Blood Flow and Vascular Function in Cystic Fibrosis (CF-FLOW)

Role of Blood Flow and Vascular Function on Exercise Capacity in Cystic Fibrosis

Cystic fibrosis (CF) has many health consequences. A reduction in the ability to perform exercise in patients with CF is related to greater death rates, steeper decline in lung function, and more frequent lung infections. However, the physiological mechanisms for this reduced exercise capacity are unknown. The investigators laboratory recently published the first evidence of systemic vascular dysfunction in patients with CF. Therefore, it is reasonable to suspect that the blood vessels are involved with exercise intolerance in CF. This study will look at how 1) blood flow and 2) artery function contribute to exercise capacity in CF.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Sildenafil (Acute-1 hour); Drug: Placebo; Drug: Sildenafil (Subchronic-4 weeks)

Detailed Description

The most disturbing aspect of Cystic Fibrosis (CF) is the associated premature death. Low exercise capacity predicts death in patients with CF and is also associated with a steeper decline in lung function and more lung infections. A critical barrier to improving exercise tolerance in patients with CF is the investigators lack of knowledge regarding the different physiological mechanisms which contribute to their lower exercise capacity. We have compelling data to indicate that the blood vessels may contribute to the low exercise capacity in CF. The impact of this proof of concept investigation will test Phosphodiesterase Type 5 inhibitors (PDE5) inhibitors as a potential therapy in CF and will explore blood flow and endothelial function as potential mechanisms which contribute to exercise intolerance in CF. Improvements in exercise capacity will not only contribute to a better quality of live for patients with CF, it will also increase longevity in these patients.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Augusta University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria.

• Diagnosis of CF and healthy controls
• Men and women (greater than 18 yrs. old)
• Resting oxygen saturation (room air) greater than 90%
• Forced expiratory volume (FEV1) percent predicted greater than 30%
• Patients with or without CF related diabetes
• Traditional CF-treatment medications
• Ability to perform reliable/reproducible pulmonary function tests (PFT)
• Clinically stable for 2 weeks (no exacerbations or need for antibiotic treatment within 2 weeks of testing or major change in medical status)

Exclusion Criteria.

• Children less than 17 years old
• Body mass less than 20 kg
• A diagnosis of pulmonary arterial hypertension (PAH)
• FEV1 less than 30% of predicted
• Resting oxygen saturation (SpO2) less than 90%
• Self-reported to be a smoker
• Current use of any vaso-active medications
• History of migraine headaches
• Pregnant or nursing at the time of the investigation
• A clinical diagnosis of cardiovascular disease, hypertension, or CF related diabetes

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Acute Study: Sildenafil first, then Placebo; In randomized order, on two separate days, endothelial function and exercise capacity will be determined 1 hour following a single dose of sildenafil (50 mg) or placebo.	Drug: Sildenafil (Acute-1 hour); Vascular function will be assessed 1 hour following oral ingestion of sildenafil (50 mg); Other Names: Viagra; Revatio; Drug: Placebo; Sugar pill designed to mimic the sildenafil treatment
Experimental: Acute Study: Placebo first, then Sildenafil; In randomized order, on two separate days, endothelial function and exercise capacity will be determined 1 hour following a single dose of sildenafil (50 mg) or placebo.	Drug: Sildenafil (Acute-1 hour); Vascular function will be assessed 1 hour following oral ingestion of sildenafil (50 mg); Other Names: Viagra; Revatio; Drug: Placebo; Sugar pill designed to mimic the sildenafil treatment
Experimental: Sub-Chronic Study Sildenafil; Following the acute study, patients will be instructed to take 20 mg of sildenafil, three times a day, for 4 weeks. Endothelial function will be determined within 48 hours following the last dose.	Drug: Sildenafil (Subchronic-4 weeks); Vascular function will be assessed 4 weeks following 20 mg three times per day (TID) of sildenafil for four weeks; Other Names: Viagra; Revatio

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute Study: Percentage Flow-Mediated Dilation (FMD)	FMD determined one hour after ingestion of 50 mg Sildenafil or placebo	pre-treatment Baseline and 1 hour post-treatment
Baseline Diameter	Brachial Artery Diameter during FMD (pre-occlusion or "baseline")	pre-treatment Baseline and following 4 weeks sub-chronic treatment
Peak Diameter	Peak Brachial Artery Diameter during FMD (post-occlusion)	pre-treatment Baseline and following 4 weeks sub-chronic treatment
Absolute Change in Diameter	Absolute change in brachial artery diameter taken from the FMD assessment	pre-treatment Baseline and following 4 weeks sub-chronic treatment
FEV1 (% Predicted)	Forced Expiratory Volume in the first second expressed as a percent predicted.	pre-treatment Baseline, 1 hour post-treatment, and following 4 weeks sub-chronic treatment
VO2 Peak (Absolute)	absolute (L/min) peak oxygen consumption during maximal exercise test	pre-treatment Baseline, 1 hour post-treatment, and following 4 weeks sub-chronic treatment
VO2 Peak (Relative)	relative (mL/kg/min) peak oxygen consumption during maximal exercise test	pre-treatment Baseline, 1 hour post-treatment, and following 4 weeks sub-chronic treatment
VO2 Peak (Percent Predicted)	Maximal Oxygen consumption expressed as percent predicted taken from maximal exercise test.	pre-treatment Baseline and 1 hour post-treatment, and 4 weeks sub-chronic treatment
VE Peak	peak ventilation (L/min) during maximal exercise test	pre-treatment Baseline, 1 hour post-treatment, and following 4 weeks sub-chronic treatment
RER Peak	peak respiratory exchange ratio during maximal exercise test	pre-treatment Baseline, 1 hour post-treatment, and following 4 weeks sub-chronic treatment

Collaborators and Investigators

• Sponsor: Augusta University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Ryan Harris, Ph.D., Augusta University

Publications and helpful links

General Publications

• Rodriguez-Miguelez P, Seigler N, Ishii H, Crandall R, McKie KT, Forseen C, Harris RA. Exercise Intolerance in Cystic Fibrosis: Importance of Skeletal Muscle. Med Sci Sports Exerc. 2021 Apr 1;53(4):684-693. doi: 10.1249/MSS.0000000000002521.

Helpful Links

• Laboratory of Integrative Vascular and Exercise Physiology

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2014
• Primary Completion (Actual): July 1, 2018
• Study Completion (Actual): July 1, 2018

Study Registration Dates

• First Submitted: February 4, 2014
• First Submitted That Met QC Criteria: February 6, 2014
• First Posted (Estimate): February 7, 2014

Study Record Updates

• Last Update Posted (Actual): April 24, 2020
• Last Update Submitted That Met QC Criteria: April 23, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Exercise Capacity; Cystic Fibrosis; inflammation; oxidative stress; Lung Disease; pulse wave velocity; flow-mediated dilation; endothelial function; arterial stiffness; Sildenafil; Nitric Oxide; pulmonary function test; CF; Revatio; Muscle Function; Viagra
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: DK100783; R21DK100783 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES