O2 Transport and Utilization in Health and Lung Disease

Role of Nitric Oxide Coupling in Muscle Dysfunction With COPD

Skeletal muscle dysfunction is a frequent and clinically relevant systemic manifestation of Chronic Pulmonary Obstructive Disease (COPD), which is still poorly understood. Therefore, the focus of this study is on the role of a deficit in tetrahydrobiopterin and nitric oxide synthase uncoupling induced by chronic oxidative stress on metabolic and vascular abnormalities in skeletal muscle of patients suffering from COPD.

Study Overview

• Status: Withdrawn
• Conditions: Oxidative Stress; COPD; Tetrahydrobiopterin Deficiency
• Intervention / Treatment: Drug: Placebo oral tablet; Drug: Tetrahydrobiopterin

Detailed Description

The purpose of this study is to assess the efficacy of supplementation with tetrahydrobiopterin (BH4) for improving vascular and muscle function in patients with COPD and healthy controls.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Amherst, Massachusetts, United States, 01003
      • Institute of Applied Life Sciences
      • Contact: Gwenael Layec, PhD; Phone Number: 413-345-2739; Email: glayec@umass.edu
      • Contact: Mary Emma Searles; Email: msearles@umass.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• All subjects must be between the age of 18 and 85 years;
• For the COPD cohort, patients with a diagnosis of stable COPD (i.e., those not experiencing an acute exacerbation of symptoms) and spirometric evidence of airway obstruction (FEV1 <80% predicted, FEV/FVC<0.70);
• Ability to perform motor tests;
• Ability to provide informed consent

Exclusion Criteria:

• uncontrolled hypertension;
• hyperlipidemia;
• recent exacerbation;
• Major cardiovascular event procedure (<3 months);
• Pregnancy
• known significant hepatic, renal disease, active substance abuse
• contraindication to MRI, claustrophobia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: acute BH4/Tetrahydrobiopterin treatment; Oral supplement, Pill, 10 mg/kg of body weight	Drug: Tetrahydrobiopterin; Oral, Single dose
Placebo Comparator: Placebo; Oral supplement, Pill, Placebo pill with inert excipient	Drug: Placebo oral tablet; Single dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mitochondrial function	PCr recovery kinetics	4 hours
intracellular PO2	Myoglobin oxygenation	4 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
systemic blood markers of oxidative stress	blood markers	4 hours
Peripheral Blood flow	Exercise Blood flow by Doppler Ultrasound	4 hours

Collaborators and Investigators

• Sponsor: University of Massachusetts, Amherst

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2021
• Primary Completion (Estimated): August 1, 2022
• Study Completion (Estimated): August 1, 2022

Study Registration Dates

• First Submitted: July 3, 2019
• First Submitted That Met QC Criteria: July 8, 2019
• First Posted (Actual): July 10, 2019

Study Record Updates

• Last Update Posted (Estimated): December 19, 2023
• Last Update Submitted That Met QC Criteria: December 12, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Exercise; Mitochondria; Vascular function; BH4
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Phenylketonurias
• Other Study ID Numbers: 2018-4815

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: 6 months post-publication
• IPD Sharing Access Criteria: Within 6 months after the data have been published, and upon written request, a limited, de-identified, anonymized dataset will be created pursuant to the Data use Agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No