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

Phase 3

Active, not recruiting

• Conditions: Frontotemporal Dementia
• Interventions: Drug: AL001; Drug: Placebo; Drug: Open label - AL001

• Registration Number: NCT04374136
• Lead Sponsor: Alector Inc.

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2020-04-23
• Study First Submitted QC: 2020-04-30
• Study First Posted: 2020-05-05
• Study Start: 2020-07-23
• Status Verified: 2024-07
• Last Update Submitted: 2024-10-17
• Last Update Posted: 2024-10-21
• Primary Completion: 2025-09-01
• Study Completion: 2027-10-11

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 110

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).

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
AL001	AL001	AL001 every 4 weeks
Placebo	Placebo	Placebo every 4 weeks
Open label - AL001	Open label - AL001	AL001 every 4 weeks

Primary Outcome Measures

Name	Time	Method
Evaluation of efficacy of AL001 as measured by the CDR® plus NACC FTLD-SB	Through study completion, on average up to 96 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Evaluation of safety and tolerability of AL001: Incidence of adverse events	Baseline to 96 weeks	Incidence of adverse events
Change in Clinical Global Impression-Severity (CGI-S) Score	Baseline to 96 weeks	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.
Change in Clinical Global Impression-Improvement (CGI-I) Score	Baseline to 96 weeks	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.
Change in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Score	Baseline to 96 weeks	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.
Pharmacodynamic Biomarkers	Baseline to 96 weeks	Change in magnetic resonance imaging and blood-based biomarkers and optional CSF biomarkers (neurofilament light chain and progranulin)

Trial Locations

Locations (61)

Hospital Clinico San Carlos; 🇪🇸 Madrid, Spain

Karolinska Universitetssjukhuset Huddinge - PPDS; 🇸🇪 Huddinge, Sweden

Dignity Health; 🇺🇸 Phoenix, Arizona, United States

University of California San Diego; 🇺🇸 La Jolla, California, United States

University of Colorado; 🇺🇸 Aurora, Colorado, United States

University of Miami Medical Center; 🇺🇸 Miami, Florida, United States

Emory University; 🇺🇸 Atlanta, Georgia, United States

Indiana University Health Neuroscience Center; 🇺🇸 Indianapolis, Indiana, United States

University of Kansas Alzheimer's Disease Center; 🇺🇸 Fairway, Kansas, United States

Johns Hopkins University School of Medicine; 🇺🇸 Baltimore, Maryland, United States

Mayo Comprehensive Cancer Center - PPDS; 🇺🇸 Rochester, Minnesota, United States

Irving Institute for Clinical and Translational Research; 🇺🇸 New York, New York, United States

University of North Carolina at Chapel Hill; 🇺🇸 Chapel Hill, North Carolina, United States

University Of Cincinnati Gardner Neuroscience institute; 🇺🇸 Cincinnati, Ohio, United States

Case Western Reserve University; 🇺🇸 Cleveland, Ohio, United States

Oregon Health and Science University; 🇺🇸 Portland, Oregon, United States

University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

Houston Methodist Institute for Academic Medicine; 🇺🇸 Houston, Texas, United States

University of Texas Health Science Center at San Antonio; 🇺🇸 San Antonio, Texas, United States

Froedtert and The Medical College of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States

CENydET S.R.L.; 🇦🇷 Retiro, Ciudad Autónoma de BuenosAires, Argentina

Fundación Para La Lucha Contra Las Enfermedades Neurológicas de La Infancia; 🇦🇷 Buenos Aires, Argentina

INECO Castaño; 🇦🇷 San Juan, Argentina

Box Hill Hospital; 🇦🇺 Box Hill, Australia

Royal Prince Alfred Hospital; 🇦🇺 Camperdown, Australia

The Queen Elizabeth Hospital; 🇦🇺 Woodville, Australia

UZ Leuven; 🇧🇪 Leuven, Vlaams Brabant, Belgium

Felix Platter Spital; 🇨🇭 Basel, Switzerland

The University of Western Ontario; 🇨🇦 London, Canada

Sunnybrook Research Institute - University of Toronto; 🇨🇦 Toronto, Canada

CHU de Toulouse Hopital PURPAN; 🇫🇷 Toulouse, Haute-Garonne, France

Hopital Charles Nicolle - Hospital; 🇫🇷 Rouen, Seinne-Maritime, France

CHU de Bordeaux; 🇫🇷 Bordeaux, France

CHRU Lille; 🇫🇷 Lille, France

Groupe Hospitalier Pitié Salpétrière; 🇫🇷 Paris, France

Uniklinik Köln; 🇩🇪 Köln, Germany

Universitätsklinikum Ulm; 🇩🇪 Ulm, Germany

Eginitio University General Hospital of Athens - 1st University Neurology Clinic; 🇬🇷 Athens, Attica, Greece

University General Hospital of Alexandroupolis - Department of Neurology; 🇬🇷 Alexandroupoli, Evros, Greece

Azienda Unita Sanita Locale (ASL) di Reggio Emilia - IRCCS; 🇮🇹 Reggio Emilia, Emilia Romagna, Italy

Fondazione Istituto G.Giglio; 🇮🇹 Cefalù, Palermo, Italy

Nuovo Ospedale Civile S. Agostino-Estense di Baggiovara; 🇮🇹 Baggiovara, Italy

IRCCS Istituto delle Scienze Neurologiche di Bologna; 🇮🇹 Bologna, Italy

ASST degli Spedali Civili di Brescia - Spedali Civili di Brescia; 🇮🇹 Brescia, Italy

IRCCS - Centro S. Giovanni di Dio Fatebenefratelli; 🇮🇹 Brescia, Italy

Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico; 🇮🇹 Milano, Italy

Fondazione IRCCS Di Rilievo Nazionale Istituto Nazionale Neurologico Carlo Besta; 🇮🇹 Milano, Italy

PIA Fondazione Panico; 🇮🇹 Tricase, Italy

Erasmus MC; 🇳🇱 Rotterdam, Netherlands

Centro Hospitalar E Universitário de Coimbra EPE; 🇵🇹 Coimbra, Portugal

Centro Hospitalar de Lisboa Norte, EPE - Hospital de Santa Maria; 🇵🇹 Lisboa, Portugal

Hospital CUF Descobertas; 🇵🇹 Lisboa, Portugal

Centro Hospitalar do Porto - Hospital de Santo António; 🇵🇹 Porto, Portugal

Hospital Universitario Marques de Valdecilla; 🇪🇸 Santander, Cantabria, Spain

Hospital Clinic de Barcelona; 🇪🇸 Barcelona, Spain

Hospital Universitario de Donostia; 🇪🇸 Donostia-san Sebastián, Spain

Hospital Universitario de La Princesa; 🇪🇸 Madrid, Spain

Dokuz Eylul University; 🇹🇷 Izmir, Balcova, Turkey

Istanbul University Medical Faculty; 🇹🇷 Istanbul, Fatih, Turkey

University College London; 🇬🇧 London, United Kingdom