Altitude Sickness Prevention and Efficacy of Comparative Treatments
Condition: Acute Mountain Sickness
MeSH terms: Altitude Sickness
Study type: Interventional
Phase: Phase 3

Summary: 
      This study is designed to be the first to examine the novel drug budesonide for prevention of
      acute mountain sickness in comparison to acetazolamide and in the context of rapid ascent to
      high altitude. The investigators will accomplish these objectives with a prospective, double
      blinded view of a large population of hikers who are ascending at their own rate in a true
      hiking environment.
    

Detailed description: 
      Enrollment:

      A total of One hundred healthy male and female participants (group of 25 at a time) will be
      enrolled by study administrators at Owens Valley Lab, White Mountain Research Station.
      Pregnant women will be excluded. The study enrollment period will run for approximately 12
      days over 4 weekends in August 2016. Advertisement of the study at sea level locals in and
      around Stanford University as well as email chains with other outdoor groups will attempt to
      gather a cohort of sea-level participants.

      Study:

      Eligible participants will be randomized in a double blind fashion the morning of ascent to
      acetazolamide 125 mg PO bid and empty inhaler, budesonide (200 mcg) inhaler bid and visually
      matched placebo pill, or visually matched placebo and empty inhaler. After informed consent
      is signed, participants will complete the baseline demographics sheet, LLQ, have pulse
      oximetry readings, and perform pulmonary function testing prior to taking the study
      medications. Participants will take the study capsules and inhaler before they leave from
      OVL, in order to reveal any significant acute adverse reactions before they leave for higher
      altitude. In the highly unlikely event of an adverse reaction, the participant will be in
      close proximity to study administrators who will have first aid medicines to treat allergic
      reactions (Benadryl, Ranitidine, Prednisone, Epinephrine), and communication to BAR where the
      code can be broken for medical evaluation. In the morning healthy participants without
      adverse reactions will drive to the Barcroft Gate 11,700', continue on foot to the Barcroft
      Research Station (BAR) at 12,500'. The study subjects will be allowed to hike at their own
      pace with minimal restrictions including no travel above 13,054' (Barcroft Summit). The
      participants will spend the night at BAR where they will be evaluated within 6 hours of their
      arrival and the morning after (LLQ, pulse oximetry, pulmonary function testing, side effects
      data, and compliance). After data collection the morning after arrival, the study will be
      completed for each participant. Participants with significant illness will be removed from
      the trial and appropriate safety measures taken (Twenty-four hour access to truck evacuation
      to lower elevations at OVL - the definitive treatment for AMS). Every effort will be made to
      secure the incomplete data of those who abort the study early. The highest scoring AMS data
      will be used for primary and secondary outcome analysis.

      Procedures:

      Two data collection timelines will be coordinated, one within 6 hours of subjects arrival to
      BAR and the second the morning after a night of sleep at BAR. Five study variables will be
      assessed including LLQ, pulse oximetry, pulmonary function testing, side effects data, and
      compliance. The LLQ is a widely used standardized self-report clinical survey used for the
      quantitation of AMS. A diagnosis of AMS on the LLQ requires a score of 2 or greater with the
      mandatory presence of headache and at least one of the following symptoms: dizziness or
      lightheadedness, fatigue, GI symptoms (nausea/vomiting), or difficulty sleeping. AMS symptoms
      are evaluated by establishing a space of time (several hours to one day normally) during
      which symptoms can be quantified. In this study, symptoms will be evaluated within 6 hours
      after arrival at the endpoint altitude, and then again the next morning to capture all those
      with manifestation of disease. The highest LLQ score will be used for scoring at that
      altitude, irrespective of an AMS diagnosis. This methodology takes into account the variable
      timeline for individual expression of AMS symptomatology. Oxygen saturation has a rough
      correlation with AMS symptoms, and will be measured with the use of a pulse oximeter, which
      is validated for use at high altitude (Nonin Onyx, Nonin Medical Products, Minneapolis, MN).

      Pulmonary Function Testing: Forced vital capacity (FVC), forced expiratory volume in one
      second (FEV1), and Peak Expiratory Flow Volume (PEF). will be achieved with a portable
      spirometer. Values between baseline level and altitude will be computed. Spirometry will be
      performed according to the guidelines of the American Thoracic Society.

      Side Effects Data will be recorded that the patient may be experiencing secondary to the
      interventions of inhaled budesonide or acetazolamide or placebo.

      Compliance will be verified of whether or not the subject followed intervention guidelines
      through until data completion

      Interventions:

      Commercial pharmaceutical-grade acetazolamide will be purchased by Advantage Pharmaceuticals
      and will be packed in lactulose capsules by Advantage Pharmaceuticals at their processing
      plant in Rocklin, CA. The placebo substance will be visually identical to the acetazolamide,
      and both placebo and drug will be packed in visually identical capsules. Budesonide and
      visually identical chambers will be donated by AstraZeneca. Prior studies have established
      that medicated and empty inhalants are indistinguishable by study participants. The packaging
      of the capsules and inhalants and placebo will be randomized in a 1:1:1 strategy. The first
      dose to be taken at least 4 hours before ascent for up to 100 participants in three arms:
      placebo (34 participants), Acetazolamide 125mg (33 participants), and budesonide 200 mcg (33
      participants).

      The intervention code will be prepared by Advantage Pharmaceutical using a computer-generated
      random sequence, and then placed in sealed opaque envelopes unavailable to the study
      administrators who enroll the patients. Allocation of randomized, blinded study capsules will
      occur on site at the baseline altitude on a first-come, first-served basis before each
      participant is identified in order to minimize bias. Success of blinding will be evaluated
      with a best guess of the intervention question, as well as a statistical evaluation of
      baseline characteristics to assess for an imbalance in the random allocation of study
      capsules. A sealed unblinding envelope with the randomization codes will be held by a
      researcher at BAR as well as a non-study affiliated physician at Stanford University Hospital
      in the event of an allergic reaction or need for medical intervention.

      A word about meals and accommodations: Both Owens Valley Lab and Barcroft Station have a full
      time chef on staff all year-long who prepare meals for those staying at their respective
      stations. There are a wide range of options, as it is a full kitchen, with vegetarian, vegan,
      and normal diet options. Meals are served buffet- style with participants able to eat what
      they like, and as much as they like. Although meals vary on a daily basis, an average dinner
      meal might be approximately 2,500 calories and include pasta, meatballs, salad, garlic bread,
      soup, and steamed vegetable options. If the options for the day are not suiting, the chef can
      discuss individually with the participant other options. Standard breakfasts include cereals,
      eggs, sausage, toast, oatmeal, etc. Standard lunches are usually sack-lunch varieties and are
      often sandwich options with fruit and other snacks. Throughout the day the "snack" portion of
      the kitchen is open with fruit, sandwich supplies, assortment of bars, chips, etc.
      Participants are encouraged to bring their own snacks if they have their own snack
      preferences for hiking. The stations ask that participants assist in cleaning up after
      themselves as much as possible. No drugs or alcohol are allowed. Accommodations: All
      participants will be provided with accommodations at both sites and will only be required to
      bring their own bedding (ie. sleeping bag) and towels. A single twin bed will be provided,
      arranged alone or as a bunk with no greater than 8 people per co-ed room. If participants
      would rather camp outside, that is also permitted.

      Showers and toilets are available.
    

Intervention name(s): Budesonide; Acetazolamide; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Inhaled Budesonide vs. PO Acetazolamide vs. Placebo for prevention of Acute Mountain Sickness; Inhaled Budesonide vs. PO Acetazolamide vs. Placebo for prevention of Acute Mountain Sickness; Placebo pill and sham inhaler
Other intervention name(s): entocort, pulmicort; Diamox; sugar pill
Intervention MeSH terms: Budesonide; Acetazolamide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention