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

• ClinicalTrials.gov Identifier: NCT01886378
• Recruitment Status: Completed
• First Posted: June 25, 2013
• Results First Posted: February 11, 2021
• Last Update Posted: February 11, 2021
• Sponsor: Ultragenyx Pharmaceutical Inc
• Information provided by (Responsible Party): Ultragenyx Pharmaceutical Inc

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• 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
• Intervention: Drug: UX007
• Enrollment: 29

Participant Flow

Recruitment Details
Pre-assignment Details	Following the signing of informed consent at the Screening visit, each participant continued on current long-chain fatty acid oxidation disorder (LC-FAOD) management for a 4-week Run-in Period to establish a clinical baseline. Following completion of the 4-week Run-in Period, participants discontinued any use of medium chain triglycerides (MCT) and began treatment with UX007.

Arm/Group Title	UX007
Arm/Group Description	UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
Period Title: Overall Study
Started	29
Completed 24 Weeks of UX007 Treatment	25
Completed	24
Not Completed	5
Reason Not Completed
Adverse Event	1
Withdrawal by Subject	4

Baseline Characteristics

Arm/Group Title		UX007
Arm/Group Description		UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
Overall Number of Baseline Participants		29
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	29 participants
		12.06 (5.26)
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	29 participants
	0 - 1 years	2 6.9%
	> 1 - 6 years	13 44.8%
	> 6 -18 years	8 27.6%
	> 18 years	6 20.7%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	29 participants
	Female	12 41.4%
	Male	17 58.6%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Time Adjusted-Area Under the Curve (AUC/Time) for Workload During Cycle Ergometry at Week 24
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Primary Analysis Set - Cycle Ergometry: the subset of participants in the primary analysis set (all enrolled participants who completed the 4 week Run-in Period and received at least one dose of UX007) who had at least one cycle ergometry test performed with any duration.

Arm/Group Title	UX007
Arm/Group Description:	UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
Overall Number of Participants Analyzed	7
Least Squares Mean (Standard Error); Unit of Measure: watts
	423.594 (295.54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX007
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1518
	Comments	The GEE model included the change from Baseline for each parameter as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure.
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least squares (LS) mean
	Estimated Value	423.594
	Confidence Interval	(2-Sided) 95%; -155.66 to 1002.85
	Estimation Comments	LS Mean, 95% confidence interval (CI), and p-values are based on the GEE model.

2. Primary Outcome

Title	Change From Baseline in Time-Adjusted-AUC for Respiratory Exchange Ratio (RER) During Cycle Ergometry at Week 24
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Primary Analysis Set - Cycle Ergometry: the subset of participants in the primary analysis set (all enrolled participants who completed the 4 week Run-in Period and received at least one dose of UX007) who had at least one cycle ergometry test performed with any duration.

Arm/Group Title	UX007
Arm/Group Description:	UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
Overall Number of Participants Analyzed	7
Least Squares Mean (Standard Error); Unit of Measure: respiratory exchange ratio
	-0.011 (0.0132)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX007
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3964
	Comments	The GEE model included the change from Baseline for each parameter as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure.
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	-0.011
	Confidence Interval	(2-Sided) 95%; -0.04 to 0.01
	Estimation Comments	LS Mean, 95% CI, and p-values are based on the GEE model.

3. Primary Outcome

Title	Change From Baseline in Actual Duration of Exercise During Cycle Ergometry at Week 24
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Primary Analysis Set - Cycle Ergometry: the subset of participants in the primary analysis set (all enrolled participants who completed the 4 week Run-in Period and received at least one dose of UX007) who had at least one cycle ergometry test performed with any duration.

Arm/Group Title	UX007
Arm/Group Description:	UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
Overall Number of Participants Analyzed	7
Least Squares Mean (Standard Error); Unit of Measure: minutes
	4.671 (2.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX007
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0777
	Comments	The GEE model included the change from Baseline for each parameter as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure.
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	4.671
	Confidence Interval	(2-Sided) 95%; -0.52 to 9.86
	Estimation Comments	LS Mean, 95% CI, and p-values are based on the GEE model.

4. Primary Outcome

Title	Change From Baseline in Distance Traveled During the 12-Minute Walk Test (12MWT) at Week 18
Description	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.
Time Frame	Baseline (last assessment during the 4-week run-in period), Week 18

Outcome Measure Data

Analysis Population Description

Primary Analysis Set - 12MWT: the subset of participants in the primary analysis set (all enrolled participants who completed the 4 week Run-in Period and received at least one dose of UX007) who had at least one 12MWT performed with any distance walked.

Arm/Group Title	UX007
Arm/Group Description:	UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
Overall Number of Participants Analyzed	8
Least Squares Mean (Standard Error); Unit of Measure: meters
	181.37 (104.63)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX007
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0830
	Comments	The GEE model included the change from Baseline for each parameter as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure.
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	181.37
	Confidence Interval	(2-Sided) 95%; -23.70 to 386.45
	Estimation Comments	LS Mean, 95% CI, and p-values are based on the GEE model.

5. Primary Outcome

Title	Change From Baseline in Energy Expenditure Index (EEI) During the 12MWT at Week 18
Description	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.
Time Frame	Baseline (last assessment during the 4-week run-in period), Week 18

Outcome Measure Data

Analysis Population Description

Primary Analysis Set - 12MWT: the subset of participants in the primary analysis set (all enrolled participants who completed the 4 week Run-in Period and received at least one dose of UX007) who had at least one 12MWT performed with any distance walked.

Arm/Group Title	UX007
Arm/Group Description:	UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
Overall Number of Participants Analyzed	8
Least Squares Mean (Standard Error); Unit of Measure: beats/meter
	-0.185 (0.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX007
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0320
	Comments	The GEE model included the change from Baseline for each parameter as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure.
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	-0.185
	Confidence Interval	(2-Sided) 95%; -0.35 to -0.02
	Estimation Comments	LS Mean, 95% CI, and p-values are based on the GEE model.

6. Primary Outcome

Title	Change From Baseline in Percentage of the Predicted 6-Minute Walk Test (6MWT) Distance Walked at Week 18
Description	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.
Time Frame	Baseline (last assessment during the 4-week run-in period), Week 18

Outcome Measure Data

Analysis Population Description

Primary Analysis Set - 12MWT: the subset of participants in the primary analysis set (all enrolled participants who completed the 4 week Run-in Period and received at least one dose of UX007) who had at least one 12MWT performed with any distance walked.

Arm/Group Title	UX007
Arm/Group Description:	UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
Overall Number of Participants Analyzed	8
Least Squares Mean (Standard Error); Unit of Measure: % of predicted distance (in meters)
	12.44 (7.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX007
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0850
	Comments	The GEE model included the change from Baseline for each parameter as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure.
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	12.44
	Confidence Interval	(2-Sided) 95%; -1.72 to 26.60
	Estimation Comments	LS Mean, 95% CI, and p-values are based on the GEE model.

7. Primary Outcome

Title	Change From Baseline in Physical Summary Score (PHS-10) of the Short Form 10 (SF-10) at Week 24
Description	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).
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Primary Analysis Set - SF-10: the subset of participants in the primary analysis set (all enrolled participants who completed the 4 week Run-in Period and received at least one dose of UX007) who had at least one SF-10 test performed.

Arm/Group Title	UX007
Arm/Group Description:	UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
Overall Number of Participants Analyzed	5
Least Squares Mean (Standard Error); Unit of Measure: T-score
	2.16 (2.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX007
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3754
	Comments	The LS Mean, standard error (SE), 95% CI, and 2-sided p-value are from the GEE model.
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	2.16
	Confidence Interval	(2-Sided) 95%; -2.62 to 6.94
	Estimation Comments	[Not Specified]

8. Primary Outcome

Title	Change From Baseline in Psychosocial Summary Score (PSS-10) of the SF10 at Week 24
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Primary Analysis Set - SF-10: the subset of participants in the primary analysis set (all enrolled participants who completed the 4 week Run-in Period and received at least one dose of UX007) who had at least one SF-10 test performed.

Arm/Group Title	UX007
Arm/Group Description:	UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
Overall Number of Participants Analyzed	5
Least Squares Mean (Standard Error); Unit of Measure: T-score
	0.816 (2.63)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX007
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7564
	Comments	The LS Mean, SE, 95% CI, and 2-sided p-value are from the GEE model.
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	0.816
	Confidence Interval	(2-Sided) 95%; -4.34 to 5.97
	Estimation Comments	[Not Specified]

9. Primary Outcome

Title	Change From Baseline in the Physical Component Summary Scale (PCS-12) at Week 24
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Primary Analysis Set - SF-12: the subset of participants in the primary analysis set (those who completed the 4-week run-in period and received at least one dose of UX007) who had at least one SF-12 test performed.

Arm/Group Title	UX007
Arm/Group Description:	UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
Overall Number of Participants Analyzed	5
Least Squares Mean (Standard Deviation); Unit of Measure: T-score
	8.88 (1.63)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX007
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	The GEE model included the change from Baseline for each parameter as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure.
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	8.88
	Confidence Interval	(2-Sided) 95%; 5.67 to 12.08
	Estimation Comments	[Not Specified]

10. Primary Outcome

Title	Change From Baseline in the Mental Component Summary Scale (MCS-12) at Week 24
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Primary Analysis Set - SF-12: the subset of participants in the primary analysis set (those who completed the 4-week run-in period and received at least one dose of UX007) who had at least one SF-12 test performed.

Arm/Group Title	UX007
Arm/Group Description:	UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
Overall Number of Participants Analyzed	5
Least Squares Mean (Standard Error); Unit of Measure: T-score
	9.7 (4.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX007
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0152
	Comments	The GEE model included the change from Baseline for each parameter as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure.
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	9.70
	Confidence Interval	(2-Sided) 95%; 1.87 to 17.54
	Estimation Comments	LS Mean, 95% CI, and p-values are based on the GEE model.

11. Primary Outcome

Title	Annualized Event Rate of All Major Clinical Events Pre- and Post-Treatment With UX007
Description	Major clinical events are defined as adverse events (AEs) resulting in hospitalizations, emergency room (ER) visits, and emergency intervention.
Time Frame	18 months before and after UX007 initiation

Outcome Measure Data

Analysis Population Description

Primary Analysis Set: participants who completed the 4-week run-in period and received at least one dose of UX007.

Arm/Group Title	UX007
Arm/Group Description:	UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
Overall Number of Participants Analyzed	29
Mean (Standard Deviation); Unit of Measure: events/year
Pre-UX007	1.69 (1.6081)
Post-UX007	0.877 (1.142)

12. Primary Outcome

Title	Annualized Duration Rate of All Major Clinical Events Pre- and Post-Treatment With UX007
Description	Major clinical events are defined as AEs resulting in hospitalizations, ER visits, and emergency intervention.
Time Frame	18 months before and after UX007 initiation

Outcome Measure Data

Analysis Population Description

Primary Analysis Set: participants who completed the 4-week run-in period and received at least one dose of UX007.

Arm/Group Title	UX007
Arm/Group Description:	UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
Overall Number of Participants Analyzed	29
Mean (Standard Deviation); Unit of Measure: days/year
Pre-UX007	5.961 (6.0783)
Post-UX007	2.964 (3.9733)

13. Primary Outcome

Title	Annualized Event Rate of Major Rhabdomyolysis Clinical Events Pre- and Post-Treatment With UX007
Description	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.
Time Frame	18 months before and after UX007 initiation

Outcome Measure Data

Analysis Population Description

Primary Analysis Set: participants who completed the 4-week run-in period and received at least one dose of UX007.

Arm/Group Title	UX007
Arm/Group Description:	UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
Overall Number of Participants Analyzed	29
Mean (Standard Deviation); Unit of Measure: events/year
Pre-UX007	1.303 (1.5007)
Post-UX007	0.833 (1.1513)

14. Primary Outcome

Title	Annualized Duration Rate of Major Rhabdomyolysis Clinical Events Pre- and Post-Treatment With UX007
Description	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.
Time Frame	18 months before and after UX007 initiation

Outcome Measure Data

Analysis Population Description

Primary Analysis Set: participants who completed the 4-week run-in period and received at least one dose of UX007.

Arm/Group Title	UX007
Arm/Group Description:	UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
Overall Number of Participants Analyzed	29
Mean (Standard Deviation); Unit of Measure: days/year
Pre-UX007	3.949 (4.3687)
Post-UX007	2.792 (3.8452)

15. Primary Outcome

Title	Annualized Event Rate of Major Hypoglycemia Clinical Events Pre- and Post-Treatment With UX007
Description	Major hypoglycemia clinical events are defined as those AEs resulting in hospitalizations, ER visits, and emergency intervention.
Time Frame	18 months before and after UX007 initiation

Outcome Measure Data

Analysis Population Description

Primary Analysis Set: participants who completed the 4-week run-in period and received at least one dose of UX007.

Arm/Group Title	UX007
Arm/Group Description:	UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
Overall Number of Participants Analyzed	29
Mean (Standard Deviation); Unit of Measure: events/year
Pre-UX007	0.318 (0.9053)
Post-UX007	0.023 (0.1224)

16. Primary Outcome

Title	Annualized Duration Rate of Major Hypoglycemia Clinical Events Pre- and Post-Treatment With UX007
Description	Major hypoglycemia clinical events are defined as those AEs resulting in hospitalizations, ER visits, and emergency intervention.
Time Frame	18 months before and after UX007 initiation

Outcome Measure Data

Analysis Population Description

Primary Analysis Set: participants who completed the 4-week run-in period and received at least one dose of UX007.

Arm/Group Title	UX007
Arm/Group Description:	UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
Overall Number of Participants Analyzed	29
Mean (Standard Deviation); Unit of Measure: days/year
Pre-UX007	1.414 (4.3025)
Post-UX007	0.023 (0.1224)

17. Primary Outcome

Title	Annualized Event Rate of Major Cardiac Clinical Events Pre- and Post-Treatment With UX007
Description	Major cardiac clinical events are defined as those AEs resulting in hospitalizations, ER visits, and emergency intervention.
Time Frame	18 months before and after UX007 initiation

Outcome Measure Data

Analysis Population Description

Primary Analysis Set: participants who completed the 4-week run-in period and received at least one dose of UX007.

Arm/Group Title	UX007
Arm/Group Description:	UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
Overall Number of Participants Analyzed	29
Mean (Standard Deviation); Unit of Measure: events/year
Pre-UX007	0.069 (0.2728)
Post-UX007	0.021 (0.115)

18. Primary Outcome

Title	Annualized Duration Rate of Major Cardiac Clinical Events Pre- and Post-Treatment With UX007
Description	Major cardiac clinical events are defined as those AEs resulting in hospitalizations, ER visits, and emergency intervention.
Time Frame	18 months before and after UX007 initiation

Outcome Measure Data

Analysis Population Description

Primary Analysis Set: participants who completed the 4-week run-in period and received at least one dose of UX007.

Arm/Group Title	UX007
Arm/Group Description:	UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
Overall Number of Participants Analyzed	29
Mean (Standard Deviation); Unit of Measure: days/year
Pre-UX007	0.598 (2.4054)
Post-UX007	0.149 (0.8047)

Adverse Events

Time Frame	From the first dose of UX007 through the Follow-up visit (Week 82) or 30 days following the last UX007 administration.
Adverse Event Reporting Description	Events presented are treatment-emergent. An event was considered as treatment-emergent if it occurred on or after the date of the first treatment of UX007.
Arm/Group Title	UX007
Arm/Group Description	UX007 dosing was titrated to a target dose of 25-35% of total caloric intake or maximum tolerated dose. Participants were 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.
All-Cause Mortality
	UX007
	Affected / at Risk (%)
Total	0/29 (0.00%)
Serious Adverse Events
	UX007
	Affected / at Risk (%)
Total	19/29 (65.52%)
Cardiac disorders
Cardiomyopathy Acute † 1	1/29 (3.45%)
Congenital, familial and genetic disorders
Talipes † 1	1/29 (3.45%)
Gastrointestinal disorders
Gastrointestinal Disorder † 1	1/29 (3.45%)
Gastrointestinal Haemorrhage † 1	1/29 (3.45%)
Vomiting † 1	1/29 (3.45%)
Infections and infestations
Gastroenteritis † 1	6/29 (20.69%)
Gastroenteritis Viral † 1	6/29 (20.69%)
Gastrointestinal Viral Infection † 1	2/29 (6.90%)
Upper Respiratory Tract Infection † 1	2/29 (6.90%)
Adenoviral Upper Respiratory Infection † 1	1/29 (3.45%)
Adenovirus Infection † 1	1/29 (3.45%)
Conjunctivitis † 1	1/29 (3.45%)
Coxsackie Viral Infection † 1	1/29 (3.45%)
Croup Infectious † 1	1/29 (3.45%)
Otitis Media † 1	1/29 (3.45%)
Otitis Media Acute † 1	1/29 (3.45%)
Pneumonia Mycoplasmal † 1	1/29 (3.45%)
Respiratory Tract Infection Viral † 1	1/29 (3.45%)
Roseola † 1	1/29 (3.45%)
Urinary Tract Infection † 1	1/29 (3.45%)
Viral Upper Respiratory Tract Infection † 1	1/29 (3.45%)
Metabolism and nutrition disorders
Metabolic Disorder † 1	1/29 (3.45%)
Musculoskeletal and connective tissue disorders
Rhabdomyolysis † 1	11/29 (37.93%)
Reproductive system and breast disorders
Menorrhagia † 1	1/29 (3.45%)
Respiratory, thoracic and mediastinal disorders
Atelectasis † 1	1/29 (3.45%)
Surgical and medical procedures
Infection Prophylaxis † 1	1/29 (3.45%)
1 Term from vocabulary, MedDRA 17.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	UX007
	Affected / at Risk (%)
Total	29/29 (100.00%)
Blood and lymphatic system disorders
Lymphadenopathy † 1	2/29 (6.90%)
Cardiac disorders
Tachycardia † 1	2/29 (6.90%)
Eye disorders
Eye Swelling † 1	2/29 (6.90%)
Gastrointestinal disorders
Diarrhoea † 1	16/29 (55.17%)
Vomiting † 1	13/29 (44.83%)
Abdominal Pain † 1	8/29 (27.59%)
Abdominal Pain Upper † 1	4/29 (13.79%)
Gastrointestinal Pain † 1	3/29 (10.34%)
Gastrooesophageal Reflux Disease † 1	3/29 (10.34%)
Abdominal Distension † 1	2/29 (6.90%)
Constipation † 1	2/29 (6.90%)
Flatulence † 1	2/29 (6.90%)
Nausea † 1	2/29 (6.90%)
Teething † 1	2/29 (6.90%)
General disorders
Pyrexia † 1	9/29 (31.03%)
Pain † 1	3/29 (10.34%)
Infections and infestations
Upper Respiratory Tract Infection † 1	11/29 (37.93%)
Ear Infection † 1	5/29 (17.24%)
Nasopharyngitis † 1	5/29 (17.24%)
Bronchitis † 1	4/29 (13.79%)
Gastroenteritis Viral † 1	4/29 (13.79%)
Gastrointestinal Viral Infection † 1	4/29 (13.79%)
Rhinitis † 1	4/29 (13.79%)
Viral Upper Respiratory Tract Infection † 1	4/29 (13.79%)
Conjunctivitis † 1	3/29 (10.34%)
Gastroenteritis † 1	3/29 (10.34%)
Sinusitis † 1	3/29 (10.34%)
Urinary Tract Infection † 1	3/29 (10.34%)
Otitis Media † 1	2/29 (6.90%)
Respiratory Tract Infection Viral † 1	2/29 (6.90%)
Injury, poisoning and procedural complications
Arthropod Bite † 1	3/29 (10.34%)
Fall † 1	3/29 (10.34%)
Laceration † 1	2/29 (6.90%)
Procedural Pain † 1	2/29 (6.90%)
Stoma Site Pain † 1	2/29 (6.90%)
Investigations
Blood Creatine Phosphokinase Increased † 1	3/29 (10.34%)
Carnitine Decreased † 1	2/29 (6.90%)
Metabolism and nutrition disorders
Decreased Appetite † 1	4/29 (13.79%)
Dehydration † 1	2/29 (6.90%)
Musculoskeletal and connective tissue disorders
Rhabdomyolysis † 1	8/29 (27.59%)
Myalgia † 1	5/29 (17.24%)
Arthralgia † 1	2/29 (6.90%)
Muscle Spasms † 1	2/29 (6.90%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic Naevus † 1	2/29 (6.90%)
Nervous system disorders
Headache † 1	9/29 (31.03%)
Psychiatric disorders
Anxiety † 1	2/29 (6.90%)
Irritability † 1	2/29 (6.90%)
Panic Attack † 1	2/29 (6.90%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	4/29 (13.79%)
Nasal Congestion † 1	3/29 (10.34%)
Oropharyngeal Pain † 1	3/29 (10.34%)
Rhinorrhoea † 1	2/29 (6.90%)
Sinus Congestion † 1	2/29 (6.90%)
Skin and subcutaneous tissue disorders
Acne † 1	3/29 (10.34%)
Dermatitis Allergic † 1	2/29 (6.90%)
1 Term from vocabulary, MedDRA 17.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.

Results Point of Contact

• Name/Title: Medical Information
• Organization: Ultragenyx Pharmaceutical Inc
• Phone: 1-888-756-8657
• EMail: medinfo@ultragenyx.com

Publications of Results:

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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Ultragenyx Pharmaceutical Inc
• ClinicalTrials.gov Identifier: NCT01886378
• Other Study ID Numbers: UX007-CL201; 2013-004830-14 ( EudraCT Number )
• First Submitted: June 18, 2013
• First Posted: June 25, 2013
• Results First Submitted: December 17, 2020
• Results First Posted: February 11, 2021
• Last Update Posted: February 11, 2021