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Immune Tolerance Study With Aldurazyme® (Laronidase)

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ClinicalTrials.gov Identifier: NCT00741338
Recruitment Status : Completed
First Posted : August 26, 2008
Results First Posted : July 2, 2014
Last Update Posted : July 2, 2014
Sponsor:
Collaborator:
BioMarin/Genzyme LLC
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Mucopolysaccharidosis I
Interventions Biological: Laronidase
Drug: Cyclosporine A (CsA)
Drug: Azathioprine (Aza)
Enrollment 7
Recruitment Details The study was conducted at 2 centers in Brazil and Russia between September 2008 and September 2013.
Pre-assignment Details A total of 7 participants were enrolled, 3 in Cohort 1 and 4 in Cohort 2. Of the 4 participants enrolled in Cohort 2, one participant was screen failure.
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description Tolerance Induction Period (TIP): Cyclosporine A (CsA) starting at 5 milligram per kilogram (mg/kg) orally three times daily until the target trough concentration of at least 350 nanogram per milliliter (ng/mL) (preferably 400 ng/mL) achieved along with azathioprine (Aza) 2.5 mg/kg/day orally. Once target CsA trough level achieved and maintained for at least 1 week, participants received laronidase 0.058 mg/kg (low-dose) once weekly intravenous (IV) infusion (starting from Day 1) up to Week 12. CsA and Aza were gradually discontinued. Immune Challenge Period (ICP): following TIP, laronidase dose increased to 0.12 mg/kg once weekly IV infusion for 1 week followed by 0.25 mg/kg once weekly IV infusion for 1 week and then 0.58 mg/kg (full-dose) once weekly IV infusion up to Week 39. TIP: CsA starting at 6.7 mg/kg orally three times daily until the target trough concentration of at least 350 ng/mL (preferably 400 ng/mL) achieved along with Aza 5 mg/kg orally every other day. Once target CsA trough level achieved and maintained for at least 1 week, participants received laronidase 0.058 mg/kg (low-dose) once weekly IV infusion (starting from Day 1) up to Week 18. CsA and Aza were gradually discontinued. ICP: following TIP, laronidase dose increased to 0.12 mg/kg once weekly IV infusion for 1 week followed by 0.25 mg/kg once weekly IV infusion for 1 week and then 0.58 mg/kg (full-dose) once weekly IV infusion up to Week 45.
Period Title: Overall Study
Started 3 3
Completed 3 2
Not Completed 0 1
Reason Not Completed
Adverse Event             0             1
Arm/Group Title Cohort 1 Cohort 2 Total
Hide Arm/Group Description Tolerance Induction Period (TIP): Cyclosporine A (CsA) starting at 5 milligram per kilogram (mg/kg) orally three times daily until the target trough concentration of at least 350 nanogram per milliliter (ng/mL) (preferably 400 ng/mL) achieved along with azathioprine (Aza) 2.5 mg/kg/day orally. Once target CsA trough level achieved and maintained for at least 1 week, participants received laronidase 0.058 mg/kg (low-dose) once weekly intravenous (IV) infusion (starting from Day 1) up to Week 12. CsA and Aza were gradually discontinued. Immune Challenge Period (ICP): following TIP, laronidase dose increased to 0.12 mg/kg once weekly IV infusion for 1 week followed by 0.25 mg/kg once weekly IV infusion for 1 week and then 0.58 mg/kg (full-dose) once weekly IV infusion up to Week 39. TIP: CsA starting at 6.7 mg/kg orally three times daily until the target trough concentration of at least 350 ng/mL (preferably 400 ng/mL) achieved along with Aza 5 mg/kg orally every other day. Once target CsA trough level achieved and maintained for at least 1 week, participants received laronidase 0.058 mg/kg (low-dose) once weekly IV infusion (starting from Day 1) up to Week 18. CsA and Aza were gradually discontinued. ICP: following TIP, laronidase dose increased to 0.12 mg/kg once weekly IV infusion for 1 week followed by 0.25 mg/kg once weekly IV infusion for 1 week and then 0.58 mg/kg (full-dose) once weekly IV infusion up to Week 45. Total of all reporting groups
Overall Number of Baseline Participants 3 4 7
Hide Baseline Analysis Population Description
Analysis population included all enrolled participants, including 1 participant who was screen failure.
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 3 participants 4 participants 7 participants
2.60
(1.8 to 3.5)
3.77
(3.0 to 4.2)
3.18
(1.8 to 4.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 4 participants 7 participants
Female
2
  66.7%
0
   0.0%
2
  28.6%
Male
1
  33.3%
4
 100.0%
5
  71.4%
1.Primary Outcome
Title Number of Participants Who Achieved Immune Tolerance Induction
Hide Description Immune tolerance induction success was defined as development of an anti-laronidase immunoglobulin G (IgG) antibody titer less than or equal to (<=) 1:3200 after 24 weeks of receiving full-dose (0.58 mg/kg) laronidase therapy.
Time Frame 24 weeks after start of full-dose laronidase therapy
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who received any study drug treatment.
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:
Tolerance Induction Period (TIP): Cyclosporine A (CsA) starting at 5 milligram per kilogram (mg/kg) orally three times daily until the target trough concentration of at least 350 nanogram per milliliter (ng/mL) (preferably 400 ng/mL) achieved along with azathioprine (Aza) 2.5 mg/kg/day orally. Once target CsA trough level achieved and maintained for at least 1 week, participants received laronidase 0.058 mg/kg (low-dose) once weekly intravenous (IV) infusion (starting from Day 1) up to Week 12. CsA and Aza were gradually discontinued. Immune Challenge Period (ICP): following TIP, laronidase dose increased to 0.12 mg/kg once weekly IV infusion for 1 week followed by 0.25 mg/kg once weekly IV infusion for 1 week and then 0.58 mg/kg (full-dose) once weekly IV infusion up to Week 39.
TIP: CsA starting at 6.7 mg/kg orally three times daily until the target trough concentration of at least 350 ng/mL (preferably 400 ng/mL) achieved along with Aza 5 mg/kg orally every other day. Once target CsA trough level achieved and maintained for at least 1 week, participants received laronidase 0.058 mg/kg (low-dose) once weekly IV infusion (starting from Day 1) up to Week 18. CsA and Aza were gradually discontinued. ICP: following TIP, laronidase dose increased to 0.12 mg/kg once weekly IV infusion for 1 week followed by 0.25 mg/kg once weekly IV infusion for 1 week and then 0.58 mg/kg (full-dose) once weekly IV infusion up to Week 45.
Overall Number of Participants Analyzed 3 3
Measure Type: Number
Unit of Measure: participants
0 1
2.Secondary Outcome
Title Percent Reduction of Urinary Glycosaminoglycan (uGAG) Level From Baseline to the End of Treatment/Early Withdrawal
Hide Description Urinary Glycosaminoglycan (uGAG) Levels: concentration of glycosaminoglycan (GAG) relative to creatinine in urine. A greater decrease in uGAG level indicates a greater response.
Time Frame Baseline, end of treatment/early withdrawal (up to 24 weeks after start of full-dose laronidase therapy)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who received any study drug treatment.
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:
Tolerance Induction Period (TIP): Cyclosporine A (CsA) starting at 5 milligram per kilogram (mg/kg) orally three times daily until the target trough concentration of at least 350 nanogram per milliliter (ng/mL) (preferably 400 ng/mL) achieved along with azathioprine (Aza) 2.5 mg/kg/day orally. Once target CsA trough level achieved and maintained for at least 1 week, participants received laronidase 0.058 mg/kg (low-dose) once weekly intravenous (IV) infusion (starting from Day 1) up to Week 12. CsA and Aza were gradually discontinued. Immune Challenge Period (ICP): following TIP, laronidase dose increased to 0.12 mg/kg once weekly IV infusion for 1 week followed by 0.25 mg/kg once weekly IV infusion for 1 week and then 0.58 mg/kg (full-dose) once weekly IV infusion up to Week 39.
TIP: CsA starting at 6.7 mg/kg orally three times daily until the target trough concentration of at least 350 ng/mL (preferably 400 ng/mL) achieved along with Aza 5 mg/kg orally every other day. Once target CsA trough level achieved and maintained for at least 1 week, participants received laronidase 0.058 mg/kg (low-dose) once weekly IV infusion (starting from Day 1) up to Week 18. CsA and Aza were gradually discontinued. ICP: following TIP, laronidase dose increased to 0.12 mg/kg once weekly IV infusion for 1 week followed by 0.25 mg/kg once weekly IV infusion for 1 week and then 0.58 mg/kg (full-dose) once weekly IV infusion up to Week 45.
Overall Number of Participants Analyzed 3 3
Median (Full Range)
Unit of Measure: percent change in uGAG level
-43.80
(-61.70 to -6.70)
-72.50
(-84.20 to -62.50)
Time Frame From signature of informed consent up to 30 days after end of treatment/early withdrawal (end of treatment/early withdrawal: up to 24 weeks after start of full-dose laronidase therapy).
Adverse Event Reporting Description Analysis was performed on safety population. In the event a single participant has experienced both a serious and a non-serious form of the same adverse event term, the individual has been included in the numerator ("number of affected participants") of both adverse event tables.
 
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description Tolerance Induction Period (TIP): Cyclosporine A (CsA) starting at 5 milligram per kilogram (mg/kg) orally three times daily until the target trough concentration of at least 350 nanogram per milliliter (ng/mL) (preferably 400 ng/mL) achieved along with azathioprine (Aza) 2.5 mg/kg/day orally. Once target CsA trough level achieved and maintained for at least 1 week, participants received laronidase 0.058 mg/kg (low-dose) once weekly intravenous (IV) infusion (starting from Day 1) up to Week 12. CsA and Aza were gradually discontinued. Immune Challenge Period (ICP): following TIP, laronidase dose increased to 0.12 mg/kg once weekly IV infusion for 1 week followed by 0.25 mg/kg once weekly IV infusion for 1 week and then 0.58 mg/kg (full-dose) once weekly IV infusion up to Week 39. TIP: CsA starting at 6.7 mg/kg orally three times daily until the target trough concentration of at least 350 ng/mL (preferably 400 ng/mL) achieved along with Aza 5 mg/kg orally every other day. Once target CsA trough level achieved and maintained for at least 1 week, participants received laronidase 0.058 mg/kg (low- dose) once weekly IV infusion (starting from Day 1) up to Week 18. CsA and Aza were gradually discontinued. ICP: following TIP, laronidase dose increased to 0.12 mg/kg once weekly IV infusion for 1 week followed by 0.25 mg/kg once weekly IV infusion for 1 week and then 0.58 mg/kg (full-dose) once weekly IV infusion up to Week 45.
All-Cause Mortality
Cohort 1 Cohort 2
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Cohort 1 Cohort 2
Affected / at Risk (%) Affected / at Risk (%)
Total   2/3 (66.67%)   1/3 (33.33%) 
Blood and lymphatic system disorders     
Neutropenia  1  1/3 (33.33%)  0/3 (0.00%) 
Infections and infestations     
Bronchopneumonia  1  1/3 (33.33%)  0/3 (0.00%) 
Device related infection  1  1/3 (33.33%)  0/3 (0.00%) 
Respiratory tract infection viral  1  0/3 (0.00%)  1/3 (33.33%) 
Sinusitis  1  1/3 (33.33%)  0/3 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Bronchospasm  1  1/3 (33.33%)  0/3 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 16.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Cohort 1 Cohort 2
Affected / at Risk (%) Affected / at Risk (%)
Total   3/3 (100.00%)   3/3 (100.00%) 
Blood and lymphatic system disorders     
Anaemia  1  0/3 (0.00%)  1/3 (33.33%) 
Iron deficiency anaemia  1  1/3 (33.33%)  0/3 (0.00%) 
Lymphocytosis  1  0/3 (0.00%)  1/3 (33.33%) 
Neutropenia  1  1/3 (33.33%)  1/3 (33.33%) 
Thrombocytosis  1  0/3 (0.00%)  1/3 (33.33%) 
Gastrointestinal disorders     
Abdominal pain  1  2/3 (66.67%)  0/3 (0.00%) 
Diarrhoea  1  1/3 (33.33%)  1/3 (33.33%) 
Flatulence  1  0/3 (0.00%)  1/3 (33.33%) 
Gingival cyst  1  1/3 (33.33%)  0/3 (0.00%) 
Gingival hyperplasia  1  1/3 (33.33%)  0/3 (0.00%) 
Nausea  1  1/3 (33.33%)  0/3 (0.00%) 
Umbilical hernia, obstructive  1  1/3 (33.33%)  0/3 (0.00%) 
Vomiting  1  1/3 (33.33%)  0/3 (0.00%) 
General disorders     
Chills  1  1/3 (33.33%)  0/3 (0.00%) 
Hyperthermia  1  1/3 (33.33%)  1/3 (33.33%) 
Influenza like illness  1  1/3 (33.33%)  0/3 (0.00%) 
Medical device complication  1  0/3 (0.00%)  1/3 (33.33%) 
Pyrexia  1  2/3 (66.67%)  0/3 (0.00%) 
Immune system disorders     
Drug hypersensitivity  1  1/3 (33.33%)  0/3 (0.00%) 
Infections and infestations     
Ear infection  1  0/3 (0.00%)  1/3 (33.33%) 
Folliculitis  1  1/3 (33.33%)  0/3 (0.00%) 
Giardiasis  1  1/3 (33.33%)  0/3 (0.00%) 
Gingivitis  1  0/3 (0.00%)  1/3 (33.33%) 
Impetigo  1  1/3 (33.33%)  0/3 (0.00%) 
Laryngitis viral  1  1/3 (33.33%)  0/3 (0.00%) 
Nematodiasis  1  1/3 (33.33%)  0/3 (0.00%) 
Periodontitis  1  0/3 (0.00%)  2/3 (66.67%) 
Rash pustular  1  1/3 (33.33%)  0/3 (0.00%) 
Respiratory tract infection  1  0/3 (0.00%)  1/3 (33.33%) 
Respiratory tract infection viral  1  0/3 (0.00%)  1/3 (33.33%) 
Rhinitis  1  0/3 (0.00%)  1/3 (33.33%) 
Sinusitis  1  1/3 (33.33%)  0/3 (0.00%) 
Upper respiratory tract infection  1  3/3 (100.00%)  0/3 (0.00%) 
Injury, poisoning and procedural complications     
Arthropod sting  1  1/3 (33.33%)  0/3 (0.00%) 
Head injury  1  1/3 (33.33%)  0/3 (0.00%) 
Investigations     
Blood pressure increased  1  0/3 (0.00%)  2/3 (66.67%) 
Head circumference abnormal  1  0/3 (0.00%)  1/3 (33.33%) 
Red blood cell sedimentation rate increased  1  0/3 (0.00%)  1/3 (33.33%) 
Weight decreased  1  0/3 (0.00%)  1/3 (33.33%) 
Metabolism and nutrition disorders     
Decreased appetite  1  1/3 (33.33%)  0/3 (0.00%) 
Nervous system disorders     
Ataxia  1  1/3 (33.33%)  0/3 (0.00%) 
Psychiatric disorders     
Anxiety  1  0/3 (0.00%)  1/3 (33.33%) 
Respiratory, thoracic and mediastinal disorders     
Bronchospasm  1  1/3 (33.33%)  0/3 (0.00%) 
Cough  1  2/3 (66.67%)  0/3 (0.00%) 
Rhinorrhoea  1  2/3 (66.67%)  0/3 (0.00%) 
Stridor  1  1/3 (33.33%)  0/3 (0.00%) 
Skin and subcutaneous tissue disorders     
Alopecia  1  1/3 (33.33%)  0/3 (0.00%) 
Dermatitis allergic  1  1/3 (33.33%)  0/3 (0.00%) 
Dermatitis atopic  1  2/3 (66.67%)  0/3 (0.00%) 
Erythema  1  0/3 (0.00%)  1/3 (33.33%) 
Hand dermatitis  1  0/3 (0.00%)  1/3 (33.33%) 
Heat rash  1  1/3 (33.33%)  0/3 (0.00%) 
Hypertrichosis  1  2/3 (66.67%)  0/3 (0.00%) 
Ingrowing nail  1  2/3 (66.67%)  0/3 (0.00%) 
Papule  1  1/3 (33.33%)  0/3 (0.00%) 
Prurigo  1  1/3 (33.33%)  0/3 (0.00%) 
Pruritus  1  0/3 (0.00%)  1/3 (33.33%) 
Rash  1  2/3 (66.67%)  0/3 (0.00%) 
Rash papular  1  1/3 (33.33%)  0/3 (0.00%) 
Skin maceration  1  0/3 (0.00%)  1/3 (33.33%) 
Urticaria  1  1/3 (33.33%)  1/3 (33.33%) 
Vascular disorders     
Hyperaemia  1  1/3 (33.33%)  0/3 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 16.0
Study was discontinued on September 10,2013 due to changing standards of care for this population, practical infeasibility of routinely monitoring plasma CsA in clinical setting, inconclusive results of interim analysis and not due to safety concern.
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.
If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.
Results Point of Contact
Name/Title: Trial Transparency Team
Organization: Sanofi
Responsible Party: Sanofi ( Genzyme, a Sanofi Company )
ClinicalTrials.gov Identifier: NCT00741338     History of Changes
Other Study ID Numbers: ALID02307
2007-001163-30 ( EudraCT Number )
First Submitted: August 13, 2008
First Posted: August 26, 2008
Results First Submitted: June 2, 2014
Results First Posted: July 2, 2014
Last Update Posted: July 2, 2014