Study of Cobalt's Role in Excessive Erythrocytosis Among High Altitude Dwellers in Cerro de Pasco, Peru (CoCMS)

Randomized Controlled Trial of N-acetylcysteine and Acetazolamide in Treatment of Chronic Mountain Sickness

Chronic mountain sickness is characterized by excessive red blood cell production which causes sludging of the vascular system. This high viscosity blood causes heart failure, cognitive dysfunction, and strokes. The investigators hypothesize that cobalt which has been previously been shown to be an environmental pollutant worsens the overproduction of red blood cells. The investigators plan to conduct a 6 week trial in which acetazolamide (already shown to improve chronic mountain sickness) and N-acetylcysteine (a drug that removes cobalt from the blood) are evaluated in their potential to improve chronic mountain sickness.

Study Overview

• Status: Completed
• Conditions: Erythrocytosis; Mountain Sickness
• Intervention / Treatment: Drug: Placebo pills; Drug: Acetazolamide; Drug: N-acetylcysteine

• Study Type: Interventional
• Enrollment (Actual): 85
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Peru
  • Pasco
    • Cerro de Pasco, Pasco, Peru
      • Chronic mountain sickness clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Males over 17 years of age
• Hematocrit > 70%
• Chronic Mountain Sickness score (CMS) > 6
• Able to give informed consent and follow instructions in written Spanish

Exclusion Criteria:

• CMS > 15
• Underlying lung disease, smoking, or oxygen therapy
• Asthma (bronchospasm can be caused by N-acetylcysteine)
• Phlebotomy in last 3 months
• h/o adverse reaction to acetazolamide or N-acetylcysteine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo pills	Drug: Placebo pills; 1 (or 2 in the placebo group) empty gel capsules
Active Comparator: Acetazolamide alone	Drug: Placebo pills; 1 (or 2 in the placebo group) empty gel capsules; Drug: Acetazolamide; Acetazolamide 250 mg oral once daily; Other Names: Given in gel capsules
Active Comparator: N-acetylcysteine alone	Drug: Placebo pills; 1 (or 2 in the placebo group) empty gel capsules; Drug: N-acetylcysteine; NAC 600 mg oral once daily; Other Names: Given in gel capsules
Active Comparator: Combination of N-acetylcysteine and acetazolamide	Drug: Acetazolamide; Acetazolamide 250 mg oral once daily; Other Names: Given in gel capsules; Drug: N-acetylcysteine; NAC 600 mg oral once daily; Other Names: Given in gel capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in Hematocrit, or fraction of plasma occupied by cellular elements at week 8	Spun hematocrit measured on portable machine	Baseline and week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in arterial blood gas values at week 8	Analyzed using portable machine. The values analyzed include serum pH, partial pressure of carbon dioxide, partial pressure of oxygen, and serum bicarbonate.	Baseline and week 8
Change from baseline Erythropoietin at week 8	Serum hormone that stimulates red blood cell production	Baseline and week 8
Change from baseline in serum and urine Cobalt at day 3	Will calculate spot clearance of cobalt	Baseline and day 3
Change in baseline urine protein at 8 weeks	Ratio of urine total protein to urine creatinine	Baseline and week 8
Change in baseline Chronic mountain sickness score at 8 weeks	Chronic Mountain Sickness Score Absent Mild Moderate Severe Headache 0 +1 +2 +3 Dizziness 0 +1 +2 +3 Failing Memory 0 +1 +2 +3 Fatigue 0 +1 +2 +3 Breathlessness 0 +1 +2 +3 Sleep disturbances 0 +1 +2 +3 Tinnitus 0 +1 +2 +3 Anorexia 0 +1 +2 +3 Cyanosis of lips, face, or fingers 0 +1 +2 +3 Hyperemia or prominent capillaries conjunctivae or laryngopharynx 0 +1 +2 +3	Baseline and week 8
Changes in baseline Serum electrolytes at day 3, 14 and week 8	Electrolytes, specifically monitoring serum potassium to treat serious hypokalemia (serum potassium < 3.0 meQ/L).	Baseline and Days 3, 14, and week 8

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: Universidad Peruana Cayetano Heredia; Jackson, Brian, M.S.; Thomas H Maren Foundation
• Investigators: Principal Investigator: Richard Johnson, MD, University of Colorado Denver Health Sciences Center; Principal Investigator: Abdias Hurtado, MD, Universidad Peruana Cayetano Heredia; Study Director: Richard Fuquay, MD, University of Colorado Denver Health Sciences Center

Publications and helpful links

General Publications

• Jefferson JA, Escudero E, Hurtado ME, Pando J, Tapia R, Swenson ER, Prchal J, Schreiner GF, Schoene RB, Hurtado A, Johnson RJ. Excessive erythrocytosis, chronic mountain sickness, and serum cobalt levels. Lancet. 2002 Feb 2;359(9304):407-8. doi: 10.1016/s0140-6736(02)07594-3.
• Jefferson JA, Escudero E, Hurtado ME, Kelly JP, Swenson ER, Wener MH, Burnier M, Maillard M, Schreiner GF, Schoene RB, Hurtado A, Johnson RJ. Hyperuricemia, hypertension, and proteinuria associated with high-altitude polycythemia. Am J Kidney Dis. 2002 Jun;39(6):1135-42. doi: 10.1053/ajkd.2002.33380.
• Richalet JP, Rivera-Ch M, Maignan M, Privat C, Pham I, Macarlupu JL, Petitjean O, Leon-Velarde F. Acetazolamide for Monge's disease: efficiency and tolerance of 6-month treatment. Am J Respir Crit Care Med. 2008 Jun 15;177(12):1370-6. doi: 10.1164/rccm.200802-196OC. Epub 2008 Apr 3.

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (Actual): September 1, 2013
• Study Completion (Actual): September 1, 2013

Study Registration Dates

• First Submitted: August 18, 2010
• First Submitted That Met QC Criteria: August 20, 2010
• First Posted (Estimate): August 23, 2010

Study Record Updates

• Last Update Posted (Estimate): May 15, 2015
• Last Update Submitted That Met QC Criteria: May 13, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: Acetazolamide; N-acetylcysteine; Cobalt; Excessive Erythrocytosis; Monge's Disease; Altitude Sickness; Chronic Mountain Sickness
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Hematologic Diseases; Altitude Sickness; Polycythemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Protective Agents; Carbonic Anhydrase Inhibitors; Natriuretic Agents; Diuretics; Anticonvulsants; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetazolamide; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: 10-0078