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

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)

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01609062

Enrollment

Registered

2012-05-31

Start date

2012-04-30

Completion date

2014-11-30

Last updated

2016-02-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Morquio A Syndrome, MPS IVA, Mucopolysaccharidosis 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

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.

Interventions

DRUGBMN 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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

7 Years to No maximum

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

Design outcomes

Primary

Measure	Time frame	Description
Safety Evaluation	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.

Secondary

Measure	Time frame	Description
3-minute Stair Climb Test (3MSCT)	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)	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)	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	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	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)
6-minute Walk Test (6MWT)	Baseline, Week 12, 24, and 52	Change from baseline to Week 12, 24, and 52 as measured in distance walked (meters) in 6MWT.
Cardiopulmonary Exercise Testing (CPET) - Aerobic Efficiency	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	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	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	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	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.
Cardiopulmonary Exercise Testing (CPET) - O2 Pulse	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)

Countries

Canada, Germany, United Kingdom, United States

Participant flow

Participants by arm

Arm	Count
BMN 110 Weekly at 2.0 mg/kg/Week BMN 110: Weekly IV infusions of BMN 110 at 2.0 mg/kg/week over a period of approximately 4 hours per infusion in the primary phase.	15
BMN 110 Weekly at 4.0 mg/kg/Week BMN 110: Weekly IV infusions of BMN 110 at 4.0 mg/kg/week over a period of approximately 4 hours per infusion in the primary phase.	10
Total	25

Withdrawals & dropouts

Period	Reason	FG000	FG001
Extension Phase	Anticipated surgery & transition to EAP	0	1
Extension Phase	Discontinued drug and then was pregnant	1	0
Extension Phase	Terminated by Sponsor	14	9

Baseline characteristics

Characteristic	BMN 110 Weekly at 2.0 mg/kg/Week	BMN 110 Weekly at 4.0 mg/kg/Week	Total
Age, Continuous	14.9 years STANDARD_DEVIATION 9.32	12.0 years STANDARD_DEVIATION 3.16	13.7 years STANDARD_DEVIATION 7.52
Age, Customized 12 to 18 years	3 participants	5 participants	8 participants
Age, Customized >=19 years	3 participants	0 participants	3 participants
Age, Customized 7 to 11 years	9 participants	5 participants	14 participants
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants	2 Participants	6 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	11 Participants	8 Participants	19 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 participants	0 participants	0 participants
Race/Ethnicity, Customized Asian	0 participants	0 participants	0 participants
Race/Ethnicity, Customized Black or African American	0 participants	0 participants	0 participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 participants	0 participants	0 participants
Race/Ethnicity, Customized Other	1 participants	1 participants	2 participants
Race/Ethnicity, Customized White	14 participants	9 participants	23 participants
Region of Enrollment Canada	5 participants	1 participants	6 participants
Region of Enrollment Germany	0 participants	3 participants	3 participants
Region of Enrollment United Kingdom	1 participants	1 participants	2 participants
Region of Enrollment United States	9 participants	5 participants	14 participants
Sex: Female, Male Female	12 Participants	4 Participants	16 Participants
Sex: Female, Male Male	3 Participants	6 Participants	9 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	15 / 15	10 / 10
serious Total, serious adverse events	3 / 15	2 / 10

Outcome results

Primary

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.

Time frame: Entire Study Period, up to 192 weeks or ETV (early termination visit)

Population: The primary outcome measure data is presented in more detail under the Adverse Events section.

Arm	Measure	Group	Value (NUMBER)
BMN 110 Weekly at 2.0 mg/kg/Week	Safety Evaluation	Serious Adverse Events	3 participants
BMN 110 Weekly at 2.0 mg/kg/Week	Safety Evaluation	Other (Not Including Serious) Adverse Events	15 participants
BMN 110 Weekly at 4.0 mg/kg/Week	Safety Evaluation	Serious Adverse Events	2 participants
BMN 110 Weekly at 4.0 mg/kg/Week	Safety Evaluation	Other (Not Including Serious) Adverse Events	10 participants
All Subjects	Safety Evaluation	Serious Adverse Events	5 participants
All Subjects	Safety Evaluation	Other (Not Including Serious) Adverse Events	25 participants

Secondary

3-minute Stair Climb Test (3MSCT)

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

Population: Modified Intent-to-Treat Analysis Set

Arm	Measure	Group	Value (MEAN)	Dispersion
BMN 110 Weekly at 2.0 mg/kg/Week	3-minute Stair Climb Test (3MSCT)	Week 24	-2.2 stairs/min	Standard Deviation 11.01
BMN 110 Weekly at 2.0 mg/kg/Week	3-minute Stair Climb Test (3MSCT)	Week 12	-3.7 stairs/min	Standard Deviation 13.16
BMN 110 Weekly at 2.0 mg/kg/Week	3-minute Stair Climb Test (3MSCT)	Week 52	-4.4 stairs/min	Standard Deviation 9.82
BMN 110 Weekly at 4.0 mg/kg/Week	3-minute Stair Climb Test (3MSCT)	Week 24	12.5 stairs/min	Standard Deviation 15.26
BMN 110 Weekly at 4.0 mg/kg/Week	3-minute Stair Climb Test (3MSCT)	Week 12	1.7 stairs/min	Standard Deviation 11.28
BMN 110 Weekly at 4.0 mg/kg/Week	3-minute Stair Climb Test (3MSCT)	Week 52	10.0 stairs/min	Standard Deviation 16.88
All Subjects	3-minute Stair Climb Test (3MSCT)	Week 12	-1.5 stairs/min	Standard Deviation 12.49
All Subjects	3-minute Stair Climb Test (3MSCT)	Week 52	1.3 stairs/min	Standard Deviation 14.66
All Subjects	3-minute Stair Climb Test (3MSCT)	Week 24	3.9 stairs/min	Standard Deviation 14.65

Secondary

6-minute Walk Test (6MWT)

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

Population: Modified Intent-to-Treat Analysis Set

Arm	Measure	Group	Value (MEAN)	Dispersion
BMN 110 Weekly at 2.0 mg/kg/Week	6-minute Walk Test (6MWT)	Week 24	-13.0 meters	Standard Deviation 54.12
BMN 110 Weekly at 2.0 mg/kg/Week	6-minute Walk Test (6MWT)	Week 12	14.7 meters	Standard Deviation 30.9
BMN 110 Weekly at 2.0 mg/kg/Week	6-minute Walk Test (6MWT)	Week 52	9.0 meters	Standard Deviation 48.41
BMN 110 Weekly at 4.0 mg/kg/Week	6-minute Walk Test (6MWT)	Week 24	0.1 meters	Standard Deviation 34.7
BMN 110 Weekly at 4.0 mg/kg/Week	6-minute Walk Test (6MWT)	Week 12	-8.9 meters	Standard Deviation 83.52
BMN 110 Weekly at 4.0 mg/kg/Week	6-minute Walk Test (6MWT)	Week 52	31.8 meters	Standard Deviation 54.56
All Subjects	6-minute Walk Test (6MWT)	Week 12	5.3 meters	Standard Deviation 57.55
All Subjects	6-minute Walk Test (6MWT)	Week 52	18.5 meters	Standard Deviation 51.19
All Subjects	6-minute Walk Test (6MWT)	Week 24	-7.8 meters	Standard Deviation 46.94

Secondary

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.

Time frame: Baseline, Week 12, 24, and 52

Population: Modified Intent-to-treat

Arm	Measure	Group	Value (MEAN)	Dispersion
BMN 110 Weekly at 2.0 mg/kg/Week	Adolescent Pediatric Pain Tool (APPT) - Pain Intensity	APPT Word Graphic Rating Scale Week 24	-2.2 units on a scale	Standard Deviation 3.68
BMN 110 Weekly at 2.0 mg/kg/Week	Adolescent Pediatric Pain Tool (APPT) - Pain Intensity	APPT Word Graphic Rating Scale Week 12	-2.3 units on a scale	Standard Deviation 3.37
BMN 110 Weekly at 2.0 mg/kg/Week	Adolescent Pediatric Pain Tool (APPT) - Pain Intensity	APPT Word Graphic Rating Scale Week 52	-0.8 units on a scale	Standard Deviation 3.41
BMN 110 Weekly at 4.0 mg/kg/Week	Adolescent Pediatric Pain Tool (APPT) - Pain Intensity	APPT Word Graphic Rating Scale Week 24	-1.2 units on a scale	Standard Deviation 2.87
BMN 110 Weekly at 4.0 mg/kg/Week	Adolescent Pediatric Pain Tool (APPT) - Pain Intensity	APPT Word Graphic Rating Scale Week 12	-1.2 units on a scale	Standard Deviation 2.23
BMN 110 Weekly at 4.0 mg/kg/Week	Adolescent Pediatric Pain Tool (APPT) - Pain Intensity	APPT Word Graphic Rating Scale Week 52	-0.8 units on a scale	Standard Deviation 3.04
All Subjects	Adolescent Pediatric Pain Tool (APPT) - Pain Intensity	APPT Word Graphic Rating Scale Week 12	-1.8 units on a scale	Standard Deviation 2.93
All Subjects	Adolescent Pediatric Pain Tool (APPT) - Pain Intensity	APPT Word Graphic Rating Scale Week 52	-0.8 units on a scale	Standard Deviation 3.17
All Subjects	Adolescent Pediatric Pain Tool (APPT) - Pain Intensity	APPT Word Graphic Rating Scale Week 24	-1.8 units on a scale	Standard Deviation 3.33

Secondary

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