Autologous suraL nervE Grafting to the Substantia nigrA in Patients With Synuclienopathies

Official title

A Phase I Study of the Feasibility and Safety of SuraL nervE Tissue Grafting to the Substantia nigrA in Patients With Synucleinopathies (LEAP)

Overview

This phase I double-blind study focuses on the safety and feasibility of implanting autologous peripheral nerve tissue (PNT) into the substantia nigra area of the brain in persons who have been diagnosed with either Parkinson's disease (PD) or Multiple System Atrophy (MSA). 7 participants will be enrolled, with 4 participants receiving the graft and 3 receiving a sham surgery. Eligible participants will be early in their diagnosis with a lower burden of symptoms. Participants will be followed initially for one year after surgery.

Detailed description

This phase I double blind clinical trial will be used to plan future, larger clinical trials that would test how autologous cells from the peripheral nerve may help in the repair of damaged brain cells in Parkinson's Disease (PD) or Multiple System Atrophy (MSA) and slow the progression of the diseases. We will be judging the feasibility of implanting a participant's own cells from a nerve in the leg into the substantia nigra area of the brain. Patients eligible for participation will be at an earlier in stage of the disease with symptoms being less severe and therefore would not yet qualify for DBS. The LEAP trial is a study where the first participant will receive an implantation of the cells from their own sural nerve (a nerve near the ankle), into the substantia nigra on both sides of their brain. The 6 participants who follow, will be randomized to one of two arms. The 3 participants assigned to the experimental arm will receive the graft. The 3 participants assigned to the control arm will receive a sham surgical procedure, where the sural nerve will be biopsied, and bilateral scalp incisions will be made. Those who do not receive the cells initially may be eligible to undergo another surgery at the end of the study, after un-blinding has occurred, to receive the cell implants.

Interventions

• Procedure Sural Nerve Graft to the Substantia Nigra
  Participants assigned to this arm will have the sural nerve biopsied from one of their ankles. This cellular tissue will be deposited bilaterally into the substantia nigra area of their brain by a specialized cannula via bilateral scalp incisions and skull burr holes.
• Procedure Sham surgery
  Participants assigned to this arm will have the sural nerve from one of their ankles biopsied in the same fashion as the experimental arm. Bilateral incisions will be made on the participants scalp but no burr holes into the skull and no cannula passes into the brain will occur.

Primary outcome measures

• Meet recruitment goal [Time frame: Trial opening through 12 months]

Secondary outcome measures (12)

• Study-related serious adverse events as assessed by MedDRA v.27 [Time frame: Enrollment through 12 months]
• Study-related adverse events as assessed by MedDRA v27 [Time frame: Enrollment through 6 month study visit]
• Number of deployment attempts required to deliver bilateral PNT [Time frame: During the procedure]
• Duration of procedure [Time frame: During the procedure]
• Length of hospital admission [Time frame: Admission for the procedure through hospital discharge]
• Percent of study visit completed by participants [Time frame: Enrollement through 12 month study visit]
• Change in Neuropsychological diagnosis [Time frame: Baseline and 12 months]
• Mean change in Neuropsychological assessment scores [Time frame: Baseline to 12 months]
• Mean change in Montreal Cognitive Assessment (MoCA) scores [Time frame: Baseline, 4 weeks, 6 months, and 12 months]
• Mean change of the Movement Disorder Society - Unified Parkinsons Disease Rating Scale (MDS-UPDRS) Part I scores [Time frame: 4 weeks, 6 and 12 months as compared to baseline]
• Mean change of the MDS-UPDRS Part II scores [Time frame: 4 weeks, 6 months, and 12 months compared to baseline]
• Mean change in MDS-UPDRS Part III scores [Time frame: 4 weeks, 6 and 12 months compared to baseline]

Eligibility criteria

Inclusion criteria

• Diagnosis of clinically established or clinically probable PD or MSA as defined by MDS criteria
• Disease duration greater than 2 years
• Age 40-75, inclusive
• MDS-Unified Parkinson's Disease Rating Scale (UPDRS) Part III greater than or equal to 20 points but less than or equal to 35 points, off anti-parkinsonian medication for PD or MDS-Unified Multiple System Atrophy Rating Scale (UMSARS) less than or equal to 30 points off anti-parkinsonian medication
• No MDS-UPDRS Part III score >3 on items 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.14 while off medication
• Able and willing to undergo ioflupane/SPECT
• Able to tolerate the surgical procedure
• Able to undergo all planned assessments
• Available access to the sural nerve

Exclusion criteria

• Previous PD surgery or intracranial surgery
• Ongoing major medical or psychiatric disorder incl. depression and psychosis
• Other concomitant treatment with neuroleptics
• Typical, nonparkinsonian syndrome ioflupane/SPECT signal
• Unable to undergo an MRI
• An obstructed trajectory path to the substantia nigra
• Significant microvascular disease
• Use of anticoagulants other than aspirin
• Female who is pregnant, lactating, or of child-bearing potential unwilling to use an adequate birth control method during the period of the study
• Consent capacity will be assessed and determined during and throughout a participant's neuropsychological exam. A participant who experiences a decline in consent capacity prior to surgery, will be removed from the study by the PI. A decline in consent capacity after surgery will not result in the removal of the participant in the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• University of Kentucky — Lexington

Publications

• Quintero JE, Slevin JT, Gurwell JA, McLouth CJ, El Khouli R, Chau MJ, Guduru Z, Gerhardt GA, van Horne CG. Direct delivery of an investigational cell therapy in patients with Parkinson's disease: an interim analysis of feasibility and safety of an open-label study using DBS-Plus clinical trial design. BMJ Neurol Open. 2022 Jul 14;4(2):e000301. doi: 10.1136/bmjno-2022-000301. eCollection 2022. PMID 35949912
• van Horne CG, Quintero JE, Gurwell JA, Wagner RP, Slevin JT, Gerhardt GA. Implantation of autologous peripheral nerve grafts into the substantia nigra of subjects with idiopathic Parkinson's disease treated with bilateral STN DBS: a report of safety and feasibility. J Neurosurg. 2017 Apr;126(4):1140-1147. doi: 10.3171/2016.2.JNS151988. Epub 2016 May 6. PMID 27153166
• van Horne CG, Quintero JE, Slevin JT, Anderson-Mooney A, Gurwell JA, Welleford AS, Lamm JR, Wagner RP, Gerhardt GA. Peripheral nerve grafts implanted into the substantia nigra in patients with Parkinson's disease during deep brain stimulation surgery: 1-year follow-up study of safety, feasibility, and clinical outcome. J Neurosurg. 2018 Dec 1;129(6):1550-1561. doi: 10.3171/2017.8.JNS163222. Epub 2 PMID 29451447

Identifiers

NCT: NCT06683365 · 95534 · UL1TR001998

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗