Calcitonin Gene-related Peptide Antibody in Acute Mountain Sickness

Overview

Acute mountain sickness (AMS) is a common condition that can occur when healthy people travel quickly to high altitude. Typical symptoms include headache, nausea, tiredness, dizziness, and poor sleep. In most cases, AMS improves with rest and by not climbing higher, but it can make mountaineering difficult and, in severe cases, can lead to dangerous complications. The biological mechanisms that cause high-altitude headache and AMS are not yet fully understood. Some symptoms of AMS are similar to migraine, suggesting that both conditions may share common pathways in the nervous system. One possible pathway involves calcitonin gene-related peptide (CGRP), a substance known to play an important role in migraine. Fremanezumab is an approved monoclonal antibody used to prevent migraine. It works by binding to CGRP and reducing its biological activity. This study will investigate whether a single dose of fremanezumab can also help prevent symptoms of AMS and high-altitude headache in healthy adults exposed to high altitude. To date, there are no clinical data on the effect of fremanezumab in AMS or high-altitude headache. This is a prospective, randomized, double-blind, placebo-controlled, parallel-group clinical trial. A total of 30 healthy adult volunteers will participate. Participants will be randomly assigned in a 1:1 ratio to receive either a single subcutaneous injection of fremanezumab 225 mg or placebo (saline). Neither the participants nor the investigators will know which treatment was given during the study. The study medication will be administered 1 week before ascent to Capanna Regina Margherita at 4554 meters above sea level. Participants will remain there for 46 hours under hypobaric hypoxic conditions. The main goal is to determine whether fremanezumab reduces the severity of AMS compared with placebo. AMS symptoms will be measured using the Lake Louise Score, a standard questionnaire commonly used in altitude medicine. Additional assessments will include the incidence of AMS, headache characteristics, safety outcomes, vital signs, oxygen saturation, and the use of rescue medication. Symptoms will be assessed repeatedly during the high-altitude stay. Only healthy adults aged 18 to 60 years living below 1000 meters will be eligible. People with important medical conditions, chronic headache or migraine, relevant cardiovascular or lung disease, pregnancy, or recent high-altitude exposure will be excluded. Participants will be closely monitored during the study. Rescue medication, oxygen, and descent to lower altitude will be available if needed. This study may help improve understanding of how AMS develops and whether CGRP blockade could become a new preventive strategy for high-altitude headache and AMS. It may also improve understanding of links between altitude-related headache and migraine.

cute mountain sickness (AMS) is a common condition that occurs in otherwise healthy individuals after rapid ascent to high altitude. Typical symptoms include headache, nausea, vomiting, fatigue, dizziness, and loss of appetite. In most cases, AMS is self-limiting if further ascent is avoided and sufficient rest is ensured. However, AMS can substantially impair well-being and performance at altitude, may lead to interruption of a mountain tour, and in more severe cases may require rescue or evacuation. Rarely, AMS may progress to life-threatening high-altitude cerebral edema. High-altitude headache (HAH) is one of the core symptoms of AMS and is particularly frequent at high altitude. The biological mechanisms underlying HAH and AMS are not yet fully understood. Clinical features of HAH and AMS, especially headache accompanied by nausea and vomiting, suggest overlap with migraine pathophysiology. One possible mechanistic link is the trigeminovascular system and the neuropeptide calcitonin gene-related peptide (CGRP), which is known to play a major role in migraine. Fremanezumab is a monoclonal antibody approved for migraine prevention. It binds to CGRP and prevents its biological activity. Because CGRP may also be involved in vascular and neurogenic responses to hypoxia, CGRP blockade could potentially influence the development of high-altitude symptoms. At present, there are no clinical data on the effect of fremanezumab in HAH or AMS. The aim of this study is to investigate whether a single dose of fremanezumab can reduce the severity and incidence of AMS in healthy adults exposed to high altitude under controlled field conditions. In addition, the study will assess whether CGRP blockade influences headache characteristics and safety outcomes during prolonged exposure to hypobaric hypoxia. The study may also contribute to a better understanding of shared mechanisms between altitude-related headache and migraine. This is a prospective, randomized, double-blind, placebo-controlled, parallel-group, exploratory clinical trial in healthy adult volunteers. A total of 30 participants will be enrolled and randomized in a 1:1 ratio to receive either fremanezumab 225 mg or placebo (0.9% saline solution) as a single subcutaneous injection. The study medication will be administered 1 week before ascent to high altitude. Participants, investigators, care providers, outcome assessors, and data analysts will remain blinded to treatment allocation until database lock, except in case of medical emergency requiring unblinding. Participants will undergo screening before enrolment, including informed consent, medical assessment, and confirmation of eligibility. Eligible participants are healthy adults aged 18 to 60 years, living below 1000 meters above sea level, and able to comply with study procedures. Key exclusion criteria include chronic headache or migraine, cardiovascular disease other than controlled hypertension, acute or chronic pulmonary disease, diabetes mellitus, marked hypertension, pregnancy or breastfeeding, recent high-altitude exposure, and other relevant medical conditions that could interfere with safety or interpretation of the study data. Both sexes will be included, with the aim of balanced representation. After receiving study medication, participants will ascend to Capanna Regina Margherita at 4554 meters above sea level and remain there for 46 hours under hypobaric hypoxic conditions. During this period, symptoms of AMS and headache will be assessed repeatedly. The main efficacy objective is to determine whether fremanezumab reduces AMS severity compared with placebo after 46 hours of exposure to hypobaric hypoxia at 4554 m. AMS symptoms will be assessed using the Lake Louise Score (LLS), a validated standard instrument widely used in altitude medicine. According to the protocol, symptom assessments will be performed at 7, 22, 31, and 46 hours after arrival at high altitude. The Acute Mountain Sickness-Cerebral Score (AMS-C) and the Kiel Headache Questionnaire (KHQ) will also be used to further characterize symptom burden and headache features. The secondary objectives are to evaluate whether fremanezumab reduces the incidence of AMS after 46 hours of high-altitude exposure and to assess its effects on the temporal course of AMS symptoms, headache characteristics, and safety and tolerability under hypobaric hypoxic conditions. Safety outcomes include adverse events, serious adverse events, rescue medication use, and changes in vital signs such as blood pressure, heart rate, and oxygen saturation. Because fremanezumab has not previously been studied in this setting, careful safety monitoring is a central component of the trial. Participants will be continuously observed for symptoms of altitude illness. Vital signs and neurological status will be assessed regularly. Rescue medication, including acetazolamide, dexamethasone, paracetamol, metoclopramide, and supplemental oxygen, will be available if clinically indicated. Participants may discontinue the study and descend at any time. Emergency unblinding is allowed only when knowledge of treatment allocation is necessary for participant safety. The use of placebo is considered appropriate in this exploratory proof-of-concept setting because there is currently no established role for CGRP inhibition in AMS or HAH, and a placebo-controlled design allows a clear assessment of treatment effect while minimizing bias. Participants are healthy volunteers, are fully informed before enrolment, and are closely monitored throughout the study. The randomized double-blind parallel-group design was chosen because it provides a robust framework for evaluating causal treatment effects in a setting where crossover would be impractical. The study is exploratory in nature. A total sample size of 30 participants was chosen, with 15 participants per group. According to the protocol, a formal sample size calculation was performed for the primary endpoint using assumptions derived from previous altitude studies, with the aim of detecting a clinically relevant reduction in AMS severity. Statistical analyses will include descriptive methods as well as appropriate parametric or non-parametric comparisons between groups, depending on data distribution. This study is expected to provide first clinical evidence on whether CGRP blockade with fremanezumab may be useful as a preventive strategy for AMS and high-altitude headache. Beyond possible clinical implications for altitude medicine, the findings may also improve understanding of the relationship between hypoxia-related headache and migraine biology.