Frontotemporal Dementia MedDRA version: 21.1 Level: PT Classification code 10068968 Term: Frontotemporal dementia System Organ Class: 10029205 - Nervous system disorders
Conditions
Interventions
Product Name: AL001
Product Code: AL001
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: not available
CAS Number: N/A
Current Sponsor code: AL001
Other descriptive name: AL001
Concentr
Sponsors
Alector Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Participants must meet all of the criteria specific to their applicable participant category. 1) Participant completed Study AL001-1 through the Day 57 visit and did not experience AEs that the investigator deems would prevent safe participation in Study AL001-2 2) Participant meets 1 or more of the 6 behavioral/cognitive symptoms required for a diagnosis of possible behavioral variant frontotemporal dementia (bvFTD; Rascovsky 2011) or has diagnosis of primary progressive aphasia (PPA; Gorno Tempini 2011) 3) Participant completed Study AL001-1 through the Day 43 visit and did not experience AEs that the investigator deems would prevent safe participation in Study AL001-2 4) Participant is a carrier of a loss of function GRN mutation causative of FTD and knows their mutation status 5) Participant has a CDR® plus NACC global score of 0.5, 1, or 2; and 1 or more of the 6 behavioral/cognitive symptoms required for a diagnosis of possible bvFTD (Rascovsky 2011) or a diagnosis of PPA (Gorno Tempini 2011) In addition, this is the list of the important inclusion criteria • Participants are 18 to 85 years of age • At screening, female participants must be nonpregnant and nonlactating, and at least one of the following conditions must apply - Participant is not a woman of childbearing potential (WOCBP) (either surgically sterilized or physiologically incapable of becoming pregnant, or at least 1 year postmenopausal [amenorrhea duration of 12 consecutive months with no identified cause other than menopause]) - Participant is a WOCBP and using an acceptable contraceptive method from screening until 8 weeks after the last dose of study drug. Acceptable contraception is defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, or a condom. In addition, total abstinence, in accordance with the lifestyle of the participant, is acceptable - A WOCBP must have a serum pregnancy test conducted at screening Additional requirements for pregnancy testing during and after study intervention are located in the Schedule of Assessments ( in the protocol) • Male participants, if not surgically sterilized, must agree to use acceptable contraception and not donate sperm from Day 1 until 8 weeks after the last dose of study drug. Acceptable contraception for the male participant (and his female partner) is defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, or a condom. In addition, total abstinence, in accordance with the lifestyle of the participant, is acceptable •Participant agrees not to donate blood or blood products for transfusion for the duration of the study and for 1 year after final dose of study drug •Participant is willing and has the ability to comply with the study protocol requirements, in the opinion of the investigator • Participant is willing and able to give informed consent. If the study participant is not competent, a legally authorized representative must provide informed consent on their behalf, and the participant must provide assent, in accordance with the local regulations, guidelines, and institutional review board (IRB) or independent ethics committee (IEC) •Participant has availability of a person (“study partner”) who has frequent and sufficient contact with the participant (at least 5 hours per week of in person contac
Exclusion criteria
Exclusion criteria: • Participant has a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins. • Participant has history of substance use disorder (drug or alcohol) within the past 2 years, with the exception of nicotine, as defined by the Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria (American Psychiatric Association 2013). •Participant currently has or has had an acute illness or infection that requires oral or IV antibiotics within 30 days prior to study drug administration that may affect safety assessments. •Participant has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise their ability to comply with the protocol required testing or procedures or compromise the participant's well-being, safety, or clinical interpretability. •Participant has had any surgery or hospitalization during the 30 days prior to study drug administration • Participant has history of cancer • Participant has history or presence of intracranial tumor that is clinically relevant (e.g. glioma, cerebral metastasis). • Participant is positive for hepatitis B surface antigen, hepatitis C virus antibodies, or human immunodeficiency virus 1 and 2 antibodies or antigen, or history of spirochetal infection of the CNS. • Participant has significant kidney disease as indicated by a screening creatinine clearance <30 mL/min as calculated by the central laboratory using the Cockcroft Gault formula, which remains <30 mL/min if retested. • Participant has impaired hepatic function as indicated by screening aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =2.5 the upper limit of normal (ULN) or total bilirubin =2.0 × ULN, which remains above either of these limits if retested or other abnormalities in synthetic function that are clinically significant. •Participant has had unstable or clinically significant cardiovascular disease (e.g., myocardial infarction, angina pectoris, New York Heart Association Class III or more cardiac failure) within the last 2 years. • Participant has uncontrolled hypertension. • Participant has history or presence of an abnormal ECG that is clinically significant including complete left bundle branch block, second- or third degree heart atrioventricular block, or evidence of prior acute or subacute myocardial infarction or ischemia.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the safety and tolerability of intravenous (IV) administration of AL001 over 48 weeks in asymptomatic and symptomatic carriers of a granulin (GRN) mutation causative of frontotemporal dementia (FTD) and in symptomatic carriers of a C9orf72 mutation causative of FTD.;Secondary Objective: The secondary objectives of this study are to evaluate the effect of IV administration of AL001 over 48 weeks in asymptomatic and symptomatic carriers of a GRN mutation causative of FTD and in symptomatic carriers of a C9orf72 mutation causative of FTD on the following: •Pharmacokinetics (PK) •Longitudinal plasma and CSF PGRN concentration levels •Longitudinal levels of SORT1 in WBCs;Primary end point(s): Primary Safety Endpoints: To assess the potential effect of cumulative exposure on the safety profile of AL001, the following will be evaluated by dose, such as by using tertiles of the actual dose (normalized to weight) received: • Incidence, nature, and severity of AEs and SAEs • Incidence of treatment discontinuations and study discontinuations due to AEs • Physical examination abnormalities • Neurological examination abnormalities • Changes in vital signs from baseline over time • Changes in ECGs from baseline over time • MRI abnormalities after dosing relative to baseline • Changes in clinical laboratory tests from baseline over time • Sheehan Suicidality Tracking Scale (Sheehan-STS) • Incidence of ADAs to AL001;Timepoint(s) of evaluation of this end point: AEs: will be summarized if applicable Laboratory data: at base line and at scheduled timepoints Vital signs: at base line and at scheduled timepoints ECG: at baseline and at scheduled timepoints Physical examinations: at Screening and at scheduled timepoints or as clinically indicated Neurological examinations and Sheehan-STS: At Screening and at scheduled timepoints ADA: at baseline and at scheduled timepoints | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary Pharmacokinetic (PK) Endpoints: • Serum concentration of AL001 at specified time points • AL001 PK parameters (if data permit) - Cmax - Ctrough - AUCss Secondary Pharmacodynamic (PD) Biomarker Endpoints: • The overall change from baseline in PGRN in CSF • The overall change from baseline in PGRN in plasma •The overall change from baseline in SORT1 in WBCs Exploratory PD Biomarker Endpoints: •The overall change from baseline in exploratory biomarkers of neurodegeneration, lysosomal function, and glial activity in blood, plasma, and CSF •Global and regional brain MRI atrophy measures •Neuroinflammation assessed by TSPO-PET (for UK participants who agree to participate in the optional imaging assessment only; see Appendix 3 [Section 14.3] •Correlations among exploratory fluid biomarkers, imaging measures, and COAs Exploratory Clinical Endpoints: The overall change from baseline on the scores of the instruments in the COAs •Clinical Dementia Rating Dementia Staging Instrument PLUS National Alzheimer’s Disease Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR® plus NACC FTLD) •Frontotemporal Dementia Rating Scale (FRS) •Clinician’s Global Impression-Improvement (CGI I) •Clinician’s Global Impression-Severity (CGI S) •Color Trails Test (CTT) Part 2 •Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) •Winterlight and Summerlight Lab Speech Assessments (WLA and SLA; for participants who agree to participate in these optional assessments only);Timepoint(s) of evaluation of this end point: For Pharmacokinetic (PK), at day 1, day 10, day 29, day 57, day 85, day 113, day 141, day 169, day 197, day 225, day 253, day 281, day 309, day 337 and at study completion. For Pharmacodynamic (PD), at day 1, day 10, day 29, day 57, day 85, day 113, day 141, day 169, day 197, day 225, day 253, day 281, day 309, day 337 and at study completion. | — |
Countries
Canada, Germany, Italy, Netherlands, United Kingdom, United States
Contacts
Public ContactKristina Vlaovic
Alector Inc.
Outcome results
None listed