Deep Phenotyping in Patients With ALS

Rationale for the Study

The Northeast ALS Consortium (NEALS) biorepository is an existing resource which has provided
scientists with a wide range of samples associated with clinical information. It is primarily
cross sectional in nature; longitudinal collections have been associated with a limited set
of clinical and functional assessments. The investigators goal is to continue to build this
repository with the collection protocol proposed here, to associate biofluid collection with
specific measures of upper and lower motor neuron function. This project will compliment
others to upgrade the NEALS biorepository infrastructure, including updating the computer
systems, expanding the number of sample freezers and establishing a repository in the Western
United States, and strengthening the standard operating procedures for the repository. The
project also supports existing efforts to expand the biorepository by collecting new blood
and spinal fluid samples from people with ALS.

Study Design This is a multicenter, non interventional, longitudinal study in patients with
ALS. There will be four (4) subject visits in this study: Baseline, month 6, month 12, and
month 18. At each visit, subjects will have biofluids collected, and be evaluated with
assessment tools that focus on upper and lower motor neuron burden as well as cognitive
function.

Study Objectives and Endpoints The primary objective of the study is to obtain deep
phenotyping information on patients studied at regular intervals over 18 months, in
conjunction with biofluid collection over that same time period.

The secondary objective of the study is to integrate data from this study to other ongoing
projects via the NEALS biorepository, and future collections now being planned.

Endpoints for the study are:

- Motor unit number estimation will be performed on upper extremity muscles using the
multipoint incremental technique (MIMUNE);

- Vital capacity, measured using slow vital capacity (SVC).

- Lower motor neuron excitability will be assessed with threshold tracking nerve
conduction studies (ttNCS) in the least affected intrinsic hand muscle.

- Cognitive abnormalities will be assessed using the ALS Cognitive Behavior Screen
(ALS-CBS);

- Upper motor neuron burden will be assessed using transcranial magnetic stimulation
(TMS), employing a paired pulse protocol and recording from the least affected upper
extremity intrinsic hand muscle;

- Hand held dynamometry (HHD) will be performed on 10 muscle groups tested bilaterally;

- Global function (ALSFRS-R); and

- Vital capacity, measured using slow vital capacity (SVC).

At each visit, blood will be collected and banked for biomarker discovery; CSF will be
collected at baseline, month 6, and at month 18.

Other exploratory objectives of the study (to be performed at Barrow Neurological Institute
only) will investigate to the composition of the "pellet" of processed CSF and a novel
imaging marker called MRI cytography.

Study Locations Approximately 10 Northeast ALS Consortium (NEALS) Centers in the US will
participate in the study. Sites that cannot perform the ttNCS and/or the TMS can still
participate.

Number of Planned Subjects Fifty (50) subjects will be in the study. It is estimated that 5
subjects shall be enrolled per site.

Study Population This study will be conducted in subjects who meet the El Escorial criteria
of possible, laboratory- supported probable, probable, or definite ALS. Time from diagnosis
to study entry must be 24 months or less. At screening, eligible subjects must be at least 18
years old and must provide written informed consent. Detailed criteria will be described in
the full protocol.

Duration of Study Active assessment period will be 18 months; a 1-year enrolment period is
expected.

Inclusion Criteria:

- Participants with sporadic ALS diagnosed as possible, laboratory-supported probable,
probable or definite according to the World Federation of Neurology El Escorial
criteria.

- Expected to survive >1 year (12 months) after enrollment.

- Male or female, aged 18-75.

- Ability to medically undergo lumbar puncture (LP) as determined by the investigator
(i.e., no bleeding disorder, allergy to local anesthetics, prior lumbar surgery which
might make LP difficult, a skin infection at or near the LP site, or evidence of high
intracranial pressure).

- Willingness and medical ability to comply with scheduled visits, LP for CSF
collection, laboratory tests, and other study procedures.

- Ability to understand the purpose and risks of the study and provide signed and dated
informed consent and authorization to use protected health information (PHI) in
accordance with national and local subject privacy regulations.

- Geographic accessibility to the study site.

Exclusion Criteria:

- Any contraindications to having an LP, including but not limited to: Platelet count
<100,000/µL.

- History of bleeding disorder.

- History of intolerance to the LP procedure.

- Evidence of topical or other skin infection at the LP site.

- History of allergy or other adverse reaction to local anesthetics used in the study.

- History of traumatic central nervous system injury or stroke.

- Other unspecified reasons that, in the opinion of the Investigator, make the subject
unsuitable for enrollment.

Additional criteria for sites performing TMS:

- Inability to perform either TMS or NCS studies due to insufficient motor evoked
potential (MEP) or compound muscle action potential (CMAP) amplitude.

- Contraindication to TMS studies including ferromagnetic metal in the head or neck
(potentially found in aneurysm clips, implanted medication pumps, implanted brain
stimulators, pacemakers, cochlear implants), or history of epilepsy. Dental fillings
are permitted.

Additional criteria for sites performing MRI cytography:

- Subjects who have a history of claustrophobia that cannot be adequately controlled.

- Subjects who have a physical limitation related to fitting in the bore of the magnet.

- Subjects who have a history of allergic reaction to contrast agents.

- Subjects with a pacemaker, epicardia pacemaker wires, MRI-incompatible cardiac valve
prostheses, MRI-incompatible vascular clips.

- Subjects with MRI-incompatible cochlear implants.

- Subjects with spinal nerve simulators.

- Subjects with an infusion pump.

- Subjects with metallic fragments in the eyes/orbits or in the vicinity of the brain or
major neurovascular structures of the body, subjects with an employment history which
involves exposure to welding, or subjects who have shrapnel any place in their body.

- Subjects with acute kidney injury or renal insufficiency (eGFR of <20 ml/min/1.73 m^2)
as they are at increased risk of Nephrogenic Systemic Fibrosis following
administration of gadolinium-based MRI contrast agents.

- Subjects unable to lay supine in the magnet because of orthopnea.