A Phase 3 Study to Evaluate Efficacy and Safety of AL001 in Frontotemporal Dementia (INFRONT-3)

Study Overview
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Brief Summary
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A phase 3 double blind, placebo controlled study evaluating the efficacy and safety of AL001 in participants at risk for or with frontotemporal dementia due to heterozygous mutations in the progranulin gene.

Detailed Description
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This is a phase 3 double blind, placebo controlled study evaluating the efficacy and safety of AL001 administered intravenously in participants at risk for or with frontotemporal dementia due to heterozygous mutations in the progranulin gene. Study completion marks the end of the open label extension period following the 96-week blinded portion of the study.

Official Title
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A Phase 3, Multicenter, Randomized, Double Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of AL001 in Individuals at Risk for or With Frontotemporal Dementia Due to Heterozygous Mutations in the Progranulin Gene

Conditions
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Frontotemporal Dementia

Intervention / Treatment
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* Drug: AL001
* Drug: Placebo
* Drug: Open label - AL001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Persons with a progranulin gene mutation and at risk of developing FTD symptoms as evidenced by a biomarker, or persons with a progranulin gene mutation and diagnosed with FTD. If symptomatic, one or more of the criteria for the diagnosis of possible behavioral variant FTD, or a diagnosis of Primary Progressive Aphasia. Study partner who consents to study participation and who cares for/visits the participant daily for at least 5 hours per week. Written informed consent must be obtained and documented (from the participant or, where jurisdictions allow it, from their legal decision maker). Exclusion Criteria: Dementia due to a condition other than FTD including, but not limited to, Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, Huntington disease, or vascular dementia. Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins. Current uncontrolled hypertension, diabetes mellitus or thyroid disease. Clinically significant heart disease, liver disease or kidney disease. History or evidence of clinically significant brain disease other than FTD. Females who are pregnant or breastfeeding, or planning to conceive within the study period. Any experimental vaccine or gene therapy. History of cancer within the last 5 years. Current use of anticoagulant medications (e.g., coumadin, heparinoids, apixaban). Residence in a skilled nursing facility, convalescent home, or long term care facility at screening; or requires continuous nursing care.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 85 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: AL001<br>AL001 every 4 weeks | Drug: AL001<br>* Administered via intravenous (IV) infusion<br>|
| Placebo Comparator: Placebo<br>Placebo every 4 weeks | Drug: Placebo<br>* Administered via intravenous (IV) infusion<br>|
| Experimental: Open label - AL001<br>AL001 every 4 weeks | Drug: Open label - AL001<br>* Administered via intravenous (IV) infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of efficacy of AL001 as measured by the CDR® plus NACC FTLD-SB | The Clinical Dementia Rating Dementia Staging Instrument PLUS National Alzheimer's Disease Coordinating Center frontotemporal lobar degeneration Behavior & Language Domains Sum of Boxes (CDR® plus NACC FTLD-SB) is administered by a healthcare professional and based on individual ratings of the eight domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, personal care, language and behavior. Impairment is scored on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2 and severe = 3. The 8 individual domain ratings, or box scores, were added together to give the CDR® plus NACC FTLD-SB which ranges from 0-24. Higher score indicates severe impairment. | Through study completion, on average up to 96 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Clinical Global Impression-Severity (CGI-S) Score | The CGI-S is used by a clinician to rate the severity of a participant's disease relative to the clinician's past experience with patients who have the same disease using an ordinal scale ranging from 1=normal, not at all ill; 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; and 7=among the most extremely ill patients. Higher scores indicate worsening. | Baseline to 96 weeks | 
| Change in Clinical Global Impression-Improvement (CGI-I) Score | The CGI-I is used by a clinician to rate how much a participant's disease has improved or worsened relative to baseline using an ordinal scale ranging from 1=very much improved; 2=much improved; 3=minimally improved; 4=no change from baseline; 5=minimally worse; 6= much worse; and 7=very much worse. Higher scores indicate worsening. | Baseline to 96 weeks | 
| Change in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Score | RBANS is 20 to 25 minute battery developed for cognitive assessment, detection, and characterization of dementia. RBANS includes 12 subtests that measure following 5 indices: (1)Attention Index, composed of Digit Span and Coding; (2)Language Index, consisting of Picture Naming and Semantic Fluency subtests; (3)Visuospatial/Construction Index, made up of Figure Copy and Line Orientation subtests; (4)Immediate Memory Index, composed of List Learning and Story Memory subtests, and (5)Delayed Memory Index, consisting of List Recall, List Recognition, Story Recall, and Figure Recall subtests. Completion of RBANS yields 5 index scores based on participant performance on various subtests, as well as a composite Total Index score for battery. Total index scores range from 40 to 160, and are normalized to a mean of 100 and standard deviation (SD) of 15. Higher scores indicate less impairment. | Baseline to 96 weeks | 
| Pharmacodynamic Biomarkers | Change in magnetic resonance imaging and blood-based biomarkers and optional CSF biomarkers (neurofilament light chain and progranulin) | Baseline to 96 weeks | 
| Evaluation of safety and tolerability of AL001: Incidence of adverse events | Incidence of adverse events | Baseline to 96 weeks |