Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy

• 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: University of Utah
• Collaborators: Families of Spinal Muscular Atrophy; Leadiant Biosciences, Inc.; Abbott
• Information provided by (Responsible Party): Kathryn Swoboda, University of Utah

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Spinal Muscular Atrophy	Drug: Valproic Acid and Levocarnitine; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 94 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, 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)
• Study Start Date: September 2005
• Actual Primary Completion Date: November 2007
• Actual Study Completion Date: November 2007

Arms and Interventions

Arm	Intervention/treatment
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

Outcome Measures

Primary Outcome Measures :

1. 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
2. Efficacy, Measured Through Motor Function Assessments [ Time Frame: -4wks, 0, 3 mo, 6 mo, 12 mo ]
3. 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.

Secondary Outcome Measures :

1. Quantitative Assessment of SMN mRNA From Blood Samples [ Time Frame: -4wks or 0, 3 mo, 6 mo, 12 mo ]
2. Peds QL™ Assessment: Parental Version (All), Child Versions (> 5yrs) [ Time Frame: -4wks, 0, 3mo, 6mo, 12mo ]
3. 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.
4. 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.
5. Ulnar MUNE [ Time Frame: -4 wks, 0, 3 mo, 6 mo, 12 mo ]
6. Growth and Vital Sign Parameters [ Time Frame: -4 wks, 0, 3mo, 6mo, 12mo ]
7. Nutritional Status [ Time Frame: -4 wks, 0, 3mo, 6mo, 12mo ]
8. DEXA [ Time Frame: 0, 6mo, 12mo ]
9. 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.
10. 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.

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 17 Years (Child)
• Sexes Eligible for Study: All
• 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

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

Leadiant Biosciences, Inc.

Abbott

Investigators

• Principal Investigator: Kathryn J Swoboda, M.D.; University of Utah/Primary Children's Medical Center

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kissel JT, Scott CB, Reyna SP, Crawford TO, Simard LR, Krosschell KJ, Acsadi G, Elsheik B, Schroth MK, D'Anjou G, LaSalle B, Prior TW, Sorenson S, Maczulski JA, Bromberg MB, Chan GM, Swoboda KJ; Project Cure Spinal Muscular Atrophy Investigators' Network. SMA CARNIVAL TRIAL PART II: a prospective, single-armed trial of L-carnitine and valproic acid in ambulatory children with spinal muscular atrophy. PLoS One. 2011;6(7):e21296. doi: 10.1371/journal.pone.0021296. Epub 2011 Jul 6.

Swoboda KJ, Scott CB, Crawford TO, Simard LR, Reyna SP, Krosschell KJ, Acsadi G, Elsheik B, Schroth MK, D'Anjou G, LaSalle B, Prior TW, Sorenson SL, Maczulski JA, Bromberg MB, Chan GM, Kissel JT; Project Cure Spinal Muscular Atrophy Investigators Network. SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy. PLoS One. 2010 Aug 19;5(8):e12140. doi: 10.1371/journal.pone.0012140.

• Responsible Party: Kathryn Swoboda, Associate Professor, Neurology and Pediatrics Director, Pediatric Motor Disorders Research Program, University of Utah
• ClinicalTrials.gov Identifier: NCT00227266
• Other Study ID Numbers: 13698
• First Posted: September 27, 2005
• Results First Posted: May 3, 2011
• Last Update Posted: September 26, 2011
• Last Verified: September 2011

Keywords provided by Kathryn Swoboda, 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; Pathological Conditions, Anatomical; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Central Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases; Valproic Acid; Anticonvulsants; 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