A Phase 1/2 Ascending Dose Study to Evaluate the Safety and Effects on Progranulin Levels of LY3884963 in Patients with Fronto-Temporal Dementia with Progranulin Mutations (FTD-GRN) (PROCLAIM)
- Trial ID
- 2022-502942-29-01
- Protocol
- J4B-MC-OKAA
- Sponsor
- Prevail Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety**, tolerability, and immunogenicity of three dose levels of LY3884963 administered via suboccipital injection into the cisterna magna in patients with Fronto-Temporal Dementia with Progranulin Mutations (FTD-GRN). Additionally, the study aims to quantify progranulin (PGRN) levels in blood and cerebrospinal fluid (CSF). These objectives are clinically relevant as they address the potential therapeutic effects and safety profile of LY3884963, which could provide insights into its viability as a treatment option for FTD-GRN, a condition characterized by progressive neurodegeneration.
Secondary objectives include evaluating the effect of LY3884963 on:
- Clinical Dementia Rating (CDR) staging instrument plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration domains (CDR® plus NACC FTLD).
- Neurofilament light chain (NfL) levels in blood and CSF.
Participants
The clinical trial involves a total of **30 participants** diagnosed with **Fronto-Temporal Dementia with Progranulin Mutations (FTD-GRN)**. The study population includes both male and female subjects, aged between 30 to 85 years. Participants are required to be generally ambulatory and not reliant on a walker or wheelchair, living in the community, and have a body weight between 40 kg and 110 kg with a body mass index (BMI) of 18 to 34 kg/m². The trial population was selected based on the presence of symptomatic frontotemporal dementia, including mild behavioral, cognitive, motor, or language impairment, and confirmed carrier status of a pathogenic progranulin gene (GRN) mutation. Participants must have stable use of background medications for at least 8 weeks prior to dosing and have up-to-date age- and gender-appropriate cancer screenings. Lifestyle considerations include the requirement for pneumococcal pneumonia and shingles vaccinations within 10 years of screening. The trial also involves a vulnerable population, as indicated by the inclusion of individuals with cognitive impairments. The selection criteria ensure that participants have a reliable study partner or informant to provide information on their health status and cognitive and functional abilities.
Plans and Procedures
The clinical trial is designed to evaluate the safety, tolerability, and immunogenicity of three dose levels of the investigational product **LY3884963** in patients with **Fronto-Temporal Dementia with Progranulin Mutations (FTD-GRN)**. This study is a Phase 1/2, randomized, double-blind, controlled trial with an estimated duration extending until September 2030. The trial involves ascending doses administered via suboccipital injection into the cisterna magna, with the primary objective of quantifying progranulin (PGRN) levels in blood and cerebrospinal fluid (CSF).
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, health status, and genetic confirmation of a pathogenic progranulin gene mutation. Following successful screening, participants will be randomized into different cohorts for dose administration. The trial includes multiple follow-up visits to monitor safety endpoints, such as the incidence and severity of treatment-emergent adverse events, and to measure changes in PGRN levels over time. The end-of-study visit will conclude the participant's involvement, with comprehensive assessments to evaluate the long-term effects of the treatment.
The expected length of participant involvement is up to five years, with conditions for early termination including the occurrence of severe adverse events or non-compliance with study protocols. Participants are required to have stable use of background medications and must meet specific health criteria, such as a body weight range of 40 to 110 kg and a body mass index (BMI) of 18 to 34 kg/m². The trial also mandates up-to-date vaccinations and cancer screenings as part of the inclusion criteria. The study aims to provide valuable insights into the therapeutic potential of LY3884963 for patients with FTD-GRN, contributing to the understanding of its safety and efficacy profile.
Treatment
The clinical trial involves the administration of **Rapamune** in two different dosages: 1 mg and 0.5 mg coated tablets. The active substance in Rapamune is **sirolimus**, a chemical compound classified under the ATC code L04AA10. The pharmaceutical form is a coated tablet, and the route of administration is oral. The frequency of administration is determined by the study protocol, and participant compliance is monitored through regular assessments. Rapamune is manufactured by Pfizer Europe MA EEIG and is authorized for use in the European Union.
Another treatment used in the study is **Prednisone**, available in two formulations: PREDNISONA CINFA 10 mg tablets and Prednisone Mylan Pharma 5 mg tablets. Prednisone is a glucocorticoid, classified under the ATC code H02AB. It is administered orally, and the dosing schedule is aligned with the study's requirements. Compliance is ensured through participant monitoring. PREDNISONA CINFA is produced by Laboratorios Cinfa, S.A., while Prednisone Mylan Pharma is manufactured by Mylan S.P.A.
The investigational gene therapy, **LY3884963**, utilizes an adeno-associated viral vector serotype 9 to deliver DNA encoding the wildtype GRN gene. This therapy is administered as a solution for injection via intracisternal use. The administration is performed under controlled conditions to evaluate its safety, tolerability, and effects on progranulin levels in patients with frontotemporal dementia with progranulin mutations. The therapy is developed by Eli Lilly and Company Limited.
Additionally, **Solu-Medrol** 1000 mg is used as a non-experimental treatment. It contains the active substance **methylprednisolone**, a glucocorticoid classified under the ATC code H02AB04. Solu-Medrol is provided as a solution for injection and is administered intravenously. The dosing and administration are conducted according to the study protocol, with compliance monitored through regular follow-ups. Solu-Medrol is produced by Pfizer KFT.
Efficacy
The efficacy of the investigational gene therapy LY3884963 in patients with Fronto-Temporal Dementia with Progranulin Mutations (FTD-GRN) will be assessed through primary and secondary endpoints. The primary efficacy endpoints focus on the change from baseline in **Progranulin (PGRN)** levels in blood and cerebrospinal fluid (CSF) over time. These measurements will provide insights into the therapeutic impact of LY3884963 on PGRN levels, which are critical in the context of FTD-GRN.
Secondary efficacy endpoints include the change from baseline in the Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration (NACC FTLD) sum of boxes over time, as well as changes in Neurofilament Light (NfL) levels in both blood and CSF. These parameters will be measured at specified intervals throughout the study to evaluate the broader effects of the treatment on disease progression and neuronal damage.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Men or women aged 30 to 85 years (inclusive), at the time of informed consent.
- Body weight range of ≥40 kg (88 lb) to ≤110 kg (242 lb) and a body mass index (BMI) of 18 to 34 kg/m2.
- Has symptomatic frontotemporal dementia (FTD), including mild behavioral, cognitive, motor or language impairment per Investigator’s assessment (behavioral-variant FTD, primary progressive aphasia-FTD, FTD with corticobasal syndrome, or a combination of syndromes are allowed for enrollment).
- Score ≥0.5 and ≤15 on CDR plus NACC FTLD sum of boxes (Cohorts 1-4 only). Note: In Cohort 5 only patients with CDR plus NACC FTLD with sum of boxes ≥0.5 and ≤9 AND global score of 0.5 or 1 will be enrolled.
- Stable use of background medications at least 8 weeks prior to LY3884963 dosing.
- Carrier of a pathogenic progranulin gene (GRN) mutation confirmed by the central laboratory.
- Negative screening test for Mycobacterium tuberculosis (MTB) or documented negative MTB test within 1 year prior to Screening.
- Age- and gender-appropriate cancer screenings are up to date and completed per the Investigator's judgment and local standard of care prior to Screening.
- Patient and/or patient’s legally authorized representative (LAR) (where applicable by local regulation) 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 study partner/informant (e.g., family member, friend) 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).
- Patient is generally ambulatory and not dependent on a walker or wheelchair.
- Patient is living in the community (i.e. not in a nursing home); some levels of assisted living may be permitted at the Investigator's discretion.
- Pneumococcal pneumonia and shingles vaccines are required within 10 years of Screening (allowed to be performed during Screening but must be given at least 4 weeks prior to initiation of immunosuppressant regimen).
Exclusion Criteria
- Diagnosis of a significant central nervous system (CNS) disease other than FTD that may be a cause for the patient's FTD symptoms or may confound study objectives.
- Brain or cervical spine magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) imaging indicating clinically significant abnormality considered to prevent intracisternal magna (ICM) injection.
- Hypersensitivity or contraindications to corticosteroid, and/or sirolimus use (including, but not limited to, osteoporosis with vertebral fractures within 1 year prior to Screening, poorly controlled diabetes, uncontrolled hypertension, and uncontrolled hyperlipidemia or hypercholesterolemia per Investigator’s assessment).
- Clinical evidence of peripheral symmetric sensory polyneuropathy (stable sensory mononeuropathies and radiculopathies are not exclusionary).
- Concomitant disease or condition within 6 months of Screening that could interfere with, or treatment of which might interfere with, the conduct of the study or that would, in the opinion of the Investigator, pose an unacceptable safety risk to the patient or interfere with the patient's ability to comply with study procedures.
- Clinically significant abnormalities in laboratory test results at Screening.
- Participation within 3 months prior to Screening in another therapeutic investigational drug or device study with purported disease-modifying effects on FTD, unless it can be documented that the patient received placebo only.
- Any type of prior gene or cell therapy.
- Live vaccines in the 4 weeks prior to Screening. Note: Pneumococcal vaccine and/or shingles vaccine administration is allowed at least 4 weeks prior to initiation of immunosuppressant regimen.
- Use of blood thinners (e.g., warfarin, heparin, and novel oral anticoagulants) in the 2 weeks prior to Screening or the anticipated need to initiate blood thinners during the study. Antiplatelet therapies (prophylactic aspirin, clopidogrel) are acceptable if the patient is medically able to temporarily stop 48 hours to 7 days (depending on the antiplatelet medication used) prior to and at least 48 hours after ICM injection and LP. Note: the use of blood thinners as part of prophylaxis or treatment of an emergent VTE or another AE during the study does not exclude the patient, unless there is a baseline high risk of thromboembolic events, and use of blood thinners is highly anticipated in the opinion of the Investigator.
- Contraindications or intolerance to imaging methods (MRI, MRA, and/or computed tomography [CT]), including claustrophobia and intolerance to contrast agents used for MRI, MRA, or CT (including, but not limited to, gadolinium contrast agents and iohexol).
- Contraindications to general anesthesia or deep sedation.
- Positive urine test for drugs of abuse (including opiates, amphetamines, cocaine, barbiturates, and phencyclidine) without prescription at Screening and on Day -1.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 Jan 2025 | 5 |
 France | Not Recruiting | 01 Jan 2025 | 8 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Rapamune 0.5 mg coated tablets | Other | COATED TABLETS | ORAL | — | — | PRD3342131 |
Rapamune 0.5 mg coated tablets | Other | COATED TABLETS | ORAL | — | — | PRD3342090 |
PREDNISONA CINFA 10 MG COMPRIMIDOS | Other | COMPRIMIDOS | ORAL | — | — | PRD2845105 |
Rapamune 1 mg coated tablets | Other | COATED TABLETS | ORAL | — | — | PRD505882 |
Rapamune 0.5 mg coated tablets | Other | COATED TABLETS | ORAL | — | — | PRD3342176 |
Rapamune 1 mg coated tablets | Other | COATED TABLETS | ORAL | — | — | PRD3342103 |
Rapamune 1 mg coated tablets | Other | COATED TABLETS | ORAL | — | — | PRD3342156 |
Prednisone Mylan Pharma 5 mg compresse | Other | COMPRESSE | ORAL | — | — | PRD3465897 |
Rapamune 0.5 mg coated tablets | Other | COATED TABLETS | ORAL | — | — | PRD3342146 |
Rapamune 1 mg coated tablets | Other | COATED TABLETS | ORAL | — | — | PRD3342172 |