Clinical trial NCT04903288: A Study of SmartFlow Magnetic Resonance (MR) Compatible Ventricular Cannula for Administering Eladocagene Exuparvovec to Pediatric Participants
Official title: An Open-Label Trial to Address the Safety of the SmartFlow MR-Compatible Ventricular Cannula for Administering Eladocagene Exuparvovec to Pediatric Subjects
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: AADC Deficiency
Keywords: AADC Deficiency gene therapy
Lead sponsor: PTC Therapeutics
Sponsor class: INDUSTRY
First posted: 2021-05-26
Enrollment: 13
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study will have a trial phase, extension phase, and a long-term extension phase. The primary objectives of the trial phase are to assess the pharmacodynamics (PD) of eladocagene exuparvovec treatment by evaluation of homovanillic acid (HVA) levels and to assess the safety of the SmartFlow® magnetic resonance (MR) Compatible Ventricular Cannula for administering eladocagene exuparvovec to pediatric participants with aromatic L-amino acid decarboxylase (AADC) deficiency. The extension phase is designed to capture additional clinical information for eladocagene exuparvovec through study evaluations, changes in motor development, AADC-specific symptoms, and other PD measures. The long-term extension phase is designed to capture long-term safety and efficacy data from participants treated with eladocagene exuparvovec.


Eligibility criteria: Inclusion Criteria:

* Pediatric participants must have genetically-confirmed AADC deficiency with typical clinical characteristics and decreased AADC enzyme activity in plasma.
* Cranium sufficiently developed to allow placement of ClearPoint® system for stereotactic surgery.
* Persistent neurological defects secondary to AADC deficiency despite standard medical therapy (dopamine agonists, monoamine oxidase inhibitor, pyridoxine, or other forms of vitamin B6) in the opinion of the investigator.
* Unable to ambulate independently (with or without assistive device).
* Baseline hematology, chemistry, and coagulation values within the normal pediatric laboratory value ranges, unless in the investigator's opinion the out of range values are not clinically significant with respect to the participant's suitability for surgery.
* Participant must test negative for coronavirus disease of 2019 (COVID-19) a maximum of 72 hours prior to receiving gene therapy.
* Participant must be on stable dosage for 3 months prior to baseline for all medications related to treatment of AADC deficiency, including dopamine agonists, monoamine oxidase inhibitors, anticholinergic drugs, and vitamin B6.
* Females of childbearing potential must have a negative pregnancy test at screening and baseline and agree to abstinence or double-barrier form of contraception for the duration of the study following discharge from the hospital (acceptable methods will be determined by the site).
* Males sexually active with females of childbearing potential must agree to use a barrier method of birth control during the study following discharge from the hospital.
* Parent(s)/legal guardian(s) of the participant must agree to comply with the requirements of the study, including the need for frequent and prolonged follow up.
* Parent(s)/legal guardian(s) with custody of the participant must give their consent for the participant to enroll in the study.

Exclusion Criteria:

* The participant has presence of other significant medical or neurological conditions that would create an unacceptable operative or anesthetic risk.
* Participants with pyridoxine 5'-phosphate oxidase or tetrahydrobiopterin (BH4) deficiency.
* Contraindication for imaging studies (computed tomography \[CT\] scan, PET or magnetic resonance imaging \[MRI\]), including sedation limitations or metal that would interfere with a brain MRI.
* Anti-adeno-associated virus, serotype 2 (anti-AAV2) antibody titer higher than 1:1200 or \>1 optical density value by enzyme-linked immunosorbent assay.
* Participants who have received treatment with other experimental therapies within the last 24 weeks prior to planned gene therapy administration, or any treatment ever with a gene therapy.
* Evidence of a clinically active infection.
* Females who are pregnant or breast feeding.

Primary outcomes:
measure: Change From Baseline in HVA Metabolite Level at the End of the Trial Phase
timeFrame: Baseline (Day 1), Week 8
measure: Number of Participants With Adverse Events (AEs) Associated With the Surgical Administration of Eladocagene Exuparvovec Using the SmartFlow® MR-Compatible Ventricular Cannula
timeFrame: Baseline (Day 1) up to Week 8
Secondary outcomes:
measure: Change From Baseline in Neurotransmitter Cerebrospinal Fluid (CSF) Metabolite HVA at Week 48
timeFrame: Baseline (Day 1), Week 48
measure: Change From Baseline in Positron Emission Tomography (PET) Imaging of Putaminal-Specific L-6-[18F] Fluoro-3,4-Dihydroxyphenylalnine (18F-DOPA) PET Uptake at the End of the Trial Phase (Week 8) and the Extension Phase (Week 48)
timeFrame: Baseline (Day 1), Week 8, Week 48
measure: Change From Baseline in Neurotransmitter CSF Metabolites 5-hydroxyindoleacetic Acid (5-HIAA), and 3-O-methyldopa (3-OMD) at Weeks 8 and 48
timeFrame: Baseline (Day 1), Weeks 8 and 48
measure: Number of Participants Who Attain Motor Milestones
timeFrame: Baseline (Day 1) up to Week 260
measure: Change in Peabody Developmental Motor Scale, Second Edition (PDMS-2)
timeFrame: Baseline (Day 1), Week 260
measure: Change in Bayley Scale of Infant Development, Third Edition (Bayley-III)
timeFrame: Baseline (Day 1), Week 260
measure: Change in EuroQol-5 Dimensions Youth Version (EQ-5D-Y)
timeFrame: Baseline (Day 1), Week 260
measure: Change in Body Weight
timeFrame: Baseline (Day 1), Week 260
measure: Number of Participants With AADC-Specific Symptoms
timeFrame: Baseline (Day 1) up to Week 260
measure: "Number of Participants With Treatment-Emergent Adverse Events (TEAEs) "
timeFrame: Baseline (Day 1) up to Week 260
Other outcomes:
Locations:
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Durham
country: United States
facility: Duke University Hospital
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital, Department of Pediatrics and Medical Genetics
Study officials:
References: