Please select the eligibility criteria that correspond to the clinical trial below.
Title: Multi-center Phase II Trial of Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy (SMA CARNI-VAL Trial)
Brief Summary: This is a multi-center trial to assess safety and efficacy of a combined regimen of oral valproic acid (VPA) and carnitine in patients with Spinal Muscular Atrophy (SMA) 2 to 17 years of age. Cohort 1 is a double-blind placebo-controlled randomized intention to treat protocol for SMA "sitters" 2 - 8 years of age. Cohort 2 is an open label protocol for SMA "standers and walkers" 3 - 17 years of age to explore responsiveness of efficacy outcomes. Outcome measures will include blood chemistries, functional testing, pulmonary function testing, electrophysiological evaluations, PedsQL quality of life assessment, quantitative assessments of survival motor neuron (SMN) mRNA from blood samples, growth and vital sign parameters. Six centers will enroll a total of 90 patients.


Options:
A: Inclusion Criteria:

Cohort 1

* Confirmed genetic diagnosis of 5q SMA
* SMA 2 or non-ambulatory SMA 3: all subjects must be able to sit independently for at least 3 seconds without support
* Age 2 to 8 years at time of enrollment

Cohort 2

* Confirmed genetic diagnosis of 5q SMA
* SMA subjects (SMA types 2 or 3) who can stand independently without braces or other support for up to 2 seconds, or walk independently
* Age 3 to 17 years at time of study enrollment

Exclusion Criteria:

Cohort 1

* Need for BiPAP support \> 12 hours per day
* Spinal rod or fixation for scoliosis or anticipated need within six months of enrollment
* Inability to meet study visit requirements or cooperate reliably with functional testing
* Coexisting medical conditions that contraindicate travel, testing or study medications
* Use of medications or supplements which interfere with valproic acid or carnitine metabolism within 3 months of study enrollment.
* Current use of either VPA or carnitine. If study subject is taking VPA or carnitine then patient must go through a washout period of 12 weeks before enrollment into the study
* Body Mass Index \> 90th % for age

Cohort 2

* Spinal rod or fixation for scoliosis or anticipated need within six months of enrollment
* Inability to meet study visit requirements or cooperate with functional testing
* Transaminases, amylase or lipase \> 3.0 x normal values, WBC \< 3.0 or neutropenia \< 1.0, platelets \< 100 K, or hematocrit \< 30 persisting over a 30 day period.
* Coexisting medical conditions that contraindicate travel, testing or study medications
* Use of medications or supplements which interfere with valproic acid or carnitine metabolism within 3 months of study enrollment.
* Current use of either VPA or carnitine. If study subject is taking VPA or carnitine then patient must be go through a washout period of 12 weeks before enrollment in the study.
* Body Mass Index \> 90th % for age
* Pregnant women/girls, or those intending to try to become pregnant during the course of the study.
B: 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.
C: Inclusion Criteria:

* Six or nine months of age and younger (depending on cohort) on day of vector infusion with Type 1 SMA as defined by the following features:

  * Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 mutations (deletion or point mutations) and 2 copies of SMN2.
  * Onset of disease at birth up to 6 months of age.
  * Hypotonia by clinical evaluation with delay in motor skills, poor head control, round shoulder posture and hypermobility of joints.

Exclusion Criteria:

* Active viral infection (includes HIV or serology positive for hepatitis B or C)
* Use of invasive ventilatory support (tracheotomy with positive pressure)\* or pulse oximetry \<95% saturation.
* Patients may be put on non-invasive ventilator support (BiPAP) for less than 16 hours a day at the discretion of their physician or research staff.
* Concomitant illness that in the opinion of the PI creates unnecessary risks for gene transfer
* Concomitant use of any of the following drugs: drugs for treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy or immunosuppressive therapy within 3 months of starting the trial (e.g. corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous immunoglobulin, rituximab)
* Patients with Anti-AAV9 antibody titers \>1:50 as determined by ELISA binding immunoassay.
* Abnormal laboratory values considered clinically significant (GGT \> 3XULN, bilirubin ≥ 3.0 mg/dL , creatinine ≥ 1.8 mg/dL, Hgb \< 8 or \> 18 g/Dl; WBC \> 20,000 per cmm) Participation in a recent SMA treatment clinical trial that in the opinion of the PI creates unnecessary risks for gene transfer.
* Family does not want to disclose patient's study participation with primary care physician and other medical providers.
* Patient with signs of aspiration based on a swallowing test and unwilling to use an alternative method to oral feeding.
* Patients with a single base substitution in SMN2 (c.859G\>C in exon 7) will be excluded based on predicted mild phenotype.
D: Inclusion Criteria:

* Laboratory documentation of SMN mutation/deletion consistent with a genetic diagnosis of SMA
* Clinical diagnosis of SMA type I
* Age 2 weeks to 12 months
* Written informed consent of parents/guardian

Exclusion Criteria:

* Any clinical or laboratory evidence of hepatic or pancreatic insufficiency.
* Laboratory results drawn within 14 days prior to start of study drug demonstrating:

Liver transaminases (AST, ALT), lipase, amylase: \> 1.5 x ULN White Blood Cell Count: \< 3 Neutropenia: \<1 Platelet: \<100K Hematocrit: \<30, persisting over a 30-day period

* Serious illness requiring systemic treatment and/or hospitalization within two weeks prior to study entry.
* Use of medications or supplements within 30 days of study enrollment that interfere with VPA or carnitine metabolism; that increase the potential risks of VPA or carnitine; or that are hypothesized to have a beneficial effect in SMA animal models or human neuromuscular disorders, including riluzole, valproic acid, hydroxyurea, oral use of albuterol, sodium phenylbutyrate, butyrate derivatives, creatinine, growth hormone, anabolic steroids, probenecid, oral or parenteral use of corticosteroids at entry, or agents anticipated to increase or decrease muscle strength or agents with presumed histone deacetylase (HDAC) inhibition.
* Infants who have participated in a treatment trial for SMA within 30 days of study entry or who will become enrollees in any other treatment trial during the course of this study.
* Unwillingness to travel for study assessments.
* Coexisting medical conditions that contradict use of VPA/carnitine or travel to and from study site.

Answer: A