Effect of Acetazolamide on Acute Mountain Sickness in Lowlanders Older Than 40 Years

Study Overview
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Brief Summary
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Randomized, placebo controlled trial evaluating efficacy of acetazolamide in preventing acute mountain sickness in lowlanders older than 40 years travelling from 760 m to 3'100 m.

Detailed Description
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This is a randomized, placebo-controlled, double-blind parallel trial evaluating the efficacy of acetazolamide prophylaxis in reducing the incidence of acute mountain sickness (AMS) in lowlanders older than 40 years travelling to altitude. Participants living in the Bishkek area, Kyrgyzstan (760m), will be transferred by car within 4h to the Tuja Ashu high altitude clinic (3'100 m), and stay there for 2 days. Acetazolamide 375mg/day (or placebo), will be administered before departure at 760 m and during the stay at altitude. Outcomes will be assessed during the stay at 3'100 m. An interim analysis will be carried out when 80 participants will have completed the study or after the first year. The Peto's method will be used and the trial will be stopped when pre-specified futility boundaries were crossed.

Official Title
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Acetazolamide for Prevention of Acute Mountain Sickness in Healthy Lowlanders Older Than 40 Years. Randomized Trial.

Conditions
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Acute Mountain Sickness

Intervention / Treatment
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* Drug: ACETAZOLAMIDE oral capsule
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy men and women, age 40-75 yrs, without any disease and need of medication. Born, raised and currently living at low altitude (<800m). Written informed consent. Kyrgyz ethnicity Exclusion Criteria: Any active respiratory, cardiovascular or other disease requiring regular treatment or being otherwise relevant for tolerance of hypoxia or altitude exposure. Any condition that may interfere with protocol compliance including current heavy smoking (>20 cigarettes per day or >20 pack-years with active smoking during the last 10 years), regular use of alcohol. Allergy to acetazolamide and other sulfonamides.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ACETAZOLAMIDE oral capsule<br>Acetazolamide 375mg/day (capsule @125 mg: 1 in the morning, 2 in the evening), orally. Medication starts 24 hours before ascent to 3'100m until the morning after the second night at 3'100m | Drug: ACETAZOLAMIDE oral capsule<br>* Administration of 1x125mg acetazolamide in the morning, 2x125mg in the evening, starting 24 hours before departure to 3'100m<br>|
| Placebo Comparator: PLACEBO oral capsule<br>Placebo (capsules identically looking as acetazolamide capsules: 1 in the morning, 2 in the evening), orally. Medication starts 24 hours before ascent to 3'100m until the morning after the second night at 3'100m. | Drug: Placebo oral capsule<br>* Administration of equally looking placebo capsules in the morning and evening, starting 24 hours before departure to 3'100m<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute mountain sickness (AMS), incidence | Difference between acetazolamide and placebo group in the incidence of AMS during the stay at 3'100 m. | Day 1 to 3 at 3'100m | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute mountain sickness (AMS), severity assessed by the Lake Louise score | Difference between acetazolamide and placebo group in the severity of AMS during the stay at 3'100 m. The severity of acute mountain sickness (AMS) will be assessed by the Lake Louise questionnaire (LLS), a validated questionnaire about AMS. The severity will be calculated when the presence of headache and at least one of the following symptoms is present: gastrointestinal upset, fatigue or weakness, dizziness or lightheadedness and difficulty sleeping. Each of the five questions is asked with the corresponding 0 to 3 rating of the response (0 = Not present, 1 = mild, 2 = moderate, 3 = severe). The sum of the responses on these questions is then calculated, resulting in the AMS severity. | Day 1 to 3 at 3'100m | 
| Acute mountain sickness (AMS) at 760 m with and without acetazolamide, severity | Difference between acetazolamide and placebo group in the severity of AMS at 760 m. | Day 3 at 760 m | 
| Altitude related adverse health effects (ARAHE), incidence | Difference between acetazolamide and placebo group in the incidence of ARAHE during the stay at 3'100 m. ARAHE are defined as the following: Moderate to severe AMS (Lake Louise score ≥3 and/or Environmental Symptoms questionnaire AMSc score ≥0.7) and/or any of the following: Severe hypoxemia (SpO2 at rest <80% for >30 min or <75% for >15 min, exercise oxygen desaturation SpO2 <75% for >1 min accompanied by symptoms or signs of hypoxemia) Symptomatic cardiovascular disease (arterial blood pressure systolic >200 mmHg, diastolic >110 mmHg not responding to blood pressure lowering drugs within 1 hr; chest pain with ECG signs of ischemia or new onset arrhythmia) Withdrawal from the study by the decision of the independent physician for safety reasons or by the patient. | Day 1 to 3 at 3'100m | 
| Spirometric measurement of forced expiratory volume in one second | Difference in altitude-induced change in the forced expiratory volume in one second between the acetazolamide and placebo group | Day 2 at 760m and day 2 at 3'100m | 
| Arterial partical pressure of oxygen | Difference in altitude-induced changes in arterial partical pressure of oxygen between the acetazolamide and placebo group | Day 2 at 760m and day 2 at 3'100m | 
| Drug side effects | Difference between acetazolamide and placebo group in the incidence of medication side effects during the stay at 3'100 m. | Day 1 to 3 at 3'100m | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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altitude, healthy participants older than 40 years, prevention, acetazolamide