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

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ClinicalTrials.gov Identifier: NCT00661453
Recruitment Status : Completed
First Posted : April 18, 2008
Results First Posted : June 15, 2015
Last Update Posted : June 15, 2015
Families of Spinal Muscular Atrophy
Leadiant Biosciences, Inc.
Information provided by (Responsible Party):
Kathryn Swoboda, 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.

Condition or disease Intervention/treatment Phase
Spinal Muscular Atrophy Type I Drug: Valproic Acid and Levocarnitine Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Trial of Valproic Acid and Carnitine in Infants With Spinal Muscular Atrophy Type I (CARNI-VAL Type I)
Study Start Date : April 2008
Actual Primary Completion Date : May 2012
Actual Study Completion Date : June 2012

Arm Intervention/treatment
Experimental: 1
All patients will receive VPA and carnitine.
Drug: Valproic Acid and Levocarnitine
Drug: Valproic Acid and Levocarnitine; syrup; dosage is by weight

Primary Outcome Measures :
  1. Laboratory Safety Data [ Time Frame: -2 weeks, + 2 weeks, 3 months, 6 months ]
  2. 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) [ Time Frame: -2 weeks, time 0, 3 months, 6 months ]

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

Information from the National Library of Medicine

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Ages Eligible for Study:   2 Weeks to 12 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00661453

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United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287
United States, Michigan
Children's Hospital of Michigan
Detroit, Michigan, United States, 48201
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Ohio
Ohio State University Medical Center, Dept. of Neurology
Columbus, Ohio, United States, 43210
United States, Utah
University of Utah/Primary Children's Medical Center
Salt Lake City, Utah, United States, 84132
United States, Wisconsin
University of Wisconsin Children's Hospital
Madison, Wisconsin, United States, 53792-9988
Canada, Quebec
Hospital Sainte-Justine
Montreal, Quebec, Canada, H3T 1C5
Klinikum der Universität zu Köln
Cologne, Germany, 50924
Sponsors and Collaborators
University of Utah
Families of Spinal Muscular Atrophy
Leadiant Biosciences, Inc.
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Principal Investigator: Kathryn Swoboda, M.D. University of Utah
Study Director: Sandra P Reyna, M.D. Families of Spinal Muscular Atrophy
Additional Information:
Lindstedt S, Lindstedt G. Distribution and Excretion of Carnitine in the Rat. Acta. Chem. Scand. 1961;15:701-702
Scriver C, Beautet A, Sly W, Valle D. The Metabolic Basis of Inherited Disease. New York: McGraw Hill, 1989
Schaub J, Van Hoof F, Vis H. Inborn Errors of Metabolism. New York: Raven Press, 1991

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Responsible Party: Kathryn Swoboda, Associate Professor, Neurology and Pediatrics Director, Pediatric Motor Disorders Research Program, University of Utah
ClinicalTrials.gov Identifier: NCT00661453    
Other Study ID Numbers: 25409
IND 79276
First Posted: April 18, 2008    Key Record Dates
Results First Posted: June 15, 2015
Last Update Posted: June 15, 2015
Last Verified: June 2015
Keywords provided by Kathryn Swoboda, University of Utah:
Spinal Muscular Atrophy
Valproic Acid
Additional relevant MeSH terms:
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Muscular Atrophy
Muscular Atrophy, Spinal
Spinal Muscular Atrophies of Childhood
Pathological Conditions, Anatomical
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Spinal Cord Diseases
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases
Heredodegenerative Disorders, Nervous System
Genetic Diseases, Inborn
Valproic Acid
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs