| 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 |
Part 1: To evaluate the efficacy of AL001 compared with placebo in symptomatic participants as measured by CDR® plus NACC FTLD-SB.
Part 2: To assess the long-term safety and tolerability of AL001 in participants who have completed Part 1 of the study |
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| E.2.2 | Secondary objectives of the trial |
Part 1: Secondary Efficacy:
To evaluate the efficacy of AL001 compared with placebo in symptomatic participants as measured by CGI-S.
To evaluate the efficacy of AL001 compared with placebo in symptomatic participants as measured by CGI-I
To evaluate the efficacy of AL001 compared with placebo in symptomatic participants as measured by RBANS
Pharmacodynamic and Disease Biomarkers: To evaluate the treatment effect of AL001 compared with placebo as measured by pharmacodynamic and disease pathology biomarkers in the symptomatic population, the at-risk population, and all FTD participants (both symptomatic and at-risk).
Safety Objective: To evaluate the safety and tolerability of AL001 compared with placebo as measured by safety assessments and antidrug antibodies (ADAs) in the symptomatic population, the at-risk population, and all FTD participants (both symptomatic and at-risk).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part 1:
1. Is a known carrier of a heterozygous loss-of-function GRN mutation causative of FTD with a global CDR® plus NACC FTLD score of 0 to 2, and:
• A CDR® plus NACC FTLD-SB score ≤0.5 with an elevated level of serum NfL, or
• A CDR® plus NACC FTLD-SB score of >0.5 with 1 or more of the 6 behavioral/cognitive symptoms required for a diagnosis of possible bvFTD
(Rascovsky 2011), or a diagnosis of PPA
2. Age 25 to 85 years, inclusive, at Screening
3. At Screening, women must be nonpregnant and nonlactating, and one of the following conditions must apply:
a. 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. 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, if in accordance with the lifestyle of the participant, is acceptable.
c. 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. Men 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. 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. Willing to and can comply with the study protocol requirements, in the opinion of the investigator.
7. Willing and able to give informed consent. If the patient is not competent, a legally authorized representative must provide informed consent on their behalf, and the patient must provide assent, in accordance with local regulations, guidelines, and IRB or IEC.
8. Patient has the availability of a person (“study partner”) who has frequent and sufficient contact with the patient (at least 5 hours per week of in-person contact) and who can provide accurate information to the study site regarding the patient's behavior, cognitive, and functional abilities, as well as their health, throughout the study. Requirements for the study partner include:
a. Willing and able to provide informed consent to participate in the study as a study partner.
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.
c. 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.
d. The same study partner should participate throughout the duration of Part 1 of the study. If a change in study partner is necessary, the medical monitor must be contacted.
e. Study partner agrees to provide information at investigational site visits that require partner input for COA completion.
f. Study partner agrees to accompany the participant at COA visits
Inclusion criteria applicable to those participants participating in the optional Winterlight Labs Speech Assessment (WLA) only:
1. Has available and willing study partner to administer the WLA.
2. Has WiFi access in their residence or WiFi access in a private area where the testing can take place.
3. Participants and study partners must be proficient in English, Spanish, French, Dutch or German in the investigator’s opinion.
Part 2: Participant must complete Part1, week 97:
1. Participant is willing and able to give informed consent to continue treatment with AL001. If the study participant is not competent, a legally authorized representative must provide informed consent on his or her behalf, and the participant must provide assent, in accordance with the local regulations, guidelines, and IRB or IEC.
2. Is willing and has the ability to comply with OLE requirements, in the opinion of the investigator.
3. Has availability of a person (“study partner”) who can continue to assist with assessments throughout the OLE evaluation period. (For more information please refer to the protocol or as described on PART 1, inclusion criteria number 8) |
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| E.4 | Principal exclusion criteria |
Part 1:
1. Dementia due to a condition other than FTD including, but not limited to, Alzheimer’s disease, Parkinson’s disease, Parkinsonism, REM behavior disorder, dementia with Lewy bodies, Huntington disease, or vascular dementia2.Known mutation causative of neurodegenerative disorder(s) other than heterozygous loss-of-function GRN mutations causative of FTD.3.Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins.4.Signs or symptoms of progressive supranuclear palsy or bulbar dysfunction, such as postural instability, eye problems, and swallowing difficulties5. 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 criteria6.Clinically significant vitamin B12 or folate deficiency (if treated, must be on a stable regimen for at least 3 months prior to first study treatment administration)7.Untreated hypothyroidism8.Insufficiently controlled diabetes mellitus9.Any surgery (major or emergent) or hospitalization within 30 days prior to first study treatment administration10.History of cancer except if: a.Is considered likely to be cured or in remission for at least 12M,b. Is not being actively treated and, in the opinion of the PI, is not likely to require treatment witin 3 Y, c. Is considered to have low probability of recurrence, d. For prostate cancer, has not had significant progression within the pastY, and is stable and adequately controlled,e. For localized skin basal or squamous cell carcinoma, participants should continue with screening and seek treatment for the skin carcinoma11. Positive for hepatitis B surface antigen, human immunodeficiency virus-1 or -2 antibodies or antigen, or history of spirochetal infection of the CNS. Participants with a positive hepatitis C virus antibody will be allowed if hepatitis C RNA is negative. 12. Significant kidney disease as indicated by either of the following: g. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, according to the re-expressed abbreviated (four-variable) MDRD Study equationb.Creatinine ≥2 mg/dL.13. Impaired hepatic function as indicated by screening aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5 the upper limit of normal (ULN), and total bilirubin ≥1.5 × ULN. Note: Participants with Gilbert's syndrome are eligible to participate if approved by the Medical Monitor. 14. Hematologic abnormalities as indicated by hemoglobin ≤10 g/dL; white blood cells (WBC) ≤3 000/mm3; absolute neutrophil count ≤ 1,000/mm3; or platelet count ≤150,000/mm3.15. Participants with hypertension who are not adequately and stably controlled as per the ACC/AHA 16. History or presence of an abnormal ECG that is clinically significant, or evidence of acute or subacute myocardial infarction or ischemia17. History of or concurrent clinically significant cardiovascular disease such as but not limited to myocardial infarction, angina pectoris, New York Heart Associating Class III or IV cardiac failure ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease If the condition is stable per cardiologist, then the patient can enrol at PI discretion18.Clinically significant electrolyte abnormalities 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. History or presence of clinically evident vascular disease potentially affecting the brain21.History of a clinically significant, persistent neurologic deficit, structural brain damage, or CNS trauma. 22. Resides in a skilled nursing facility, convalescent home, or long-term care facility at screening; or requires continuous nursing care (i.e., >3months)23. Unable to tolerate the required safety portion of MRI procedures (e.g., due to anxiety or claustrophobia) or has a contraindication to MRI. 24. 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
Part 2:
Part 1 participants are not eligible for continued treatment with AL001 OLE if any of the following apply:1. Part 1 participant has been admitted to a skilled nursing facility, convalescent home, or long-term care facility at screening and requires continuous nursing care (i.e., >3 months).2. Part 1 participant has a medical condition or extenuating circumstance that, in the opinion of the investigator, continued treatment with AL001 at the conclusion of Part 1 is not beneficial or safe for the participant.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1: Primary Efficacy Endpoint:
Target population: Symptomatic carriers of GRN mutation causative of FTD as defined by the inclusion and exclusion criteria.
Variable of interest: Change from baseline to Weeks 48, 72, and 96 in the CDR® plus NACC FTLD-SB.
Intercurrent events and corresponding strategy: Study treatment discontinuation/prohibited concomitant medications (Treatment Policy). All observed values of the variable of interest, regardless of whether or not the participant has discontinued treatment/taken a prohibited medication.
Population-level summary variable: Percent reduction of the placebo group change from baseline across Weeks 48, 72, and 96
Part 2: Primary Endpoint:
Incidence, nature, and severity of AEs and SAEs
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-STS
Incidence of ADAs to AL001 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1: Change in CDR® plus NACC FTLD-SB: Weeks 48, 72, and 96
Percent reduction of the placebo group values: Weeks 48, 72, and 96
Part 2: Incidence, nature, and severity of adverse events AEs and SAEs:W100 and every 4Weeks, until week 196
Physical examination abnormalities:W100 and every 4Weeks until W144; W168, W196
Neurological examination abnormalities: W100 and every 4Weeks until W144; W168, W196
Changes in vital signs: W100 and every 4Weeks until week 196
Changes in ECG:W120,144,168,196
MRI abnormalities:W144 and W196
Changes in clinical laboratory tests:W100,112,120,132,144,168,192
Sheehan-STS:W100 and every 4 weeks until W196
Incidence of ADAs to AL00:W100,112,120,144,168,196
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|
| E.5.2 | Secondary end point(s) |
Part 1: Secondary Efficacy Endpoints:
To evaluate the efficacy of AL001 compared with placebo in symptomatic participants as measured by the CDR® plus NACC FTLD-SB
Target population: Symptomatic carriers of a GRN mutation causative of FTD as defined by the inclusion and exclusion criteria.
Variable of Interest: Change from baseline to Weeks 48, 72, and 96 on the CGI-S
Intercurrent events and corresponding strategy: Study treatment discontinuation/prohibited concomitant medications (Treatment Policy). All observed values of the variable of interest, regardless of whether or not the participant has discontinued treatment/taken a prohibited medication.
Population level summary variable: Percent reduction of the placebo group change from baseline across Weeks 48, 72, and 96
To evaluate the efficacy of AL001 compared with placebo in symptomatic participants as measured by CGI-S
Target population: Target population: Symptomatic carriers of a GRN mutation causative of FTD as defined by the inclusion and exclusion criteria.
Variable of interest: Actual values at Weeks 48, 72, and 96 on the CGI-S
Intercurrent events and corresponding strategy: Study treatment discontinuation/prohibited concomitant medications (Treatment Policy). All observed values of the variable of interest, regardless of whether or not the participant has discontinued treatment/taken a prohibited medication.
Population-level summary variable: Percent reduction of the placebo group values at Weeks 48, 72, and 96
To evaluate the efficacy of AL001 compared with placebo as measured by RBANS
Target population: Symptomatic carriers of a GRN mutation causative of FTD as defined by the inclusion and exclusion criteria
Variable of interest: Change from baseline to Weeks 48, 72, and 96 on the RBANS
Intercurrent events and corresponding strategy: Study treatment discontinuation/prohibited concomitant medications (Treatment Policy). All observed values of the variable of interest, regardless of whether or not the participant has discontinued treatment/taken a prohibited medication.
Population-level summary variable: Percent reduction of the placebo group change from baseline across Weeks 48, 72, and 96
Pharmacodynamic:
PGRN concentrations in plasma and optional CSF
Neurofilament light chain (NfL) concentrations in serum and optional CSF
Structural volumetric MRI whole and regional brain volume
Safety Endpoints:
Incidence, nature, and severity of adverse events (AEs) and serious adverse events (SAEs)
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-STS
Incidence of ADAs to AL001
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part 1: Secondary Efficacy:
To evaluate the efficacy of AL001 compared with placebo as measured by
CGI-S: Change from baseline to Weeks 48, 72, and 96
CGI-I: at Weeks 48, 72, and 96
RBANS: Change from baseline to Weeks 48, 72, and 96
PD
MRI every 24W
PGRN:0,8,12,16,24,32,40,48,72,96
NfL: pre-screening, Screening, every 8 weeks until week 48,72,96
Safety:
Incidence, nature, and severity of AEs and SAEs: screening and every next 4 Week, until week 96
Physical examination: every 4weeks
Neurological examination: every 4 weeks
Changes in vital signs: screening and every 4W
Changes in ECG: every 24W
MRI: Screening,W48 and 96
Changes in clinical laboratory tests: screening, every 8W and 12W after week 48
Sheehan-STS: Screening and every 4W
ADAs: Week 0, 12,24,48,72,96 |
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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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| Argentina |
| Switzerland |
| Australia |
| Canada |
| United Kingdom |
| United States |
| Belgium |
| France |
| Germany |
| Greece |
| Italy |
| Netherlands |
| Portugal |
| Spain |
| Sweden |
| Türkiye |
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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 | 7 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 22 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 22 |
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