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

• ClinicalTrials.gov Identifier: NCT01609062
• Recruitment Status: Terminated
• First Posted: May 31, 2012
• Results First Posted: February 1, 2016
• Last Update Posted: February 1, 2016
• Sponsor: BioMarin Pharmaceutical
• Information provided by (Responsible Party): BioMarin Pharmaceutical

Tracking Information

• First Submitted Date: May 24, 2012
• First Posted Date: May 31, 2012
• Results First Submitted Date: November 12, 2015
• Results First Posted Date: February 1, 2016
• Last Update Posted Date: February 1, 2016
• Study Start Date: April 2012
• Actual Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 24, 2015)

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 Measures (submitted: May 29, 2012)

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 Measures (submitted: December 24, 2015)

• 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 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.

Original Secondary Outcome Measures (submitted: May 29, 2012)

• 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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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)
• 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 Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Mucopolysaccharidosis IVA
• Morquio A Syndrome
• MPS IVA

Intervention

• 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
• 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

Study Arms

• Experimental: BMN 110 Weekly at 2.0 mg/kg/week
  Intervention: Drug: BMN 110
• Experimental: BMN 110 Weekly at 4.0 mg/kg/week
  Intervention: Drug: BMN 110

• Publications *: 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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: May 29, 2012): 25
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: November 2014
• Actual Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 7 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Germany, United Kingdom, United States

Administrative Information

• NCT Number: NCT01609062
• Other Study ID Numbers: MOR-008
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: BioMarin Pharmaceutical
• Study Sponsor: BioMarin Pharmaceutical
• Collaborators: Not Provided

Investigators

• Study Director: Adam Shaywitz, MD PhD; BioMarin Pharmaceutical

• PRS Account: BioMarin Pharmaceutical
• Verification Date: December 2015