Peripheral Modulation of Muscle Stiffness and Spasticity

This is a single-center, double-blind, randomized, placebo-controlled, sequential Phase II trial of human recombinant hyaluronidase injections in individuals with post-stroke upper limb muscle stiffness. The investigators will recruit 50 subjects, 25 males and 25 females, who will be randomized to receive either hyaluronidase plus saline (treatment arm, n=25) or normal saline (control arm, n=25) injections (first injection) in Phase 1 of the study over 5 visits that will test all 3 study aims. Then subjects will join the Phase 2 to receive a second injection, where the treatment arm will receive the placebo and the placebo arm will receive the treatment. It is expected that approximately 50 participants will be enrolled to produce 42 evaluable participants. This design will ensure that all subjects receive the drug treatment, which will facilitate recruitment. The injecting physician, the assessors, and the patients will be blind to group assignment. Randomization will be initiated by the IDS pharmacy as per the study statistician. All patients will be assessed at seven visits over 9 weeks of the study: Visit 1 - screening and baseline assessment of aims 1 and 2 (week 1-2); Visit 2 - pre-injection MRI for aim 3 (week 1-2); Visit 3 - first injection (week 2); Visit 4 - post-injection MRI (week 3-5); Visit 5 - post-injection follow up for aims 1 and 2 (week 3-5); CROSSOVER TO OPPOSITE TREATMENT ARM Visit 6 - Second injection (week 6); Visit 7 - post-injection follow-up for aims 1 and 2/ final study visit (week 7-9). There will be no MRI assessment after the second injection as the technique is adequately sensitive to demonstrate changes with a small sample size. The investigators will follow the patients for approximately 9 weeks in this study. After obtaining informed consent, subjects will be screened to ensure that the subjects meet study criteria.

Study Overview

• Status: Recruiting
• Conditions: Muscle Spasticity
• Intervention / Treatment: Drug: Hyaluronidase; Drug: Placebo

Detailed Description

1. To test the effect of hyaluronidase injections on upper limb outcomes. The investigators will test the hypothesis that compared to placebo, human recombinant hyaluronidase injections will increase total passive ROM across the affected shoulder, elbow and forearm as measured by motion analysis (primary outcome), isometric muscle strength or force generation capacity using MVC on EMG, reduce upper limb motor impairment as measured by the Fugl-Meyer (FM) scale, and improve function as measured by the Wolf Motor Function Test (WMFT).
2. To evaluate the effect of hyaluronidase on neural and non-neural components of muscle stiffness. The investigators will test the hypothesis that compared to placebo, IM hyaluronidase will modulate the passive and potentially also the active component of the stretch reflex, reduce stiffness and improve arm motor control.
3. To determine the effect of hyaluronidase on intramuscular GAG content. The investigators will test the hypothesis that compared to placebo, IM hyaluronidase will reduce the T1rho relaxation times in the biceps and triceps muscles of the affected arm.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Azin Etemadimanesh, MD; Phone Number: 410-955-1347; Email: aetemad2@jhmi.edu
• Study Contact Backup: Name: Robert Nickl, PhD; Phone Number: 4109551381; Email: rnickl1@jhmi.edu

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Recruiting
      • Paria Arfa Fatollahkhani, MD, M.Sc.
      • Contact: Paria Arfa Fatollahkhani, MD, MSc; Email: parfafa1@jhmi.edu
      • Principal Investigator: Ning Cao, MD
      • Contact: Robert Nickl, PhD; Phone Number: 410-955-1381; Email: rnickl1@jhmi.edu

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Ischemic or hemorrhagic stroke 4-180 months prior
• Moderately-severe muscle stiffness
• Lack of full passive and active range of motion in at least 2/4 areas (shoulder, elbow, forearm, wrist) in the hemiparetic upper limb;
• Willingness to have MRI, complete all clinical assessments, and comply with study protocols;
• Ability to give informed consent and HIPPA certifications; and

Exclusion Criteria:

• treatment of spasticity with Botulinum toxin or intrathecal baclofen within the past six months, phenol injections within the past 12 months, or ongoing adjustment of anti-spastic medications;
• other neurologic condition that may affect motor response (e.g., Parkinson's disease, ALS, MS);
• clinically significant cognitive dysfunction with score <19 on Folstein's Mini Mental Status Examination or depression with score >10 on the PHQ-9;
• pregnancy;
• known hypersensitivity to hyaluronidase;
• claustrophobia;
• standard contraindications for MRI
• Any condition that will preclude the patient from completing the protocol as determined by the PI

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Arm; Hyaluronidase plus saline	Drug: Hyaluronidase; HYLENEX recombinant, diluted with 0.9% Sodium Chloride Injection; Other Names: Hylenex
Placebo Comparator: Control Arm; Normal Saline	Drug: Placebo; 0.9% Sodium Chloride Injection; Other Names: Normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total upper limb passive range of motion	passive range of motion in shoulder, elbow and forearm joints	9 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total upper limb active range of motion	active range of motion in shoulder, elbow and forearm joints	9 weeks
Change in upper limb Fugl-Meyer Assessment Score	measures motor impairment in the affected upper limb, Score range is 0-66, and a higher score indicates a better outcome	9 weeks
Change in Wolf-Motor Function Test (WMFT) Score	Measures upper extremity function following stroke, Includes 6 items, with a 0-5 score range for each item, and a higher score indicates a better outcome	9 weeks

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Investigators: Principal Investigator: Ning Cao, MD, Johns Hopkins University

Study record dates

Study Major Dates

• Study Start (Actual): October 11, 2021
• Primary Completion (Estimated): November 16, 2024
• Study Completion (Estimated): November 16, 2024

Study Registration Dates

• First Submitted: October 3, 2017
• First Submitted That Met QC Criteria: October 9, 2017
• First Posted (Actual): October 11, 2017

Study Record Updates

• Last Update Posted (Estimated): December 1, 2023
• Last Update Submitted That Met QC Criteria: November 29, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Cerebral Palsy; Stroke; Muscle Spasticity; Muscle Stiffness; Hyperreflexia
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Manifestations; Muscle Hypertonia; Muscle Spasticity
• Other Study ID Numbers: IRB00273264

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.: No