Clinical trial NCT02500082: Triheptanoin (UX007) to Treat Citrate Transporter Deficiency
Official title: Compassionate Use of Triheptanoin (UX007) to Treat Citrate Transporter Deficiency
Study type: EXPANDED_ACCESS
Overall status: NO_LONGER_AVAILABLE
Conditions: Citrate Transporter Deficiency
SLC13A5 Gene Mutation
Keywords: citrate transporter deficiency
SLC13A5 gene
citric acid cycle
energy metabolism
Lead sponsor: Boston Children's Hospital
Sponsor class: OTHER
First posted: 2015-07-16
Sex: ALL
Minimum age (years): 4
Maximum age (years): 9
Standard ages: CHILD

Brief summary: The purpose of this study is to determine whether triheptanoin (UX007) is effective in the treatment of neurological symptoms related to citrate transporter deficiency (SLC13A5 gene mutation).

Detailed description: This compassionate use research study has been developed to study an investigational drug, triheptanoin (UX007), for the treatment of neurological symptoms related to citrate transporter deficiency, a disease with no existing treatment. The hypothesis is that triheptanoin will restore deficient energy metabolism in these patients, leading to improved seizure control, mental clarity, and physical strength.

Based on the literature, the SLC13A5 gene product is a citrate transporter. However, there is the possibility that other compounds are transported as well. The gene may be expressed in human neurons and function at the level of the plasma membrane. The hypothesis is that the transport of citrate across the plasma membrane from the extracellular space into the cytoplasm plays a role in maintaining the pool size of citrate in both the cytoplasm and mitochondrial matrix. Triheptanoin therapy may increase the metabolism of odd-chain fatty acids in neuronal mitochondria and thereby increase the levels of succinyl-CoA, leading to an increase in citrate concentrations. The increased level of citrate in the mitochondrial matrix may lead to an increased efflux of citrate from the matrix to the cytoplasm, thus increasing the cytoplasmic pool of citrate and allowing the malfunctioning citrate transporter to be bypassed. If successful, triheptanoin treatment will improve neuronal function and lead to an improvement in CNS function for patients.

While investigators will follow the course of subjects with considerable interest and may use some of the collected data for clinical research, this study is done for humanitarian reasons.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of citrate transporter deficiency due to mutations in the SLC13A5 gene.
* Presentation with severe global developmental delay and seizures.

Exclusion Criteria:

* Valproate is an AED that partially inhibits the TCA cycle via alpha-ketoglutarate dehydrogenase and should not be administered to subjects taking UX007.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Boston
country: United States
facility: Department of Neurology, Boston Children's Hospital
state: Massachusetts
Study officials:
affiliation: Boston Children's Hospital
name: Irina A Anselm, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Johannessen CU, Petersen D, Fonnum F, Hassel B. The acute effect of valproate on cerebral energy metabolism in mice. Epilepsy Res. 2001 Dec;47(3):247-56. doi: 10.1016/s0920-1211(01)00308-4.
citation: Pascual JM, Liu P, Mao D, Kelly DI, Hernandez A, Sheng M, Good LB, Ma Q, Marin-Valencia I, Zhang X, Park JY, Hynan LS, Stavinoha P, Roe CR, Lu H. Triheptanoin for glucose transporter type I deficiency (G1D): modulation of human ictogenesis, cerebral metabolic rate, and cognitive indices by a food supplement. JAMA Neurol. 2014 Oct;71(10):1255-65. doi: 10.1001/jamaneurol.2014.1584.
citation: Thevenon J, Milh M, Feillet F, St-Onge J, Duffourd Y, Juge C, Roubertie A, Heron D, Mignot C, Raffo E, Isidor B, Wahlen S, Sanlaville D, Villeneuve N, Darmency-Stamboul V, Toutain A, Lefebvre M, Chouchane M, Huet F, Lafon A, de Saint Martin A, Lesca G, El Chehadeh S, Thauvin-Robinet C, Masurel-Paulet A, Odent S, Villard L, Philippe C, Faivre L, Riviere JB. Mutations in SLC13A5 cause autosomal-recessive epileptic encephalopathy with seizure onset in the first days of life. Am J Hum Genet. 2014 Jul 3;95(1):113-20. doi: 10.1016/j.ajhg.2014.06.006.