The objectives of the study are:• To understand the phenotypic heterogeneity and phenotype/genotype correlation and natural history of ALSP.• To develop and evaluate biomarkers for assessing disease progression in patients with ALSP.• To create the…
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Brief title
Condition
- Neurological disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pharmacodynamic Endpoints
• Change from Baseline to Months 12, 24 and 36 in neurofilament light chain
(NfL) in blood
• Change from Baseline to Months 12, 24 and 36 in NfL, cytokine panel, soluble
TREM2, and soluble CSF1R in CSF in subjects who provide informed consent
to participate in an optional CSF Biomarker Sub-study
• Change from Baseline to Months 6, 12, 18, 24, 30, 36 in structural and
volumetric MRI
Clinical Outcome Endpoints
Cognitive Assessments
• Change from Baseline to Months 6, 12, 18, 24, 30 and 36 in the Montreal
Cognitive Assessment (MoCA)
• Change from Baseline to Months 6, 12, 18, 24, 30 and 36 in the Clinical
Dementia Rating Scale plus National Alzheimer*s Coordinating Center-
Frontotemporal Lobar Degeneration (CDR®+NACC FTLD)
• Change from Baseline to Months 6, 12, 18, 24, 30 and 36 in the Brief
Assessment of Cognition (BAC) battery.
Motor Assessments (Ambulatory Subjects)
• Change from Baseline to Months 6, 12, 18, 24, 30 and 36 in the 2 Minute Walk
Test (2MWT)
• Change from Baseline to Months 6, 12, 18, 24, 30 and 36 in the Timed Up and
Go (TUG) test
Severity of Illness Assessments
• Clinical Global Impression - Change (CGI C) responses at Months 6, 12, 18,
24, 30 and 36
• Clinical Global Impression - Change (PGI C) responses at Months 6, 12, 18,
24, 30 and 36
Other Functional and Psychiatric Assessments
• Change from Baseline to Months 6, 12, 18, 24, 30 and 36 in the Functional
Activities Questionnaire (FAQ)
• Change from Baseline to Months 6, 12, 18, 24, 30 and 36 in the
Neuropsychiatric Inventory - 12-Item Version (NPI-12)
• Change from Baseline to Months 6, 12, 18, 24, 30 and 36 in the Cortical
Basal ganglia Functional Scale (CBFS)
• Change from Baseline to Months 6, 12, 18, 24, 30 and 36 in the Zarit
Burden Interview
Safety Endpoints
• Adverse events (AEs)
• Columbia-Suicide Severity Rating Scale (C-SSRS)
Secondary outcome
.
Background summary
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)
is a fatal and rapidly progressing rare, genetic disease for which no
definitive treatment options are available. ALSP is primarily inherited as an
autosomal dominant disorder with colony stimulating factor 1 receptor (CSF1R)
gene mutations (Sundal & Wszolek, 2017; Du et al, 2019; Leng et al, 2019).
CSF1R gene mutations are specific diagnostic features of patients with ALSP. As
phosphatase and kinase proteins associated with the CSF1R gene regulate
functions of macrophages, microglia, and neuronal pathways, disturbances of
these proteins due to gene mutation may also be implicated in
neuropathophysiology of ALSP (Rademakers et al, 2011; Lynch et al, 2016; Kraya
et al, 2019). The strong link between CSF1R mutations and pathologic microglia
has resulted in further classification of CSF1R-related leukoencephalopathy as
a central nervous system (CNS) primary microgliopathy (Han et al, 2020).
The structural, genetic, and neuropathophysiological abnormalities of ALSP lead
to the onset of neurologic symptoms, such as moderate to severe motor and
neuropsychiatric impairments (Sundal & Wszolek, 2017; Konno et al, 2018;
Oosterhoff et al, 2018; Tian et al, 2019; Kempthorne et al, 2020; Zhan et al,
2020; Zhou et al, 2020). Currently used therapies for ALSP are targeted for
temporary relief of motor and sensory symptoms and for the treatment of
complications. These treatments provide limited supportive care and modest
improvements in quality of life as the disorder progresses but do not address
the most debilitating symptoms, such as cognitive decline. In addition, these
treatments have no effects on the underlying disease process and do not slow
the progression of the disorder. Hematopoietic stem cell transplantation (HSCT)
has been investigated as a potential treatment for ALSP, with occasional
success in sporadic cases (Eichler et al, 2016; Mochel et al, 2019; Gelfand et
al, 2020). However, HSCT therapy is associated with major complications, has
shown potential beneficial effects in only a small number of patients, and has
not been evaluated in controlled trials. Thus, there is a significant unmet
medical need for novel therapies to treat patients with ALSP (Balassa et al,
2019).
Vigil Neurosciences, Inc, is developing VGL101, a monoclonal antibody of
triggering receptor on myeloid cells 2 (TREM2) agonist, for the treatment of
ALSP. The response of microglial cells to changes in the environment of the CNS
is activated through TREM2 and its associated protein kinase complex, DAP12
(Konishi & Kiyama, 2018). The TREM2/DAP12 signal functions as the primary
regulator that transforms microglia from a homeostatic to a neural
disease-associated state and produces an anti inflammatory response and
neurotrophic factors to protect injured neurons and to enable nerve tissue
regeneration. The activation of TREM2 by VGL101 is expected to slow disease
progression and enhance the neural tissue repair mechanisms regulated by
microglia.
This natural history study will collect data to contribute to the development
of future novel therapies, such as VGL101, that focus on the
neuropathophysiological features that underlie ALSP and that are essential to
reverse, delay, or stop progression of this debilitating disorder.
Study objective
The objectives of the study are:
• To understand the phenotypic heterogeneity and phenotype/genotype correlation
and natural history of ALSP.
• To develop and evaluate biomarkers for assessing disease progression in
patients with ALSP.
• To create the foundation for a future synthetic control arm and provide
run-in data for patients who qualify for interventional studies.
Study design
This is a non-interventional, prospective, multicenter, observational, natural
history study of patients with ALSP and asymptomatic carriers of CSF1R gene
mutations, the causative mutation for ALSP. Potential study participants will
be screened for study eligibility. Individuals who satisfy the study inclusion
and exclusion criteria and who provide written informed consent will be
enrolled in the study and followed for up to 24 months.
Clinic visits to assess disease status will be conducted at Screening/Baseline
and at Months 6, 12, 18, and 24. Each clinic visit will include clinical
assessments (cognitive, motor, functional, psychiatric, severity of illness,
and caregiver burden assessments) and imaging studies. Blood for biomarker
analysis will be collected at Screening/Baseline and at Months 12 and 24.
Adverse events (AEs) and concomitant medications and procedures will be
recorded throughout the 24-month study.
An optional sub-study to evaluate levels of biomarkers in cerebrospinal fluid
(CSF) is also included in this study and will be conducted at select study
sites. A CSF sample will be obtained at Screening/Baseline and at Months 12 and
24 from subjects who provide informed consent to participate in the optional
CSF Biomarker Sub-study.
Study burden and risks
The participants of this study will make at least 5 visits for this study.
During these visits, subjects will be subjected to:
- Blood sampling (for biomarker analysis)
- Optional CSF Biomarker sample (sub-study)
- COVID-19 testing (per standard of care)
- Urine drug testing
- Pregnancy testing
- Measure weight and height
- Clinical outcome Assessments (cognition-, performance- and clinician-rated
scales)
- Complete questionnaires
- MRI
The risks of participation in the study are primarily those associated with
collection of blood and cerebrospinal fluid (CSF) samples for biomarker
analyses.
Technology Square, 8th Floor 300
Cambridge MA 02139
US
Technology Square, 8th Floor 300
Cambridge MA 02139
US
Listed location countries
Age
Inclusion criteria
General and Administrative
1. Male or female subjects aged >=18 years on the day the informed consent form
(ICF) is signed.
2. Subjects who are able, in the opinion of the investigator, to understand the
nature of the study and to comply with the protocol requirements,
including scheduled visits, blood sampling, and other study procedures,
or who have a caregiver or legal guardian who can
understand and assist the subject in complying with the protocol
requirements.
3. Subjects who are willing and able to refrain from use of any prohibited
medication/treatments that are not permitted by the protocol
throughout the study period.
4. Subjects who receive approval of sponsor medical personnel as to final
suitability for the study.
Inclusion Criteria - Subjects With Definitive ALSP
5. Subjects who have documentation of a gene mutation in the CSF1R gene (prior
to enrollment).
6. Subjects who fulfill both of the following criteria (a and b):
a. More than two findings of clinical signs or symptoms in any of the following
categories:
i. Cognitive impairment or psychiatric problem
ii. Pyramidal signs on neurological examination
iii. Extrapyramidal signs, such as rigidity, tremor, abnormal gait, or
bradykinesia
iv. Epilepsy
b. MRI findings consistent with ALSP: specially, bilateral cerebral white
matter lesions with or without thinning of the corpus callosum (Konno et al,
2018;
Appendix 3, Section 10.3).
NOTE: Subjects with other causes of leukoencephalopathy, including vascular
dementia, multiple sclerosis, or leukodystrophy (e.g.,
adrenoleukodystrophy, Krabbe disease, metachromatic
leukodystrophy), will be excluded.
7. Subjects who, in the investigator*s opinion, have demonstrated clinical
progression of their ALSP within the past year.
8. Subjects who have a score of >=12 on the MoCA.
9. Subjects who are ambulatory with or without aids (cane, crutches, etc) or,
if restricted to a wheelchair, are still able to wheel self, transfer in
and out of wheelchair, and walk up to 5 meters with or without aid.
NOTE: 7 subjects that are non-ambulatory for reasons other than progression of
ALSP may be enrolled.
10. Subjects who meet the criteria for definitive ALSP must have a designated
caregiver who spends at least 4 hours per week with them. The caregiver
must be able and willing to assist the subject in complying with the
study requirements, be able to provide information during study visits,
and be willing to sign a caregiver ICF.
Inclusion Criteria - Subjects With Prodromal ALSP
11. Subjects who have documentation of a gene mutation in CSF1R gene (prior to
enrollment).
12. MRI findings consistent with ALSP: specifically, bilateral cerebral white
matter lesions with or without thinning of the corpus callosum (Konno et al,
2018;
Appendix 3, Section 10.3). Prodromal subjects may have none or up to
and including 2 ALSP-related clinical signs or symptoms (i.e., they do not meet
the clinical criteria outlined in 6a as *more than two*).
13. Subjects who meet the criteria for prodromal ALSP and who, at later study
visits,
meet the criteria for definitive ALSP should have a designated caregiver for
subsequent visits who spends at least 4 hours per week with them unless
otherwise approved by the sponsor and/or medical monitor. The caregiver must be
able and willing to assist the subject in complying with the study
requirements, be
able to provide information during study visits, and be willing to sign a
caregiver
ICF
Informed Consent
14. Subjects who are capable of providing written informed consent, including
signing and dating the ICF, or who have a caregiver/legal
guardian who can provide written informed consent (with subject assent).
Screening Assessments
15. Woman of childbearing potential must have a negative urine pregnancy test
at Screening/Baseline.
Exclusion criteria
Medical Conditions
1. Subjects with any neurological or psychiatric diseases that can produce
cognitive, motor, or behavioral impairment similar to ALSP,
including, but not limited to, Alzheimer*s disease, frontotemporal
dementia, ALS, stroke, Huntington disease, multiple sclerosis,
Parkinson*s disease, and Down syndrome, or with active alcohol/drug
abuse.
2. Subjects with any concurrent diagnosis that may confound neuropsychological
testing (e.g., hearing impairment, visual impairment).
3. Subjects with any concurrent diagnosis that may confound ambulation
measurements (e.g., amputee).
4. Subjects with contraindications for undergoing a lumbar puncture, such as
bleeding disorders, increased intracranial pressure, or
abnormal spinal anatomy.
NOTE: Only for subjects who participate in the optional CSF Biomarker
Sub-study.
5. Subjects who are unable to undergo MRI. (e.g., implants not compatible
for MRI, claustrophobia, inability to remain still that will prevent
acquisition of a good quality scan)
6. Female subjects who are pregnant, planning pregnancy in the next 12 months,
or breastfeeding.
7. Subjects who are at significant risk of suicidal or violent behavior, in the
opinion of the investigator. If a subject answers *yes* to the
Question 4 or 5 on the C SSRS, a risk assessment should be done by a
qualified healthcare professional to assess whether it is
safe for the subject to participate in the study.
8. Subjects with a current history of major medical illness, such as renal
failure, congestive heart failure, or advanced pulmonary
disease, that could put the subject at additional risk if participating
in the study.
9. Subjects with a history of cancer that required active treatment in the last
5 years, with the exception of in situ cervical cancer and
basal cell carcinoma of the skin.
10. Subjects with any condition or situation that, in the opinion of the
investigator or sponsor medical personnel, may place the subject
at significant risk, confound the study results, or interfere
significantly with the subject's participation in the study.
11. Subjects who have previously undergone HSCT or plan to undergo HSCT
within 12 months prior to Screening/Baseline visit.
Prior/Current Clinical Study Experience
12. Subjects who are concurrently enrolled in an investigational drug or device
study or who received an investigational product within 30 days of 5 half-lives
before signing the ICF.
Note: Subjects who are receiving VGL101 in a clinical study may enroll after
conclusion of their participation in the VGL101 clinical study
Other Exclusion Criteria
13. Subjects who are involved, directly or indirectly, in the conduct or
administration of this study as an investigator, sub-investigator,
study coordinator, or other study staff member.
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 |
|---|---|
| CCMO | NL78271.075.21 |