E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
A type of dementia that causes problems with behaviour and language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10068968 |
E.1.2 | Term | Frontotemporal dementia |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | 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). |
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E.2.2 | 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:
Secondary Objective:
Clinical outcome assessments (COAs)
Secondary Pharmacodynamic (PD) Objective:
Disease pathology biomarkers
Secondary Safety Objective:
Safety assessments and antidrug antibodies (ADAs)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Each participant must meet all of the following criteria to be enrolled in this study.
Key Inclusion Criteria:
• Known progranulin genetic mutation causing FTD.
• CDR plus NACC-FTLD score 0-2.
• If symptomatic, one of the criteria for the diagnosis of probable behavioral variant FTD or FTD-semantic subtype or FTD-Progressive Nonfluent Aphasia.
• Study partner who consents to study participation and who cares for/visits the patient daily for at least 5 hours per week.
• Written informed consent must be obtained and documented (from the patient or, where jurisdictions allow it, from their legal decision maker).
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E.4 | Principal 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 except:
If considered to be cured
If not being actively treated with anti-cancer therapy or radiotherapy and, in the opinion of the investigator, not likely to require treatment in the ensuing 3 years
Is considered to have low probability of recurrence
For prostate cancer, no significant progression over the previous 2 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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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
•The CDR® plus NACC FTLD-SB
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E.5.1.1 | 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. |
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E.5.2 | Secondary end point(s) |
Secondary Endpoints:
•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
•MRI abnormalities
•Changes in clinical laboratory tests from baseline over time
•Sheehan-Suicidality Tracking Scale (Sheehan STS)
•Incidence of ADAs to AL001
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E.5.2.1 | 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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 31 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Belgium |
Canada |
France |
Germany |
Italy |
Netherlands |
Portugal |
Spain |
Sweden |
Switzerland |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 30 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |