Hyaluronidase for Muscle Spasms
Recruiting in Palo Alto (17 mi)
+2 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Johns Hopkins University
Must not be taking: Botulinum toxin, Baclofen, Phenol, others
Disqualifiers: Parkinson's, ALS, MS, others
Prior Safety Data
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?This trial tests if using a special enzyme can help people who have stiff arm muscles after a stroke. The enzyme works by reducing substances that cause muscle tightness, which may improve arm movement and strength. This new therapy aims to reduce muscle stiffness by breaking down certain substances in the muscles.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but you cannot participate if you have had certain treatments for muscle stiffness recently or are adjusting anti-spastic medications.
What data supports the effectiveness of the drug hyaluronidase for muscle spasms?
Research shows that hyaluronidase is effective in facilitating drug absorption and hydration in medical settings, which suggests it may help in conditions requiring enhanced tissue absorption. Additionally, it has been used successfully in the central nervous system for other conditions, indicating potential for broader therapeutic applications.
12345Is hyaluronidase generally safe for use in humans?
Hyaluronidase has been used safely for over 50 years, with recombinant human hyaluronidase showing reduced allergic risks and no allergic reactions in a study of 100 people. However, some people may develop antibodies or have allergic reactions, especially at the injection site, but serious reactions are rare.
46789Eligibility Criteria
This trial is for individuals who had a stroke 6-120 months ago and are experiencing moderate to severe muscle stiffness in their upper limb. They must be able to consent, undergo MRI scans, and follow the study's procedures. Excluded are those with recent spasticity treatments, other neurological conditions like Parkinson's or ALS, significant cognitive issues or depression, pregnancy, hyaluronidase allergy, claustrophobia or MRI contraindications.Inclusion Criteria
I had a stroke between 4 months and 15 years ago.
I experience significant muscle stiffness.
Willingness to have MRI, complete all clinical assessments, and comply with study protocols
+2 more
Exclusion Criteria
I've had treatments for muscle stiffness in the last year.
Clinically significant cognitive dysfunction with score <19 on Folstein's Mini Mental Status Examination or depression with score >10 on the PHQ-9
Any condition that will preclude the patient from completing the protocol as determined by the PI
+5 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive hyaluronidase or saline injections to test effects on muscle stiffness and spasticity
15 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial tests human recombinant hyaluronidase injections against saline (placebo) in reducing muscle stiffness post-stroke. It's double-blind and placebo-controlled with two phases ensuring all participants receive treatment at some point over nine weeks with seven visits including MRIs before the first injection but not after the second.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Treatment ArmExperimental Treatment1 Intervention
Hyaluronidase plus saline
Group II: Control ArmPlacebo Group1 Intervention
Normal Saline
Hyaluronidase is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Human Recombinant Hyaluronidase for:
- Subcutaneous urography
- Extravasation of contrast agents
- Off-label use for muscle stiffness and spasticity
🇪🇺 Approved in European Union as Hyalase for:
- Subcutaneous urography
- Extravasation of contrast agents
- Off-label use for muscle stiffness and spasticity
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Johns Hopkins School of MedicineBaltimore, MD
Johns Hopkins UniversityBaltimore, MD
Paria Arfa Fatollahkhani, MD, M.Sc.Baltimore, MD
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Who Is Running the Clinical Trial?
Johns Hopkins UniversityLead Sponsor
Sheikh Khalifa Stroke InstituteCollaborator
References
Use of hyaluronidase in the central nervous system. [2004]Hyaluronidase, an enzyme which depolymerizes the mucopolysaccharide hyaluronic acid, appears to be tolerated by the human central nervous system and in the anterior chamber of the rabbit eye. Two patients with hydrocephalus and meningomyelocele had their condition curtailed by intraventricular injections of hyaluronidase, and in a third patient its use permitted delay of shunting. It was apparently effective in preventing a reaccumulation of cystic fluid in an intramedullary neurofibroma, and in reversing adverse effects of adhesive arachnoiditis of the spinal cord. Hylauronidase seems worthy of further investigation in disorders of the central nervous system.
Initial experiences with subcutaneous recombinant human hyaluronidase. [2022]We report here our retrospective observations on the use of recombinant human hyaluronidase (rHuPH20) for the facilitation of subcutaneous hydration and drug infusion. Thirty-two patients were treated with rHuPH20 in a hospice setting over a 6-month period. Of these, 26 received this agent to enhance hypodermoclysis with standard hydration fluids for symptom control of delirium, myoclonus and mild to moderate dehydration. Flow rates up to 500 mL/hr were attained without difficulty. Electrolyte replacement in hydration fluid was achieved without incident in 5 patients receiving potassium and in 1 patient receiving both potassium and magnesium. In addition to use for hydration, 6 patients received recombinant human hyaluronidase to enhance subcutaneous infusion of 9 medications, primarily because the medication dosage required subcutaneous flow rates greater than the standard 3 mL/hr. There were no significant adverse events. Induration at the infusion site occurred in 1 patient receiving hydration and higher than expected serum lidocaine concentration was observed in another patient. Based on our positive initial experience with recombinant human hyaluronidase, there is interest in expanding its use in our facility in both the inpatient and outpatient settings.
The additional effect of hyaluronidase in lumbar interlaminar epidural injection. [2021]To evaluate the effect of hyaluronidase in lumbar interlaminar epidural injection (LIEI) for low back pain and sciatica.
Heterologous expression of rTsHyal-1: the first recombinant hyaluronidase of scorpion venom produced in Pichia pastoris system. [2022]In general, hyaluronidases have a broad potential application on medicine and esthetics fields. Hyaluronidases from animal venoms cleave hyaluronan present in the extracellular matrix, acting as spreading factors of toxins into the tissues of the victim. However, the in-depth characterization of hyaluronidase from animal venoms has been neglected due to its instability and low concentration in the venom, which hamper its isolation. Thus, heterologous expression of hyaluronidase acts as a biotechnological tool in the obtainment of enough amounts of the enzyme for structural and functional studies. Therefore, this study produced a recombinant hyaluronidase from Tityus serrulatus scorpion venom, designated as rTsHyal-1, in the Pichia pastoris system. Thus, a gene for TsHyal-1 (gb|KF623285.1) was synthesized and cloned into the pPICZαA vector (GenScript Corporation) for heterologous expression in P. pastoris. rTsHyal-1 was expressed in laboratorial scale in a buffered minimal medium containing methanol (BMM) for 96 h with daily addition of methanol. Expression of rTsHyal-1 resulted in a total protein yield of 0.266 mg/mL. rTsHyal-1 partially purified through cation exchange chromatography presented a specific activity of 1097 TRU/mg, against 838 TRU/mg for the final expressed material, representing a 1.31-fold purification. rTsHyal-1 has molecular mass of 49.5 kDa, and treatment with PNGase F and analysis by mass spectrometry (MALDI-TOF) indicated a potential N-glycosylation of 4.5 kDa. Additionally, de novo sequencing of rTsHyal-1, performed in MALDI-TOF and Q Exactive Orbitrap MS, resulted in 46.8% of protein sequence coverage. rTsHyal-1 presents the highest substrate specificity to hyaluronan followed by chondroitin-6-sulfate, chondroitin-4-sulfate, and dermatan sulfate and showed an optimum activity at pH 6.0 and 40 °C. These results validate the biotechnological process for the heterologous expression of rTsHyal-1. This is the first recombinant hyaluronidase from scorpion venoms expressed in the P. pastoris system with preserved enzyme activity.
Development of a New Type of Recombinant Hyaluronidase Using a Hexahistidine; Possibilities and Challenges in Commercialization. [2019]Hyaluronidases enhance therapeutic drug transport by breaking down the hyaluronan barrier to lymphatic and capillary vessels, facilitating their tissue absorption. Commercially available hyaluronidases are bovine in origin; however, they pose risks such as bovine spongiform encephalopathy. The present study aimed to develop a novel, highly active hyaluronidase and assess its function. Therefore, in order to find the most efficient active hyaluronidase, we produced several shortened hyaluronidases with partial removal of the N- or C-terminal regions. Moreover, we created an enzyme that connected six histidines onto the end of the hyaluronidase C-terminus. This simplified subsequent purification using Ni2+ affinity chromatography, making it feasible to industrialize this highly active recombinant hyaluronidase which exhibited catalytic activity equal to that of the commercial enzyme. Therefore, this simple and effective isolation method could increase the availability of recombinant hyaluronidase for research and clinical purposes.
Assessment and implication of the allergic sensitivity to a single dose of recombinant human hyaluronidase injection: a double-blind, placebo-controlled clinical trial. [2007]Animal-extracted injectable hyaluronidases have been used safely for more than 50 years to increase the dispersion and absorption of coadministered drugs and fluids; however, concern still exists about the allergic and immunological risks of these products. Hylenex recombinant, a novel formulation of recombinant human hyaluronidase, has been developed as an alternative to these animal-derived hyaluronidases. Because recombinant human hyaluronidase is a human (nonforeign) protein manufactured into a purer preparation than the animal extracts, it is expected to convey reduced allergic and immunologic risks. The recombinant human hyaluronidase product was well tolerated in this double-blind, placebo-controlled, single-dose study. No allergic reactions were observed among the 100 volunteer subjects who were injected intradermally. These findings supported the US Food and Drug Administration approval of the recombinant human hyaluronidase product.
[Animal experimental studies on immunogenicity, humoral response and danger of anaphylaxis in parenteral administration of hyaluronidase]. [2009]The widespread intravenous application of hyaluronidase rises questions for its potential immunogenicity, formation of humoral antibodies, and danger of anaphylaxis. In experiments on 21 rabbits and 40 rats, the authors searched for precipitating antibodies after subcutaneous, intramuscular, and intravenous application of hyaluronidase in doses equivalent to the human. Intravenous and intramuscular shots of 150 to 75 000 IU of Hylase were applied in order to test anaphylaxis. By all proving procedures antibodies against Hylase were found. The formation of antibodies occurred earlier and in higher concentrations after subcutaneous and intramuscular application. The antibodies belonged to the IgG group. One third of the animals showed anaphylactic responses at doses which were 13 to 630 times as high. 26 per cent of human patients developed antibodies after application of Hylase. No anaphylactic reactions were observed in 17 patients with antibodies when intravenous application of hyaluronidase was continued. In the dosage used in the man anaphylactic response is obviously rare though it is possible.
Corneal toxicity of intraocular hyaluronidase. [2003]The purpose of this study was to examine the corneal toxicity of different preparations of intraocular hyaluronidase. SDS-PAGE analysis of bovine testicular hyaluronidase (Wydase) and chromatographically purified hyaluronidase (Sigma) was performed. These two preparations were injected into the anterior chamber of rabbits in amounts ranging from 1.5-150 IU (Wydase) and 1.5-300 IU (Sigma). A third set of rabbit eyes received Wydase vehicle alone or in combination with Sigma hyaluronidase. Treated control eyes were injected with saline. Slit lamp examination and indirect ophthalmoscopy were performed preoperatively and on postoperative days 1 and 7. Light microscopy of the corneas was performed. SDS-PAGE of Wydase revealed numerous protein impurities, while Sigma demonstrated one protein band consistent with mammalian hyaluronidase. Persistent corneal edema, severe anterior chamber fibrin, and endothelial necrosis, were seen in the majority of eyes injected with Wydase in amounts of 50 IU and greater (n = 11). Thirty percent (30%) of the eyes injected with the Sigma preparation (n = 11) had localized corneal opacity similar to 50% of eyes injected with saline (n = 2). Of the rabbit eyes injected with the Wydase vehicle (n = 19), 68% had toxic changes. Intracameral injection of Wydase is toxic to the rabbit cornea in amounts of 50 IU and greater. A chromatographically purified preparation showed only transient local toxicity. Toxicity of Wydase may be due to protein impurities and the thimerosal-containing vehicle.
Allergic reaction to hyaluronidase use after hyaluronic acid filler injection. [2015]Hyaluronic acid (HA) is biocompatible, easy to use and reversible. HA fillers are considered to be safe, although some complications can occur. At this time, hyaluronidase is used off-label for correction. A 41-year-old woman presented to our clinic for focal erythematous plaque on hyaluronidase injection site. She got the injection for correction of HA filler excess. The skin lesion continued for 7 days. Histopathologic findings were nonspecific. On intradermal skin test, allergic reaction to hyaluronidase were confirmed. Adverse effects of this hyaluronidase are uncommon with local injection site reactions most frequently reported. Allergy to hyaluronidase should be included in the differential diagnosis when focal erythema and swelling occur after hyaluronidase injection.
Hirayama disease - Early MRI diagnosis of subacute medullary ischemia: A case report. [2022]Hirayama disease (HD) is a rare, benign, and self-limiting motor neuron disorder that results in selective motor impairment of the C7-T1 myotomes. It is characterized by progressive, unilateral, or bilateral asymmetric muscle atrophy of the distal upper extremities and myelopathy.
Hirayama Disease: A 15-Year-Old Male With Progressive Distal Right Upper Extremity Weakness. [2023]Hirayama disease is a rare neuromuscular disorder characterized by abnormal forward displacement of the cervical spinal cord, resulting in focal ischemic changes of anterior horn cells.
Hirayama's disease: an Italian single center experience and review of the literature. [2020]Hirayama's disease (HD), is a benign, self-limited, motor neuron disease, characterized by asymmetric weakness and atrophy of one or both distal upper extremities. In the present study we report the clinical, electrophysiological and MRI features of a group of Italian patients, with review of the literature. Moreover we propose an optimized MRI protocol for patients with suspected or diagnosed HD in order to make an early diagnosis and a standardized follow up.
Is there cervical spine muscle weakness in patients with Hirayama disease? A morphological study about cross-sectional areas of muscles on MRI. [2021]Patients with Hirayama disease (HD) present with a larger range of neck flexion and show signs of cervical spine instability. Cervical spine stability largely relies on cervical spine muscles. The purpose of this study was to compare the cross-sectional areas (CSAs) of cervical spine muscles between patients with HD and healthy controls, providing some insights into whether there is cervical spine muscle weakness and incongruence in HD patients.
Emerging Therapies for Spastic Movement Disorders. [2020]Spasticity develops as a result of central nervous system (CNS) injury; however, secondary changes within the muscles and connective tissue also contribute to muscle stiffness. The hyaluronan hypothesis postulates that the accumulation of hyaluronan promotes the development of muscle stiffness. Intramuscular injections of the enzyme hyaluronidase, which hydrolyzes long-chained hyaluronan polymers to smaller polymers, was shown to reduce muscle stiffness and increase passive and active range of motion in patients with spasticity. These results provide preliminary evidence of the hyaluronan hypothesis and suggest an emerging therapy to reduce muscle stiffness using the enzyme hyaluronidase.