A Study to Evaluate, Safety, Tolerability, Pharmacodynamic (PD) Markers and Pharmacokinetics (PK) of AP-101 in Participants With Amyotrophic Lateral Sclerosis (ALS)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety, tolerability, PK, and PD of AP-101 in participants with fALS and sALS.

Official Title
-----------------
A Phase 2a, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate Safety, Tolerability, Pharmacodynamic Markers, and Pharmacokinetics of AP-101 in Patients With Familial Amyotrophic Lateral Sclerosis (fALS) and Sporadic Amyotrophic Lateral Sclerosis (sALS)

Conditions
-----------------
Amyotrophic Lateral Sclerosis

Intervention / Treatment
-----------------
* Drug: AP-101
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: All participants must adhere to contraception restrictions Female participants of childbearing potential must adhere to contraception restrictions Have possible, clinically probable, clinically probable-laboratory supported or definite familial or sporadic ALS in accordance with the El-Escorial criteria or who have a diagnosis of ALS as defined by the Gold Coast Criteria; progressive motor impairment documented by history or repeated clinical examination, preceded by normal motor development, and presence of upper and lower motor neuron dysfunction in at least 1 body region or lower motor neuron dysfunction in at least 2 body regions and investigations excluding other conditions In familial ALS participants, a confirmed pathogenic superoxide dismutase 1 (SOD1) mutation Onset of symptoms (i.e, weakness) within past 24 months prior to screening, at the time of obtaining informed consent Have slow vital capacity (SVC) of greater than or equal to (> or =) 50 percentage (%) of predicted values. Participants with SVC of <50% of predicted values may be permitted to enter the open-label extension, based on the opinion of the investigator Absence of bilevel positive airway pressure (BiPAP)/proportional assist ventilation (PAV) > 4 hours for symptoms attributable to ALS. Use of a CPAP for pre-existing conditions will be allowed If on riluzole, must be on a stable dose. If on edaravone, must have completed 2 cycles and are expected to remain on the same dose throughout the study Able to provide informed consent which includes compliance with the requirements and restrictions Have venous access sufficient to allow for blood sampling Have clinical laboratory test results within the normal reference range for the population or study site, or results with acceptable deviations that are judged to be not clinically significant by the investigator Exclusion Criteria: Have participated or currently participating in another clinical trial within 12 weeks of baseline (Day 1) Have undergone a tracheostomy for ALS symptoms Are on nasal intermittent positive pressure ventilation (NIPPV) >4 hours per day for the treatment of ALS related symptoms Have other causes of neuromuscular weakness Have cognitive impairment, severe disease in the cardiovascular, hematological, renal system, neurodegenerative disease, pulmonary disorder, or psychiatric illness Pregnant or nursing women Have been exposed to any antisense treatment targeting SOD1 within 6 months of the baseline visit Have undergone stem cell therapy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AP-101<br>AP-101 is administered by IV. | Drug: AP-101<br>* Participants receive AP-101 by intravenous infusion (IV).<br>|
| Placebo Comparator: Placebo<br>Placebo is administered by IV. | Drug: Placebo<br>* Participants receive placebo by IV.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the study intervention. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. SAE is defined as any untoward medical occurrence that, at any dose: results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, other situations. | From start of the study up to Week 51 | 
| Number of Participants with Abnormalities in Vital Signs, Clinical Laboratory Assessments, Physical and Neurological Examinations, Electrocardiograms (ECGs) |  | From start of the study up to Week 51 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Elimination half-life (t1/2) of AP-101 in Serum |  | Predose up to Week 51 | 
| Area Under the Drug Concentration-Time Curve (AUC) |  | Predose up to Week 51 | 
| Concentration at End of Infusion (Cat EOI) |  | Week 24 | 
| Change From Baseline in AP-101 Levels in the Cerebrospinal Fluid (CSF) up to Week 24 |  | Baseline, up to Week 24 | 
| Change From Baseline in Neurofilament Light Chain and Phospho-Neurofilament Heavy Chain Levels in the Cerebrospinal Fluid (CSF) up to Week 51 |  | Baseline, up to Week 51 | 
| Change From Baseline in Neurofilament Light Chain and Phospho-Neurofilament Heavy Chain Levels in Plasma up to Week 51 |  | Baseline, up to Week 51 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Familial Amyotrophic Lateral Sclerosis, Sporadic Amyotrophic Lateral Sclerosis