Trial Outcomes & Findings for Immune Tolerance Study With Aldurazyme® (Laronidase) (NCT NCT00741338)

Last Updated: 2014-07-02

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

7 participants

Primary outcome timeframe

24 weeks after start of full-dose laronidase therapy

Results posted on

2014-07-02

Participant Flow

The study was conducted at 2 centers in Brazil and Russia between September 2008 and September 2013.

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.

Participant milestones

Participant milestones
Measure	Cohort 1 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.	Cohort 2 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 Study STARTED	3	3
Overall Study COMPLETED	3	2
Overall Study NOT COMPLETED	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort 1 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.	Cohort 2 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 Study Adverse Event	0	1

Baseline Characteristics

Immune Tolerance Study With Aldurazyme® (Laronidase)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1 n=3 Participants 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.	Cohort 2 n=4 Participants 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 n=7 Participants Total of all reporting groups
Age, Continuous	2.60 years n=5 Participants	3.77 years n=7 Participants	3.18 years n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants

PRIMARY outcome

Timeframe: 24 weeks after start of full-dose laronidase therapy

Population: Safety population included all participants who received any study drug treatment.

Outcome measures

Outcome measures
Measure	Cohort 1 n=3 Participants 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.	Cohort 2 n=3 Participants 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.
Number of Participants Who Achieved Immune Tolerance Induction	0 participants	1 participants

SECONDARY outcome

Timeframe: Baseline, end of treatment/early withdrawal (up to 24 weeks after start of full-dose laronidase therapy)

Population: Safety population included all participants who received any study drug treatment.

Urinary Glycosaminoglycan (uGAG) Levels: concentration of glycosaminoglycan (GAG) relative to creatinine in urine. A greater decrease in uGAG level indicates a greater response.

Outcome measures

Outcome measures
Measure	Cohort 1 n=3 Participants 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.	Cohort 2 n=3 Participants 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.
Percent Reduction of Urinary Glycosaminoglycan (uGAG) Level From Baseline to the End of Treatment/Early Withdrawal	-43.80 percent change in uGAG level Interval -61.7 to -6.7	-72.50 percent change in uGAG level Interval -84.2 to -62.5

Adverse Events

Cohort 1

Serious events: 2 serious events

Other events: 3 other events

Deaths: 0 deaths

Cohort 2

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Cohort 1 n=3 participants at risk 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.	Cohort 2 n=3 participants at risk 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.
Blood and lymphatic system disorders Neutropenia	33.3% 1/3 • 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). 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.	0.00% 0/3 • 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). 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.
Infections and infestations Bronchopneumonia	33.3% 1/3 • 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). 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.	0.00% 0/3 • 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). 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.
Infections and infestations Device related infection	33.3% 1/3 • 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). 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.	0.00% 0/3 • 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). 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.
Infections and infestations Respiratory tract infection viral	0.00% 0/3 • 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). 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.	33.3% 1/3 • 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). 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.
Infections and infestations Sinusitis	33.3% 1/3 • 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). 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.	0.00% 0/3 • 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). 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.
Respiratory, thoracic and mediastinal disorders Bronchospasm	33.3% 1/3 • 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). 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.	0.00% 0/3 • 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). 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.

Other adverse events

Additional Information

Trial Transparency Team

Sanofi

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER