CARNIVAL Type I: Valproic Acid and Carnitine in Infants With Spinal Muscular Atrophy (SMA) Type I

Phase 1

Completed

• Conditions: Spinal Muscular Atrophy Type I
• Interventions: Drug: Valproic Acid and Levocarnitine

• Registration Number: NCT00661453
• Lead Sponsor: University of Utah

Brief Summary

This is a multi-center trial to test safety and evaluate early treatment intervention with valproic acid and carnitine in moderating SMA symptoms of Type I infants.

Detailed Description

Spinal muscular atrophy (SMA) is a genetic disorder that results in severe muscle weakness. It is one of the most common conditions causing muscle weakness in children. Patients with SMA most often develop weakness as babies or young children. Most people with SMA gradually lose muscle strength and abilities over time. Babies with the severe infantile form of SMA, SMA type I, usually lose abilities and strength quickly over a few weeks or months.

Valproic acid (VPA) is a medicine that has been used for many years to treat patients with epilepsy. Recent research suggests that VPA may be able to upregulate expression of a backup copy of the SMN gene in SMA patient cell lines. In addition, some preliminary data suggests it may prolong survival in animal models of SMA. Because VPA can deplete carnitine in children with SMA Type I, carnitine is added to help prevent possible toxicity.

In this multi-center trial, we will evaluate the effects of VPA/carnitine on infants with SMA type I. A variety of outcome measures, including assessment of safety, will be performed at each study visit to follow the course of the disease. The protocol includes two baseline visits over a period of two weeks, two clinical assessments on medication at 3 and 6 months, and then 6 months additional followup via telephone. Total duration of the study will be approximately 12 months.

Study Timeline

• Study Start: 2008-04
• Study First Submitted: 2008-04-14
• Study First Submitted QC: 2008-04-14
• Study First Posted: 2008-04-18
• Primary Completion: 2012-05
• Study Completion: 2012-06
• Status Verified: 2015-06
• Results First Submitted: 2015-06-01
• Results First Submitted QC: 2015-06-01
• Last Update Submitted: 2015-06-01
• Results First Posted: 2015-06-15
• Last Update Posted: 2015-06-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 40

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
1	Valproic Acid and Levocarnitine	All patients will receive VPA and carnitine.

Primary Outcome Measures

Name	Time	Method
Anthropometric Measures of Nutritional Status (Body Mass Index [BMI] Z-scores, Weight for Length Ratios, Lean/Fat Mass Via DEXA, Growth Parameters, and Triceps Skinfold Measures)	-2 weeks, time 0, 3 months, 6 months
Laboratory Safety Data	-2 weeks, + 2 weeks, 3 months, 6 months

Secondary Outcome Measures

Name	Time	Method
Functional Motor Assessments: TIMPSI Scores	-2 weeks, time 0, 3 months, 6 months
Quantitative SMN mRNA and Protein Measures	-2 weeks, time 0 , 3 months, or 6 months
Primary Caregiver Functional Rating Scale for SMA Type I Subjects (PCFRS)	time 0, and monthly for 12 months
Maximum Ulnar CMAP Amplitude/Area and MUNE	-2 weeks, time 0, 3 months, 6 months
Time to Death or Ventilator Dependence (Defined as >16 Hours/Day)	monthly
Whole Body DEXA Scanning for Lean Body Mass and Total Bone Mineral Density/ Content	-2 weeks or time 0, 3 months, 6 months

Trial Locations

Locations (8)

University of Wisconsin Children's Hospital; 🇺🇸 Madison, Wisconsin, United States

Children's Hospital of Michigan; 🇺🇸 Detroit, Michigan, United States

Klinikum der Universität zu Köln; 🇩🇪 Cologne, Germany

Hospital Sainte-Justine; 🇨🇦 Montreal, Quebec, Canada

Ohio State University Medical Center, Dept. of Neurology; 🇺🇸 Columbus, Ohio, United States

Johns Hopkins University; 🇺🇸 Baltimore, Maryland, United States

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States

University of Utah/Primary Children's Medical Center; 🇺🇸 Salt Lake City, Utah, United States