: 125mg pill, twice daily for 5 days	Drug: Nifedipine extended release; Drug: Methazolamide
Experimental: Metformin Metformin: 500mg pill, once daily for 2 days, then 500mg twice daily at altitude (3 days)	Drug: Metformin
Placebo Comparator: Placebo Sugar pill manufactured to look like all other investigational products	Drug: Placebo
Experimental: Nitrite Nitrite: 20mg pill, three times daily for 5 days	Drug: Nitrite

Outcome Measures

Primary Outcome Measures

1. Change in Environmental Symptoms Questionnaire at High Altitude [Baseline and during high altitude exposure (3 days, AM/PM)]

   Self-reported assessment of AMS symptoms (headache, lightheaded, dizzy, etc.). The 11-item Environmental Symptoms Questionnaire measures Acute Mountain Sickness symptoms (nausea, weakness, lightheadedness, dizziness, headache, etc.). Possible scores range from 0 to 55 (0-5 per item), with higher scores indicating a better outcome.

2. Change in Lake Louise AMS Scoring System at High Altitude [Baseline and during high altitude exposure (3 days, AM/PM)]

   Self-reported assessment of AMS symptoms (headache, nausea, vomiting, dizziness, fatigue and difficultly sleeping). The Lake Louise AMS Scoring System measures symptoms of altitude sickness. Possible scores range from 0 to 16, with higher scores indicating a worse outcome.

3. Change in Army Physical Fitness Test (APFT) at High Altitude [Baseline, 1st day at high altitude]

   Timed 2 mile run, push-ups, sit-ups, and pull-ups. The Army Physical Fitness Test (APFT) measures physical fitness. Higher scores indicate a better outcome. A score of 60 is considered minimum "passing" score. The maximum possible score is 300, indicating the highest level of physical fitness.

4. Change in Uphill Hike at High Altitude [2nd day at altitude]

   Timed 3.1 mile uphill run/hike, with weighted back-pack

5. Change in Defense Automated Neurobehavioral Assessment (DANA) Reaction Time at High Altitude [Baseline and and 1st day at high altitude]

   Battery of nine cognitive function tests. The Defense Automated Neurobehavioral Assessment (DANA) measures cognitive function and was used to measure mean reaction time. Possible scores range from 180 to 500 milliseconds, with lower scores indicating a better outcome.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 30 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• healthy,

• young (18-30 years old) men who can meet APFT requirements for special operation forces (SOF) training as outlined by the US Army (42 push ups, 53 sit-ups, 6 pull-ups, 2 mile run in < 15 min 54 s)

Exclusion Criteria:

• women;

• smokers;

• participants with diseases or disorders known to be affected by hypoxia or the drugs used in this study, such as hypotension, anemia, sickle cell trait or disease, and diabetes;

• participants with a history of significant head injury, migraines or seizures;

• participants taking any medication (over-the-counter or prescription) or herbal supplements;

• participants with known flavonoid allergies;

• participants with known allergies to metformin;

• participants with known hypersensitivity reaction to nifedipine;

• participants with known allergies to sulfonamide-based drugs;

• participants with inability to be headache-free when consuming the amount of caffeine in two six ounce cups of coffee or less per day;

• exposure to high altitude above 1000m in the previous three months; or

• participants who have been on an airline flight over six hours (the lowered cabin pressure for an extended period of time approximates exposure to high altitude);

• participants who are unable to achieve the minimum physical criteria required for SOF training

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alma College	Alma	Michigan	United States	48801

Sponsors and Collaborators

• University of Colorado, Denver
• Alma College

Investigators

• Principal Investigator: Robert Roach, PhD, University of Colorado Anschutz Medical Campus, Altitude Research Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT02463357
• Other Study ID Numbers: 15-0254
• First Posted: Jun 4, 2015
• Last Update Posted: Mar 30, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by University of Colorado, Denver: Exercise, Aerobic; Cognitive Function
• Additional relevant MeSH terms: Altitude Sickness; Metformin; Nifedipine; Methazolamide; Quercetin

Study Results

Participant Flow

Pre-assignment Detail	49 participants were excluded after consent/enrollment but prior to starting the study because some subjects did not meet baseline criteria, and others had to be excluded due to resource limitations.

Arm/Group Title	Quercetin	Nifedipine+Methazolamide	Metformin	Placebo	Nitrite
Arm/Group Description	Quercetin: 500mg pill, twice daily for 5 days Quercetin	Nifedipine extended release: 30mg pill, twice daily for 5 days; Methazolamide: 125mg pill, twice daily for 5 days Nifedipine extended release Methazolamide	Metformin: 500mg pill, once daily for 2 days, then 500mg twice daily at altitude (3 days) Metformin	Sugar pill manufactured to look like all other investigational products Placebo	Nitrite: 20mg pill, three times daily for 5 days Nitrite
Period Title: Overall Study
STARTED	20	20	20	19	20
COMPLETED	19	20	20	19	19
NOT COMPLETED	1	0	0	0	1

Baseline Characteristics

Arm/Group Title	Quercetin	Nifedipine+Methazolamide	Metformin	Placebo	Nitrite	Total
Arm/Group Description	Quercetin: 500mg pill, twice daily for 5 days Quercetin	Nifedipine extended release: 30mg pill, twice daily for 5 days; Methazolamide: 125mg pill, twice daily for 5 days Nifedipine extended release Methazolamide	Metformin: 500mg pill, once daily for 2 days, then 500mg twice daily at altitude (3 days) Metformin	Sugar pill manufactured to look like all other investigational products Placebo	Nitrite: 20mg pill, three times daily for 5 days Nitrite	Total of all reporting groups
Overall Participants	20	20	20	19	20	99
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	20 100%	20 100%	20 100%	19 100%	20 100%	99 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	22.6 (3.0)	21.9 (2.6)	21.7 (2.0)	21.3 (1.4)	22.0 (2.1)	21.9 (2.27)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Male	20 100%	20 100%	20 100%	19 100%	20 100%	99 100%
Region of Enrollment (participants) [Number]
United States	20 100%	20 100%	20 100%	19 100%	20 100%	99 100%

Outcome Measures

1. Primary Outcome

Title	Change in Environmental Symptoms Questionnaire at High Altitude
Description	Self-reported assessment of AMS symptoms (headache, lightheaded, dizzy, etc.). The 11-item Environmental Symptoms Questionnaire measures Acute Mountain Sickness symptoms (nausea, weakness, lightheadedness, dizziness, headache, etc.). Possible scores range from 0 to 55 (0-5 per item), with higher scores indicating a better outcome.
Time Frame	Baseline and during high altitude exposure (3 days, AM/PM)

Outcome Measure Data

Analysis Population Description

Two participants who withdrew from the study were not analyzed.

Arm/Group Title	Quercetin	Nifedipine+Methazolamide	Metformin	Placebo	Nitrite
Arm/Group Description	Quercetin: 500mg pill, twice daily for 5 days Quercetin	Nifedipine extended release: 30mg pill, twice daily for 5 days; Methazolamide: 125mg pill, twice daily for 5 days Nifedipine extended release Methazolamide	Metformin: 500mg pill, once daily for 2 days, then 500mg twice daily at altitude (3 days) Metformin	Sugar pill manufactured to look like all other investigational products Placebo	Nitrite: 20mg pill, three times daily for 5 days Nitrite
Measure Participants	19	19	20	19	20
Baseline	0.132 (0.179)	0.122 (0.214)	0.080 (0.132)	0.069 (0.109)	0.121 (0.240)
Change at 3 days	-0.088 (0.214)	-0.073 (0.224)	0.128 (0.425)	0.035 (0.184)	0.044 (0.380)

2. Primary Outcome

Title	Change in Lake Louise AMS Scoring System at High Altitude
Description	Self-reported assessment of AMS symptoms (headache, nausea, vomiting, dizziness, fatigue and difficultly sleeping). The Lake Louise AMS Scoring System measures symptoms of altitude sickness. Possible scores range from 0 to 16, with higher scores indicating a worse outcome.
Time Frame	Baseline and during high altitude exposure (3 days, AM/PM)

Outcome Measure Data

Analysis Population Description

Two participants who withdrew from the study were not analyzed.

Arm/Group Title	Quercetin	Nifedipine+Methazolamide	Metformin	Placebo	Nitrite
Arm/Group Description	Quercetin: 500mg pill, twice daily for 5 days Quercetin	Nifedipine extended release: 30mg pill, twice daily for 5 days; Methazolamide: 125mg pill, twice daily for 5 days Nifedipine extended release Methazolamide	Metformin: 500mg pill, once daily for 2 days, then 500mg twice daily at altitude (3 days) Metformin	Sugar pill manufactured to look like all other investigational products Placebo	Nitrite: 20mg pill, three times daily for 5 days Nitrite
Measure Participants	19	19	20	19	20
Baseline	0.00 (0.00)	0.150 (0.489)	0.150 (0.671)	0.00 (0.00)	0.250 (1.118)
Change at Day 3	0.053 (0.229)	0.150 (0.875)	0.750 (2.124)	0.632 (1.012)	0.474 (1.896)

3. Primary Outcome

Title	Change in Army Physical Fitness Test (APFT) at High Altitude
Description	Timed 2 mile run, push-ups, sit-ups, and pull-ups. The Army Physical Fitness Test (APFT) measures physical fitness. Higher scores indicate a better outcome. A score of 60 is considered minimum "passing" score. The maximum possible score is 300, indicating the highest level of physical fitness.
Time Frame	Baseline, 1st day at high altitude

Outcome Measure Data

Analysis Population Description

Two participants who withdrew from the study were not analyzed.

Arm/Group Title	Quercetin	Nifedipine+Methazolamide	Metformin	Placebo	Nitrite
Arm/Group Description	Quercetin: 500mg pill, twice daily for 5 days Quercetin	Nifedipine extended release: 30mg pill, twice daily for 5 days; Methazolamide: 125mg pill, twice daily for 5 days Nifedipine extended release Methazolamide	Metformin: 500mg pill, once daily for 2 days, then 500mg twice daily at altitude (3 days) Metformin	Sugar pill manufactured to look like all other investigational products Placebo	Nitrite: 20mg pill, three times daily for 5 days Nitrite
Measure Participants	19	19	20	19	20
Baseline	247.2 (25.1)	251.0 (29.4)	254.1 (26.9)	251.5 (23.9)	252.1 (24.9)
Change at Day 1	-27.5 (23.1)	-59.2 (22.7)	-32.9 (20.5)	-23.0 (27.0)	-26.1 (20.3)

4. Primary Outcome

Title	Change in Uphill Hike at High Altitude
Description	Timed 3.1 mile uphill run/hike, with weighted back-pack
Time Frame	2nd day at altitude

Outcome Measure Data

Analysis Population Description

Two participants who withdrew from the study were not analyzed.

Arm/Group Title	Quercetin	Nifedipine+Methazolamide	Metformin	Placebo	Nitrite
Arm/Group Description	Quercetin: 500mg pill, twice daily for 5 days Quercetin	Nifedipine extended release: 30mg pill, twice daily for 5 days; Methazolamide: 125mg pill, twice daily for 5 days Nifedipine extended release Methazolamide	Metformin: 500mg pill, once daily for 2 days, then 500mg twice daily at altitude (3 days) Metformin	Sugar pill manufactured to look like all other investigational products Placebo	Nitrite: 20mg pill, three times daily for 5 days Nitrite
Measure Participants	19	19	20	19	20
Mean (Standard Deviation) [seconds]	4685 (364.4)	4993 (595.4)	5005 (975.9)	4819 (685.1)	4953 (670.5)

5. Primary Outcome

Title	Change in Defense Automated Neurobehavioral Assessment (DANA) Reaction Time at High Altitude
Description	Battery of nine cognitive function tests. The Defense Automated Neurobehavioral Assessment (DANA) measures cognitive function and was used to measure mean reaction time. Possible scores range from 180 to 500 milliseconds, with lower scores indicating a better outcome.
Time Frame	Baseline and and 1st day at high altitude

Outcome Measure Data

Analysis Population Description

Seven participants were not analyzed due to lack of data collection at baseline.

Arm/Group Title	Quercetin	Nifedipine+Methazolamide	Metformin	Placebo	Nitrite
Arm/Group Description	Quercetin: 500mg pill, twice daily for 5 days Quercetin	Nifedipine extended release: 30mg pill, twice daily for 5 days; Methazolamide: 125mg pill, twice daily for 5 days Nifedipine extended release Methazolamide	Metformin: 500mg pill, once daily for 2 days, then 500mg twice daily at altitude (3 days) Metformin	Sugar pill manufactured to look like all other investigational products Placebo	Nitrite: 20mg pill, three times daily for 5 days Nitrite
Measure Participants	17	19	19	17	18
Baseline	308.0 (34.7)	302.2 (49.5)	312.3 (46.1)	333.9 (41.5)	310.7 (29.32)
Change from baseline at day 1	-0.5 (27.8)	14.2 (26.6)	-8.3 (37.9)	0.5 (30.6)	-4.6 (30.8)

Adverse Events

Arm/Group Title	Quercetin		Nifedipine+Methazolamide		Metformin		Placebo		Nitrite
Arm/Group Description	Quercetin: 500mg pill, twice daily for 5 days Quercetin		Nifedipine extended release: 30mg pill, twice daily for 5 days; Methazolamide: 125mg pill, twice daily for 5 days Nifedipine extended release Methazolamide		Metformin: 500mg pill, once daily for 2 days, then 500mg twice daily at altitude (3 days) Metformin		Sugar pill manufactured to look like all other investigational products Placebo		Nitrite: 20mg pill, three times daily for 5 days Nitrite
All Cause Mortality
	Quercetin		Nifedipine+Methazolamide		Metformin		Placebo		Nitrite
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)		0/20 (0%)		0/19 (0%)		0/20 (0%)
Serious Adverse Events
	Quercetin		Nifedipine+Methazolamide		Metformin		Placebo		Nitrite
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)		0/20 (0%)		0/19 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Quercetin		Nifedipine+Methazolamide		Metformin		Placebo		Nitrite
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/20 (5%)		0/20 (0%)		2/20 (10%)		1/19 (5.3%)		1/20 (5%)
Gastrointestinal disorders
Vomiting	1/20 (5%)	1	1/20 (5%)	1	0/20 (0%)	0	1/19 (5.3%)	1	1/20 (5%)	1
General disorders
Dehydration	0/20 (0%)	0	0/20 (0%)	0	1/20 (5%)	1	1/19 (5.3%)	1	0/20 (0%)	0
Infections and infestations
URI/ILI (Flu-like illness)	1/20 (5%)	20	1/20 (5%)	20	0/20 (0%)	0	0/19 (0%)	0	0/20 (0%)	0
Psychiatric disorders
Anxiety attack	0/20 (0%)	0	0/20 (0%)	0	1/20 (5%)	1	0/19 (0%)	0	0/20 (0%)	0

Limitations/Caveats

[Not Specified]

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.