A Study to Evaluate Effectiveness and Safety of AL001 in Frontotemporal Dementia

Overview

About this study

The primary purpose of this study is 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).

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

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 ofserum 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 (Rascovsky et al 2011), or a diagnosis of PPA (Gorno-Tempini et al 2011) (symptomatic participants). 
  • Participants are 25 to 85 years of age, inclusive, at screening.
  • At screening, female participants must be nonpregnant and nonlactating, and 1 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 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. 
  • 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.
  • 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.
  • Participant is willing to and can 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 provideassent, in accordance with the local regulations, guidelines, and institutional review board or independent ethics committee.
  • 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.
    • 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;
    • 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;
    • 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.

Exclusion Criteria:

  • 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.
  • Participant has a known mutation causative of neurodegenerative disorder(s) other than heterozygous loss-of-function GRN mutations causative of FTD.
  • Participant has a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins.
  • 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 (American Psychiatric Association 2013).
  • Participant currently has or has had an acute illness that requires or required systemic antibiotics within 30 days prior to study treatment administration.
  • 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).
  • 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). 
  • Participant has insufficiently controlled diabetes mellitus (e.g., hemoglobin A1C ≥8%).
  • Participant has had any surgery (major or emergent) or hospitalization within 30 days prior to study treatment administration.
  • Participant has a history of cancer except if it:
    • Is considered likely to be cured;
    • 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;
    • 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.
  • Participant is 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); (e.g., syphilis, borreliosis, or Lyme disease). Participants with a positive hepatitis C virus antibody will be allowed if hepatitis C RNA is negative.
  • Participant has significant kidney disease as indicated by either of the following:
    • Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m^2, according to the re-expressed abbreviated (four-variable) Modification of Diet in Renal Disease (MDRD) Study equation,
      • Note: MDRD equation is as follows: eGFR (mL/min/1.73 m^2) = 175 × (standardized serum creatinine) - 1.154 × (Age) - 0.203 × (0.742 if female) × (1.212 if black); or
    • Creatinine ≥ 2 mg/dL.
  • Participant has impaired hepatic function as indicated by screening aspartate aminotransferase or alanine aminotransferase ≥ 2.5  the upper limit of normal (ULN), or total bilirubin ≥ 2.0 × ULN. Note: Participants with Gilbert's syndrome are eligible to participate if approved by the Medical Monitor.
  • 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.
  • Participant has or has had unstable or clinically significant cardiovascular disease (e.g., myocardial infarction, angina pectoris, New York Heart Association Class III or IV cardiac failure) within the past 2 years.
  • Participant has uncontrolled hypertension (e.g., repeated supine diastolic blood pressure >95 mm Hg).
  • Participant has a history or presence of an abnormal electrocardiogram (ECG) that is clinically significant, including complete left bundle branch block, second- or third-degree atrioventricular block, or evidence of acute or subacute myocardial infarction or ischemia.
  • Participant has history of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular hypertrophy) or clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia). Note: Participants with premature ventricular contractions are eligible to participate.
  • 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.
  • Participant has history or presence of clinically evident vascular disease potentially affecting the brain (e.g., 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 (e.g., abscess or brain tumor such as meningioma) that has the potential to affect cognitive function; or intracranial tumor that is clinically relevant (e.g., glioma, cerebral metastasis).
  • Participant has history of a clinically significant, persistent neurologic deficit, structural brain damage, or CNS trauma.
  • Participant resides in a skilled nursing facility, convalescent home, or long-term care facility at screening; or requires continuous nursing care.
  • Participant is unable to tolerate MRI procedures 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.
  • 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. Medication-Related Criteria: The following medications are prohibited for a prespecified duration prior to study start, as indicated, and during the entire period of study participation (participants who start these medications during the study may be withdrawn from study treatment):
  • Any cannabinoids at least 90 days prior to study treatment administration unless approved by the Medical Monitor. Note: Use is not permitted within 8 hours before any COA.
  • Any benzodiazepines and tricyclic antidepressants, at least 90 days prior to study treatment administration. Note: Short-term use of benzodiazepines (not more than 3 times per month) or use as premedication prior to lumbar puncture or MRI procedures is allowed; however, use is not permitted within 8 hours before any COA.
  • Any stimulant medication (e.g., amphetamine, dextroamphetamine, dexmethylphenidate, lisdexamfetamine, methylphenidate) unless prescribed as a stable regimen for at least 90 days prior to study treatment administration. 
  • Any passive immunotherapy (immunoglobulin) or other long-acting biologic agent that is under evaluation to prevent or postpone cognitive decline within 1 year of screening.
  • Any prior exposure to an anti-Sortilin antibody; use of any experimental oral therapy, biologic therapy, or any other investigational treatment within 90 days or 5 half-lives prior to study treatment administration, whichever is longer.
  • Any experimental vaccine or gene therapy.
  • Typical (first-generation) antipsychotic or neuroleptic medication within 6 months prior to study treatment administration except as needed for brief treatment of a nonpsychiatric indication (e.g., emesis).
    • Use of atypical (second-generation) antipsychotic medications or use of pimavanserin is allowed if treated with a stable regimen for at least 90 days prior to study treatment administration.
  • Anticoagulation (e.g., coumadin, heparinoids, apixaban) medications within 90 days prior to study treatment administration. Note: Use of aspirin or antiplatelet medication is allowed.
  • Systemic immunosuppressive therapy use or anticipated systemic immunosuppressive therapy use during the study.
    • Use of prednisone ≤ 10 mg/day or an equivalent corticosteroid is allowed if treated with a stable regimen for at least 90 days prior to study treatment administration and hemoglobin > 9 g/dL, WBC count > 3 000/mm^3, absolute neutrophil count >1 500/mm^3, and platelet count >100 000/mm^3.
  • Chronic use of opioids (including long-acting opioid medication) within 90 days prior to study treatment administration.
    • Intermittent short-term use (<1 week) of opioid medications for pain is permitted except within 2 days or 5 half-lives (whichever is longer) prior to any COA.
  • Chronic use of barbiturates or hypnotics within 90 days prior to study treatment administration.
  • Intermittent short-term (< 1 week) use of a short-acting hypnotic medication for sleep or anxiety is allowed except within 2 days or 5 half-lives (whichever is longer) prior to any COA.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Bradley Boeve, M.D.

Open for enrollment

Contact information:

Kevin Nelson B.S.

(507) 284-9295

Nelson.Kevin1@mayo.edu

More information

Publications

Publications are currently not available

Study Results Summary

Not yet available

Supplemental Study Information

Not yet available

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CLS-20515235

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