A Study of UX007 (Triheptanoin) in Participants With Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD)

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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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

Intervention / Treatment
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* Drug: UX007


Participation Criteria
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Eligibility Criteria
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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

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>UX007 dosing titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants are followed to evaluate the effects of UX007 over 24 weeks (Treatment Period), then continued treatment in the Extension Period for an additional 54 weeks for a total of 78 weeks of treatment. | Drug: UX007<br> <br> * Other names: C7 oil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Time Adjusted-Area Under the Curve (AUC/Time) for Workload During Cycle Ergometry at Week 24 | To evaluate the impact 24 weeks of treatment with UX007 has on exercise intolerance, the change from Baseline in time adjusted-AUC (AUC/time) for workload during 40-minute cycle ergometry tests at Week 24 were assessed using the generalized estimation equation (GEE) model. A cycle ergometer can measure the work performed by an individual over time during physical exercise, the work was measured every 10 minutes from 0 to 40 minutes at Baseline and Week 24. The GEE model included the change from Baseline as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure. An increase in AUC is reflective of improved exercise tolerance; a negative change from Baseline indicates worsening. | Baseline, Week 24 | 
| Change From Baseline in Time-Adjusted-AUC for Respiratory Exchange Ratio (RER) During Cycle Ergometry at Week 24 | Change from baseline in time-adjusted-AUC for respiratory exchange ratio (RER) during cycle ergometry at Week 24, assessed using the GEE model, which included change from baseline as dependent variable, time as categorical variable, and adjusted for baseline measurement with compound symmetry covariance structure. RER during exercise is calculated as volume of carbon dioxide/volume of oxygen. RER measures whether carbohydrates or fats are being used as fuel. RER ≥1.0 indicates carbohydrates are the predominate fuel source. RER <1.0 and RER >0.70 indicates both fats and carbohydrates are the predominate fuel source. RER approximately =0.70 means fat is the predominant fuel source. RER would be expected to be lower, at similar exercise intensities, if a participant is able to utilize fat as an energy source. Therefore, an increase in RER (positive change from baseline) would suggest participants are still utilizing carbohydrates rather than fat, reflective a physiological response. | Baseline, Week 24 | 
| Change From Baseline in Actual Duration of Exercise During Cycle Ergometry at Week 24 | To evaluate the impact of 24 weeks of treatment with UX007 on exercise intolerance, the change from Baseline in actual duration of exercise during 40-minute cycle ergometry tests at Week 24 was assessed using the GEE model. The GEE model included the change from Baseline as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure. Duration of exercise is expected to increase as exercise tolerance improves. | Baseline, Week 24 | 
| Change From Baseline in Distance Traveled During the 12-Minute Walk Test (12MWT) at Week 18 | To evaluate the impact 18 weeks of treatment with UX007 has on muscle function, the change from Baseline in distance traveled during a 12MWT at Week 18 was assessed using the GEE model. The GEE model included the change from Baseline as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure. Distance traveled during the 12MWT is expected to increase as muscle function increases. | Baseline (last assessment during the 4-week run-in period), Week 18 | 
| Change From Baseline in Energy Expenditure Index (EEI) During the 12MWT at Week 18 | To evaluate the impact 18 weeks of treatment with UX007 has on muscle function, the change from Baseline of EEI during the 12MWT at Week 18 was assessed using the GEE model. The GEE model included the change from Baseline as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure. EEI is quantified as the post-test heart rate minus the pre-test heart rate (in beats/min) divided by overall velocity, and is valued in beats/meter. A decrease in EEI when walking a similar distance or no change when walking longer distances, may indicate improved exercise tolerance. | Baseline (last assessment during the 4-week run-in period), Week 18 | 
| Change From Baseline in Percentage of the Predicted 6-Minute Walk Test (6MWT) Distance Walked at Week 18 | To evaluate the impact 18 weeks of treatment with UX007 has on muscle function, the change from Baseline in the percentage of the predicted distance traveled during the first 6 minutes (6MWT) of the 12MWT at Week 18 was assessed using the GEE model. A participant's mathematical formula to calculate their percent predicted (PP) distance walked in the 6MWT was based on their demographics at baseline. For participants < 20 years old, the formula used was referenced from (Gieger, et. al. 2007) which calculated PP distance walked based on age, gender, and height. For participants >= 20 years old, the formula used was referenced from (Gibbons, et. al. 2001) and calculated the PP distance walked based on age and gender. The GEE model included the change from Baseline as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure. Percent predicted values are expected to increase as muscle function increases. | Baseline (last assessment during the 4-week run-in period), Week 18 | 
| Change From Baseline in Physical Summary Score (PHS-10) of the Short Form 10 (SF-10) at Week 24 | To evaluate the impact treatment with UX007 has on functional disability and health in participants between 5 and 17 years of age, change from Baseline in the T-scores of the PHS-10 were assessed at Week 24 and analyzed using the GEE model. The GEE model included the change from Baseline as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure. The SF-10 Health Survey for Children is a 10-item caregiver-completed assessment designed to measure children's health-related quality of life. The PHS-10 of the SF-10 is scored such that higher scores indicate more favorable functioning. The T-score based scoring signifies that scale scores are centered so that a score of 50 corresponds to the average score in a comprehensive sample of US population (scale scores are standardized to a mean of 50 and a standard deviation of 10). | Baseline, Week 24 | 
| Change From Baseline in Psychosocial Summary Score (PSS-10) of the SF10 at Week 24 | To evaluate the impact treatment with UX007 has on functional disability and health in participants between 5 and 17 years of age, changes from Baseline in the T-scores of the PSS-10 were assessed at Week 24 and analyzed using the GEE model. The GEE model included the change from Baseline as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure. The PSS-10 of the SF-10 is scored such that higher scores indicate more favorable functioning. The T-score based scoring signifies that scale scores are centered so that a score of 50 corresponds to the average score in a comprehensive sample of US population (scale scores are standardized to a mean of 50 and a standard deviation of 10). Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of more favorable functioning/better health. | Baseline, Week 24 | 
| Change From Baseline in the Physical Component Summary Scale (PCS-12) at Week 24 | Changes from baseline in T-scores as assessed by the PCS-12 Short-Form Health Survey, version 2 (SF-12v2) at Week 24 were assessed using the GEE model, which included the change from Baseline as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure. PCS-12 scores were calculated from the individual responses to those questions that contribute to physical health. Raw scores range from 0 to 100 with higher scores indicating better health. The T-score based scoring signifies that scale scores are centered so that a score of 50 corresponds to the average score in the US general population (scale scores are standardized to a mean of 50 and a standard deviation of 10). Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of more favorable functioning/better health. | Baseline, Week 24 | 
| Change From Baseline in the Mental Component Summary Scale (MCS-12) at Week 24 | Changes from baseline of T-scores as assessed by the MCS-12 of the SF-12v2 at Week 24 were assessed using the GEE model, which included the change from Baseline as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure. MCS-12 scores were calculated from the individual responses to those questions that contribute to mental health. Raw scores range from 0 to 100 with higher scores indicating better health. The T-score based scoring signifies that scale scores are centered so that a score of 50 corresponds to the average score in the US general population (scale scores are standardized to a mean of 50 and a standard deviation of 10). Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of more favorable functioning/better health. | Baseline, Week 24 | 
| Annualized Event Rate of All Major Clinical Events Pre- and Post-Treatment With UX007 | Major clinical events are defined as adverse events (AEs) resulting in hospitalizations, emergency room (ER) visits, and emergency intervention. | 18 months before and after UX007 initiation | 
| Annualized Duration Rate of All Major Clinical Events Pre- and Post-Treatment With UX007 | Major clinical events are defined as AEs resulting in hospitalizations, ER visits, and emergency intervention. | 18 months before and after UX007 initiation | 
| Annualized Event Rate of Major Rhabdomyolysis Clinical Events Pre- and Post-Treatment With UX007 | Rhabdomyolysis is a condition in which damaged skeletal muscle breaks down rapidly. Major rhabdomyolysis clinical events are defined as those AEs resulting in hospitalizations, ER visits, and emergency intervention. | 18 months before and after UX007 initiation | 
| Annualized Duration Rate of Major Rhabdomyolysis Clinical Events Pre- and Post-Treatment With UX007 | Rhabdomyolysis is a condition in which damaged skeletal muscle breaks down rapidly. Major rhabdomyolysis clinical events are defined as those AEs resulting in hospitalizations, ER visits, and emergency intervention. | 18 months before and after UX007 initiation | 
| Annualized Event Rate of Major Hypoglycemia Clinical Events Pre- and Post-Treatment With UX007 | Major hypoglycemia clinical events are defined as those AEs resulting in hospitalizations, ER visits, and emergency intervention. | 18 months before and after UX007 initiation | 
| Annualized Duration Rate of Major Hypoglycemia Clinical Events Pre- and Post-Treatment With UX007 | Major hypoglycemia clinical events are defined as those AEs resulting in hospitalizations, ER visits, and emergency intervention. | 18 months before and after UX007 initiation | 
| Annualized Event Rate of Major Cardiac Clinical Events Pre- and Post-Treatment With UX007 | Major cardiac clinical events are defined as those AEs resulting in hospitalizations, ER visits, and emergency intervention. | 18 months before and after UX007 initiation | 
| Annualized Duration Rate of Major Cardiac Clinical Events Pre- and Post-Treatment With UX007 | Major cardiac clinical events are defined as those AEs resulting in hospitalizations, ER visits, and emergency intervention. | 18 months before and after UX007 initiation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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UX007, FAOD, VLCAD, CPT II, CPT2, CPT 2, LCHAD, Triheptanoin, TFP, C7