Anaplerotic Therapy Using Triheptanoin for Patients With Glycogen Storage Disease Type I

Glycogen Storage Disease Type I Clinical Trial

Official title:

Anaplerotic Therapy Using Triheptanoin for Patients With Glycogen Storage Disease Type I

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03665636
• Other study ID #: Pro00103582
• Status: Completed
• Phase: Early Phase 1
• Start date: October 16, 2020
• Est. completion date: October 21, 2021

Study information

• Verified date: December 2021
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will be an open-label, prospective, interventional feasibility pilot project to study the efficacy, safety, and tolerability of UX007 (triheptanoin) on reducing hypoglycemic events in patients with GSD I. Subjects will serve as their own control. Five (5) subjects who are treatment naïve to UX007 (triheptanoin) and are already on standard dietary therapy for GSDI will be enrolled. The primary objective is to evaluate the efficacy, safety, and tolerability of UX007 (triheptanoin) in patients with GSD I. The secondary objectives include evaluating the effect of UX007 (triheptanoin) on maintaining the duration of normoglycemia between meals based on glucose monitoring (Preventing and reducing the frequency of hypoglycemia); reduction/stabilization of the dose of cornstarch; and the prevention of increased liver steatosis based on ultrasound with elastography.

Description:

Prior to first study appointment: A medical record review will be done prior to the appointment to confirm the diagnosis of GSD I. For interested subjects who are not already known to the investigators (i.e., patients of the Duke University Medical Center), a release of protected health information will be signed by the potential subjects to obtain records that can be used to confirm diagnosis. Baseline / Visit 1: Study subjects will be instructed to come to the DUMC to review and sign the informed consent document. At that time, complete medical history and complete physical examination will be obtained. Blood and urine will be collected for laboratory assessments. Height, weight, and vital signs (blood pressure, pulse, respiration) will be collected. A nutritional history and review of diet dairy collected three days prior to the visit will be reviewed by a study dietitian. The blood glucose monitoring log for the three days prior to the visit will also be reviewed the study dietitian and MD. Study staff will collect concomitant medications and adverse event collection will begin once dosing with UX007 is initiated. An ultrasound with elastography will be conducted at the DUMCs radiology department and reviewed and a report generated by a radiologist. Safety Phone Contact: Subjects will be called by study staff the day after they start the UX007 and again 4 weeks later to assess nutritional history, review of glucose diary, review of dosing compliance, and to obtain an updated weight. Study staff will also review adverse events (AE/SAE) and concomitant medications during these calls. If a subject experiences an AE/SAE they will be contacted every two weeks until the AE/SAE is resolved. 2, 4, and 6 Month/Early Termination Visits: Same procedures will be conducted as at the baseline visit, with the exception of the ultrasound with elastography, which will only be collected again at the 6 Month/Early Termination Visit. Post-termination Phone Contact: 2-6 weeks after the 6 month/early termination visit study staff will contact the subject to collect an interim medical history, evaluation of nutritional history, review of glucose diary as well as review of adverse events and concomitant medications. An updated weight will also be obtained.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 4
• Est. completion date: October 21, 2021
• Est. primary completion date: October 21, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Month to 65 Years

Eligibility

Inclusion Criteria:

• Naive to UX007 (triheptanoin)
• Confirmed documented diagnosis of GSDI: confirmation may be based on mutation analysis, liver biopsy, or enzyme testing
• Willing and able to complete all aspects of the study through the end of the study, including visits and tests, documentation of symptoms, blood sugar and dietary log, and administration of UX007 (triheptanoin); minors in the study must have a parent/legally authorized representative who is willing and able to assist in all applicable study requirements

Exclusion Criteria:

• Have a history of severe inflammatory bowel disease, or severe chronic diarrhea per the PI discretion on conventional doses of cornstarch
• Patient is on any other form of medium chain triglyceride (MCT) during the time of the study. Patients will be asked to stop any nutritional compound that includes MCT oil one week (7 days) prior to baseline.
• Have any co-morbid conditions, including major organ-system disease(s) that in the opinion of the Investigator, places the subject at increased risk of complications, interferes with study participation or compliance, or confounds study objectives
• Pregnancy
• Patients on continuous feeds, with a diagnosis of diabetes, and/or a diagnosis of any other inborn error or metabolism

Related Conditions & MeSH terms

• Glycogen Storage Disease
• Glycogen Storage Disease Type I
• Metabolic Diseases

Intervention

Drug:
• Triheptanoin
This is an open-label study. The UX007 (triheptanoin) starting dose will be 0.25 - 0.5 g/kg and titrated to a maximum of 2.5g/kg depending the on the subject's tolerance. The dose may be reduced if not tolerated. The compound will be administered 3-4 times per day, either at the end of a meal or with a snack. It should be given at least 2 hours apart from any cornstarch dose to allow each to act independent of one another, and to prevent the risk of increased gastrointestinal side effects. The doses may be held during episodes of gastroenteritis or diarrhea.

Locations

Country	Name	City	State
United States	Duke University Medical Center	Durham	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Areeg El-Gharbawy	Ultragenyx Pharmaceutical Inc

Country where clinical trial is conducted

United States, 

References & Publications (8)

Chou JY, Matern D, Mansfield BC, Chen YT. Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex. Curr Mol Med. 2002 Mar;2(2):121-43. Review. — View Citation

Das AM, Lücke T, Meyer U, Hartmann H, Illsinger S. Glycogen storage disease type 1: impact of medium-chain triglycerides on metabolic control and growth. Ann Nutr Metab. 2010;56(3):225-32. doi: 10.1159/000283242. Epub 2010 Mar 30. — View Citation

Farah BL, Sinha RA, Wu Y, Singh BK, Lim A, Hirayama M, Landau DJ, Bay BH, Koeberl DD, Yen PM. Hepatic mitochondrial dysfunction is a feature of Glycogen Storage Disease Type Ia (GSDIa). Sci Rep. 2017 Mar 20;7:44408. doi: 10.1038/srep44408. — View Citation

Fernandes J, Pikaar NA. Ketosis in hepatic glycogenosis. Arch Dis Child. 1972 Feb;47(251):41-6. — View Citation

Gu L, Zhang GF, Kombu RS, Allen F, Kutz G, Brewer WU, Roe CR, Brunengraber H. Parenteral and enteral metabolism of anaplerotic triheptanoin in normal rats. II. Effects on lipolysis, glucose production, and liver acyl-CoA profile. Am J Physiol Endocrinol Metab. 2010 Feb;298(2):E362-71. doi: 10.1152/ajpendo.00384.2009. Epub 2009 Nov 10. — View Citation

Nagasaka H, Hirano K, Ohtake A, Miida T, Takatani T, Murayama K, Yorifuji T, Kobayashi K, Kanazawa M, Ogawa A, Takayanagi M. Improvements of hypertriglyceridemia and hyperlacticemia in Japanese children with glycogen storage disease type Ia by medium-chain triglyceride milk. Eur J Pediatr. 2007 Oct;166(10):1009-16. Epub 2007 Jan 6. — View Citation

Rasmussen BB, Holmbäck UC, Volpi E, Morio-Liondore B, Paddon-Jones D, Wolfe RR. Malonyl coenzyme A and the regulation of functional carnitine palmitoyltransferase-1 activity and fat oxidation in human skeletal muscle. J Clin Invest. 2002 Dec;110(11):1687-93. — View Citation

Roe CR, Mochel F. Anaplerotic diet therapy in inherited metabolic disease: therapeutic potential. J Inherit Metab Dis. 2006 Apr-Jun;29(2-3):332-40. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Blood glucose level	Reviewing the change in blood glucose levels from baseline to 6 month visit	Baseline and 6 months
Secondary	Dietary intake	Reviewing the change in fat, protein, and carbohydrate intake, after adding the intervention, from baseline to 6 month visit	Baseline and 6 months
Secondary	Liver steatosis assessment	Reviewing the change fatty infiltration (steatosis) using ultrasound elastography from baseline to 6 months visit. This technique will the degree of steatosis which is reflected by echogenicity and stiffness that is measured by 2D ultrasound shear wave speed measurements.	Baseline and 6 months
Secondary	Liver size assessment	Reviewing the change in liver size using ultrasound elastography from baseline to 6 months visit. This technique will provide liver size at both timepoints.	Baseline and 6 months
Secondary	Laboratory metabolic control markers	Reviewing laboratory markers indicative of metabolic control which include glucose, triglycerides, and uric acid measured in mg/dl from baseline to 6 month visit	Baseline and 6 months
Secondary	Other laboratory metabolic control markers	Reviewing lactate levels as a main indicator of metabolic control measured in mMol/L from baseline to 6 month visit	Baseline and 6 months