CARNI-VAL Clinical Trial Results for Spinal Muscular Atrophy Published from Project Cure SMA Network.
August 19, 2010.

Project Cure SMA Trial Group Publishes Results from the SMA CARNI-VAL Trial Part I: Double-Blind, Randomized, Placebo-Controlled Trial of L-Carnitine and Valproic Acid in Spinal Muscular Atrophy.  The paper was published today in the online Journal PLoS ONE.  This clinical trial was fully funded by Families of SMA.

The study did not demonstrate functional improvement after a six month treatment with VPA and L-Carnitine.  Though the trial as designed failed to show that VPA is helpful for this SMA population, it did confirm the earlier FSMA-supported open label trial that the combination with L-Carnitine VPA is safe for children with SMA, with one consideration. Excessive weight gain is a problem for children with SMA as they grow older, and treatment with VPA may exacerbate that tendency. 

Project Cure SMA is a clinical trials network of seven sites located in the United States and Canada, funded fully by Families of SMA, which has included $7 million in funding to support the Project Cure SMA trials sites and associated infrastructure.   The network to date has focused on testing existing drugs and validating outcome measures for use in future clinical trials that may lead to a treatment for Spinal Muscular Atrophy.  Recently, an international expansion of these efforts has involved FSMA’s international Partners in Argentina and Germany.   One major goal for the project is having an operational clinical network with sufficient sites, as well as proven endpoints, to conduct pivotal SMA drug trials will help attract and encourage biotech and pharmaceutical companies to invest in SMA drug development.

CARNI-VAL Trial Part I is an FDA approved multicenter clinical trial designed to recruit Spinal Muscular Atrophy (SMA) affected children. Two cohorts of subjects were enrolled in this study, a non-ambulatory group of “sitters” and an ambulatory group of “walkers”.   This study presents results for the first group: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2-8 years of age. Sixty-one subjects with SMA were enrolled in 6 centers as part of Project Cure SMA clinical trial network (University of Utah, University of Wisconsin-Madison Health Sciences; Wayne State University; Ohio State Biomedical; Johns Hopkins Medical and Ste. Justine Hospital) and randomly selected 1:1 to Valproic Acid (VPA) and L-Carnitine, or placebo treatment for the first six months; all received active treatment the subsequent six months.  

The intent of this study was to evaluate the potential for benefit of this drug combination in children with SMA, and had several objectives in addition to evaluation of the drug itself.  The secondary objectives were to assess the safety of VPA / Carnitine in children with SMA and to assess the selected methods (outcome measures) used to assess drug efficacy in a multi-center setting, i.e. to evaluate the best means to study this or any other drug for SMA.

The study did not demonstrate functional improvement after a six month treatment with VPA and L-carnitine.  However, it did yield critically important insights. “The first trials of any drug in a new field of medicine are difficult”, said one of the study authors, Dr Tom Crawford, “because investigators have only their own untested ideas as to how best to construct a study. The design of any trial requires assumptions about which patients will be most responsive, the best duration of treatment, what means of assessment are most able to show improvement, and other choices.  Each is critical to a trial’s ability to demonstrate benefit of treatment. Although negative, from this trial the community has learned a lot that will make future trials much more powerful.”

Please click here to read about a potential new clinical trial endpoint that was tested during the CARNI-VAL trial.

Though the trial as designed failed to show that VPA is helpful for this SMA population, it did confirm the earlier FSMA-supported open label trial that the combination with L-Carnitine VPA is safe for children with SMA, with one consideration. Excessive weight gain is a problem for children with SMA as they grow older, and treatment with VPA may exacerbate that tendency.  It is possible that a trial with a different combination of patient selection, duration, primary outcome variable, and with greater attention to weight gain, might have had a more favorable result. However, the use of VPA and L-carnitine cannot be recommended at this time based upon this trial.

“While we are obviously disappointed in the negative results of the trial, through this study we have gained valuable insights in performing clinical trials in young children with SMA.” said Dr. John Kissel, Director of the SMA Clinic at Nationwide Children’s Hospital/The Ohio State University and Project Cure investigator. “These insights will help us more efficiently and effectively evaluate future therapeutic agents.  We also learned a great deal about the importance of controlling for certain variables, especially weight gain, when testing any agent in SMA."

Two Project Cure SMA trials testing VPA in other SMA populations and for different durations are ongoing.  The first is a double-blind randomized placebo-controlled study in ambulant adults with Type III SMA called VALIANT, which is being conducted at The Ohio State University by Dr. John Kissel.  This study will be concluded in November of this year.  The second is an open label study in type I infants called the CARNI-VAL Type I Trial.  Results from both are expected in 2011.

Please click here to read the paper.

Please click here to read a more comprehensive discussion of the implications of these trial results in a recent “Compass Newsletter.”

“Families of SMA is pleased to have the results published by Project Cure SMA Clinical Trial Network from the cohort 1 of the CARN-VAL Trial.  Funding clinical trial initiatives achieves multiple goals for our community.  It allows for the development and testing of new trial outcome measures for all SMA populations, for the completion of actual trials to test repurposed drugs for safety and efficacy in SMA patients, and for building the needed infrastructure, including adequate regional representation of experienced trial sites across the US, for future trials of novel drugs specifically designed for SMA”, says Jill Jarecki, Ph.D., Research Director of Families of SMA. 

This was registered at: ClinicalTrials.gov NCT00227266.

About Project Cure SMA: 

In 2001, Families of Spinal Muscular Atrophy established and single-handedly funded a clinical trials network called Project Cure SMA.  This network has conducted natural history studies that increase our understanding of Spinal Muscular Atrophy disease progression, built models for designing SMA clinical trials, and now runs clinical trials with existing drugs.

Families of SMA’s investment of $7 Million to date in five multi-center clinical trials is helping to test existing drugs that may lead to a treatment for Spinal Muscular Atrophy.  In addition, as novel drugs currently being designed for SMA become available, having a fully operational clinical network with a sufficient number of sites to conduct pivotal SMA drug trials will help attract and encourage biotech and pharmaceutical companies to invest in SMA drug development.
Click here to read more on the network.