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Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy

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ClinicalTrials.gov Identifier: NCT00227266
Recruitment Status : Completed
First Posted : September 27, 2005
Results First Posted : May 3, 2011
Last Update Posted : September 26, 2011
Sponsor:
Collaborators:
Families of Spinal Muscular Atrophy
Leadiant Biosciences, Inc.
Abbott
Information provided by (Responsible Party):
Kathryn Swoboda, University of Utah

Tracking Information
First Submitted Date  ICMJE September 23, 2005
First Posted Date  ICMJE September 27, 2005
Results First Submitted Date March 19, 2010
Results First Posted Date May 3, 2011
Last Update Posted Date September 26, 2011
Study Start Date  ICMJE September 2005
Actual Primary Completion Date November 2007   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 31, 2011)
  • Safety Labs [ Time Frame: -4 wks, 0, 2 wks, 3 mo, 6 mo, 9 mo, 12 mo for safety labs; throughout for AEs ]
    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 ]
  • Modified Hammersmith Change From Baseline to 6 Months [ Time Frame: 0 months, 6 months ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 23, 2005)
  • Cohort 1:
  • 1.Safety
  • 2.Functional Status/Strength as assessed via Modified Hammersmith Functional Motor Scale (MHFMS)
  • Cohort 2:
  • 1.Safety labs:
  • 2.Project Cure Functional Motor Scale for SMA
  • 3.Myometry > 5 yrs (CITEC) right-sided grip, elbow flexion, knee extension
Change History Complete list of historical versions of study NCT00227266 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 31, 2011)
  • Quantitative Assessment of SMN mRNA From Blood Samples [ Time Frame: -4wks or 0, 3 mo, 6 mo, 12 mo ]
  • Peds QL™ Assessment: Parental Version (All), Child Versions (> 5yrs) [ Time Frame: -4wks, 0, 3mo, 6mo, 12mo ]
  • 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) ]
    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) ]
    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 ]
  • Growth and Vital Sign Parameters [ Time Frame: -4 wks, 0, 3mo, 6mo, 12mo ]
  • Nutritional Status [ Time Frame: -4 wks, 0, 3mo, 6mo, 12mo ]
  • DEXA [ Time Frame: 0, 6mo, 12mo ]
  • 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) ]
    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) ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 23, 2005)
  • Cohorts 1 & 2
  • 1.Pulmonary Function Testing:
  • 2.Quantitative assessment of SMN mRNA from blood samples
  • 3.Peds QL™ assessment: parental version (all), child versions (> 5yrs)
  • 4.Max CMAP amplitude/area
  • 5.Ulnar MUNE
  • 6.Growth and vital sign parameters
  • 7.Nutritional Status
Current Other Outcome Measures  ICMJE Not Provided
Original Other Outcome Measures  ICMJE Not Provided
 
Descriptive Information
Brief Title  ICMJE Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy
Official Title  ICMJE 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.
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.
Study Type  ICMJE Interventional
Study Phase Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Spinal Muscular Atrophy
Intervention  ICMJE
  • Drug: Valproic Acid and Levocarnitine
    VPA,sprinkle cap; Levocarnitine, syrup; dosage is by weight
    Other Names:
    • Depakote
    • VPA
    • Carnitor
  • Drug: Placebo
Study Arms
  • 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.
    Interventions:
    • Drug: Valproic Acid and Levocarnitine
    • 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.
    Intervention: Drug: Valproic Acid and Levocarnitine
  • 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.
    Intervention: Drug: Valproic Acid and Levocarnitine
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 31, 2011)
94
Original Enrollment  ICMJE
 (submitted: September 23, 2005)
90
Actual Study Completion Date November 2007
Actual Primary Completion Date November 2007   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender
Sexes Eligible for Study: All
Ages 2 Years to 17 Years   (Child)
Accepts Healthy Volunteers No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00227266
Other Study ID Numbers  ICMJE 13698
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Kathryn Swoboda, University of Utah
Study Sponsor  ICMJE University of Utah
Collaborators  ICMJE
  • Families of Spinal Muscular Atrophy
  • Leadiant Biosciences, Inc.
  • Abbott
Investigators  ICMJE
Principal Investigator: Kathryn J Swoboda, M.D. University of Utah/Primary Children's Medical Center
PRS Account University of Utah
Verification Date September 2011

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP