Clinical trial NCT02156674
Conditions: Maroteaux-Lamy Syndrome
Keywords: Maroteaux-Lamy Syndrome mucopolysaccharide VI MPS VI
Sponsor: Masonic Cancer Center, University of Minnesota
Start date: 2016-01-26; Completion date: 2019-12-01
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single center study in which Naglazyme® will be given weekly for two years in patients with Maroteaux-Lamy syndrome, also known as mucopolysaccharide VI (MPS VI), who have previously been treated with an allogeneic transplant.

Detailed description:

Arms: arm 1: weekly Naglazyme® infusion for 2 years
Interventions: intervention 1: Naglazyme®
Intervention descriptions: intervention 1: 1 mg per kg of body weight administered once weekly as an intravenous infusion

Protocol documents:
Prot_SAP_000.pdf: 
University of Minnesota 
Blood and Marrow Transplantation Program 
 
 
Study of Administration of Intravenous Naglazyme® Following 
Allogeneic Transplantation for Maroteaux-Lamy Syndrome 
MT2014-08R 
 
 
 
Principal Investigator: 
Elizabeth Braunlin, MD, PhD 
 
Co-Investigators: 
Paul Orchard, MD 
Chester B. Whitley PhD, MD 
Rene Pierpont, PhD* 
Bradley S Miller, MD, PhD* 
Jeanine Utz, PharmD* 
*Co-I’s who will not consent subjects 
 
Biostatistician: 
Qing Cao, MS 
 
 
 
 
 
Version Date: 
December 4, 2015 
 
 
 
 
Confidential 


MT2014-08R:  Naglazyme Following Allogeneic Transplantation for Maroteaux-Lamy Syndrome 
 
 
 
 
 
 
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CPRC #2014LS014 
Revision History 
Revision 
Number 
Version 
Date 
Summary of Changes 
Consent 
change? 
 
03/17/2014 
original to CPRC 
 
 
04/17/2014 
revision to CPRC 
 
 
05/05/2014 
original version to IRB 
section 7.2 – designate research related testing with an R 
schema and section 3.1:  correct time from transplant as > 2 
years not within 2 years 
cover page: remove administrative personnel  
throughout 
document: 
Sara 
Johnson 
as 
study 
coordinator/contact person 
n/a 
1 
12/04/2015 
schema and section 3 – update inclusion/exclusion criteria 
• Add pre-screening details 
• Permit enrollment of patients who are receiving or 
previously received Naglazyme 
• Clarify proof of engraftment must be within previous year 
schema, synopsis and sections 4, 5.1 and 7.1 – update to 
include pre-screening plan  
section 4 – require enrollment within 6 months of initial 
enrollment (previously 1 year) 
section 7 – add pre-screening section, edits to evaluations 
during treatment, and correct section 7.4 section header as no 
assessments are required at the local medical facility 
section 8 – update to current language, delete reference to 
infusion form in appendix I as this will be a separate document. 
replace appendix I with an eligibility checklist 
update to current template language especially sections 8 and 
9.4 
other minor edits and clarifications 
update title page with current investigators (add Drs. Peirpont, 
and Miller, delete Drs Shapiro and Polgreen), indicate which 
co-I’s will not consent subjects. 
yes plus 
new 
screening 
consent 
 
PI Contact Information: 
Elizabeth Braunlin, MD, PhD 
Department of Pediatrics 
Pediatric Cardiology 
MB554 East Building 
2450 Riverside Ave S  
Minneapolis, MN 55454 
Office:  612-626-2833/612-626-2755 
Fax:  612-626-2467 
Email:  braun002@umn.edu 
 
 


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Table of Contents 
Protocol Synopsis ....................................................................................................................... 5 
Schema....................................................................................................................................... 6 
1 
Objectives ........................................................................................................................... 7 
1.1 
Primary Objective ........................................................................................................ 7 
1.2 
Secondary Objectives .................................................................................................. 7 
2 
Background and Study Rationale ........................................................................................ 7 
2.1 
Overview of MPS VI..................................................................................................... 7 
2.2 
Hematopoietic Cell Transplantation (HCT) for MPS VI ................................................. 7 
2.3 
The Case for Use of Intravenous Administration of Enzyme after HCT ...................... 14 
2.4 
Potential Assessments of Patient Response .............................................................. 16 
2.5 
Dosing Rational and Assessments of Potential Toxicity ............................................. 19 
3 
Patient Selection ............................................................................................................... 20 
3.1 
Inclusion Criteria ........................................................................................................ 21 
3.2 
Exclusion Criteria ....................................................................................................... 21 
4 
Patient Registration ........................................................................................................... 21 
4.1 
Registration with the Masonic Cancer Center Clinical Trials Office ............................ 21 
4.2 
Patients Who Are Registered and Do Not Receive Study Treatment ......................... 22 
5 
Treatment Plan .................................................................................................................. 22 
5.1 
Baseline Assessment/Identification of a Local Medical Facility .................................. 22 
5.2 
Dosage and Administration ........................................................................................ 22 
5.3 
Duration of Therapy ................................................................................................... 23 
5.4 
Duration of Study Participation .................................................................................. 24 
6 
Naglazyme Preparation, Administration, Availability and Expected Side Effects ................ 24 
6.1 
Dosage Forms and Strengths .................................................................................... 24 
6.2 
Preparation for Administration ................................................................................... 24 
6.3 
Premedication............................................................................................................ 25 
6.4 
Drug Procurement ..................................................................................................... 26 
6.5 
Contraindications ....................................................................................................... 26 
6.6 
Warnings and Precautions ......................................................................................... 26 
6.7 
Clinical Trials Experience .......................................................................................... 28 
6.8 
Immunogenicity ......................................................................................................... 30 
6.9 
Post-marketing Experience ........................................................................................ 30 
6.10 
Use in Specific Populations ....................................................................................... 31 
6.11 
Use in Pregnancy ...................................................................................................... 31 
7 
Required Observations/Testing ......................................................................................... 32 


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7.1 
Pre-Screening (after signing pre-screening consent) ................................................. 32 
7.2 
Assessments to Be Performed at the University of Minnesota ................................... 32 
7.3 
Specific Disease Related Evaluations ........................................................................ 32 
7.4 
Treatment at Local Medical Facility and Collection of Urine GAG .............................. 34 
7.5 
Description of Study Assessments ............................................................................. 34 
8 
Adverse Event Reporting ................................................................................................... 39 
8.1 
Definitions .................................................................................................................. 39 
8.2 
Adverse Event Documentation .................................................................................. 40 
8.3 
Required Expedited Reporting:  Local Medical Facilities to MCC Study Coordinator . 40 
8.4 
Required Reporting: MCC to U of MN IRB, BioMarin, and MCC SAE Coordinator ..... 42 
9 
Study Data Collection and Monitoring ................................................................................ 43 
9.1 
Data Management ..................................................................................................... 43 
9.2 
Case Report Forms ................................................................................................... 43 
9.3 
Data and Safety Monitoring Plan (DSMP) .................................................................. 44 
9.4 
Monitoring .................................................................................................................. 44 
9.5 
Record Retention ....................................................................................................... 44 
10 Statistical Considerations .................................................................................................. 45 
10.1 
Statistical Endpoints .................................................................................................. 45 
10.2 
Statistical Analysis ..................................................................................................... 45 
10.3 
Sample Size Justification ........................................................................................... 45 
10.4 
Monitoring Guidelines: Stopping Rules ...................................................................... 45 
11 Ethical Considerations ....................................................................................................... 46 
11.1 
Good Clinical Practice ............................................................................................... 46 
11.2 
Ethical Considerations ............................................................................................... 46 
11.3 
Institutional Board Review (IRB) ................................................................................ 46 
11.4 
Informed Consent ...................................................................................................... 46 
12 References ........................................................................................................................ 47 
Appendix I – Eligibility Checklist ................................................................................................ 52 
 


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Protocol Synopsis 
Study of Administration of Intravenous Naglazyme® Following Allogeneic 
Transplantation for Maroteaux-Lamy Syndrome 
Study Design: 
This is a single center study in which Naglazyme® will be given weekly for 
two years in patients with Maroteaux-Lamy syndrome, also known as 
mucopolysaccharide VI (MPS VI), who have previously been treated with an 
allogeneic transplant. 
 
Primary 
Objective: 
The primary objective of this study is to evaluate the efficacy of weekly 
Naglazyme given for 2 years to patients with Maroteaux-Lamy syndrome 
after allogeneic transplantation as measured by the change in urinary GAG 
excretion; the change in endurance and mobility as measured by the 6-
minute walk test and standard tests of range of motion and mobility; and the 
change in neurocognitive ability. 
 
Secondary 
Objectives: 
The secondary objectives of this study are: 
• to measure the development of antibodies, including neutralizing antibodies, 
associated with weekly Naglazyme® infusion in this patient population;  
• to evaluate the impact of these antibodies on cardiorespiratory and skeletal 
parameters as measured by the 6-minute walk test and standard tests of 
range of motion and mobility, and the change in neurocognitive ability 
Inclusion 
Criteria: 
• Mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome) 
treated with a prior allogeneic transplant >2 years previously 
• Persons who have received or are currently receiving Naglazyme may be 
considered for enrollment 
• >10% engraftment based on most recent testing (within previous year) 
• Willing to commit to traveling to the University of Minnesota every 6 
months for 2 years 
• Written informed consent with parent/guardian consent for children < 18 
years of age or persons unable to consent with minor assent if appropriate 
Exclusion 
Criteria: 
 Pregnant or breastfeeding  
• 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 
Accrual 
Objective: 
10 evaluable patients 
 
 
 


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Schema 
 
 
Patient Population:  Mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome) 
treated with an allogeneic transplant more than 2 years prior to study enrollment and > 10% 
engraftment on most recent testing (patients need not have been transplanted at the University 
of Minnesota)  
 
 
Disease specific testing will be performed per section 7.3.   
 
Non-local patients will be treated with Naglazyme at a medical facility close to their home with 
mandatory visits to the University of Minnesota every 6 months   
Arrangements will be made with the patient for the shipping urine to UMN for urine GAG testing 
for the 1st 30 days of enzyme and at months 3, 9, 15 and 21. 
 
 
If meets pre-
screening 
requirements 
and patient still 
interested - 
travel to UMN to 
complete Study 
enrollment 
procedures 
Naglazyme® 1.0 mg/kg IV 
once a week for 2 years 
unless unacceptable side 
effect, non-compliance or at 
the discretion of the 
participant, family or provider 
if there are adverse events 
Pre-Screening 
Information 
Packet to 
potential 
participant 
If patient 
returns signed 
screening 
documents - 
confirm 
engraftment 
status 


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1 
Objectives 
1.1 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of weekly 
Naglazyme given for 2 years to patients with Maroteaux-Lamy syndrome after 
allogeneic transplantation as measured by the change in urinary GAG excretion; 
the change in endurance and mobility as measured by the 6-minute walk test and 
standard tests of range of motion and mobility; and the change in neurocognitive 
ability. 
 
1.2 
Secondary Objectives 
The secondary objectives of this study are: 
• 
to measure the development of antibodies, including neutralizing antibodies, 
associated with weekly Naglazyme® infusion in this patient population  
• 
to evaluate the impact of these antibodies on cardiorespiratory and skeletal 
parameters as measured by the 6-minute walk test, pulmonary, function test 
and standard tests of range of motion and mobility 
 
2 
Background and Study Rationale 
2.1 
Overview of MPS VI 
Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome, OMIM 253200) is an 
inherited lysosomal storage disease resulting from the deficiency of functional 
enzyme N-galactosamine 4-sulfatase (arylsulfatase B, ARSB) (Neufeld and 
Muenzer, 2001).  This enzyme is responsible for the degradation of dermatan 
sulfate, an essential glycosaminoglycan (GAG) found within the extracellular 
matrix of connective tissue.  Accumulation of dermatan sulfate in MPS VI results in 
the clinical picture of small stature, dysostosis multiplex, joint pain and stiffness, 
coarsened facial features, corneal clouding, conductive hearing losses, 
macroglossia, upper airway obstruction, restrictive pulmonary disease, cardiac 
valve disease and cervical cord compression from dural thickening and 
atlantoaxial instability.  Urinary GAG excretion >200µg/mg creatinine is associated 
with an accelerated clinical course while urinary GAG levels below 100µg/mg 
creatinine appears to predict longer survival and a milder phenotype (Swiedler, 
2005). 
2.2 
Hematopoietic Cell Transplantation (HCT) for MPS VI  
The first HCT for MPS VI was performed on a 12 year old girl in 1983 at the 
University of Minnesota and thereafter was performed regularly in several centers 
from 1984 until ~2000 (Krivit, 1984; Herskhovitz, 1999).  Because cognitive decline 
was not considered to be present in MPS VI (in contrast to severe MPS I) and 


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because the reported long-term HCT-associated mortality has been estimated to 
be 30-35%, recent treatment guidelines have recommended HCT for MPS VI only 
if ERT fails (Giugliani, 2007; Prasad, 2010).  Thus, due to small numbers of widely-
dispersed recipients (Turbeville, 2011), the long-term benefits of HCT in MPS VI 
have remained limited to isolated case reports without a systematic review of 
benefits. 
 
2.2.1 
Demographics of patients undergoing HCT for MPS VI 
Turbeville et al (2011) have summarized the survival outcome of HCT for MPS VI 
for 45 patients (24M, 21F) whose data has been recorded with the Center for 
International Blood and Marrow Transplant Research (CIBMTR) from 1982-2007.  
Diagnosis had been made at a median age of 1 year (range <1-9 years) with HCT 
occurring only at a median age of 5 years (range 1-22 years).  This much older age 
at transplant is in marked contrast to HCT performed for severe MPS I (performed 
as early as possible in infancy and – unless extenuating circumstances exist – 
before 2 years of age) and may account for part of the post-HCT findings noted 
below.  Two-thirds of the transplants occurred between 1982 and 2000.  Patient 
country of origin was United States (60%), followed by Saudi Arabia (18%) with 5 
countries (Australia, Brazil, China, England, Japan) accounting for the remaining 
22% of patients.  Detailed information on urinary GAG excretion, enzyme level and 
mutation were not included in this work thus precluding an assessment of severity 
of disease. 
 
2.2.2 
HCT procedure and survival for MPS VI 
Two-thirds of the patients (N=30) underwent conditioning with cyclophosphamide 
and busulfan; total body irradiation was part of conditioning in an additional 13%.  
Bone marrow was the most common graft source (74%) with cord (24%) or 
peripheral (1%) accounting for the remainder.  Unrelated-donors accounted for 
60% and HLA-identical sibling or other related donor for the remaining 40% of 
transplant source (Turbeville).  Information on the enzyme level of the donor 
(normal or heterozygous) was not included.  
 
Overall survival for these 45 patients was 78% (range 65-89%) at one year, and 
66% (range 52-79%) at three years after transplant.  Survival was better in 
transplants performed before 1995 (79% 3 year survival), suggesting that those 
transplanted 
in 
larger 
centers 
may 
have 
fared 
better. 
 
With 
HCT, 
hepatosplenomegaly (HSM) quickly resolved, skin coarseness lessened, nasal 
secretions decreased and upper airway obstruction improved (Table 1).   Cognition 
remained intact and usually within the normal range (Ahmed, 2013).  Despite these 
favorable findings, multiple organ systems remain un- or partially-corrected after 
HCT. 
 
 


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2.2.3 
Systems remaining abnormal after HCT in MPS VI  
2.2.3.1  
Urinary GAG excretion remains abnormal.   It has been 
repeatedly shown that urinary GAG excretion after HCT, although 
improved from baseline values, may not achieve normal values (Table 1).  
Hershkovitz (1999) has found this in 4 transplanted MPS patients after 1-
9 years of follow-up; Whitley and Utz (2010) showed that urinary GAG 
was elevated in a single patient despite 20 years of successful 
engraftment; and finally Sohn (2012) showed it in a single patient 10 
years after HCT. 
 
2.2.3.2  
Growth and endocrine function remain impaired.  
Despite successful engraftment small stature is consistently found long-
term after HCT for MPS VI with heights as much as 10 standard 
deviations below normal for age reported (Table 1).  A relationship to age 
at transplant has not yet been studied.  Endocrine abnormalities are not 
routinely sought but appear to be common. Primary ovarian failure, 
hypogonadotrophic hypogonadism and elevated IGF-1 have all been 
reported after HCT in MPS VI.  These findings are very similar to the 
endocrine and growth data of 48 children with MPS IH treated with HCT 
reported by Polgreen et al (2008) between 1983 and 2002, who had 
survived more than 1 year after HCT.   In this study there was a very high 
prevalence of short stature (71% at last evaluation) and endocrinopathy 
(27% subclinical or clinical hypothyroidism, 7-40% GH deficiency) in 
children with MPS IH after HCT. 
 
This growth failure is likely multifactorial, due to hormonal deficiencies, 
i.e. - high prevalence of thyroid disease and growth hormone (GH) 
deficiency, and mechanical abnormalities , i.e. - known progression of 
skeletal disease after HCT (Oussoren, 2011), local accumulation of GAG, 
and abnormalities in the growth plate in MPS likely causing local GH 
resistance and impaired bone growth.  Although not significantly 
associated with short stature in this study, the use of irradiation in the 
bone marrow transplant preparative regimen is thought to cause 
resistance to GH and insulin-like growth factor-1 (IGF-1) (Brauner, 1997). 
 
2.2.3.3  
Mobility is improved but skeletal manifestations 
(dysostosis multiplex) and contractures persist.  Mobility is reported 
to be improved in the majority of MPS VI HCT recipients who have been 
observed to ‘run better’, ‘walk long distances’, and swim.  Despite this 
improvement, joint contractures of the elbows and knees have been 
reported and carpal tunnel surgery is often required (Table 1).  Dysostosis 
multiplex- 
the 
radiographic 
constellation 
of 
characteristic 
bone 
abnormalities including kyphosis and scoliosis with anterior beaking of 
vertebrae, hip dysplasia, and genu valgum- is characteristic of MPS VI 


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(Garcia, 2010; White, 2013).  These changes persist and progress after 
successful HCT in MPS VI; surgical correction has been required for hips 
and knees and lumbar fractures have been noted.  Low whole body bone 
mineral density measured by DXA is present in individuals with MPS I, II 
and VI (Polgreen 2013). 
 
The etiology of these bony abnormalities, compounded by frequent joint 
contractures, has yet to be determined for any MPS syndrome.  Animal 
model studies have indicated abnormalities in osteoclasts (responsible for 
bone resorption), osteoblasts (bone formation), and chondrocytes 
(Oussoren, 2011).  Studies of the growth plates in both human and 
animal models of MPS have shown vacuolated chondrocytes due to GAG 
accumulation and a loss of the usual columnar architecture of the growth 
plate.  HCT has also been associated with abnormalities of bone density 
(Mosstoufi-Moab, 2012). 
 
2.2.3.4  
Obstructive sleep apnea and pulmonary function – 
mixed results after HCT.  Obstructive sleep apnea has been found to 
occur commonly in individuals with MPS VI with more severe hypoxemia 
and more sleep disruption occurring in pubertal or post-pubertal 
individuals (Lin, 2010).  Lin speculated that macroglossia, adenotonsillar 
hypertrophy, excessive GAG deposition in the tracheobronchial mucosa, 
restrictive lung disease and decreased abdominal dimension due to 
lumbar hyperlordosis and hepatosplenomegaly all contributed the 
progressive nature of this finding.  After HCT obstructive sleep apnea was 
reported resolved or improved in 4 patients with MPS VI; snoring was 
decreased in one patient; CPAP pressure lowered in another; and a final 
patient who previously had been a mouth breather became a nose 
breather with engraftment.  The patient in whom CPAP pressure had 
been decreased had only 6 months of follow-up but had undergone HCT 
at 12 years of age for progressive airway obstruction with severe 
obstructive sleep apnea and desaturation, and extreme airway narrowing 
documented by CT with concern for future total airway obstruction. 
 
  
 


Table 1.  Summary of findings after HCT in patients with MPS VI.      
Parameter 
              Study 
McGovern 
(1986) 
Imaizumi (1994) 
Alvaro 
(1998) 
Hershkovitz  
(1999) 
Lee (2000) 
Wang 
(2008) 
Do Cormo 
(2010) 
Whitley 
(2010) 
Sillence (2011) 
Sohn (2012) 
Age at 
transplant 
13 yr ( F) 
13.75 yr 
12 yr  (M) 
3-9.5 yrs  (2M, 2F) 
5.8  yr  (M) 
10 yr  (F) 
22 months ( M) 
1.5 yr(M) 
3 yr ( F) 
5 yr ( )F 
Years follow-up 
3.25 yr 
4 yr 
0.5 yr 
1-9 yrs 
15 months 
12 yrs 
13 yrs 
20 yrs 
1 yr 
10 yrs 
Urine GAG/cr 
ratio 
‘Normal values’ 
Decreased 
No data 
7—81; 15,222 
No data 
‘normal’ 
No data 
7-8.53 
Normal 
92.24 
Growth 
No change -
short stature 
Improved  
No data 
<3 centile 
Some growth 
‘Slow’ 
Short stature  
Short 
stature 
‘growing and 
developing well’ 
-10 SD < nl 
Mobility 
Improved  
Walked >200 
meters compared 
to 50 M before 
transplant 
No data 
Improved in all pts 
Runs better and 
can walk long 
distances 
Walks, 
bikes  on 
own 
Swims 
No data 
Improved but 
delayed 
425.6 
feet/12 
minutes 
Skeletal system 
No change 
noted 
No change 
No data 
Less lordosis; 
dysostosis multiplex 
persists in all; 
progressive hip 
changes – surgery in 
2 pts 
Knee 
contractures 
remain; no 
resolution 
skeletal 
deformities 
No change 
Large head, 
‘skeletal 
alterations’ 
No data 
Minimal 
progression 
gibbus and 
metatarsus 
adductus 
Deformities 
present 
including 
lumbar 
vertebral 
fractures 
Upper 
extremities 
Improved ROM 
Improved  
No data 
Carpal tunnel surgery 
Fingers less stiff; 
contractures of 
elbows remain 
Bathes on 
own 
Articular 
limitation 
No data 
No data 
Contractures 
persist 
Respiratory 
Resolution 
OSA 
No data 
↓CPAP 
↓OSA- 1 pt; 
Now a nose 
breather, not 
mouth breather 
↓snoring,  
↓URI  
↓SOB with 
exercise 
Mouth breather 
No OSA 
Resolution 
OSA* 
No data 
Cardiac 
Improved cor 
pulmonale 
No progression of 
cardiac and 
valvular 
dysfunctions 
No data 
Myocardium 
improved; valves 
unchanged 
No data 
No 
significant 
change 
Heart murmur 
Normal 
function 
No change – 
mitral 
regurgitation, 
normal LV 
function 
Moderate 
aortic 
and 
mitral 
insufficiency 
unchanged 
ENT 
No data 
No data 
↓otorrhea 
Conductive hearing 
loss – 3 pts; 
Sensorineural hearing 
loss – 1 pt 
Resolution dysphonia 
and hoarseness – 2 
pts 
↓suppurative 
middle ear 
effusion 
No data 
Macroglossia, 
gingival 
hyperplasia 
present 
Abnormal teeth 
No data 
Some improved 
hearing; 
resolution 
tonsillar and 
adenoid 
hypertrophy* 
No data 
Ophthalmologic  
Subjective 
improvement 
No improvement 
No data 
Continued corneal 
clouding 
Continued 
corneal clouding 
No data 
Glaucoma, 
corneal opacity 
Corneal 
clouding 
No data 
Corneal 
opacity present 
Spinal cord 
No data   
No data 
No data 
No cervical cord 
compression or 
atlantoaxial instability 
No data 
No data 
Odontoid 
hypoplasia 
present 
No data 
No data 
None stated 
Skin  
Remains 
coarse 
Less tight 
↓coarseness 
↓coarseness 
↓coarseness 
No data 
Hypertrichosis  
No data 
↓coarseness* 
↓coarseness 
Liver/spleen 
Normalized 
↓hepatomegaly  
↓HSM 
No data  
Resolution HSM 
No data 
No data 
No data 
Resolution 
HSM* 
No HSM 
Endocrine 
No data 
 
No data 
Abnormalities present 
No data 
No data 
No data 
None 
found 
No data 
↑IGF-1 present 
Neuropsych 
normal  
 
 
Uncertain  
In school 
University 
In school 
No data 
No data 
No data 
1. Range GAG/cr ratio 1-5;   
2. Range GAG/cr ratio  2-15;   
3. Normal <6.5 mgGAG/mmol cr;   
4. Normal <85 Unit CPC/g cr 
*Resolution of tonsillar and adenoid hypertrophy, HSM, OSA and cutaneous features occurred during ERT before HCT


Naglazyme Following Allogeneic Transplantation for Maroteaux-Lamy Syndrome 
 
 
 
 
 
 
 
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Pulmonary function testing, reported in 6 untreated MPS VI patients aged 
7.6-17.4 years of age, has shown that restrictive pulmonary disease was 
present in 4 of them (Lin, 2013).  Abnormalities of pulmonary function 
increased with age with virtually all post-pubertal MPS patients showing 
evidence of dysfunction.  Post-HCT formal pulmonary function testing has 
been reported in only one patient (Sohn, 2012), a 15 year old recipient 
who showed decreased FEV1 and FVC (65% and 55% predicted, 
respectively) some 10 years after HCT.  Since no pulmonary function 
testing had been performed prior to HCT, the effect of HCT in this single 
patient cannot be judged although the findings suggest continued 
moderate to severe restrictive pulmonary disease, perhaps due to the 
continued skeletal abnormalities. 
 
2.2.3.5  
Cardiac function remains normal but valves continue 
to be abnormal.  While myocardial performance is usually normal, 
thickened, regurgitant and/or stenotic valves, as well as ventricular 
hypertrophy, are a common finding in untreated MPS VI (Braunlin, 2013).  
After successful HCT, ventricular function has been reported to continue 
to be normal in MPS VI (Table 1) – just as has been reported after HCT 
for severe MPS I (Braunlin, 2003).  Similarly, just as in post-HCT severe 
MPS I, cardiac valves in MPS VI do not appear to benefit from HCT.  
Thickened and regurgitant mitral and aortic valves remain present despite 
long-term successful engraftment.  It is speculated that the avascular 
nature of cardiac valve tissue precludes population of this tissue by 
normal donor cells. 
 
2.2.3.6  
ENT function is partially corrected by HCT.  The ENT 
manifestations of MPS include otitis media with effusion, mixed 
conductive and sensorineural hearing loss, macroglossia, mandibular 
abnormalities, abnormalities of dentition and bite, and adenotonsillar 
hypertrophy (Simmons, 2005).  Decreased otorrhea and suppurative 
middle ear effusions have been reported after HCT.  Although some 
improvement in hearing has been reported after HCT, continued 
conductive hearing loss and a new finding of sensorineural hearing loss 
have been reported despite engraftment (Table 1).  Macroglossia and 
abnormal dentition have persisted late after HCT in at least one 
individual.  Adenotonsillar hypertrophy, dysphonia and hoarseness, by 
contrast, appear to have resolved in 2 others after HCT for MPS VI. 
 
2.2.3.7  
Ophthalmologic 
abnormalities 
persist. 
 
Corneal 
clouding, glaucoma and optic nerve abnormalities from GAG deposition 
within ocular tissue, surrounding tissues or the brain have all been 
described in untreated MPS VI (Fahnehjelm, 2012). Despite successful 


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engraftment, corneal clouding and glaucoma continue to persist after 
HCT in MPS VI (Table 1). 
 
2.2.3.8  
Thoracic, but not cervical, cord abnormalities have 
been reported after HCT.  Cervical cord compression, one of the most 
common and serious complications of untreated MPS VI, is thought to be 
due to dysplasia of the odontoid process, diffuse thickening of the dura 
and extradural tissues from GAG deposition and atlantoaxial instability 
(Jurecka 2012).  A review of the literature showed that spastic 
tetraparesis and hyperreflexia was the most common presentation. 
Surgical decompression was performed in the majority of these patients 
and all procedures resulted in improvement.  No case of cervical cord 
compression in MPS VI has been reported after HCT (Table 1) although 
Ahmed and colleagues (2013) did find one MPS VI patient who required 
thoracic (T11-12) cord decompression after HCT.   
 
2.2.3.9  
Neurocognitive 
complications. 
 
Abnormalities 
are 
frequently found in the brain MRI of children with MPS VI (Azevedo, 
2013) with more than 90% of those studied showing the presence of 
dilated perivascular spaces, 76% having white matter lesions, 66% with 
hydrocephalus and 47% with cerebral atrophy.  Correlations were found 
between age and both normalized white matter lesion load and 
normalized cerebral volume supporting the progressive nature of the 
disease.  Normalized IQs did not correlate with MRI findings. After HCT a 
preliminary report (Ahmed, 2013) shows that ventricular size appears 
smaller in a small group of MPS VI subjects when compared to those 
receiving ERT; intervention for hydrocephalus has not been reported after 
HCT (Table 1).  A comprehensive evaluation of the brain MRI findings 
and correlation to cervical cord issues has not been reported. 
 
2.2.3.10  Summary of outcome after HCT for MPS VI.  HCT clearly 
improves the health of patients with MPS VI by decreasing GAG 
accumulation within organs where tissue-specific donor hematopoietic 
cells reside.  However, it is undeniable that significant morbidity of the 
disease persists in these patients despite a “successful” transplant. 
Globally, these complications may include continued corneal clouding, 
hearing deficits, cardiac and pulmonary difficulties.  Importantly, despite 
“successful” transplantation, many of the MPS VI patients continue to 
have abnormal urinary GAG excretion, develop significant orthopedic 
difficulties, including spinal changes, limitations of range of motion, 
shoulder, knee and hip changes, as well as carpal tunnel syndrome and 
“trigger digits”.  Many of these changes limit function, cause discomfort, 
and may require surgical intervention. 
 


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Quality of life is significantly impacted for children with MPS due to the 
persistence of skeletal abnormalities, contractures, and severe short 
stature.  These patients, despite a successful transplant procedure, often 
require multiple orthopedic surgeries, frequently need to wear a brace for 
abnormal spine curvatures, and live with significant pain, typically on a 
daily basis.  In part due to this bone disease, their short stature can be 
quite severe, frequently -3 to -6 standard deviations below the mean 
height for age and gender.  Short stature this severe limits activities of 
daily living, and can negatively impact social development, socio-
economic status, and career advancement. 
2.3 
The Case for Use of Intravenous Administration of Enzyme after HCT 
Whitley and Utz (2010) have provided evidence that ERT improves the metabolic 
correction provided by HCT.  Urinary 
GAG levels, which had remained 
slightly greater than normal 20 years 
after successful HCT in a 22 year old 
male with MPS VI, progressively 
declined below the age specific 
normal range after administration of a 
single dose of Naglazyme® (see 
Figure). 
Urinary 
GAG 
levels 
continued to decline for the entire 
study period of 10 days.  This not 
only 
raises 
the 
possibility 
that 
intravenous 
enzyme 
reaches 
sanctuaries 
inaccessible 
to 
the 
effects of HCT but also suggests that 
ERT dosing schedules may need to be individualized. 
 
Long-term administration of ERT after HCT has been reported (Sohn, 2012) in a 
single 15 year old female patient with MPS VI who had undergone successful 
HCT 10 years previously.  Weekly infusions of Naglazyme® over 18 months 
resulted in an increased growth velocity from 2cm/year to 4.5 cm/year; 70% 
increase in the 12-minute walk test; improvement in range of motion of several 
upper and lower extremity joints; ~30% improvement in the 3-minute stair climb 
and improvement in facial features.  Increased distance travelled in the 12-
minute walk test was not only sustained, but continued to improve during the 18 
month follow-up period.  Urinary GAG declined by 50% and reached the normal 
range.  It was hypothesized by the authors that the increased joint mobility and 
growth accounted for the remarkable increase in 12-minute walk test. 
  
HCT provides a continuous, but not necessarily equal, metabolic correction for 
each patient undergoing the process as has been documented in a study of MPS 


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I post-HCT recipients (Church, 2007).  In these MPS I patients, post-HCT 
enzyme levels as well as residual substrate (as determined by urinary GAG) not 
only depended upon the recipient status (genotype, age, peri-transplant 
complications) but also upon the donor and whether full donor chimerism 
occurred after transplantation. In Church’s MPS I patients activity of post-HCT 
leukocyte α-L-iduronidase level varied widely ranging from 7.1µmol/g/h in mixed 
chimerism recipients who had a heterozygous donor to 24.8µmol/g/h in full donor 
chimerism recipients who had a donor with normal enzyme levels.  Residual 
substrate was tightly and inversely related to enzyme activity.  It is clear that 
these same factors exist for individuals with MPS VI undergoing HCT and can 
lead to a considerable variability in metabolic correction. 
 
By contrast, the delivery and distribution of enzyme with ERT differs from HCT.  
In MPS VI, Naglazyme®, delivered by weekly infusion, has a peak plasma 
concentration that occurs at between 120 and 240 minutes into the infusion but is 
not 
measureable in the plasma within 10 minutes following completion of the infusion 
(see figure above, Harmatz, 2005).   In humans the mean elimination half-life in 
patients during initial week of infusion ranges from 6 to 21 minutes (Package 
insert).  The AUCo – t of Naglazyme® increased from the 1 to the 2nd infusion but 
remained stable thereafter.  Urinary GAG excretion dropped by ~75% from 
baseline values but did not normalize during the 96 weeks in which it was 
measured (Harmatz, 2005).  Anti-rASB antibodies developed and the regressed 
during this time but did not appear to affect GAG excretion. Despite the lack of 
urinary GAG normalization, the administration of intravenous Naglazyme® 
significantly decreased urinary GAG, led to improvement in the 6 and 12 minute 
walk tests and 3 minute stair climb, as well as a significant increase in growth 
rate and height (Harmatz, 2008).   
 
As recombinant galsulfase (Naglazyme®) is FDA approved for MPS VI, we 
hypothesize that the addition of intermittent intravenous dosing of Naglazyme® 
may benefit patients following transplantation. The primary objective of this study 
will include measurements that have been previously been shown to improve in 
single patients with MPS VI after HCT: namely, urinary GAG excretion, 


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endurance and mobility.  However, it is possible that adverse effects or toxicity 
may be observed in patients with MPS VI who have previously undergone 
transplantation, as the use of Naglazyme® has been tested long term in only one 
patient within this population (Sohn, 2012). We therefore propose a study with to 
determine if antibody formation is observed and to gather information regarding 
the effect of antibody formation on outcome parameters, with the intent of 
ultimate long-term administration of ERT to MPS VI HCT recipients. 
2.4 
Potential Assessments of Patient Response 
2.4.1 Orthopedic Parameters of Response to Therapy: Methods of Bone 
Assessment.  Given the rapid change in bone size and shape during growth, 
along with the tremendous individual variability in maturity and growth rates, non-
invasive assessment of bone mass and density, such as dual energy x-ray 
absorptiometry (DXA) in pediatric populations presents numerous challenges, 
even in healthy populations (Baim, 2008). Those challenges are magnified in 
clinical populations such as MPS where the bone is uniquely shaped and growth 
rates are even more varied than in healthy children (Polgreen 2013). Despite 
these challenges, peripheral quantitative computed tomography (pQCT) presents 
a feasible way to assess important components of bone density, geometry and 
strength in this population as well as detect earlier changes in bone in response 
to treatment compared to CXA... This is discussed in detail as follows. 
    
Peripheral 
quantitative 
computer 
tomography 
(pQCT). 
 
Peripheral 
quantitative computed tomography (pQCT) provides a 3-dimensional image of 
peripheral bones (tibia, radius and distal femur) thus reducing size-related errors. 
Testing by pQCT also has a higher resolution than DXA and is able to assess 
cortical and trabecular bone volumetric density (vBMD, mg/mm3) separately 
(Zemel, 2008, 2011). This is particularly important in clinical trials as the 
trabecular bone may be earlier and disproportionately affected by disease or 
pharmaceutical intervention. In addition to cortical and trabecular density, pQCT 
provides measures of bone geometry (total and cortical bone area) and 
estimates of bone strength (section modulus and strength strain index) (Zemel, 
2011).  A study using pQCT has assessed bone density, geometry and strength 
in long-term survivors of HCT (Moustafi-Moab, 2012) where significant deficits in 
trabecular volumetric bone mineral density, cortical geometry and muscle area 
were found years after transplantation.  In this study both total body irradiation 
and growth hormone deficiency were significant risk factors for musculoskeletal 
defects.  These factors may play a role in MPS VI HCT recipients and deserve 
investigation. 
 
2.4.1.1 Use of pQCT:  We have collected tibia and radius pQCT scans 
on more than 50 children with MPS and found abnormal bone geometry 
and relatively thin cortical bone (Figure 2). We were able to successfully 
scan at least one limb in most children. We use a flexible arm holder that 


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allows for better and more comfortable positioning, as movement based 
on discomfort can interfere with the imaging. 
  
2.4.1.2.  Markers of Bone Turnover:  Biomarkers of bone turnover have 
been used in adult populations to predict fracture risk (Miller, 2005), to 
monitor the treatment effect of bisphosphonate therapy (Bonnick, 2006), 
and to monitor metastatic disease (Hannon, 2006). Decreased 
osteocalcin has been reported in 50% of adults with Gaucher disease, a 
lysosomal storage disease associated with low bone density and bone 
complications (Van Dussen, 2011). 
 
2.4.1.3.  Radiographic Assessment of Spine and Lower Extremity 
Changes:  Anterior hypoplasia of the lumbar vertebrae causing lumbar 
gibbus and progressive lordosis, hip dysplasia and luxation, progressive 
genu valgum are common findings in MPS VI (Garcia, 2010).  To 
evaluate these parameters, X-rays with local read will be performed for 
changes in the spine (scoliosis series) and for lower extremity 
abnormalities with X-rays of the knees and hips.     
 
2.4.2 Assessment of Joint Mobility and Dexterity.  Untreated MPS VI 
patients exhibit the most severe limitations in shoulder flexion, followed by knee 
extension and elbow flexion (Cardoso-Santos, 2008).  Hand grip strength was 
compromised in all patients in this study and pinch strength showed a positive 
correlation with age.  Limitation of shoulder flexion occurred early and was not 
associated with age suggesting it may be an important clinical diagnostic 
element.  Limitation of elbow flexion interferes with activities of daily life such as 
brushing teeth, combing hair, self-care after toilet. 
 
A. 
B. 
Figure 2. Image of tibia scan with excessive movement (A) in 
MPS I patient (female, age 11 yrs), and (B) a good scan at the 
same site in MPS II patient (male, age 13 yrs). 


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Physical and occupational therapists skilled in the assessment patients with MPS 
will see the enrolled patients, and assess the range of motion/flexibility at the 
designated time points.  Dexterity will be evaluated by timed testing using the 9-
block peg (Reuben, 2013).   
 
2.4.3 Endurance Testing and Gait Analysis: To determine if enzyme infusion 
provides benefit leading to the potential for increased activity, the standard-12 
minute walk test will be performed in accordance with published standards 
(Solway, 2001).  This test has been extensively utilized in determining the effect 
of ERT in improving ambulation in subjects with MPS VI (Harmatz, 2008) and will 
provide the most comparable measure of change for subjects after HCT who 
receive ERT. 
 
The assessment of gait involves more than measuring the distance walked. The 
kinematic gait analysis is a quantitative method.  It describes movements of the 
major joints and gait components of the lower extremity through wearable 
sensors mounted on the lower extremity. Quantitative gait analysis provides 
information about velocity, cadence, step length, and base of support. Slower 
gait speed and shorter step length have been documented in MPS disorders. In 
addition gait kinematics provides key information about angular displacements of 
lower limb joints. It is of particular interest in MPS as joint disease causing joint 
stiffness is one of major factors affecting gait pattern. Another advantage of 
wearable kinematic sensors is low cost and good portability. Gait analysis can be 
a sensitive measure of disease severity and treatment response. 
 
2.4.4 Cardiac Function:  Enrolled patients will have clinical evaluations 
including physical examination, an ECHO and EKG to monitor cardiac changes.  
2.4.5 Neurocognitive Imaging and Testing: We have previously studied 41 
children with MPS IH who were treated with HCT at the University of Minnesota 
(Bjoraker, 2006) and found that treatment of MPS IH with HCT resulted in an 
overall improvement in neuropsychological functioning compared to historical 
controls not treated with HCT.  However, there continued to be limitations in the 
development of 4 measured domains that constitute adaptive functioning: 
communication, daily living skills, socialization, and motor skills, even after HCT 
treatment.  Preliminary neurocognitive testing in subjects with MPS VI have been 
reported by us (Ahmed, 2013). While IQ is normal in MPS VI patients whether 
treated with HCT or ERT, attention span is below average for both.  We have 
also determined that volumetric findings on MRI are consistent with functional 
findings (Kovac, 2013)  with gray matter volumes not different from normal 
controls, but white matter volumes, especially corpus callosum, significantly 
smaller than normal controls, which likely affects function as seen functionally by 
poor attentional deployment. Enrolled subjects (n=6), who are ERT naïve, will 
undergo brain and cervical spine MRI as well as neurocognitive testing, to define 


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parameters as indicated above, at baseline and annually during the proposed 
trial. 
2.5 Dosing Rational and Assessments of Potential Toxicity   
The use of Naglazyme® has been assessed in an open-labeled Phase I/II study 
(Harmatz, 2004) and in a placebo-controlled, double-blind Phase III study with 
extension to 260 weeks (Harmatz, 2006; Harmatz, 2008).  Weekly infusion 
dosage of 1mg/kg was determined to be well tolerated and to provide rapid 
decline in urinary GAG levels as well as rapid improvement in endurance in 
patients with rapidly progressing disease in Phase I/II studies (Harmatz, 2004).  
This is the standard dosing of drug stated in the package insert for Naglazyme®.   
In the open-labeled Phase I/II study (Harmatz, 2004), there were 7 serious 
adverse events (SAEs) during the first 48 weeks of treatment.  Two of these 
events were deemed unrelated to infusion: mild desaturation during sleep in one 
patient that did not vary from baseline findings, and development of brain glioma 
and adenocarcinoma occurring approximately 10 months after the patient 
withdrew from the trial due to an unrelated genetic mutation.  None of the 
remaining five SAEs (hypoxia during routine tracheostomy change, vasovagal 
syncope during intravenous line insertion, paratracheal skin hypertrophy, 
worsening Eustachian tube dysfunction, and bilateral carpal tunnel syndrome) 
were deemed related to study drug.  There were no reports of allergic reactions 
(urticarial, angioedema).  Thirty-one AEs occurred during drug infusion: all were 
assessed as mild and all resolved.  Events deemed related to drug infusion 
included hypotension, tachypnea, skin irritation on neck and chest, pain at IV 
insertion site and a 3-second run of ventricular tachycardia.   During the first 48 
weeks of treatment, 126 AEs were reported with the following assessed as 
possibly related to drug infusion:  lethargy (2), hypotension (1), itching (4), 
rash/skin irritation (4) and intermittent joint popping (1).  
 
In the placebo controlled Phase III trial the incidence of total AEs, severe AEs 
and serious AEs in subjects allocated to Naglazyme® was similar to that of 
subjects receiving placebo (Harmatz, 2010).  Although all patients experienced 
AEs during this 260 week study, only 560 (14%) of AEs were related to 
treatment.  The majority of AEs were mild to moderate in nature; 83 of the total 
AEs (2%) and 10 of 560 were treatment-related AEs were described as severe.  
Two severe AEs occurring during infusion included one subject who, at Week 18 
of treatment, experienced ‘apnea’ requiring intubation 75 minutes into the 
infusion, likely related to diphenhydramine premedication; the second who, at 
Week 167 of treatment, developed laryngeal edema, facial edema and urticarial 
responding 
to 
interruption 
of 
treatment, 
additional 
antihistamine 
and 
corticosteroid treatment.  Non-severe events included respiratory distress, fever, 
mild angioedema with anaphylactoid reaction, and exacerbation of asthma 
several hours after infusion.  All cases responded to decreasing the infusion rate 


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and administering additional medications.  Treatment was not discontinued 
because of these reactions. 
 
Package insert for Naglazyme® indicates that anaphylaxis and severe allergic 
reactions have been seen in patient during, and up to 24 hours after, infusion. 
Type III immune-mediated reactions, including membranous glomerulonephritis 
in a single patient (who was successfully re-challenged) have been reported.  
MPS patients are susceptible to fluid volume overload and a risk of 
cardiorespiratory failure is present in such patients.  It is advised that patients 
using supplemental oxygen or CPAP should have this support readily available 
during infusion in the event of an infusion related reaction or drowsiness from 
pre-treatment with antihistamines. 
 
Infusion 
related 
reactions, 
some 
severe, 
occurred 
frequently 
despite 
pretreatment with antihistamine and, in some cases, antipyretic.  Serious 
reactions included laryngeal edema, apnea, pyrexia, urticarial, respiratory 
distress and anaphylactoid reaction.  Sever adverse reactions included urticarial, 
chest pain, rash, dyspnea, apnea, laryngeal edema and conjunctivitis.  The most 
common drug-related infusion reactions were pyrexia, chills, rash, urticarial, 
dyspnea, nausea, vomiting, abdominal pain, hypertension and headache.  
Infusion related reactions were seen as early as Week 1 and as late as Week 
146; 70% of patients experienced recurrent infusion reactions during the course 
of the infusions.  
 
Interestingly, nearly all of the subjects developed IgG antibodies against 
Naglazyme® (Harmatz, 2004; Harmatz, 2010) by 30 weeks of treatment.  
Despite the presence of antibody, subjects (with rare exception) still experienced 
positive clinical benefit and GAG excretion.  There appeared to be no constant 
predictive relationship between antibody titer, neutralizing or IgE antibodies, 
infusion-associated reactions, urinary GAG or endurance measures.  Antibody 
development was not associated with significant complement depletion during 
infusion but the majority of patients who experienced infusion-associated 
reactions (IARs) had high antibody titers although there were many exceptions 
(Harmatz, 2006).   
 
3 
Patient Selection  
Patients will be referred from other health care providers or self-referred for 
consideration in this protocol.  While there will be every effort to seek out minority 
patients, the patient population is dependent upon the referral pattern.  It is expected 
that this study will enroll patients from throughout North America.  Costs associated with 
travel to and housing during studies at the University will be borne by the funder per 
negotiated budget. 


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Potential participants will be mailed a study information packet which will include two 
copies of the screening consent/a release of information form and the current treatment 
consent.  After reviewing the packet information and if still interested the participant will 
be asked to sign and return the screening consent and the release of information form to 
permit pre-screening to occur (primarily confirm donor engraftment).  If the participant 
meets engraftment criteria, arrangements will be made for travel to the University of 
Minnesota for a multi-day baseline visit which will include review and formal written 
consent to the study using the current treatment form. 
3.1 
Inclusion Criteria 
• Mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome) treated 
with an allogeneic transplant more than 2 years prior to enrollment – patients 
need not have been transplanted at the University of Minnesota  
• Persons who have received or are currently receiving Naglazyme may be 
considered for enrollment  
• >10% engraftment based on most recent testing (within previous year) – 
confirmed during pre-screening 
• If female of child-bearing age, willing to defer pregnancy for the duration of the 
trial 
• Willing to commit to traveling to the University of Minnesota every 6 months for 
the duration of the trial (2 years) 
• Written informed consent prior to the performance of any study related 
procedures with parent/guardian consent for children < 18 years of age or 
persons unable to consent with minor assent if appropriate.  
3.2 
Exclusion Criteria 
• Is pregnant or breastfeeding at screening or baseline, or planning to become 
pregnant (self or partner) at any time during the study.  Pregnancy Category B:  
Adequate and well-controlled studies have not been conducted with Naglazyme 
in pregnant women. Patients who become pregnant will be discontinued from 
study. 
• 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 
 
4 
Patient Registration  
4.1 
Registration with the Masonic Cancer Center Clinical Trials Office 
Potential patients will initially be registered in OnCore upon receipt of a signed 
screening consent.  If the patient later signs the treatment consent and 
completes the study screen/baseline visit, the registration in OnCore will be 
updated.  Otherwise the patient will be considered a screen failure and OnCore 
will be updated to reflect this status. 


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4.2 
Patients Who Are Registered and Do Not Receive Study Treatment 
Patients will have 6 months to enroll into the study after the initial evaluation at 
the University of Minnesota.  If a patient is registered to the study, and is later 
found not able to begin the study treatment, for whatever reason, the patient will 
be removed from study and treated at the physician’s discretion.  The Study 
Coordinator or designee will update OnCore of the patient’s non-treatment status 
and notify the Principal Investigator. Study data will be collected until the time the 
patient is off study.  The reason for removal from study will be clearly document 
in OnCore.  The patient will be replaced, if possible. 
 
5 
Treatment Plan  
5.1 
Baseline Assessment/Identification of a Local Medical Facility  
All potential patients will be assessed at the University of Minnesota according to 
the schedule of assessments in section 7.2 after completion of an initial 
screening per section 3..   
 
 
It is expected that this study will enroll patients from throughout North America.  
During the baseline assessment, arrangements will be made with an appropriate 
medical facility close to the family’s home for administration of some or all of the 
weekly treatments between the required minimum every 6 month visit at the 
University of Minnesota. 
5.2 
Dosage and Administration 
It is anticipated the vast majority of Naglazyme administration will take place at a 
medical facility close the family’s home.  Medical oversight, decision to treat or 
not, and drug administration/monitoring will be based on the clinical judgment of 
the local medical team with consideration of the following standard of care 
guidelines. 
 
The recommended dosage regimen of Naglazyme is 1 mg per kg of body weight 
administered once weekly as an intravenous infusion.  Weekly is defined as once 
during a calendar week with a +/- 1 day window permitted. 
 
There are no recommended dose modifications, only dose delays and infusion 
time adjustment as detailed below. 
 
Pre-treatment Assessment/Dose Delay:  Patients should be briefly assessed 
prior to each dose for general health status.  Treatment may be delayed weekly if 
medically indicated or at the patient’s family request (i.e. illness, travel); however, 
a break of more than 4 weeks between Naglazyme doses will result in removal 
from study. 


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Consider delaying Naglazyme infusions in patients who present with an acute 
febrile or respiratory illness because of the possibility of acute respiratory 
compromise during infusion of Naglazyme.  Refer to section 6.6.4 for additional 
information. 
Pre-medication Guidelines:  Patients should be treated approximately 30 
minutes to one hour prior to each infusion with non-sedating antihistamines such 
as citrazine or loratadine.  Antipyretics may be administered at the discretion of 
the investigator.  If a patient has a history of infusion reactions or other risk 
factors (e.g., history of allergies), a sedating antihistamine such a 
diphenylhydramine may be administered, and premedication with additional 
agents such as steroids maybe considered.  Refer to section 6.6.5 for additional 
information. 
 
The total volume of the infusion should be delivered over a period of time of no 
less than 4 hours.  Naglazyme should be diluted with 0.9% Sodium Chloride 
Injection, USP, to a final volume of 250 mL and delivered by controlled 
intravenous infusion using an infusion pump.  The initial infusion rate should be 6 
mL per hour for the first hour.  If the infusion is well tolerated, the rate of infusion 
may be increased to 80 mL per hour for the remaining 3 hours.  The infusion time 
can be extended up to 20 hours if infusion reactions occur. 
 
For patients 20 kg and under or those who are susceptible to fluid volume 
overload, physicians may consider diluting Naglazyme in a volume of 100 mL 
[see Warnings and Precautions (section 6.6 and specifically section 6.6.3)].  The 
infusion rate (mL per hour) should be decreased so that the total infusion 
duration remains no less than 4 hours. 
5.3 
Duration of Therapy 
Naglazyme® every week, based on the schedule of the patient and potential 
confounding factors (illness, travel, etc.), will continue for 2 years unless one of 
the following occurs.  The decision to stop therapy may be based on the 
following: 
• 
Unacceptable side effects 
• 
A change in therapy is felt to be in the best interest of the patient 
• 
More than 4 week break between Naglazyme® doses 
• 
Patient/parent withdraws consent 
• 
Patient/parent preference 
 
At the conclusion of the study, subjects may elect to continue receiving 
Naglazyme® under the care of their local providers although no further 
evaluations will be supported by BioMarin as part of this study after the first two 


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years of therapy.  The feasibility of continued therapy may of course be 
dependent on continued insurance coverage, and is therefore not assured.  
5.4 
Duration of Study Participation 
Study participation will be for 2 years with the 24 month visit at the University of 
Minnesota the final study related visit.  If treatment is discontinued earlier, a final 
study visit to the University of Minnesota will be scheduled. 
 
 
6 
Naglazyme Preparation, Administration, Availability and 
Expected Side Effects  
Refer to the prescribing information for Naglazyme available through 
www.naglazyme.com/ 
6.1 
Dosage Forms and Strengths 
Injection; 5 mL vials (5 mg per 5 mL). 
6.2 
Preparation for Administration 
Each vial of Naglazyme provides 5 mg of galsulfase (expressed as protein 
content) in 5 mL of solution and is intended for single use only.  Do not use the 
vial more than one time.   
 
The concentrated solution for infusion must be diluted with 0.9% Sodium 
Chloride Injection, USP, using aseptic techniques.  Prepare Naglazyme using 
low-protein-binding containers and administer the diluted Naglazyme solution to 
patients using a low-protein-binding infusion set equipped with a low-protein-
binding 0.2 µm in-line filter.  There is no information on the compatibility of diluted 
Naglazyme with glass containers. 
 
Instructions for Use 
Prepare and use Naglazyme according to the following steps.  Use aseptic 
techniques. 
a. 
Determine the number of vials to be used based on the patient’s weight and 
the recommended dose of 1 mg per kg: 
- Patient’s weight (kg) × 1 mL/kg of NAGLAZYME = Total number of nL of 
NAGLAZYME 
- Total number of Nl of NAGLAZYME ÷ 5 mL per vial = Total number of 
vials 
- Round up to the next whole vial.  Remove the required number of vials 
from the refrigerator to allow them to reach room temperature.  Do not 
allow vials to remain at room temperature longer than 24 hours prior to 
dilution.  Do not heat of microwave vials. 


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b. Before withdrawing the NAGLAZYME solution from the vial, visually inspect 
each vial for particulate matter and discoloration.  The NAGLAZYME solution 
should be clear to slightly opalescent and colorless to pale yellow.  Some 
translucency may be present in the solution.  Do not use if the solution is 
discolored or it there is particulate matter in the solution. 
 
c. From a 250 mL infusion bag of 0.9% Sodium Chloride Injection, USP, 
withdraw and discard a volume equal to the volume of NAGLAZYME solution 
to be added.  If using a 100 mL infusion bag, this step is not necessary. 
 
d. Slowly withdraw the calculated volume of NAGLAZYME from the appropriate 
number of vials using caution to avoid excessive agitation.  Do not use a filter 
needle, as this may cause agitation.  Agitation may denature NAGLAZYME, 
rendering it biologically inactive. 
 
e. Slowly add the NAGLAZYME solution to the 0.9% Sodium Chloride Injection, 
USP, using care to avoid agitation of the solutions.  Do not use a filter needle. 
 
f. Gently rotate the infusion bag to ensure proper distribution of NAGLAZYME.  
Do not shake the solution. Administer the diluted NAGLAZYME solution to 
patients using a low-protein-binding infusion set equipped with a low-protein-
binding 0.2 µm in-line filter. 
 
NAGLAZYME does not contain preservatives; therefore, after dilution with saline, 
the infusion bags should be used immediately.  If immediate use is not possible, 
the diluted solution must be stored refrigerated at 2oC to 8oC (36oF to 48oF) and 
administered within 48 hours from the time of dilution to completion of 
administration.  Other than during infusion, do not store the diluted NAGLAZYME 
solution at room temperature.  Any unused product or waste material must be 
discarded and disposed of in accordance with local requirements. 
 
NAGLAZYME must not be infused with other products in the infusion tubing.  The 
compatibility of NAGLAZYME in solution with other products has not been 
evaluated. 
6.3 
Premedication 
After 
pre-infusion 
assessments, 
all 
patients 
should 
be 
treated 
approximately 30 minutes to one hour prior to each infusion with non-
sedating antihistamines such as citrazine or loratadine.  Antipyretics may 
be administered at the discretion of the investigator.  If a patient has a 
history of infusion reactions or other risk factors (e.g., history of allergies), 
a sedating antihistamine such a diphenylhydramine may be administered, 


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and premedication with additional agents such as steroids maybe 
considered. 
6.4 
Drug Procurement 
NAGLAZYME is commercially available.  The cost of the drug will be billed to the 
patient’s health insurance/health plan. 
 
During the baseline assessment, arrangements will be made with an appropriate 
medical facility close to the family’s home for administration of some or all of the 
weekly treatments between the required minimum every 6 month visit at the 
University of Minnesota. 
 
While at the University of Minnesota and with BioMarin Patient & Physician 
Support (BPPS), insurance coverage will be verified.   
 
In addition, if the local medical facility cannot or prefer not to oversee the 
administration of weekly Naglazyme, Fairview Home Infusion (FHI) will facilitate 
arrangement of local administration of the drug.   
6.5 
Contraindications 
 
None. 
6.6 
Warnings and Precautions 
6.6.1 Anaphylaxis and Allergic Reactions 
Anaphylaxis and severe allergic reactions have been observed in patients during 
and up to 24 hours after NAGLAZYME infusion.  Some of the reactions were life-
threatening and included anaphylaxis, shock, respiratory distress, dyspnea, 
bronchospasm, laryngeal edema, and hypotension.  If anaphylaxis or other 
severe allergic reactions occur, NAGLAZYME should be immediately 
discontinued, and appropriate medical treatment  
should 
be 
initiated. 
In 
patients who have experience anaphylaxis or other severe allergic reactions 
during infusion with NAGLAZYME, caution should be exercised upon 
rechallenge; appropriately trained personnel and equipment for emergency 
resuscitation(including epinephrine) should be available during infusion. 
6.6.2 Immune-Mediated Reactions 
Type 
III 
immune 
complex-mediated 
reactions, 
including 
membranous 
glomerulonephritis have been observed with NAGLAZYME, as with other 
enzyme replacement therapies.  If immune-mediated reactions occur, 
discontinuation of the administration of NAGLAZYME should be considered, and 
appropriate medical treatment initiated.  The risks and benefits of re-
administering NAGLAZYME following an Immune-mediated reaction should be 
considered.  Some patients have successfully been rechallenged and have 


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continued to receive NAGLAZYME under close clinical supervision [see Adverse 
Reactions]. 
6.6.3 Risk of Acute Cardiorespiratory Failure 
Caution should be exercised when administering NAGLAZYME to patients 
susceptible to fluid volume overload; such as in patients weighing 20 kg or less, 
patients with acute underlying respiratory illness, or patients with compromised 
cardiac and/or respiratory function, because congestive heart failure may result.  
Appropriate medical support and monitoring measures should be readily 
available during NAGLAZYME infusion, and some patients may require 
prolonged observation times that should be based on the  individual needs of 
the patient. [see Adverse Reactions]. 
6.6.4 Acute Respiratory Complications Associated with Administration 
Sleep apnea is common in MPS VI patients and antihistamine pretreatment may 
increase the risk of apneic episodes.  Evaluation of airway patency should be 
considered prior to initiation of treatment.  Patients using supplemental oxygen or 
continuous positive airway pressure (CPAP) during sleep should have these 
treatments readily available during infusion in the event of an infusion reaction, or 
extreme drowsiness/sleep induced by antihistamine use. 
 
Consider delaying NAGLAZYME infusions in patients who present with an acute 
febrile or respiratory illness because of the possibility of acute respiratory 
compromise during infusion of NAGLAZYME. 
6.6.5 Infusion Reactions 
Because of the potential for infusion reactions, patients should receive 
antihistamines with or without antipyretics prior to infusion. Despite routine 
pretreatment with antihistamines, infusion reactions, some severe, occurred in 33 
of 59 (56%) patients treated with NAGLAZYME.  Serious adverse reactions 
during infusion included laryngeal edema, apnea, pyrexia, urticarial, respiratory 
distress, angioedema, and anaphylactoid reaction.  Severe adverse reactions 
included urticarial, chest pain, rash, dyspnea, apnea, laryngeal edema, and 
conjunctivitis. 
 
The most common symptoms of drug-related infusion reactions were pyrexia, 
chills, rash, urticaria, dyspnea, nausea, vomiting, pruritus, erythema, abdominal 
pain, hypertension, and headache.  Respiratory distress, chest pain, 
hypotension, angioedema, conjunctivitis, tremor, and cough were also reported.  
Infusion reactions began as early as Week 1 and as late as Week 146 of 
NAGLAZYME treatment.  Twenty-three of 33 patients (70%) experienced 
recurrent infusion reactions during multiple infusions though not always in 
consecutive weeks. 
 


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Symptoms typically abated with slowing or temporary interruption of the infusion 
and administration of additional antihistamines, antipyretics, and occasionally 
corticosteroids.  Most patients were able to complete their infusions.  Subsequent 
infusions were managed with a slower rate of NAGLAZYME administration, 
treatment with additional prophylactic antihistamines, and in the event of a more 
severe reaction, treatment with prophylactic corticosteroids. 
 
If severe infusion reactions occur, immediately discontinue the infusion of 
NAGLAZYME and initiate appropriate treatment.  The risk and benefits of re-
administering NAGLAZYME following a severe reaction should be considered. 
 
No factors were identified that predisposed patients to infusion reactions.  There 
was no association between severity of infusion reactions and titer of anti-
galsulfase antibodies 
6.7 
Clinical Trials Experience 
Because clinical trials are conducted under widely varying conditions, adverse 
reaction rates observed in the clinical trials of a drug cannot be directly compared 
to rates observed in the clinical trials of another drug and may not reflect the 
rates observed in clinical practice. 
 
NAGLAZYME was studied in a randomized, double-blind, placebo-controlled trial 
in which 19 patients received weekly infusions of 1 mg/kg NAGLAZYME and 20 
patients received placebo; of the 39 patients 66% were female, and 62% were 
White, non-Hispanic.  Patients were aged 5 years to 29 years.  NAGLAZYME-
treated patients were approximately 3 years older than placebo-treated patients 
(mean age 13.7 years versus 10.7 years, respectively). 
 
Serious adverse reactions experienced in this trial include apnea, pyrexia, and 
respiratory distress.  Severe adverse reactions include chest pain, dyspnea, 
laryngeal edema, and conjunctivitis.  The most common adverse reactions 
requiring interventions were infusion reactions. 
 
Table 2 from package insert (PI) summarizes the adverse reactions that occurred 
in the placebo-controlled trial in at least 2 patients more in the NAGLAZYME-
treated group than in the placebo-treated group. 
 
 
 


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PI Table 2: Adverse Reactions that Occurred in the Placebo-Controlled Trial in at 
least 2 Patients More in the NAGLAZYME Group than in the Placebo Group 
 
MedDRA Preferred 
Term 
NAGLAZYME 
(n = 19) 
PLACEBO 
(n = 20*) 
No. Patients (%) 
No. Patients (%) 
All 
19 (100) 
20 (100) 
Abdominal Pain 
9 (47) 
7 (35) 
Ear Pain 
8 (42) 
4 (20) 
Arthralgia 
8 (42) 
5 (25) 
Pain 
6 (32) 
1 (5) 
Conjunctivitis 
4 (21) 
0 
Dyspnea 
4 (21) 
2 (10) 
Rash 
4 (21) 
2 (10) 
Chills 
4 (21) 
0 
Chest Pain 
3 (16) 
1 (5) 
Pharyngitis 
2 (11) 
0 
Areflexia 
2 (11) 
0 
Corneal opacity 
2 (11) 
0 
Gastroenteritis 
2 (11) 
0 
Hypertension 
2 (11) 
0 
Malaise 
2 (11) 
0 
Nasal congestion 
2 (11) 
0 
Umbilical Hernia 
2 (11) 
0 
Hearing Impairment 
2 (11) 
0 
*One of the 20 patients in the placebo group dropped out after Week 4 infusion 
 
Four open-label clinical trials were conducted in MPS VI patients aged 3 months 
to 29 years with NAGLAZYME administered at doses of 0.2 mg/kg (n=2), 1 
mg/kg (n=55), and 2 mg/kg (n=2).  The mean exposure to the recommended 
dose of NAGLAZYME (1 mg/kg) was 138 weeks (range 54 to 261 weeks).  Two 
infants (12.1 months and 12.7 months) were exposed to 2 mg/kg of 
NAGLAZYME for 105 and 81 weeks, respectively. 
 
In addition to those listed in Table 2, common adverse reactions observed in the 
open-label trials include pruritus, urticaria, pyrexia, headache, nausea, and 
vomiting.  The most common adverse reactions requiring interventions were 
infusion reactions.  Serious adverse reactions included laryngeal edema, 


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urticaria, angioedema, and other allergic reactions.  Severe adverse reactions 
included urticaria, rash, and abdominal pain. 
 
Observed adverse events in four open-label studies (up to 261 weeks treatment) 
were not different in nature or severity to those observed in the placebo-
controlled study.  No patients discontinued during open-label treatment with 
NAGLAZYME due to adverse events. 
6.8 
Immunogenicity 
Ninety-eight percent (53/54) of patients treated with NAGLAZYME and evaluable 
for the presence of antibodies to galsulfase developed anti-galsulfase IgG 
antibodies within 4 to 8 weeks of treatment (in four clinical studies).  In 19 
patients treated with NAGLAZYME from the placebo-controlled study, serum 
samples were evaluated for a potential relationship of anti-galsulfase antibody 
development to clinical outcome measures.  All 19 patients treated with 
NAGLAZYME developed antibodies specific to galsulfase; however, the analysis 
revealed no consistent predictive relationship between total antibody titer, 
neutralizing or IgE antibodies, and infusion-associated reactions, urinary 
glycosaminoglycan (GAG) levels, or endurance measures.  Antibodies were 
assessed for the ability in inhibit enzymatic activity but not cellular uptake. 
 
The data reflect the percentage of patients whose test results were considered 
positive for antibodies to galsulfase using specific assays and are highly 
dependent on the sensitivity and specificity of the assay.  Additionally, the 
observed incidence of antibodies in an assay may be influenced by several 
factors including sample handling, timing of sample collection, concomitant 
medications, and underlying disease.  For these reasons, comparison of the 
incidence of antibodies to galsulfase with the incidence of antibodies to other 
products may be misleading. 
6.9 
Post-marketing Experience 
The following adverse reactions have been identified during post-approval use of 
NAGLAZYME.  Because these reactions are reported voluntarily from a 
population of uncertain size, it is not always possible to reliably estimate their 
frequency or establish a causal relationship to drug exposure. 
  
In addition to infusion reactions reported in clinical trials, serious reactions which 
occurred during NAGLAZYME infusion in the worldwide marketing experience 
include anaphylaxis, shock, hypotension, bronchospasm, and respiratory failure. 
 
Additional infusion reactions included pyrexia, erythema, pallor, bradycardia, 
tachycardia, hypoxia, cyanosis, tachypnea, and paresthesia. 
 


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During postmarketing surveillance, there has been a single case of membranous 
nephropathy and rare cases of thrombocytopenia reported.  In the case of 
membranous nephropathy, renal biopsy revealed galsulfase-immunoglobulin 
complexes in the glomeruli.  With both membranous nephropathy and 
thrombocytopenia, patients have been successfully rechallenged and have 
continued to receive NAGLAZYME. 
6.10 
Use in Specific Populations 
6.10.1 Pediatric Use 
Clinical studies with NAGLAZYME were conducted in 56 patients, ages 5 to 29 
years, with the majority of these patients in the pediatric age group [see Clinical 
Studies].  In addition, an open-label study was conducted in four infants (3 
months to 12.7 months) treated with 1 mg/kg (n=2) or 2 mg/kg (n=2) of 
NAGLAZYME.  Safety results in infants were consistent with results observed in 
patients 5 to 29 years old [see Adverse Reactions]. 
6.10.2 Geriatric Use 
Clinical studies of NAGLAZYME did not include patients older than 29 years of 
age.  It is not known whether older patients respond differently from younger 
patients. 
6.11 
Use in Pregnancy 
Pregnancy Category B:  Adequate and well-controlled studies have not been 
conducted with Naglazyme in pregnant women. Patients who become pregnant 
will be discontinued from study. 
 
 


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7 
Required Observations/Testing 
7.1 
Pre-Screening (after signing pre-screening consent) 
Confirm diagnosis, transplant date (must be at least 2 years post for study 
enrollment) and meets > 10% donor engraftment after receipt of a signed pre-
screening consent. 
7.2 
Assessments to Be Performed at the University of Minnesota 
Assessment 
Baseline 
Every 6 
months 
Final study visit 
(24 month visit) 
Consent 
x 
 
 
Demographics 
x 
 
 
Medical History 
x 
x 
x 
Medication history 
x 
x 
x 
Monitor signs and symptoms 
spinal cord compression 
x 
x 
x 
Monitor for adverse events 
x 
x 
x 
Physical Exam 
x 
x 
x 
Height 
x 
 
x 
Weight 
x 
x 
x 
Specific Disease Related 
Evaluations 
Refer to section 7.3 
7.3 
Specific Disease Related Evaluations  
 
R = Research 
Evaluation Performed                                           Month 
on Study 
0 
3 
6 
9 
12 
15 
18 
21 
24 
1.  Metabolic and Biomarker Testing 
• Full metabolic panel 
X 
 
X 
 
X 
 
X 
 
X 
• Total and non-HDL cholesterol; Troponin, BNP 
X 
 
 
 
X 
 
 
 
X 
• Pregnancy testing for post-menarche females  
X 
 
 
 
X 
 
 
 
X 
• Urine and plasma GAG quantitative  
R 
 
R 
 
R 
 
R 
 
R 
• Quantitative urine GAG 3 times prior to initial infusion, 
and then daily for the first 30 days after infusion1 
X 
 
 
 
 
 
 
 
 
• Urine GAG every 3 months1 
 
X 
X 
X 
X 
X 
X 
X 
X 
2.  Endocrine Assessment 
• IGF-1, IGF-BP3, TSH, free T4 
X 
 
 
 
X 
 
 
 
X 
• LH-ICMA, FSH, ultrasensitive estradiol or total 
testosterone for girls ≥ 8 yrs and boys ≥ 9 yrs 
X 
 
 
 
X 
 
 
 
X 
• 25-OH Vitamin D 
X 
 
 
 
X 
 
 
 
X 
3.  Inflammatory/immunology2 
• Anti-Naglazyme antibody 
R 
 
R 
 
R 
 
R 
 
R 
• Anti-Naglazyme inhibiting antibody 
R 
 
R 
 
R 
 
R 
 
R 


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Evaluation Performed                                           Month 
on Study 
0 
3 
6 
9 
12 
15 
18 
21 
24 
4.  Transplant testing 
• Engraftment3(perform more frequently if clinically 
indicated) 
X 
X 
X 
 
X 
 
X 
 
X 
• Mutation analysis 
X 
 
 
 
 
 
 
 
 
5.  Ophthalmologic evaluation 
• Consultation 
X 
 
 
 
X 
 
 
 
X 
6.  Audiology testing 
X 
 
 
 
X 
 
 
 
X 
7.  Cardiology 
• Consultation 
X 
 
R 
 
X 
 
R 
 
X 
• EKG 
X 
 
R 
 
X 
 
R 
 
X 
• ECHO 
X 
 
R 
 
X 
 
R 
 
X 
8. Pulmonary testing 
• Pulmonary function testing 
X 
 
R 
 
X 
 
R 
 
X 
9.  Neurologic testing 
• Neuropsychology evaluation 
X 
 
R4 
 
X 
 
R4 
 
X 
• Pain assessment   
R 
 
R 
 
R 
 
R 
 
R 
• QOL SF36 (>18) or CHQ (<18 years of age) , HAQ 
R 
 
R 
 
R 
 
R 
 
R 
• MRI of brain and C-spine with read (CMRR site) 
R 
 
 
 
R 
 
 
 
R 
10.  Orthopedic Assessment 
• Peripheral Quantitative CT (pQCT) done at 
DCRU/CTSI 
R 
 
 
 
R 
 
 
 
R 
• Scoliosis series with read 
X 
 
 
 
 
 
 
 
X 
• X-ray for genu valgum, hip dysplasia with read 
X 
 
 
 
 
 
 
 
X 
• Bone Age – L hand and wrist (< 21 years only) 
X 
 
 
 
 
 
 
 
 
• Gait assessment (including goniometry, ROM 
measurements on lower limbs) 
R 
 
 
 
R 
 
 
 
R 
• Formation testing (bone specific alkaline phosphatase, 
osteocalcin) 
R 
 
 
 
R 
 
 
 
R 
• Resorption testing (C-telopeptide, deoxypyridoline) 
R 
 
 
 
R 
 
 
 
R 
11. Ortho Functional Assessments 
• 6-minute walk test, Sitting/standing height, Arm span  
(PT) 
R 
 
R 
 
R 
 
R 
 
R 
• Upper extremity muscle strength (hand dynamometer) 
and ROM 
R 
 
R 
 
R 
 
R 
 
R 
• Lower extremity muscle strength (Biodex) 
R 
 
R 
 
R 
 
R 
 
R 
• Upper extremity dexterity testing (PT) 
R 
 
R 
 
R 
 
R 
 
R 
 
1. For visits performed at a local medical facility, each subject will store daily urine specimens in a small 
freezer, purchased by the study with funds budgeted by BioMarin, and will ship specimens with pre-
paid shipping label to the University of Minnesota Send-out Lab. U of MN staff will ship to Mayo for 
testing. 
2. Performed by BioMarin 


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3. Applies only to patients transplanted at UMN; for non-UMN transplants - results will be requested 
from the transplant center (done as part of SOC follow-up).  In these cases, time points in the protocol 
cannot be adhered to and will not constitute a deviation. 
4. Abbreviated evaluation to include attention and adaptive skills 
7.4 
Treatment at Local Medical Facility and Collection of Urine GAG  
A Study Start-Up packet will be provided at the time a local medical facility is 
identified.   
 
For treatments that occur at the patient’s local medical facility, arrangements will 
be made with the study coordinator to communicate all pertinent assessments 
and treatment information. 
 
For days 1 to 30 for the first month and at months 3, 9, 15 and 21 all patient 
specimens will be sent by overnight service to the University of Minnesota using 
the provided FedEx shipping/billing label.  No protocol required laboratory tests 
will be run at the local facility. 
 
Daily morning urine GAG will be collected by the subject and stored in a small 
freezer (provided by the study).  Urine specimens will be couriered weekly on dry 
ice by scheduled pick-up to the University of Minnesota using the provided pre-
paid shipping/billing label.  The specimens will be inspected, repackaged and 
sent to Mayo Laboratories for measurement of quantitative urinary GAG.   
7.5 
Description of Study Assessments 
Anthropometry 
Standard anthropometric measurements will be taken: standing and sitting 
height, weight, arm span, lower segment length.  Height will be measured 
standing without shoes and sitting on a stool and the average of three 
measurements by the same observer using identical technique with a wall 
mounted stadiometer. Each subject will be repositioned between each 
measurement. Height SDS will be calculated based on the National Center for 
Health Statistics 2000 data as provided by the Center for Disease Control.  
Weight to be measured once with subject in light clothing or dressing gown with 
shoes removed.  Arm span is measured between the ends of each middle finger.  
Lower segment is measured from the pubic symphysis to the floor.   
 
Physical examination and vitals 
Pubertal staging will be determined by physical examination of breast or 
testicular volume (by orchiometer) and pubic hair as described by Tanner.  
 
Medical history 
A general medical history will be obtained including concurrent illnesses and 
medications.  Ongoing evaluations will be performed by Pharmacology (Jeanine 


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Utz, PharmD) to determine potential drug interactions and to educate the 
subjects and their families about the delivery of the enzyme as well as the 
importance of the collection of the initial daily urinary GAG.    
 
Laboratory evaluations 
Insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 
(IGFBP-3) are both produced in the liver in response to GH and thus reflect the 
level of GH secretion.  
 
Thyroid stimulating hormone (TSH) is the pituitary hormone which stimulates the 
thyroid gland to produce thyroid hormones, including thyroxine (T4).  Low free T4 
and elevated TSH indicates primary hypothyroidism, low free T4 and low TSH is 
secondary (central) hypothyroidism, and normal free T4 with an elevated TSH is 
subclinical hypothyroidism. 
 
Pubertal stage is assessed by physical examination.  Evaluation of the pituitary-
gonadal axis is done through laboratory testing of luteinizing hormone (LH) and 
follicle stimulating hormone (FSH) which are produced in the pituitary and 
stimulate the gonads to produce testosterone or estradiol.    
 
All endocrinology lab tests will be done by the Fairview University Laboratory, 
Minneapolis, MN, except for LH-ICMA which will be sent to Esoterix and markers 
of bone turnover which will be performed by the University of Minnesota Cytokine 
Laboratory.   
 
Pulmonary function tests 
Routine pulmonary function testing will include spirometry, and pulse oximetry.  It 
is recognized that some very young children (younger than 5 or 6 years) may not 
be able to complete all of the testing requirements.  In these situations, 
documentation should be placed in the medical record and it will not be 
considered a protocol deviation. 
 
 
Peripheral quantitative computed tomography (pQCT) 
Detailed measures of bone mass and strength will be assessed using pQCT 
(XCT-3000, Orthometrix Inc., White Plains, NY). PQCT is a non-invasive 
technique that allows for 3-dimensional assessment of bone volumetric density, 
bone geometry and estimates of bone strength. Images will be taken at the 34, 
38, and 66% sites of the left tibia and the 34 and 38% sites of the non-dominant 
radius measured from the proximal end of the distal growth plate. Standardized 
procedures for participant positioning and data analysis will be used for all scans. 
Image processing and calculation of bone parameters will be completed using 
the manufacturer’s software (version 5.5) and thresholds established in the 
literature and in our previous work.  


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Bone outcomes will include measurements of the mass and tissue density (BMC, 
mg and vBMD, mg/cm3) for both cortical and trabecular bone compartments. 
Total bone cross sectional area (CSA, mm2) and cortical thickness (mm) provide 
meaningful measures of bone geometry at cortical sites, and structural estimates 
of bone bending strength will be calculated using the cross-sectional moment of 
inertia (CSMI, mm4) and section modulus (Z, mm3) as outcomes.  
 
Bone age 
Plain radiographs of the left hand and wrist for individuals <21 years of age will 
be taken for bone age evaluation and interpreted by a University of Minnesota 
Pediatric Radiologist.   
 
Markers of bone turnover/biomarkers 
Blood samples will be obtained for serum osteocalcin (OC), bone-specific 
alkaline phosphatase (BSAP), carboxyterminal telopeptide α1 chain of type I 
collagen (CTX)], and urine for deoxypyridinoline and pyridinoline and compared 
to normative data from healthy children obtained for a separate study.  The 
University of Minnesota Cytokine Research Laboratory will be performing the 
bone marker assays.  Samples will be analyzed at the end of the study to 
eliminate inter-assay variability.   
 
Radiographs 
Data from radiographs of the spine and lower extremities will be collected and, to 
ensure patient safety, will undergo a formal read by radiology at the University of 
Minnesota.  These will include a scoliosis series and xrays for genu valgum and 
hip dysplasia.   
 
Brain and cervical spine MRI 
Cervical cord compression is a common, potentially lethal, abnormality in 
individuals with MPS VI.  Increased mobility, as has been found with the 
administration of ERT, has increased the risk of symptomatic cord compression 
in individuals with MPS VI (Horovitz, 2011; Jurecka, 2012) and has been 
prominently displayed in the package insert.  Subjects will undergo cervical spine 
MRI with read prior to initiation of ERT and annually thereafter.  Similarly, as 
hydrocephalus is a known finding in MPS VI, subjects will undergo brain MRI with 
read prior to initiation of ERT and annually thereafter.  Real-time interpretation of 
both cervical and brain MRI are required for patient safety.  In addition, as 
developed by the University of Minnesota group, volumetric assessment of brain 
(quantifying white matter, gray matter, ventricle, hippocampus, corpus callosum 
volumes) and diffusion tensor imaging, (quantifying connectivity in the brain using 
the corpus callosum as the region of interest) may be performed.   
 
 


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Cardiac Echo 
Mitral and aortic valve regurgitation and stenosis as well as ventricular 
hypertrophy are common findings in MPS VI (Braunlin, 2013).  Case reports after 
HCT suggest that valve findings are not improved despite engraftment (Table 1).  
Definition of the cardiac valve findings in any of the MPS syndromes requires 
careful and reproducible evaluation.  Sonographers at the University of 
Minnesota have extensive experience producing reliable and useful imaging of 
the cardiac findings in the MPS syndromes.  Subjects will undergo cardiac 
ultrasound at the University prior to initiation of ERT and annually thereafter. 
 
Table 4.  Echo parameters to be obtained in MPS VI subjects undergoing 
Naglazyme infusion after HCT. 
Echo Imaging Parameter 
M-mode 
2-dimension 
Doppler 
LV chamber dimension 
X 
X 
 
LV wall thicknesses 
X 
X 
 
Aortic root diameter 
X 
X 
 
LV function 
X 
X 
 
RV pressure 
 
 
X 
Aortic stenosis/regurgitation 
 
 
X 
Mitral stenosis/regurgitation 
 
 
X 
Pulmonary stenosis/regurgitation 
 
 
X 
Tricuspid stenosis/regurgitation 
 
 
X 
Other abnormalities 
X 
X 
X 
Neuropsychological testing 
Subjects will undergo full neuropsychological testing annually and abbreviated 
testing for attention and adaptive skills at the six-month interval visits (Section 
7.3).  Subjects will complete a Medical Outcomes Questionnaire annually.  This 
questionnaire is designed to provide an overall assessment of clinical health and 
allows comparison of scores between treatment groups (Ahmed, 2013).    
 
 
 


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Table 5.  Neuropsychological tests to be performed on MPS VI subjects 
receiving weekly Naglazyme infusions after HCT 
TEST ADMINISTERED (total testing time 2-3 hours) 
INTELLIGENCE 
Wechsler Abbreviated Scale of Intelligence Second Edition (WASI-II)  
ATTENTION/EXECUTIVE FUNCTION 
Test of Variables of Attention (TOVA) 
LEARNING & MEMORY 
California Verbal Learning Test, Children's Version (CVLT-C) ≤16yrs 
California Verbal Learning Test, Second Edition (CVLT-II) >17yrs 
Behavior Rating Inventory of Executive Function, Adult form (BRIEF)  
Quality of Life and Social-Emotional: SF-36 
Vineland Adaptive Behavior Scales-II (Parent/Caregiver Rating Form) 
Brief Symptom Inventory (BSI) >13yrs 
 
Motor function, endurance and dexterity measurements 
Impaired joint mobility and upper extremity dexterity remain significant co-
morbidities despite successful HCT in MPS VI (see Table 1).  In this respect, the 
outcome of HCT is comparable to that found in MPS I HCT recipients.  A recent 
systematic literature survey of orthopedic issues affecting MPS I HCT recipients 
found that motor functioning was hampered by reduced joint mobility, decreased 
hand dexterity, delayed motor development and longitudinal growth (van der 
Linder, 2011).  In MPS I HCT recipients’ development of independent walking 
was often delayed due to hospitalization for HCT and due to orthopedic issues.  
Once developed, the quality of gait was abnormal – reduced walking speed, 
shortened step length and increased energy expenditure early in life – but this 
normalized by 4 years of age.  Importantly, 25% of HCT recipients lost 
independent unaided gait at an average of 6 years after HCT due to orthopedic 
issues of hip dislocation and genu valgum.  While many fewer individuals with 
MPS VI have undergone HCT, dysostosis multiplex, impaired joint mobility and 
the need for hip surgery have all been reported as long-term findings after 
successful HCT (Table 1).  The 6 minute walk has served as the standard 
measure of mobility and overall cardiopulmonary fitness in all clinical trials of 
ERT in MPS VI (Harmatz, 2008) and will be employed annually in the MPS VI 
HCT recipients.  This measure is well validated for adults and children (Reuben, 
2013) and is routinely performed by respiratory therapists by standardized 
protocols in our institution.  Marked improvement in one MPS VI post-HCT 
subject has been reported by Sohn (2012).    
Manual dexterity is a critical component necessary for independence in the 
activities of daily living:  the ability to dress one’s self, perform daily rituals of 
washing and toileting, eat with standard utensils, open and close doors, turn 


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pages of a book, type on a keyboard – all require a measurement of manual 
dexterity.  Dexterity will be tested by timed completion of the Roylan 9-hole 
pegboard test (Reuben, 2013).  This validated test is being used in ongoing 
clinical trials with MPS IV (Morquio) subjects (A. Jester, unpublished 
communication, 2013).   
 
Hand grip strength will be measured in both hands with a mechanical hand held 
dynamometer with the subject in a seated position.  The shoulder will be in a 
neutral position, the elbow flexed to 90 degrees midway between pronation and 
supination and the forearm supported on the arm of the chair.  The grip size of 
the dynamometer will be adjusted for the comfort of the participant 91.  Each 
participant will squeeze the hand held dynamometer three times with each hand.  
All three values will be recorded.  Dominant hand will be noted. 
 
8 
Adverse Event Reporting 
Toxicity and adverse events will be classified according to NCI's Common Terminology 
Criteria for Adverse Events V 4.0 (CTCAE).  A copy of the CTCAE can be downloaded 
from the CTEP home page http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf 
8.1 
Definitions 
BioMarin Standard Language for Adverse Event Reporting: IST Program, 
Naglazyme 
Adverse Events 
According to the ICH definition, an adverse event (AE) is any untoward medical 
occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product, and that does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not 
considered related to the investigational product. 
 
This definition includes intercurrent illnesses or injuries that represent an 
exacerbation (increase in frequency, severity, or specificity) of pre-existing 
conditions.  Whenever possible, it is preferable to record a diagnosis as the AE term 
rather than a series of terms relating to a diagnosis.  
 
Adverse event information will be collected in an ongoing fashion through patient 
reporting AEs to their physician or health care provider.  Seriousness and 
relatedness will be assessed by the treating physician, with appropriate reporting. 
 


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A designated primary contact person based at the treatment center will be 
responsible for the collection and reporting of AEs for patients participating in the 
program.   
 
Serious Adverse Events 
A serious adverse event (SAE) is defined as any AE that: 
• 
Results in death 
• 
Is life threatening, that is, places the subject at immediate risk of death from 
the event as it occurred.  This definition does not include a reaction that, had 
it occurred in a more severe form, might have caused death 
• 
Requires in-patient hospitalization or prolongation of an existing in-patient 
hospitalization. Admission of a subject to the hospital as an in-patient as a 
result of an AE, even if the subject is released on the same day, qualifies as 
hospitalization 
• 
Results in persistent or significant disability or incapacity. An event qualifies 
as resulting in a persistent or significant disability or incapacity if it involves a 
substantial disruption of the subject’s ability to carry out usual life functions.  
This definition is not intended to include experiences of relatively minor or 
temporary medical significance. 
• 
Is a congenital anomaly or birth defect, that is, an AE that occurs in the child 
or fetus of a subject exposed to Naglazyme prior to conception or during 
pregnancy 
• 
Is an important medical event that does not meet any of the above criteria, 
but may jeopardize the subject or require medical or surgical intervention to 
prevent one of the outcomes listed above. 
 
More than one of the above criteria may apply to any specific event. 
8.2 
Adverse Event Documentation 
For the purposes of this study, targeted adverse events and unexpected events 
will be collected by the local health care provider completing the targeted toxicity 
form  at baseline just prior to each Naglazyme infusion and again 1 hour after the 
infusion end (+/- 15 minutes) as part of the drug log.  Refer to the form for 
specific details.  
 
8.3 
Required Expedited Reporting:  Local Medical Facilities to MCC 
Study Coordinator 
Expedited reporting by the local treating medical facility/staff within 1 working day 
of knowledge to the MCC Study Coordinator is required for the following 
situations: 
 
 


Naglazyme Following Allogeneic Transplantation for Maroteaux-Lamy Syndrome 
 
 
 
 
 
 
 
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Event 
Form to Use 
Any event that meets the definition of 
serious (defined in section 8.1) regardless of 
relationship 
MCC SAE reporting form 
Any grade 3 or 4 infusion related  reaction 
(per section 10.4) 
Stopping Rule Event Form (in 
addition to SAE form if it meets the 
definition of serious) 
Pregnancy 
MCC SAE reporting form 
 
All toxicity assessments are based on the Common Terminology Criteria for 
Adverse 
Events 
(CTCAE) 
available 
as 
a 
pdf 
download 
at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf  or as a smart phone app from the app store.  
The grading is also reflected in the targeted toxicity forms. 
 
Local medical staff should not wait to collect additional information that fully 
documents the event before notifying the MCC Study Coordinator.  Additional 
information may be submitted as it becomes available as follow-up reports.  In 
the event of pregnancy, every effort should be made to follow the patient through 
resolution of the pregnancy (termination or delivery) and report the resolution to 
the MCC Study Coordinator.  
 
The MCC research staff will be responsible for forwarding all events meeting the 
definition for expedited reporting in section 8.4 to BioMarin and the University of 
Minnesota Institutional Review Board. 
 
Local medical facilities are responsible for adhering to all local reporting 
requirements (if applicable).    
 
 


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8.4 
Required Reporting: MCC to U of MN IRB, BioMarin, and MCC SAE 
Coordinator 
8.4.1 Pregnancy 
Pregnancy in a subject being treated with the product should be reported 
immediately (within 24 hours of becoming aware of the pregnancy) to BioMarin 
Pharmacovigilance by using the MCC SAE form or FDA 3500A (MedWatch 
Form).  Every effort should be made to follow the patient through resolution of the 
pregnancy (termination or delivery) and report the resolution of the MCC SAE 
form or FDA 3500A (MedWatch Form) to BioMarin Pharmacovigilance. 
8.4.2 SAE and Pregnancy Reporting – IND exempt studies 
All serious, adverse events (SAEs) and pregnancy reports whether or not 
considered drug-related should be reported to BioMarin Pharmacovigilance 
(contact information below) within 24 hours of receipt by investigator/sponsor by 
using the MCC SAE form or FDA 3500A (MedWatch From).  
 
Clinicians should not wait to collect additional information that fully documents the 
event before notifying BioMarin’s Drug Safety Department of an SAE or pregnancy.  
BioMarin may be required to report certain SAEs to regulatory authorities within 7 
calendar days of being notified about the event; therefore, it is important that 
clinicians submit additional information requested by BioMarin as soon as it 
becomes available. 
Agency 
Criteria for reporting 
Timeframe 
Form to 
Use 
Submission 
address/fax numbers 
Copy AE 
to: 
U of MN 
IRB 
Events requiring prompt reporting including, but not 
limited to unanticipated death of a locally enrolled 
subject(s); new or increased risk; any adverse event  
that require a change to the protocol or consent form 
or any protocol deviation that resulting in harm  
refer to 
http://www.research.umn.edu/irb/guidance/ae.html#.
VC7xraI0-sh  
Within 5 
business 
days of 
event 
discovery 
 
Report 
Form 
irb@umn.edu 
 
SAE 
Coordinat
or 
mcc-saes 
@umn.ed
u 
Bio Marin 
(refer to 
sections 
8.4.1 and 
8.4.2) 
Any event that is serious regardless of 
relationship 
 
Any infusion related reaction regardless of 
seriousness 
 
Pregnancy  
Upon 
knowledge 
with an 
annual 
summary 
of all 
SAE’s 
MCC 
SAE or 
FDA 
3500A 
BioMarin Pharmaceutical 
Inc 
105 digital Drive 
Novato, CA 94949 
Phone: 415-506-6179 
Fax: 415-532-3144 
Email: 
drugsafety@bmrn.com  
 
MCC SAE 
Coordinator 
Any stopping rule event 
upon 
reporting 
stopping 
rule 
form 
SAE Coordinator 
mcc-saes@umn.edu 
Not  
applicable 


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Reporting of SAEs to the IRB will be done in compliance with the standard operating 
procedures and policies of the IRB and with applicable regulatory requirements.   
 
Contact information for BioMarin’s Drug Safety Department is as follows: 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA  94949 
Phone: (415) 506-6179 
Fax: 
(415) 532-3144 
Email: drugsafety@bmrn.com 
 
 
The SAE Coordinator will provide the Masonic Cancer Center’s Data and Safety 
Monitoring Council (DSMC) with the SAE in an appropriate format depending on the 
individual SAE (as reported or in a summary format). 
 
9 Study Data Collection and Monitoring 
9.1 
Data Management 
This study will report clinical data using The Online Enterprise Research 
Management Environment (OnCoreTM), a web based Oracle® database utilizing 
study specific electronic case report forms.  Key study personnel at the University 
of Minnesota are trained on the use of OnCore and will comply with protocol 
specific instructions embedded within the OnCore.   
9.2 
Case Report Forms 
Participant data will be collected using protocol specific electronic case report 
forms (e-CRF) developed within OnCore based on its library of standardized 
forms.  The e-CRF will be approved by the study’s Principal Investigator and one 
of the Biostatistician prior to release for use.  The Study Coordinator or designee 
will be responsible for registering the patient into OnCore at time of study entry, 
completing e-CRF based on the patient specific calendar, and updating the 
patient record until the end of study participation.  Source data will be sent to the 
University Of Minnesota Study Coordinator from local medical facilities for entry 
into OnCore.   
 
 


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9.3 
Data and Safety Monitoring Plan (DSMP) 
The study’s Data and Safety Monitoring Plan will be in compliance with the 
University of Minnesota Masonic Cancer Center's Data & Safety Monitoring Plan 
(DSMP), which can be accessed at: 
http://www.cancer.umn.edu/prod/groups/ahc/@pub/@ahc/@mcc/documents/conten
t/ahc_content_487799.pdf 
 
 
For the purposes of data and safety monitoring, this study is classified as high 
risk (local investigator initiated study).  Therefore the following requirements will 
be fulfilled: 
 
 
The Masonic Cancer Center Data and Safety Monitoring Council (DSMC) will 
review the study’s progress at least quarterly. 
 
The PI will comply with at least twice yearly monitoring of the project by the 
Masonic Cancer Center monitoring services. 
 
The PI will oversee the submission of all reportable adverse events per the 
definition of reportable in section 8.4 to the Masonic Cancer Center’s SAE 
Coordinator and the University of Minnesota IRB.   
 
In addition, at the time of the continuing review with the University of Minnesota 
IRB, a copy of the report with any attachments will be submitted to the Cancer 
Protocol Review Committee (CPRC). 
9.4 
Monitoring 
The investigator will permit study-related monitoring, audits, and inspections by 
the sponsor-investigator and/or sponsor/investigator designee, IRB, government 
regulatory bodies, and University of Minnesota compliance groups.  The 
investigator will make available all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data, etc.).  
The investigator will ensure the capability for inspections of applicable study-
related facilities (e.g. pharmacy, diagnostic laboratory, etc.) will be available for 
trial related monitoring, audits, or regulatory inspections. 
 
Local medical facilities will not be subject to study related monitoring but will be 
required to provide relevant infusion related clinical notes and targeted toxicity 
forms to serve as source documentation. 
9.5 
Record Retention 
The investigator will retain study records including source data, copies of case 
report form, consent forms, HIPAA authorizations, and all study correspondence 
in a secured facility for at 6 years after the study file is closed with the IRB.   
 


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In addition, the Clinical Trials Office (CTO) will keep a master log of all patients 
participating in the study with sufficient information to allow retrieval of the 
medical records for that patient.  
 
Please contact the CTO before destroying any study related records. 
 
10 
Statistical Considerations 
This is a study with a known small number of available subjects designed for the 
purpose evaluating safety and efficacy of administration of Naglazyme after 
hematopoietic cell transplantation (HCT). 
10.1 
Statistical Endpoints 
The primary endpoints listed below will be monitored as used to decide whether 
Naglazyme can be recommended after successful HCT. 
• 
Change in urinary GAG excretion 
• 
Change in distance traveled in 6 minute walk and standard tests of range 
of motion and mobility 
• 
Change in neurocognitive ability 
 
The secondary endpoints will be the development of antibodies including 
neutralizing antibodies with weekly Naglazyme therapy and the impact of these 
antibodies on cardiorespiratory and skeletal parameters as measured by the 6-
minute walk test and standard tests of range of motion and mobility, and the 
change in neurocognitive ability 
10.2 
Statistical Analysis 
Simple descriptive statistics such as proportions, means, standard deviations, 
medians and ranges will be used to estimate the various parameters in this 
study. The estimate with 95% confidence interval will be calculated for the 
primary endpoints.  
10.3 
Sample Size Justification 
Since the number of known MPS VI subjects who have received HCT is known to 
be 45 worldwide, a sample size of ten patients will be employed to estimate the 
study parameters. 
10.4 
Monitoring Guidelines: Stopping Rules 
Early stopping rule will be used to monitor the excess toxicity. Stopping rules 
were developed using Pocock stopping boundaries (Ivanova 2005).  
 
Grade III-IV infusion related reaction will be monitored so that the study will stop 
and the protocol will be re-evaluated if the toxicity rate exceeds the boundary. 
Given a hypothesized toxicity rate of 10%, a maximum tolerated rate of 20% and 


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a sample size of 10 patients, the upper stopping boundary for toxicity is 2 out of 
2, 3 out of 4, 4 out 8 and 5 at any time. If the true toxicity rate is as high as 50% 
then the chance of early stopping is 72% and the expected sample size is 6.4. 
11 
Ethical Considerations 
11.1 
Good Clinical Practice 
The study will be conducted in accordance with the appropriate regulatory 
requirement(s).  The investigator will be thoroughly familiar with the appropriate 
use of the study treatment/procedures.  Essential clinical documents will be 
maintained to demonstrate the validity of the study and the integrity of the data 
collected.  Master files should be established at the beginning of the study, 
maintained for the duration of the study and retained according to the appropriate 
regulations.   
11.2 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki.  The IRB will review all appropriate study documentation 
in order to safeguard the rights, safety and well-being of the patients.  The study 
will only be conducted at sites where IRB/IEC approval has been obtained.  The 
protocol, Investigator’s Brochure, informed consent, written information given to 
the patients, safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB by the investigator.   
11.3 
Institutional Board Review (IRB) 
Before the initiation of this study, this protocol will have been reviewed and 
approved by the Human Subjects Committees at the University of Minnesota, as 
defined by FDA regulations (21 CFR Part 56). 
 
IRB approval of any future modifications of the protocol or consent form for this 
study will be given in writing. Unanticipated adverse effects must be reported to 
the IRB. The IRB will receive notification of the completion of the study. The 
investigators will maintain an accurate and complete record of all submissions 
made to the IRB, including a list of all reports and documents submitted. 
11.4 
Informed Consent 
The principles of informed consent described in FDA Regulations (21 CFR Part 
50) will be followed to comply with Food and Drug Administration regulations. A 
patient will give written consent prior to study participation which must be signed 
and dated before the conduct of any study related procedures. The original 
consent will be retained by the investigator as part of the study records. A copy of 
the consent form will be given to the patient. 
 
 


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12 
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Appendix I – Eligibility Checklist 
Study of Administration of Intravenous Naglazyme® Following Allogeneic 
Transplantation for Maroteaux-Lamy Syndrome (MT2014-08R) 
Eligibility Checklist – page 1 of 1 
Patient initials   
      
 
Patient ID
 
 
 
 
1st 2 initials of first name + 1st 2 initials of last name 
        Seq # (i.e. 01, 02, 03, etc.) 
 
 
INCLUSION CRITERIA  
A "NO" response to any of the following disqualifies the patient from study entry. 
 
EXCLUSION CRITERIA 
A "YES" response to any of the following disqualifies the patient from study entry. 
 
 
Yes      No 
7. Is pregnant or breastfeeding at screening or baseline, or planning to 
become pregnant (self or partner) at any time during the study. 
 
 
8. 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 
 
 
 
  
Date consent form signed:  
 
 
 
 
Having obtained consent and reviewed each of the inclusion/exclusion criteria, I verify 
that this patient is:  
 
  Eligible 
  Ineligible   Date registered   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of person verifying eligibility 
 
 
Date 
  
 
 
Yes      No 
1. 
Mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome) 
treated with an allogeneic transplant more than 2 years prior to enrollment – 
patients need not have been transplanted at the University of Minnesota 
 
 
2. Persons who have received or are currently receiving Naglazyme may be 
considered for enrollment  
 
 
3. >10% engraftment based on most recent testing (within previous year) – 
confirmed during pre-screening 
 
 
4. If female of child-bearing age, willing to defer pregnancy for the duration of 
the trial 
 
 
5. Willing to commit to traveling to the University of Minnesota every 6 months 
for the duration of the trial (2 years) 
 
 
6. 
Written informed consent prior to the performance of any study related 
procedures with parent/guardian consent for children < 18 years of age or 
persons unable to consent with minor assent if appropriate