Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy

This study has been completed.
Sponsor:
Collaborators:
Families of Spinal Muscular Atrophy
Sigma Tau Pharmaceuticals, Inc.
Abbott
Information provided by (Responsible Party):
Kathryn Swoboda, University of Utah
ClinicalTrials.gov Identifier:
NCT00227266
First received: September 23, 2005
Last updated: September 22, 2011
Last verified: September 2011
  Purpose

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.


Condition Intervention Phase
Spinal Muscular Atrophy
Drug: Valproic Acid and Levocarnitine
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Multi-center Phase II Trial of Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy (SMA CARNI-VAL Trial)

Resource links provided by NLM:


Further study details as provided by University of Utah:

Primary Outcome Measures:
  • Safety Labs [ Time Frame: -4 wks, 0, 2 wks, 3 mo, 6 mo, 9 mo, 12 mo for safety labs; throughout for AEs ] [ Designated as safety issue: Yes ]
    Participants will have labs drawn regularly to maintain appropriate dosing and monitor liver function

  • Efficacy, Measured Through Motor Function Assessments [ Time Frame: -4wks, 0, 3 mo, 6 mo, 12 mo ] [ Designated as safety issue: Yes ]
  • Modified Hammersmith Change From Baseline to 6 Months [ Time Frame: 0 months, 6 months ] [ Designated as safety issue: No ]
    Comparison of Modified Hammersmith Change from baseline to 6 months. Scores range from 0 to 40. A higher score indicates a better outcome. This scale is used to assess gross motor abilities of non-ambulant children with SMA in multiple research trials as well as in clinical settings.


Secondary Outcome Measures:
  • Quantitative Assessment of SMN mRNA From Blood Samples [ Time Frame: -4wks or 0, 3 mo, 6 mo, 12 mo ] [ Designated as safety issue: No ]
  • Peds QL™ Assessment: Parental Version (All), Child Versions (> 5yrs) [ Time Frame: -4wks, 0, 3mo, 6mo, 12mo ] [ Designated as safety issue: Yes ]
  • Max CMAP Amplitude (Mean) [ Time Frame: 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available) ] [ Designated as safety issue: Yes ]
    The maximum Compound Motor Action Potential (CMAP) is a measurement obtained through EMG testing that is associated with disease progression. In this study, we measure the maximum CMAP by stimulating one nerve in the hand and measuring the response of the muscle. This is done multiple times, the outcome used is the highest peak, or response observed.

  • Max CMAP Amplitude Median [ Time Frame: 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available) ] [ Designated as safety issue: Yes ]
    The maximum Compound Motor Action Potential (CMAP) is a measurement obtained through EMG testing that is associated with disease progression. In this study, we measure the maximum CMAP by stimulating one nerve in the hand and measuring the response of the muscle. This is done multiple times, the outcome used is the highest peak, or response observed.

  • Ulnar MUNE [ Time Frame: -4 wks, 0, 3 mo, 6 mo, 12 mo ] [ Designated as safety issue: Yes ]
  • Growth and Vital Sign Parameters [ Time Frame: -4 wks, 0, 3mo, 6mo, 12mo ] [ Designated as safety issue: Yes ]
  • Nutritional Status [ Time Frame: -4 wks, 0, 3mo, 6mo, 12mo ] [ Designated as safety issue: Yes ]
  • DEXA [ Time Frame: 0, 6mo, 12mo ] [ Designated as safety issue: Yes ]
  • Max CMAP Area (Mean) [ Time Frame: 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available) ] [ Designated as safety issue: Yes ]
    The maximum Compound Motor Action Potential (CMAP) area is a measurement obtained through EMG testing that is associated with disease progression. In this study, we measure the maximum CMAP by stimulating one nerve in the hand and measuring the response of the muscle. This procedure is repeated multiple times. The maximum area is the response that results in the largest area under the response curve.

  • Max CMAP Area (Median) [ Time Frame: 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available) ] [ Designated as safety issue: Yes ]
    The maximum Compound Motor Action Potential (CMAP) area is a measurement obtained through EMG testing that is associated with disease progression. In this study, we measure the maximum CMAP by stimulating one nerve in the hand and measuring the response of the muscle. This procedure is repeated multiple times. The maximum area is the response that results in the largest area under the response curve.


Enrollment: 94
Study Start Date: September 2005
Study Completion Date: November 2007
Primary Completion Date: November 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Cohort 1a
Patients in Cohort 1a - Placebo Comparator, will be on a placebo for 6 months and then will switch to the active treatment. Dosage of the VPA will start at 10-20 mg/kg/day divided into two or tree doses. The dose will be adjusted to achieve a therapeutic trough level of 50-120 micrograms/ml. VPA will be given in the form of 125 mg sprinkle capsules. Dosage for Carnitor will be 50 mg/kg/day with a maximum dose of 10000 mg/day divided into two doses. Carnitor elixir comes as 500 mg/5 ml. All subjects will be given Carnitor or equivalent placebo in the liquid form.
Drug: Valproic Acid and Levocarnitine
VPA,sprinkle cap; Levocarnitine, syrup; dosage is by weight
Other Names:
  • Depakote
  • VPA
  • Carnitor
Drug: Placebo
Active Comparator: Cohort 1b
Cohort 1b - Active Comparator will be on treatment throughout the study. Dosage of the VPA will start at 10-20 mg/kg/day divided into two or tree doses. The dose will be adjusted to achieve a therapeutic trough level of 50-120 micrograms/ml. VPA will be given in the form of 125 mg sprinkle capsules. Dosage for Carnitor will be 50 mg/kg/day with a maximum dose of 10000 mg/day divided into two doses. Carnitor elixir comes as 500 mg/5 ml. All subjects will be given Carnitor in the liquid form.
Drug: Valproic Acid and Levocarnitine
VPA,sprinkle cap; Levocarnitine, syrup; dosage is by weight
Other Names:
  • Depakote
  • VPA
  • Carnitor
Experimental: Cohort 2
Cohort 2 pts are on open-label treatment throughout. Dosage of the VPA will start at 10-20 mg/kg/day divided into two or tree doses. The dose will be adjusted to achieve a therapeutic trough level of 50-120 micrograms/ml. VPA will be given in the form of 125 mg sprinkle capsules. Dosage for Carnitor will be 50 mg/kg/day with a maximum dose of 10000 mg/day divided into two doses. Carnitor elixir comes as 500 mg/5 ml. All subjects will be given Carnitor or equivalent placebo in the liquid form.
Drug: Valproic Acid and Levocarnitine
VPA,sprinkle cap; Levocarnitine, syrup; dosage is by weight
Other Names:
  • Depakote
  • VPA
  • Carnitor

Detailed Description:

This is a multi-center phase II trial 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. Subjects will undergo two baseline assessments over 4 to 6 week period, then will be randomized to treatment or placebo for the next six months. All subjects will then be placed on active treatment for the subsequent six month period. Cohort 2 is an open label protocol for SMA "standers and walkers" 3 - 17 years of age to explore responsiveness of efficacy outcomes. Subjects will undergo two baseline assessments over a four to six week period, followed by one year active treatment with VPA and carnitine. Outcome measures are performed every 3 to 6 months, and 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.

  Eligibility

Ages Eligible for Study:   2 Years to 17 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00227266

Locations
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, Ohio
Ohio State University
Columbus, Ohio, United States, 43210-1228
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
Sponsors and Collaborators
University of Utah
Families of Spinal Muscular Atrophy
Sigma Tau Pharmaceuticals, Inc.
Abbott
Investigators
Principal Investigator: Kathryn J Swoboda, M.D. University of Utah/Primary Children's Medical Center
  More Information

Additional Information:
Publications:
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

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Kathryn Swoboda, Associate Professor, Neurology and Pediatrics Director, Pediatric Motor Disorders Research Program, University of Utah
ClinicalTrials.gov Identifier: NCT00227266     History of Changes
Other Study ID Numbers: 13698
Study First Received: September 23, 2005
Results First Received: March 19, 2010
Last Updated: September 22, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Utah:
Spinal Muscular Atrophy (SMA)
SMA Type 2
SMA Type 3

Additional relevant MeSH terms:
Muscular Atrophy
Muscular Atrophy, Spinal
Atrophy
Spinal Cord Diseases
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Pathological Conditions, Anatomical
Signs and Symptoms
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases
Carnitine
Valproic Acid
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Anticonvulsants
Central Nervous System Agents
Therapeutic Uses
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Antimanic Agents
Tranquilizing Agents

ClinicalTrials.gov processed this record on July 29, 2014