Clinical trial NCT02232477
Conditions: Mucopolysaccharidosis I Cognitive Decline
Sponsor: agnes chen
Start date: 2014-08-01; Completion date: 2020-02-01
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a five-year extension study of the pilot study, "Intrathecal Enzyme Replacement for Cognitive Decline in MPS I". Participants must have completed the pilot study to participate in this study.

Detailed description:

Arms: arm 1: laronidase 1.74 mg IT q 3 months for five years
Interventions: intervention 1: Intrathecal recombinant human alpha iduronidase
Intervention descriptions: intervention 1: Intrathecal recombinant human alpha iduronidase every 3 months

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Title: An extension study of intrathecal enzyme replacement for cogniƟve decline in 
mucopolysaccharidosis I 
NCT number: NCT02232477 
Document date: 8 May 2019 


 
Page 1 of 63 
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Protocol Title 
Study Number MIRC-002 (100) 
An extension study of intrathecal enzyme replacement for cognitive 
decline in mucopolysaccharidosis I 
RDCRN Protocol #6728 
HSC Review History 
Version 2.6 
Principal Investigator 
Agnes Chen, MD 
 
 
 
1. Objectives 
 
Safety   
To evaluate the long-term safety of intrathecal recombinant human α-L-
iduronidase (rhIDU), approved as Aldurazyme® [laronidase] for the treatment of 
cognitive impairment in patients with mucopolysaccharidosis I (MPS I). 
 Evaluate the long-term safety of administering rhIDU intrathecally in MPS I 
subjects 
 Evaluate the presence and effect of an immune response to the 
administered rhIDU 
 Determine whether there are any other unexpected effects of rhIDU on the 
safety of MPS I subjects 
 
Outcome 
To evaluate the long-term effects of a limited number of intrathecal injections of 
rhIDU to stabilize or reverse neuropsychological deficits in non-transplanted MPS 
I patients.   
 Neuropsychological: through an established battery of outcome measures 
 Clinical: including subject reported changes, neurologic examination and 
walk testing ability  
 Radiologic: including 3 Tesla brain MRI and diffusion tensor imaging to 
look at volumes, morphology, diffusion abnormalities and white matter 
fiber tracking. 
 Biochemical: measures of GAG storage within the CSF 
 
 
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The primary outcome measure will be the mean intra-subject change in 
memory score on the Hopkins Verbal Learning Test between 
baseline/screening for MIRC-002 and the subject’s final visit of the extension 
study. 
 
2. 
Background 
Mucopolysaccharidosis I (MPS I) is an inherited lysosomal storage disease due 
to deficiency of α-L-iduronidase.  Deficiency or absence of α-L-iduronidase 
causes accumulation of glycosaminoglycans (GAG) throughout the body.  
Excess GAG storage causes joint pain and stiffness, difficulty breathing, valvular 
heart disease, and other problems leading to progressive disability and often 
death. 
 
MPS I is a heterogeneous disease with several clinical phenotypes ranging from 
the most severe, Hurler syndrome, to the attenuated forms, Hurler-Scheie and 
Scheie.  Patients with all forms of MPS I suffer from central nervous system 
disease, including cognitive decline, hydrocephalus, spinal cord compression, 
hearing loss, and vision difficulties.  Patients with the most severe form of MPS I 
develop slowing in cognitive development that usually appears after age one and 
thereafter accelerates.  By age 3 years, most of these children fall into the range 
of mental retardation as defined by standard intelligence tests (Shapiro and 
Balthazar 2000). 
 
Although patients with milder forms of MPS I may not have grossly observable 
problems with cognition, these patients do have learning difficulties that are 
apparent in school and with neuropsychological testing.  In a series of 29 
attenuated MPS I patients, 34% manifested problems in speech/language 
development by clinical report (Vijay and Wraith, 2005).  In a case study of three 
siblings with Hurler-Scheie, decline of cognitive function was seen on 
neuropsychological testing, specifically with problems encoding new information 
and spatial ability (Fig. 1, Bjoraker et al., 2005, 2006).  In a study comparing 
Hurler patients after hematopoietic stem cell transplantation (HSCT) and Hurler-
Scheie patients on intravenous enzyme replacement therapy (ERT), Hurler-
Scheie patients did comparatively worse in memory and spatial testing (Shapiro 
et al., 2006). 
 
An ongoing pilot study of hematopoietic stem cell transplantation (HSCT)-treated 
Hurler patients and ERT-treated attenuated MPS I patients (Hurler-Scheie and 
Scheie) is examining brain structure and function (Shapiro et al., 2007).  Along 
with extensive neuropsychological testing, this study is employing a 3 Tesla MRI 
to look at volumetrics of the hippocampus compared to other regions, as well as 
diffusion tensor imaging and tractography to examine white matter connectivity of 
afferent and efferent pathways from the hippocampus to the rest of the brain.  
Preliminary results on neuropsychological testing support previously described 
findings of decline in learning and spatial ability. In attenuated MPS I patients, IQ, 
recognition memory and spatial working memory (controlled for IQ) correlated 
 
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with age, with older patients being more impaired. Attenuated MPS I patients 
were more impaired than HSCT-treated severe MPS I patients on the California 
Verbal Learning Test (CVLT), a test of memory encoding and spatial working 
memory.  In addition, preliminary MRI findings demonstrate that patients with 
attenuated MPS I have statistically significant smaller hippocampal volumes than 
patients with Hurler syndrome treated with HSCT and that these hippocampal 
volumes correlate with functional deficit in memory.  In addition, abnormal 
patterns of white matter diffusion have been found in both groups, with more 
abnormal patterns seen in the severe than the attenuated group (Shapiro et al., 
2007).   
 
 
 
 
Hurler Scheie patient 1
40
50
60
70
80
90
100
110
8
10
16
18
Age
Full Scale IQ
Memory score
Hurler Scheie patient 2
40
50
60
70
80
90
100
110
6
8
14
16
Age
Full Scale IQ
Memory score
Hurler Scheie patient 3
40
50
60
70
80
90
100
110
4
6
12
13
Age
Full Scale IQ
Memory score
Fig. 1:  Memory and intelligence 
quotient testing in three siblings 
with Hurler-Scheie form of MPS I 
receiving intravenous rhIDU.  
Average decline is 2 points per 
year.  Courtesy of K Bjoraker 
and E Shapiro. 
 
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Most patients with MPS I develop hydrocephalus, which is thought to be due to 
GAG storage in the arachnoid granulations affecting CSF reabsorption (Neufeld 
and Muenzer, 2001).  Hydrocephalus can cause chronic, painful headaches, and 
may require a ventriculoperitoneal shunt to relieve pressure in the brain.  In most 
cases, it is not the primary cause of the serious cognitive deterioration.   
 
Hematopoietic stem cell transplantation is available to treat the brain and spinal 
cord as well as the physical aspects of the disease (Peters et al., 1998).  
However, HSCT has high rates of mortality and morbidity.  A recent series of 
transplanted Hurler patients demonstrated a mortality of 14% related to initial 
transplant and 56% morbidity, which comprised acute and chronic graft versus 
host disease, veno-occlusive disease, and pulmonary complications (Boelens et 
al., 2007).  HSCT is also not generally used for patients with the attenuated 
(Hurler-Scheie and Scheie) forms of MPS I, even those with demonstrated 
cognitive defects, because little benefit for cognitive impairment has been 
shown in MPS I patients transplanted after age 2 years (Whitley et al., 1993).  
Thus, alternative treatments for central nervous system (CNS) disease in MPS I 
are needed for patients who have no suitable donor, are unwilling to risk the 
transplant, do not qualify for HSCT, or are not completely disease-free following 
the procedure.   
 
Enzyme replacement therapy given intrathecally has been shown to achieve high 
levels of iduronidase and reduce GAG storage in the brain, spinal cord and spinal 
meninges in the canine model (Kakkis et al., 2004; Dickson et al., 2007).  In the 
brain, GAG storage levels became normal in all nineteen treated MPS I dogs 
(Fig. 2).  When intrathecal enzyme replacement was stretched out to monthly 
and quarterly (every 3 months) dosing, there was no significant difference 
between iduronidase levels and quantitative reduction of GAG storage in the 
brain compared to weekly dosing.  
 
 
 
MPS I patients have been treated with intrathecal rhIDU for spinal cord 
compression as part of an earlier clinical trial (MIRC-001, BB IND 12561, 
Fig. 2:  Quantitative glycosaminoglycan 
(GAG) storage in brain of normal dogs, 
untreated MPS I dogs, and MPS I dogs 
treated with IT rhIDU.  Brain GAG levels 
in the IT-treated dogs reached normal 
levels regardless of age or treatment 
regimen (Dickson et al., 2007). 
 
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NCT00215527).  Three adult subjects have completed the study.  In addition, 
one adult and three children with MPS I have been treated worldwide with 
intrathecal rhIDU off-study for cord or brainstem compression.   Subjective 
improvement was noted in all 3 of the patients for whom data are available in at 
least 3 major CNS symptoms.  These included ability to move legs, reduced pain 
in the legs, back and/or neck, bladder/bowel incontinence, restless legs, 
numbness/tingling of the feet, fatigue, and improved hand use.  Improvement in 
neurologic examination occurred in all three patients as measured by 
pain/temperature asymmetries, strength, deep tendon reflexes, and range of 
motion.  In addition, one eight-year old, wheelchair-bound patient gained the 
ability to walk with support during treatment (Giugliani et al., 2007).  Monthly 
intrathecal rhIDU injections have been well tolerated.  Adverse events with >1 
occurrence included headache, pain in buttocks, back pain, neck pain, 
pneumonia, low platelet count, anemia, and sore throat.  One subject developed 
CSF pleocytosis which responded to a short course of oral steroids.  Two 
subjects with hydrocephalus and implanted shunts at study entry developed 
apparently transient elevated CSF opening pressure.  Serious adverse events 
have included one death, two episodes of pneumonia, one episode of hypoxia 
with respiratory distress following anesthesia, and one corneal transplantation.  
All were judged unrelated to study drug. 
 
This study is an extension of the current ongoing clinical trial of intrathecal 
enzyme replacement for cognitive decline in MPS I (MIRC-002, NCT00852358).  
Thus far, there have been no serious adverse events related to study drug.  The 
AEs possibly related to study drug include back, neck, buttock and groin pain, 
transient blurry vision and headache and mild CSF pleocytosis.    
 
 
We propose an extension of our study to examine the long-term effects of 
intrathecal enzyme replacement on cognition.  In order to document improvement 
with intrathecal ERT, neuropsychological testing, clinical testing, and imaging 
modalities will be employed.  Multiple cognitive domains will be tested with an 
established battery of neuropsychological tests that have documented validity in 
patients with storage diseases (Shapiro et al., 2006). Magnetic resonance 
imaging of the brain will be used to document abnormalities and changes in 
volume and morphology.  In addition, brain diffusion tensor imaging (DTI) will be 
employed to characterize diffusion abnormalities and perform fiber tracking.  DTI 
and fiber tracking register diffusion patterns of water to follow axonal transport in 
the brain.  Preliminary results in attenuated MPS I patients show DTI and fiber 
tracking to be abnormal in some patients (Fig. 3, Shapiro et al., 2012). DTI has 
been used to quantify improvement following hematopoietic stem cell 
transplantation in the lysosomal storage disorder, Krabbe disease (Provenzale et 
al., 2005).   
 
 
 
 
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To summarize, many people with mild and moderate forms of MPS I suffer from 
cognitive decline, poor performance in school, and behavior difficulties. There is 
essentially no treatment for these problems.  These patients are not candidates 
for hematopoietic stem cell transplantation, and intravenous enzyme replacement 
therapy does not treat these central nervous system symptoms.  Data from the 
canine model of MPS I show that intrathecal rhIDU can penetrate the brain, 
spinal cord, and meninges, reducing GAG storage to normal levels.  Data from 
human subjects have shown that intrathecal therapy is safe, and that it leads to 
clinical improvement in spinal cord compression symptoms and signs on 
neurologic examination.  In this study, we plan to extend the evaluation of IT 
rhIDU to the stabilization or reversal of cognitive decline in MPS I patients. 
 
3. 
Setting of the Human Research 
The study will be conducted at the Los Angeles Biomedical Research Institute at 
Harbor-UCLA (LAB-HUCLA), Children’s Hospital Oakland Research Institute 
Fig. 3:  FA maps for MPS IH and MPS IA participants matched for age and gender. The figures 
below show the assigned colors for FA in the white matter tracts for the following directions: red 
= medio-lateral (left–right), green = anterior–posterior (front–back) and blue = superior–inferior 
(up–down). Data below the figure are from these two participants. (Shapiro et al., Mol Genet 
Metab 2012) 
 
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(CHORI) and the University of Minnesota (UMN). Additional study sites may be 
added as subjects are identified.  Specific details are below: 
 Recruitment: Subjects will be recruited from participants in the MIRC-
002 study at LAB-HUCLA and CHORI. 
 Procedures: Procedures will be performed at LAB-HUCLA, CHORI, 
and additional study sites that are added as subjects are recruited to 
the study. The addition of any new study site will be contingent upon 
approval by their local institutional review board (IRB), and the IRB at 
LAB-HUCLA.  Neuropsychological testing will be performed at UMN. 
 Regulations:  The IRBs at CHORI and UMN will oversee the research 
at these respective sites, with LAB-HUCLA the primary site 
responsible. 
 
4. 
Resources Available to Conduct the Human Research 
Since subjects will be recruited from among participants enrolled in the pilot 
(MIRC-002) study: 
 All participants are accessible for recruitment  
 67%  are anticipated to be enrolled in the proposed study 
 Study staff have previously been involved with participants and their families 
through the pilot study, so are familiar with local culture and attitudes toward 
clinical research.       
Time requirement for the Principal Investigator to conduct and complete the 
proposed study within the agreed trial period is projected to be 8 hours per week. 
Site study staff at the LAB-HUCLA include six members:  two co-Primary 
Investigators, two pharmacists, one Study Coordinator, and one laboratory staff.  
Study staff at the CHORI site include three members:  one site PI, one 
pharmacist and one study coordinator.  Study staff at the UMN include two 
members:  one site PI and one study coordinator.  All study staff have completed 
appropriate training regarding protection of human research subjects, Good 
Clinical Practices, and HIPAA, and have previously participated in other clinical 
research trials.  
 
Inpatient study treatments are conducted at the hospital in an area designated 
for clinical research and study evaluations are completed in separate outpatient 
clinical research facilities.  Principal Investigators have hospital privileges at 
their respective sites and non-study staff resources are available at each 
hospital should study participants require medical or psychological support as a 
result of an anticipated consequence of the research study.   
 
 
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A site initiation meeting will be scheduled to discuss the study overview and 
protocol with all study staff, and to review regulatory issues, study procedures 
including study drug preparation, administration and accountability logging, 
documentation and investigators’ responsibilities.  As all study staff participated 
in the pilot (MIRC-002) clinical trial, site initiation visits will not be undertaken.  
 
5. 
Prior Approvals 
This study will require the following approvals prior to initiation at LAB-
HUCLA: 
 NIH 
 IRB 
 UCLA CTSI 
In addition, the protocol will be filed to the Investigational New Drug Application 
(IND) for MIRC-002 (BB IND 104,354) at least thirty days prior to the initiation of 
the study. 
 
 
6. 
Study Design 
6.1. Recruitment Methods 
Subjects will be recruited from participants in the pilot (MIRC-002) study. 
Recruitment will take place after the subject has completed the end-study visit 
and the investigator has deemed that the subject meets criteria for screening 
(see Inclusion and Exclusion criteria).  Therefore, no study advertisements will 
be utilized for recruitment.  
Subjects will be informed that financial compensation is not available and that 
their participation in this study is entirely voluntary. 
 
6.2. Inclusion and Exclusion Criteria 
6.2.1. Inclusion criteria 
1. The subject has completed the MIRC-002 study of intrathecal enzyme 
replacement therapy for cognitive decline in mucopolysaccharidosis I 
2. Age six years or older. 
3. Subject and/or guardian willing and able to provide written informed 
consent.  
 
4. Negative urine pregnancy test at screening (non-sterile females of child-
bearing potential only) 
 
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5. Currently using two acceptable methods of birth control as determined by 
the investigator and willing to continue to use acceptable birth control 
during their participation in the study (non-sterile females of child-bearing 
potential who are sexually active only) 
6. Willing and able to comply with study procedures.  For example, the 
subjects must be able to complete written and computer-based testing.  
The subjects must be able to lie still in the MRI scanner for at least 40 
minutes without sedation.    
6.1.1. 
Exclusion criteria 
1. The subject has undergone hematopoietic stem cell transplantation 
2. Recent initiation of intravenous Aldurazyme® therapy with less than 6 
months of therapy.  Subjects who have been receiving Aldurazyme® 
therapy for more than 6 months, and those who have never received 
Aldurazyme® therapy, will be allowed to enroll 
3. Pregnant or lactating, or considering pregnancy 
4. Receipt of an investigational drug or procedure other than intrathecal 
Aldurazyme® within 30 days of enrollment 
5. A condition, medical or other, that prevents participation in the study, 
including severe auditory or visual impairment, significant lumbar 
pathology, lumbar catheter, or recent major surgery within 6 weeks that 
would preclude their ability to participate. 
6. Infusion reactions to intravenous or intrathecal Aldurazyme® therapy that 
are life-threatening or require emergent intervention such as epinephrine, 
cardiopulmonary resuscitation, or hospitalization 
7. The subject has severely impaired spinal CSF flow, demonstrated by 
failure of appearance of radionuclide in the basal cisterns by 4 hours after 
intra-lumbar administration. 
8. The subject has a coagulopathy, as identified by a platelet count of less 
than 50,000, an INR of 1.5 or greater, or a PTT that is 1.5 times the upper 
limit of normal for the laboratory from which it was drawn. 
 
6.2. 
Local Number of Subjects 
We expect to recruit subjects who have completed the MIRC-002 study. The total 
number of expected subjects in MIRC-002 is 6 subjects. Up to 6 subjects will be 
screened and up to 6 subjects will be enrolled in the MIRC-002(100) extension 
study at all sites.  
 
6.3. 
Study-Wide Number of Subjects 
We expect to recruit subjects who have completed the MIRC-002 study. The total 
number of expected subjects in MIRC-002 is 6 subjects. Up to 6 subjects will be 
 
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screened and up to 6 subjects will be enrolled in the MIRC-002(100) extension 
study at all sites. 
 
6.4. 
Study Timelines 
The duration of each subject’s participation in the study is expected to be five 
years. We anticipate enrolling these subjects over a 4-year period. The estimated 
date of completion of the study is 10 years following the onset of the study. 
 
7. 
Procedures Involved in the Human Research 
This study is a five-year open-label, prospective trial in 6 MPS I subjects age six 
years or greater who have completed a 24-month open label study (MIRC-002).  
Potentially eligible subjects who (or, if appropriate whose parents or guardians) 
have provided signed, written informed consent will first participate in a baseline 
screening phase.  This will occur at least six months after subjects have 
completed the MIRC002 pilot study.  During baseline screening, the subjects will 
receive the baseline evaluations outlined below, and their eligibility will be 
determined.  Every three months, subjects will receive intrathecal recombinant 
human α-L-iduronidase (IT rhIDU) approved as Aldurazyme® [laronidase] for the 
treatment of cognitive impairment in patients with mucopolysaccharidosis I (MPS 
I).  Neuropsychological testing and MRI will be performed at baseline and at one 
year intervals.  Safety will be monitored continuously throughout the subject’s 
study participation through recording all adverse events (AEs) and periodically 
performing clinical and laboratory evaluations.   
 
Study subjects will receive intrathecal enzyme therapy only during the study; 
intrathecal enzyme therapy will not be administered at the end of the five-year 
period.  If further intrathecal enzyme is desired, the subject may enroll in further 
intrathecal research if another study is available.   
 
To assure that subjects enrolling in the trial have maximum access to alternative 
therapy, subjects will be asked to receive counseling regarding other available 
appropriate medical and surgical alternatives prior to enrollment in this trial.   
 
7.1. 
Study Rationale 
In MPS I, GAG storage in the brain can cause substantial neurologic morbidity.  
In its most severe form, Hurler syndrome, patients are mentally retarded, but 
evidence of progressive cognitive decline can also be seen in patients with less 
severe forms of MPS I, Scheie and Hurler-Scheie syndromes.  GAG storage can 
also obstruct CSF reabsorption with resultant hydrocephalus, which can also 
contribute to mental decline, in addition to causing debilitating headaches.  
Treatment of the hydrocephalus often requires implanting a ventricular-peritoneal 
shunt to relieve CSF pressure.  Currently there is no treatment for cognitive 
 
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decline in MPS I, except for early HSCT that is offered to young Hurler patients 
only.  Essentially, patients with Scheie or Hurler-Scheie syndromes have no 
treatment available for cognitive decline.  Intrathecal rhIDU may provide benefit 
for these patients for whom HSCT was not an option.  It may also provide an 
alternative non-surgical treatment for the hydrocephalus that results from GAG 
storage at CSF reabsorption sites. 
 
This study is limited to patients six years and older with milder forms of MPS I 
because the older and less severely affected subjects will be able to comply with 
the examinations and will therefore be more accurately assessed.   
 
Neuropsychological evaluations in children younger than age six would require a 
different battery of tests, and therefore, the data would not be compatible.  
Younger children would also require general anesthesia for all of the procedures, 
increasing the risk to patients participating in the study.  In addition, older 
subjects do not have HSCT as a therapeutic option.  Finally, less affected MPS I 
patients make some enzyme on their own and may be less likely to have an 
immune reaction to rhIDU.  For these reasons, we have selected a study 
population of mild to moderate MPS I patients, age six or above, with 
documented cognitive decline that is attributable to their disease. 
 
7.2. 
Schedule of Study Evaluations 
After obtaining informed consent, the investigator will conduct the study as 
outlined in the following sections.  Table 1 summarizes the nature of the 
assessments and treatments and their timelines. Refer to Study Operations 
Manual for guidelines regarding test assessments and procedures for 
handling/shipment of all central laboratory samples. 
 
Table 1 Schedule of study assessments and treatments 
Month Number 
Baseline 
Visit 1/Odd 
Numbered 
Visits 
Visit 2/Even 
Numbered 
Visits 
End Study  
Neuropsychological 
testing 
X 
 
yearly 
 
MRI of brain 
X 
 
yearly 
 
Clinical tests 
 
 
 
 
History and Physical 
examination 
X 
X 
X 
X 
Neurologic 
examination 
X 
X 
X 
X 
Photography and 
video (optional) 
X 
X 
X 
X 
Six-minute walk test 
X 
X 
X 
X 
Subjective response of 
clinical symptoms 
X 
X 
X 
X 
FIM scoring 
X 
X 
X 
X 
 
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Laboratory tests (CSF)  
 
 
 
 
  Protein, glucose, cell    
count 
 
X 
X 
 
  GAG levels 
 
X 
X 
 
  Anti-rhIDU antibody 
 
X 
X 
 
  CSF iduronidase assay 
 
X 
X 
 
Laboratory tests 
(blood) 
 
 
 
 
Anti-rhIDU antibody 
X 
X 
X 
X 
CBC, Chem panel 20, 
Coagulation studies 
X 
X 
X 
X 
Neurophysiologic test 
 
 
 
 
  CSF flow study 
X 
 
 
 
Investigator Global 
Assessment 
X 
X 
X 
X 
Treatments  
Intrathecal rhIDU 
 
X 
X 
 
Visits occur at three-month intervals starting from Visit One.  There may be a variable 
period between Baseline/Screening and Visit One from five days to three months.  If the 
period between Baseline/Screening and Visit One is less than one week, then all of the 
other assessments do not need to be repeated for Visit One.   
 
7.3. 
Screening and qualification 
A variable length screening phase will begin with a history and physical and 
neuropsychological evaluation to assess the patient for entry criteria.  Patients 
meeting enrollment criteria will enter the study; patients not meeting enrollment 
criteria will not be enrolled. 
 
7.4. 
Pregnancy testing 
Female subjects of child-bearing potential will be required to submit a urine 
pregnancy test (urine beta-hCG) at baseline and at each study visit.  Subjects 
testing positive will be withdrawn from the study.  Sexually-active subjects of 
child-bearing potential will be required to use two acceptable methods of birth 
control (as determined by the investigator) during the study period. 
 
7.5. 
Dose Selection 
Based on the canine studies, 1 mg of rhIDU in a 20 kg dog with about 20cc of 
CSF (approximately 1 cc of CSF per kg body weight) resulted in 300 fold normal 
levels of enzyme in the meninges (the target tissue of this study), which are far 
above the levels necessary for effectively treatment. This dose is 0.05 mg/kg 
body weight, and 0.05 mg/cc CSF.  Meningeal GAG reduction ranged from 57-
70%, and pathologic studies showed that the majority of storage in cells is 
reduced or eliminated.  This dose appears to be sufficient to achieve substantial 
reduction.   At the lower 0.3 mg dose (0.015 mg/kg body weight or 0.015 mg/cc 
 
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CSF), substantial levels were also observed in the normal dogs in the brain 
suggesting that even at this dose meningeal levels would be far above required 
levels for treatment.   
 
For an MPS I patient of 60 kg, there is about 120 cc of CSF.  To obtain the same 
concentration as the 1 mg dose in dogs requires 6 mg of enzyme.  Given the 
large fold excess (300 fold normal) achieved in the meninges at this dose, and 
since this is the first treatment in humans, a lower 1.74 mg dose (volume 3 cc) 
approximates the human dose comparable to the lower 0.3 mg dose studied in 
the dogs (0.029 mg/kg body weight, or 0.0145 mg/cc CSF)   Higher doses could 
be considered in the future, if the data from this study suggest that higher doses 
are needed and safety is demonstrated at the lower dose.        
 
By using 3 cc of enzyme with 6 cc of Elliotts B® solution in a 9 cc total injection 
volume, the enzyme is diluted 3 fold to reduce the impact of the high phosphate 
buffer and low pH of the drug formulation. The Elliotts B® solution is approved in 
the US and has been used routinely for the purpose of reducing the acidity of 
chemotherapy drugs during intrathecal administration. 
 
7.6. 
Intrathecal enzyme replacement 
The subject will be taken to a procedure room and placed on continuous pulse 
oximetry.  Vital signs (pulse, respirations, blood pressure, pulse oximetry) will be 
recorded every 15 minutes.  Temperature will be recorded before the procedure, 
then after the procedure on an every 4 hour schedule as described below. 
Equipment and medications necessary for resuscitation will be in the room, along 
with qualified personnel.  A peripheral intravenous catheter will be placed in a 
superficial vein, usually an arm, for administration of medication.  The subject will 
receive 5 mg of midazolam (or as determined to be patient-appropriate for 
conscious sedation) with a normal saline flush.  Depending on the hospital 
situation and local practice, general anesthesia may be preferred and is up to the 
discretion of the investigator with the consent of the subject, and approval of the 
local IRB or ethics committee. 
A local anesthetic (lidocaine dose as appropriate) will be administered in the skin 
and underlying tissue above the chosen interspace.  A small spinal needle will be 
inserted under sterile conditions into the lumbar spinal sac. A small amount of 
CSF (roughly 6-10 mL) will be collected for laboratory evaluations (refer to 
Section 7.7.4.1 below).   
A dose of 3 ml of Aldurazyme (0.58mg/ml) or about 1.74 mg of recombinant α-L-
iduronidase will be combined slowly and gently in a syringe with 6 cc Elliotts B® 
(or other equivalent solution as described below in Section 22.1) for a total 
volume of 9 mL.  The syringe should be slowly inverted to mix, taking care to 
avoid creating small bubbles, shaking or shear in the solution.  Dilution of the 
enzyme in Elliotts B® should be mixed immediately prior to injection.  The Elliotts 
 
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B®-Aldurazyme® mixture should be administered as soon as possible and not 
later than 2 hours following mixing. 
The diluted enzyme will be administered via lumbar puncture and given slowly 
over 2-3 minutes.  The subject will be watched closely during enzyme 
administration for any adverse clinical reactions. After enzyme administration, the 
subject will lie supine in Trendelenberg (head below the level of the legs) for a 
period of one hour with monitoring continued.   If the subject is unable to tolerate 
the Trendelenberg position, he or she may lie down in a position of comfort.  The 
subject should be observed for another 3 hours supine or lying down in an 
alternative position of comfort.   Subjects will remain hospitalized for a minimum 
of 24 hours from the time of the intrathecal injection.  During hospitalization, vital 
signs, including pulse, respiration, blood pressure, pulse oximetry, and 
temperature will be checked every 4 hours.  Neuro checks, including assessment 
of level of consciousness, sensation and movement, will be done q15 minutes 
during the first hour post-procedure, then hourly for the next 3 hours, and q4 
hours thereafter during the 24 hour inpatient monitoring period.  Discharge may 
not occur if any headache or pain greater than baseline for the subject are 
present.  New narcotic analgesics may not be administered on an outpatient 
basis to study subjects. Family members will be provided clear instructions 
regarding the post discharge monitoring of the subject for anticipated adverse 
events.  The day following discharge from the inpatient unit, the subject will 
return for an outpatient visit.  A physical and neurologic examination and interim 
history will be performed. Re-hospitalization will occur if new neurologic 
symptoms, signs, or pain (greater than the subject’s baseline) are present at this 
follow up visit.  The above procedure will be followed for all subjects for all 
treatment visits.  
 
Radiologically-guided lumbar puncture may be required in certain individuals due 
to body habitus or other factors.  This will be performed under fluoroscopy or 
ultrasound guidance at the discretion of the investigator.  
 
7.7. 
Other Study Procedures 
7.7.1. 
Cognition   
Neuropsychological testing will be performed at baseline and yearly using the 
following tests: 
 
 CANTAB - the Cambridge Neuropsychological Test Assessment Battery (a 
sensitive and precise computerized non-language assessment battery that 
captures changes in cognitive performance on tests sensitive to frontal and 
temporal lobe functions [touch sensitive hardware and software required]),    
 WASI - Wechsler Abbreviated Scale of Intelligence (4 subtest form - brief IQ 
measure), 
 
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 Hopkins Verbal Learning Test (measure of verbal declarative memory –  
multiple forms available for repeat testing), this is the primary  outcome 
variable 
 Brief Visual-spatial Learning Test (measure of visual declarative memory –  
multiple forms available for repeat testing), and 
 TOVA (Test of Variables of Attention – computerized test of attention  
[hardware and software are needed]) 
 
 
7.7.2. 
Magnetic resonance imaging  
MRI of the brain will be performed on a 3T MR scanner at baseline and 
yearly.  MRI will be used to document changes in the following: 
 Volumes:  Whole brain, white matter, gray matter, hippocampal, caudate and 
ventricular volumes will be calculated using specialized software.  Volumetric 
studies will use T1-weighted high-resolution structural MRI images, converted 
into 176 slices with a resolution of 1 mm isotropic voxels.  As efforts to obtain 
a precise and reliable automated program have not been successful, manual 
measurement is needed for hippocampal structures, using the Image J v1.38 
or later software.  Reliability will be ensured within and across raters. 
 White matter changes and Virchow-Robin spaces:  assessed using the 
methodology in Matheus et al. 2004.  See Appendix C. 
 Diffusion Tensor Imaging and Tractography to examine white matter structure 
and function will use 12 directional diffusion weighted imaging to calculate 
fractional anisotropy (FA) with the corpus callosum measure on the 
midsagittal section as the Region of Interest (ROI).  We will also examine 
connectivity of the afferent and efferent pathways from the hippocampus to 
the rest of the brain using the fornix as the ROI if possible. 
 
If a subject has a programmable ventriculoperitoneal shunt, it may need to be 
reprogrammed after the MRI.  This should be supervised by a neurosurgeon or 
physician trained to analyze and reset the programmable shunt.  The analysis 
and reprogramming of the shunt may require up to three plain x-rays of the 
shunt. 
 
The neuropsychological tests and brain MRI may be done as part of a separate 
study being conducted at the University of Minnesota.  If these tests have been 
performed within 60 days of enrollment in MIRC-002, then this data may be used 
as baseline data for this extension study. 
 
7.7.3. 
Clinical evaluations 
Clinical evaluations as described below will be completed at the study site and 
documented on Case Report Forms.   
 
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7.7.3.1. 
History and Physical Examination  
A history and physical examination will be performed at each visit.  A detailed 
and thorough medical history will be obtained at screening.  Specific information 
relating to any prior or existing medical conditions/surgical procedures involving 
the following systems: Infectious Diseases, Allergy, 
Metabolic/Endocrine/Nutritional, Hematopoietic, Musculoskeletal, Dermatologic, 
HEENT (Head, Ears, Eyes, Nose, and Throat), Breasts, Respiratory (including 
supplemental O2, presence/absence of tracheostomy, mechanical ventilation 
requirement), Cardiovascular, Gastrointestinal/Hepatic, Genitourinary/Renal, 
Neurologic (ambulatory status), and Psychiatric/Psychosocial.   An interim history 
will be obtained at each subsequent visit. 
 
Each physical examination will include the following physical observations: 
General Appearance, Skin, HEENT, Lymph Nodes, Heart, Chest, Abdomen 
(including degree of Hepatosplenomegaly), Extremities/Joints.   A Snellen test 
will be performed at each visit by a standard, age or intellect-appropriate eye 
chart 20 feet from the subject in a well-lighted, indoor space, with each eye 
examined individually while the opposite eye is covered. 
 
If clinically significant worsening from the baseline medical status or vital signs 
status is noted, the change will be documented as an AE on the appropriate data 
collection sheet and will be followed as an adverse event consistent with the 
procedure outlined in Section 11.3.  Clinical significance is defined as any 
variation in physical findings, which has medical relevance resulting in an 
alteration in medical care. 
 
7.7.3.2. 
Neurologic examination   
A neurologic examination including mental status, cranial nerves, motor, sensory, 
associated motor, and reflexes will be conducted at each visit.  Mental status 
exam will include assessment of level of consciousness and the Mini-Mental 
State Examination (MMSE).  Although more commonly used as a screening 
exam in adults, the MMSE has been studied in children as young as age four, 
and has been shown to correlate with chronologic and mental age  (Ouvrier et 
al.,1993).  We will use the minor modifications to the MMSE as detailed in the 
Ouvrier paper (Appendix A). 
 
7.7.3.3. 
Photography and Video 
Photographs and/or video of the subjects may be taken at baseline and each visit 
to record the subject’s appearance, posture, gait, physical and neurologic 
findings, and document any changes occurring in the subjects with time.  
Photography and video is optional at the discretion of the investigator and willing 
participation of the subject. 
 
7.7.3.4. 
Six minute walk test 
 
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The subject will be given a six-minute walk test according to American Thoracic 
Society guidelines (ATS statement, 2002), except that the course distance will be 
15 meters. 
 
7.7.3.5. 
Subjective response of clinical symptoms   
The subject will be asked at baseline to verify if they have the following 
symptoms: headache, memory loss, difficulty concentrating, decreased ability to 
function at work or school or in their daily life. Also, the subject may identify 
additional CNS symptoms that concern them.  At each subsequent visit, the 
symptoms should be scored by the subject as no change (score 0), slightly better 
(+1), moderately better (+2), much better (+3), slightly worse (-1), moderately 
worse (-2) or much worse (-3).    
 
7.7.3.6. 
Independence of functioning scale 
A modified Functional Independence Measure (FIM) score will be determined 
(Maynard et al., 1997).  The modified FIM will evaluate the following areas of 
functioning:  self-care, sphincter control, mobility, and locomotion.  The subject 
will be asked to assign a score to each item in these areas.  A parent or guardian 
may assist the subject in completion of the FIM score.  Further description of the 
FIM score is detailed in Appendix B. 
 
7.7.4. 
Laboratory tests 
The following laboratory tests will be performed as described with test reports 
forwarded to the designated study staff. 
 
7.7.4.1. 
CSF analyses  
7.7.4.1.1. 
CSF chemistry and cell counts  
Approximately 6-10 mL of CSF, roughly equivalent to the injection volume, will be 
withdrawn from each subject at each lumbar puncture for all CSF evaluations. A 
portion of this sample (~ 1 cc) will be used for determination of glucose, protein, 
and cell counts.  Specimens will be collected and processed at each study site in 
a laboratory conforming to the local standards and regulations.  The subject’s 
levels will be compared to age-matched normative controls from that laboratory.   
 
7.7.4.1.2. 
CSF GAG content  
A portion of the CSF (~1cc) will be frozen and shipped on dry ice to a specialty 
laboratory 
for 
subsequent 
glycosaminoglycan 
analysis. 
 
Sulfated 
glysocaminoglycans will be assayed using a modification of the dimethylene blue 
dye method as published (Whitley et al., 1989).  The GAG quantities will be 
determined by comparison to standards of dermatan sulfate. 
 
7.7.4.1.3. 
CSF Iduronidase Assay  
 
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A portion of the CSF (~2-4 cc) will be frozen and, if applicable, shipped on dry ice 
to the Harbor-UCLA laboratory for subsequent assay of iduronidase activity by 
fluorometric assay. 25 µl CSF will be incubated at 37º C for 1 h with 25 µl of 6mM 
4-methylumbilliferyl α-L iduronide substrate.  The reaction will be stopped with 1 
ml glycine carbonate buffer (400 mM, ph 10).  Samples will be read by 
spectrofluorometer, wavelength 365 excitation/440 emission.  Iduronidase activity 
is expressed in nmol of converted substrate per hour per ml CSF. 
 
7.7.4.1.4. 
CSF ELISA for α-L-iduronidase specific 
antibodies 
A portion of the CSF (~ 2-4 cc) collected will be frozen and shipped on dry ice to 
a specialty laboratory for subsequent anti-iduronidase antibody analysis.  
Antibodies specific for iduronidase are detected by standard ELISA protocol 
using anti-human IgG labeled with alkaline phosphatase as the secondary 
antibody. 
 
7.7.4.1.5. 
Additional CSF 
The remainder of the CSF collected (~ 2-6 cc) may be frozen and stored at the LAB-
HUCLA for future studies.   
7.7.4.2. 
Serum analyses  
7.7.4.2.1. 
Serum ELISA for α-L-iduronidase specific antibodies  
Blood samples are collected from each subject in a serum separator tube at 
baseline and at three month intervals.  Approximately 2.5-5 cc of blood will be 
collected.  These samples spun down and the serum quick frozen, then shipped 
on dry ice to Harbor-UCLA Medical Center (Torrance, CA) for subsequent anti-
iduronidase antibody analysis.  Antibodies specific for iduronidase are detected 
by standard ELISA protocol using anti-human IgG labeled with alkaline 
phosphatase as the secondary antibody. 
 
7.7.4.2.2. 
Complete blood count (CBC) and serum 
chemistries 
Standard blood specimens for CBC and comprehensive metabolic panel 
chemistries will be collected in the institution-specific tube and analyzed by the 
local laboratory.  The serum chemistries will evaluate electrolytes (sodium, 
potassium, chloride, calcium), bicarbonate, glucose, BUN, creatinine, 
magnesium, phosphate, hepatic enzymes (AST and ALT), total protein, albumin, 
bilirubin, and alkaline phosphatase.  Other chemistries may be obtained if 
clinically indicated in the opinion of the investigator.  
 
 
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7.7.4.2.3. 
Coagulation studies 
Standard blood specimens for prothrombin time (PT), partial thromboplastin time 
(PTT), and international normalized ratio (INR) will be collected in the institution-
specific tube and analyzed by the local laboratory. 
 
7.7.5. 
Neurophysiologic evaluation 
 
7.7.5.1. 
CSF flow study 
At baseline screening, the subject will undergo a CSF flow study.  This study is 
performed by injecting radionuclide (e.g. 99mTechnetium-DTPA) into the lumbar 
cistern.  Access to the lumbar cistern may require fluoroscopic-guided assistance 
due to body habitus or disease-related changes to the lumbar bony and 
ligamentous structures.  Images will be obtained using a scintillation camera as 
the radionuclide flows caudally.  Time to appearance of the radionuclide to 
specific CSF compartments will be compared to established norms (Chamberlain 
1998).  This study will guide our decision as to whether a lumbar approach for 
the intrathecal injection can be performed. 
 
7.7.6. Investigator global assessment   
At each study assessment, the Principal Investigator will use data from the 
clinical assessments, laboratory studies, neurophysiologic assessments, and 
imaging studies to assign a global assessment score to each subject.  Each 
score will be assessed in comparison to the subject’s baseline.  Scoring will be 
done as follows: 
+3 – Marked improvement 
+2 – Moderate improvement 
+1 – Mild improvement 
0 – No change 
-1 – Mild decline 
 
-2 – Moderate decline 
-3 – Marked decline 
 
The Principal Investigator will be asked to justify the decision in a comment 
section on the CRF. 
 
7.8. 
Safety and Outcome Endpoints  
Safety will be monitored continuously throughout the subject’s study participation 
through recording all adverse events (AEs) and periodically performing clinical 
and laboratory evaluations.  Also refer to Section 11.6 for a description of a Data 
 
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and Safety Monitoring Board for additional evaluation of the endpoints described 
below.  
7.8.1. 
Safety Endpoints 
7.8.1.1. 
History and Physical Examination 
A detailed and thorough medical history will be obtained at screening as 
described in the methods.  Data will be qualitative. 
 
A detailed and thorough physical examination will be performed at each visit as 
described in the methods.  Data will be qualitative.  
 
If clinically significant worsening from the baseline medical status or vital signs 
status is noted, the change will be documented as an AE on the appropriate data 
collection sheet and will be followed as an adverse event consistent with the 
procedure outlined in Section 11.3.  Clinically significant worsening is defined as 
variation decline in physical findings that has medical relevance and results in an 
alteration in medical care. 
 
7.8.1.2. 
Laboratory Evaluations  
7.8.1.2.1. 
CSF chemistry and cell counts  
Glucose, protein, and cell counts will be recorded in their standard units.  The 
subject’s levels will be compared to age-matched normative controls from that 
laboratory.  Data will be kept as quantitative, continuous variables, and each 
subject assessed for change over the study period.  
 
 
7.8.1.2.2. 
Complete blood count and chemistries  
Blood for a complete blood count and serum chemistries (including basic 
chemistries, liver function tests, renal function tests) will be performed according 
to the schedule above.  Analyses will be performed at a local clinical laboratory.  
Age-appropriate normal values for the laboratory will be used for comparison. 
 
The investigator must score all abnormal laboratory values as either clinically 
significant (CS) or not clinically significant (NCS).  Some laboratory values may 
be outside of the normal value range because of the underlying disease.  As in 
routine practice the investigator should use clinical judgment when considering 
clinical significance.  Clinical significant worsening is defined as any variation in 
laboratory parameters that has medical relevance and results in an alteration in 
medical care. 
 
If clinically significant laboratory worsening from baseline is noted, the changes 
will be documented on the appropriate adverse event form and will be followed 
as an adverse event consistent with the procedure outlined in Sections 11.1, 
 
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11.2, and 11.3.  The investigator will also assess the relationship of all clinically 
significant abnormal values to program drug as being none, remote, possible, 
probable, or definite. 
 
7.8.2. 
Outcome Endpoints 
7.8.2.1. 
Neuropsychological evaluations 
Neuropsychological testing will be performed at baseline and yearly as described 
in Section 7.7.1.  Data will be quantitative.  The primary  outcome variable is the 
score on the Hopkins Verbal Learning Test. 
 
7.8.2.2. 
MRI of Brain  
MRI will be performed at baseline and yearly as described in Section 7.7.2.  
Volumetric data and scoring for white matter changes and perivascular spaces 
will be quantitative.  Diffusion tensor imaging and tractography data will be 
quantitative.  Analysis of MRI results will be performed at the end of the study; 
however, if there are incidental findings of clinical significance found during the 
study, these will be reported to the PI.   
 
7.8.2.3. 
Clinical Evaluations   
7.8.2.3.1. 
History and Physical Examination 
 
A detailed and thorough medical history will be obtained at screening as 
described in the methods.   Data will be qualitative. 
 
A detailed and thorough physical examination will be performed at each visit as 
described in the methods.  Data will be qualitative.  
 
Any clinically significant worsening from the baseline medical status and vital 
signs status will be documented as an AE on the appropriate data collection 
sheet and will be followed as an adverse event consistent with the procedure 
outlined in Section 11.3.  Clinical significance is defined as any variation in 
physical findings that has medical relevance and results in an alteration in 
medical care. 
 
7.8.2.3.2. 
Neurologic examinations   
A full neurologic examination including mental status, cranial nerves, motor, 
sensory, associated motor, and reflexes will be conducted at each visit throughout 
the study period (refer to Section 7.7.3.2 for further information).  Data will be 
qualitative. 
 
7.8.2.3.3. 
Six minute walk test 
The six minute walk test will be performed at each visit.  Borg scale results for 
before and after the test will be kept as ordinal variables for each subject at each 
 
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visit.  Before and after results will be compared at each visit to determine change 
over time.   
 
The distance walked and laps walked will be continuous variables.  Means and 
standard deviations for the changes made by the subjects over the study period 
will be calculated. 
 
7.8.2.3.4. 
Subjective improvement   
Subjective accounts will be recorded and kept as qualitative data. 
 
7.8.2.3.5. 
Independence of functioning scale 
Functional Independence Measure (FIM) score will be performed at each visit 
(Maynard et al., 1997).  The FIM score is calculated as described in Appendix B.  
Change in the FIM score for each subject with time will be calculated.   
 
7.8.2.4. 
Laboratory tests 
CSF GAG content 
 
At the each lumbar puncture, a portion of CSF will be quick frozen for subsequent 
glycosaminoglycan analysis.   Sulfated glysocaminoglycans will be assayed using 
a modification of the Alcian Blue method of Bjornsson as published (Whitley et al., 
1989).  The GAG quantities will be determined by comparison to standards of 
dermatan sulfate. 
 
7.8.2.4.1. 
CSF ELISA for α-L-iduronidase specific 
antibodies 
CSF antibody levels will be performed according to the schedule above.  Titers 
will be recorded as OD units/mL.  An antibody titer > 20 OD units/mL is 
considered positive.  Data will be kept as quantitative, continuous variables, and 
each subject assessed for change over the study period.  A mean and standard 
deviation for the pre and post-treatment antibody levels may be calculated.  
Titers will be sent for analysis every six months. 
 
7.8.2.4.2. 
Serum 
ELISA 
for 
α-L-iduronidase 
specific 
antibodies  
Serum antibody levels will be performed according to the schedule above.  Titers 
will be recorded as OD units/mL.  An antibody titer > 20 OD units/mL is 
considered positive.  Data will be kept as quantitative, continuous variables, and 
each subject assessed for change over the study period.  A mean and standard 
deviation for the pre and post-treatment antibody levels may be calculated.  
Titers will be sent for analysis every six months. 
 
 
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8. 
Data and Specimen Banking 
CSF and serum specimens will be stored at -20 degrees C without identifiers at 
Los Angeles Biomedical Research Institute for at least 11 years.  Specimens will 
be accessed for study tests by qualified laboratory personnel.  Access to 
specimens by other investigators will be granted          contingent upon IRB 
approval and informed consent of study participants. 
 
The clinical information collected for this study will be stored at the Data 
Management and Coordinating Center at the University of South Florida in 
Tampa, FL and also sent to a Federal data repository. All retrospective data 
(from the beginning of the study) and all ongoing prospective data will be 
collected. The data management center uses several layers of protection for the 
clinical data stored there. It meets all of the local and federal security 
requirements for research datacenters. Information is stored only using a study 
ID. 
 
While the study is active, access to the stored data and specimens will be limited 
to approved study staff.  After the study is closed, local access will be limited to 
the site’s Principal Investigator(s).  Authorized study staff with access to stored 
specimens and/or data have completed training that included GCP, HIPAA, and if 
applicable, an overview of the study database.  Access to the data by other 
investigators will be granted contingent upon IRB approval and informed consent 
of study participants 
  
Data to be stored for each study participant include:   
 Medical history and physical 
 Neurologic examination including mental status, cranial nerves, motor, 
sensory, associated motor, and reflexes  
 Standard blood CBC and comprehensive metabolic panel chemistries 
 
Blood serum chemistries, including electrolytes (sodium, potassium, 
chloride, calcium), bicarbonate, glucose, BUN, creatinine, magnesium, 
phosphate, hepatic enzymes (AST and ALT), total protein, albumin, bilirubin, 
and alkaline phosphatase.  Other chemistries may be obtained if clinically 
indicated in the opinion of the investigator. 
 Coagulation studies, including prothrombin time (PT), partial 
thromboplastin time (PTT), and international normalized ratio (INR) 
 CSF glucose, protein, and cell counts  
 CSF opening pressure 
 ELISA anti-IDU antibody 
 Serum glycosaminoglycans (GAG) levels 
 
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 Brain MRI data, including white matter changes and Virchow-Robin 
spaces, volumes, diffusion tensor imaging and tractography 
 Hopkins Verbal Learning Test 
 Six minute walk test with Borg scale results  
 Functional Independence Measure (FIM) score 
 Subjects’ subjective improvement scores   
 Global assessment score based on subject’s clinical assessments, 
laboratory studies, neurophysiologic assessments, and imaging studies 
 
9. 
Data Management  
9.1. 
Overview 
This study will evaluate changes in neuropsychological, radiological, clinical, 
biochemical measures, and safety after 5 years of intrathecal injections of rhIDU 
in six MPS-I subjects.  The statistical goal is estimation of the magnitude of these 
changes and their heterogeneity and calculation of rates of adverse events.   
 
9.2. 
Study Size 
 
A study size analysis was done for the pilot study.  As this study is only open to 
subjects that have completed the pilot study, the maximum number of subjects 
available for this study is six. 
 
9.3. Data analysis methods 
A descriptive summary of subject characteristics at baseline will be made with 
frequencies and percentages for categorical variables, and with mean and 
standard deviation or median and quartiles, depending on statistical distribution, 
and range for continuous measurements.  Some analyses specified below 
require that continuous observed or derived measures have statistical properties 
such as normal distributions. If there is evidence that statistical requirements are 
not met, transformations to achieve those requirements will be performed. If such 
transformations are not possible, non-parametric analogues to the proposed 
parametric methods will be substituted. 
 
9.3.1. 
Analysis Populations 
The safety population will include all subjects enrolled in the study. 
 
The outcome population will include all subjects in the study that received at least 
one dose of study medication and have at least one post-baseline measurement.   
 
 
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The study population will be compared to available normative data for age, as 
well as data from age-matched MPS I subjects not receiving IT rhIDU.   
 
9.3.2. 
Study Conduct 
Information about the study conduct will be summarized.  Specifically details 
about the number of subjects completing or discontinuing the study will be 
summarized along with the reason for discontinuation.  In addition, information 
about duration of enrollment and number of intrathecal doses will be 
summarized. 
 
9.3.3. 
Safety analyses 
Four categories of measurements related to safety will be examined: 
 
9.3.3.1. 
Laboratory evaluations: CSF and anti-IDU antibody 
Absolute, percent, and reference range change in CSF glucose, protein, and cell 
counts from the month 0 visit to the subsequent month visits will be calculated for 
each subject, and summarized over subjects with means, standard deviations, 
and 95% confidence intervals. Frequency and percent of subjects with values 
outside their reference range will be reported. 
 
Absolute and percent change ELISA anti-IDU antibody from the month 0 visit to 
the subsequent month visits will be calculated for each subject, and summarized 
over subjects with means, standard deviations, and 95% confidence intervals. 
Frequency and percent of subjects with values outside their reference range for 
the subject’s age will be calculated. 
 
9.3.3.2. 
   History and physical examination 
At each visit, each subject will be classified as experiencing an adverse event if 
clinically significant worsening from baseline medical status, as described in 
Section 7.8.1.1, has occurred. The frequency and percent of subjects 
experiencing such an event will be tabulated for each visit. 
 
 
9.3.3.3. 
   Standard CBC and Chemistry Measurements 
At each visit, each subject will be classified as experiencing an adverse event if 
there is clinically significant CBC or chemistry panel worsening from baseline, as 
described in Section 7.8.1.2.4. The frequency and percent of subjects 
experiencing such an event will be tabulated for each visit. 
 
9.3.3.4. 
   Other Adverse Events 
Other adverse events and unexpected adverse events from the time of injection 
to the time of subsequent injection will be recorded for each subject. The 
frequency and percent of subjects experiencing any such event will be tabulated 
for each post-injection interval, and for the entire month 0 to end study interval. 
 
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9.3.4. 
Primary outcome analyses 
The outcome population will be used for all outcome analyses. The primary 
outcome analysis will assess cumulative outcome on the Hopkins Verbal 
Learning Test (the primary outcome variable) after multiple injections.  
 
Secondary outcome analyses will examine additional outcomes and time points.  
Five categories of measurements related to outcome will be examined: 
 Neuropsychological testing 
 Brain MRI results 
 Clinical signs and symptoms of cognitive decline 
 Biochemical results 
 
9.3.4.1. 
Primary outcome variable and analysis 
The mean change from baseline for the Hopkins Verbal Learning Test will be 
presented over time. Changes will be analyzed through the 5-year study period. 
Summary statistics of mean changes, standard deviations, and 95% confidence 
intervals will be presented.  
 
9.3.4.2. 
Secondary outcome variables and analyses 
9.3.4.2.1. 
Neuropsychological testing 
Other neuropsychological measures such as IQ will be analyzed using the same 
method as described for the primary analysis. 
 
9.3.4.2.2. 
Brain MRI 
Brain MRI data will be analyzed in three data sets: 
 White matter changes and Virchow-Robin spaces will be assessed using the 
methodology in Matheus et al. 2004, see Appendix C.   Absolute and percent 
change from the month 0 visit to the final study visit in each of the MRI scores 
will be calculated for each subject.  Summary statistics of means, standard 
deviations, and 95% confidence intervals will be presented. 
 Volumes:  Whole brain, white matter, gray matter, hippocampal, caudate and 
ventricular volumes will be calculated. Absolute and percent change from the 
month 0 visit to the final study visit in each of the MRI scores will be 
calculated for each subject.  Summary statistics of means, standard 
deviations, and 95% confidence intervals will be presented. 
 Diffusion Tensor Imaging and Tractography:  Fractional anisotropy values will 
be used to evaluate white matter structure and function.  These variables will 
be analyzed using the same method as the MRI volume data above. 
 
 
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9.3.4.2.3. Clinical signs and symptoms of cognitive decline 
Absolute and percent change from the month 0 visit to final study visit in (1) the 
MMSE, (2) the six-minute walk test, and (3) the FIM scale will be calculated for 
each subject, and summarized by presenting means, standard deviations, and 
95% confidence intervals. 
 
Each subject’s total subjective improvement score from the day 0 visit to the final 
study visit will be calculated as the mean (of up to the five clinical areas) of the 
sum of all the subjective scores. These changes will be summarized by 
presenting means, standard deviations, and 95% confidence intervals. 
 
 
9.3.4.2.4. 
Biochemical  
Absolute and percent change from the month 0 visit to the final study visit in 
glycosaminoglycans (GAG), will be calculated for each subject, and summarized 
by presenting means, standard deviations, and 95% confidence intervals.  
 
 
10. Confidentiality 
Local transport of the Case Report Forms, source documents and specimens will 
be limited to the site’s authorized staff.  Study participants and/or respective 
guardians will be informed that information that identifies them or their child will 
be used only for the purpose of the study; this includes information that can help 
study personnel locate or contact them as well as information related to their or 
their child’s medical condition (medical records, for example).   
 
Data and specimens will be stored locally for at least 11 years as previously 
described.  While the study is active, access to the stored data and specimens 
will be limited to approved study staff.  After the study is closed, local access will 
be limited to the site’s PI(s).   
 
11. Certificate of Confidentiality 
To help protect participant privacy, a Letter of Confidentiality has been obtained 
from the National Institutes of Health (NIH).  With this Certificate, the researchers 
cannot be forced to disclose information that may identify a study participant, 
even by a court subpoena, in any federal, state, or local civil, criminal, 
administrative, legislative, or other proceedings.  The researchers will use the 
Certificate to resist any demands for information that would identify a participant, 
except as explained below. 
 
The Certificate cannot be used to resist a demand for information from personnel 
of the United States Government that is used for auditing or evaluation of 
Federally funded projects or for information that must be disclosed in order to 
meet the requirements of the federal Food and Drug Administration (FDA). 
 
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Even with the Certificate of Confidentiality, the investigators continue to have 
ethical obligations to report child abuse or neglect and to prevent an individual 
from carrying out any threats to do serious harm to themselves or others.  If 
keeping information private would immediately put the study participant or 
someone else in danger, the investigators would release information to protect 
the participant or another person. 
 
Department of Health and Human Services (DHHS) personnel may request 
identifying information for purposes of performing audits, carrying out 
investigations of DHHS grant recipients, or evaluating DHHS funded research 
projects. 
 
12. Provisions to Monitor the Data to Ensure the Safety of 
subjects 
12.1. Adverse Events  
Subjects in this study will be closely monitored during the enzyme administration 
and for one hour afterward with frequent (every 15 minutes) vital signs and 
continuous pulse oximetry.  The subject will be able to contact the investigator or 
other appropriate personnel to report adverse events occurring later.  These will 
be treated with appropriate medical care where applicable.  Adverse events that 
are unanticipated will be reported within 10 working days to the institutional 
review board. 
 
An adverse event (AE) is any undesirable physical, psychological or behavioral 
effect (an unfavorable and unintended sign, symptom or disease) experienced by 
a subject during their participation in an investigational study whether or not 
product-related.  This includes any untoward signs or symptoms experienced by 
the subject from the time of signing of the informed consent until completion of 
the study.  Adverse events may include, but are not limited to: 
 Subjective or objective symptoms spontaneously offered by the patient or 
subject and/or observed by the investigator or medical staff. 
 Laboratory abnormalities of clinical significance. 
 Disease signs, symptoms and/or laboratory abnormalities already existing 
prior to the use of the study medication are not considered adverse events 
after treatment unless they reoccur after the subject has recovered from 
the pre-existing condition or they represent an exacerbation in intensity or 
frequency. 
 
All reportable AEs will be assigned a relationship to the study drug by the 
principal investigator.  A drug-related AE is an event with a plausible time 
relationship to drug intake that cannot be explained by the disease or other 
drugs. 
 
 
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Any AEs experienced by the subject, from the time of signing the Informed 
Consent Form through the completion of study participation, will be reported as 
described (see Section 11.3) and recorded on the CRF.  If AEs are present when 
the patient completes study participation, the subject will be re-evaluated within 
two weeks of completion and the results of this re-evaluation will be recorded on 
the CRF.  If AEs are not resolved, additional follow-up will be performed as 
appropriate.  All reportable AEs must be reported to the RDCRN within 20 
working days of the notification of the event or of the site becoming aware of the 
event. 
 
Local institutional reporting requirements to IRBs, any CTSA oversight committee 
and the FDA, if appropriate, remain the responsibility of the site investigator and 
the Principal Investigator. 
 
An unanticipated adverse event is defined as any adverse event, the specificity 
or severity of which is not consistent with the risks of information described in the 
protocol, and the event is related or possibly related to participation in the 
research, and suggests that the research places subjects or others at a greater 
risk or harm (including physical, psychological, economic, or social harm) than 
was previously known or recognized. Expected adverse events are those that are 
known to be associated with or have the potential to arise as a consequence of 
participation in the study. 
 
12.2. Serious Adverse Events  
A serious adverse event (SAE) is defined as any adverse event that results in 
any of the following outcomes: 
 Death 
 Life-threatening experience 
 Required or prolonged inpatient hospitalization 
 Persistent or significant disability/incapacity 
 Congenital anomaly/birth defects 
Life-threatening experience: Any adverse event that places the patient, in the 
view of the reporter, at immediate risk of death from the adverse event as it 
occurred, i.e., does not include an adverse event that had it occurred in a more 
severe form, might have caused death. 
Persistent or significant disability/incapacity: The adverse event that resulted in a 
substantial disruption of a person’s ability to conduct normal life functions. 
Important medical events based upon appropriate medical judgment, that may 
jeopardize the patient or subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above: Adverse events that may not result 
in death, be life-threatening, or require hospitalization may be considered a 
serious adverse event when, based upon appropriate medical judgment, they 
 
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may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
The investigator will be asked to assess the severity of the adverse drug/biologic 
experience using the following categories: mild, moderate and severe.  This 
assessment is subjective and the investigator should use medical judgment to 
compare the reported adverse event to similar type events observed in clinical 
practice.  Below are listed guidelines for severity assessment: 
 Mild:  Symptom(s) barely noticeable to the subject/patient or does not 
make the subject/patient uncomfortable.  The adverse event does not 
influence performance or functioning.  Prescription drugs are not ordinarily 
needed for relief of symptom(s). 
 Moderate: Symptom(s) of a sufficient severity to make the subject/patient 
uncomfortable.  Performance of daily activities is influenced.  Treatment of 
symptom(s) may be needed. 
 Severe: Symptom(s) of a sufficient severity to cause the subject/patient 
severe discomfort.  Severity may cause cessation of treatment with the 
study drug.  Treatment for symptom(s) may be given. 
 
12.3. Adverse Event and Serious Adverse Event Reporting 
The necessity and time requirements for reporting of SAEs are as follows: 
 
All SAEs and subject terminations will be reported to the Principal Investigator 
within 24 hours. 
 
All SAEs will be reported to the Principal Investigator and to the RDCRN through 
the DMCC Adverse Event Data Management System within 24 hours of the 
investigator’s first knowledge of the event, even if the experience does not 
appear to be related to the study drug.  This also includes those events that are 
unexpected/unanticipated or is considered life-threatening/disabling or results in 
the death of a subject. 
 
For all SAEs, a detailed written description that includes copies of relevant 
patient records, autopsy reports, and other documents will be collected. 
 
Additionally, the IRB must be notified in writing of any events falling into these 
categories.  It is the responsibility of the investigator to notify the IRB within 24 
hours if the event is unanticipated or is considered life-threatening/ disabling or 
results in the death of a subject. All other reportable SAEs must be reported 
within 5 working days (of learning of the event).  
 
All AEs and SAEs will be noted on the CRF, with a full description including the 
nature, date and time of onset and resolution, determination of seriousness, 
severity, corrective treatment, outcome, and relationship to study drug.  
 
 
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Flowchart for Adverse Event Reporting 
 
Adverse 
Event
Serious 
Adverse Event?
Within 24 hrs
•Report to Principal Investigator
•Report to RDCRN through DMCC 
Adverse Event Data Mgmt System 
(AEDMS)
Unanticipated?
Within 24 hrs
•Report to LA BioMed IRB
•Report to LA BioMed GCRC/DSMB
Within 7 calendar days
•Report to FDA (15 calendar days for 
written report)
Go to *
Unanticipated?
Within 10 working days
•Report to LA BioMed IRB
•Report to LA BioMed
GCRC/DSMB
Within 20 working days
•Record on CRF/DMCC 
AEDMS
*
Within 20 working days
•Record on CRF/DMCC 
AEDMS
Report as scheduled to 
the GCRC/DSMB
 
 
12.4. Institutional Review Board 
The study will be approved by the institutional review board (IRB) at each 
respective study site.  All investigators must obtain IRB approval.   
 
12.5. Food and Drug Administration Investigational New Drug 
Application 
A new IND has been filed to the FDA [1,354].  The investigator and all study 
personnel will conduct the study according to FDA requirements. 
 
 
12.6. Data and Safety Monitoring Board (DSMB) 
The DSMB will review the research protocol, informed consent documents and 
plans for data safety and monitoring, evaluate the progress of the trial, including 
periodic assessments of data quality and timeliness, number of subjects 
screened, number enrolled, number dropped with reason for discontinuation, 
interim and cumulative data from all study sites, adverse events and serious 
adverse events, performance of the trial sites, and other factors that can affect 
study outcome.  The establishment of a DSMB was recommended because of 
the inherent risks, the multicenter nature of the trial, and the significant financial 
 
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interest involved in this research.  At the initial DSMB meeting, the DSMB will 
approve the study protocol and consider data elements  to be included in the 
periodic reports to the DSMB.  See DSMB Charter.  During the initial meeting, 
the DSMB will also develop the Standard Operating Procedure of the DSMB.  
This SOP will be forwarded to the LABiomed IRB and GCRC for review. 
 
The DSMB will provide the Sponsor-Investigator with the minutes from the open 
sessions of the DSMB meetings and summary report with any recommendations 
for future study conduct (continuation, modification or termination of the study).  
The Sponsor-Investigator will provide copies of the minutes, reports and 
recommendations to each site’s co-investigators, the LABiomed IRB, and the 
GCRC Advisory Committee.   
 
This study protocol will also be reviewed and approved by the National Institutes 
of Health (NIH). This is an interventional study that meets the federal definition of 
moderate risk.    
 
The Principal Investigator has primary oversight of this clinical trial. The Principal 
Investigator and the Steering Committee will review accrual patterns, adverse 
events, data quality, and protocol compliance on an annual basis. 
 
12.7. Local Reporting 
The investigator will prepare a periodic report to include target, interval and 
cumulative data in a tabular format for subjects enrolled at Harbor-UCLA Medical 
Center and for the entire study as follows:  
 Number of subjects screened 
 Number of subjects enrolled  
 Number of subjects not qualified for enrollment based on screening with 
reason for screen failure 
 Dropout number with reason for dropout and stage of study at dropout. 
 Completion number 
 All adverse events with severity and attribution.  During the period 
between the treatments and the follow-up period, the rates of adverse 
event related to underlying disease and routine illnesses (URI, headaches, 
muscle aches, etc.) and traumatic injuries are not expected to be different 
than usual and will not be reported as unexpected AEs but will be tracked 
and reported as AEs for the DSMB reports.   
 For all serious adverse events (SAEs) and all unexpected adverse events 
(UAEs), the clinical summary will also be provided in a cumulative fashion.  
For SAEs and UAEs, IRB and GCRC policy on adverse event reporting 
will be followed. 
 
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To ensure subject confidentiality, all subjects will be identified by a numerical 
identifier only.   
 
The primary monitor for this study is the DSMB.  The data and safety monitoring 
board will be comprised of three persons: a statistician, a neurologist, and a 
pediatrician geneticist.  All DSMB members will be external to the Los Angeles 
Biomedical Research Institute at Harbor-UCLA Medical Center, and shall have 
no financial interest in the institute, Aldurazyme, or in the companies that 
manufacture and distribute Aldurazyme (i.e. BioMarin Pharmaceutical, Inc. and 
Genzyme Corp.).  
 
A separate DSMB charter will be drafted and approved by all board members 
prior to reviewing any data.  The members of this DSMB should not have 
substantial conflicts of interest and have no substantive financial ties to the 
applicant or to the proposed research and will be required to submit an affidavit 
to these effects.   
 
The board will convene every four months at the inception, during, and at the end 
of the study period.  Due to the small number of subjects and the relatively small 
number of visits, every 4 months is recommended to allow review of relevant 
data.  An emergency meeting of the DSMB may be called at any time by the 
DSMB Chairperson or the Sponsor-Investigator should question of subject safety 
arise. 
 
12.8. RDCRN Adverse Event Data Management System 
(AEDMS) 
Upon entry of a serious adverse event by a site investigator, the DMCC created 
Adverse Event Data Management System (AEDMS) will immediately notify the 
Principal Investigator. The Principal Investigator is responsible for notifying 
NINDS staff. 
 
Serious adverse events: The site investigator determines causality (definitely not 
related, probably not related, possibly related, probably related, definitely related) 
of the adverse event. The DSMB will also review the SAE incident report. 
 
The DSMB may request further information if necessary and possibly suggest 
changes to the protocol or consent form to the NINDS as a consequence of 
adverse events. A back-up notification system is in place so that any delays in 
review by the DSMB chair beyond a specified period of time are forwarded to a 
secondary reviewer. The Adverse Event Data Management System (AEDAMS) 
maintains audit trails and stores data (and data updated) and communication 
related to any adverse event in the study. 
 
Non-serious expected adverse events Except those listed above as immediately 
reportable, non-serious expected adverse events that are reported to or 
observed by the investigator or a member of his/her research team will be 
 
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submitted to the DMCC in a timely fashion (within 20 working days). The events 
will be presented in tabular form and given to the DSMB on a quarterly basis or 
as requested.  Local site investigators are also required to fulfill all reporting 
requirements of their local institutions. 
 
The DMCC will post aggregate reports of all adverse events (serious/not serious 
and expected, unexpected) for site investigators and IRBs. 
 
All reported adverse events will be classified using the current version of the 
Common Terminology Criteria for Adverse Events (CTCAE) developed and 
maintained by CTEP at National Cancer Institute. 
12.9.  Unanticipated Problem Reporting 
The Office for Human Research Protections (OHRP) considers unanticipated 
problems involving risks to subjects or others to include, in general, any incident, 
experience, or outcome that meets all of the following criteria: 
unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as 
the IRB-approved research protocol and informed consent document; and 
(b) the characteristics of the subject population being studied; 
related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the 
research); and 
suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
Per the definition, only a subset of adverse events would be characterized as 
unanticipated problems. There are other types of incidents, experiences, and 
outcomes that are not considered adverse events, but are characterized as 
unanticipated problems (e.g., breach of confidentiality or other incidents involving 
social or economic harm). 
Incidents or events that meet the OHRP criteria for unanticipated problems are to be 
reported to the IRB, per local institutional reporting requirements. Local institutional 
reporting requirements to IRBs, any GCRC oversight committee and the FDA, if 
appropriate, remain the responsibility of the treating physician and the Study Chair. 
12.10. 
Discontinuation Guidelines 
 
The participation of all study subjects will be halted pending review by the NIH, 
DSMB and IRB for the following reasons: 
 
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 WHO Grade 3 toxicity (such as a seizure or meningitis) is experienced by 
2 or more subjects 
 Death or WHO Grade 4 toxicity is experienced by 1 or more subjects 
If one of the above conditions are met, the study will be placed on hold (no new 
enrollment, and a halt to all study procedures on enrolled subjects), and the PI 
will notify the NIH, IRB and DSMB within 24 hours. 
 
This study may be also suspended or closed if:  
 Accrual has been met 
 The study objectives have been met 
 The Study Chair / Study Investigators believe it is not safe for the study to 
continue 
 The RDCRN DSMB suspends or closes the trial 
 The NIH suspends or closes the trial 
 The FDA suspends or closes the trial 
 
 
13. Data Quality Assurance 
All required data will be recorded on the CRF.  All missing data will be explained.  
If a space is blank because the item was not done, the item will be marked “ND.”  
If the item is unknown, item will be marked “UNK.”  If the item is not applicable to 
the individual case, the space will be marked with a “NA.”  If the item is not 
available, it will be marked with “NAV.”  All entries will be recorded in black ink.  If 
an entry error has been made, a single straight line will be drawn through the 
wrong entry and the correct data will be entered above it and initialed and dated.  
ERRORS MAY NOT BE ERASED AND WHITEOUT MAY NOT BE USED. 
 
The CRFs will be reviewed manually at the study site for completeness.  All data 
will be entered into a study database for analysis and reporting.  Any data 
captured electronically (e.g., laboratory data) will be electronically transferred to 
the database.  Upon completion of data entry, the database will receive a quality 
assurance (QA) check to ensure acceptable accuracy and completeness. 
 
13.1. Data Quality and Monitoring 
As much as possible data quality is assessed at the data entry point using 
intelligent on-line forms. Data element constraints, whether independent range 
and/or format limitations or ‘relative’ referential integrity limitations, can be 
enforced by all methods employed for data input. QA reports assess data quality 
post-data entry. As we note, data quality begins with the design of the data 
collection forms and procedures and incorporates reasonable checks to minimize 
transcription and omission errors. Of the more important quality assurance 
measures are the internal validity checks for reasonableness and consistency. In 
addition to those describes above, we propose to build these checks into the 
 
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initial tables and cross tabulations that should reveal any remaining data quality 
issues. 
 
All study data will be collected via systems created in collaboration with the 
RDCRN Data Management and Coordinating Center and will comply with all 
applicable guidelines regarding subject confidentiality and data integrity. 
 Data Monitoring: The RDCRN DMCC identifies missing or unclear data 
and generates a data query to the consortium administrator contact.  
 Data Delinquency Tracking: The Data Management and Coordinating 
Center will monitor data delinquency on an ongoing basis.   
 
13.2.  Registration 
Registration of participants on this protocol will employ an interactive data system 
in which the clinical site will attest to the participant’s eligibility as per protocol 
criteria and obtain appropriate informed consent. IRB approval for the protocol 
must be on file at the DMCC before accrual can occur from the clinical site. 
 
The DMCC will use a system of coded identifiers to protect participant 
confidentiality and safety.  Each participant enrolled will be assigned a local 
identifier by the enrollment site.  This number can be a combination of the site 
identifier (location code) and a serial accession number.  Only the registering site 
will have access to the linkage between this number and the personal identifier of 
the subject.  When the participant is registered to participate in the study, using 
the DMCC provided web-based registration system, the system will assign a 
participant ID number.  Thus each participant will have two codes: the local one 
that can be used by the registering site to obtain personal identifiers and a 
second code assigned by the DMCC.  For all data transfers to the DMCC both 
numbers will be required to uniquely identify the subject.  In this fashion, it is 
possible to protect against data keying errors, digit transposition or other 
mistakes when identifying a participant for data entry since the numbers should 
match to properly identify the participant.   
 
 
13.3. Data Entry 
Data will be collected on the Case Report Forms during the study visit and 
subsequently from source documents (laboratory and test reports).  Data will 
then be entered into online electronic case report forms as previously described. 
Using encrypted communication links, on-line forms will be developed that 
contain the requisite data fields. 
Refer to Section 11.6 regarding periodic evaluation of the data by a Data 
and Safety Monitoring Board. 
13.4.  Protocol Deviations 
 
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 A protocol deviation is an unintentional departure from the approved protocol’s 
procedures.  If the deviation does not increase risk or decrease benefit or; does 
not have a significant effect on the subject’s rights, safety or welfare; and/or on 
the integrity of the data, these deviations will be reported as a note-to-file in the 
subject’s binder. 
If the deviation increases risk or decreases benefit, affects the subject’s rights, 
safety, or welfare, or the integrity of the data, these deviations will be reported to 
the IRB as soon as reasonably possible after the deviation is discovered. Local 
Institutional guidelines and additional reporting requirements for protocol 
deviations should be followed. 
 
14. Withdrawal of Subjects 
 
14.1. Subject withdrawal 
A subject (or the legal guardian acting on behalf of the subject) is free to 
withdraw consent and discontinue participation in the study at any time, and 
without prejudice to further treatment, according to standard clinical practice.  A 
subject who decides to discontinue participation in the study should be contacted 
to obtain information about the reason(s) for discontinuation and collection of any 
potential AEs.   
 
All data acquired prior to termination for the reasons outlined below will be 
included in the primary analysis unless a participant withdraws consent.  A 
subject's participation in the study may be discontinued at any time at the 
discretion of the investigator.  The following may be justifiable reasons for the 
investigator to remove a subject from the study: 
 The subject is uncooperative or non-compliant with the protocol. 
 The subject develops an exclusion criterion or concurrent disease. 
 The subject develops a condition or adverse event that, in the opinion 
of the investigator, contraindicates the continuation of treatment. 
 The subject desires a surgical procedure or other alternative 
treatment for cognitive decline. 
The reason for withdrawal should be clearly described.  Withdrawn subjects may 
not re-enter the study.  Follow-up procedures will be required if the subject 
discontinues as a result of an adverse event.  Follow-up may include completing 
the study assessments scheduled at the final visit. Every effort will be made to 
conduct a final study visit with the participant, and participants will be followed 
clinically until, if applicable, all adverse events resolve. 
 
If a subject or the subject’s legal guardian, acting on behalf of the subject, 
discontinues participation in the study, or the subject is discontinued by the 
 
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investigator, the Patient Completion/Discontinuation Case Report Form (CRF) 
describing the reason for discontinuation must be completed.  Any AEs 
experienced up to the point of discontinuation must be documented on the AE 
CRF.  If AEs are present when the subject withdraws from the study, the subject 
will be re-evaluated within two weeks of withdrawal.  If AEs are not resolved, 
additional follow-up will be performed, as appropriate. 
 
14.2. Termination of Subject Participation 
The investigator may choose to terminate a subject’s participation in the study at 
any time. Conditions that may warrant termination of study participation include, 
but are not limited to: 
 The discovery of an unexpected, serious, or unacceptable risk to 
subjects enrolled in the study 
 Insufficient adherence to protocol requirements. 
Subjects who withdraw or are withdrawn from the study will not receive further  
evaluations unless warranted by an ongoing adverse event.  
15. Risks to Subjects 
15.1. Human trials 
In the current study, there have been no drug-related severe adverse events 
(SAEs).  Due to the nature of the disease, MPS I subjects have had multiple 
disease-related SAEs.  These include surgery for spinal cord compression, 
lumbar spine surgery, severe muscle cramping, worsening of previous 
psychiatric disease.  One subject was diagnosed with prostate cancer during the 
study, but this is likely not drug nor disease-related.    
 
In the spinal cord compression trial, no drug-related severe adverse events 
(SAEs) occurred; one subject experienced a non-drug-related SAE (pneumonia), 
one subject experienced several moderate adverse events due to systemic MPS 
disease, one subject died 2 days after receiving IT rhIDU.  Autopsy results 
showed no evidence of central nervous system (CNS) abnormality, including no 
evidence of CNS inflammation. 
 
15.2. Seizures 
In early canine experiments with IT rhIDU, hyperventilation and/or brief seizures 
occurred in some dogs that received undiluted IT rhIDU.  Seizures occurred in 
the immediate post-treatment (recovery) period; no seizure occurred between 
treatments.  The problem was attributed to the formulation buffer. Dilution of 1:3 
by volume in Elliotts B artificial CSF solution prevented these side effects in all 
subsequent animals.  In addition, no seizure, hyperventilation, or posturing has 
been reported in the seven MPS I patients who have received IT rhIDU 
worldwide.  If a seizure were to occur, intravenous midazolam or other 
benzodiazepine drug could be given to manage this short term complication.   
 
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15.3. Chemical irritation  
The acidity (pH 5.5), phosphate concentration, osmolarity, and the presence of 
trace amounts of polysorbate 80 in the Aldurazyme® formulation could cause 
chemical irritation within the CSF space.  By diluting the enzyme in Elliotts B®, 
the pH effect is blunted as it is for commonly used intrathecal chemotherapy 
agents such as methotrexate (pH 8.5) or cytarabine (pH 5).   Dilution also lowers 
the phosphate concentration and osmolarity of the solution.  Polysorbate 80, 
which is required to stabilize rhIDU in the formulation, is present at very low 
quantities (0.001%). Very low total dose amounts will be given (0.03 micrograms 
per dose).  Polysorbate 80 is generally seen as a mild irritant and is present in 
various foods, drugs, and cosmetics.  The every 3 month dosing schedule should 
provide sufficient time for recovery if modest irritation occurs.   
 
15.4. Immune response and immune-mediated meningitis  
The data in the MPS I dog suggest that an immune response can occur and 
results in a mild-moderate meningitis.  One subject in the spinal cord 
compression trial had a CSF lymphocytosis up to 37, but did not have 
meningismus clinically.  She was given a short course of oral steroids and 
subsequent CSF cell counts were normal.  Human patients have tolerized over 
time to IV rhIDU administration unlike the dogs which do not tolerize without a 
special tolerance regimen (Kakavanos et al., 2003).   Study subjects who have 
recently initiated intravenous Aldurazyme, with fewer than 6 months of enzyme 
treatment, will be excluded because increasing titers during the first 3 months 
might, in theory, increase the risk for immune-mediated meningitis.  After 6 
months, the titers have stabilized or begun to decline in most cases.  Study 
subjects who have never received Aldurazyme prior to beginning this study are 
not thought to be at increased risk, and will be allowed to participate. 
 
Any immune response will be monitored via clinical history, anti-iduronidase 
antibody titers, CSF cell counts and MRI scans.    If a reaction were to occur, it 
could be managed by providing pretreatment with glucocorticoids such as 
methylprednisolone.  The single subject who developed an increased CSF 
leukocyte count did respond to a short course of oral steroids and pretreatment 
with steroids for subsequent doses.   For human patients with clinical reactions to 
intravenous rhIDU, pretreatment with steroids can prevent the acute infusion-
associated reaction and minimize the clinical adverse impact.  
  
 
15.5. Risks from study procedures 
 
Spinal tap:  Subjects may experience some discomfort from the spinal tap.  This 
may include back pain, headache, lightheadedness and feeling faint.  It is also 
possible and rare that a spinal headache may develop.  More serious and rare 
 
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side effects from a spinal tap include paralysis, nerve injury, spinal hematoma, 
spinal herniation, and death. 
 
Sedation medicine given for the spinal tap may cause sleepiness, nausea, 
vomiting, blurry vision, light-headedness, chills, yawning, loss of balance, 
nervousness, confusion, hallucinations, anxiety, restlessness, sleep problems, 
nightmares, and feeling happy or unhappy.  Subjects may also experience 
stomach discomfort, an acid taste, coughing, hiccoughs, excessive drooling, 
and/or throwing up.  The chance of these side effects occurring is low, and they 
are usually temporary and not serious.  Rarely, some people who receive the 
medicine have slurred speech, tingling or other sensation, rapid eye movements, 
and other movements including convulsion-type movements.   
 
More serious side effects can occur from the sedation medication; these include 
difficulty breathing, not breathing, heart beating too slow or too fast, or an allergic 
reaction.   
 
The numbing cream and the other medicine given to numb the subject’s back 
may also cause side effects.  These include shivering, nausea, numbness, light-
headedness, nervousness, feeling scared, confusion, dizziness, drowsiness, 
ringing in the ears, blurred vision, seeing double, feeling hot or cold, twitching, 
shaking, convulsions, fainting, and feeling happy.  The chance of these side 
effects occurring is low, and they are usually temporary and not serious.  Some 
people who receive the medicines have pain, redness, or swelling on the spot on 
their body where the medicine is injected.  These are also usually temporary and 
not serious.   
 
More serious side effects can occur, including loss of consciousness, breathing 
too slow, not breathing, irregular heartbeat, and death.  The chance of these 
serious side effects occurring is very low, and the study doctor and her staff will 
take every precaution to prevent them or treat them immediately. 
 
Spinal tap using fluoroscopy:   If the study doctor needs fluoroscopy to guide 
the spinal tap, the subject will receive a dose of radiation.  The radiation dose is 
about 2500 millirads per minute of exposure time.  The total dose for each 
procedure is expected to be between 2000 and 13,800 millirads, depending on 
how long the procedure takes and how difficult it is to insert the needle into the 
spinal canal.  A millirad is a unit of measurement for radiation.  No amount of 
radiation is considered safe.  
 
Although each organ will receive a different dose, the amount of radiation 
exposure that subjects will receive from each of these procedures is equal to a 
whole body exposure of between 6 and 47 years of exposure to natural 
background radiation (radiation we receive every day from environment).    
 
 
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For the sake of comparison, other estimated doses of medical radiation are: 
chest x-ray (25 millirads), set of dental x-rays (750 millirads) and barium enema 
x-ray (2000 millirads).  Non-medical doses are: natural radiation exposure living 
at sea level (100 millirads each year) and watching TV 1 hour each day (1 
millirads each year). 
 
Aldurazyme:  Some people who receive Aldurazyme have a flu-like illness or 
rash.  These are the most common side effects with Aldurazyme treatment and 
are not usually serious.  Less common side effects include chest pain, numbness 
or tingling, jaundice, swelling of the face, arms, or legs, or increased reflexes.  
These are usually temporary and not usually serious, but may cause discomfort.   
 
Some people may have pain, swelling, redness, or an infection in the area on the 
body where the Aldurazyme is injected.  During the Aldurazyme treatment, some 
people experience flushing, fever, headache, rash, cough, difficulty breathing, 
itching, hives, and swelling of the lips, eyes, or throat.   
 
More serious side effects include low blood pressure, an allergic reaction, 
bleeding, and difficulty breathing.  Symptoms of an allergic reaction include rash, 
itching, swelling of the lips, face, or throat, difficulty breathing, and low blood 
pressure. 
 
Aldurazyme given into the spinal fluid is a new treatment and has been 
given to a very small number of people (less than 20) in this manner. It may 
have side effects that are not known at this time.  The following side effects 
may be possible:  convulsions, rapid breathing, muscle twitching, pain, or 
meningitis.  Meningitis is an irritation in the tissue surrounding the spinal cord and 
brain that may cause neck pain, stiffness, headache, back pain, difficulty sitting 
and walking, and other problems.  It is not known whether these side effects will 
be temporary or permanent or what their likelihood will be. 
 
One study patient died 1 ½ days after receiving Aldurazyme treatment by 
injection into the spinal canal.  Tests done to determine the cause of death 
showed no signs of meningitis (infection and/or inflammation of the brain).  
It was concluded that this patient’s death was not directly related to 
treatment with Aldurazyme and that this patient died due to the underlying 
MPS disease.   
 
Aldurazyme contains a chemical named “polysorbate 80.”  This chemical is 
present in various foods, dyes, and other household products.  It is generally 
thought to be safe.  The effects of polysorbate 80 when put into the spinal fluid 
are not known, but it may possibly cause irritation of the tissues surrounding the 
spinal cord, or it may cause other problems that are not known.  The polysorbate 
80 may stay in the spinal tissues or brain for the rest of the subject’s life.  The 
amount of polysorbate 80 in Aldurazyme is extremely low, but it may accumulate 
over time with each dose.  While polysorbate 80 is thought to be safe, it is not 
 
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known whether this build up in the spinal tissues or brain may be potentially 
harmful. 
 
As with any medical treatment, unexpected reactions or side effects can occur.   
Because they cannot all be predicted and because of the underlying MPS I 
disease, significant injury or even death could occur during this treatment. 
 
Insertion of a small tube/catheter into a vein:  The effects of inserting a 
catheter into a vein are usually some pain, bleeding and/or a bruise where the 
catheter is inserted. Occasionally the area around the vein may swell. Serious 
complications such as a blood clot or infection may occur but these are rare. 
Some people feel faint when having needles or catheters inserted or blood 
drawn. 
 
Magnetic resonance imaging (MRI):  There are no known risks from the MRI. 
Because a strong magnet is used to do these measurements, no one with a 
pacemaker or other type of metallic implant should have the procedure done.  
Being in a tunnel-like enclosure may cause subjects with claustrophobia to 
become anxious.   
 
Subjects who are very anxious about the MRI may receive sedation medicine.  
Risks of sedation medicine are the same as those reviewed above under risks of 
a spinal tap.   
 
If the subject has a programmable ventriculoperitoneal shunt, it may need to be 
reprogrammed after the MRI.  This may require up to three plain x-ray films to be 
taken of the shunt.  If x-rays are performed, the subject will be exposed to a small 
amount of radiation exposure, about 7.3 millirads per x-ray.  The x-rays are 
necessary to make sure that the shunt is reprogrammed correctly.  Please see 
the above section “Spinal tap using fluoroscopy” and the below section “Spinal 
Fluid Flow Study” for more information on radiation doses.   
 
If your programmable ventriculoperitoneal shunt is turned off by the MRI 
machine, there is a small risk that the subject could develop hydrocephalus.  A 
specialist will evaluate the subject if this occurs and appropriate treatment will be 
given.   
 
Six-minute walk test:  Subjects may feel discomfort during the six-minute walk 
test. Other risks include difficulty breathing, breathing fast, sweating, leg cramps, 
chest pain, lightheadedness, looking pale, or staggering.  A subject could fall or 
otherwise become injured during the test.    In some cases, these may be serious 
and require emergency medical treatment.  Rarely, a person may have a heart 
attack and potentially die during the test.  The chance of these serious side 
effects occurring is very low, and the study doctor and her staff will take every 
precaution to prevent them or treat them immediately.   
 
 
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Pictures and Videotaping:  For subjects who agree to being videotaped or 
having pictures of them taken, there is a possibility that his or her confidentiality 
might be breached and his or her identity might be revealed. Every effort will be 
made to protect subject’s confidentiality.   
 
Neuropsychological testing: There are no significant risks involved in 
neuropsychological testing; however, the subject may experience some anxiety 
or may become tired during the testing.  
 
Spinal Fluid Flow study: This test involves a spinal tap which may cause some 
discomfort.  This may include back pain, headache, lightheadedness and feeling 
faint.  A spinal headache is also a rare, but possible risk of this procedure.  The 
sections above discuss the risks of a spinal tap and spinal tap using fluoroscopy 
in detail. This flow study also involves injection of a small amount of radioactive 
material (radionuclide) into the spinal fluid.   
 
Below is a table below that lists the estimated radiation dose for a 2 mCi injection 
of Tc-99m DTPA.  Please note that 2mCi is the highest dose that an adult could 
receive in this study.  The actual dose may be lower depending on the subject’s 
weight. 
 
Radiation Dose Based on a 2 mCi injection of Tc-99m DTPA 
Organ 
5 year old 
10 year 
old 
15 year 
old 
Adult 
Bone Surfaces(millirads) 
56 
38 
30 
24 
Red Marrow(millirads) 
37 
25 
20 
16 
Urinary Bladder Wall(millirads) 
640 
430 
720 
570 
Ovaries(milirads) 
67 
45 
51 
41 
Kidneys(millirads) 
100 
70 
51 
42 
Testes(millirads) 
57 
36 
38 
28 
Effective Dose 
Equivalent(millirem) 
89 
60 
74 
61 
Note: the radiation doses in this table were based on the assumptions and 
models given in the document(s) entitled: “Radiation Dose Estimates to Adults 
and Children From Various Radiopharmaceuticals” (revised: 04/30/96) Radiation 
Internal Dose Information Center, Oak Ridge Institute for Science and Education. 
 
For the sake of comparison, other estimated doses of medical radiation are: 
chest x-ray (25 millirads), set of dental x-rays (750 millirads) and barium enema 
x-ray (2000 millirads). Non-medical doses are: natural radiation exposure living at 
sea level (100 millirads each year) and watching TV 1 hour each day (1 millirad 
each year). 
Reproductive Risks: There are unknown reproductive risks associated with 
Aldurazyme; therefore, pregnant subjects are excluded from this study.  
  
 
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15.6. Unknown responses 
The subjects will be monitored for a number of possible events using clinical 
laboratory studies and imaging studies to complement clinical evaluations.  The 
Institutional Review Boards (IRBs) involved with this protocol would be notified of 
course if such events were to occur.   
 
 
16. Potential Benefits to Subjects 
The goal of this study is to evaluate whether IT rhIDU injections can stabilize or 
improve cognitive decline in human subjects with MPS I.  Cognitive decline can 
be manifested by disturbances in memory, language, executive function, and 
visuospatial deficits.  Such declines result in difficulties in school, work, activities 
of daily living, and interpersonal relationships.  Given that no current treatment 
option is available for these problems, IT rhIDU may provide the only therapy for 
these damaging and progressive symptoms. 
 
It is unclear what the expected magnitude and duration of these effects will be.  
We know from canine data that reduction in brain glycosaminoglycan storage 
after a single rhIDU intrathecal injection lasts at least 3 months; hence, the 
reason for q3month injections.  In addition, it is possible that the IT rhIDU will 
also treat other central nervous system manisfestations of MPS I disease, 
including spinal cord compression, hydrocephalus, and headache. 
 
 
17. Provisions to Protect the Privacy Interests of Subjects 
The subject’s privacy will be protected by performing all study procedures in a 
private room; this includes obtaining consent and medical history, performing 
exams, and tests.  The only personnel that will be present will be the study 
investigator, study coordinator, and staff, such as nurses, who perform 
procedures under the direction of the study investigator.  Any other persons will 
need explicit consent of the subject to be present.  Subjects will be made to feel 
at ease by limiting the number of personnel present, and encouraging the subject 
to ask questions and notify the staff if he or she is uncomfortable in any way.  
 
The Protected Health Information (PHI) Authorization details exactly what will 
happen to the subject’s PHI, and who is allowed to view the PHI.  Privacy of the 
subject’s PHI will be maintained by never posting the subject’s name in the 
outpatient clinic or the inpatient ward.  The protocol number is used instead.  The 
subject’s medical record is kept out of view at the nursing station, and only the 
research team is allowed to access it.  The research record is kept in a locked 
office, in a locked file cabinet, and only members of the research team have 
access to the office.  Subjects will be made aware that their name or records will 
not be given out without their consent, unless required by law. 
 
 
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Privacy issues related to the research will be covered in the consent.  
These include the likelihood that the results of this research, including the 
subject’s tests, photographs, videotapes, x-rays may be published to 
inform other physicians and scientists.   Subjects will be made aware that 
their name or records will not be given out without their consent, unless 
required by law. 
 
Subjects will be told that information that identifies them or their child will be used 
only for the purpose of the study. They will be told that this includes information 
that can help study personnel locate or contact them as well as information 
related to their or their child’s medical condition (medical records, for example). 
 
The following protected health information may be used or disclosed in 
connection with the research: 
Personal information: 
■ Name 
■ Address (including ZIP code only) 
■ All elements of dates (except year) for dates directly related to an individual, 
e.g., birthday, date of death, date of hospitalization 
■ Medical record number 
■ Health plan beneficiary number 
■ Telephone number or Fax number 
■ Full face photographic image and any comparable image 
Linked with the following medical information: 
■ Face Sheet 
■ Physician Attestation/ICD Codes 
■ Discharge Summary 
■ History & Physical 
■ Outpatient/Short Stay Record 
■ Operative/Procedure Report 
■ Emergency Room Records 
■ Progress Notes/Notes 
■ All Consultation Reports 
■ All Labs 
■ All EKGs 
■ Echocardiogram 
■ MRI/MRA Scan Reports 
■ CSF Flow Study Report 
■ Ankle-Arm Blood Pressures 
■ Lumbar Puncture Report 
■ All Pathology Reports 
■ Neuropsychological Testing Reports 
 
The following people, organizations or other groups may use, disclose, or receive 
the subject’s protected health information: 
 
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■ The investigators at both sites (LA BioMed and the Children’s Hospital 
Oakland Research Institute) 
■ The investigator’s research staff at both sites 
■ The Institutional Review Board’s at both sites 
■ LA BioMed and CHORI staff charged with protecting your safety 
■ Food and Drug Administration (FDA) 
■ National Institutes of Health (NIH) 
■ LA BioMed Accounting for purposes of paying for travel expenses  
■ Data Management and Coordination Center of the University of South 
Florida 
 
Subjects’ protected health information will be used for up to 11 years after the 
date they sign the protected health information authorization. Subjects or their 
guardians will be informed of their right to take back (revoke) this authorization at 
any time by signing a form available from the researcher, or by writing a note 
requesting this and then signing it. In some circumstances, 
however, they may not be able to have previously collected information removed 
from the study if the loss of this protected health information could stop the 
research from reaching a successful end, such as finding out whether a drug 
being tested is safe and effective or not. 
 
Subjects will be informed of their rights, including the right to inspect or copy the 
protected health information they are authorizing the investigator to collect about 
you/your child.  
 
They will be informed that if the research involves disclosure of their protected 
health information to someone or some organization that is not covered by the 
privacy laws, then their information might not be protected. 
 
18. Compensation for Research-Related Injury 
Subjects will be told of the availability of emergency care should they become 
injured, but it will not necessarily be free of charge.   
 
19. Economic Burden to Subjects 
Subjects may incur costs due to lost work days. Travel including air, ground 
transportation, hotel and modest food costs will be reimbursed by the study. 
 
20. Consent Process 
Informed consent will be obtained by study investigators in a private area, such 
as a small conference room, office, or consultation room. Subjects will be given 
the informed consent document to read ahead of time in their preferred 
language. They will be allowed at least two days to read this consent in advance 
of the informed consent signing. Investigators will follow SOP: Informed Consent 
Process for Research (HRP-090) when obtaining informed consent for this 
 
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research. Translators will be provided for the informed consent process if the 
subject’s preferred language is not English. Subjects or their guardians will be 
asked about their willingness to continue with the study at each visit.  
 
Children under the age of 18 years may participate in the study. Permission will 
be obtained from both parents unless one parent is deceased, unknown, 
incompetent, or not reasonably available, or when only one parent has legal 
responsibility for the care and custody of the child. A legal guardian with 
documentation of this status may provide permission for the child to participate in 
the study. Children under age 18 years but at least 12 years of age will be asked 
to assent to the study using a separate, child assent form.  
 
Minor subjects will be re-consented upon reaching 18 years of age to 
demonstrate their willingness to continue in the study. 
 
If the subject cannot read, an impartial witness will be present during the entire 
consent discussion to attest that the information in the consent form and any 
other information provided was accurately explained to, and 
apparently understood by, the subject, and that consent is freely given. 
The witness may be a family member or friend. The witness may not be a person 
involved in the design, conduct, or reporting of the research study.  
After the explanation of the study, the principal investigator will make an 
assessment as to whether the subject/representative understands the 
information provided.  He/she will assure that the subject does not feel pressured 
by time or other factors to make a decision.  He/she will assure that the subject 
understands that there is a voluntary choice to make and that the subject is 
capable of making and communicating an informed choice.  If these assurances 
cannot be made, the investigator will determine that the subject is incapable of 
consent, and the subject will not enter the study. 
 
Special provision for subjects who are adults incapable of consent:  This is a 
protocol that is designed to study patients with cognitive impairment and it is also 
a treatment protocol with potential to benefit subjects with cognitive impairment.  
Thus, there is an ethical conflict between providing the opportunity of possible 
treatment to a special population, and protecting their rights to decline treatment.   
 
The following additional safeguards and consent procedure will be 
undertaken before allowing an adult incapable of consent to participate in 
this research: 
 
1.       An appropriate surrogate per California law will be identified.    
 
2.      The investigator will describe the research to the participant (to the extent compatible with the subject’s 
understanding) and indicate the intent to obtain surrogate consent.  This will be documented. 
 
3.       If the research participant expresses resistance or dissent to being in the research or to the use of the 
surrogate consent by word or gesture, she will be excluded from the research study. 
 
 
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4.       The surrogate will complete a “Self-Certification of Surrogate Decision Makers for Potential Subject’s 
Participation in University of California Research” (Appendix E).  It certifies that the surrogate knows the 
subject very well and believes that they can carry out her preferences. 
 
5.       If the subject and the surrogate agree to participation in the study, then the surrogate will sign the 
informed consent form and the subject will sign the assent form. 
 
6.       If the cognitive ability of the subject changes, then the subject will be re-evaluated for 
decision-making capacity and will be consented if she gains the ability to consent.    
 
21. Process to Document Consent in Writing 
We will follow SOP: Written Documentation of Consent (HRP-091) to obtain 
documentation of informed consent. 
 
 
22. Vulnerable Populations 
The study will enroll children. Pregnant women are excluded from participation, 
due to uncertainty over harm to the fetus. Prisoners will not be enrolled, due to 
inability to travel for study visits. Adults unable to consent will be allowed to enroll 
if the above safeguards are followed. 
 
23.   Drugs or Devices 
23.1    Investigational Product 
Recombinant human -L-iduronidase (rhIDU) is a polypeptide with an apparent 
molecular weight of 82,000 Daltons.  It is supplied in 5.0 mL Type I glass tubing 
vials each containing 5.0 mL of the investigational product.  The vial is sealed 
with a siliconized, grey stopper and capped with an aluminum tamper evident 
crimp top. Recombinant human α-L-iduronidase is FDA-approved for intravenous 
use in humans (Aldurazyme®, BioMarin Pharmaceutical Inc., Novato, California).   
 
The solution in each vial contains a nominal laronidase concentration of 0.58 
mg/mL and a pH of approximately 5.5.  The extractable volume of 5.0 mL from 
each vial provides 2.9 mg laronidase, 43.9 mg sodium chloride, 63.5 mg sodium 
phosphate monobasic monohydrate, 10.7 mg sodium phosphate dibasic 
heptahydrate, and 0.05 mg polysorbate 80. Aldurazyme does not contain 
preservatives; vials are for single use only and stored in a refrigerator at 4˚C.  
The final product is a solution that is clear to slightly opalescent, and colorless to 
pale yellow. 
 
For administration to subjects, Aldurazyme® will be diluted with between 6 mL to 
8 mL of Elliotts B® Solution (Ben Venue Laboratories, Inc., Bedford, Ohio).  
Elliotts B® solution is a buffered intrathecal electrolyte/dextrose injection 
developed as a diluent for intrathecal chemotherapy.  Its composition is roughly 
similar to human cerebrospinal fluid in pH, electrolyte composition, glucose 
content, and osmolarity.  It is FDA-approved in the United States for intrathecal 
 
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use in humans.  In areas where Elliotts B® is not available, an equivalent solution 
may be made by a pharmacist.  This solution would be prepared from sterile 
component solutions to be equivalent in sodium, chloride, potassium, dextrose, 
bicarbonate, pH, and osmolarity to Elliotts B® solution. 
23.2 Packaging and Labeling 
The Aldurazyme vials will be obtained from a commercial source.  The labeling in 
commercial territories will be as approved by that territorial regulatory authority.   
 
Drug will be stored and dispensed by the investigational pharmacy service at 
each site. 
 
24 Multi-Site Human Research 
This is a multi-site study. All sites will have the most current version of the 
protocol, consent document, and HIPAA authorization.  All required approvals will 
be obtained at each site (including approval by the site’s HSC of record) prior to 
site initiation. All modifications will be communicated to sites, and approved 
(including approval by the site’s HSC of record) before the modification is 
implemented. All engaged participating sites will safeguard data as required by 
local information security policies. All local site investigators will be monitored at 
six month intervals by study personnel to ensure that they conduct the study 
appropriately.  All non-compliance with the study protocol or applicable 
requirements will be reported in accordance with local policy. 
 
Study sites will be informed of substantial study problems including unexpected 
serious adverse events, problems with the investigational product, subject 
withdrawal or the closure of the study within 24 hours of the investigator’s first 
knowledge of the event. Interim results will be communicated to study sites on an 
annual basis. 
 
 
25 Community-Based Participatory Research 
Not applicable. 
 
 
26 Sharing of Results with Subjects 
Sharing of interim results with subjects or their physicians is not planned. 
Exceptions include adverse events or test results that require medical attention 
or medical care in order to prevent further harm to the subject.  
 
 
 
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APPENDIX A 
 
Mini-Mental State Exam, modified slightly for children (Ouvrier et. 
al. 1993) 
 
 
 
 
 
 
 
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APPENDIX B 
 
Functional Independence Measure Score 
 
Each area of functioning is evaluated and scored by the subject on a 7 point 
scale.  Scores of 6 or 7 are considered “Independent,” and 5 or below considered 
“Dependent.” 
 
7 = Complete independence.  The activity is typically performed safely, without 
modification, assistive devices or aids, and within reasonable time. 
6 = Modified independence.  The activity requires an assistive device and/or 
more than reasonable time and/or is not performed safely. 
5 = Supervision or setup.  No physical assistance is needed, but cuing, coaxing, 
or setup is required. 
4 = Minimal contact assistance.  Subject requires no more than touching and 
expends 75% or more of the effort required in the activity. 
3 = Moderate assistance.  Subject requires more than touching and expends 50-
75% of the effort required in the activity. 
2 = Maximal assistance.  Subject expends 25-50% of the effort required in the 
activity. 
1 = Total assistance.  Subject expends 0-25% of the effort required in the activity. 
 
Areas of functioning addressed: 
 Self-care -- Eating, grooming, bathing, dressing-upper body, dressing-
lower body, and toileting are evaluated on the 7-point scale 
 Sphincter control -- Bladder and bowel management are each 
rated on the 7-point scale. 
 Mobility -- Transfer to bed, chair, or wheelchair, transfer to toilet, 
and transfer to tub or shower are graded on the scale.   
 Locomotion -- Walking/wheelchair and stairs 
A total FIM score is assigned.  A score of 1 is entered if the subject is not 
testable in that area.  The score will be an integer from 13 to 91. 
 
 
 
 
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APPENDIX C 
 
MRI of brain:  Scoring system 
 
Abnormal signal intensity: 
Lesions will be estimated as to size (3 dimensions) and number, and will be 
divided by location into basal ganglia, white matter, and cortex.  Signal changes 
observed on T2 images will be graded on a scale from 0-3, where 0 is absent, 1 
is patchy and confined to the periventricular area, 2 is patchy but in other white 
matter areas as well as periventricular, and 3 is diffuse.  
 
Enlargement of perivascular space:   
Enlargement of the perivascular space will be classified in five brain regions: 
periventricular and subcortical white matter, corpus callosum, basal ganglia, 
thalami, and brainstem.  These regions will be scored for enlargement on a scale 
from 0-3, where 0 is no enlargement, 1 is < 3mm enlargement, 2 is between 3 
and 8 mm enlargement, and 3 is > 8 mm of enlargement. 
Other findings, such as brain atrophy and megacisterna magna will be graded on 
a scale from 0-3, with 0 as absent, 1 as mild, 2 as moderate, and 3 as severe.  
Additional abnormalities will also be noted.    
 
 
 
 
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APPENDIX D 
 
Declaration of Helsinki 
 
Recommendations guiding physicians in biomedical research involving human 
subjects 
 
Adopted by the 18th World Medical Assembly Helsinki, Finland, June 1964 and 
amended by the 29th World Medical Assembly, Tokyo, Japan, October 1975 35th 
World Medical Assembly, Venice, Italy, October 1983, 41st World Medical 
Assembly, Hong Kong, September 1989 and the 48th General Assembly, 
Somerset West, Republic of South Africa, October 1996 
 
I. 
Introduction 
 
It is the mission of the physician to safeguard the health of the people.  His or her 
knowledge and conscience are dedicated to the fulfilment of this mission. 
 
The Declaration of Geneva of the World Medical Association binds the physician 
with the words, “The Health of my patient will be my first consideration,” and the 
International Code of Medical Ethics declares that, “A physician shall act only in 
the patient’s interest when providing medical care which might have the effect of 
weakening the physical and mental condition of the patient.” 
 
The purpose of biomedical research involving human subjects must be to 
improve diagnostic, therapeutic and prophylactic procedures and the 
understanding of the aetiology and pathogenesis of disease. 
 
In current medical practice most diagnostic, therapeutic or prophylactic 
procedures involve hazards.  This applies especially to biomedical research. 
 
Medical progress is based on research, which ultimately must rest in part on 
experimentation involving human subjects. 
 
In the field of biomedical research a fundamental distinction must be recognised 
between medical research in which the aim is essentially diagnostic or 
therapeutic for a patient, and medical research, the essential object of which is 
 
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purely scientific and without implying direct diagnostic or therapeutic value to the 
person subjected to the research. 
 
Special caution must be exercised in the conduct of research, which may affect 
the environment, and the welfare of animals used for research must be 
respected. 
 
Because it is essential that the results of laboratory experiments be applied to 
human beings to further scientific knowledge and to help suffering humanity, the 
World Medical Association has prepared the following recommendations as a 
guide to every physician in biomedical research involving human subjects.  They 
should be kept under review in the future.  It must be stressed that the standards 
as drafted are only a guide to physicians all over the world.  Physicians are not 
relieved from criminal, civil and ethical responsibilities under the laws of their own 
countries. 
 
II. 
Basic Principles 
 
1. Biomedical research involving human subjects must conform to generally 
accepted scientific principles and should be based on adequately performed 
laboratory and animal experimentation and on a thorough knowledge of the 
scientific literature. 
 
2. The design and performance of each experimental procedure involving human 
subjects should be clearly formulated in an experimental protocol which should 
be transmitted for consideration, comment and guidance to a specially appointed 
committee independent of the Investigator and the Sponsor provided that this 
independent committee is in conformity with the laws and regulations of the 
country in which the research experiment is performed. 
 
3. Biomedical research involving human subjects should be conducted only by 
scientifically qualified persons and under the supervision of a clinically competent 
medical person.  The responsibility for the human subject must always rest with a 
medically qualified person and never rest on the subject of the research, even 
though the subject has given his or her consent. 
 
4. Biomedical research involving human subjects cannot legitimately be carried out 
unless the importance of the objective is in proportion to the inherent risk to the 
subject. 
 
 
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5. Every biomedical research project involving human subjects should be preceded 
by careful assessment of predictable risks in comparison with foreseeable 
benefits to the subject or to others.  Concern for the interests of the subject must 
always prevail over the interests of science and society. 
 
6. The right of the research subject to safeguard his or her integrity must always be 
respected.  Every precaution should be taken to respect the privacy of the 
subject and to minimise the impact of the study on the subject’s physical and 
mental integrity and on the personality of the subject. 
 
7. Physicians should abstain from engaging in research projects involving human 
subjects unless they are satisfied that the hazards involved are believed to be 
predictable.  Physicians should cease any investigation if the hazards are found 
to outweigh the potential benefits. 
 
8. In publication of the results of his or her research, the physician is obliged to 
preserve the accuracy of the results.  Reports of experimentation not in 
accordance with the principles laid down in this Declaration should not be 
accepted for publication. 
 
9. In any research on human beings, each potential subject must be adequately 
informed of the aims, methods, anticipated benefits and potential hazards of the 
study and the discomfort it may entail.  He or she should be informed that he or 
she is at liberty to abstain from participation in the study and that he or she is free 
to withdraw his or her consent to participation at any time.  The physician should 
then obtain the subject’s freely given informed consent, preferably in writing. 
 
10. When obtaining informed consent for the research project the physician should 
be particularly cautious if the subject is in a dependent relationship to him or her 
or may consent under duress.  In that case a physician who is not engaged in the 
investigation and who is completely independent of this official relationship 
should obtain the informed consent. 
 
11. In case of legal incompetence, informed consent should be obtained from the 
legal guardian in accordance with national legislation.  Where physical or mental 
incapacity makes it impossible to obtain informed consent, or when the subject is 
a minor, permission from the responsible relative replaces that of the subject in 
accordance with national legislation. 
 
 
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12. Whenever the minor child is in fact able to give consent, the minor’s consent 
must be obtained in addition to the consent of the minor’s legal guardian. 
 
13. The research protocol should always contain a statement of the ethical 
considerations involved and should indicate that the principles enunciated in the 
present Declaration are complied with. 
 
III. 
Medical Research Combined with Professional Care  
(Clinical Research) 
 
1. In the treatment of the sick person, the physician must be free to use a new 
diagnostic and therapeutic measure if, in his or her judgement, it offers hope of 
saving life and re-establishing health or alleviating suffering. 
 
2. The potential benefits, hazards and discomfort of a new method should be 
weighed against the advantages of the best current diagnostic and therapeutic 
methods. 
 
3. In any medical study, every patient - including those of a control group, if any - 
should be assured of the best-proven diagnostic and therapeutic method.  This 
does not exclude the use of inert placebo in studies where no proven diagnostic 
or therapeutic method exists. 
 
4. The refusal of the patient to participate in a study must never interfere with the 
physician-patient relationship. 
 
5. If the physician considers it essential not to obtain informed consent, the specific 
reasons for this proposal should be stated in the experimental protocol for 
transmission to the independent committee (I, 2). 
 
6. The physician can combine medical research with professional care, the 
objective being the acquisition of new medical knowledge only to the extent that 
its potential diagnostic or therapeutic value of the patient justifies medical 
research. 
 
IV. 
Non-Therapeutic Biomedical Research Involving Human Subjects (Non-
Clinical Biomedical Research) 
 
 
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1. In the purely scientific application of medical research carried out on a human 
being, it is the duty of the physician to remain the protector of the life and health 
of that person on whom biomedical research is being carried out. 
 
2. The subject should be a volunteer - either a healthy person or patient for whom 
the experimental design is not related to the patient’s illness. 
 
3. The Investigator or the investigating team should discontinue the research if, in 
his/her judgement, it may be harmful to the individual if continued. 
 
4. In research on man, the interest of science and society should never take 
precedence over considerations related to the well being of the subject. 
 
 
Protection of Human Subjects (21 CFR Part 50) 
 
Informed consent must be obtained from every patient before he or she enters a 
study.  It must be given freely and not under duress.  Consent must be 
documented by use of a consent form that has been approved by the IRB and 
signed by the patient or the patient’s legally authorized representative.  The 
Department of Health and Human Services suggests that when minors are 
involved, a parent or guardian should sign the consent form.  If the minor is an 
adolescent, his or her signature should also be included.  Non-English-speaking 
patients must be presented with a consent form written in a language that they 
understand.  A copy of the signed consent form must be given to the patient 
signing it.  Another copy must be kept in the Investigator’s files and made 
available to Sponsor and FDA representatives upon request.  If, for any reason, 
patient risk increases as the study progresses, the patient must sign a revised 
consent form that has been approved by the IRB.  Before the study begins, a 
sample of the consent form must be provided to the Sponsor.  The FDA may 
reject otherwise scientifically valid studies if proper informed consent has not 
been obtained from all patients. 
 
Only in the case of a life-threatening incident may a study drug be used without 
prior signed consent.  In such an emergency situation, separate certifications 
must be written both by a physician not participating in the study and by the 
Investigator.  The certifications, along with the protocol and informed consent, 
must be sent to the IRB within five working days.  In this situation, the 
Investigator may not administer any subsequent study drug to that patient until 
informed consent and IRB approval are obtained. 
 
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A. 
BASIC ELEMENTS OF INFORMED CONSENT 
 
Every consent form must include the following eight elements: 
 A statement that the study involves research, an explanation of the purpose 
of the research and the expected duration of the patient’s participation, a 
description of the procedures to be followed, and identification of any 
procedures that are experimental; 
 A description of any reasonably foreseeable risks or discomforts to the 
patient; 
 A description of any benefits to the patient or to others that may be 
reasonably expected from the research; 
 A disclosure of appropriate alternative procedures or course of treatment, if 
any, that might be advantageous to the patient; 
 A statement describing the extent, if any, to which confidentiality of records 
identifying the patient will be maintained and noting the possibility that the 
FDA and Sponsor representatives may inspect the records; 
 An explanation as to whether any compensation or medical treatments are 
available if injury occurs for research involving more than minimal risk.  The 
explanation should involve a description of the compensation or treatment 
available or a statement describing where further information may be 
obtained; 
 An explanation of whom to contact for answers to pertinent questions about 
the research and the patient’s rights, and whom to contact in the event of a 
research-related injury; and, 
 A statement that participation is voluntary, that refusal to participate will 
involve no penalty or loss of benefits to which the patient is otherwise 
entitled, and that the patient may discontinue participation at any time 
without penalty or loss of benefits to which the patient is otherwise entitled. 
 
B. 
ADDITIONAL ELEMENTS OF INFORMED CONSENT 
When appropriate, one or more of the following elements of information shall also 
be included in the consent form: 
 
A statement that the particular treatment or procedure may involve risks to the 
patient (or to the embryo or fetus, if the patient is or may become pregnant) 
which are currently unforeseeable;. 
 
 
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Anticipated circumstances under which the Investigator without regard to the 
patient’s consent may terminate the patient’s participation; 
 
Any additional costs the patient might incur from participation in the research; 
 
The consequences of a patient's decision to withdraw from the research and 
procedures for orderly termination of participation by the patient; 
 
A statement that significant new findings developed during the course of the 
research that might affect the patient's willingness to continue participation will be 
provided to the patient; and, 
 
The approximate number of patients involved in the study. 
 
Nothing in these regulations is intended to limit the authority of a physician to 
provide emergency medical care to the extent the physician is permitted to do so 
under applicable federal, state, or local laws. 
 
Informed consent allows the patient to fully understand his or her participation 
and serves to protect the Investigator and Sponsor from potential negligence 
claims.  A fully informed patient is the best protection against such claims. 
 
The informed consent requirements in these regulations are not intended to 
preempt any applicable federal, state, or local laws that require additional 
information to be disclosed in order that informed consent is legally effective.  
Some states, such as California and Oregon, require further action on the 
Investigator's part concerning subject consent. 
 
 
 
 
 
 
 
 
 
 
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APPENDIX E 
 
Self-Certification of Surrogate Decision Makers for Potential Subject’s 
Participation in University of California Research 
 
 
 
 
 
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