Study to Assess the Safety, Tolerability, and Pharmacodynamic (PD) Effects of FRM-0334 in Subjects With Prodromal to Moderate Frontotemporal Dementia With Granulin Mutation

Study Overview
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Brief Summary
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The purposes of this study are to investigate the safety, tolerability, and pharmacodynamics of FRM-0334 in subjects with prodromal to moderate frontotemporal dementia with granulin mutation.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalating, Phase 2a Safety, Tolerability, and Pharmacodynamic Study of Two Doses of an Histone Deacetylase Inhibitor (FRM-0334) in Subjects With Prodromal to Moderate Frontotemporal Dementia With Granulin Mutation

Conditions
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Granulin Mutation

Intervention / Treatment
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* Drug: FRM-0334
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ages aged ≥21 and ≤75 years Genotyped positive for a FTD-GRN mutation, and aware of it Prodromal to moderate FTD-GRN Resides in a stable living situation, living at home, senior residential setting, or an institutional setting without the need for continuous (ie, 24-hour) nursing care Proficiency (oral and written) in the language in which study-related documents, including the ICF and standardized tests, will be administered Able to swallow capsules Be in good general health, willing and able to comply with the protocol requirements, and expected to complete the study as designed (in the judgment of the investigator) Exclusion Criteria: Clinically significant abnormalities on physical examination, medical history, ECG, vital signs, laboratory values, or unstable medical or psychiatric illness Females who are pregnant, breastfeeding, or planning to become pregnant during the study

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 75 Years

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FRM-0334; Arm 1<br>low dose, Capsule, Once Daily, Day 1 through Day 28 | Drug: FRM-0334<br> <br> |
| Experimental: FRM-0334; Arm 2<br>high dose, Capsule, Once Daily, Day 1 through Day 28 | Drug: FRM-0334<br> <br> |
| Placebo Comparator: Placebo Comparator; Arm 3<br>Placebo, Capsule, Once Daily, Day 1 through Day 28 | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the safety and tolerability of FRM-0334 | Number and percentage of subjects with AEs Number and percentage of subjects with SAEs Number and percentage of subjects who discontinue due to AEs Number and percentage of subject deaths | Baseline to Day 28 or Early Termination | 
| Assess the pharmacodynamic (PD) effects of FRM-0334 on the change from baseline in plasma concentrations of progranulin (PGRN) after 28 days |  | Baseline to Day 28 or Early Termination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the pharmacodynamic effects of FRM-0334 on the change from baseline in cerebrospinal fluid (CSF) concentrations of PGRN after 28 days | Change in CSF progranulin concentration from baseline | Baseline and Day 28 | 
| Characterize the plasma concentrations of FRM-0334 and metabolites following once daily dosing for 28 days | Cmax, Ctrough, tmax, t1/2, λz, AUC(0-τ), CL/F, Cav in plasma | Day 1 to Day 28 or Early Termination | 
| Characterize the CSF concentrations of FRM-0334 and metabolites following once daily dosing for 28 days | Cmax, Ctrough, tmax, t1/2, AUC0-τ, CL/F, Cav in CSF | Day 1 to Day 28 or Early Termination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Histone deacetylase inhibitor, Frontotemporal dementia, Granulin