Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD) Extension Study for Subjects Previously Enrolled in Triheptanoin Studies

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the long-term safety and efficacy of UX007 in participants with LC-FAOD. The secondary objectives of this study are to evaluate the effect of UX007 on energy metabolism in LC-FAOD and evaluate the impact of UX007 on clinical events associated with LC-FAOD.

Official Title
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An Open-label Long-Term Safety and Efficacy Extension Study in Subjects With Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD) Previously Enrolled in UX007 or Triheptanoin Studies

Conditions
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Carnitine Palmitoyltransferase (CPT I or CPT II) Deficiency, Very Long Chain Acyl-CoA Dehydrogenase (VLCAD) Deficiency, Long-chain 3-hydroxy-acyl-CoA Dehydrogenase (LCHAD) Deficiency, Trifunctional Protein (TFP) Deficiency, Carnitine-acylcarnitine Translocase (CACT) Deficiency

Intervention / Treatment
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* Drug: UX007


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 6 months of age or older Prior participation in a clinical study assessing UX007/triheptanoin treatment for LC FAOD. Study Sponsors/Collaborators include: Oregon Health & Science University, University of Pittsburgh, and Ultragenyx Pharmaceutical (ClinicalTrials.gov Identifiers: NCT01379625, NCT01461304, and NCT01886378). Patients who received UX007/triheptanoin treatment as part of other clinical studies; investigator sponsored trials (IST); expanded access/compassionate use treatment programs; or patients who are treatment naïve (i.e., naïve to both UX007 and food-grade triheptanoin), have failed conventional therapy and, in the opinion of the Investigator and Sponsor, have documented clear unmet need, may also be eligible at the discretion of the Sponsor Confirmed diagnosis of LC-FAOD including: CPT I or CPT II deficiency, VLCAD deficiency, LCHAD deficiency, TFP deficiency, or CACT deficiency. Information on diagnosis will be obtained from medical records and should include confirmed diagnosis by results of acylcarnitine profiles, fatty acid oxidation probe studies in cultured fibroblasts, and/or mutation analysis Willing and able to complete all aspects of the study through the end of the study, including visits and tests, documentation of symptoms and diet, and administration of study medications. 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, after the nature of the study has been explained and prior to any research-related procedures. Females of child-bearing potential must have a negative urine pregnancy test at Baseline and be willing to have additional pregnancy tests during the study. Females considered not of child-bearing potential include those who have not experienced menarche, are post-menopausal (defined as having no menses for at least 12 months without an alternative medical cause), or are permanently sterile due to total hysterectomy, bilateral salpingectomy, or bilateral oophorectomy Participants of child-bearing potential or fertile males with partners of child-bearing potential who are sexually active must consent to use a highly effective method of contraception as determined by the Investigator from the period following the signing of the informed consent through 30 days after last dose of study drug Exclusion Criteria: Diagnosis of medium-chain acyl coenzyme A dehydrogenase (MCAD) deficiency, short- or medium-chain FAOD, ketone body metabolism defect, propionic acidemia or methylmalonic acidemia Patient qualifies for any other clinical trial designed to progressively evaluate the safety and efficacy of triheptanoin in LC-FAOD Any known hypersensitivity to triheptanoin that, in the judgment of the Investigator, places the subject at increased risk for adverse effects Pregnant and/or breastfeeding an infant at Screening or planning to become pregnant (self or partner) at any time during the study 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, or unwilling to discontinue prohibited medications

Ages Eligible for Study
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Minimum Age: 6 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: UX007<br>Participants previously treated with UX007 or treatment-naive participants will begin or continue treatment with daily open-label UX007 while maintaining their other dietary restrictions. | Drug: UX007<br>* Administered orally (PO) with food or by gastrostomy tube, at the target dose range of 25-35% of total calories.<br>* Other names: C7;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized LC-FAOD Major Clinical Events (MCEs) Rate: 18 Months Pre- and Entire UX007 Period Comparison for UX007-CL201-Rollover Cohort | The annualized LC-FAOD MCE rate, inclusive of skeletal myopathy (rhabdomyolysis), hepatic (hypoglycemia) and cardiomyopathy events, defined as any visit to the emergency room (ER)/acute care, hospitalization, emergency intervention (i.e. any unscheduled administration of therapeutics at home or in the clinic), or any similar event whether caused primarily by LC-FAOD or by an intercurrent illness complicated by LC-FAOD. The annualized event rate was calculated at the number of events divided by the duration of data collection period in days/365.25 | Pre-UX007 treatment period (up to 18 months) and post-UX007 treatment period (up to 2072 days) | 
| Annualized LC-FAOD MCEs Rate: 18 Months Pre- and Entire UX007 Period Comparison for IST/Other Cohort and Triheptanoin-Naïve Cohort | The annualized LC-FAOD MCE rate, inclusive of skeletal myopathy (rhabdomyolysis), hepatic (hypoglycemia) and cardiomyopathy events, defined as any visit to the emergency room (ER)/acute care, hospitalization, emergency intervention (i.e. any unscheduled administration of therapeutics at home or in the clinic), or any similar event whether caused primarily by LC-FAOD or by an intercurrent illness complicated by LC-FAOD. The annualized event rate was calculated at the number of events divided by the duration of data collection period in days/365.25 | Pre-UX007 treatment period (up to 18 months) and post-UX007 treatment period (up to 2072 days) | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) or Serious TEAEs | An adverse event (AE) was defined as any untoward medical occurrence, whether or not considered drug related. A serious adverse event (SAE) results in any of the following outcomes: death; a life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or disability; a congenital anomaly/birth defect; an important medical event. AEs were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (mild=1, moderate=2, severe=3, life-threatening=4, death=5). | Post-UX007 treatment through the end of treatment (up to 2072 days) plus 30-35 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Echocardiogram (ECHO) Parameters Over Time: Left Ventricular Mass Index (LVMI) |  | Baseline, Month 12, Month 24, Month 36, Month 48, Month 60 | 
| Change From Baseline in ECHO Parameters Over Time: Left Ventricular Mass (LVM) |  | Baseline, Month 12, Month 24, Month 36, Month 48, Month 60 | 
| Change From Baseline in ECHO Parameters Over Time: Left Ventricular Diameter (LVD) |  | Baseline, Month 12, Month 24, Month 36, Month 48, Month 60 | 
| Change From Baseline in ECHO Parameters Over Time: Left Ventricular Ejection Fraction (LVEF) |  | Baseline, Month 12, Month 18, Month 24, Month 30, Month 36, Month 48, Month 60 | 
| Change From Baseline in ECHO Parameters Over Time: LVEF Z-Score (Pediatric Participants) | The Z-scores express the deviation (or how far away) the measure is from the mean LVEF based on the size or age of the pediatric participants: Z-score=0 indicates the participant is exactly the same as the mean of the healthy general population. Z-score=-1 indicates it's 1 standard deviation below the mean of the healthy population. Z-score=+1 indicates it's 1 standard deviation above the mean. | Baseline, Month 12, Month 24, Month 36 | 
| Change From Baseline in ECHO Parameters Over Time: Left Ventricular Shortening Fraction (LVSF) | Fractional shortening is calculated by measuring the percentage change in left ventricular diameter during systole. A negative value indicates less ventricular/muscular contractility, and a positive value indicates more ventricular/muscular contractility. | Baseline, Month 12, Month 24, Month 30, Month 36, Month 48, Month 60 | 
| Change From Baseline in ECHO Parameters Over Time: LVSF Z-Score (Pediatric Participants) | The Z-scores express the deviation (or how far away) the measure is from the mean LVSF based on the size or age of the pediatric participants: Z-score=0 indicates the participant is exactly the same as the mean of the healthy general population. Z-score=-1 indicates it's 1 standard deviation below the mean of the healthy population. Z-score=+1 indicates it's 1 standard deviation above the mean. | Baseline, Month 12, Month 24, Month 36, Month 48, Month 60 | 
| Annualized Duration Rate of All MCEs | The annualized duration rate of LC-FAOD MCEs, inclusive of skeletal myopathy (rhabdomyolysis), hepatic (hypoglycemia) and cardiomyopathy events, and defined as any visit to the ER/acute care, hospitalization, emergency intervention (i.e. any unscheduled administration of therapeutics at home or in the clinic), or any similar event whether caused primarily by LC-FAOD or by an intercurrent illness complicated by LC-FAOD. The annualized duration rate is calculated as the total duration (days) of events divided by the duration of data collection period in days/365.25. | Post-UX007 treatment through the end of the study (up to 2072 days) | 
| Annualized Event Rate of Rhabdomyolysis MCEs | The annualized event rate of LC-FAOD major events of skeletal myopathy (rhabdomyolysis), defined as any visit to the ER/acute care, hospitalization, emergency intervention (i.e. any unscheduled administration of therapeutics at home or in the clinic), or any similar event whether caused primarily by LC-FAOD or by an intercurrent illness complicated by LC-FAOD. The annualized event rate was calculated at the number of events divided by the duration of data collection period in days/365.25. | Post-UX007 treatment through the end of the study (up to 2072 days) | 
| Annualized Duration Rate of Rhabdomyolysis MCEs | The annualized duration rate of LC-FAOD skeletal myopathy (rhabdomyolysis) MCEs, defined as any visit to the ER/acute care, hospitalization, emergency intervention (i.e. any unscheduled administration of therapeutics at home or in the clinic), or any similar event whether caused primarily by LC-FAOD or by an intercurrent illness complicated by LC-FAOD. The annualized duration rate is calculated as the total duration (days) of events divided by the duration of data collection period in days/365.25. | Post-UX007 treatment through the end of the study (up to 2072 days) | 
| Annualized Event Rate of Cardiomyopathy MCEs | The annualized event rate of LC-FAOD major events inclusive of cardiomyopathy events, defined as any visit to the ER/acute care, hospitalization, emergency intervention (i.e. any unscheduled administration of therapeutics at home or in the clinic), or any similar event whether caused primarily by LC-FAOD or by an intercurrent illness complicated by LC-FAOD. The annualized event rate was calculated at the number of events divided by the duration of data collection period in days/365.25. | Post-UX007 treatment through the end of the study (up to 2072 days) | 
| Annualized Duration Rate of Cardiomyopathy MCEs | The annualized duration rate of LC-FAOD cardiomyopathy MCEs, defined as any visit to the ER/acute care, hospitalization, emergency intervention (i.e. any unscheduled administration of therapeutics at home or in the clinic), or any similar event whether caused primarily by LC-FAOD or by an intercurrent illness complicated by LC-FAOD. The annualized duration rate is calculated as the total duration (days) of events divided by the duration of data collection period in days/365.25 | Post-UX007 treatment through the end of the study (up to 2072 days) | 
| Annualized Event Rate of Hypoglycemic MCEs | The annualized event rate of LC-FAOD major events of hepatic (hypoglycemia) events, defined as any visit to the ER/acute care, hospitalization, emergency intervention (i.e. any unscheduled administration of therapeutics at home or in the clinic), or any similar event whether caused primarily by LC-FAOD or by an intercurrent illness complicated by LC-FAOD. The annualized event rate was calculated at the number of events divided by the duration of data collection period in days/365.25. | Post-UX007 treatment through the end of the study (up to 2072 days) | 
| Annualized Duration Rate of Hypoglycemic MCEs | The annualized duration rate of LC-FAOD hepatic (hypoglycemia) MCEs, defined as any visit to the ER/acute care, hospitalization, emergency intervention (i.e. any unscheduled administration of therapeutics at home or in the clinic), or any similar event whether caused primarily by LC-FAOD or by an intercurrent illness complicated by LC-FAOD. The annualized duration rate is calculated as the total duration (days) of events divided by the duration of data collection period in days/365.25. | Post-UX007 treatment through the end of the study (up to 2072 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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UX007, Triheptanoin, Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD), carnitine palmitoyltransferase (CPT I or CPT II) deficiency, very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) deficiency, trifunctional protein (TFP) deficiency, carnitine-acylcarnitine translocase (CACT) deficiency, C7