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

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
BioMarin Pharmaceutical
ClinicalTrials.gov Identifier:
NCT01609062
First received: May 24, 2012
Last updated: December 24, 2015
Last verified: December 2015
  Purpose
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.

Condition Intervention Phase
Mucopolysaccharidosis IVA
Morquio A Syndrome
MPS IVA
Drug: BMN 110
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by BioMarin Pharmaceutical:

Primary Outcome Measures:
  • Safety Evaluation [ Time Frame: Entire Study Period, up to 192 weeks or ETV (early termination visit) ] [ Designated as safety issue: Yes ]

    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) [ Time Frame: Baseline, Week 12, 24, and 52 ] [ Designated as safety issue: No ]
    Change from baseline to Week 12, 24, and 52 as measured in distance walked (meters) in 6MWT.

  • 3-minute Stair Climb Test (3MSCT) [ Time Frame: Baseline, Week 12, 24, and 52 ] [ Designated as safety issue: No ]
    Change from baseline to Week 12, 24, and 52 as measured in speed (stairs/min) in 3MSCT.

  • Respiratory Function Test (MVV and FVC) [ Time Frame: Baseline, Week 12, 24, and 52 ] [ Designated as safety issue: No ]

    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) [ Time Frame: Baseline, Week 12, 24, and 52 ] [ Designated as safety issue: No ]

    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 [ Time Frame: Baseline, Week 25 and 52 ] [ Designated as safety issue: No ]

    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 [ Time Frame: Baseline, Week 25 and 52 ] [ Designated as safety issue: No ]

    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 [ Time Frame: Baseline, Week 25 and 52 ] [ Designated as safety issue: No ]

    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 [ Time Frame: Baseline, Week 25 and 52 ] [ Designated as safety issue: No ]

    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 [ Time Frame: Baseline, Week 25 and 52 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week 25 and 52 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week 25 and 52 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week 12, 24, and 52 ] [ Designated as safety issue: No ]

    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.



Enrollment: 25
Study Start Date: April 2012
Study Completion Date: November 2014
Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: BMN 110 Weekly at 2.0 mg/kg/week Drug: BMN 110
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.
Other Names:
  • N-acetylgalactosamine-6-sulfatase
  • N-acetylgalactosamine-6-sulfate
  • sulfatase
  • galactose-6-sulfatase
  • GALNS
  • enzyme replacement therapy
  • ERT
  • elosulfase alfa
Experimental: BMN 110 Weekly at 4.0 mg/kg/week Drug: BMN 110
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.
Other Names:
  • N-acetylgalactosamine-6-sulfatase
  • N-acetylgalactosamine-6-sulfate
  • sulfatase
  • galactose-6-sulfatase
  • GALNS
  • enzyme replacement therapy
  • ERT
  • elosulfase alfa

  Eligibility

Ages Eligible for Study:   7 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01609062

Locations
United States, California
Oakland, California, United States
United States, Illinois
Chicago, Illinois, United States
United States, New York
New York, New York, United States
United States, Texas
Houston, Texas, United States
Canada, Alberta
Calgary, Alberta, Canada
Canada, Ontario
Toronto, Ontario, Canada
Canada, Quebec
Montreal, Quebec, Canada
Sherbrook, Quebec, Canada
Germany
Hamburg, Germany
United Kingdom
Belfast, Northern Ireland, United Kingdom
Manchester, United Kingdom
Sponsors and Collaborators
BioMarin Pharmaceutical
Investigators
Study Director: Adam Shaywitz, MD PhD BioMarin Pharmaceutical
  More Information

Responsible Party: BioMarin Pharmaceutical
ClinicalTrials.gov Identifier: NCT01609062     History of Changes
Other Study ID Numbers: MOR-008 
Study First Received: May 24, 2012
Results First Received: November 12, 2015
Last Updated: December 24, 2015
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United Kingdom: National Institute for Health Research
United Kingdom: Research Ethics Committee
Germany: Ethics Commission
Germany: Federal Institute for Drugs and Medical Devices
Canada: Health Canada

Keywords provided by BioMarin Pharmaceutical:
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

Additional relevant MeSH terms:
Mucopolysaccharidoses
Mucopolysaccharidosis IV
Syndrome
Carbohydrate Metabolism, Inborn Errors
Connective Tissue Diseases
Disease
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Metabolic Diseases
Metabolism, Inborn Errors
Mucinoses
Pathologic Processes

ClinicalTrials.gov processed this record on May 22, 2016