An Observational Study Evaluating Anti-Idursulfase Serum Antibody Response in Hunter Syndrome Patients

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00882921
• Collaborator: (none)
• Enrollment: 26
• Locations: 6
• Actual Duration (Months): 51.8
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The objective of this study is to evaluate the effect of anti-idursulfase antibodies on idursulfase safety (measured by infusion related adverse events) between patients who develop anti-idursulfase antibodies and patients who do not after long-term idursulfase enzyme replacement therapy (ERT).

Condition or Disease	Intervention/Treatment	Phase
Hunter Syndrome	Biological: Idursulfase

Detailed Description

This study is being conducted to satisfy post-marketing commitments to monitor anti-idursulfase antibody development in Hunter syndrome patients after long-term idursulfase enzyme replacement therapy. The study will be conducted as a sub-study within the Hunter Outcome Survey (HOS). Hunter syndrome patients in the HOS who have previously received idursulfase as well as treatment-naive patients who will begin idursulfase treatment within 30 days of study enrollment will be included.

Study Design

• Study Type: Observational
• Actual Enrollment: 26 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: A Multi-Center Observational Study Evaluating Anti-Idursulfase Serum Antibody Response in Hunter Syndrome Patients Enrolled in the Hunter Outcome Survey (HOS) Receiving Idursulfase Enzyme Replacement Therapy
• Actual Study Start Date: Oct 14, 2008
• Actual Primary Completion Date: Feb 8, 2013
• Actual Study Completion Date: Feb 8, 2013

Arms and Interventions

Arm	Intervention/Treatment
Elaprase Idursulfase 0.5 mg/kg Weekly	Biological: Idursulfase; Patients received idursulfase as prescribed by their physician following locally approved prescribing information. Patients will not be provided idursulfase by Shire Human Genetic Therapies, Inc. or the HOS.; Other Names: Elaprase

Outcome Measures

Primary Outcome Measures

1. Infusion-Related Adverse Event (IRAE) Rates Between IgG Anti-idursulfase Antibody Positive (Ab+) and Anti-idursulfase IgG Antibody Negative (Ab-) Patients [Baseline to 109 Weeks]

   The primary analysis of how presence of antibodies affected IRAE rates was performed based on a negative binomial regression model. This was done to account for potentially differential follow-up time between antibody groups.

Secondary Outcome Measures

1. Change From Baseline in uGAG Levels to 109 Weeks [Baseline to 109 Weeks]

   Urine GAG

Eligibility Criteria

Criteria

• Ages Eligible for Study: 5 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Patients must meet all of the following criteria to be considered eligible for enrollment:

• The patient is male and enrolled in the HOS (i.e., meets the entry criteria of a documented diagnosis of Hunter syndrome)

• The patient is ≥ 5 years-old

• The patient is on idursulfase treatment or scheduled to begin idursulfase treatment within 30 days of study enrollment

• The patient, patient's parent(s), or patient's legally authorized guardian must have voluntarily signed an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved informed consent form after all relevant aspects of the study have been explained and discussed with the patient, patient's parent(s), or patient's legally authorized guardian.

Exclusion Criteria:

Patients who meet any of the following criteria are not eligible for this study:

• The patient has received biologic/ERT products other than idursulfase, or other investigational product(s) for any reason within 30 days prior to study entry.

• The patient has a life expectancy of < 2 years

• The patient is unable to comply with the protocol, e.g., has a clinically relevant medical condition making implementation of the protocol difficult; has an uncooperative attitude; is unable to return for safety evaluations; or is otherwise unlikely to complete the study, as determined by the Investigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital & Research Center Oakland	Oakland	California	United States	94609
2	Children's Hospitals and Clinics of Minnesota, Division of Genetics	Minneapolis	Minnesota	United States	55404
3	Hospital de Clinicas de Porto Alegre, Servico de Genetica Medica	Porto Alegre	RS	Brazil	90035-903
4	Birmingham Children's Hospital	Birmingham		United Kingdom	B46NH
5	Great Ormond Street Hospital	London		United Kingdom	WC1N 3JH
6	Central Manchester University Hospitals, St. Mary's Hospital	Manchester		United Kingdom	M139WL

Sponsors and Collaborators

• Shire

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT00882921
• Other Study ID Numbers: HGT-ELA-042
• First Posted: Apr 17, 2009
• Last Update Posted: Jun 8, 2021
• Last Verified: May 1, 2021

• Keywords provided by Shire: MPS 2; MPSII; hunter's disease treatment; enzyme replacement therapy; hunter's disease; iduronate 2 sulfatase; mps diagnosis; mps symptoms; iduronate sulfatase; MPS II treatment; chronic ear infection; hunters syndrome; mps ii therapy; MPS2; hunter's syndrome; Hunter syndrome; elaprase; lysosomal storage disease; hunter syndrome therapy; mps society; hunter syndrome treatment; hunter's syndrome treatment; mucopolysaccharides; mps ii; idursulfase; hunters disease; enlarged adenoids; ert treatment; hunter disease; lysosomal storage disorder
• Additional relevant MeSH terms: Mucopolysaccharidosis II; Syndrome

Study Results

Participant Flow

Arm/Group Title	Elaprase® (0.5 mg/kg)
Arm/Group Description
Period Title: Overall Study
STARTED	26
COMPLETED	15
NOT COMPLETED	11

Baseline Characteristics

Arm/Group Title	Elaprase® (0.5 mg/kg)
Arm/Group Description
Overall Participants	26
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	12.82 (8.012)
Age, Customized (Count of Participants)
<12 years	17 65.4%
≥12 Years	9 34.6%
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	26 100%
Region of Enrollment (Count of Participants)
BRAZIL	6 23.1%
UNITED KINGDOM	14 53.8%
UNITED STATES	6 23.1%

Outcome Measures

1. Primary Outcome

Title	Infusion-Related Adverse Event (IRAE) Rates Between IgG Anti-idursulfase Antibody Positive (Ab+) and Anti-idursulfase IgG Antibody Negative (Ab-) Patients
Description	The primary analysis of how presence of antibodies affected IRAE rates was performed based on a negative binomial regression model. This was done to account for potentially differential follow-up time between antibody groups.
Time Frame	Baseline to 109 Weeks

Outcome Measure Data

Analysis Population Description

The Safety Population was defined as all enrolled patients who received any portion of a dose of Elaprase.

Arm/Group Title	Idursulfase (Elaprase) 0.5 mg/kg Weekly
Arm/Group Description	Idursulfase: Patients will receive idursulfase as prescribed by their physician following locally approved prescribing information. Patients will not be provided idursulfase by Shire or the HOS.
Measure Participants	26
Ab+ (n =13)	0.0121
Ab- (n = 13)	0.0042
Ab+ (age adjusted)(n = 13)	0.0055
Ab- (age adjusted)(n = 13)	0.0026

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Idursulfase (Elaprase) 0.5 mg/kg Weekly
	Comments	The groups compared are Ab+ vs Ab-
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1309
	Comments
	Method	Negative Binomial Model
	Comments
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	2.873
	Confidence Interval	(2-Sided) 95%; 0.731 to 11.296
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Idursulfase (Elaprase) 0.5 mg/kg Weekly
	Comments	The groups compared are Ab+ (age adjusted) vs Ab- (age adjusted)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2718
	Comments
	Method	Negative Binomial Model
	Comments
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	2.082
	Confidence Interval	(2-Sided) 95%; 0.563 to 7.706
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in uGAG Levels to 109 Weeks
Description	Urine GAG
Time Frame	Baseline to 109 Weeks

Outcome Measure Data

Analysis Population Description

The Safety Population was defined as all enrolled patients who received any portion of a dose of Elaprase. The primary analysis of how presence of antibodies affected IRAE rates was performed based on a negative binomial regression model. This was done to account for potentially differential follow-up time between antibody groups.

Arm/Group Title	Elaprase
Arm/Group Description	Idursulfase 0.5 mg/kg Weekly Idursulfase: Patients will receive idursulfase as prescribed by their physician following locally approved prescribing information. Patients will not be provided idursulfase by Shire or the HOS.
Measure Participants	15
Mean (Standard Deviation) [mcg/mg]	-74.07 (246.663)

Adverse Events

Arm/Group Title	Elaprase® (0.5 mg/kg)
Arm/Group Description
All Cause Mortality
	Elaprase® (0.5 mg/kg)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Elaprase® (0.5 mg/kg)
	Affected / at Risk (%)	# Events
Total	16/26 (61.5%)
Congenital, familial and genetic disorders
Arnold-Chiari malformation	1/26 (3.8%)	1
Gastrointestinal disorders
Abdominal distension	1/26 (3.8%)	1
Abdominal pain	1/26 (3.8%)	2
Dental caries	1/26 (3.8%)	1
Inguinal hernia, obstructive	1/26 (3.8%)	1
General disorders
Hernia obstructive	1/26 (3.8%)	1
Multi-organ failure	1/26 (3.8%)	1
Pain	1/26 (3.8%)	1
Infections and infestations
Central line infection	2/26 (7.7%)	2
Lower respiratory tract infection	3/26 (11.5%)	3
Pneumonia	1/26 (3.8%)	1
Upper respiratory tract infection	2/26 (7.7%)	2
Injury, poisoning and procedural complications
Seroma	1/26 (3.8%)	1
Investigations
Brain stem auditory evoked response	1/26 (3.8%)	1
Musculoskeletal and connective tissue disorders
Cervical spinal stenosis	1/26 (3.8%)	1
Nervous system disorders
Carpal tunnel syndrome	2/26 (7.7%)	3
Convulsion	5/26 (19.2%)	6
Grand mal convulsion	1/26 (3.8%)	1
Hydrocephalus	1/26 (3.8%)	1
Neurological decompensation	1/26 (3.8%)	1
Syringomyelia	1/26 (3.8%)	1
Psychiatric disorders
Agitation	2/26 (7.7%)	2
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/26 (3.8%)	1
Bronchial hyperreactivity	1/26 (3.8%)	1
Dysphonia	1/26 (3.8%)	1
Increased upper airway secretion	1/26 (3.8%)	1
Respiratory distress	1/26 (3.8%)	1
Respiratory failure	1/26 (3.8%)	1
Respiratory tract congestion	1/26 (3.8%)	1
Sleep apnoea syndrome	1/26 (3.8%)	1
Surgical and medical procedures
Aortic valve replacement	1/26 (3.8%)	1
Catheterisation venous	1/26 (3.8%)	1
Gastrostomy tube insertion	1/26 (3.8%)	1
Spinal operation	1/26 (3.8%)	1
Tonsillectomy	1/26 (3.8%)	1
Other (Not Including Serious) Adverse Events
	Elaprase® (0.5 mg/kg)
	Affected / at Risk (%)	# Events
Total	24/26 (92.3%)
Ear and labyrinth disorders
Deafness	2/26 (7.7%)	2
Ear pain	3/26 (11.5%)	9
Eye disorders
Eye pruritus	2/26 (7.7%)	2
Eye swelling	2/26 (7.7%)	2
Gastrointestinal disorders
Abdominal pain	4/26 (15.4%)	4
Constipation	6/26 (23.1%)	8
Diarrhoea	6/26 (23.1%)	11
Gastrooesophageal reflux disease	2/26 (7.7%)	2
Nausea	2/26 (7.7%)	2
Vomiting	6/26 (23.1%)	13
General disorders
Adverse drug reaction	2/26 (7.7%)	5
Asthenia	2/26 (7.7%)	2
Catheter related complication	3/26 (11.5%)	7
Fatigue	3/26 (11.5%)	3
Gait disturbance	2/26 (7.7%)	2
Influenza like illness	2/26 (7.7%)	2
Infusion site extravasation	2/26 (7.7%)	5
Pain	2/26 (7.7%)	2
Pyrexia	14/26 (53.8%)	43
Immune system disorders
Seasonal allergy	2/26 (7.7%)	2
Infections and infestations
Balanitis candida	2/26 (7.7%)	3
Catheter site infection	2/26 (7.7%)	3
Central line infection	2/26 (7.7%)	2
Ear infection	9/26 (34.6%)	20
Gastroenteritis	4/26 (15.4%)	4
Influenza	4/26 (15.4%)	8
Lower respiratory tract infection	9/26 (34.6%)	23
Nasopharyngitis	3/26 (11.5%)	9
Oral candidiasis	3/26 (11.5%)	5
Otitis externa	4/26 (15.4%)	5
Otitis media	3/26 (11.5%)	4
Pharyngitis	2/26 (7.7%)	4
Staphylococcal infection	2/26 (7.7%)	2
Upper respiratory tract infection	12/26 (46.2%)	25
Injury, poisoning and procedural complications
Contusion	3/26 (11.5%)	4
Fall	9/26 (34.6%)	14
Post procedural haemorrhage	2/26 (7.7%)	2
Investigations
Body temperature increased	2/26 (7.7%)	5
Musculoskeletal and connective tissue disorders
Arthralgia	7/26 (26.9%)	10
Back pain	5/26 (19.2%)	5
Mobility decreased	2/26 (7.7%)	2
Musculoskeletal pain	3/26 (11.5%)	3
Musculoskeletal stiffness	2/26 (7.7%)	2
Pain in extremity	4/26 (15.4%)	7
Nervous system disorders
Carpal tunnel syndrome	2/26 (7.7%)	2
Convulsion	6/26 (23.1%)	53
Dizziness	3/26 (11.5%)	4
Grand mal convulsion	2/26 (7.7%)	7
Headache	6/26 (23.1%)	31
Paraesthesia	2/26 (7.7%)	4
Petit mal epilepsy	5/26 (19.2%)	6
Poor quality sleep	2/26 (7.7%)	2
Somnolence	2/26 (7.7%)	2
Psychiatric disorders
Agitation	2/26 (7.7%)	2
Insomnia	3/26 (11.5%)	4
Respiratory, thoracic and mediastinal disorders
Choking	2/26 (7.7%)	2
Cough	11/26 (42.3%)	25
Epistaxis	2/26 (7.7%)	6
Obstructive airways disorder	2/26 (7.7%)	2
Oropharyngeal pain	6/26 (23.1%)	9
Productive cough	3/26 (11.5%)	3
Rales	2/26 (7.7%)	4
Rhinorrhoea	5/26 (19.2%)	9
Sleep apnoea syndrome	3/26 (11.5%)	3
Upper respiratory tract congestion	2/26 (7.7%)	2
Wheezing	2/26 (7.7%)	3
Skin and subcutaneous tissue disorders
Rash	6/26 (23.1%)	6
Skin chapped	2/26 (7.7%)	2
Surgical and medical procedures
Central venous catheter removal	2/26 (7.7%)	2
Vascular disorders
Flushing	2/26 (7.7%)	5
Hypertension	2/26 (7.7%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Shire's agreements with investigators vary. All agreements provide Shire the right to embargo communications regarding trial results prior to public release for a period ≤180 days from the time submitted to Shire for review. Shire does not prohibit publication, but can require the removal of confidential information (excluding trial results) and can request postponement of a single-center publication until after disclosure of the trial's multi-center publication.