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Extension of Study TKT024 Evaluating Long-Term Safety and Clinical Outcomes in MPS II Patients Receiving Idursulfase

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ClinicalTrials.gov Identifier: NCT00630747
Recruitment Status : Completed
First Posted : March 7, 2008
Results First Posted : March 17, 2014
Last Update Posted : August 7, 2015
Sponsor:
Information provided by (Responsible Party):
Shire

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Hunter Syndrome
Mucopolysaccharidosis II (MPS II)
Intervention Biological: Idursulfase
Enrollment 94
Recruitment Details This study allows participants in double-blind phase of Study TKT024 (NCT00069641), a 1 year Phase 2/3 registration study, to continue long-term idursulfase therapy and to allow placebo participants in TKT024 to receive active idursulfase treatment. The first participant enrolled on 13 Sep 2004. The study was conducted at 52 sites in 17 countries.
Pre-assignment Details Participants were screened for entry based on their known medical histories and previous participation in the TKT024 study. Participants had to have completed Week 53 final evaluations in the TKT024 study. Participants were not to have received any treatment with an investigational therapy other than idursulfase within 60 days of study entry.
Arm/Group Title Idursulfase (0.5 mg/kg, IV, Once-weekly)
Hide Arm/Group Description Idursulfase 0.5 milligram per kilogram (mg/kg) administered by intravenous (IV) infusion once-weekly.
Period Title: Overall Study
Started 94
Participants Treated in Phase I of Study 94
Completed 85
Not Completed 9
Reason Not Completed
Death             1
Transferred to Study TKT031NPU             7
Returned to country of origin             1
Arm/Group Title Idursulfase (0.5 mg/kg, IV, Once-weekly)
Hide Arm/Group Description Idursulfase 0.5 mg/kg administered by IV infusion once-weekly.
Overall Number of Baseline Participants 94
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 94 participants
<=18 years
70
  74.5%
Between 18 and 65 years
24
  25.5%
>=65 years
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 94 participants
14.52  (6.634)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 94 participants
Female
0
   0.0%
Male
94
 100.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 94 participants
Hispanic or Latino
15
  16.0%
Not Hispanic or Latino
79
  84.0%
Unknown or Not Reported
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 94 participants
American Indian or Alaska Native
3
   3.2%
Asian
5
   5.3%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
6
   6.4%
White
78
  83.0%
More than one race
0
   0.0%
Unknown or Not Reported
2
   2.1%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 94 participants
Europe 40
North America 34
South America 20
Baseline Percent Predicted Forced Vital Capacity (FVC)  
Mean (Standard Deviation)
Unit of measure:  Percent predicted FVC
Number Analyzed 94 participants
56.160  (14.897)
Baseline Distance Walked in the 6-minute Walk Test (6MWT)  
Mean (Standard Deviation)
Unit of measure:  Meters (m)
Number Analyzed 94 participants
400.3  (100.25)
Baseline Passive Joint Range of Motion (JROM)   [1] 
Mean (Standard Deviation)
Unit of measure:  Percentage of JROM
Number Analyzed 94 participants
67.44  (9.042)
[1]
Measure Description: Global JROM (% normal range of motion) is the average of 11 ratios multiplied by 100. Ratios are Left/Right means of passive range of motion in Shoulder (Flexion/Extension, Abduction, Internal/External Rotation), Elbow (Flexion/Extension), Wrist (Flexion/Extension), Index Finger (Flexion/Extension [Combined MCP, PIP, DIP motion]), Hip (Flexion/Extension, Abduction, Internal/External Rotation), Knee (Flexion/Extension), and Ankle (Dorsiflexion) divided by the normal range (American Academy of Orthopedic Surgeons and American Medical Association).
Baseline Combined Liver and Spleen Volume  
Mean (Standard Deviation)
Unit of measure:  Cubic centimeters (cc)
Number Analyzed 94 participants
1504.8  (417.21)
Baseline Normalized Urine Glycosaminoglycans (GAG) Levels  
Mean (Standard Deviation)
Unit of measure:  microgram(mcg)GAG/mg creatinine
Number Analyzed 94 participants
361.96  (136.132)
Baseline Cardiac Left Ventricular Mass Index (LVMI)  
Mean (Standard Deviation)
Unit of measure:  Gram per meter^2 (g/m^2)
Number Analyzed 94 participants
97.64  (36.606)
1.Primary Outcome
Title Change From Baseline in Mean Percent Predicted Forced Vital Capacity (FVC) at Week 105
Hide Description Determined by spirometry. The change is calculated as Week 105 minus baseline.
Time Frame Baseline and at Week 105
Hide Outcome Measure Data
Hide Analysis Population Description
All participants for whom percent predicted FVC were recorded at baseline and at Week 105.
Arm/Group Title Idursulfase (0.5 mg/kg, IV, Once-weekly)
Hide Arm/Group Description:
Idursulfase 0.5 mg/kg administered by IV infusion once-weekly.
Overall Number of Participants Analyzed 85
Mean (Standard Error)
Unit of Measure: percent predicted FVC
-0.056  (1.059)
2.Primary Outcome
Title Change From Baseline in Mean Distance Walked in the 6-minute Walk Test (6MWT) at Week 105
Hide Description Determined on a walking course. The change was calculated as Week 105 minus baseline.
Time Frame Baseline and at Week 105
Hide Outcome Measure Data
Hide Analysis Population Description
All participants for whom distance walked was recorded at baseline and at Week 105.
Arm/Group Title Idursulfase (0.5 mg/kg, IV, Once-weekly)
Hide Arm/Group Description:
Idursulfase 0.5 mg/kg administered by IV infusion once-weekly.
Overall Number of Participants Analyzed 85
Mean (Standard Error)
Unit of Measure: meters (m)
23.0  (7.94)
3.Secondary Outcome
Title Change From Baseline in Mean Passive Joint Range of Motion (JROM) at Week 105
Hide Description Change was calculated as Week 105 minus baseline. Global JROM (% normal range of motion) is the average of 11 ratios multiplied by 100. Ratios are Left/Right means of passive range of motion in Shoulder (Flexion/Extension, Abduction, Internal/External Rotation), Elbow (Flexion/Extension), Wrist (Flexion/Extension), Index Finger (Flexion/Extension [Combined Metacarpophalangeal joint (MCP), Proximal interphalangeal joint (PIP), Distal interphalangeal joint (DIP) motion]), Hip (Flexion/Extension, Abduction, Internal/External Rotation), Knee (Flexion/Extension), and Ankle (Dorsiflexion) divided by the normal range (American Academy of Orthopedic Surgeons and American Medical Association).
Time Frame Baseline and at Week 105
Hide Outcome Measure Data
Hide Analysis Population Description
All participants for whom passive JROM were recorded at baseline and at Week 105.
Arm/Group Title Idursulfase (0.5 mg/kg, IV, Once-weekly)
Hide Arm/Group Description:
Idursulfase 0.5 mg/kg administered by IV infusion once-weekly.
Overall Number of Participants Analyzed 84
Mean (Standard Error)
Unit of Measure: percentage of JROM
0.63  (0.640)
4.Secondary Outcome
Title Change From Baseline in Mean Combined Liver and Spleen Volume at Week 105
Hide Description Determined by Magnetic Resonance Imaging (MRI). The change was calculated as Week 105 minus baseline.
Time Frame Baseline and at Week 105
Hide Outcome Measure Data
Hide Analysis Population Description
All participants for whom combined liver and spleen volume were recorded at baseline and at Week 105.
Arm/Group Title Idursulfase (0.5 mg/kg, IV, Once-weekly)
Hide Arm/Group Description:
Idursulfase 0.5 mg/kg administered by IV infusion once-weekly.
Overall Number of Participants Analyzed 79
Mean (Standard Error)
Unit of Measure: cubic centimeters (cc)
-325.5  (36.84)
5.Secondary Outcome
Title Change From Baseline in Mean Normalized Urine Glycosaminoglycans (GAG) Levels at Week 105
Hide Description Determined by urine testing. The change was calculated as Week 105 minus baseline.
Time Frame Baseline and at Week 105
Hide Outcome Measure Data
Hide Analysis Population Description
All participants for whom normalized urine GAG levels were recorded at baseline and at Week 105.
Arm/Group Title Idursulfase (0.5 mg/kg, IV, Once-weekly)
Hide Arm/Group Description:
Idursulfase 0.5 mg/kg administered by IV infusion once-weekly.
Overall Number of Participants Analyzed 87
Mean (Standard Error)
Unit of Measure: mcg GAG/mg creatinine
-238.25  (13.333)
6.Secondary Outcome
Title Change From Baseline in Mean Cardiac Left Ventricular Mass Index (LVMI) at Week 105
Hide Description Determined by echocardiogram. LVMI indexed to body surface area (g/m^2). The change was calculated as Week 105 minus baseline.
Time Frame Baseline and at Week 105
Hide Outcome Measure Data
Hide Analysis Population Description
All participants for whom cardiac LVM were recorded at baseline and at Week 105.
Arm/Group Title Idursulfase (0.5 mg/kg, IV, Once-weekly)
Hide Arm/Group Description:
Idursulfase 0.5 mg/kg administered by IV infusion once-weekly.
Overall Number of Participants Analyzed 71
Mean (Standard Error)
Unit of Measure: g/m^2
3.28  (3.826)
Time Frame Adverse events were assessed throughout the duration of the TKT024EXT study. Adverse events were monitored from the time the first participant signed the informed consent until approximately 30 days after the last study visit.
Adverse Event Reporting Description The "Serious Adverse Events" table lists all serious adverse events that occurred during the study regardless of a relationship to the study drug. The "Other Adverse Events" table lists those non-serious adverse events that were were determined to be possibly related to the study drug.
 
Arm/Group Title Idursulfase (0.5 mg/kg, IV, Once-weekly)
Hide Arm/Group Description Idursulfase 0.5 mg/kg administered by IV infusion once-weekly.
All-Cause Mortality
Idursulfase (0.5 mg/kg, IV, Once-weekly)
Affected / at Risk (%)
Total   --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Idursulfase (0.5 mg/kg, IV, Once-weekly)
Affected / at Risk (%) # Events
Total   38/94 (40.43%)    
Cardiac disorders   
Arrhythmia (Not Otherwise Specified [NOS])  1  1/94 (1.06%)  1
Atrial Fibrillation  1  1/94 (1.06%)  1
Left Ventricular Failure  1  1/94 (1.06%)  1
Pericardial Effusions  1  1/94 (1.06%)  1
Supraventricular Tachycardia  1  1/94 (1.06%)  1
Ear and labyrinth disorders   
Tympanic Membrane Disorder NOS  1  1/94 (1.06%)  1
Gastrointestinal disorders   
Abdominal Hernia  1  1/94 (1.06%)  1
Abdominal Pain NOS  1  2/94 (2.13%)  2
Abdominal Strangulated Hernia  1  2/94 (2.13%)  2
Appendicitis  1  2/94 (2.13%)  2
Diarrhea NOS  1  1/94 (1.06%)  1
Inguinal Hernia NOS  1  1/94 (1.06%)  1
Umbilical Hernia NOS  1  3/94 (3.19%)  3
Vomiting NOS  1  1/94 (1.06%)  1
General disorders   
Catheter Related Complications  1  1/94 (1.06%)  1
Hernia NOS  1  1/94 (1.06%)  1
Infections and infestations   
Bacteraemia  1 [1]  3/94 (3.19%)  3
Bronchopneumonia NOS  1  1/94 (1.06%)  1
Endocarditis Bacterial NOS  1  1/94 (1.06%)  1
Lobar Pneumonia NOS  1  1/94 (1.06%)  1
Otitis Media Chronic NOS  1  2/94 (2.13%)  2
Otitis Media NOS  1  1/94 (1.06%)  1
Otitis Media Serous Chronic NOS  1  1/94 (1.06%)  1
Otitis Media Serous NOS  1  1/94 (1.06%)  1
Pneumonia NOS  1 [2]  3/94 (3.19%)  3
Soft Tissue Infection NOS  1  1/94 (1.06%)  1
Upper Respiratory Tract Infection NOS  1  1/94 (1.06%)  2
Injury, poisoning and procedural complications   
Airway Complication of Anaesthesia  1  1/94 (1.06%)  1
Femur Fracture  1  1/94 (1.06%)  1
Skin Laceration  1  1/94 (1.06%)  1
Musculoskeletal and connective tissue disorders   
Acquired Claw Toe  1  1/94 (1.06%)  1
Joint Contracture  1  2/94 (2.13%)  2
Osteonecrosis  1  1/94 (1.06%)  1
Pain in Foot  1  1/94 (1.06%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Neurilemmoma  1  1/94 (1.06%)  1
Nervous system disorders   
Carpal Tunnel Syndrome  1  7/94 (7.45%)  7
Headache  1  1/94 (1.06%)  1
Hydrocephalus  1  1/94 (1.06%)  1
Hypoaesthesia  1  1/94 (1.06%)  1
Spinal Cord Compression NOS  1  3/94 (3.19%)  4
Psychiatric disorders   
Psychosomatic Disease  1  1/94 (1.06%)  1
Renal and urinary disorders   
Urinary Retention  1  1/94 (1.06%)  1
Respiratory, thoracic and mediastinal disorders   
Asthma Aggravated  1  1/94 (1.06%)  1
Epistaxis  1  1/94 (1.06%)  1
Foreign Body Aspiration  1  1/94 (1.06%)  1
Hypoxia  1  1/94 (1.06%)  2
Obstructive Airways Disorder NOS  1  2/94 (2.13%)  2
Respiratory Distress  1  1/94 (1.06%)  1
Tracheal Stenosis  1  1/94 (1.06%)  1
Skin and subcutaneous tissue disorders   
Rash Macular  1 [3]  1/94 (1.06%)  1
Vascular disorders   
Poor Venous Access  1 [4]  10/94 (10.64%)  10
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (5.1)
[1]
2 events of bacteraemia were at least possibly related to study drug as determined by the investigator.
[2]
1 event of pneumonia NOS was at least possibly related to study drug as determined by the investigator.
[3]
This event of rash macular was at least possibly related to study drug as determined by the investigator.
[4]
1 event of poor venous access was at least possibly related to study drug as determined by the investigator.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Idursulfase (0.5 mg/kg, IV, Once-weekly)
Affected / at Risk (%) # Events
Total   94/94 (100.00%)    
Blood and lymphatic system disorders   
Anaemia nos  1  5/94 (5.32%)  5
Carpal tunnel syndrome  1  19/94 (20.21%)  20
Dizziness  1  18/94 (19.15%)  27
Headache  1  53/94 (56.38%)  296
Hypoaesthesia  1  8/94 (8.51%)  11
Insomnia  1  5/94 (5.32%)  6
Migraine nos  1  5/94 (5.32%)  6
Cardiac disorders   
Atrioventricular block first degree  1  8/94 (8.51%)  9
Dilatation atrial  1  5/94 (5.32%)  6
Tachycardia nos  1  8/94 (8.51%)  24
Ventricular hypertrophy  1  6/94 (6.38%)  6
Ear and labyrinth disorders   
Cerumen impaction  1  13/94 (13.83%)  17
Ear haemorrhage  1  5/94 (5.32%)  5
Ear pain  1  24/94 (25.53%)  34
Otorrhoea  1  27/94 (28.72%)  88
Eye disorders   
Conjunctivitis  1  5/94 (5.32%)  5
Visual acuity reduced  1  5/94 (5.32%)  5
Gastrointestinal disorders   
Abdominal pain nos  1  34/94 (36.17%)  73
Constipation  1  11/94 (11.70%)  15
Diarrhoea nos  1  32/94 (34.04%)  78
Dyspepsia  1  7/94 (7.45%)  19
Flatulence  1  5/94 (5.32%)  5
Gastroenteritis nos  1  10/94 (10.64%)  12
Loose stools  1  5/94 (5.32%)  5
Nausea  1  24/94 (25.53%)  44
Toothache  1  7/94 (7.45%)  9
Umbilical hernia nos  1  5/94 (5.32%)  5
Vomiting nos  1  39/94 (41.49%)  102
General disorders   
Catheter site pain  1  5/94 (5.32%)  5
Chest pain  1  9/94 (9.57%)  19
Fall  1  12/94 (12.77%)  19
Fatigue  1  12/94 (12.77%)  22
Gait abnormal  1  7/94 (7.45%)  8
Influenza like illness  1  11/94 (11.70%)  33
Injection site extravasation  1  6/94 (6.38%)  8
Malaise  1  7/94 (7.45%)  12
Pain nos  1  9/94 (9.57%)  16
Pyrexia  1  57/94 (60.64%)  187
Rigors  1  11/94 (11.70%)  17
Hepatobiliary disorders   
Hepatomegaly  1  5/94 (5.32%)  5
Immune system disorders   
Seasonal allergy  1  6/94 (6.38%)  10
Infections and infestations   
Ear infection nos  1  36/94 (38.30%)  91
Furuncle  1  5/94 (5.32%)  5
Influenza  1  7/94 (7.45%)  11
Localised infection  1  5/94 (5.32%)  5
Lower respiratory tract infection nos  1  7/94 (7.45%)  11
Otitis media nos  1  22/94 (23.40%)  37
Otitis media serous nos  1  7/94 (7.45%)  9
Pneumonia nos  1  7/94 (7.45%)  9
Respiratory tract infection nos  1  6/94 (6.38%)  12
Sinusitis nos  1  9/94 (9.57%)  16
Skin fungal infection nos  1  8/94 (8.51%)  9
Tinea pedis  1  6/94 (6.38%)  21
Tonsillitis  1  6/94 (6.38%)  6
Tooth caries nos  1  7/94 (7.45%)  8
Upper respiratory tract infection nos  1  47/94 (50.00%)  106
Upper respiratory tract infection viral nos  1  9/94 (9.57%)  13
Viral infection nos  1  10/94 (10.64%)  12
Injury, poisoning and procedural complications   
Abrasion nos  1  17/94 (18.09%)  24
Arthropod bite  1  9/94 (9.57%)  11
Head injury  1  9/94 (9.57%)  9
Limb injury nos  1  7/94 (7.45%)  9
Post procedural pain  1  15/94 (15.96%)  25
Thermal burn  1  5/94 (5.32%)  6
Investigations   
Neutrophil count decreased  1  8/94 (8.51%)  8
White blood cell count decreased  1  5/94 (5.32%)  6
Musculoskeletal and connective tissue disorders   
Arthralgia  1  39/94 (41.49%)  81
Back pain  1  23/94 (24.47%)  39
Musculoskeletal stiffness  1  5/94 (5.32%)  7
Myalgia  1  11/94 (11.70%)  13
Neck pain  1  17/94 (18.09%)  24
Pain in foot  1  5/94 (5.32%)  7
Pain in limb  1  29/94 (30.85%)  59
Respiratory, thoracic and mediastinal disorders   
Asthma nos  1  6/94 (6.38%)  7
Bronchitis nos  1  6/94 (6.38%)  7
Bronchospasm nos  1  8/94 (8.51%)  19
Cough  1  53/94 (56.38%)  155
Dyspnoea nos  1  14/94 (14.89%)  24
Epistaxis  1  8/94 (8.51%)  23
Nasal congestion  1  38/94 (40.43%)  100
Nasopharyngitis  1  39/94 (41.49%)  84
Pharyngitis  1  46/94 (48.94%)  102
Productive cough  1  7/94 (7.45%)  11
Rhinitis allergic nos  1  7/94 (7.45%)  9
Rhinitis nos  1  14/94 (14.89%)  20
Rhinorrhoea  1  31/94 (32.98%)  70
Rhonchi  1  5/94 (5.32%)  6
Sneezing  1  6/94 (6.38%)  7
Wheezing  1  15/94 (15.96%)  28
Skin and subcutaneous tissue disorders   
Acne nos  1  14/94 (14.89%)  17
Contusion  1  9/94 (9.57%)  10
Eczema  1  7/94 (7.45%)  9
Erythema  1  11/94 (11.70%)  35
Pruritus  1  11/94 (11.70%)  27
Rash macular  1  6/94 (6.38%)  11
Rash nos  1  20/94 (21.28%)  60
Rash papular  1  6/94 (6.38%)  8
Rash pruritic  1  10/94 (10.64%)  16
Skin lesion nos  1  9/94 (9.57%)  13
Urticaria nos  1  14/94 (14.89%)  54
Vascular disorders   
Flushing  1  9/94 (9.57%)  32
Hypotension NOS  1  6/94 (6.38%)  7
Pallor  1  8/94 (8.51%)  8
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (5.1)
This study design was open-label, and the lack of a concurrently followed placebo group limits the strength of the observations, because the progression of the disease is variable and has not been well described.
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.
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.
Results Point of Contact
Name/Title: Dr. Arian Pano, Medical Director
Organization: Shire Human Genetic Therapies
Phone: 781-482-0875
Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT00630747     History of Changes
Other Study ID Numbers: TKT024EXT
2004-002743-27 ( EudraCT Number )
First Submitted: February 28, 2008
First Posted: March 7, 2008
Results First Submitted: February 27, 2012
Results First Posted: March 17, 2014
Last Update Posted: August 7, 2015