Examples

A Randomized Controlled Trial Comparing Ginkgo Biloba versus Acetazolamide, Acetazolamide plus Ginkgo, and Placebo for the Prevention of Acute Mountain Sickness.

 

Student

Sean McGarry 
HMC Box #679                                                              
smm493@psu.edu
x8470

Primary Sponsor

Dr. Andrew S Freiburg
717-531-6012
717-531-4789 fax
afreiberg@psu.edu

Project Researchers

  • Luanne Freer, M.D., FACEP (principal investigator)
  • Erick Hung, B.A. (project coordinator)
  • Budda Basnyat, M.D.
  • Peter Hackett, M.D., FACEP

 

Introduction

With the rising popularity in adventure travel and tourism to high altitude alpine regions, there has been an increased interest in the treatment and prevention of acute mountain sickness (AMS). Defined by the Lake Louise Consensus Group, AMS consists of the presence of headache in an unacclimatized person who has recently arrived at an altitude above 2500 m plus the presence of one or more of the following: gastrointestinal symptoms, insomnia, dizziness, lassitude, or fatigue [1]. Acute mountain sickness is not only a nuisance; it is partly responsible for the increased morbidity and mortality at high altitude.

Background

Many studies have repeatedly shown acetazolamide to be an effective prophylactic agent against AMS [2,3], but its use may be limited in some individuals. First, it is only available by prescription in the United States, which may hinder access to the drug. Second, lack of tolerance to adverse side effects such as paresthesias, nausea, and increased diuresis make the drug a less than optimal choice. Other drugs, particularly dexamethasone, have also been proven to be an effective prophylactic agent [3,4], but like acetazolamide, dexamethasone too has the same limiting factors of availability and side effects. Therefore, a search for a safe, easily obtainable, and effective prophylactic alternative continues.

Ginkgo biloba is a dioecious tree with a history of use in traditional Chinese medicine. In recent years, extract of the leaves have been used as a dietary supplement in the United States. In addition to its recent use as a therapeutic agent in a variety of disorders including Alzheimer’s disease, cerebrovascular dysfunction, and peripheral vascular disorders [5], evidence suggests that ginkgo may prevent illness due to high altitude hypoxemia [6]. Benefits such as its availability over-the-counter and a side-effect profile similar to placebo, suggesting that ginkgo biloba may be used safely [7], warrants further investigation into its direct comparison to acetazolamide as an alternative for the prevention of AMS. In addition, effective prevention dosages are still unresolved for both gingko biloba and acetazolamide [3,4,6], and further study is needed to determine the effective prophylactic dosing for both medications.

Research Question

Is prophylactic ginkgo biloba more efficacious in the prevention of acute mountain sickness (AMS) than acetazolamide, acetazolamide plus ginkgo, and placebo during gradual ascent?

Setting

Lukla, Nepal (2850 m) will serve as the base of ascent which will culminate at Gorak Shep (5160 m) on the Everest trekking route.

Method and Design

During late Spring and early Summer 2004, tourists visiting Lukla, Nepal will be asked if they plan to trek to Gorak Shep on the way to Everest Base Camp. If no, they will not be asked to participate in the study. For those answering in the affirmative, researchers will ask them if they would like to participate in a prevention study for AMS and take one of four possible medications on their trek up to Gorak Shep. Participants agreeing to participate in the study will be given a written consent form (Fig. 3) which they will be required to sign in order to participate in the study. Research assistants will provide verbal instructions to each study participant on the benefits and risks of participating in the research study. A questionnaire (Fig. 1) will be presented to all study participants that have given consent. The Lake Louise Self-Report Questionnaire (LLSR) (Fig. 2) a studied and validated scoring system to diagnose AMS [1], will be presented to all participants who will be asked to complete the LLSR prior to enrollment into the study. Researchers will also assess the LLCA and LLF for each potential study participant.

Inclusion criteria for the study will include:

  1. No signs of or symptoms of AMS,
  2. Age 18 years or older,
  3. An itinerary to travel to Gorak Shep in 10-days or less, and
  4. A functional ability to read and speak the English language.

 

Exclusion criteria for the study will include:

  1. Signs or symptoms of AMS (LLSR>/= 3 plus a headache),
  2. Known allergy to gingko biloba or acetazolamide,
  3. Pregnancy or likely possibility of pregnancy,
  4. Allergy to sulfa-based drugs,
  5. Recent use (less than 7 days) of acetazolamide, gingko biloba, or dexamethasone, and
  6. Currently taking coumadin. Following consent and enrollment, study participants will be randomized into one of four treatment arms.

 

Randomization will include blindly selecting pre-coded packages containing one of the four study drugs for the enrollee and giving the drug to the enrollee to take prophylactically while trekking up to Gorak Shep. The University of Pennsylvania Investigational Drug Service will provide the study medications. Oxygen saturation readings will also be measured at the time of enrollment and recorded on the questionnaire.

Once a participant has been enrolled in the study, they will be given a ten-day supply of ginkgo (120 mg bid), acetazolamide (125 mg bid), ginkgo plus acetazolamide (combined as one pill bid), or placebo (bid) to be started in Lukla. All enrollees will be asked to check in at identifiable checkpoints at Namche Bazaar (3440 m), Pheriche (4240 m) or Dingboche (4360 m), and Gorak Shep (5160 m). At the check-in, enrollees will be asked to fill out another LLSR as well as the Time of Ascent Questionnaire (TOA) (Fig. 4). In addition, researchers will complete the LLCA, LLF, and oxygen saturation scores on each study enrollee. At enrollment or each check-in, any subject with significant AMS (pre-defined criteria below) will be advised to descend or to remain at the current altitude until the resolution of symptoms. If there is no resolution in symptoms after 24-48 hours, researchers will advise study enrollees to descend to a lower altitude, not to re-ascend for at least 48 hours after the onset of symptoms, and if needed to seek definitive medical care in either the Khunde (Namche Bazaar), Pheriche, or Everest Base Camp medical clinics. Any study enrollee with medical questions pertaining to the study will be instructed to contact the research station or seek medical advice in Khunde, Pheriche, or Everest Base Camp.

Significant AMS

  1. LLSR + LLCA >/= 6;
  2. A score of 3 on any individual item of the LLSR;
  3. A score on question 1 or 2 of LLCA >/= 2;
  4. LLF of 3;
  5. Resting oxygen saturation </= 70%

 

Study enrollees will each possess a study completion card given to them at their enrollment in Lukla. Researchers will ask enrollees to complete the information card at the end of the study. Enrollees will drop off their information cards at Gorak Shep or at any one of the research stations on their way down the mountain. They will be asked to check whether they successfully completed the study or withdrew from the study. For those withdrawing from the study, they will indicate whether they were

  1. Medication noncompliant,
  2. Developed AMS,
  3. Developed another medical illness preventing completion of the study,
  4. Changed their itinerary to Gorak Shep (i.e did not arrive in Gorak Shep in 10-days or less from the time of enrollment), or
  5. Had significant side effects from the study medications requiring discontinuation of the medication.

 

Data Analysis

For analysis of the results, the primary endpoint will be the development of AMS. Differences in the incidence of AMS between patients randomized to ginkgo, acetazolamide, ginkgo plus acetazolamide, and placebo will be analyzed using the Fisher’s exact test. A p-value of less than 0.05 will be considered to indicate statistical significance. In order for our study to have a power of 80% and show statistical significance, a sample size of 36 is needed in each arm. This calculation is taken from an incidence of AMS above 4000m (where the study will take place) with placebo of 67% [8]. In order to allow for patient drop out, noncompliance, and other factors that may cause them to withdraw from the study after enrollment, we plan on enrolling 288 trekkers (72 trekkers per arm) in Lukla for the study.

Time Frame

  • Enrollment: April 2004
  • Data Collection: April 2004
  • Data Analysis: May 2004 – August 2004

 

Research Assistants

We have recruited twenty medical students and nurses from the United States, the U.K., and Australia to enroll patients in Lukla and to conduct the research for the study in Namche, Pheriche, and Gorak Shep (see Researcher Information Packet).  Researchers in Lukla will be will be responsible for enrolling study participants.  Enrollment will consist of enlisting people into the study, explaining what the study is about, obtaining basic study participant demographics, handing out the double-blinded, randomized medications to the study participants, instructing the study participants on how to adhere to the medications, and answering any questions that the study participants may have.  Research assistants in Namche, Pheriche, Dingboche, and Gorak Shep will be responsible for surveying the study participants as they trek up to Everest Base Camp in an effort to determine whether or not they have developed or have any signs or symptoms of acute mountain sickness (AMS).  They will use the Lake Louise Questionnaire to determine whether or not the study participants have AMS.  In addition, they will be complete the Time-of-Ascent (TOA) form for each study participant so that we can control for each participant’s rate of ascent.  For those patients with signs or symptoms of AMS, researchers will answer their questions, guide them on how to manage their symptoms, and if needed direct them to the nearest clinic if their symptoms continue to progress.

Facilities

Identifiable checkpoints at Lukla (2850 m), Namche (3450 m), Pheriche (4240 m), Dingboche, and Gorak Shep (5160 m).

References

  1. Roach RC, Bartsch P, Oelz O, Hackett PH, Lake Louise AMS Scoring Consensus Committee. The Lake Louise acute mountain sickness scoring system. In: Sutton JR, Houston CS, Coates G, Eds. Hypoxia and molecular medicine. Burlington, Vermont. Charles S Houston, 1993:272-4.
  2. Ellsworth AJ, Larson EB, Strickland D. A randomized trial of dexamethasone and acetazolamide for acute mountain sickness prophylaxis. American Journal of Medicine. 1987;83:124-30.
  3. Ellsworth AJ, Meyer EF, Larson EB. Acetazolamide or dexamethasone use versus placebo to prevent acute mountain sickness on Mount Rainier. West L Med. 1991;154:289-93.
  4. Hackett PH, Roach RC, Wood RA, et al. Dexamethasone for prevention and treatment of acute mountain sickness. Aviation Space and Environmental Medicine. 1988;59:950-4.
  5. Chang JY, Chang MN. Medicinal uses of Ginkgo biloba. Today’s Therapeutic Trends. 1997;15:63-74.
  6. Leadbetter G, Maakestad K, Olson S. Ginkgo biloba reduces the incidence and severity of acute mountain sickness. High Altitude Medicine and Biology. 2001;2:110.
  7. LeBars PL, Katz MN, Berman N. A placebo-controlled, double blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGB Study Group. JAMA. 1997;278:1327-1332.
  8. Dumont L, Chahe M.  Efficacy and harm of pharmacological prevention of acute mountain sickness: quantitative systematic review. British Medical Journal. 2000;329:29.

 

Significance

The significance of this project to the field of wilderness and environmental medicine is threefold.  First, this project will be able to compare ginkgo biloba versus acetazolamide, acetazolamide plus ginkgo biloba, and placebo for the prevention of acute mountain sickness in a double-blinded randomized control trial that takes place in a highly-traveled wilderness setting to which the data will be directly applicable.  The results from this study can easily be translated to travelers in high altitude wilderness regions since it is in this very setting in which the research will take place.  Second, this data will continue to promote knowledge for better AMS prophylactic medications in the field of high altitude medicine and to get a better understanding of prevention dosing for each of the study medications.  Third, this research will provide much needed scientific support for herbal medications such as ginkgo biloba in the field of medicine.

Funding and IRB Approval

In Summer 2003, the study received a Wilderness Medical Society Houston Award.  The Houston Award will fully cover the funding needed to purchase the study medications and the randomization costs for the study.

Total costs for the project (as reported by the University of Pennsylvania Investigational Drug Service) are estimated at $3,402 which include:

 

  • Startup costs: $600
  • Manufacturing: $1,188
  • Purchases: $362
  • Packaging/Randomization: $1,152
  • Study Closure: $100
  • Total: $3,402
  • IRB Approval has been approved by the Nepal Health Research Council (NHRC).