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

• Sponsor: Ultragenyx Pharmaceutical Inc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02230566
• Collaborator: (none)
• Enrollment: 12
• Locations: 4
• Arms: 4
• Duration (Months): 17
• Patients Per Site: 3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The Phase 3 study will use a novel randomized, intra-subject placebo-controlled, single crossover design, referred to as Blind Start, to evaluate the safety and efficacy of UX003. The Blind Start is a novel design whereby participants will be randomized to 1 of 4 groups, each representing a different treatment sequence, and will cross over to UX003 at different pre-defined time points in a blinded manner. All groups will receive a minimum of 24 weeks treatment with 4 mg/kg UX003 every other week (QOW).

Condition or Disease	Intervention/Treatment	Phase
MPS 7; Sly Syndrome; Mucopolysaccharidosis; MPS VII	Drug: UX003; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Placebo-Controlled, Blind-Start, Single-Crossover Phase 3 Study to Assess the Efficacy and Safety of UX003 rhGUS Enzyme Replacement Therapy in Patients With MPS 7
• Study Start Date: Dec 1, 2014
• Actual Primary Completion Date: May 1, 2016
• Actual Study Completion Date: May 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A: 4 mg/kg UX003 4 mg/kg UX003 QOW through Week 46	Drug: UX003; UX003 is a sterile concentrate formulation of rhGUS for intravenous infusion; Other Names: recombinant human beta-glucuronidase rh-β-glucuronidase rhGUS
Experimental: Group B: 8 Weeks Placebo then 4 mg/kg UX003 Placebo QOW for the first 8 weeks followed by 4 mg/kg UX003 QOW through Week 46	Drug: UX003; UX003 is a sterile concentrate formulation of rhGUS for intravenous infusion; Other Names: recombinant human beta-glucuronidase rh-β-glucuronidase rhGUS ; Other: Placebo; Placebo consisting of the UX003 formulation buffer (without rhGUS); Other Names: Reference therapy
Experimental: Group C: 16 Weeks Placebo then 4 mg/kg UX003 Placebo QOW for the first 16 weeks followed by 4 mg/kg UX003 QOW through Week 46	Drug: UX003; UX003 is a sterile concentrate formulation of rhGUS for intravenous infusion; Other Names: recombinant human beta-glucuronidase rh-β-glucuronidase rhGUS ; Other: Placebo; Placebo consisting of the UX003 formulation buffer (without rhGUS); Other Names: Reference therapy
Experimental: Group D: 24 Weeks Placebo then 4 mg/kg UX003 Placebo QOW for the first 24 weeks followed by 4 mg/kg UX003 QOW through Week 46	Drug: UX003; UX003 is a sterile concentrate formulation of rhGUS for intravenous infusion; Other Names: recombinant human beta-glucuronidase rh-β-glucuronidase rhGUS ; Other: Placebo; Placebo consisting of the UX003 formulation buffer (without rhGUS); Other Names: Reference therapy

Outcome Measures

Primary Outcome Measures

1. European Union (EU) and Rest of World: Percentage Change From Baseline in Urinary Glycosaminoglycan (uGAG) Dermatan Sulfate (DS) at UX003 Treatment Week 24 [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]

   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.

Secondary Outcome Measures

1. Multi-Domain Responder Index (MDRI) Score at UX003 Treatment Week 24 [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]

   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).

2. Change From Baseline in 6-Minute Walk Test (6MWT) at UX003 Treatment Week 24 [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]

   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.

3. Change From Baseline in Pulmonary Function Testing: Percentage of Predicted Forced Vital Capacity (FVC%Pred) at UX003 Treatment Week 24 [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]

   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.

4. Change From Baseline in Pulmonary Function Testing: Maximum Ventilatory Ventilation (MVV) at UX003 Treatment Week 24 [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]

   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.)

5. Change From Baseline in Shoulder Flexion and Extension Maximum Range of Motion at UX003 Treatment Week 24 [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]

   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.

6. Change From Baseline in Uncorrected Visual Acuity at UX003 Treatment Week 24 [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]

   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.

7. Change From Baseline in Bruininks-Oseretsky Test of Motor Proficiency (BOT-2) Scores at UX003 Treatment Week 24 [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]

   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.

8. Change From Baseline in Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale at UX003 Treatment Week 24 [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]

   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.

9. Percentage of Individual Clinical Response (ICR) Responders at UX003 Treatment Week 24 [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]

   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%.

10. Change From Baseline in Impactful Clinical Problem Total Score at UX003 Treatment Week 24 [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]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 5 Years to 35 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Confirmed diagnosis of MPS 7 based on leukocyte or fibroblast glucuronidase enzyme assay or genetic testing.

• Elevated urinary glycosaminoglycan (uGAG) excretion at a minimum of 3-fold over the mean normal for age (at Screening).

• Apparent clinical signs of lysosomal storage disease as judged by the Investigator, including at least one of the following: enlarged liver and spleen, joint limitations, airway obstruction or pulmonary problems, limitation of mobility while still ambulatory.

• Aged 5 - 35 years, inclusive.

• Willing and able to provide written informed consent, or in the case of subjects under the age of 18 (or 16 years, depending on the region), provide written assent (if required) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures.

• Sexually active subjects must be willing to use acceptable highly effective methods of contraception while participating in the study and for 30 days following the last dose.

• Females of childbearing potential must have a negative pregnancy test at Screening and be willing to have additional pregnancy tests during the study. Females considered not of childbearing potential include those who have not experienced menarche, or have had tubal ligation at least one year prior to Screening, or who have had total hysterectomy.

• Naïve to treatment with UX003.

Exclusion Criteria:

• Undergone a successful bone marrow or stem cell transplant or has any degree of detectable chimaerism with donor cells.

• Major surgery within 3 months prior to study entry or planned major surgery during the study that may not allow safe participation in the study.

• Presence or history of any hypersensitivity to rhGUS or its excipients that, in the judgment of the Investigator, places the subject at increased risk for adverse effects.

• Pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) at any time during the study.

• Use of any investigational product (drug or device or combination) within 30 days prior to Screening, or requirement for any investigational agent prior to completion of all scheduled study assessments.

• Presence of a condition of such severity and acuity that, in the opinion of the Investigator, warrants immediate surgical intervention or other treatment or may not allow safe participation in the study.

• Concurrent disease or condition, or laboratory abnormality that, in the view of the Investigator, places the subject at high risk of poor treatment compliance or of not completing the study, or would interfere with study participation or introduce additional safety concerns.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Oakland	Oakland	California	United States	94609
2	Children's Hospital of Orange County	Orange	California	United States	92868
3	Miami Children's Hospital	Miami	Florida	United States	33155
4	University of Minnesota	Minneapolis	Minnesota	United States	55455

Sponsors and Collaborators

• Ultragenyx Pharmaceutical Inc

Investigators

• Principal Investigator: Paul Harmatz, MD, UCSF Benioff Children's Hospital Oakland
• Principal Investigator: Raymond Wang, MD, Children's Hospital of Orange County
• Principal Investigator: Mislen Bauer, MD, Nicklaus Children's Hospital f/k/a Miami Children's Hospital
• Principal Investigator: Chester Whitley, MD, University of Minnesota

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ultragenyx Pharmaceutical Inc
• ClinicalTrials.gov Identifier: NCT02230566
• Other Study ID Numbers: UX003-CL301
• First Posted: Sep 3, 2014
• Last Update Posted: Jul 30, 2020
• Last Verified: Jul 1, 2020

• Keywords provided by Ultragenyx Pharmaceutical Inc: MPS 7; Sly Syndrome; Mucopolysaccharidosis; MPS VII; Enzyme Replacement Therapy; Mucopolysaccharidosis type 7; rare disease; lysosomal storage disease; metabolic disorder
• Additional relevant MeSH terms: Mucopolysaccharidoses; Mucopolysaccharidosis VII

Study Results

Participant Flow

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
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

Baseline Characteristics

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
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 Participants	3	3	3	3	12
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	13.13 (1.656)	12.50 (4.004)	20.77 (3.004)	15.23 (8.633)	15.41 (5.492)
Sex: Female, Male (Count of Participants)
Female	3 100%	2 66.7%	3 100%	0 0%	8 66.7%
Male	0 0%	1 33.3%	0 0%	3 100%	4 33.3%

Outcome Measures

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
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

Outcome Measure Data

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
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.
Measure Participants	12
Least Squares Mean (Standard Error) [percentage change]	-64.82 (2.468)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX003 4 mg/kg
	Comments
	Type of Statistical Test	Superiority
	Comments
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
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-64.82
	Confidence Interval	(2-Sided) 95%; -69.66 to -59.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Multi-Domain Responder Index (MDRI) Score at UX003 Treatment Week 24
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

Outcome Measure Data

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
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.
Measure Participants	12
Mean (Standard Deviation) [units on a scale]	0.5 (0.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX003 4 mg/kg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0527
	Comments
	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
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

Outcome Measure Data

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
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.
Measure Participants	9
Least Squares Mean (Standard Error) [meters]	20.8 (16.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX003 4 mg/kg
	Comments
	Type of Statistical Test	Superiority
	Comments
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
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	20.8
	Confidence Interval	(2-Sided) 95%; -12.0 to 53.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Pulmonary Function Testing: Percentage of Predicted Forced Vital Capacity (FVC%Pred) at UX003 Treatment Week 24
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

Outcome Measure Data

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
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.
Measure Participants	1
Mean (Standard Deviation) [percentage predicted FVC]	0 (NA)

5. Secondary Outcome

Title	Change From Baseline in Pulmonary Function Testing: Maximum Ventilatory Ventilation (MVV) at UX003 Treatment Week 24
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

Outcome Measure Data

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
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.
Measure Participants	0

6. Secondary Outcome

Title	Change From Baseline in Shoulder Flexion and Extension Maximum Range of Motion at UX003 Treatment Week 24
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

Outcome Measure Data

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
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.
Measure Participants	12
Shoulder flexion - left	-6.5 (4.86)
Shoulder extension - left	-1.5 (4.83)
Shoulder flexion - right	-1.8 (3.54)
Shoulder extension - right	-3.4 (3.48)
Tighter shoulder flexion	-9.4 (4.6)
Tighter shoulder extension	-6.7 (3.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX003 4 mg/kg
	Comments	Shoulder Flexion - Left
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1778
	Comments
	Method	GEE
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-6.5
	Confidence Interval	(2-Sided) 95%; -16.1 to 3.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX003 4 mg/kg
	Comments	Shoulder Extension - Left
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7632
	Comments
	Method	GEE
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 95%; -10.9 to 8.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	UX003 4 mg/kg
	Comments	Shoulder Flexion - Right
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6034
	Comments
	Method	GEE
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-1.8
	Confidence Interval	(2-Sided) 95%; -8.8 to 5.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	UX003 4 mg/kg
	Comments	Shoulder Extension - Right
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3332
	Comments
	Method	GEE
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-3.4
	Confidence Interval	(2-Sided) 95%; -10.2 to 3.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	UX003 4 mg/kg
	Comments	Tighter Shoulder Flexion
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0415
	Comments
	Method	GEE
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-9.4
	Confidence Interval	(2-Sided) 95%; -18.4 to -0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	UX003 4 mg/kg
	Comments	Tighter Shoulder Extension
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0563
	Comments
	Method	GEE
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-6.7
	Confidence Interval	(2-Sided) 95%; -13.6 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in Uncorrected Visual Acuity at UX003 Treatment Week 24
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

Outcome Measure Data

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
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.
Measure Participants	7
Left eye	1 (0.63)
Right eye	0.9 (0.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX003 4 mg/kg
	Comments	for the left eye
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1140
	Comments
	Method	GEE
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; -0.2 to 2.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX003 4 mg/kg
	Comments	for the right eye
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0906
	Comments
	Method	GEE
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 95%; -0.1 to 1.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in Bruininks-Oseretsky Test of Motor Proficiency (BOT-2) Scores at UX003 Treatment Week 24
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

Outcome Measure Data

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
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.
Measure Participants	11
Balance	0.8 (0.46)
Fine motor precision	-0.2 (0.23)
Manual dexterity	0.2 (0.21)
Running speed and agility	0.2 (0.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX003 4 mg/kg
	Comments	Scale-BALANCE
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0883
	Comments
	Method	GEE
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; -0.1 to 1.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX003 4 mg/kg
	Comments	Scale: FINE MOTOR PRECISION
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3528
	Comments
	Method	GEE
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.7 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	UX003 4 mg/kg
	Comments	Scale-MANUAL DEXTERITY
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4094
	Comments
	Method	GEE
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.1020
	Comments
	Method	GEE
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; 0.0 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline in Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale at UX003 Treatment Week 24
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

Outcome Measure Data

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
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.
Measure Participants	12
Least Squares Mean (Standard Error) [units on a scale]	3.4 (2.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX003 4 mg/kg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1953
	Comments
	Method	GEE
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	3.4
	Confidence Interval	(2-Sided) 95%; -1.8 to 8.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Percentage of Individual Clinical Response (ICR) Responders at UX003 Treatment Week 24
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

Outcome Measure Data

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
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.
Measure Participants	12
Number (95% Confidence Interval) [percentage of participants]	25 833.3%

11. Secondary Outcome

Title	Change From Baseline in Impactful Clinical Problem Total Score at UX003 Treatment Week 24
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

Outcome Measure Data

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
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.
Measure Participants	12
Least Squares Mean (Standard Error) [units on a scale]	-1.2 (0.92)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX003 4 mg/kg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2022
	Comments
	Method	GEE
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-1.2
	Confidence Interval	(2-Sided) 95%; -3.0 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

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
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		UX003 Active Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		2/12 (16.7%)
Immune system disorders
Anaphylactoid reaction	0/9 (0%)		1/12 (8.3%)
Injury, poisoning and procedural complications
Craniocerebral injury	0/9 (0%)		1/12 (8.3%)
Other (Not Including Serious) Adverse Events
	Placebo		UX003 Active Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/9 (100%)		12/12 (100%)
Ear and labyrinth disorders
Ear pain	1/9 (11.1%)		0/12 (0%)
Eye disorders
Eye pain	1/9 (11.1%)		0/12 (0%)
Gastrointestinal disorders
Diarrhoea	0/9 (0%)		3/12 (25%)
Vomiting	2/9 (22.2%)		3/12 (25%)
Abdominal pain	1/9 (11.1%)		1/12 (8.3%)
Abdominal pain lower	0/9 (0%)		1/12 (8.3%)
Abdominal pain upper	0/9 (0%)		1/12 (8.3%)
Abnormal faeces	0/9 (0%)		1/12 (8.3%)
Rectal haemorrhage	0/9 (0%)		1/12 (8.3%)
Cheilosis	1/9 (11.1%)		0/12 (0%)
General disorders
Infusion site extravasation	1/9 (11.1%)		4/12 (33.3%)
Oedema	1/9 (11.1%)		1/12 (8.3%)
Pyrexia	1/9 (11.1%)		1/12 (8.3%)
Catheter site bruise	0/9 (0%)		1/12 (8.3%)
Chills	0/9 (0%)		1/12 (8.3%)
Infusion site bruising	0/9 (0%)		1/12 (8.3%)
Infusion site swelling	0/9 (0%)		1/12 (8.3%)
Peripheral swelling	0/9 (0%)		1/12 (8.3%)
Infusion site discomfort	1/9 (11.1%)		0/12 (0%)
Immune system disorders
Anaphylactoid reaction	0/9 (0%)		1/12 (8.3%)
Seasonal allergy	1/9 (11.1%)		1/12 (8.3%)
Infections and infestations
Upper respiratory tract infection	3/9 (33.3%)		5/12 (41.7%)
Ear infection	1/9 (11.1%)		1/12 (8.3%)
Cellulitis	0/9 (0%)		1/12 (8.3%)
Conjunctivitis	0/9 (0%)		1/12 (8.3%)
Gastrointestinal viral infection	0/9 (0%)		1/12 (8.3%)
Oral herpes	0/9 (0%)		1/12 (8.3%)
Rash pustular	0/9 (0%)		1/12 (8.3%)
Urinary tract infection	0/9 (0%)		1/12 (8.3%)
Otitis media acute	1/9 (11.1%)		0/12 (0%)
Injury, poisoning and procedural complications
Excoriation	1/9 (11.1%)		1/12 (8.3%)
Contusion	0/9 (0%)		1/12 (8.3%)
Post-traumatic neck syndrome	0/9 (0%)		1/12 (8.3%)
Tooth fracture	0/9 (0%)		1/12 (8.3%)
Fall	1/9 (11.1%)		0/12 (0%)
Craniocerebral injury	0/9 (0%)		1/12 (8.3%)
Investigations
Body temperature increased	1/9 (11.1%)		0/12 (0%)
Metabolism and nutrition disorders
Dehydration	0/9 (0%)		1/12 (8.3%)
Decreased appetite	1/9 (11.1%)		0/12 (0%)
Musculoskeletal and connective tissue disorders
Pain in extremity	3/9 (33.3%)		4/12 (33.3%)
Arthralgia	0/9 (0%)		1/12 (8.3%)
Arthritis	0/9 (0%)		1/12 (8.3%)
Joint range of motion decreased	0/9 (0%)		1/12 (8.3%)
Musculoskeletal stiffness	0/9 (0%)		1/12 (8.3%)
Joint swelling	0/9 (0%)		1/12 (8.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma	0/9 (0%)		1/12 (8.3%)
Nervous system disorders
Ataxia	0/9 (0%)		1/12 (8.3%)
Clonus	0/9 (0%)		1/12 (8.3%)
Dysstasia	0/9 (0%)		1/12 (8.3%)
Headache	0/9 (0%)		1/12 (8.3%)
Psychiatric disorders
Post-traumatic stress disorder	0/9 (0%)		1/12 (8.3%)
Depression	1/9 (11.1%)		0/12 (0%)
Insomnia	1/9 (11.1%)		0/12 (0%)
Renal and urinary disorders
Urinary incontinence	0/9 (0%)		1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Cough	2/9 (22.2%)		3/12 (25%)
Dyspnoea exertional	0/9 (0%)		1/12 (8.3%)
Nasal obstruction	0/9 (0%)		1/12 (8.3%)
Productive cough	0/9 (0%)		1/12 (8.3%)
Rhinorrhoea	0/9 (0%)		1/12 (8.3%)
Epistaxis	1/9 (11.1%)		0/12 (0%)
Skin and subcutaneous tissue disorders
Rash	1/9 (11.1%)		3/12 (25%)
Urticaria	1/9 (11.1%)		1/12 (8.3%)
Pruritus	0/9 (0%)		1/12 (8.3%)
Rash macular	1/9 (11.1%)		0/12 (0%)
Rash papular	1/9 (11.1%)		0/12 (0%)
Skin ulcer	1/9 (11.1%)		0/12 (0%)
Vascular disorders
Hypertension	1/9 (11.1%)		0/12 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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. The sponsor cannot require changes to the communication and cannot extend the embargo.