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Safety and Exercise Study of Two Doses of BMN 110 for Morquio A Syndrome

Primary Purpose

Mucopolysaccharidosis IVA, Morquio A Syndrome, MPS IVA

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
BMN 110
BMN 110
Sponsored by
BioMarin Pharmaceutical
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Mucopolysaccharidosis IVA focused on measuring Mucopolysaccharidosis IVA Type A, MPS IVA Type A, Mucopolysaccharidosis IVA, MPS IVA, Morquio A Syndrome, Lysosomal Storage Disorder, LSD, N-acetylgalactosamine-6-sulfatase, N-acetylgalactosamine-6-sulfate, sulfatase, galactose-6-sulfatase, GALNS, enzyme replacement therapy, ERT, MOR-008, CPET, MST, muscle strength test, physiological effect

Eligibility Criteria

7 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Is willing and able to provide written, signed informed consent (or patient's legally authorized representative) after the nature of the study has been explained and prior to performance of any research- related procedure. Also, patients who do not meet country and local age requirements for informed consent must be willing and able to provide written assent (if required) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to performance of any research-related procedure.
  • Has documented clinical diagnosis of Morquio A Syndrome (MPS IVA) based on clinical signs and symptoms of MPS IVA and documented reduced fibroblast or leukocyte N-acetylgalactosamine-6-sulfatase (GALNS) enzyme activity or genetic testing confirming diagnosis of MPS IVA.
  • Is at least 7 years of age
  • Is able to walk ≥ 200 meters as assessed by the 6-minute Walk Test (6MWT)
  • If sexually active, is willing to use an acceptable method of contraception while participating in the study
  • If female of childbearing potential, must have a negative pregnancy test at the Screening Visit and be willing to have additional pregnancy tests during the study
  • Is willing and able to perform all study procedures, including cardiopulmonary exercise testing (CPET)

Exclusion Criteria:

  • Inability to perform an exercise test due to limited mobility
  • Body weight greater than 95 kg at Screening
  • Severe, untreated sleep apnea as measured during Screening with a home sleep testing device
  • Patients with a history of, or current condition of sleep apnea or sleep disordered breathing under adequate treatment may be enrolled if approved by the medical monitor.
  • Requirement for supplemental oxygen
  • Use of ventilator assistance in the 3 months prior to study entry
  • Use of positive airway pressure (continuous positive airway pressure, CPAP, or bilevel airway pressure) for treatment of sleep apnea or sleep disordered breathing is allowed if settings have been stable for at least 1 month prior to study entry, and is approved by the medical monitor.
  • Has a concurrent disease or condition, including but not limited to, symptomatic cervical spine instability, clinically significant spinal cord compression, or severe cardiac disease that would interfere with study participation, or pose a safety risk, as determined by the Investigator
  • Has previous hematopoietic stem cell transplant (HSCT)
  • Has received previous treatment with BMN 110
  • Has a known hypersensitivity to BMN 110 or its excipients
  • Has had major surgery within 3 months prior to study entry or is planning to have a major surgery during the duration of the study
  • Use of any other investigational product (IP) or investigational medical device within 30 days prior to the beginning of the Screening Period or requires any investigational agent prior to completion of all scheduled study assessments
  • Is pregnant or breastfeeding during the Screening Period or planning to become pregnant (self or partner) at any time during the study
  • Has a concurrent disease or condition that may interfere with study participation or safety, and/or ability to perform study procedures as determined by the Investigator
  • Has any condition that, in the view of the Investigator, poses a safety risk to the patient
  • Has any condition that, in the view of the Investigator, places the patient at high risk of poor treatment compliance or of not completing the study

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

BMN 110 Weekly at 2.0 mg/kg/week

BMN 110 Weekly at 4.0 mg/kg/week

Arm Description

Outcomes

Primary Outcome Measures

Safety Evaluation
The primary objective of the study is to evaluate the safety of weekly infusions of BMN 110; the safety variables included Adverse Events (AEs). The primary outcome measure data is presented in more detail under the Adverse Events section.

Secondary Outcome Measures

6-minute Walk Test (6MWT)
Change from baseline to Week 12, 24, and 52 as measured in distance walked (meters) in 6MWT.
3-minute Stair Climb Test (3MSCT)
Change from baseline to Week 12, 24, and 52 as measured in speed (stairs/min) in 3MSCT.
Respiratory Function Test (MVV and FVC)
Respiratory Function was assessed by spirometry in accordance with American Thoracic Society standards. Percent change from baseline to Week 12, 24, and 52 as measured by Maximum Voluntary Ventilation (MVV, L/min) Percent change from baseline to Week 12, 24, and 52 as measured by Forced Vital Capacity (FVC, L)
Normalized Urine Keratan Sulfate (uKS)
Urinary KS was measured by a quantitative method and normalized using the sample urinary creatinine measurement. Percent change from baseline to Week 12, 24, and 52 in normalized urine keratan sulfate (ug/mg).
Cardiopulmonary Exercise Testing (CPET) - Duration of Exercise
Subjects performed maximal incremental exercise testing using an electronically braked upright cycle ergometer. Cycle ergometry is a method of CPET that may be feasible in subjects who have orthopedic, peripheral vascular, or neurological limitations that restrict weight bearing. Change from baseline to Week 25 and 52 as measured by the CPET Duration of Exercise (min)
Cardiopulmonary Exercise Testing (CPET) - Peak Workload
Subjects performed maximal incremental exercise testing using an electronically braked upright cycle ergometer. Cycle ergometry is a method of CPET that may be feasible in subjects who have orthopedic, peripheral vascular, or neurological limitations that restrict weight bearing. Percent change from baseline to Week 25 and 52 as measured by the CPET Peak workload (watt)
Cardiopulmonary Exercise Testing (CPET) - O2 Pulse
Subjects performed maximal incremental exercise testing using an electronically braked upright cycle ergometer. Cycle ergometry is a method of CPET that may be feasible in subjects who have orthopedic, peripheral vascular, or neurological limitations that restrict weight bearing. Percent change from baseline to Week 25 and 52 as measured by the CPET O2 pulse (ml/beat)
Cardiopulmonary Exercise Testing (CPET) - Aerobic Efficiency
Subjects performed maximal incremental exercise testing using an electronically braked upright cycle ergometer. Cycle ergometry is a method of CPET that may be feasible in subjects who have orthopedic, peripheral vascular, or neurological limitations that restrict weight bearing. Percent change from baseline to Week 25 and 52 as measured by the CPET Aerobic Efficiency (ml/watt). Note that decline in Aerobic Efficiency translate into an improvement
Muscle Strength Testing (MST) - Knee Extension Test
Change from baseline to Week 25 and 52 as measured by the peak force in MST knee extension test (newton meters).
Muscle Strength Testing (MST) - Knee Flexion Test
Percent change from baseline to Week 25 and 52 as measured by the peak force in MST knee flexion test (newton meters).
Muscle Strength Testing (MST) - Elbow Flexion Test
Percent change from baseline to Week 25 and 52 as measured by the peak force in MST elbow flexion test (newton meters).
Adolescent Pediatric Pain Tool (APPT) - Pain Intensity
The APPT is a validated, multidimensional tool to evaluate pain in children, adolescents, and young adults. The complete APPT is measured in three parts - Part 1 of the APPT scale determines the subject's pain locations using a body template. Part 2 of the APPT scale determines the intensity of the pain using a 10 cm visual analog scale (VAS) with the lowest point of the scale (0) labeled No Pain and the highest point on the scale (10) labeled Worst Possible Pain. Intermediate regions of the sale were labeled with 3 intermediate descriptors (Little Pain, Medium Pain, and Large Pain). Part 3 of the APPT scale characterizes the pain by tracking the number and percentage of words selected by subjects to describe their pain from a total of 57 choices. Part 2 corresponds most closely to other typically used pain scales (based on VAS) and for this reason the results from Part 2 are presented here. Change from baseline to Week 12, 24, and 52 in pain intensity.

Full Information

First Posted
May 24, 2012
Last Updated
December 24, 2015
Sponsor
BioMarin Pharmaceutical
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1. Study Identification

Unique Protocol Identification Number
NCT01609062
Brief Title
Safety and Exercise Study of Two Doses of BMN 110 for Morquio A Syndrome
Official Title
A Randomized, Double-Blind, Pilot Study of the Safety and Physiological Effects of Two Doses of BMN 110 in Patients With Mucopolysaccharidosis IVA (Morquio A Syndrome)
Study Type
Interventional

2. Study Status

Record Verification Date
December 2015
Overall Recruitment Status
Terminated
Study Start Date
April 2012 (undefined)
Primary Completion Date
November 2014 (Actual)
Study Completion Date
November 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
BioMarin Pharmaceutical

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The primary objective of this study was to evaluate the safety of a 2.0 mg/kg/week and a 4.0 mg/kg/week of BMN 110 in patients with Morquio A syndrome for up to 196 weeks. Secondary objectives were to investigate the effect of the two doses on exercise capacity for up to 196 weeks. In addition, the pharmacokinetic (PK) parameters of both doses of BMN 110 was assessed.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Mucopolysaccharidosis IVA, Morquio A Syndrome, MPS IVA
Keywords
Mucopolysaccharidosis IVA Type A, MPS IVA Type A, Mucopolysaccharidosis IVA, MPS IVA, Morquio A Syndrome, Lysosomal Storage Disorder, LSD, N-acetylgalactosamine-6-sulfatase, N-acetylgalactosamine-6-sulfate, sulfatase, galactose-6-sulfatase, GALNS, enzyme replacement therapy, ERT, MOR-008, CPET, MST, muscle strength test, physiological effect

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
25 (Actual)

8. Arms, Groups, and Interventions

Arm Title
BMN 110 Weekly at 2.0 mg/kg/week
Arm Type
Experimental
Arm Title
BMN 110 Weekly at 4.0 mg/kg/week
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
BMN 110
Other Intervention Name(s)
N-acetylgalactosamine-6-sulfatase, N-acetylgalactosamine-6-sulfate, sulfatase, galactose-6-sulfatase, GALNS, enzyme replacement therapy, ERT, elosulfase alfa
Intervention Description
Weekly IV infusions of BMN 110 at 2.0 mg/kg/week over a period of approximately 4 hours per infusion for up to 192 weeks.
Intervention Type
Drug
Intervention Name(s)
BMN 110
Other Intervention Name(s)
N-acetylgalactosamine-6-sulfatase, N-acetylgalactosamine-6-sulfate, sulfatase, galactose-6-sulfatase, GALNS, enzyme replacement therapy, ERT, elosulfase alfa
Intervention Description
Weekly IV infusions of BMN 110 at 4.0 mg/kg/week over a period of approximately 4 hours per infusion for 27 weeks, and will eventually transition to 2.0 mg/kg/week for up to an additional 166 weeks.
Primary Outcome Measure Information:
Title
Safety Evaluation
Description
The primary objective of the study is to evaluate the safety of weekly infusions of BMN 110; the safety variables included Adverse Events (AEs). The primary outcome measure data is presented in more detail under the Adverse Events section.
Time Frame
Entire Study Period, up to 192 weeks or ETV (early termination visit)
Secondary Outcome Measure Information:
Title
6-minute Walk Test (6MWT)
Description
Change from baseline to Week 12, 24, and 52 as measured in distance walked (meters) in 6MWT.
Time Frame
Baseline, Week 12, 24, and 52
Title
3-minute Stair Climb Test (3MSCT)
Description
Change from baseline to Week 12, 24, and 52 as measured in speed (stairs/min) in 3MSCT.
Time Frame
Baseline, Week 12, 24, and 52
Title
Respiratory Function Test (MVV and FVC)
Description
Respiratory Function was assessed by spirometry in accordance with American Thoracic Society standards. Percent change from baseline to Week 12, 24, and 52 as measured by Maximum Voluntary Ventilation (MVV, L/min) Percent change from baseline to Week 12, 24, and 52 as measured by Forced Vital Capacity (FVC, L)
Time Frame
Baseline, Week 12, 24, and 52
Title
Normalized Urine Keratan Sulfate (uKS)
Description
Urinary KS was measured by a quantitative method and normalized using the sample urinary creatinine measurement. Percent change from baseline to Week 12, 24, and 52 in normalized urine keratan sulfate (ug/mg).
Time Frame
Baseline, Week 12, 24, and 52
Title
Cardiopulmonary Exercise Testing (CPET) - Duration of Exercise
Description
Subjects performed maximal incremental exercise testing using an electronically braked upright cycle ergometer. Cycle ergometry is a method of CPET that may be feasible in subjects who have orthopedic, peripheral vascular, or neurological limitations that restrict weight bearing. Change from baseline to Week 25 and 52 as measured by the CPET Duration of Exercise (min)
Time Frame
Baseline, Week 25 and 52
Title
Cardiopulmonary Exercise Testing (CPET) - Peak Workload
Description
Subjects performed maximal incremental exercise testing using an electronically braked upright cycle ergometer. Cycle ergometry is a method of CPET that may be feasible in subjects who have orthopedic, peripheral vascular, or neurological limitations that restrict weight bearing. Percent change from baseline to Week 25 and 52 as measured by the CPET Peak workload (watt)
Time Frame
Baseline, Week 25 and 52
Title
Cardiopulmonary Exercise Testing (CPET) - O2 Pulse
Description
Subjects performed maximal incremental exercise testing using an electronically braked upright cycle ergometer. Cycle ergometry is a method of CPET that may be feasible in subjects who have orthopedic, peripheral vascular, or neurological limitations that restrict weight bearing. Percent change from baseline to Week 25 and 52 as measured by the CPET O2 pulse (ml/beat)
Time Frame
Baseline, Week 25 and 52
Title
Cardiopulmonary Exercise Testing (CPET) - Aerobic Efficiency
Description
Subjects performed maximal incremental exercise testing using an electronically braked upright cycle ergometer. Cycle ergometry is a method of CPET that may be feasible in subjects who have orthopedic, peripheral vascular, or neurological limitations that restrict weight bearing. Percent change from baseline to Week 25 and 52 as measured by the CPET Aerobic Efficiency (ml/watt). Note that decline in Aerobic Efficiency translate into an improvement
Time Frame
Baseline, Week 25 and 52
Title
Muscle Strength Testing (MST) - Knee Extension Test
Description
Change from baseline to Week 25 and 52 as measured by the peak force in MST knee extension test (newton meters).
Time Frame
Baseline, Week 25 and 52
Title
Muscle Strength Testing (MST) - Knee Flexion Test
Description
Percent change from baseline to Week 25 and 52 as measured by the peak force in MST knee flexion test (newton meters).
Time Frame
Baseline, Week 25 and 52
Title
Muscle Strength Testing (MST) - Elbow Flexion Test
Description
Percent change from baseline to Week 25 and 52 as measured by the peak force in MST elbow flexion test (newton meters).
Time Frame
Baseline, Week 25 and 52
Title
Adolescent Pediatric Pain Tool (APPT) - Pain Intensity
Description
The APPT is a validated, multidimensional tool to evaluate pain in children, adolescents, and young adults. The complete APPT is measured in three parts - Part 1 of the APPT scale determines the subject's pain locations using a body template. Part 2 of the APPT scale determines the intensity of the pain using a 10 cm visual analog scale (VAS) with the lowest point of the scale (0) labeled No Pain and the highest point on the scale (10) labeled Worst Possible Pain. Intermediate regions of the sale were labeled with 3 intermediate descriptors (Little Pain, Medium Pain, and Large Pain). Part 3 of the APPT scale characterizes the pain by tracking the number and percentage of words selected by subjects to describe their pain from a total of 57 choices. Part 2 corresponds most closely to other typically used pain scales (based on VAS) and for this reason the results from Part 2 are presented here. Change from baseline to Week 12, 24, and 52 in pain intensity.
Time Frame
Baseline, Week 12, 24, and 52

10. Eligibility

Sex
All
Minimum Age & Unit of Time
7 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Is willing and able to provide written, signed informed consent (or patient's legally authorized representative) after the nature of the study has been explained and prior to performance of any research- related procedure. Also, patients who do not meet country and local age requirements for informed consent must be willing and able to provide written assent (if required) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to performance of any research-related procedure. Has documented clinical diagnosis of Morquio A Syndrome (MPS IVA) based on clinical signs and symptoms of MPS IVA and documented reduced fibroblast or leukocyte N-acetylgalactosamine-6-sulfatase (GALNS) enzyme activity or genetic testing confirming diagnosis of MPS IVA. Is at least 7 years of age Is able to walk ≥ 200 meters as assessed by the 6-minute Walk Test (6MWT) If sexually active, is willing to use an acceptable method of contraception while participating in the study If female of childbearing potential, must have a negative pregnancy test at the Screening Visit and be willing to have additional pregnancy tests during the study Is willing and able to perform all study procedures, including cardiopulmonary exercise testing (CPET) Exclusion Criteria: Inability to perform an exercise test due to limited mobility Body weight greater than 95 kg at Screening Severe, untreated sleep apnea as measured during Screening with a home sleep testing device Patients with a history of, or current condition of sleep apnea or sleep disordered breathing under adequate treatment may be enrolled if approved by the medical monitor. Requirement for supplemental oxygen Use of ventilator assistance in the 3 months prior to study entry Use of positive airway pressure (continuous positive airway pressure, CPAP, or bilevel airway pressure) for treatment of sleep apnea or sleep disordered breathing is allowed if settings have been stable for at least 1 month prior to study entry, and is approved by the medical monitor. Has a concurrent disease or condition, including but not limited to, symptomatic cervical spine instability, clinically significant spinal cord compression, or severe cardiac disease that would interfere with study participation, or pose a safety risk, as determined by the Investigator Has previous hematopoietic stem cell transplant (HSCT) Has received previous treatment with BMN 110 Has a known hypersensitivity to BMN 110 or its excipients Has had major surgery within 3 months prior to study entry or is planning to have a major surgery during the duration of the study Use of any other investigational product (IP) or investigational medical device within 30 days prior to the beginning of the Screening Period or requires any investigational agent prior to completion of all scheduled study assessments Is pregnant or breastfeeding during the Screening Period or planning to become pregnant (self or partner) at any time during the study Has a concurrent disease or condition that may interfere with study participation or safety, and/or ability to perform study procedures as determined by the Investigator Has any condition that, in the view of the Investigator, poses a safety risk to the patient Has any condition that, in the view of the Investigator, places the patient at high risk of poor treatment compliance or of not completing the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Adam Shaywitz, MD PhD
Organizational Affiliation
BioMarin Pharmaceutical
Official's Role
Study Director
Facility Information:
City
Oakland
State/Province
California
Country
United States
City
Chicago
State/Province
Illinois
Country
United States
City
New York
State/Province
New York
Country
United States
City
Houston
State/Province
Texas
Country
United States
City
Calgary
State/Province
Alberta
Country
Canada
City
Toronto
State/Province
Ontario
Country
Canada
City
Montreal
State/Province
Quebec
Country
Canada
City
Sherbrook
State/Province
Quebec
Country
Canada
City
Hamburg
Country
Germany
City
Belfast
State/Province
Northern Ireland
Country
United Kingdom
City
Manchester
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
29159458
Citation
Berger KI, Burton BK, Lewis GD, Tarnopolsky M, Harmatz PR, Mitchell JJ, Muschol N, Jones SA, Sutton VR, Pastores GM, Lau H, Sparkes R, Shaywitz AJ. Cardiopulmonary Exercise Testing Reflects Improved Exercise Capacity in Response to Treatment in Morquio A Patients: Results of a 52-Week Pilot Study of Two Different Doses of Elosulfase Alfa. JIMD Rep. 2018;42:9-17. doi: 10.1007/8904_2017_70. Epub 2017 Nov 21.
Results Reference
derived

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Safety and Exercise Study of Two Doses of BMN 110 for Morquio A Syndrome

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