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

Phase I/II Trial of Valproic Acid and Carnitine in Infants With Spinal Muscular Atrophy Type I (CARNI-VAL Type I)

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.

Study Overview

• Status: Completed
• Conditions: Spinal Muscular Atrophy Type I
• Intervention / Treatment: Drug: Valproic Acid and Levocarnitine

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 Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Hospital Sainte-Justine
• Germany
  • Cologne, Germany, 50924
    • Klinikum der Universität zu Köln
• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Children's Hospital of Michigan
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Medical Center, Dept. of Neurology
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah/Primary Children's Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-9988
      • University of Wisconsin Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 weeks to 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Laboratory Safety Data	-2 weeks, + 2 weeks, 3 months, 6 months
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

Secondary Outcome Measures

Outcome Measure	Time Frame
Time to Death or Ventilator Dependence (Defined as >16 Hours/Day)	monthly
Primary Caregiver Functional Rating Scale for SMA Type I Subjects (PCFRS)	time 0, and monthly for 12 months
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
Maximum Ulnar CMAP Amplitude/Area and MUNE	-2 weeks, time 0, 3 months, 6 months
Whole Body DEXA Scanning for Lean Body Mass and Total Bone Mineral Density/ Content	-2 weeks or time 0, 3 months, 6 months

Collaborators and Investigators

• Sponsor: University of Utah
• Collaborators: Leadiant Biosciences, Inc.; Families of Spinal Muscular Atrophy
• Investigators: Principal Investigator: Kathryn Swoboda, M.D., University of Utah; Study Director: Sandra P Reyna, M.D., Families of Spinal Muscular Atrophy

Publications and helpful links

General Publications

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• Bromberg MB, Swoboda KJ. Motor unit number estimation in infants and children with spinal muscular atrophy. Muscle Nerve. 2002 Mar;25(3):445-7. doi: 10.1002/mus.10050.
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• Gilliam TC, Brzustowicz LM, Castilla LH, Lehner T, Penchaszadeh GK, Daniels RJ, Byth BC, Knowles J, Hislop JE, Shapira Y, et al. Genetic homogeneity between acute and chronic forms of spinal muscular atrophy. Nature. 1990 Jun 28;345(6278):823-5. doi: 10.1038/345823a0.
• Melki J, Lefebvre S, Burglen L, Burlet P, Clermont O, Millasseau P, Reboullet S, Benichou B, Zeviani M, Le Paslier D, et al. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies. Science. 1994 Jun 3;264(5164):1474-7. doi: 10.1126/science.7910982.
• Monani UR, Lorson CL, Parsons DW, Prior TW, Androphy EJ, Burghes AH, McPherson JD. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet. 1999 Jul;8(7):1177-83. doi: 10.1093/hmg/8.7.1177.
• Campbell L, Potter A, Ignatius J, Dubowitz V, Davies K. Genomic variation and gene conversion in spinal muscular atrophy: implications for disease process and clinical phenotype. Am J Hum Genet. 1997 Jul;61(1):40-50. doi: 10.1086/513886.
• Lefebvre S, Burlet P, Liu Q, Bertrandy S, Clermont O, Munnich A, Dreyfuss G, Melki J. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet. 1997 Jul;16(3):265-9. doi: 10.1038/ng0797-265.
• Monani UR, Sendtner M, Coovert DD, Parsons DW, Andreassi C, Le TT, Jablonka S, Schrank B, Rossoll W, Prior TW, Morris GE, Burghes AH. The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(-/-) mice and results in a mouse with spinal muscular atrophy. Hum Mol Genet. 2000 Feb 12;9(3):333-9. doi: 10.1093/hmg/9.3.333. Erratum In: Hum Mol Genet. 2007 Nov 1;16(21):2648. Rossol, W [corrected to Rossoll, W].
• Feldkotter M, Schwarzer V, Wirth R, Wienker TF, Wirth B. Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Am J Hum Genet. 2002 Feb;70(2):358-68. doi: 10.1086/338627. Epub 2001 Dec 21.
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• Chang JG, Hsieh-Li HM, Jong YJ, Wang NM, Tsai CH, Li H. Treatment of spinal muscular atrophy by sodium butyrate. Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9808-13. doi: 10.1073/pnas.171105098.
• Andreassi C, Jarecki J, Zhou J, Coovert DD, Monani UR, Chen X, Whitney M, Pollok B, Zhang M, Androphy E, Burghes AH. Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients. Hum Mol Genet. 2001 Nov 15;10(24):2841-9. doi: 10.1093/hmg/10.24.2841.
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Study record dates

Study Major Dates

• Study Start: April 1, 2008
• Primary Completion (Actual): May 1, 2012
• Study Completion (Actual): June 1, 2012

Study Registration Dates

• First Submitted: April 14, 2008
• First Submitted That Met QC Criteria: April 14, 2008
• First Posted (Estimate): April 18, 2008

Study Record Updates

• Last Update Posted (Estimate): June 15, 2015
• Last Update Submitted That Met QC Criteria: June 1, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: Spinal Muscular Atrophy; SMA; Valproic Acid
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Genetic Diseases, Inborn; Neuromuscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Spinal Cord Diseases; Heredodegenerative Disorders, Nervous System; Motor Neuron Disease; Muscular Atrophy; Atrophy; Muscular Atrophy, Spinal; Spinal Muscular Atrophies of Childhood; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Anticonvulsants; Antimanic Agents; Valproic Acid
• Other Study ID Numbers: 25409; IND 79276