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CARNIVAL Type I: Valproic Acid and Carnitine in Infants With Spinal Muscular Atrophy (SMA) Type I

Primary Purpose

Spinal Muscular Atrophy Type I

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Valproic Acid and Levocarnitine
Sponsored by
University of Utah
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Spinal Muscular Atrophy Type I focused on measuring Spinal Muscular Atrophy, SMA, Valproic Acid

Eligibility Criteria

2 Weeks - 12 Months (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Laboratory documentation of SMN mutation/deletion consistent with a genetic diagnosis of SMA
  • Clinical diagnosis of SMA type I
  • Age 2 weeks to 12 months
  • Written informed consent of parents/guardian

Exclusion Criteria:

  • Any clinical or laboratory evidence of hepatic or pancreatic insufficiency.
  • Laboratory results drawn within 14 days prior to start of study drug demonstrating:

Liver transaminases (AST, ALT), lipase, amylase: > 1.5 x ULN White Blood Cell Count: < 3 Neutropenia: <1 Platelet: <100K Hematocrit: <30, persisting over a 30-day period

  • Serious illness requiring systemic treatment and/or hospitalization within two weeks prior to study entry.
  • Use of medications or supplements within 30 days of study enrollment that interfere with VPA or carnitine metabolism; that increase the potential risks of VPA or carnitine; or that are hypothesized to have a beneficial effect in SMA animal models or human neuromuscular disorders, including riluzole, valproic acid, hydroxyurea, oral use of albuterol, sodium phenylbutyrate, butyrate derivatives, creatinine, growth hormone, anabolic steroids, probenecid, oral or parenteral use of corticosteroids at entry, or agents anticipated to increase or decrease muscle strength or agents with presumed histone deacetylase (HDAC) inhibition.
  • Infants who have participated in a treatment trial for SMA within 30 days of study entry or who will become enrollees in any other treatment trial during the course of this study.
  • Unwillingness to travel for study assessments.
  • Coexisting medical conditions that contradict use of VPA/carnitine or travel to and from study site.

Sites / Locations

  • Johns Hopkins University
  • Children's Hospital of Michigan
  • Duke University Medical Center
  • Ohio State University Medical Center, Dept. of Neurology
  • University of Utah/Primary Children's Medical Center
  • University of Wisconsin Children's Hospital
  • Hospital Sainte-Justine
  • Klinikum der Universität zu Köln

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

1

Arm Description

All patients will receive VPA and carnitine.

Outcomes

Primary Outcome Measures

Laboratory Safety Data
Anthropometric Measures of Nutritional Status (Body Mass Index [BMI] Z-scores, Weight for Length Ratios, Lean/Fat Mass Via DEXA, Growth Parameters, and Triceps Skinfold Measures)

Secondary Outcome Measures

Time to Death or Ventilator Dependence (Defined as >16 Hours/Day)
Primary Caregiver Functional Rating Scale for SMA Type I Subjects (PCFRS)
Functional Motor Assessments: TIMPSI Scores
Quantitative SMN mRNA and Protein Measures
Maximum Ulnar CMAP Amplitude/Area and MUNE
Whole Body DEXA Scanning for Lean Body Mass and Total Bone Mineral Density/ Content

Full Information

First Posted
April 14, 2008
Last Updated
June 1, 2015
Sponsor
University of Utah
Collaborators
Families of Spinal Muscular Atrophy, Leadiant Biosciences, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT00661453
Brief Title
CARNIVAL Type I: Valproic Acid and Carnitine in Infants With Spinal Muscular Atrophy (SMA) Type I
Official Title
Phase I/II Trial of Valproic Acid and Carnitine in Infants With Spinal Muscular Atrophy Type I (CARNI-VAL Type I)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2015
Overall Recruitment Status
Completed
Study Start Date
April 2008 (undefined)
Primary Completion Date
May 2012 (Actual)
Study Completion Date
June 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Utah
Collaborators
Families of Spinal Muscular Atrophy, Leadiant Biosciences, Inc.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a multi-center trial to test safety and evaluate early treatment intervention with valproic acid and carnitine in moderating SMA symptoms of Type I infants.
Detailed Description
Spinal muscular atrophy (SMA) is a genetic disorder that results in severe muscle weakness. It is one of the most common conditions causing muscle weakness in children. Patients with SMA most often develop weakness as babies or young children. Most people with SMA gradually lose muscle strength and abilities over time. Babies with the severe infantile form of SMA, SMA type I, usually lose abilities and strength quickly over a few weeks or months. Valproic acid (VPA) is a medicine that has been used for many years to treat patients with epilepsy. Recent research suggests that VPA may be able to upregulate expression of a backup copy of the SMN gene in SMA patient cell lines. In addition, some preliminary data suggests it may prolong survival in animal models of SMA. Because VPA can deplete carnitine in children with SMA Type I, carnitine is added to help prevent possible toxicity. In this multi-center trial, we will evaluate the effects of VPA/carnitine on infants with SMA type I. A variety of outcome measures, including assessment of safety, will be performed at each study visit to follow the course of the disease. The protocol includes two baseline visits over a period of two weeks, two clinical assessments on medication at 3 and 6 months, and then 6 months additional followup via telephone. Total duration of the study will be approximately 12 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Spinal Muscular Atrophy Type I
Keywords
Spinal Muscular Atrophy, SMA, Valproic Acid

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
40 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
All patients will receive VPA and carnitine.
Intervention Type
Drug
Intervention Name(s)
Valproic Acid and Levocarnitine
Intervention Description
Drug: Valproic Acid and Levocarnitine; syrup; dosage is by weight
Primary Outcome Measure Information:
Title
Laboratory Safety Data
Time Frame
-2 weeks, + 2 weeks, 3 months, 6 months
Title
Anthropometric Measures of Nutritional Status (Body Mass Index [BMI] Z-scores, Weight for Length Ratios, Lean/Fat Mass Via DEXA, Growth Parameters, and Triceps Skinfold Measures)
Time Frame
-2 weeks, time 0, 3 months, 6 months
Secondary Outcome Measure Information:
Title
Time to Death or Ventilator Dependence (Defined as >16 Hours/Day)
Time Frame
monthly
Title
Primary Caregiver Functional Rating Scale for SMA Type I Subjects (PCFRS)
Time Frame
time 0, and monthly for 12 months
Title
Functional Motor Assessments: TIMPSI Scores
Time Frame
-2 weeks, time 0, 3 months, 6 months
Title
Quantitative SMN mRNA and Protein Measures
Time Frame
-2 weeks, time 0 , 3 months, or 6 months
Title
Maximum Ulnar CMAP Amplitude/Area and MUNE
Time Frame
-2 weeks, time 0, 3 months, 6 months
Title
Whole Body DEXA Scanning for Lean Body Mass and Total Bone Mineral Density/ Content
Time Frame
-2 weeks or time 0, 3 months, 6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Weeks
Maximum Age & Unit of Time
12 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Laboratory documentation of SMN mutation/deletion consistent with a genetic diagnosis of SMA Clinical diagnosis of SMA type I Age 2 weeks to 12 months Written informed consent of parents/guardian Exclusion Criteria: Any clinical or laboratory evidence of hepatic or pancreatic insufficiency. Laboratory results drawn within 14 days prior to start of study drug demonstrating: Liver transaminases (AST, ALT), lipase, amylase: > 1.5 x ULN White Blood Cell Count: < 3 Neutropenia: <1 Platelet: <100K Hematocrit: <30, persisting over a 30-day period Serious illness requiring systemic treatment and/or hospitalization within two weeks prior to study entry. Use of medications or supplements within 30 days of study enrollment that interfere with VPA or carnitine metabolism; that increase the potential risks of VPA or carnitine; or that are hypothesized to have a beneficial effect in SMA animal models or human neuromuscular disorders, including riluzole, valproic acid, hydroxyurea, oral use of albuterol, sodium phenylbutyrate, butyrate derivatives, creatinine, growth hormone, anabolic steroids, probenecid, oral or parenteral use of corticosteroids at entry, or agents anticipated to increase or decrease muscle strength or agents with presumed histone deacetylase (HDAC) inhibition. Infants who have participated in a treatment trial for SMA within 30 days of study entry or who will become enrollees in any other treatment trial during the course of this study. Unwillingness to travel for study assessments. Coexisting medical conditions that contradict use of VPA/carnitine or travel to and from study site.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kathryn Swoboda, M.D.
Organizational Affiliation
University of Utah
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Sandra P Reyna, M.D.
Organizational Affiliation
Families of Spinal Muscular Atrophy
Official's Role
Study Director
Facility Information:
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Children's Hospital of Michigan
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Ohio State University Medical Center, Dept. of Neurology
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
University of Utah/Primary Children's Medical Center
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Facility Name
University of Wisconsin Children's Hospital
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792-9988
Country
United States
Facility Name
Hospital Sainte-Justine
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3T 1C5
Country
Canada
Facility Name
Klinikum der Universität zu Köln
City
Cologne
ZIP/Postal Code
50924
Country
Germany

12. IPD Sharing Statement

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CARNIVAL Type I: Valproic Acid and Carnitine in Infants With Spinal Muscular Atrophy (SMA) Type I

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