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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Alector LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

29 Jun 2020 → 7 Jan 2026

Decision date (initial)

2024-10-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2023-506873-36-00

EudraCT number

2019-004066-18

ClinicalTrials.gov

NCT04374136

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the efficacy of AL001 compared with placebo in symptomatic participants as measured by the CDR plus NACC FTLD-SB

Secondary objectives 3

1. To evaluate the efficacy of AL001 compared with placebo in symptomatic participants as measured by CGI-S
2. To evaluate the efficacy of AL001 compared with placebo in symptomatic participants as measured by CGI-I
3. To evaluate the efficacy of AL001 compared with placebo in symptomatic participants as measured by RBANS

Conditions and MedDRA coding

Frontotemporal dementia (FTD)

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002997-PIP01-21

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

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 (Gorno-Tempini 2011).
2. Age 25 to 85 years, inclusive, at Screening. Note: For participants in France, inclusion criterion #2 is: 2. At risk participants (with a CDR® plus NACC FTLD-SB score ≤0.5) who are 45 to 85 years of age, inclusive, at Screening, or symptomatic participants (with a CDR® plus NACC FTLD-SB >0.5) who are 25 to 85 years of age, inclusive, at Screening.
3. At Screening, women must be nonpregnant and nonlactating, and 1 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 post-menopausal [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 (eg, combined oral contraceptive pill) or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm, cervical cap, or condom. In addition, total abstinence, if in accordance with the lifestyle of the participant, is acceptable. c. 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 (eg, 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 institutional review board (IRB) or independent ethics committee (IEC). Note: For participants in Germany, inclusion criterion #7 is: 7. Willing and able to give informed consent. Participants who are not capable of comprehending the nature, significance, and implications of the clinical trial cannot participate in the trial.
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, as follows: − At-risk participants (CDR® plus NACC FTLD-SB score ≤0.5) require the study partner at the COA visits only. − Symptomatic participants (CDR® plus NACC FTLD-SB score >0.5) require the study partner at each visit. − At-risk participants who become symptomatic (CDR® plus NACC FTLD-SB >0.5) during the study treatment period require the study partner at each visit moving forward through Study Completion.
9. Note: For participants in France, an additional criterion (#9) applies: 9. In accordance with local regulations, at-risk participants must have a family history of FTD. 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.

Exclusion criteria 24

1. Dementia due to a condition other than FTD including, but not limited to, Alzheimer’s disease, Parkinson’s disease, dementia with Parkinsonism, rapid eye movement (REM) behavior disorder, dementia with Lewy bodies, Huntington disease, or vascular dementia.
2. 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 difficulties.
5. 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 (American Psychiatric Association 2013).
6. 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 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. Insufficiently controlled diabetes mellitus (eg, hemoglobin A1C ≥8%).
9. Any surgery (major or emergent) or hospitalization within 30 days prior to first study treatment administration.
10. Participant has a history of cancer except if it: a. Is considered likely to be cured or in remission for at least 12 months, 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 (eg, tamoxifen), d. For prostate cancer, has not had significant progression within the past 2 years, and is stable and adequately controlled, e. For localized skin basal cell carcinoma or squamous cell carcinoma, the participant should continue with screening and seek treatment for the skin carcinoma. Note: For participants in Germany, exclusion criterion #10 is: 10. Participant has a history of cancer.
11. Positive for hepatitis B surface antigen, human immunodeficiency virus 1 or 2 antibodies or antigen, or history of spirochetal infection of the central nervous system (CNS) (eg, syphilis, borreliosis, or Lyme disease). Participants with a positive or equivocal hepatitis C virus antibody will be allowed to enroll if hepatitis C RNA is confirmed negative.
12. 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 (4-variable) Modification of Diet in Renal Disease (MDRD) Study equation, Note: MDRD equation is as follows: eGFR (mL/min/1.73 m2) = 175 × (standardized serum creatinine) – 1.154 × (Age) – 0.203 × (0.742 if female) × (1.212 if Black)*, or b. Creatinine ≥2 mg/dL Note: *In France, if the participant screened is Black, the coefficient of 1.000 should be utilized where “(1.212 if Black)” is noted. This will result in an additional safety margin for Black participants.
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. Note: For participants in Germany and France, exclusion criterion #13 is: 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 ≥2.0 × ULN. Note: Participants with Gilbert’s syndrome are eligible to participate if approved by the Medical Monitor.
14. Clinically significant 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 American College of Cardiology/American Heart Association (ACC/AHA) guidelines.
16. History or presence of an abnormal electrocardiogram (ECG) that is clinically significant, including complete left bundle branch block, second- or thirddegree atrioventricular block, or evidence of acute or subacute myocardial infarction or ischemia.
17. History of or concurrent clinically significant cardiovascular disease such as but not limited to myocardial infarction, angina pectoris, New York Heart Association Class III or IV cardiac failure, ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease (eg, severe left ventricular systolic dysfunction, left ventricular hypertrophy). If the condition is stable per the consulting cardiologist, then the patient can enroll at the Investigator’s discretion.
18. Clinically significant electrolyte abnormalities (eg, hypokalemia, hypomagnesemia, hypocalcemia).
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 brain (eg, clinically significant carotid or vertebral artery stenosis or plaque; cerebral hemorrhage or infarct greater than 1 cm3; 3 or more lacunar infarcts in any location; cerebral contusion; encephalomalacia; intracranial aneurysm; arteriovenous malformation; subdural hematoma); hydrocephalus; space occupying lesions (eg, abscess or brain tumor such as meningioma) that have the potential to affect cognitive function; or intracranial tumor that is clinically relevant (eg, glioma, cerebral metastasis).
21. 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 (ie, >3 months).
23. Unable to tolerate the required safety portion (as defined in the imaging manual) of MRI procedures (eg, due to anxiety or claustrophobia) or has a contraindication to MRI, including, but not limited to, the presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in the eyes, skin, or body that are not compatible with an MRI scan; or any other clinical history or examination finding that would pose a potential hazard in combination with MRI. Use of conscious sedation is allowed to aid with tolerance of imaging procedures.
24. Has a medical condition or extenuating circumstance that, in the opinion of the Investigator, might compromise the participant’s ability to comply with the protocol-required testing or procedures, or compromise the participant’s wellbeing, safety, or clinical interpretability.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from baseline to Weeks 48, 72, and 96 in the CDR® plus NACC FTLD-SB.

Secondary endpoints 3

1. Change from baseline to Weeks 48, 72, and 96 on the CGI-S.
2. Actual values at Weeks 48, 72, and 96 on the CGI-I.
3. Change from baseline to Weeks 48, 72, and 96 on the RBANS.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Alector LLC

Sponsor organisation

Alector LLC

Address

131 Oyster Point Boulevard

City

South San Francisco

Postcode

94080-2029

Country

United States

Scientific contact point

Organisation

Alector LLC

Contact name

Clinical Trial Information Desk

Public contact point

Organisation

Alector LLC

Contact name

Clinical Trial Information Desk

Third parties 14

Locations

9 EU/EEA countries · 22 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 152 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications