Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy

NCT00227266 | Completed Phase 2 Results DMC

• 1 other identifier: 13698
• Study Type: interventional
• Target: 94
• Locations: 2 countries
• Sites: 6

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.

Conditions

Spinal Muscular Atrophy

Keywords

Spinal Muscular Atrophy (SMA); SMA Type 2; SMA Type 3

Outcome Measures

Primary Outcomes (3)

• Safety Labs

  Participants will have labs drawn regularly to maintain appropriate dosing and monitor liver function

  -4 wks, 0, 2 wks, 3 mo, 6 mo, 9 mo, 12 mo for safety labs; throughout for AEs

• Efficacy, Measured Through Motor Function Assessments

  -4wks, 0, 3 mo, 6 mo, 12 mo

• Modified Hammersmith Change From Baseline to 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.

  0 months, 6 months

Secondary Outcomes (10)

• Quantitative Assessment of SMN mRNA From Blood Samples

  -4wks or 0, 3 mo, 6 mo, 12 mo

• Peds QL™ Assessment: Parental Version (All), Child Versions (> 5yrs)

  -4wks, 0, 3mo, 6mo, 12mo

• Max CMAP Amplitude (Mean)

  1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)

• Max CMAP Amplitude Median

  1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)

• Ulnar MUNE

  -4 wks, 0, 3 mo, 6 mo, 12 mo

Study Arms (3)

Cohort 1a

PLACEBO COMPARATOR

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; Drug: Placebo

Cohort 1b

ACTIVE COMPARATOR

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

Cohort 2

EXPERIMENTAL

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

Interventions

Valproic Acid and Levocarnitine DRUG

VPA,sprinkle cap; Levocarnitine, syrup; dosage is by weight

Also known as: Depakote, VPA, Carnitor

Cohort 1a; Cohort 1b; Cohort 2

Placebo DRUG

Cohort 1a

Eligibility Criteria

• Age: 2 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Utah: lead
• Families of Spinal Muscular Atrophy: collaborator
• Leadiant Biosciences, Inc.: collaborator
• Abbott: collaborator

Study Sites (6)

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Children's Hospital of Michigan

Detroit, Michigan, 48201, United States

Location

Ohio State University

Columbus, Ohio, 43210-1228, United States

Location

University of Utah/Primary Children's Medical Center

Salt Lake City, Utah, 84132, United States

Location

University of Wisconsin Children's Hospital

Madison, Wisconsin, 53792-9988, United States

Location

Hospital Sainte-Justine

Montreal, Quebec, H3T 1C5, Canada

Location

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MeSH Terms

Conditions

Muscular Atrophy, Spinal

Interventions

Valproic Acid; Carnitine

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids; Trimethyl Ammonium Compounds; Quaternary Ammonium Compounds; Amines

Results Point of Contact

• Title: Sandra Reyna, M.D.
• Organization: University of Utah

sreyna@genetics.utah.edu

801-581-3551

Study Officials

• Kathryn J Swoboda, M.D.

  University of Utah/Primary Children's Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 23, 2005
• First Posted: September 27, 2005
• Study Start: September 1, 2005
• Primary Completion: November 1, 2007
• Study Completion: November 1, 2007
• Last Updated: March 19, 2025
• Results First Posted: May 3, 2011

Record last verified: 2011-09

Locations

US (5); CA (1)