Primary ObjectivePart1: To evaluate the safety and tolerability of intravenous (IV) administration of AL001 over up to 96 weeks in asymptomatic and symptomatic carriersof a granulin (GRN) mutation causative of frontotemporal dementia (FTD) and in…
ID
Source
Brief title
Condition
- Dementia and amnestic conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Safety Endpoints:
To assess the potential effect of cumulative exposure on the safety profile of
AL001, the following will be evaluated by dose, such as by using tertiles of
the actual dose (normalized to weight) received:
• Incidence, nature, and severity of AEs and SAEs
• Incidence of treatment discontinuations and study discontinuations due to AEs
• Physical examination abnormalities
• Neurological examination abnormalities
• Changes in vital signs from baseline over time
• Changes in ECGs from baseline over time
• MRI abnormalities after dosing relative to baseline
• Changes in clinical laboratory tests from baseline over time
• Sheehan Suicidality Tracking Scale (Sheehan-STS)
• Incidence of ADAs to AL001
Secondary outcome
Secondary PK Endpoints:
• Serum concentration of AL001 at specified timepoints
• AL001 PK parameters (if data permit)
o Cmax
o Ctrough
o AUCss
Secondary PD Biomarker Endpoints:
• The overall change from baseline in PGRN in CSF
• The overall change from baseline in PGRN in plasma
Background summary
Frontotemporal dementia (FTD) is the second most common early-onset form of
dementia after Alzheimer*s disease, afflicting approximately 60,000 Americans
(Tatton 2014) and 113,000 people in the European Union, Norway, Iceland, and
Liechtenstein combined (EMA 2016).
Frontotemporal dementia is typified by prominent executive dysfunction,
behavioral and personality changes, and language deficits. A family history is
present in approximately 40% of FTD cases, with about 10% showing an autosomal
dominant pattern of inheritance, indicating a strong genetic component.
Granulin (GRN) mutations account for up to 20% of all heritable FTD cases, and
5 to 10% of all cases of FTD are caused by a loss-of-function mutation in 1
allele of GRN. Heterozygous GRN deficiency almost invariably leads to
development of FTD, making GRN a causal gene for the disease.
C9orf72 hexanucleotide repeat expansions are also a significant contributor to
FTD pathology. Expansion of a non-coding hexanucleotide repeat in C9orf72 is
the most common single cause of FTD, representing approximately 25% of familial
cases and 6% of sporadic FTD cases.
FTD patients with GRN and C9orf72 mutations exhibit a common pathology in
frontotemporal degeneration associated with TDP-43 protein-related
accumulation.Therapeutics targeted at reducing TDP-43 pathology and restoring
lysosomal function may thus
also slow FTD disease progression in patients with either GRN or C9orf72
mutations.
Given the marked behavioral and personality changes of FTD and early onset of
the disease, FTD patient care represents a significant burden for caregivers,
families, and society.
Study objective
Primary Objective
Part1: To evaluate the safety and tolerability of intravenous (IV)
administration of AL001 over up to 96 weeks in asymptomatic and symptomatic
carriers
of a granulin (GRN) mutation causative of frontotemporal dementia (FTD) and in
symptomatic carriers of a C9orf72 mutation causative of FTD.
Part2: The primary objective of the optional OLE period of the study is to
assess the long-term safety and tolerability of IV administration of
AL001 in participants who have completed 96 weeks of treatment on Part 1 of the
study.
Secondary Objectives
Part1: The secondary objectives of this study are to evaluate the effect of IV
administration of AL001 over up to 96 weeks in asymptomatic and
symptomatic carriers of a GRN mutation causative of FTD and in symptomatic
carriers of a C9orf72 mutation causative of FTD on the
following:
• Pharmacokinetics (PK)
Longitudinal plasma and CSF PGRN concentration levels
•Longitudinal levels of Sortilin in WBCs
Part 2: to assess the long-term effect of IV administration of AL001 in
participants who have completed 96 weeks of treatment on Part 1 on the
following:
• Pharmacokinetics
• Longitudinal plasma progranulin concentration levels
• Longitudinal blood and plasma levels of exploratory pharmacodynamic
biomarkers of neurodegeneration, lysosomal function, and glial activity
• MRI measures to evaluate changes in the brain; Correlations among exploratory
fluid PD biomarkers, imaging PD measures, and clinical
outcome assessments (COAs)• Clinical progression as measured by COAs
Exploratory Objectives
The exploratory objectives of this study are to assess the effect of IV
administration of AL001 over up to 96 weeks in asymptomatic and symptomatic
carriers of a GRN mutation causative of FTD and in symptomatic carriers of a
C9orf72 mutation causative of FTD on the following:
• Longitudinal blood, plasma, and CSF concentration levels of exploratory
pharmacodynamic (PD) biomarkers of neurodegeneration, lysosomal function, and
microglial activity
in the brain
• Correlations among exploratory fluid PD biomarkers, imaging PD measures, and
clinical outcome assessments (COAs)
• Clinical progression as measured by COAs
Study design
This is a Phase 2, multicenter, open-label study evaluating the safety,
tolerability, PK, PD, and effect on COAs of AL001 administered intravenously
(96-week dosing period), in asymptomatic and symptomatic FTD-GRN mutation
carriers and in symptomatic frontotemporal dementia patients with C9orf72
hexanucleotide repeat expansion mutations (FTD-C9orf72).
The study has two parts: A phase 2 open-label treatment period (Part 1),
followed by an open-label extension (OLE) period (Part 2). Part 1 is a 96-week
evaluation of the safety, tolerability, pharmacokinetic (PK), pharmacodynamic
(PD), and clinical effect of AL001 administered intravenously
(60 mg/kg, every 4 weeks [q4w]), for a total of 25 doses (96-week dosing
period), in asymptomatic and symptomatic carriers of loss-of-function GRN
mutations causative of FTD, and in symptomatic carriers of C9orf72
hexanucleotide repeat expansion mutations causative of FTD. Part 2 is an
optional OLE for eligible participants who have completed the 96-week Part 1
treatment period. The OLE period will evaluate the long-term safety and
tolerability of AL001 administered at the same dose and regimen as Part 1 (60
mg/kg, q4w), for up to a total of 25 doses (96-week optional OLE period).
Two cohorts will be enrolled: a GRN Cohort and a C9orf72 Cohort. Both cohorts
will enroll symptomatic patients with FTD;
Frontotemporal dementia patients must have a diagnosis of possible or probably
bvFTD or PPA.
All participants will be administered open-label, IV AL001 at the study site
(over a 96-week dosing period). The primary objective of this Phase 2 study is
to assess safety and tolerability of dosing of IV AL001. Secondary and
exploratory objectives include evaluating the PK and the preliminary
effect of AL001 on PD biomarkers and COAs in asymptomatic and symptomatic
participants.
Intervention
The study will include a screening period (within 6 weeks prior to Day 1), a
treatment period (96 weeks), and a follow-up period (8 weeks
after the last dose of AL001) with a follow-up visit at Week 105 (study
completion).
Study burden and risks
This study requires that the patient will visit the hospital 29 times over a
period of 2 years. A visit will take 4 to 5 hours.
During the study, the following will take place:
- body weight.
- the patient receives the study drug
- AEs.
- record the use of medication and vitamin supplements
- physical examination.
- neurological examination.
- ECGs
- vital signs
- bloodsamples and collect urine
- We will ask the patient and study partner to complete several questionnaires.
For some parts the patient will be asked to do some tasks like drawing or
counting and one questionnaire is used to assess suicidal thoughts and behaviors
- lumbar punctures to collect cerebrospinal fluid.
- MRIs
- Pregnancy test from blood and urine will be performed if the patient is
female of child bearing potential. The patient is not allowed to be pregnant
in this study.
All drugs may cause certain side effects and discomforts. The most common
discomforts are listed below. There may also be side effects and discomforts
that are not yet known.
In the Phase 1 study, a total of 64 participants were enrolled. There are no
serious side effects related to AL001 or study discontinuations because of any
side effect. The most common discomforts reported from participants in studies
with AL001 were headache, vomiting, lipase increase (measure of an inflamed or
injured pancreas), anemia (low blood cell count), myalgia (muscle pain), and
upper respiratory tract infection (infection of the nasal passages or sinuses).
There is a chance that the body will produce antibodies against AL001, that an
infusion reaction will occur, or that a hypersensitivity reaction will be
triggered.
The studies in the context of the study also have risks:
- Blood tests can hurt or cause a blood shed.
-Lumbar puncture can cause the following complaints and complications:
headache, temporary numbness or pain in legs, back and neck pain, dizziness,
fainting, pain at the location of the spinal catheter, inflammation or
infection (in rare cases this can cause meningitis), bleeding and nerve damage.
Risks related to genetic testing: It is not inconceivable that the patient
should answer questions about having a genetic test carried out when he / she
applies for life or disability insurance. It cannot be excluded that the
insurer will attach consequences to this. It could also be that during the
inspection sometimes things are discovered that are not yet treatable
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Age
Inclusion criteria
Part 1: Protspective participants must meet all of the following criteria
specific to their
applicable participant category. These bullet points are some of the
important criteria within each category:
1) Completed Study AL001-1 through the Day 57 visit and did
not experience AEs that the investigator deems would prevent safe
participation in Study AL001-2.
2) Meets 1 or more of the 6 behavioral/cognitive symptoms
required for a diagnosis of possible behavioral variant frontotemporal
dementia (bvFTD; Rascovsky 2011) or has diagnosis of primary
progressive aphasia (PPA; Gorno Tempini 2011)
3) Prospective participant is a carrier of a loss of function GRN mutation
causative of
FTD-GRN
4) Is a carrier of a hexanucleotide repeat expansion C9orf72
mutation causative of FTD and knows their mutation status
5) Has a CDR® plus NACC global 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 2011) or a diagnosis of PPA (Gorno Tempini
2011)
In addition, this is the list of the important inclusion criteria:
• Participants are 18 to 85 years of age.
• At screening, female prospective participants must be nonpregnant and
nonlactating, and at least one of the following conditions must apply:
- 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 using an acceptable contraceptive method
from screening until 8 weeks after the last dose of study drug.
Acceptable contraception is defined as using hormonal contraceptives 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 final dose of
study
intervention are located in the Schedules of Assessments (Table 14-1 and table
14-2 in
the protocol).
• Male prospective participants, if not surgically sterilized, must agree to use
acceptable contraception and not donate sperm from Day 1 until 10 weeks
after the last dose of study drug. Acceptable contraception for the male
patient when having sexual intercourse with a WOCBP who is not currently
pregnany is defined as using a condom. In addition, WOCBP partners must use
hormonal
contraceptives 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.
• Agrees not to donate blood or blood products for
transfusion for the duration of the study and for 1 year after final dose of
study drug.
• Is willing and has the ability to comply with the study
protocol.
• 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).
• 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 cognitive and functional abilities as well as their health
throughout the study, agrees to provide information at site visits that
require partner input for COA completion, and signs the necessary
consent form. (Note: asymptomatic participants require the study
partner at the COA visits only; symptomatic participants require the
study partner at each visit) Inclusion criteria applicable to those UK, US,
or Canadian participants participating in the optional Winterlight Labs
Speech Assessment (WLA) only:
-participant has available and willing study partner to administer the
WLA
-participant has WiFi access in their residence or WiFi access in a private
area where the testing can take place
-US, UK, or Canadian participants who are proficient in English in the
investigator's opinion
Part 2: participants must complete Part 1, 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
their 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. The
study partner must have frequent and sufficient contact with the
participant , and must have sufficient cognitive capacity; can be the
same individual as in Part 1.
Exclusion criteria
Deel 1:
• History of severe allergic, anaphylactic, or
other hypersensitivity reactions to chimeric, human, or humanized
antibodies or fusion proteins.
• History of substance use disorder (drug or alcohol)
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).
•Current acute illness or active infection requiring oral or IV antibiotics
within 30 days prior to study drug
administration that may affect safety assessments.
• History of surgery, hospitalization, or clinically significant
infection requiring oral or IV antibiotics during the 30 days prior to
screening.
• Has planned procedure or surgery during the study that
would interfere with the ability to perform study assessments.
• History of seizures, with the exception of
childhood febrile seizures.
• Has clinically, significant systemic immunocompromised
condition because of continuing effects of immune suppressing
medication.
• Has major depressive disorder or history of schizophrenia,
schizoaffective disorder, or bipolar disorder.
• Has history of cancer
• Has history or presence of intracranial tumor that is
clinically relevant.
• Has any clinically significant medical condition or
laboratory abnormality that precludes the participant's safe participation
in and completion of the study.
• Positive for hepatitis B surface antigen, hepatitis C virus
antibodies, or human immunodeficiency virus 1 and 2 antibodies or
antigen, or history of spirochetal infection of the CNS.
• Significant kidney disease as indicated by a screening
creatinine clearance <30 mL/min as calculated by the central laboratory
using the Cockcroft Gault formula, which remains <30 mL/min if
retested.
• 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, which
remains above either of these limits if retested or other abnormalities in
synthetic function that are clinically significant.
• Has, within the last 2 years, had unstable or clinically
significant cardiovascular disease.
• Participant has uncontrolled hypertension.
• Participant has history or presence of an abnormal ECG that is
clinically significant including complete left bundle branch block,
secondor third degree heart atrioventricular block, or evidence of prior
acute or subacute myocardial infarction or ischemia.
• Participant has QT interval corrected using Fridericia formula (QTcF)
Related Exclusion Criteria please refer to the protocol
Part 2:
Part 1 participants are not eligible for continued treatment with AL001
optional 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 CDR® plus NACC FTLD global score >2 during
Part 1.
3. 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-00138-20-NL |
| ClinicalTrials.gov | NCT03987295 |
| CCMO | NL70050.078.19 |