Mucopolysaccharidosis IVA (Morquio A Syndrome) Clinical Trial
Official title:
A Multicenter Open-Label, Phase 3B Study to Evaluate the Efficacy and Safety of BMN 110 in Australian Patients With Mucopolysaccharidosis IVA (Morquio A Syndrome)
There is currently no treatment for MPS IVA other than supportive care for the clinical
manifestations of the disease. Enzyme replacement therapy (ERT) with BMN 110 to replace the
deficient GALNS is a potential new treatment option for MPS IVA patients. BMN 110, containing
recombinant human GALNS (rhGALNS) developed by BioMarin is expected to reduce the
progressive, pathologic accumulation of KS, and improve signs and symptoms of the disease.
The objective of this Phase 3B open label study (110-502) will be to evaluate the safety and
tolerability of 2.0 mg/kg/week (qw) of BMN 110 in Australian patients with MPS IVA. In
addition, a number of secondary and tertiary efficacy endpoints will also be investigated.
The dose and regimen of BMN 110 have been selected on the basis of data from a Phase 1/2
clinical study with BMN 110, nonclinical and in vitro studies with BMN 110, and clinical and
nonclinical data from other enzyme replacement therapies.
Extension Phase is included per amendment dated 10Mar 2014: To provide patients enrolled in
the Initial Phase access to BMN 110 until commercial product becomes available in Australia
and continue to assess long-term safety
STUDY DESIGN AND PLAN: This is a multicenter, open-label Phase 3B study designed to evaluate
the safety and efficacy of BMN 110 in Australian patients with MPS IVA. Approximately 10
patients in Australia with a confirmed diagnosis of MPS IVA will be enrolled in this study.
Eligible patients will receive weekly infusion of BMN 110 2.0 mg/kg until BMN 110 becomes
commercially available in Australia.
Screening [Week -4]. After obtaining informed consent, information on demographics,
concomitant medication(s) use and medical history (including pre-study growth data) will be
collected; blood will be drawn for confirming MPS IVA diagnosis by enzymatic test (when
applicable); and, blood and urine for clinical laboratory tests will be collected.
Electrocardiogram (ECG), routine physical examination including standard neurological
examination, vital signs; and cervical spine (flexion-extension) imaging by either
radiographs, or a Magnetic Resonance Imaging (MRI) or CT scan may be collected during
Screening visit. Adverse Events (AEs)/Serious Adverse Events (SAEs) will also be monitored
and collected.
Baseline Visit [Week 1, Day -1]. Upon confirmation of eligibility by confirmed diagnosis of
MPS IVA by enzymatic test, negative pregnancy tests at Baseline (in women of childbearing
age) and medical history, patients will be enrolled in the study and will complete following
assessments: urine KS and urine creatinine, vital signs, routine physical examination
including standard neurological examination, body weight (for verifying dose), clinical
laboratory assessments, immunogenicity tests, ECG, 6MW test, 3MSC test and RFT will be
performed and AEs/SAEs and concomitant medication use will be collected. In addition,
anthropometric parameters (including height) will be measured, pain assessment test
(Adolescent Pediatric Pain Tool [APPT], pain tool in children, adolescents, and adults) will
be administered; and PedsQL (QOL questionnaire for pediatric patients) or SF-36 (QOL
questionnaire for adult patients) questionnaire will also be completed during this visit.
Patients who have abnormal overnight pulse oximetry readings will be assessed for sleep
apnea, the results of which will be calculated using the Apnea-Hypopnea Index (AHI) at
Baseline, Week 25, Week 49 and ETV.
Treatment Visit 1 [Week 1, Day 1]. Patients will receive the first dose of BMN 110 by
intravenous (IV) infusion. Assessments on Day 1 will include vital signs, routine physical
examination including standard neurological examination, and concomitant medication use and
AEs/SAEs. All assessments will be performed prior to treatment, except AEs/SAEs which are
collected continuously throughout the study. Immunogenicity lab tests are completed only in
the event of an Infusion Associated Reaction.
Treatment Visits [Weeks 2-48]. Patients will be treated weekly with BMN 110 for 48 weeks.
Prior to each weekly treatment, patients will have vital signs and routine physical
examination including standard neurological examination. Concomitant medications and AEs/SAEs
are collected at every visit. Body weight will be determined every 4 weeks after the Day -1
visit to confirm dose volume. Immunogenicity lab tests are completed only in the event of an
Infusion Associated Reaction.
Efficacy Assessment Visits [Weeks 25 and 49]. The following data will be collected during
weeks 25 and 49: clinical laboratory tests, urine KS and creatinine levels, immunogenicity
test, ECG, 6MW test, 3MSC test, RFTs and anthropometric measurements. The patients will also
complete the APPT test,and PedsQL or SF-36 questionnaire (as appropriate). Patients who have
abnormal overnight pulse oximetry readings will be assessed for sleep apnea. Immunogenicity
lab tests are completed only in the event of an Infusion Associated Reaction.
Additional Safety Assessment during Week 49 Visit. In addition to the efficacy and safety
assessments listed above, cervical spine radiographs (flexion-extension) or MRI or CT scan
will also be collected during the Week 49 visit.
Extension Phase [Required Safety and Recommended Efficacy Assessments]: Treatment Visits
Patients will be treated weekly with BMN110 starting at week 49, following completion of all
applicable efficacy assessments, until BMN110 becomes commercially available in Australia.
Patients will have vital signs, concomitant medications and AEs/SAEs collected at every
visit. Additional blood samples for total IgE and drug specific IgE testing will be drawn and
analyzed for patients who experience a severe IAR, experience an IAR requiring cessation of
infusion, anaphylaxis or a serious hypersensitivity event.
Safety Assessments: Treatment Visits [Every 4 weeks]. Body weight will be obtained every 4
weeks after the Day 1 visit to confirm dose volume. Treatment Visits [Every 24 weeks]. In
addition to the assessments performed at weekly treatment visits, the patients will undergo
pregnancy test (as appropriate).
Efficacy Assessments [Recommended every 24 weeks starting with Week 73]: Routine physical
examination including standard neurological examination, clinical laboratory assessments,
urine KS and creatinine levels, ECG, 6MW test, 3MSC test, RFTs and anthropometric
measurements. The patients will also complete the APPT test, and PedsQL or SF-36
questionnaire (as appropriate), cervical spine imaging and sleep apnea test (if applicable).
Patients who have abnormal overnight pulse oximetry readings will be assessed for sleep
apnea.
End of Study Visit (EOS). The patients will be monitored for AEs and SAEs for up to 30 days
post drug infusion. During Week 53 the EOS Visit, patients will be evaluated for AEs/SAEs and
will have vital signs taken, routine physical examination including standard neurological
examination will be performed, and information on concomitant medication use will be
collected.
Patient withdrawal: Patients may withdraw voluntarily from receiving BMN 110 at any time, in
which case they will be encouraged to continue to undergo study assessments. Data from such
patients will be utilized for further characterization of the natural progression of MPS IVA.
Patients may also withdraw entirely from study participation at any time.
Safety The study period during which all non-serious AEs and SAEs will be reported begins
after informed consent is obtained and through 30 days after the last study visit or 30 days
after the last drug infusion, whichever comes first. Starting on the first Screening Day and
continuing through the end of the study or Early Termination Visit , AEs/SAEs will be
monitored and recorded, and routine physical examination including standard neurological
examination will be conducted in all patients. During the Initial Phase, routine physical
examination including standard neurological examination will be conducted in all patients.
During the Extension phase, physical examinations including neurologic examinations are
recommended, but not required.
Some patients may experience infusion associated reactions (IARs) associated with the
administration of study drug, thus it will be required that prophylactic antihistamine will
be administered prior to each study drug infusion. Antipyretic pretreatment may be given at
the Investigator's discretion. The internal Data Monitoring Committee (DMC) will monitor the
safety of BMN 110 in patients and may review any severe or serious IARs that occur in
patients during the study until approval from the United States Food and Drug Administration
or the European Medicines Agency to commercialize BMN 110 is received. Vital signs will be
measured just before, during, and immediately following the study drug infusion. Adverse
events and changes in concomitant medication Safety assessments will be performed throughout
the study. Physical examinations including neurological examination will be performed at
Screening and all visits up to and including the Week 49 Visit.
Radiographs (flexion-extension) or MRI or CT scans of the cervical spine are required at
Screening and at Week 49. Clinical laboratory tests, Electrocardiograms (ECG) are required at
Screening, Baseline, Weeks 25 and 49 Visits. Blood samples will be collected at Baseline,
Weeks 25 and 49 for TAb and NAb testing. NAb will not be performed if TAb is negative.
Samples for Total IgE will be collected at Baseline and stored for testing. For patients who
experience a severe infusion associated reaction (IAR), experience an IAR requiring cessation
of infusion, anaphylaxis or a serious hypersensitivity event, shortly after cessation of the
infusion, the Baseline total IgE sample will be analyzed and additional blood samples for
total IgE and drug-specific IgE testing will be drawn and run. Immediate testing for total
IgE will be taken shortly after cessation of the study drug infusion. Drug-specific IgE will
also be tested, but must be collected no sooner than 8 hours post infusion and no later than
just before the next scheduled infusion the following week due to rhGALNS interference with
the detection assay. A sample taken the day after the IAR, anaphylactic or serious
hypersensitivity event would be preferred but may not be practical. If the sample is
positive, the extra volume of serum may be used to further characterize the drug-specific IgE
assay. As patients may experience hypersensitivity reactions associated with the
administration of BMN 110, all patients will be pretreated with an appropriate dose of
antihistamine medication approximately 30 minutes to 1 hour prior to infusion. Antipyretic
medications may also be given at the discretion of the Investigator. On infusion days, vital
signs will be measured at a minimum of: immediately before (less than 30 minutes) the
infusion, every 30 minutes for the first hour of the infusion, every hour for the remainder
of the infusion, and immediately (less than 30 minutes) after the infusion. Patients will
also be monitored by continuous pulse oximetry during infusion and for at least 60 minutes
after the infusion is completed. AEs/SAEs and changes in concomitant medication will be
recorded throughout the study. AEs/SAEs will be graded according to the National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).
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