Clinical trial NCT01886378: A Study of UX007 (Triheptanoin) in Participants With Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD)
Official title: An Open-label Phase 2 Study to Assess Safety and Clinical Effects of UX007 in Subjects With Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Long-chain Fatty Acid Oxidation Disorders (LC-FAOD)
Carnitine Palmitoyltransferase (CPT II) Deficiency
Very Long Chain Acyl-CoA Dehydrogenase (VLCAD) Deficiency
Longchain 3-hydroxy-acyl-CoA Dehydrogenase (LCHAD) Deficiency
Trifunctional Protein (TFP) Deficiency
Keywords: FAOD
VLCAD
CPT II
CPT2
CPT 2
LCHAD
UX007
Triheptanoin
TFP
C7
Lead sponsor: Ultragenyx Pharmaceutical Inc
Sponsor class: INDUSTRY
First posted: 2013-06-25
Enrollment: 29
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The primary objective of the study was to evaluate the impact of UX007 on acute clinical pathophysiology associated with LC-FAOD following 24 weeks of treatment.


Eligibility criteria: Inclusion Criteria:

* Confirmed diagnosis of CPT II, VLCAD, LCHAD, or TFP deficiency, based on results of acylcarnitine profiles, fatty acid oxidation probe studies in cultured fibroblasts, and/or mutation analysis obtained from medical records.
* Male or female, at least 6 months of age
* Willing and able to complete all aspects of the study through the end of the study. If a minor, have a caregiver(s) willing and able to assist in all applicable study requirements.
* Provide written informed consent (subjects aged ≥ 18 years), or provide written assent (where appropriate) and have a legally authorized representative willing and able to provide written informed consent
* Willing and able to provide access to medical records charting the last 18-24 months of care prior to the study initiation, or from birth for those subjects less than 18 months of age
* No history of serious adverse reactions or known hypersensitivity to triheptanoin
* Currently managed on a stable treatment regimen (including diet), which may include low-fat/high-carbohydrate diet, avoidance of fasting, carnitine and/or medium-chain triglyceride (MCT) oil. The treatment regimen (including diet) should be stable for the last 60 days to assure that changes in the subject's condition are not confounded by recent changes in the treatment regimen that could affect the 4 week run-in evaluation period. Once study drug treatment has started, must be willing to maintain all aspects of the subject's treatment regimen and diet unchanged, other than discontinuation of MCT oil, in order to avoid potential variability of response due to variations in dietary intake.
* Have severe LC-FAOD, as evidenced by ANY ONE of the following significant clinical manifestations despite therapy:

  * Chronic Elevated Creatine Kinase (CK) with Major Clinical Events: Elevated mean CK levels over the last 6 months -1 year (defined as ≥ 2X upper limit of age/gender-matched normal, or ≥ 500 units/L if age-matched reference not established) not associated with an acute rhabdomyolysis event, AND at least two major clinical events (as defined in the protocol) in the last year, or at least four major clinical events over the last two years,
  * Episodic Elevated CK with Reported Muscle Dysfunction: Episodes of elevated CK levels over the last 6 months -1 year (defined as ≥ 2X upper limit of age/gender-matched normal, or ≥ 500 units/L if age-matched reference is not established) not associated with an acute rhabdomyolysis event, AND patient report of frequent muscle fatigue, exercise intolerance, or limitation of exercise,
  * Highly Elevated CK but Asymptomatic: More seriously elevated mean CK levels (defined as ≥ 4X upper limit of age/gender-matched normal, or ≥ 1000 units/L if age-matched reference is not established) consistent with substantial chronic muscle rupture over the last 6 months-1 year, regardless of frequency of hospitalizations or ER events,
  * Frequent Severe Major Medical Episodes (at least 3 within the past year, or 5 within 2 years) of hypoglycemia, rhabdomyolysis, or exacerbation of cardiomyopathy \[CM\], requiring emergency room \[ER\]/acute care visits or hospitalizations,
  * Severe Susceptibility to Hypoglycemia (serum glucose \<60 mg/dL) after short periods of fasting (less than 4-12 hours, depending on age), with at least 2 events in the last year that require ongoing prophylactic management, OR recurrent symptomatic hypoglycemia (blood glucose levels or clinical symptoms of hypoglycemia) at home requiring intervention ≥ 2 times per week,
  * Evidence of Functional Cardiomyopathy (with echocardiogram (ECHO) within past 90 days documenting poor ejection fraction \[EF\]) requiring ongoing medical management
* Females who have reached menarche must have a negative pregnancy test at Screening. If sexually active, subject must be willing to use acceptable method of contraception and have additional pregnancy tests during the study.

Exclusion Criteria:

* Diagnosis of carnitine-acylcarnitine translocase (CACT) or CPT I
* Diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, short- or medium-chain FAOD, ketone body metabolism defect, propionic acidemia or methylmalonic acidemia
* Enrolled in a clinical study involving concurrent use of an investigational drug product within the last 30 days, or unwilling to discontinue use of a prohibited medication or other substance that may confound study objectives
* Unwilling to sign informed consent or release of medical records
* Have any co-morbid conditions, including unstable 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

Primary outcomes:
measure: Change From Baseline in Time Adjusted-Area Under the Curve (AUC/Time) for Workload During Cycle Ergometry at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in Time-Adjusted-AUC for Respiratory Exchange Ratio (RER) During Cycle Ergometry at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in Actual Duration of Exercise During Cycle Ergometry at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in Distance Traveled During the 12-Minute Walk Test (12MWT) at Week 18
timeFrame: Baseline (last assessment during the 4-week run-in period), Week 18
measure: Change From Baseline in Energy Expenditure Index (EEI) During the 12MWT at Week 18
timeFrame: Baseline (last assessment during the 4-week run-in period), Week 18
measure: Change From Baseline in Percentage of the Predicted 6-Minute Walk Test (6MWT) Distance Walked at Week 18
timeFrame: Baseline (last assessment during the 4-week run-in period), Week 18
measure: Change From Baseline in Physical Summary Score (PHS-10) of the Short Form 10 (SF-10) at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in Psychosocial Summary Score (PSS-10) of the SF10 at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in the Physical Component Summary Scale (PCS-12) at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in the Mental Component Summary Scale (MCS-12) at Week 24
timeFrame: Baseline, Week 24
measure: Annualized Event Rate of All Major Clinical Events Pre- and Post-Treatment With UX007
timeFrame: 18 months before and after UX007 initiation
measure: Annualized Duration Rate of All Major Clinical Events Pre- and Post-Treatment With UX007
timeFrame: 18 months before and after UX007 initiation
measure: Annualized Event Rate of Major Rhabdomyolysis Clinical Events Pre- and Post-Treatment With UX007
timeFrame: 18 months before and after UX007 initiation
measure: Annualized Duration Rate of Major Rhabdomyolysis Clinical Events Pre- and Post-Treatment With UX007
timeFrame: 18 months before and after UX007 initiation
measure: Annualized Event Rate of Major Hypoglycemia Clinical Events Pre- and Post-Treatment With UX007
timeFrame: 18 months before and after UX007 initiation
measure: Annualized Duration Rate of Major Hypoglycemia Clinical Events Pre- and Post-Treatment With UX007
timeFrame: 18 months before and after UX007 initiation
measure: Annualized Event Rate of Major Cardiac Clinical Events Pre- and Post-Treatment With UX007
timeFrame: 18 months before and after UX007 initiation
measure: Annualized Duration Rate of Major Cardiac Clinical Events Pre- and Post-Treatment With UX007
timeFrame: 18 months before and after UX007 initiation
Secondary outcomes:
Other outcomes:
Locations:
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Tampa
country: United States
facility: University of Southern Florida
state: Florida
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Medical Center
state: Tennessee
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
city: London
country: United Kingdom
facility: National Hospital for Neurology and Neurosurgery
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
Study officials:
affiliation: Ultragenyx Pharmaceutical
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Vockley J, Burton B, Berry GT, Longo N, Phillips J, Sanchez-Valle A, Tanpaiboon P, Grunewald S, Murphy E, Humphrey R, Mayhew J, Bowden A, Zhang L, Cataldo J, Marsden DL, Kakkis E. UX007 for the treatment of long chain-fatty acid oxidation disorders: Safety and efficacy in children and adults following 24weeks of treatment. Mol Genet Metab. 2017 Apr;120(4):370-377. doi: 10.1016/j.ymgme.2017.02.005. Epub 2017 Feb 7.
citation: Vockley J, Burton B, Berry GT, Longo N, Phillips J, Sanchez-Valle A, Tanpaiboon P, Grunewald S, Murphy E, Bowden A, Chen W, Chen CY, Cataldo J, Marsden D, Kakkis E. Results from a 78-week, single-arm, open-label phase 2 study to evaluate UX007 in pediatric and adult patients with severe long-chain fatty acid oxidation disorders (LC-FAOD). J Inherit Metab Dis. 2019 Jan;42(1):169-177. doi: 10.1002/jimd.12038.
citation: Vockley J, Longo N, Madden M, Dwyer L, Mu Y, Chen CY, Cataldo J. Dietary management and major clinical events in patients with long-chain fatty acid oxidation disorders enrolled in a phase 2 triheptanoin study. Clin Nutr ESPEN. 2021 Feb;41:293-298. doi: 10.1016/j.clnesp.2020.11.018. Epub 2020 Dec 25.