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

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

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)

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.

Detailed Summary:
Sponsor: BioMarin Pharmaceutical

Current Primary Outcome: Safety Evaluation [ Time Frame: Entire Study Period, up to 192 weeks or ETV (early termination visit) ]

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.



Original Primary Outcome: Descriptive summary of clinical safety assessments [ Time Frame: Continuously for up to 29 weeks or more ]

Safety will be deteremined by the following factors:

Incidence of AEs, including SAEs, changes in physical examinations including neurological exams, vital signs, ECGs, Immunogenicity tests, standard clinical laboratory tests, and concomitant medications.



Current Secondary Outcome:

  • 6-minute Walk Test (6MWT) [ Time Frame: Baseline, Week 12, 24, and 52 ]
    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 ]
    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 ]

    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 ]

    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 ]

    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 ]

    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 ]

    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 ]

    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 ]
    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 ]
    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 ]
    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 ]

    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

    Original Secondary Outcome:

    • Change in endurance using a summarized analysis of the percentage change in 6 Minute Walk Test (6MWT) and 3 Minute Stair Climb (3MSC) values from the Screening visit. [ Time Frame: Up to 29 weeks or more ]
      Timepoints: Screening Visit, Week 12, and Week 24
    • Change in absolute peak oxygen uptake from the Screening visit using cardio pulmonary exercise testing (CPET) to evaluate the effect on overall exercise capacity. [ Time Frame: Up to 29 weeks or more for Cohort A only ]

      All Cohort A will perform maximal exercise testing using an electronically braked up-right cycle ergometer. Expired oxygen and CO2 will be analyzed via an expired gas analysis system, heart rate will be monitored by continuous 3-lead ECG, and oxygen saturation will be measured bia pulse oximetry. A computer will be used to calculate breath by breath minute ventilation, oxygen uptake, CO@ production and respiratory exchange ratio (RER) from conventional equations.

      Timepoints: Screening and Week 25 for Cohort A

    • Change in respiratory function using a summarized analysis of the percentage change in Spirometry, MVV, DLCO, and TLC values from the Screening visit. [ Time Frame: Up to 29 weeks or more ]
      Timepoints: Screening, Week 12, and Week 24
    • Correlation of the effect on muscle strength between Screening and Week 25 using an isokinetic dynamometer. [ Time Frame: Up to 29 weeks or more ]
      Timepoints: Screening and Week 25
    • Change in cardiac function as characterized by an Echocardiogram compared at Screening and Week 24 [ Time Frame: Up to 29 weeks or more ]
      Timepoints: Screening and Week 24
    • Change in pain as determined by the Adolescent Pediatric Pain Tool, compared and correlated to the Screening Visit. [ Time Frame: Up to 29 weeks or more ]
      Timepoints: Screening, Week 12, and Week 24
    • Noncompartmental analysis of the area under the plasma concentration curve and the maximum observed plasma concentration of the pharmacokinetics for BMN 110 at 2.0 mg/kg/week and 4.0 mg/kg/week, over time. [ Time Frame: Up to 29 weeks or more ]
      Timepoints: Week 0 and Week 23
    • Change in plasma and urinary KS over time as determine by descriptive statistics. [ Time Frame: Up to 29 weeks or more ]
      Timepoints: Screening, Week 1, Week 2, Week 4, Week 6, Week 12, and Week 24


    Information By: BioMarin Pharmaceutical

    Dates:
    Date Received: May 24, 2012
    Date Started: April 2012
    Date Completion:
    Last Updated: December 24, 2015
    Last Verified: December 2015