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Phase 1/2 Clinical Trial of LY3884963 in Patients With Frontotemporal Dementia With Progranulin Mutations (FTD-GRN) (PROCLAIM)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04408625
Recruitment Status : Recruiting
First Posted : May 29, 2020
Last Update Posted : January 17, 2024
Sponsor:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
Prevail Therapeutics

Brief Summary:
Study J4B-MC-OKAA is a Phase 1/2, multi-center, open-label ascending dose, first-in-human study that will evaluate the safety and effect of intra-cisternal LY3884963 administration on progranulin protein (PGRN) levels in patients with frontotemporal dementia with progranulin mutations (FTD-GRN). Two escalating dose (low dose and medium dose) cohorts are planned, as well as one bridging cohort which will allocate patients to receive either low or medium dose. The duration of the study is 5 years. During the first year, patients will be evaluated for the effect of LY3884963 on safety, tolerability, immunogenicity, biomarkers, and efficacy. Patients will follow up for an additional 4 years to monitor safety and changes on selected biomarkers and clinical outcomes.

Condition or disease Intervention/treatment Phase
Frontotemporal Dementia Biological: LY3884963 Drug: Methylprednisolone Drug: Optional Sirolimus Drug: Optional Prednisone Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 23 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : November 9, 2020
Estimated Primary Completion Date : August 31, 2029
Estimated Study Completion Date : August 31, 2029


Arm Intervention/treatment
Experimental: Initial Cohort - Low dose Biological: LY3884963
Participants will receive a single dose of LY3884963, administered intra cisterna magna

Drug: Methylprednisolone
IV pulses every 2 weeks in the first 3 months.

Drug: Optional Sirolimus
At the investigators discretion following steroid tolerability issues, patients may receive a loading dose, followed by maintenance dose, followed by dose tapering; administered as concomitant medication

Drug: Optional Prednisone
If needed and at the investigator discretion, Oral Prednisone may be added to the immunosuppression regimen

Experimental: Initial Cohort - Medium dose Biological: LY3884963
Participants will receive a single dose of LY3884963, administered intra cisterna magna

Drug: Methylprednisolone
IV pulses every 2 weeks in the first 3 months.

Drug: Optional Sirolimus
At the investigators discretion following steroid tolerability issues, patients may receive a loading dose, followed by maintenance dose, followed by dose tapering; administered as concomitant medication

Drug: Optional Prednisone
If needed and at the investigator discretion, Oral Prednisone may be added to the immunosuppression regimen

Experimental: Bridging Cohort - Low dose
Participants enrolled in the Bridging Cohort will be assigned to either low or medium dose in an alternating manner
Biological: LY3884963
Participants will receive a single dose of LY3884963, administered intra cisterna magna

Drug: Methylprednisolone
IV pulses every 2 weeks in the first 3 months.

Drug: Optional Sirolimus
At the investigators discretion following steroid tolerability issues, patients may receive a loading dose, followed by maintenance dose, followed by dose tapering; administered as concomitant medication

Drug: Optional Prednisone
If needed and at the investigator discretion, Oral Prednisone may be added to the immunosuppression regimen

Experimental: Bridging Cohort - Medium dose
Participants enrolled in the Bridging Cohort will be assigned to either low or medium dose in an alternating manner
Biological: LY3884963
Participants will receive a single dose of LY3884963, administered intra cisterna magna

Drug: Methylprednisolone
IV pulses every 2 weeks in the first 3 months.

Drug: Optional Sirolimus
At the investigators discretion following steroid tolerability issues, patients may receive a loading dose, followed by maintenance dose, followed by dose tapering; administered as concomitant medication

Drug: Optional Prednisone
If needed and at the investigator discretion, Oral Prednisone may be added to the immunosuppression regimen




Primary Outcome Measures :
  1. Number of Adverse Events (AEs), Serious Adverse Events (SAEs), and Adverse Events Leading to discontinuation [ Time Frame: 5 Years ]
  2. Sum of adverse reactions (ARs) and suspected ARs [ Time Frame: 5 years ]
  3. Sum of serious ARs and serious suspected ARs [ Time Frame: 5 years ]
  4. Incidence of procedure or treatment-emergent AEs [ Time Frame: 5 years ]
    Measured by brain and spine MRI

  5. Change in PGRN immunogenicity in blood [ Time Frame: Baseline and Month 12 ]
    PGRN: progranulin protein. Measured by level of antibodies and ELISPOT

  6. Change in PGRN immunogenicity in CSF [ Time Frame: Baseline and Month 12 ]
    CSF: cerebrospinal fluid

  7. Change in AAV9 immunogenicity in blood [ Time Frame: Baseline and Month 12 ]
    Measured by level of antibodies and ELISPOT.

  8. Change in AAV9, PGRN, and NfL immunogenicity in CSF [ Time Frame: Baseline and Month 12 ]
    Measured by levels of antibodies.

  9. Change in PGRN levels in blood [ Time Frame: Baseline and Month 12 ]
  10. Change in PGRN levels in CSF [ Time Frame: Baseline and Month 12 ]

Secondary Outcome Measures :
  1. Change in CDR plus NACC FTLD [ Time Frame: Baseline and Month 12 ]
    CDR: Clinical Dementia Rating staging instrument. NACC FTLD: National Alzheimer's Coordinating Center frontotemporal lobar degeneration domains

  2. Change in NfL levels in blood [ Time Frame: Baseline and Month 12 ]
    NfL: neurofilament light chain

  3. Change in NfL levels in CSF [ Time Frame: Baseline and Month 12 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   30 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 lbs) to ≤110 kg (242 lb) and a 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.
  • Stable use of background medications at least 8 weeks prior to LY3884963 dosing.
  • Carrier of a pathogenic progranulin gene (GRN) mutation.
  • Negative screening test for Mycobacterium tuberculosis (MTB) or documented negative MTB test within 1year prior to screening.
  • Age- and gender-appropriate cancer screenings are up-to-date and completed.
  • Patient and/or patient's legally authorized representative has the ability to understand the purpose and risks of the study, and provide written informed consent and authorization to use protected health information.
  • 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.
  • Patient is not dependent on a walker or wheelchair.
  • Patient is living in the community (i.e. not in nursing home); some levels of assisted living may be permitted at the discretion of the investigator.
  • 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 CNS (central nervous system) disease other than frontotemporal dementia (FTD) that may cause FTD symptoms or confound study objectives.
  • Brain or cervical spine magnetic resonance image (MRI)/MRA imaging showing clinically significant abnormality considered to prevent intracisternal magna (ICM) injection.
  • Hypersensitivity or contraindications to corticosteroid, and/or sirolimus use.
  • 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 laboratory test result abnormalities assessed 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 in the 2 weeks prior to screening, or anticipated use of blood thinners during the study. Antiplatelet therapies 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 (MRA, MRI, 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.

Other protocol-defined inclusion/exclusion criteria may apply


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04408625


Contacts
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Contact: Prevail Therapeutics (917) 336-9310 prevail.patients@lilly.com

Locations
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United States, Florida
PPD Phase 1 Clinic, 100 West Gore Street, Suite 202 Recruiting
Orlando, Florida, United States, 32806
Contact: Sarah Poissant    689-216-3100    sarah.poissant@ppd.com   
United States, Pennsylvania
Hospital of the University of Pennsylvania, 3 West Gates Building, 3400 Spruce Street Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Dahlia Kamel    215-662-6134    kamel.dahlia@pennmedicine.upenn.edu   
Australia, New South Wales
Royal Prince Alfred Hospital, Brain & Mind Research Institute, 94 Mallet Street Recruiting
Camperdown, New South Wales, Australia, 2050
Contact: Cassandra Kaizik    02 9515 4540    cassandra.kaizik@sydney.edu.au   
Belgium
UZ Leuven, Neurologie Herestraat 49 Recruiting
Leuven, Belgium, 3000
Contact: Carine Schildermans    3126345500    carine.schildermans@uzleuven.be   
France
Le Ber, Institut du Cerveau et de la Moelle Epinière Active, not recruiting
Paris, France, 75013
Spain
Hospital Clinic de Barcelona, Villaroel 170 Servicio de Neurología Recruiting
Barcelona, Spain, 08036
Contact: Beatriz Bosch Capdevila, PhD    [+34] 934518240 ext 3088    beabc6@hotmail.com/bbosch@clinic.cat   
Hospital Universitario de Donostia, Servicio De Neurologia, Consultas Externas Neurologia, San Sebastian, Guipúzcoa Recruiting
San Sebastian, Spain, 20014
Contact: Fermin Moreno    +39 443007027    fermin.morenoizco@osakidetza.eus   
United Kingdom
University College London,Queen Square, Dementia Research Building, London, Recruiting
London, United Kingdom, WC1N 3BG
Contact: Miguel Alvarez       miguel.alvarez.13@ucl.ac.uk   
Sponsors and Collaborators
Prevail Therapeutics
Eli Lilly and Company
Investigators
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Study Director: Olga Uspenskaya-Cadoz, MD, PhD Prevail Therapeutics
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Responsible Party: Prevail Therapeutics
ClinicalTrials.gov Identifier: NCT04408625    
Other Study ID Numbers: J4B-MC-OKAA (PRV-FTD101)
First Posted: May 29, 2020    Key Record Dates
Last Update Posted: January 17, 2024
Last Verified: January 2024

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Prevail Therapeutics:
Fronto-Temporal Dementia
Frontotemporal Dementia
Progranulin Mutations
FTD-GRN
Gene Therapy
Dementia Gene Therapy
AAV9
Additional relevant MeSH terms:
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Dementia
Frontotemporal Dementia
Aphasia, Primary Progressive
Pick Disease of the Brain
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Neurodegenerative Diseases
Frontotemporal Lobar Degeneration
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Aphasia
Speech Disorders
Language Disorders
Communication Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Sirolimus
Prednisone
Methylprednisolone
Methylprednisolone Acetate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Anti-Inflammatory Agents