Phase 1/2 Clinical Trial of PR001 in Infants With Type 2 Gaucher Disease (PROVIDE)

Study Overview
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Brief Summary
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J3Z-MC-OJAB is an open-label, Phase 1/2, multicenter study to evaluate the safety and efficacy of single-dose LY3884961 (formerly PR001) in infants diagnosed with Type 2 Gaucher disease (GD2). For each patient, the study will be approximately 5 years in duration. During the first 12 months after dosing, patients will be evaluated for the effects of LY3884961 on safety, tolerability, immunogenicity, biomarkers, and efficacy. Patients will be followed up for an additional 4 years to monitor safety and changes on selected biomarkers and clinical outcomes.

Official Title
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An Open-label, Phase 1/2 Study to Evaluate the Safety and Efficacy of Single-dose LY3884961 in Infants With Type 2 Gaucher Disease

Conditions
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Gaucher Disease, Type 2

Intervention / Treatment
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* Biological: LY3884961
* Drug: Methylprednisolone
* Drug: Sirolimus
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Bi-allelic GBA1 mutations consistent with a diagnosis of GD2 confirmed by the central laboratory. Clinical diagnosis of GD2 Parent/legal guardian has the ability to understand the purpose and risks of the study and provide written informed consent and authorization to use protected health information in accordance with national and local privacy regulations. Patient has a reliable informant (i.e., parent/legal guardian) willing and able to participate in the study as a source of information on the patient's health status and cognitive and functional abilities (including providing input into the rating scales). Exclusion Criteria: Diagnosis of a significant CNS disease other than GD2 that may be a cause for the patient's GD symptoms or may confound study objectives. Achieved independent gait. Severe peripheral symptoms of GD which, in the opinion of the Investigator, would pose an unacceptable risk to the patient or interfere with the patient's ability to comply with study procedures or interfere with the conduct of the study. Concomitant disease, condition, or treatment which, in the opinion of the Investigator, would pose an unacceptable risk to the patient or interfere with the patient's ability to comply with study procedures or interfere with the conduct of the study. Use of any GD treatment-related SRT. Use of strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) or P-glycoprotein (P-gp) medications, herbals, or over-the-counter agents. Any type of prior gene or cell therapy. Live vaccine Immunizations within 4 weeks, or non-live vaccines within 2 weeks prior to the start of required immunosuppressive regimen. Use of blood thinners. Antiplatelet therapies are acceptable if the patient is medically able to temporarily stop them from 7 days prior to dosing and through at least 48 hours after the intracisternal injection and lumbar puncture. Use of systemic immunosuppressant or corticosteroid therapy other than protocol-specified (topical or inhaled preparations for dermatological conditions or asthma are allowed). Participation in another investigational drug or device study within the past 3 months. Brain MRI (magnetic resonance imaging) and MRA (magnetic resonance angiography) showing clinically significant abnormality deemed a contraindication to intracisternal injection. Clinically significant laboratory test result abnormalities assessed at screening. Contraindications or intolerance to radiographic visualization methods (e.g. MRI, MRA, CT), and intolerance to contrast agents used for MRI or CT scans. Contraindications to general anesthesia or sedation. Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 0 Months
Maximum Age: 24 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Dose<br> | Biological: LY3884961<br>* Participants will receive a single dose of LY3884961 administered intracisternally.<br>Drug: Methylprednisolone<br>* Single IV pulse administered as concomitant medication.<br>Drug: Sirolimus<br>* Loading dose, followed by maintenance doses, followed by dose tapering; administered as concomitant medication.<br>Drug: Prednisone<br>* Administered orally as concomitant medication, followed by dose tapering.<br>|
| Experimental: High Dose<br> | Biological: LY3884961<br>* Participants will receive a single dose of LY3884961 administered intracisternally.<br>Drug: Methylprednisolone<br>* Single IV pulse administered as concomitant medication.<br>Drug: Sirolimus<br>* Loading dose, followed by maintenance doses, followed by dose tapering; administered as concomitant medication.<br>Drug: Prednisone<br>* Administered orally as concomitant medication, followed by dose tapering.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events (AEs), Serious Adverse Events (SAEs), and Adverse Events leading to discontinuation |  | Year 5 | 
| Immunogenicity of AAV9 and GCase in blood |  | Up to Year 2 | 
| Immunogenicity of AAV9 and GCase in CSF |  | Up to Year 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to death |  | Baseline until event or study completion, up to Year 5 | 
| Time to clinical event | Clinical event defined as tracheostomy/invasive ventilation, and/or percutaneous endoscopic gastrostomy (PEG) tube placement, and/or nasogastric (NG) tube placement | Baseline until event or study completion, up to Year 5 | 
| Change in cognitive function | Measured using Bayley Scales of Infant and Toddler Development (BSID-III) | Months 6, 12 and up to Year 3 | 
| Change in cognitive function | Measured using Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV) as appropriate. (Not all patients begin the study at birth. Only patients who are age 36 months at the designated study visits will be assessed using this measure) | Study Month 12 and up to Study Year 3 | 
| Change in motor skills | Change from baseline in motor function using Gross Motor Function Measure (GMFM-88). | Months 6, 12 and up to Year 3 | 
| Change in motor skills | Change from baseline in motor function using the BSID-III. | Months 6, 12 and up to Year 3 | 
| Change in Clinical Global Impressions (Severity) | Change from baseline in the clinical severity of illness (CGI-Severity {CGI-S}). | Months 6, 12 and up to Year 5 | 
| Clinical Global Impressions (Improvement) | Clinical improvement from baseline (CGI-Improvement [CGI-I]). | Months 6, 12 and up to Year 5 | 
| Change in adaptive behavior and functioning | Change from baseline in adaptive functioning using the Vineland Adaptive Behavior Scale (VABS-2) (2nd edition) | Months 6 and 12 and up to Year 3 | 
| Change in most troubling symptoms | Change from baseline in the Visual Analog Scale for the Most Troubling Symptoms (VAS-MTS) | Months 6, 12 and up to Year 5 | 
| Change in behavioral symptoms | Change from baseline in the Child Behavior Checklist (CBCL) | Months 6, 12 and up to Year 5 | 
| Change in GCase (glucocerebrosidase) enzyme activity levels in blood |  | Up to Year 5 | 
| Change in GCase enzyme activity levels in CSF (cerebrospinal fluid) |  | Up to Year 3 | 
| Change in glycolipid levels in blood |  | Up to Year 5 | 
| Change in glycolipid levels in CSF |  | Up to Year 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AAV9, GBA, Gene Therapy, Glucocerebrosidase, GBA1 mutation, Infants, Gaucher Disease, GD, Gaucher, Type 2 Gaucher, Neuronopathic Gaucher, nGD