Tadalafil as Adjuvant Therapy for DMD

Tadalafil as an Adjuvant to Therapy for Duchenne Muscular Dystrophy

This project will assess the vascular responsiveness in leg muscles of boys with Duchenne muscular dystrophy (DMD) to one single dose of tadalafil, a common vasodilator drug, using non-invasive techniques (MRI or Doppler ultrasound) and exercise testing. These findings will provide proof of concept for a subsequent intervention study to demonstrate efficacy of longer-term tadalafil to counter sympathetic vasoconstriction and slow disease progression in DMD. It will also inform whether a group of patients do not respond to the drug.

Study Overview

• Status: Recruiting
• Conditions: Duchenne Muscular Dystrophy
• Intervention / Treatment: Drug: Tadalafil; Drug: Tadalafil

Detailed Description

This project will target up to 25 ambulatory boys with DMD aged 7-13 years. Because the vascular impact of tadalafil is immediate, we will confirm that the drug target is valid target in lower extremities by assessing the change in post-exercise microvascular perfusion using Blood Oxygen Level-Dependent (BOLD) MRI or change in post-exercise hyperemia using Doppler ultrasonography. We will also assess the functional impact of the drug through exercise testing. Patients will be randomized to undergo the above-mentioned assessments with or without the study drug on two separate visits. Time function tests, MRI-based fat fraction and inflammation measurements will also be obtained in all patients, thus characterizing disease severity and provide a sampling of information on whether a subset of patients do not respond to the drug. This information may be used to inform future trials as to the appropriate target population for PDE5i as well as account for potential failures in a previously published phase 3 clinical trial.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32610
      • Recruiting
      • University of Florida
      • Contact: Tanja Taivassalo; Phone Number: 352-294-8748; Email: ttaivassalo@ufl.edu
      • Principal Investigator: Tanja Taivassalo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 13 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of DMD confirmed by 1) clinical history with features before the age of five, 2) physical examination, 3) elevated serum creatine kinase level and 4) absence of dystrophin expression, as determined by immunostaining or Western blot (<2%) and/or DNA confirmation of dystrophin mutation.
• Minimum entry age of 7.0 years
• Ambulatory

Exclusion Criteria:

• Older than 13.0 years of age
• Contraindication to an MR examination (e.g. aneurysm clip, severe claustrophobia, magnetic implants)
• Presence of unstable medical problems
• Presence of a secondary condition that impacts muscle function or muscle metabolism (e.g. myasthenia gravis, endocrine disorder, mitochondrial disease)
• Contraindications to Tadalafil (use of nitrates, alpha-adrenergic blockers, other PDE5A inhibitors)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tadalafil plus BOLD-MRI (Schedule A); The intervention is the same as in Schedule B; this arm will use BOLD-MRI as the technique to monitor drug impact on skeletal muscle.	Drug: Tadalafil; Patient will be randomized to one dose of 0.6 mg/kg tadalafill on one of two study visits. On both visits, assessments (MRI, exercise testing, clinical function) will be performed 3 hours after time of dosing.; Other Names: Cialis; Drug: Tadalafil; Patient will be randomized to one dose of 0.6 mg/kg tadalafill on one of two study visits. On both visits, assessments (Doppler US, exercise testing, clinical function) will be performed 3 hours after time of dosing.; Other Names: Cialis
Experimental: Tadalafil plus Doppler ultrasound (Schedule B); The intervention is the same as in Schedule A; this arm will use Doppler ultrasound as the technique to monitor drug impact on skeletal muscle.	Drug: Tadalafil; Patient will be randomized to one dose of 0.6 mg/kg tadalafill on one of two study visits. On both visits, assessments (MRI, exercise testing, clinical function) will be performed 3 hours after time of dosing.; Other Names: Cialis; Drug: Tadalafil; Patient will be randomized to one dose of 0.6 mg/kg tadalafill on one of two study visits. On both visits, assessments (Doppler US, exercise testing, clinical function) will be performed 3 hours after time of dosing.; Other Names: Cialis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in post-contractile BOLD response after tadalafil dosing	MRI technique to measure microvascular function in skeletal muscle	MRI will be done 3 hours after dosing/no-dosing on two separate study visits
Change in post-exercise hyperemia after tadalafil dosing	Doppler ultrasound will be used to measure blood flow	Doppler ultrasound will be done 3 hours after dosing/no-dosing on two separate study visits

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in submaximal exercise capacity after tadalafil dosing	incremental cardiopulmonary exercise testing on cycle ergometer will be performed to measure heart rate and parameters of exercise performance.	Cycle testing will be done 4 hours after dosing/no-dosing on two separate study visits

Collaborators and Investigators

• Sponsor: University of Florida
• Investigators: Principal Investigator: Tanja Taivassalo, University of Florida

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2021
• Primary Completion (Estimated): October 20, 2024
• Study Completion (Estimated): January 20, 2025

Study Registration Dates

• First Submitted: January 4, 2022
• First Submitted That Met QC Criteria: January 4, 2022
• First Posted (Actual): January 19, 2022

Study Record Updates

• Last Update Posted (Estimated): January 31, 2024
• Last Update Submitted That Met QC Criteria: January 30, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: exercise; therapy; vasodilator; treatment strategy
• Additional Relevant MeSH Terms: Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Muscular Disorders, Atrophic; Muscular Dystrophies; Muscular Dystrophy, Duchenne; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Tadalafil
• Other Study ID Numbers: IRB202102391; OCR41391 (Other Identifier: UF OnCore)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes