Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy

Spinal Muscular Atrophy Clinical Trial

Official title:

Multi-center Phase II Trial of Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy (SMA CARNI-VAL Trial)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00227266
• Other study ID #: 13698
• Status: Completed
• Phase: Phase 2
• First received: September 23, 2005
• Last updated: September 22, 2011
• Start date: September 2005
• Est. completion date: November 2007

Study information

• Verified date: September 2011
• Source: University of Utah
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 94
• Est. completion date: November 2007
• Est. primary completion date: November 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 2 Years to 17 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Atrophy
• Muscular Atrophy
• Muscular Atrophy, Spinal
• Spinal Muscular Atrophy

Intervention

Drug:
• Valproic Acid and Levocarnitine
VPA,sprinkle cap; Levocarnitine, syrup; dosage is by weight
• Placebo

Locations

Country	Name	City	State
Canada	Hospital Sainte-Justine	Montreal	Quebec
United States	Johns Hopkins University	Baltimore	Maryland
United States	Ohio State University	Columbus	Ohio
United States	Children's Hospital of Michigan	Detroit	Michigan
United States	University of Wisconsin Children's Hospital	Madison	Wisconsin
United States	University of Utah/Primary Children's Medical Center	Salt Lake City	Utah

Sponsors (4)

Lead Sponsor	Collaborator
University of Utah	Abbott, Families of Spinal Muscular Atrophy, Sigma Tau Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (42)

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* Note: There are 42 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Primary	Efficacy, Measured Through Motor Function Assessments		-4wks, 0, 3 mo, 6 mo, 12 mo	Yes
Primary	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	No
Secondary	Quantitative Assessment of SMN mRNA From Blood Samples		-4wks or 0, 3 mo, 6 mo, 12 mo	No
Secondary	Peds QL™ Assessment: Parental Version (All), Child Versions (> 5yrs)		-4wks, 0, 3mo, 6mo, 12mo	Yes
Secondary	Max CMAP Amplitude (Mean)	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.	1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)	Yes
Secondary	Max CMAP Amplitude Median	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.	1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)	Yes
Secondary	Ulnar MUNE		-4 wks, 0, 3 mo, 6 mo, 12 mo	Yes
Secondary	Growth and Vital Sign Parameters		-4 wks, 0, 3mo, 6mo, 12mo	Yes
Secondary	Nutritional Status		-4 wks, 0, 3mo, 6mo, 12mo	Yes
Secondary	DEXA		0, 6mo, 12mo	Yes
Secondary	Max CMAP Area (Mean)	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.	1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)	Yes
Secondary	Max CMAP Area (Median)	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.	1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)	Yes