A Study of UX003 Recombinant Human Beta-Glucuronidase (rhGUS) Enzyme Replacement Therapy in Subjects With Mucopolysaccharidosis Type 7, Sly Syndrome (MPS 7)

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ClinicalTrials.gov Identifier: NCT02432144

Recruitment Status : Completed

First Posted : May 1, 2015

Results First Posted : July 30, 2019

Last Update Posted : July 30, 2020

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

Ultragenyx Pharmaceutical Inc

Study Type	Interventional
Study Design	Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Conditions	Sly Syndrome MPS VII Mucopolysaccharidosis Mucopolysaccharidosis VII
Intervention	Drug: UX003
Enrollment	12

Participant Flow

Recruitment Details	Participants with mucopolysaccharidosis VII (MPS 7) who were UX003 treatment-naïve or previously enrolled and treated in a prior clinical study of UX003 could enroll into this treatment and extension study provided all eligibility criteria had been met for a given participant.
Pre-assignment Details	Ten of 12 participants entered this extension study at study Week 0 with ongoing UX003 treatment for the prior 24 or 48 weeks in study UX003-CL301 [NCT02230566]; 2 participants had a large gap between studies (61 weeks between doses).


Arm/Group Title	UX003
Arm/Group Description	4 mg/kg UX003 every other week (QOW...
Arm/Group Description	4 mg/kg UX003 every other week (QOW)
Period Title: Overall Study
Started	12
Completed ^[1]	11
Not Completed	1
Reason Not Completed
Participant Non-Compliance	1
[1] Includes 8 participants who switched to commercially available vestronidase alfa before Week 144.

Baseline Characteristics

Arm/Group Title		UX003
Arm/Group Description		4 mg/kg UX003 QOW
Arm/Group Description		4 mg/kg UX003 QOW
Overall Number of Baseline Participants		12
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	12 participants
		16.56 (5.466)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	12 participants
	Female	8 66.7%
	Male	4 33.3%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	12 participants
	Hispanic or Latino	6 50.0%
	Not Hispanic or Latino	6 50.0%
	Unknown or Not Reported	0 0.0%
Race/Ethnicity, Customized Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	12 participants
White		9 75.0%
Other, Not Specified		3 25.0%
Urinary Glycosaminoglycans (uGAG) Mean (Standard Deviation) Unit of measure: G GAG/g creatinine
	Number Analyzed	12 participants
		1.54848 (0.413237)

Outcome Measures

1.Primary Outcome


Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation
Description	An adverse event (AE) is defined as any untoward medical occurrence, w...
Description	An adverse event (AE) is defined as any untoward medical occurrence, whether or not considered drug related. A serious AE is an AE that at any dose, results in any of the following outcomes: death; a life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; a congenital anomaly/birth defect; or is an important medical event. AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), Grade 5 (death). TEAEs were defined as reported AEs with onset during the treatment.
Time Frame	From first dose of study drug until 30 days after the last dose of study drug. Mean duration of UX003 treatment was 100.5 weeks.

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all enrolled participants who received at least one dose of investigational product in this study.


Arm/Group Title	UX003
Arm/Group Description:	4 mg/kg UX003 QOW
Arm/Group Description:	4 mg/kg UX003 QOW
Overall Number of Participants Analyzed	12
Measure Type: Count of Participants Unit of Measure: Participants
TEAEs	12 100.0%
Serious TEAEs	4 33.3%
Treatment-Related TEAEs	9 75.0%
Treatment-Related Serious TEAEs	1 8.3%
Grade 3 or 4 TEAEs	3 25.0%
TEAEs Leading to Treatment Discontinuation	0 0.0%
TEAEs Leading to Study Discontinuation	0 0.0%
TEAEs Leading to Death	0 0.0%

2.Secondary Outcome


Title	Percent Change From Baseline Over Time in Urinary Glycosaminoglycan (uGAG) Excretion (Liquid Chromatography-Tandem Mass Spectrometry, Dermatan Sulfate)
Description	First morning void urine was evaluated for uGAG concentration and norm...
Description	First morning void urine was evaluated for uGAG concentration and normalized to urinary creatinine concentration.
Time Frame	Baseline (prior to the first dose of study drug in UX003-CL301), Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all enrolled participants who received at least one dose of investigational product in this study; participants with an assessment at given time point.


Arm/Group Title		UX003
Arm/Group Description:		4 mg/kg UX003 QOW
Arm/Group Description:		4 mg/kg UX003 QOW
Overall Number of Participants Analyzed		12
Mean (Standard Deviation) Unit of Measure: percentage change in uGAG excretion
Week 0	Number Analyzed	12 participants
Week 0		-62.19 (16.133)
Week 12	Number Analyzed	11 participants
Week 12		-67.31 (13.953)
Week 24	Number Analyzed	12 participants
Week 24		-64.03 (14.669)
Week 36	Number Analyzed	11 participants
Week 36		-60.58 (23.552)
Week 48	Number Analyzed	10 participants
Week 48		-57.04 (23.611)
Week 60	Number Analyzed	9 participants
Week 60		-72.25 (18.609)
Week 72	Number Analyzed	9 participants
Week 72		-78.52 (10.367)
Week 84	Number Analyzed	8 participants
Week 84		-80.89 (10.023)
Week 96	Number Analyzed	8 participants
Week 96		-82.39 (6.011)
Week 108	Number Analyzed	7 participants
Week 108		-82.19 (6.551)
Week 120	Number Analyzed	5 participants
Week 120		-88.74 (4.023)
Week 132	Number Analyzed	4 participants
Week 132		-89.22 (3.662)
Week 144	Number Analyzed	4 participants
Week 144		-91.62 (1.827)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX003
	Comments	Week 0
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	P-values are from generalized estimating equation (GEE) model including baseline value and visit (in this study) as a categorical variable. The covariance structure within subjects is assumed to be exchangeable.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-62.28
	Confidence Interval	(2-Sided) 95% -71.98 to -52.59
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4.946
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX003
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	P-values are from a GEE model including baseline value and visit (in this study) as a categorical variable. The covariance structure within subjects is assumed to be exchangeable.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-67.18
	Confidence Interval	(2-Sided) 95% -73.49 to -60.86
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.224
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	UX003
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	P-values are from a GEE model including baseline value and visit (in this study) as a categorical variable. The covariance structure within subjects is assumed to be exchangeable.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-64.12
	Confidence Interval	(2-Sided) 95% -71.99 to -56.24
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4.016
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	UX003
	Comments	Week 36
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	P-values are from a GEE model including baseline value and visit (in this study) as a categorical variable. The covariance structure within subjects is assumed to be exchangeable.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-60.80
	Confidence Interval	(2-Sided) 95% -72.54 to -49.06
	Parameter Dispersion	Type: Standard Error of the Mean Value: 5.992
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	UX003
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	P-values are from a GEE model including baseline value and visit (in this study) as a categorical variable. The covariance structure within subjects is assumed to be exchangeable.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-57.85
	Confidence Interval	(2-Sided) 95% -71.87 to -43.82
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	From first dose of study drug until 30 days after the last dose of study drug. Mean duration of UX003 treatment was 100.5 weeks.
Adverse Event Reporting Description	TEAEs, defined as reported AEs with onset during the treatment, are presented.

Arm/Group Title	UX003
Arm/Group Description	4 mg/kg UX003 QOW
Arm/Group Description	4 mg/kg UX003 QOW
All-Cause Mortality
	UX003
	Affected / at Risk (%)
Total	0/12 (0.00%)
Serious Adverse Events Serious Adverse Events
	UX003
	Affected / at Risk (%)
Total	4/12 (33.33%)
Infections and infestations
Gastroenteritis ^† 1	1/12 (8.33%)
Injury, poisoning and procedural complications
Head Injury ^† 1	1/12 (8.33%)
Nervous system disorders
Headache ^† 1	1/12 (8.33%)
Respiratory, thoracic and mediastinal disorders
Asthmatic Crisis ^† 1	1/12 (8.33%)
Bronchospasm ^† 1	1/12 (8.33%)
Interstitial Lung Disease ^† 1	1/12 (8.33%)
Skin and subcutaneous tissue disorders
Urticaria ^† 1	1/12 (8.33%)
1 Term from vocabulary, MedDRA 19.0 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	UX003
	Affected / at Risk (%)
Total	12/12 (100.00%)
Blood and lymphatic system disorders
Eosinophilia ^† 1	1/12 (8.33%)
Cardiac disorders
Pericardial Effusion ^† 1	1/12 (8.33%)
Tachycardia ^† 1	1/12 (8.33%)
Ear and labyrinth disorders
Ear Pain ^† 1	2/12 (16.67%)
Otorrhoea ^† 1	1/12 (8.33%)
Eye disorders
Conjunctivitis Allergic ^† 1	2/12 (16.67%)
Eye Pruritus ^† 1	1/12 (8.33%)
Lacrimation Increased ^† 1	1/12 (8.33%)
Gastrointestinal disorders
Aphthous Ulcer ^† 1	1/12 (8.33%)
Diarrhoea ^† 1	2/12 (16.67%)
Dyspepsia ^† 1	1/12 (8.33%)
Gastrooesophageal Reflux Disease ^† 1	3/12 (25.00%)
Gingival Bleeding ^† 1	1/12 (8.33%)
Haematochezia ^† 1	1/12 (8.33%)
Lip Ulceration ^† 1	1/12 (8.33%)
Nausea ^† 1	2/12 (16.67%)
Oesophagitis ^† 1	1/12 (8.33%)
Tooth Discolouration ^† 1	1/12 (8.33%)
Tooth Loss ^† 1	1/12 (8.33%)
Toothache ^† 1	1/12 (8.33%)
Vomiting ^† 1	4/12 (33.33%)
General disorders
Chest Pain ^† 1	1/12 (8.33%)
Fatigue ^† 1	1/12 (8.33%)
Gait Disturbance ^† 1	1/12 (8.33%)
Infusion Site Extravasation ^† 1	5/12 (41.67%)
Infusion Site Swelling ^† 1	2/12 (16.67%)
Oedema Peripheral ^† 1	2/12 (16.67%)
Pyrexia ^† 1	2/12 (16.67%)
Immune system disorders
Seasonal Allergy ^† 1	1/12 (8.33%)
Infections and infestations
Abscess Neck ^† 1	1/12 (8.33%)
Acarodermatitis ^† 1	1/12 (8.33%)
Conjunctivitis ^† 1	1/12 (8.33%)
Ear Infection ^† 1	2/12 (16.67%)
Folliculitis ^† 1	1/12 (8.33%)
Furuncle ^† 1	1/12 (8.33%)
Impetigo ^† 1	1/12 (8.33%)
Nasopharyngitis ^† 1	2/12 (16.67%)
Otitis Externa ^† 1	1/12 (8.33%)
Otitis Media ^† 1	1/12 (8.33%)
Otitis Media Acute ^† 1	2/12 (16.67%)
Pharyngitis ^† 1	1/12 (8.33%)
Rhinitis ^† 1	3/12 (25.00%)
Root Canal Infection ^† 1	1/12 (8.33%)
Sinusitis ^† 1	1/12 (8.33%)
Soft Tissue Infection ^† 1	1/12 (8.33%)
Tinea Pedis ^† 1	1/12 (8.33%)
Tooth Infection ^† 1	1/12 (8.33%)
Upper Respiratory Tract Infection ^† 1	7/12 (58.33%)
Viral Infection ^† 1	1/12 (8.33%)
Injury, poisoning and procedural complications
Arthropod Bite ^† 1	1/12 (8.33%)
Fall ^† 1	1/12 (8.33%)
Head Injury ^† 1	1/12 (8.33%)
Laceration ^† 1	1/12 (8.33%)
Ligament Sprain ^† 1	2/12 (16.67%)
Skin Abrasion ^† 1	2/12 (16.67%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	2/12 (16.67%)
Back Pain ^† 1	1/12 (8.33%)
Dactylitis ^† 1	1/12 (8.33%)
Joint Range Of Motion Decreased ^† 1	1/12 (8.33%)
Joint Stiffness ^† 1	1/12 (8.33%)
Joint Swelling ^† 1	1/12 (8.33%)
Muscle Twitching ^† 1	1/12 (8.33%)
Pain In Extremity ^† 1	2/12 (16.67%)
Scoliosis ^† 1	1/12 (8.33%)
Spinal Instability ^† 1	1/12 (8.33%)
Trigger Finger ^† 1	1/12 (8.33%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acrochordon ^† 1	1/12 (8.33%)
Skin Papilloma ^† 1	1/12 (8.33%)
Nervous system disorders
Brain Compression ^† 1	1/12 (8.33%)
Cervical Cord Compression ^† 1	1/12 (8.33%)
Headache ^† 1	2/12 (16.67%)
Hydrocephalus ^† 1	1/12 (8.33%)
Lethargy ^† 1	2/12 (16.67%)
Memory Impairment ^† 1	1/12 (8.33%)
Paraesthesia ^† 1	1/12 (8.33%)
Sensory Disturbance ^† 1	1/12 (8.33%)
Sinus Headache ^† 1	1/12 (8.33%)
Psychiatric disorders
Insomnia ^† 1	1/12 (8.33%)
Somnambulism ^† 1	1/12 (8.33%)
Renal and urinary disorders
Pollakiuria ^† 1	2/12 (16.67%)
Respiratory, thoracic and mediastinal disorders
Asthma ^† 1	1/12 (8.33%)
Bronchospasm ^† 1	1/12 (8.33%)
Cough ^† 1	4/12 (33.33%)
Epistaxis ^† 1	1/12 (8.33%)
Nasal Congestion ^† 1	3/12 (25.00%)
Rhinitis Allergic ^† 1	2/12 (16.67%)
Rhinorrhoea ^† 1	2/12 (16.67%)
Sinus Congestion ^† 1	1/12 (8.33%)
Sleep Apnoea Syndrome ^† 1	1/12 (8.33%)
Upper Respiratory Tract Congestion ^† 1	2/12 (16.67%)
Skin and subcutaneous tissue disorders
Dermatitis ^† 1	1/12 (8.33%)
Dermatitis Atopic ^† 1	1/12 (8.33%)
Erythema ^† 1	1/12 (8.33%)
Macule ^† 1	1/12 (8.33%)
Papule ^† 1	1/12 (8.33%)
Pruritus ^† 1	1/12 (8.33%)
Rash ^† 1	2/12 (16.67%)
Rash Maculo-Papular ^† 1	1/12 (8.33%)
Rash Papular ^† 1	2/12 (16.67%)
Rash Pruritic ^† 1	1/12 (8.33%)
Urticaria ^† 1	4/12 (33.33%)
Vascular disorders
Hypertension ^† 1	1/12 (8.33%)
Hypotension ^† 1	1/12 (8.33%)
1 Term from vocabulary, MedDRA 19.0 † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

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

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

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Medical Information
Organization:	Ultragenyx Pharmaceutical Inc
Phone:	1-888-756-8567
EMail:	medinfo@ultragenyx.com

Publications of Results:

Wang RY, da Silva Franco JF, Lopez-Valdez J, Martins E, Sutton VR, Whitley CB, Zhang L, Cimms T, Marsden D, Jurecka A, Harmatz P. The long-term safety and efficacy of vestronidase alfa, rhGUS enzyme replacement therapy, in subjects with mucopolysaccharidosis VII. Mol Genet Metab. 2020 Mar;129(3):219-227. doi: 10.1016/j.ymgme.2020.01.003. Epub 2020 Jan 11. Erratum In: Mol Genet Metab. 2020 Sep - Oct;131(1-2):285.

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

Tandon PK, Kakkis ED. The multi-domain responder index: a novel analysis tool to capture a broader assessment of clinical benefit in heterogeneous complex rare diseases. Orphanet J Rare Dis. 2021 Apr 19;16(1):183. doi: 10.1186/s13023-021-01805-5.

Layout table for additonal information

Responsible Party:	Ultragenyx Pharmaceutical Inc
ClinicalTrials.gov Identifier:	NCT02432144
Other Study ID Numbers:	UX003-CL202 2015-001875-32 ( EudraCT Number )
First Submitted:	April 22, 2015
First Posted:	May 1, 2015
Results First Submitted:	July 10, 2019
Results First Posted:	July 30, 2019
Last Update Posted:	July 30, 2020

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