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A Phase 3 Study of UX003 Recombinant Human Betaglucuronidase (rhGUS) Enzyme Replacement Therapy in Patients With Mucopolysaccharidosis Type 7 (MPS 7)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02230566
Recruitment Status : Completed
First Posted : September 3, 2014
Results First Posted : February 16, 2018
Last Update Posted : January 4, 2019
Sponsor:
Information provided by (Responsible Party):
Ultragenyx Pharmaceutical Inc

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions MPS 7
Sly Syndrome
Mucopolysaccharidosis
MPS VII
Interventions Drug: UX003
Other: Placebo
Enrollment 12
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Group A: 4 mg/kg UX003 Group B: 8 Weeks Placebo Then 4 mg/kg UX003 Group C: 16 Weeks Placebo Then 4 mg/kg UX003 Group D: 24 Weeks Placebo Then 4 mg/kg UX003
Hide Arm/Group Description 4 mg/kg UX003 every other week (QOW) through Week 46 Placebo QOW for the first 8 weeks followed by 4 mg/kg UX003 QOW through Week 46 Placebo QOW for the first 16 weeks followed by 4 mg/kg UX003 QOW through Week 46 Placebo QOW for the first 24 weeks followed by 4 mg/kg UX003 QOW through Week 46
Period Title: Overall Study
Started 3 3 3 3
Completed 3 3 3 3
Not Completed 0 0 0 0
Arm/Group Title Group A: 4 mg/kg UX003 Group B: 8 Weeks Placebo Then 4 mg/kg UX003 Group C: 16 Weeks Placebo Then 4 mg/kg UX003 Group D: 24 Weeks Placebo Then 4 mg/kg UX003 Total
Hide Arm/Group Description 4 mg/kg UX003 QOW through Week 46 Placebo QOW for the first 8 weeks followed by 4 mg/kg UX003 QOW through Week 46 Placebo QOW for the first 16 weeks followed by 4 mg/kg UX003 QOW through Week 46 Placebo QOW for the first 24 weeks followed by 4 mg/kg UX003 QOW through Week 46 Total of all reporting groups
Overall Number of Baseline Participants 3 3 3 3 12
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 3 participants 3 participants 3 participants 3 participants 12 participants
13.13  (1.656) 12.50  (4.004) 20.77  (3.004) 15.23  (8.633) 15.41  (5.492)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 3 participants 3 participants 12 participants
Female
3
 100.0%
2
  66.7%
3
 100.0%
0
   0.0%
8
  66.7%
Male
0
   0.0%
1
  33.3%
0
   0.0%
3
 100.0%
4
  33.3%
1.Primary Outcome
Title European Union (EU) and Rest of World: Percentage Change From Baseline in Urinary Glycosaminoglycan (uGAG) Dermatan Sulfate (DS) at UX003 Treatment Week 24
Hide Description

Baseline was defined as the average of all assessments prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect was subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Percent change from baseline in uGAG DS was analyzed by generalized estimating equation (GEE) modeling based on observed data. The GEE model included included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within subjects was assumed to be exchangeable.

In the United States (US), this was considered a secondary outcome measure. Per guidance from the Food and Drug Administration (FDA), no primary efficacy variable was declared in the US. Efficacy was to be based on the totality of the clinical data on a per participant basis.

Time Frame Baseline (defined as the average of all assessments prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.
Arm/Group Title UX003 4 mg/kg
Hide Arm/Group Description:
Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.
Overall Number of Participants Analyzed 12
Least Squares Mean (Standard Error)
Unit of Measure: percentage change
-64.82  (2.468)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection UX003 4 mg/kg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.0001
Comments P-values are from GEE model including baseline value, and the post UX003 Treatment Week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.
Method GEE
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean
Estimated Value -64.82
Confidence Interval (2-Sided) 95%
-69.66 to -59.98
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Multi-Domain Responder Index (MDRI) Score at UX003 Treatment Week 24
Hide Description MDRI score, calculated as the total response score at UX003 Treatment Week 24 across 6 domains: 6-Minute Walk Test, forced vital capacity predicted value, shoulder flexion, visual acuity, and Bruininks-Oseretsky Test of Motor Proficiency fine motor and gross motor capacity. For each domain, a minimally important difference (MID) was pre-specified. Changes from before treatment (baseline) to 24 weeks after treatment in each domain variable were scored against pre-specified MIDs. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) An improvement or decline ≥ MID was scored either as a +1 or -1, respectively, and a change <MID was scored as 0. The integration of benefit occurred by summing the responses (-1, +1, 0) across all 6 domain variables to derive the MDRI score, with a range of -6 (greatest possible decline) to +6 (greatest possible improvement).
Time Frame Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.
Arm/Group Title UX003 4 mg/kg
Hide Arm/Group Description:
Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.
Overall Number of Participants Analyzed 12
Mean (Standard Deviation)
Unit of Measure: units on a scale
0.5  (0.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection UX003 4 mg/kg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0527
Comments [Not Specified]
Method t-test
Comments P value from t-test of "no change" (0 change) from baseline
3.Secondary Outcome
Title Change From Baseline in 6-Minute Walk Test (6MWT) at UX003 Treatment Week 24
Hide Description The total distance walked (in meters) in a 6-minute period was measured. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) A positive change from Baseline indicates improvement. Change from baseline in 6MWT was analyzed by GEE modeling based on observed data. The GEE model included all participants who had non-missing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.
Time Frame Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.
Arm/Group Title UX003 4 mg/kg
Hide Arm/Group Description:
Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.
Overall Number of Participants Analyzed 9
Least Squares Mean (Standard Error)
Unit of Measure: meters
20.8  (16.75)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection UX003 4 mg/kg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2137
Comments P-values are from GEE model including baseline value, and the post UX003 Treatment Week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.
Method GEE
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean
Estimated Value 20.8
Confidence Interval (2-Sided) 95%
-12.0 to 53.7
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Change From Baseline in Pulmonary Function Testing: Percentage of Predicted Forced Vital Capacity (FVC%Pred) at UX003 Treatment Week 24
Hide Description Spirometry was administered to participants who did not require invasive ventilatory support or have a tracheostomy and measured percentage of predicted FVC. The percent predicted values were calculated after testing using published normative data. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) No GEE analysis was performed for FVC due to the limitation of the sample size.
Time Frame Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.
Arm/Group Title UX003 4 mg/kg
Hide Arm/Group Description:
Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.
Overall Number of Participants Analyzed 1
Mean (Standard Deviation)
Unit of Measure: percentage predicted FVC
0 [1]   (NA)
[1]
1 participant evaluated
5.Secondary Outcome
Title Change From Baseline in Pulmonary Function Testing: Maximum Ventilatory Ventilation (MVV) at UX003 Treatment Week 24
Hide Description Spirometry was administered to participants who did not require invasive ventilatory support or have a tracheostomy to measure MVV. The percent predicted values were calculated after testing using published normative data. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.)
Time Frame Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
Hide Outcome Measure Data
Hide Analysis Population Description
No change from baseline was calculated and no GEE analysis was performed due to lack of data at baseline and/or UX003 Treatment Week 24.
Arm/Group Title UX003 4 mg/kg
Hide Arm/Group Description:
Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
6.Secondary Outcome
Title Change From Baseline in Shoulder Flexion and Extension Maximum Range of Motion at UX003 Treatment Week 24
Hide Description Goniometry was used to measure (in degrees) the maximum passive shoulder range of motion in both flexion and extension. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in shoulder flexion-left was analyzed by GEE modeling based on observed data. The GEE model included all participants who had non-missing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.
Time Frame Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.
Arm/Group Title UX003 4 mg/kg
Hide Arm/Group Description:
Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.
Overall Number of Participants Analyzed 12
Least Squares Mean (Standard Error)
Unit of Measure: degrees
Shoulder flexion - left Number Analyzed 12 participants
-6.5  (4.86)
Shoulder extension - left Number Analyzed 11 participants
-1.5  (4.83)
Shoulder flexion - right Number Analyzed 12 participants
-1.8  (3.54)
Shoulder extension - right Number Analyzed 11 participants
-3.4  (3.48)
Tighter shoulder flexion Number Analyzed 12 participants
-9.4  (4.6)
Tighter shoulder extension Number Analyzed 11 participants
-6.7  (3.53)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection UX003 4 mg/kg
Comments Shoulder Flexion - Left
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1778
Comments [Not Specified]
Method GEE
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean
Estimated Value -6.5
Confidence Interval (2-Sided) 95%
-16.1 to 3.0
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection UX003 4 mg/kg
Comments Shoulder Extension - Left
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7632
Comments [Not Specified]
Method GEE
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean
Estimated Value -1.5
Confidence Interval (2-Sided) 95%
-10.9 to 8.0
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection UX003 4 mg/kg
Comments Shoulder Flexion - Right
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6034
Comments [Not Specified]
Method GEE
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean
Estimated Value -1.8
Confidence Interval (2-Sided) 95%
-8.8 to 5.1
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection UX003 4 mg/kg
Comments Shoulder Extension - Right
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3332
Comments [Not Specified]
Method GEE
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean
Estimated Value -3.4
Confidence Interval (2-Sided) 95%
-10.2 to 3.4
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection UX003 4 mg/kg
Comments Tighter Shoulder Flexion
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0415
Comments [Not Specified]
Method GEE
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean
Estimated Value -9.4
Confidence Interval (2-Sided) 95%
-18.4 to -0.4
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection UX003 4 mg/kg
Comments Tighter Shoulder Extension
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0563
Comments [Not Specified]
Method GEE
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean
Estimated Value -6.7
Confidence Interval (2-Sided) 95%
-13.6 to 0.2
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Change From Baseline in Uncorrected Visual Acuity at UX003 Treatment Week 24
Hide Description Visual acuity was measured (corrected and uncorrected) using a standard eye chart and recorded for each eye independently. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. The change in the number of lines from pre-treatment baseline to 24 weeks of treatment was evaluated. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) A positive change from baseline indicates improvement. Change from baseline in uncorrected visual acuity was analyzed by GEE modeling based on observed data. The GEE model included all participants who had non-missing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.
Time Frame Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.
Arm/Group Title UX003 4 mg/kg
Hide Arm/Group Description:
Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.
Overall Number of Participants Analyzed 7
Least Squares Mean (Standard Error)
Unit of Measure: lines
Left eye 1  (0.63)
Right eye 0.9  (0.51)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection UX003 4 mg/kg
Comments for the left eye
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1140
Comments [Not Specified]
Method GEE
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean
Estimated Value 1.0
Confidence Interval (2-Sided) 95%
-0.2 to 2.2
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection UX003 4 mg/kg
Comments for the right eye
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0906
Comments [Not Specified]
Method GEE
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean
Estimated Value 0.9
Confidence Interval (2-Sided) 95%
-0.1 to 1.8
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Change From Baseline in Bruininks-Oseretsky Test of Motor Proficiency (BOT-2) Scores at UX003 Treatment Week 24
Hide Description BOT-2 was administered to evaluate treatment-related changes in 4 domains assessing both fine and gross motor function: balance (score 0 to 37), fine motor precision (score 0 to 41), manual dexterity (score 0 to 45), and running speed/agility (score 0 to 52). Higher scores indicate more motor proficiency; a positive change from baseline indicates improvement. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in BOT-2 was analyzed by GEE modeling based on observed data. The GEE model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.
Time Frame Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.
Arm/Group Title UX003 4 mg/kg
Hide Arm/Group Description:
Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Balance Number Analyzed 6 participants
0.8  (0.46)
Fine motor precision Number Analyzed 11 participants
-0.2  (0.23)
Manual dexterity Number Analyzed 11 participants
0.2  (0.21)
Running speed and agility Number Analyzed 5 participants
0.2  (0.12)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection UX003 4 mg/kg
Comments Scale-BALANCE
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0883
Comments [Not Specified]
Method GEE
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean
Estimated Value 0.8
Confidence Interval (2-Sided) 95%
-0.1 to 1.7
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection UX003 4 mg/kg
Comments Scale: FINE MOTOR PRECISION
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3528
Comments [Not Specified]
Method GEE
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean
Estimated Value -0.2
Confidence Interval (2-Sided) 95%
-0.7 to 0.2
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection UX003 4 mg/kg
Comments Scale-MANUAL DEXTERITY
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4094
Comments [Not Specified]
Method GEE
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean
Estimated Value 0.2
Confidence Interval (2-Sided) 95%
-0.2 to 0.6
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection UX003 4 mg/kg
Comments Scale-RUNNING SPEED AND AGILITY
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1020
Comments [Not Specified]
Method GEE
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean
Estimated Value 0.2
Confidence Interval (2-Sided) 95%
0.0 to 0.4
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Change From Baseline in Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale at UX003 Treatment Week 24
Hide Description The PedsQL 18-item scale is comprised of 3 dimensions: general fatigue (6 items), sleep/rest fatigue (6 items) and cognitive fatigue (6 items). Each item has a 5-point Likert response scale that is reverse scored and transformed to a 0 to 100 scale with higher scores indicating less fatigue. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in PedsQL total fatigue score was analyzed by GEE modeling based on observed data. The GEE model included all participants who had non-missing baseline and ≥1 post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.
Time Frame Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.
Arm/Group Title UX003 4 mg/kg
Hide Arm/Group Description:
Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.
Overall Number of Participants Analyzed 12
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
3.4  (2.64)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection UX003 4 mg/kg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1953
Comments [Not Specified]
Method GEE
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean
Estimated Value 3.4
Confidence Interval (2-Sided) 95%
-1.8 to 8.6
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Percentage of Individual Clinical Response (ICR) Responders at UX003 Treatment Week 24
Hide Description Percentage of participants who were ICR responders based on MID criteria at Week 24. At the Randomization visit, the physician queried the participant or parent/caregiver about signs and symptoms of MPS VII that interfered most with the participant’s daily life. Answers were mapped to an appropriate clinical outcome measure (e.g., difficulty walking could map to the 6MWT; breathing problems to FVC). The clinical outcome ranked with the highest impact on daily life that could be reliably completed by the participant and met a threshold level of impairment was selected as the ICR for that participant. ICR response was assessed based on a positive change (according to pre-specified MID criteria) of each participant’s ICR. Agresti–Coull confidence interval with nominal coverage ≥ 95%.
Time Frame Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.
Arm/Group Title UX003 4 mg/kg
Hide Arm/Group Description:
Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.
Overall Number of Participants Analyzed 12
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
25
(8.3 to 53.8)
11.Secondary Outcome
Title Change From Baseline in Impactful Clinical Problem Total Score at UX003 Treatment Week 24
Hide Description The 3 most impactful clinical problems as reported by the subject/parent/caregiver during the Clinical Problem Evaluation were scored on a Likert scale from 1 (very little problem) to 7 (an extreme amount) at randomization and post-randomization visits. At post-randomization visits, each clinical problem was again scored for impact on daily activities. Total scores ranged from 3 to 21; lower scores reflect less impact on daily life. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) The change from baseline up to UX003 Treatment Week 24 were analyzed by GEE modeling, including baseline value, and the post-UX003 initiation treatment week as a categorical variable. The covariance structure within participants is assumed to be exchangeable.
Time Frame Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.
Arm/Group Title UX003 4 mg/kg
Hide Arm/Group Description:
Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.
Overall Number of Participants Analyzed 12
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-1.2  (0.92)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection UX003 4 mg/kg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2022
Comments [Not Specified]
Method GEE
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean
Estimated Value -1.2
Confidence Interval (2-Sided) 95%
-3.0 to 0.6
Estimation Comments [Not Specified]
Time Frame Safety information was collected for all participants who received any study drug from signing the informed consent form through 30 days after last dose of study drug. Mean treatment duration for UX003 was 36.0 weeks, and for placebo was 15.8 weeks.
Adverse Event Reporting Description Treatment-emergent adverse events (TEAEs) are presented. Given that the study has only has 12 participants, and a by arm/group analysis would include no more than 3 participants per arm/group, the TEAE summary was planned to present data by treatment only.
 
Arm/Group Title Placebo UX003 Active Treatment
Hide Arm/Group Description Participants received placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study, based on the blind-start design. Participants received 4 mg/kg UX003 QOW per group assignment (based on the blind-start design) and were dosed through Week 46. All groups received a minimum of 24 weeks of treatment with UX003.
All-Cause Mortality
Placebo UX003 Active Treatment
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo UX003 Active Treatment
Affected / at Risk (%) Affected / at Risk (%)
Total   0/9 (0.00%)   2/12 (16.67%) 
Immune system disorders     
Anaphylactoid reaction  1 [1]  0/9 (0.00%)  1/12 (8.33%) 
Injury, poisoning and procedural complications     
Craniocerebral injury  1 [2]  0/9 (0.00%)  1/12 (8.33%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 19.0
[1]
CTCAE grade 3 treatment-related anaphylactoid reaction secondary to an infusion rate error occurring during the first hour of UX003 administration.
[2]
CTCAE grade 2 non-related craniocerebral injury as a result of falling off the bed. Computed tomography scan of the head did not show intracranial bleeding nor acute intracranial injury.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo UX003 Active Treatment
Affected / at Risk (%) Affected / at Risk (%)
Total   9/9 (100.00%)   12/12 (100.00%) 
Ear and labyrinth disorders     
Ear pain  1  1/9 (11.11%)  0/12 (0.00%) 
Eye disorders     
Eye pain  1  1/9 (11.11%)  0/12 (0.00%) 
Gastrointestinal disorders     
Diarrhoea  1  0/9 (0.00%)  3/12 (25.00%) 
Vomiting  1  2/9 (22.22%)  3/12 (25.00%) 
Abdominal pain  1  1/9 (11.11%)  1/12 (8.33%) 
Abdominal pain lower  1  0/9 (0.00%)  1/12 (8.33%) 
Abdominal pain upper  1  0/9 (0.00%)  1/12 (8.33%) 
Abnormal faeces  1  0/9 (0.00%)  1/12 (8.33%) 
Rectal haemorrhage  1  0/9 (0.00%)  1/12 (8.33%) 
Cheilosis  1  1/9 (11.11%)  0/12 (0.00%) 
General disorders     
Infusion site extravasation  1  1/9 (11.11%)  4/12 (33.33%) 
Oedema  1  1/9 (11.11%)  1/12 (8.33%) 
Pyrexia  1  1/9 (11.11%)  1/12 (8.33%) 
Catheter site bruise  1  0/9 (0.00%)  1/12 (8.33%) 
Chills  1  0/9 (0.00%)  1/12 (8.33%) 
Infusion site bruising  1  0/9 (0.00%)  1/12 (8.33%) 
Infusion site swelling  1  0/9 (0.00%)  1/12 (8.33%) 
Peripheral swelling  1  0/9 (0.00%)  1/12 (8.33%) 
Infusion site discomfort  1  1/9 (11.11%)  0/12 (0.00%) 
Immune system disorders     
Anaphylactoid reaction  1  0/9 (0.00%)  1/12 (8.33%) 
Seasonal allergy  1  1/9 (11.11%)  1/12 (8.33%) 
Infections and infestations     
Upper respiratory tract infection  1  3/9 (33.33%)  5/12 (41.67%) 
Ear infection  1  1/9 (11.11%)  1/12 (8.33%) 
Cellulitis  1  0/9 (0.00%)  1/12 (8.33%) 
Conjunctivitis  1  0/9 (0.00%)  1/12 (8.33%) 
Gastrointestinal viral infection  1  0/9 (0.00%)  1/12 (8.33%) 
Oral herpes  1  0/9 (0.00%)  1/12 (8.33%) 
Rash pustular  1  0/9 (0.00%)  1/12 (8.33%) 
Urinary tract infection  1  0/9 (0.00%)  1/12 (8.33%) 
Otitis media acute  1  1/9 (11.11%)  0/12 (0.00%) 
Injury, poisoning and procedural complications     
Excoriation  1  1/9 (11.11%)  1/12 (8.33%) 
Contusion  1  0/9 (0.00%)  1/12 (8.33%) 
Post-traumatic neck syndrome  1  0/9 (0.00%)  1/12 (8.33%) 
Tooth fracture  1  0/9 (0.00%)  1/12 (8.33%) 
Fall  1  1/9 (11.11%)  0/12 (0.00%) 
Craniocerebral injury  1  0/9 (0.00%)  1/12 (8.33%) 
Investigations     
Body temperature increased  1  1/9 (11.11%)  0/12 (0.00%) 
Metabolism and nutrition disorders     
Dehydration  1  0/9 (0.00%)  1/12 (8.33%) 
Decreased appetite  1  1/9 (11.11%)  0/12 (0.00%) 
Musculoskeletal and connective tissue disorders     
Pain in extremity  1  3/9 (33.33%)  4/12 (33.33%) 
Arthralgia  1  0/9 (0.00%)  1/12 (8.33%) 
Arthritis  1  0/9 (0.00%)  1/12 (8.33%) 
Joint range of motion decreased  1  0/9 (0.00%)  1/12 (8.33%) 
Musculoskeletal stiffness  1  0/9 (0.00%)  1/12 (8.33%) 
Joint swelling  1  0/9 (0.00%)  1/12 (8.33%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Skin papilloma  1  0/9 (0.00%)  1/12 (8.33%) 
Nervous system disorders     
Ataxia  1  0/9 (0.00%)  1/12 (8.33%) 
Clonus  1  0/9 (0.00%)  1/12 (8.33%) 
Dysstasia  1  0/9 (0.00%)  1/12 (8.33%) 
Headache  1  0/9 (0.00%)  1/12 (8.33%) 
Psychiatric disorders     
Post-traumatic stress disorder  1  0/9 (0.00%)  1/12 (8.33%) 
Depression  1  1/9 (11.11%)  0/12 (0.00%) 
Insomnia  1  1/9 (11.11%)  0/12 (0.00%) 
Renal and urinary disorders     
Urinary incontinence  1  0/9 (0.00%)  1/12 (8.33%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  2/9 (22.22%)  3/12 (25.00%) 
Dyspnoea exertional  1  0/9 (0.00%)  1/12 (8.33%) 
Nasal obstruction  1  0/9 (0.00%)  1/12 (8.33%) 
Productive cough  1  0/9 (0.00%)  1/12 (8.33%) 
Rhinorrhoea  1  0/9 (0.00%)  1/12 (8.33%) 
Epistaxis  1  1/9 (11.11%)  0/12 (0.00%) 
Skin and subcutaneous tissue disorders     
Rash  1  1/9 (11.11%)  3/12 (25.00%) 
Urticaria  1  1/9 (11.11%)  1/12 (8.33%) 
Pruritus  1  0/9 (0.00%)  1/12 (8.33%) 
Rash macular  1  1/9 (11.11%)  0/12 (0.00%) 
Rash papular  1  1/9 (11.11%)  0/12 (0.00%) 
Skin ulcer  1  1/9 (11.11%)  0/12 (0.00%) 
Vascular disorders     
Hypertension  1  1/9 (11.11%)  0/12 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 19.0
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.
Results Point of Contact
Name/Title: Kim Mooney, Associate Director, Patient Advocacy Medical Services
Organization: Ultragenyx Pharmaceutical Inc
Phone: 408-981-3526
Responsible Party: Ultragenyx Pharmaceutical Inc
ClinicalTrials.gov Identifier: NCT02230566     History of Changes
Other Study ID Numbers: UX003-CL301
First Submitted: August 22, 2014
First Posted: September 3, 2014
Results First Submitted: November 29, 2017
Results First Posted: February 16, 2018
Last Update Posted: January 4, 2019