Please select the eligibility criteria that correspond to the clinical trial below.
Title: An Open-label, Escalating Dose Study to Assess the Safety, Tolerability and Dose-range Finding of a Single Intrathecal Dose of ISIS 396443 in Patients With Spinal Muscular Atrophy
Brief Summary: This objectives of this study are to evaluate the safety, tolerability, and pharmacokinetics of a single dose of nusinersen (ISIS 396443) administered intrathecally to participants with Spinal Muscular Atrophy (SMA).


Options:
A: Key Inclusion Criteria:

* Documented Survival Motor Neuron1 (SMN1) homozygous gene deletion
* Clinical signs attributable to Spinal Muscular Atrophy (SMA)
* Able to complete all study procedures, measurements and visits and parent/participant has adequately supportive psychosocial circumstances, in the opinion of the investigator
* Estimated life expectancy \> 2 years from Screening
* Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is planned for study procedure

Key Exclusion Criteria:

* Respiratory insufficiency defined by the need for invasive or non-invasive ventilation during a 24 hour period
* Presence of a gastric feeding tube
* Previous scoliosis surgery or scoliosis surgery planned during the duration of the study that would interfere with the lumbar puncture (LP) injection procedure
* Hospitalization for surgery or pulmonary event within the last 2 months or planned during the study
* Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy
* History of brain or spinal cord disease that would interfere with LP procedures or cerebrospinal fluid (CSF) circulation
* Presence of an implanted shunt for the draining of CSF or an implanted Central Nervous System (CNS) catheter
* History of bacterial meningitis
* Clinically significant abnormalities in hematology or clinical chemistry parameters
* Treatment with another investigational drug, biological agent, or device within 1-month of Screening or 5 half-lives of study agent whichever is longer. Any history of gene therapy or cell transplantation
* Ongoing medical condition that would interfere with the conduct and assessments of the study. Examples are medical disability (e.g. wasting or cachexia, severe anemia, etc.) that would interfere with the assessment of safety or would compromised the ability of the participant to undergo study procedures

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
B: Key Inclusion Criteria:

* Parent or guardian has signed informed consent and, if indicated per participant's age and institutional guidelines, participant has signed informed assent
* Be medically diagnosed with Spinal Muscular Atrophy (SMA)
* Have onset of clinical signs and symptoms consistent with SMA at greater than 6 months of age
* Be able to sit independently, but has never had the ability to walk independently
* Have Motor Function Score (Hammersmith Functional Motor Scale - Expanded) greater than or equal to 10 and less than or equal to 54 at Screening
* Be able to complete all study procedures, measurements and visits and parent or guardian and subject has adequately supportive psychosocial circumstances, in the opinion of the Investigator
* Have an estimated life expectancy of greater than 2 years from Screening, in the opinion of the Investigator
* Meet age-appropriate institutional criteria for use of anesthesia and sedation, if use is planned for study procedures
* For subjects who have reached reproductive maturity, satisfy study contraceptive requirements

Key Exclusion Criteria:

* Respiratory insufficiency, defined by the medical necessity for invasive or non-invasive ventilation for greater than 6 hours during a 24 hour period, at Screening
* Medical necessity for a gastric feeding tube, where the majority of feeds are given by this route, as assessed by the Site Investigator
* Severe contractures or severe scoliosis evident on X-ray examination at Screening
* Hospitalization for surgery (i.e., scoliosis surgery, other surgery), pulmonary event, or nutritional support within 2 months of Screening or planned during the duration of the study
* Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period
* History of brain or spinal cord disease, including tumors, or abnormalities by magnetic resonance imaging (MRI) or computed tomography (CT) that would interfere with the LP procedures or cerebrospinal fluid (CSF) circulation
* Presence of an implanted shunt for the drainage of CSF or an implanted central nervous system (CNS) catheter
* History of bacterial meningitis
* Dosing with IONIS-SMN Rx in any previous clinical study
* Prior injury (e.g., upper or lower limb fracture) or surgical procedure which impacts the subject's ability to perform any of the outcome measure testing required in the protocol and from which the subject has not fully recovered or achieved a stable baseline
* Clinically significant abnormalities in hematology or clinical chemistry parameters or electrocardiogram (ECG), as assessed by the Site Investigator, at the Screening visit that would render the subject unsuitable for inclusion
* Treatment with another investigational drug (e.g., oral albuterol or salbutamol, riluzole, carnitine, creatine, sodium phenylbutyrate, et.c), biological agent, or device within 1-month of Screening or 5 half-lives of study agent, whichever is longer. Treatment with valproate or hydroxyurea within 3-months of Screening. Any history of gene therapy, antisense oligonucleotide therapy, or cell transplantation.
* Ongoing medical condition that according to the Site Investigator would interfere with the conduct and assessments of the study. Examples are medical disability (e.g., wasting or cachexia, severe anemia, etc.) that would interfere with the assessment of safety or would compromise the ability of the subject to undergo study procedures.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
C: Key Inclusion Criteria:

* Genetic documentation of 5q SMA (homozygous gene deletion or mutation)
* Onset of clinical signs and symptoms consistent with SMA at ≥ 21 days and \<6 months (180 days) of age
* At study entry, receiving adequate nutrition and hydration (with or without gastrostomy), in the opinion of the Site Investigator
* Body weight \>5th percentile for age using Center of Disease Control and Prevention (CDC) guidelines
* Medical care meets and is expected to continue to meet guidelines set out in the Consensus Statement for Standard of Care in SMA (Wang et al. 2007), in the opinion of the Site Investigator
* Gestational age of 35 to 42 weeks and gestation body weight ≥2 kg
* Reside within approximately 9 hours ground-travel distance from a participating study center for the duration of the study. Residence \>2 hours ground-travel distance from a study center must obtain clearance from the Site Investigator and the study Medical Monitor
* Able to complete all study procedures, measurements and visits and parent or guardian/participant has adequately supportive psychosocial circumstances, in the opinion of the Site Investigator

Exclusion Criteria:

* Hypoxemia (O2 saturation awake \<96% or O2 saturation asleep \<96%, without ventilation support)
* Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period
* History of brain or spinal cord disease that would interfere with the lumbar puncture (LP) procedures, CSF circulation, or safety assessments
* Presence of an implanted shunt for the drainage of cerebrospinal fluid (CSF) or an implanted central nervous system (CNS) catheter
* History of bacterial meningitis
* Clinically significant abnormalities in hematology or clinical chemistry parameters, as assessed by the Site Investigator, at screening that would render the participant unsuitable for inclusion
* Treatment with another investigational drug (e.g., albuterol, riluzole, carnitine, creatine, sodium phenylbutyrate, salbutamol, valproate, hydroxyurea etc), biological agent, or device within 90 days prior to enrollment or anytime during the study. Any history of gene therapy or cell transplantation
* The participants parent(s) or legal guardian(s) is unable to understand the nature, scope, and possible consequences of the study, or does not agree to comply with the protocol defined schedule of assessments
* Ongoing medical condition that according to the Site Investigator would interfere with the conduct and assessments of the study. Examples are medical disability other than SMA that would interfere with the assessment of safety or would compromise the ability of the participant to undergo study procedures

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
D: Inclusion Criteria:

* Patients must have a diagnosis of SMA, confirmed by genetic testing
* Only patients 2 years of age and older at enrollment will be eligible

Exclusion Criteria:

* Patients taking any medications with known hepatotoxicity, congenital metabolic disorders or on multiple anticonvulsant medications
* Patients taking medications which may interact with VPA
* Patients on ventilatory support for more than 16 hours per day
* Patients currently enrolled in other treatment trials

Answer: A