|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Medical condition in easily understood language
|A type of dementia that causes problems with behaviour and language
|Diseases [C] - Nervous System Diseases [C10]
|E.1.2 Medical condition or disease under investigation
|System Organ Class
|10029205 - Nervous system disorders
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|To evaluate the efficacy of AL001 compared with placebo in carriers of progranulin gene (GRN) mutations causative of frontotemporal dementia (FTD) as measured by 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).
|Secondary objectives of the trial
|The secondary objectives of this study are to evaluate the clinical effects, safety, and tolerability of AL001 compared with placebo in carriers of GRN mutations causative of FTD as measured by:
Clinical outcome assessments (COAs)
Secondary Pharmacodynamic (PD) Objective:
Disease pathology biomarkers
Secondary Safety Objective:
Safety assessments and antidrug antibodies (ADAs)
|Trial contains a sub-study
|Principal inclusion criteria
|Each participant must meet all of the following criteria to be enrolled in this study.
Key Inclusion Criteria:
•Participant is a known carrier of a heterozygous loss-of-function GRN mutation causative of FTD, with either:
•A global CDR® plus NACC FTLD score of 0 and an elevated level of serum NfL as measured on the Simoa NF-Light Advantage Kit assay (pre-symptomatic participants) or,
• A global CDR® plus NACC FTLD score of 0.5, 1, or 2; and 1 or more of the
6 behavioral/cognitive symptoms required for a diagnosis of possible bvFTD, or a diagnosis of PPA (symptomatic participants).
General Inclusion Criteria:
2. Presymptomatic participants (with a global CDR® plus NACC FTLD score of 0) are 45 to 85 years of age, inclusive, at screening, or symptomatic participants (with a global CDR® plus NACC FTLD score of 0.5,1, or 2) are 25 to 85 years of age, inclusive, at screening
3. At screening, female participants must be nonpregnant and nonlactating, and 1 of the following conditions must apply:
a. 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]).
b. Participant is a WOCBP and agrees to use an acceptable contraceptive method from screening until 10 weeks after the last dose of study treatment. Acceptable contraception is defined as using hormonal contraceptives (e.g. combined oral contraceptive pill) 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 described in the Schedules of Assessments.
4. Male participants must agree to use acceptable contraception and not donate sperm from Day 0 until 10 weeks after the last dose of study treatment. Acceptable contraception for the male participant when having sexual intercourse with a WOCBP who is not currently pregnant is defined as using a condom. In addition, WOCBP partners must use hormonal contraceptives (e.g. combined oral contraceptive pill) or an intrauterine device.
5. Participant agrees not to donate blood or blood products for transfusion for the duration of the study and for 1 year after the final dose of study treatment.
6. Participant is willing to and can comply with the study protocol requirements, in the opinion of the investigator.
7. 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).
8. 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 contact), can provide accurate information regarding the participant’s behavior, cognitive, and functional abilities as well as their health throughout the study, agrees to provide information at investigational site visits that require partner input for COA completion, and gives the necessary informed consent.
a. Pre-symptomatic participants (global CDR® plus NACC FTLD score of 0) require
the study partner at the COA visits only; symptomatic participants require the
study partner at each visit. Pre-symptomatic participants who become symptomatic
(global CDR® plus NACC FTLD score of 0.5 or greater) during the study treatment period require the study partner at each visit moving forward through Study Completion.
b. The study partner must have sufficient cognitive capacity to accurately report upon the participant’s behavior, cognitive, and functional abilities in the opinion of the investigator. The study partner should be in sufficiently good general health to
have a high likelihood of maintaining the same level of interaction with the participant and participation in study procedures throughout the study duration.
c. The same study partner should participate throughout the duration of the study. If a change in study partner is necessary, the Medical Monitor must be contacted.
|Principal exclusion criteria
|1. Participant has 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.
2. Participant has a known mutation causative of neurodegenerative disorder(s) other than heterozygous loss-of-function GRN mutations causative of FTD.
3. Participant has a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins.
4. Participant has a history of moderate or severe substance use disorder within the past
2 years, with the exception of nicotine, as defined by the Diagnostic and Statistical
Manual of Mental Disorders, fifth edition criteria
5. Participant currently has or has had an acute illness that requires or required systemic antibiotics within 30 days prior to study treatment administration.
6. Participant has clinically significant vitamin B12 or folate deficiency (if treated, must be on a stable regimen for at least 3 months prior to study treatment administration).
7. Participant has untreated hypothyroidism (if treated, thyroid supplementation dose must be stable for at least 3 months with a normal thyroid-stimulating hormone level prior to study treatment administration).
8. Participant has insufficiently controlled diabetes mellitus (e.g., hemoglobin A1C
9. Participant has had any surgery (major or emergent) or hospitalization within 30 days prior to study treatment administration.
10. Participant has a history of cancer except if it:
a.Is considered likely to be cured; b.Is not being actively treated with anticancer therapy or radiation and in the opinion of the investigator, is not likely to require treatment in the ensuing
3 years; c.Is considered to have low probability of recurrence (with supporting documentation from the treating oncologist if possible), including participants with ongoing antihormonal treatment (e.g., tamoxifen);d.For prostate cancer, has not had significant progression within the past 2 years.
11. Participant is positive for hepatitis B surface antigen, human immunodeficiency
virus-1 or -2 antibodies or antigen, or history of spirochetal infection of the CNS (e.g., syphilis, borreliosis, or Lyme disease). Participants with a positive hepatitis C virus antibody will be allowed if hepatitis C RNA is negative.
12. Participant has significant kidney disease as indicated by either of the following:
a. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, according to the re-expressed abbreviated (four-variable) MDRD Study equation
b.Creatinine ≥2 mg/dL.
13. 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. Note: Participants with Gilbert's syndrome are eligible to participate
14. Participant has hematologic abnormalities as indicated by hemoglobin ≤9 g/dL; white blood cells (WBC) ≤3 000/mm3; absolute neutrophil count ≤1 500/mm3; or platelet count ≤100 000/mm3.
15. Participant has or has had unstable or clinically significant cardiovascular disease within the past 2 years.
16. Participant has uncontrolled hypertension (e.g., repeated supine diastolic blood pressure [BP] >95 mm Hg).
17. Participant has a history or presence of an abnormal ECG that is clinically significant, or evidence of acute or subacute myocardial infarction or ischemia.
18. Participant has history of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease or clinically significant electrolyte abnormalities Note: Participants with premature ventricular contractions are eligible to participate.
19. For participants who consent to lumbar puncture, participant has contraindication to lumbar dural puncture, including coagulopathy, concomitant anticoagulation medication (except for a platelet inhibitor such as aspirin), thrombocytopenia, or other factor(s) that precludes safe lumbar puncture.
20. Participant has history or presence of clinically evident vascular disease potentially affecting the brain
21. Participant has history of a clinically significant, persistent neurologic deficit, structural brain damage, or CNS trauma.
22. Participant resides in a skilled nursing facility, convalescent home, or long-term care facility at screening; or requires continuous nursing care.
23. Participant is unable to tolerate MRI procedures or has a contraindication to MRI
24. 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
|E.5 End points
|Primary end point(s)
|Primary Efficacy Endpoint:
•The CDR® plus NACC FTLD-SB
|Timepoint(s) of evaluation of this end point
|Baseline and weeks 16, 32 and 48 for symptomatic patients and baseline and weeks 16,32, 48, 64, 80 and 96 for pre symptomatic patients.
|Secondary end point(s)
•Clinical Global Impression-Severity (CGI S)
•Clinical Global Impression-Improvement (CGI I)
•The changes from baseline in the scores of the following COAs:
o Frontotemporal Dementia Rating Scale (FRS)
o Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
Secondary PD Endpoints:
•The changes from baseline in the following:
o Structural volumetric magnetic resonance imaging (MRI) whole and regional brain volume
o Progranulin protein (PGRN) concentrations in plasma and optional cerebrospinal fluid
(CSF) o Neurofilament-light chain (NfL)
concentrations in serum and optional CSF
Secondary Safety Endpoints:
•Incidence, nature, and severity of adverse events and serious adverse events
•Physical examination abnormalities
•Neurological examination abnormalities
•Changes in vital signs from baseline over time
•Changes in electrocardiograms from baseline over time
•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
|Secondary endpoints: every 16 weeks.
PD endpoints: MRI every 24 weeks PGRN and NfL measurements every 8 weeks and safety assessments every 4 weeks.
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days