Clinical trial NCT00928447
Conditions: Dermatitis, Allergic Contact
Keywords: rHuPH20 Recombinant Human hyaluronidase
Sponsor: Halozyme Therapeutics
Start date: 2009-06-23; Completion date: 2009-09-13
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the effect and safety of rHuPH20 or placebo for the prevention and treatment of skin allergic reaction to nickel. The study drug and placebo will be administered by intradermal injection.

Detailed description:
This study will involve 2 regimens which will run in parallel. Each participant's upper back will be divided into 2 equal spaces for Regimen 1 and 2. Each of the 4 treatment sites in each space will be independently randomized to placebo or rHuPH20 treatment in a 1:1 ratio. Thus, each participant will serve as their own control. Regimen 1 will evaluate the treatment of cutaneous reactions to nickel and Regimen 2 will evaluate the prevention as well as the treatment of cutaneous reactions to nickel. At screening, the nickel sulfate concentration (1%, 2.5%, or 5%) applied to the skin of the upper back with a patch, that will cause no more than a ++ reaction according to the scale of the International Contact Dermatitis Research Group (ICDRG) will be determined. This concentration will be used to elicit cutaneous reactions during the study period.

Arms: arm 1: Participant's upper back will be divided into 2 equal spaces and will receive Regimen 1 and 2 in 4 spaces respectively. In Regimen 1, a single row of 4 patches, each with the nickel sulfate concentration (NSC) (1, 2.5, or 5%) determined at screening, will be applied to the upper space at Day 1. After 48 hours, the patches will be removed and the reactions will be graded on the ICDRG scale. An ID injection containing rHuPH20 (3,000 Units \[U\]) will be administered once daily (QD) for 5 days at the center of each area of reaction. In Regimen 2, a single row of 4 sites in the lower space will be injected intradermally with drug rHuPH20 (3,000 U) at Day 1. Ten minutes after the injections, patches with the NSC (1, 2.5, or 5%) determined at screening will be applied to the injection sites. After 48 hours, the patches will be removed and the reactions will be graded on the ICDRG scale. As during pretreatment, an ID injection containing rHuPH20 will be then administered QD for 5 days. arm 2: Participant's upper back will be divided into 2 equal spaces and will receive Regimen 1 and 2 in 4 spaces respectively. In Regimen 1, a single row of 4 patches, each with the NSC (1, 2.5, or 5%) determined at screening, will be applied to the upper space at Day 1. After 48 hours, the patches will be removed and the reactions will be graded on the ICDRG scale. An ID injection containing placebo will be administered QD for 5 days at the center of each area of reaction. In Regimen 2, a single row of 4 sites in the lower space will be injected intradermally with placebo at Day 1. Ten minutes after the injections, patches with the NSC (1, 2.5, or 5%) determined at screening will be applied to the injection sites. After 48 hours, the patches will be removed and the reactions will be graded on the ICDRG scale. As during pretreatment, an ID injection containing placebo will be then administered QD for 5 days.
Interventions: intervention 1: rHuPH20 intervention 2: Placebo
Intervention descriptions: intervention 1: 0.25 milliliter (mL) Intradermal (ID) syringe push bolus injection of rHuPH20 intervention 2: 0.25 mL ID syringe push bolus injection of placebo control

Protocol documents:
Prot_000.pdf: 
Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
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CLINICAL TRIAL PROTOCOL 
Title: 
A Prospective, Randomized, Double-blind, Placebo-controlled, 
Single-center Study of the Intradermal Injection of rHuPH20 
or Placebo in Subjects with Nickel Allergic Contact Dermatitis 
Protocol Number: 
HALO-114-201 
Version Number: 
1.0 
Version Date: 
27 May 2009 
Sponsor: 
Halozyme Therapeutics, Inc. (Halozyme) 
11388 Sorrento Valley Road 
San Diego, California 92121 
Tel: 
 
This document and the information it contains is the property of Halozyme Therapeutics, Inc. 
and is provided for the sole and exclusive use of Investigators of this clinical investigation. The 
information in this document may not be disclosed unless such disclosure is required by Federal 
or applicable State Law or Regulations or unless there is prior written consent from Halozyme 
Therapeutics, Inc. Subject to the foregoing, this information may be disclosed only to those 
persons involved in the clinical investigation who have a need to know, and who share the 
obligation not to further disseminate this information. 
NCT# 00928447


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TABLE OF CONTENTS 
1. 
BACKGROUND AND RATIONALE ........................................................................ 6 
1.1. 
Hyaluronidases and rHuPH20 ......................................................................................6 
1.2. 
Eczema, Spongiosis, and the Role of Hyaluronan ........................................................9 
1.3. 
Rationale for Intra-dermal Injection of rHuPH20 in Subjects with Nickel 
Allergic Contact Dermatitis ........................................................................................10 
2. 
STUDY OBJECTIVES ............................................................................................. 11 
2.1. 
Primary Objective .......................................................................................................11 
2.2. 
Secondary Objectives ................................................................................................ 11 
2.3. 
Descriptive-Only Parameters ......................................................................................11 
3. 
STUDY DESIGN ...................................................................................................... 12 
3.1. 
Overview of Study Design ..........................................................................................12 
3.2. 
Duration Of Time On Study ...................................................................................... 13 
3.3. 
Planned Total Sample Size .........................................................................................13 
3.4. 
Stopping Rules ........................................................................................................... 14 
4. 
STUDY POPULATION .............................................................................................15 
4.1. 
Inclusion Criteria ....................................................................................................... 15 
4.2. 
Exclusion Criteria ...................................................................................................... 15 
4.3. 
Prohibitions and Restrictions During the Study .........................................................16 
4.4. 
Assessments ............................................................................................................... 16 
5. 
STUDY METHODS AND PROCEDURES ............................................................. 17 
5.1. 
Study Procedures by Visit ......................................................................................... 17 
5.1.1. 
Screening Visit (Visit 1; Day -21 to Day -14) ........................................................... 17 
5.1.2. 
Baseline (Visit 2; Day 1) ........................................................................................... 18 
5.1.3. 
Visit 3:  Treatment Day 3 ...........................................................................................19 
5.1.4. 
Visit 4 - 5: Treatment Days 4 - 5 ............................................................................... 19 
5.1.5. 
Visit 6 - 7: Treatment Days 6 - 7 .............................................................................. 20 
5.1.6. 
Follow-up Visit: Day 14 ............................................................................................20 
5.2. 
Subject Replacement/Completion Criteria .................................................................21 
5.3. 
Study Methods and Procedures ................................................................................. 21 
5.3.1. 
Informed Consent ...................................................................................................... 21 
5.3.2. 
Inclusion/Exclusion Criteria Review ..........................................................................21 


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5.3.3. 
Demographics ............................................................................................................ 21 
5.3.4. 
Medical History ......................................................................................................... 21 
5.3.5. 
Complete Physical Exam ........................................................................................... 21 
5.3.6. 
Targeted Physical Exam ............................................................................................ 21 
5.3.7. 
Vital Signs ................................................................................................................. 22 
5.3.8. 
Pregnancy Testing ..................................................................................................... 22 
5.3.9. 
Hematology. ............................................................................................................... 22 
5.3.10. 
Study Drug Administration. ....................................................................................... 22 
5.3.11. 
Determination of Nickel Sulfate Sensitivity ............................................................... 23 
5.3.12. 
Nickel Sulfate Patch .................................................................................................. 23 
5.3.13. 
Trans-Epidermal Water Loss (TEWL) .......................................................................24 
5.3.14. 
Digital Photographs ................................................................................................... 24 
5.3.15. 
Chromometer ............................................................................................................. 24 
5.3.16. 
Adverse Events .......................................................................................................... 24 
5.3.17. 
Injection Site Assessment .......................................................................................... 24 
5.3.18. 
Prior/Concomitant Medications ................................................................................. 24 
5.4. 
Premature Termination of Treatment/Withdrawal of Subjects ..................................25 
6. 
STUDY MEDICATIONS AND ADMINISTRATION ............................................ 26 
6.1. 
Study Medication ........................................................................................................26 
6.2. 
Packaging and Labeling of Study Products ................................................................26 
6.3. 
Storage and Drug Accountability of Study Products ..................................................26 
6.4. 
Randomization and Blinding ......................................................................................27 
6.5. 
Unblinding Procedures ...............................................................................................27 
7. 
ADVERSE EVENTS AND SAFETY MONITORING ............................................ 28 
7.1. 
Adverse Event Definitions ......................................................................................... 28 
7.2. 
Pre-Treatment-Emergent Adverse Events ..................................................................29 
7.3. 
Laboratory Abnormalities as Adverse Events ............................................................29 
7.4. 
Classification of Adverse Events by Severity .............................................................30 
7.5. 
Classification of Adverse Events by Relationship to Study Drug 
Administration ........................................................................................................... 30 
7.6. 
Known Toxicity Profiles of Study Drugs .................................................................. 31 
7.7. 
Reporting of Adverse Events ......................................................................................31 


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7.7.1. 
Reporting of Serious Adverse Events .........................................................................31 
7.7.2. 
Duration of Follow-Up of Adverse Events .................................................................32 
7.7.3. 
Other Information on the Reporting of Adverse Events .............................................32 
7.7.4. 
Reporting of Safety Information to the Institutional Review Board ..........................32 
7.7.5. 
Pregnancy .................................................................................................................. 32 
7.8. 
Precautions/Over-Dosage .......................................................................................... 33 
7.9. 
Prior/Concomitant Medications and Procedures ....................................................... 33 
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ............................ 34 
9. 
REGULATORY/ADMINISTRATIVE PROCEDURES AND 
DOCUMENTATION ................................................................................................ 35 
9.1. 
Ethics ......................................................................................................................... 35 
9.2. 
Institutional Review Board and Approval ..................................................................35 
9.3. 
Informed Consent .......................................................................................................36 
9.4. 
Laboratory Accreditation ............................................................................................37 
9.5. 
Drug Accountability ...................................................................................................37 
9.6. 
Protocol Compliance and Protocol Deviations ...........................................................38 
9.7. 
Protocol Amendments ............................................................................................... 38 
9.8. 
Data Collection and Case Report Forms.....................................................................39 
9.9. 
Study Initiation, Monitoring and Closeout Visits and Reports .................................. 39 
9.10. 
Study Documentation and Retention of Records ....................................................... 41 
9.11. 
Investigator’s Final Report ......................................................................................... 41 
9.12. 
Financial Disclosure .................................................................................................. 42 
9.13. 
Disclosure of Data and Publication ........................................................................... 42 
10. 
REFERENCES ...........................................................................................................44 
11. 
APPENDICES ........................................................................................................... 45 
APPENDIX A. STUDY SCHEDULE OF EVENTS ................................................................ 46 
APPENDIX B. INTERNATIONAL CONTACT DERMATITIS RESEARCH GROUP 
[ICDRG] SCORING SCALE11 ................................................................................. 48 
APPENDIX C. NICKEL SULFATE ALLERGY SYSTEM ..................................................... 49 
APPENDIX D. PHOTOGRAPHIC PROCEDURE .................................................................. 50 
APPENDIX E. ABBREVIATIONS .......................................................................................... 52 


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LIST OF TABLES 
Table 1: 
Cumulative Number of Subjects Exposed to rHuPH20 by Dose in 
Halozyme-Sponsored Clinical Studies ........................................................................ 8 
 
LIST OF FIGURES 
Figure 1: 
Study Treatment Arm Randomization ....................................................................... 22 


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1. 
BACKGROUND AND RATIONALE 
1.1. 
Hyaluronidases and rHuPH20 
Mammalian hyaluronidase preparations differing in source, species, and manufacturing process 
have been the subject of multiple investigations and regulatory approvals in Europe, the United 
States, and Asia. The extent of human administration of these products in the U.S. has been 
estimated to be in the tens of millions of patients. Additionally, patients have been treated with 
other regulatory-approved preparations of hyaluronidase in Europe and Asia. Collectively, this 
usage spans nearly 60 years of clinical history in humans. 
The U.S. Food and Drug Administration (FDA) contracted a review of the efficacy and safety of 
several hyaluronidase drug products through a program known as the Drug Efficacy Study 
Implementation (DESI). The studies were conducted by the National Academy of Sciences and 
the National Research Council. The DESI review findings published in the (Federal Register 
Sept 1970) established that hyaluronidase injection was “effective” for the following indications: 
For use as an adjunct to increase the absorption and dispersion of other injected drugs; for 
hypodermoclysis [subcutaneous fluid administration]; as an adjunct in subcutaneous urography; 
for improving the resorption of radiopaque agents. 
The hyaluronidase drugs included in the DESI reviews included injectable hyaluronidase 
preparation derived from bovine testes. Replacing animal-derived slaughterhouse products with 
recombinant human biotechnology-developed materials potentially alleviates risks associated 
with animal pathogens, transmissible spongiform encephalopathies, and allergy and 
immunogenicity to foreign proteins. 
rHuPH20 is a 447-amino acid single chain polypeptide with N-linked and O-linked glycan 
structures. rHuPH20 is synthesized in Chinese hamster ovary (CHO) cells that have been 
transfected with a plasmid containing the DNA sequence encoding the GPI-anchor deleted 
human PH20 hyaluronidase. The protein is purified through a series of chromatographic steps 
that results in a purified protein with high specific activity. rHuPH20 is up to 100 times more 
pure than the reference standard, slaughterhouse-derived hyaluronidase product based on specific 
activity. rHuPH20 depolymerizes hyaluronan (HA) by hydrolysis of the β-1,4 linkage between 
the C1 position of N-acetyl glucosamine and the C4 position of glucuronic acid. 
A drug product formulation of rHuPH20 (HYLENEX) obtained FDA approval on 2 December 
2005. The approval indication is an adjuvant to increase absorption and dispersion of other 
injected drugs; for subcutaneous fluid administration; and as an adjunct in subcutaneous 
urography for improving resorption of radiopaque agents. HYLENEX was made available as 
saleable product beginning October 2006 and as of 31 December 2008 a total of 7,284 vials of 
HYLENEX had been sold. HYLENEX was made available through a product sampling program 
beginning June 2006, and as of 31 December 2008 a total of 4,384 vials had been received at 
physician offices. Thus, cumulative patient exposure from marketed HYLENEX product outside 
of clinical studies could be a high as 11,668 based on the total vials of saleable product and 
sample product distributed and the unit dose of 150 Units per treated patient. 


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Across 19 studies, a total of 525 study subjects had been enrolled as of December 31, 2008 
among whom 510 subjects are known to have been exposed to at least one dose of 
HYLENEX/rHuPH20. Of the 510 subjects exposed to HYLENEX/rHuPH20 in clinical studies, 
100 received an intradermal injection of a test dose of 15 Units of HYLENEX and 410 subjects 
received a subcutaneous (SC) injection of HYLENEX/rHuPH20 either immediately before or 
admixed with a co-injected drug or fluid administration. Table 1 shows the cumulative number 
of subjects known to have been exposed according to the dose of HYLENEX/rHuPH20. There 
have been six studies to date in which at least some study subjects are known to have received 
more than a single exposure to HYLENEX: HZ2-07-03 (two doses per subject), 1838-003 (more 
than one dose permitted), HZ2-07-02 (a two-part study with some subjects participating in both 
parts), HZ2-07-04 (up to four doses per subject), HZ2-08-04 (up to six doses per subject) HZ2- 
08-05 (up to five doses). Table 1 presents the completed HYLENEX/rHuPH20 clinical studies. 


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Table 1: 
Cumulative Number of Subjects Exposed to rHuPH20 by Dose in Halozyme- 
Sponsored Clinical Studies 
 
Dose of rHuPH20 (Units) 
Number of Subjects Exposed (N = 510a) 
15b 
100 
150 
236 
240 
13 
288 
4 
300 
12 
750 
16 
1152 
4 
1,500 
15 
1,600 
3 
3,000 
4 
3,200 
3 
6,000 
6 
6,400 
3 
12,000 
17 
12,800 
6 
24,000 
30 
36,000 
4 
48,000 
6 
96,000 
6 
a Note: Amongst the 38 subjects exposed to rHuPH20 in Study HZ2-07-02 and 8 subjects in HZ2-08-04, only the 
patient’s highest dose from either study stage was included in this table. Eleven subjects exposed to HYLENEX in 
Study HZ2-08-05 were included among the total of 510 subjects. Their dose has not yet been verified and they are 
not listed in this table. Amongst the 38 subjects exposed to rHuPH20 in Study HZ2-07-02 and 8 subjects in HZ2- 
08-04, only the patient’s highest dose from either study stage was included in this table. The 11 patients in Study 
160602 were also included in the total of 510. However, their information was not included in the table since there 
was variability among each subject’s dose between 1050-7800 U (based on U/g of IgG). 
b The 15 Unit dose was an intradermal test dose; all other administration was subcutaneous. 
 
The most commonly reported adverse events (AEs) have been self-limited, transient, localized 
injection/infusion site observations. Comparison of the nature and incidence of AEs for 
HYLENEX versus the saline placebo in the double-blinded, placebo-controlled study designs 
shows that, with few exceptions, there were no AEs clearly attributable to HYLENEX, and in 
general the AE profile for HYLENEX was similar to that for saline placebo. The clinical data 
have not prompted any consideration of changes to the HYLENEX product label. The 
Investigator is to refer to the rHuPH20 Investigator’s Brochure (IB) Version 1.0 for all current 
safety information. 


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1.2. 
Eczema, Spongiosis, and the Role of Hyaluronan 
Spongiosis is a characteristic histopathological feature in acute eczema1. It is believed to be 
caused by the secondary loss of cohesion between epidermal cells due to the influx of tissue fluid 
into the epidermis. Serous exudate extends from the dermis; as it expands, epidermal cells 
remain in contact with each other only at the site of desmosomes, acquiring a stellate appearance 
and giving the epidermis a sponge-like morphology2. Investigators have conducted research to 
better understand the pathogenesis of spongiosis, specifically to understand whether HA may 
have a functional role in its pathogenesis. 
HA is a well-known component of the connective tissues, such as in the cartilage of joints and 
the dermis of the skin. In the human epidermis, Tammi and Wells3,4 have used hyaluronic-acid- 
binding protein (HABP) to localize HA in the matrix between keratinocytes in the middle and 
upper parts of the spinous layer. In addition, Sakai reported that even the normal stratum 
corneum contains HA supplied by keratinocytes5. 
In the process of assessing whether HA participates in epidermal hyperplasia, Maytin and 
colleagues6 delivered Streptomyces hyaluronidase (Strep H) topically to degrade epidermal HA 
and blunt the accumulation of epidermal HA after acetone application. Strep H significantly 
reduced epidermal HA levels and also significantly inhibited the development of epidermal 
hyperplasia. This reduction in epidermal thickness was not attributable to any decrease in 
keratinocyte proliferation, but rather to an apparent acceleration in terminal differentiation. 
Overall, the data showed that HA is a significant participant in the epidermal response to barrier 
injury. 
Ohtani and colleagues7 conducted a series of experiments to clarify the mechanisms for the 
influx of tissue fluid into the epidermis and the loss of cohesion between keratinocytes in acute 
eczema that results in spongiosis. First, they demonstrated increased intercellular accumulation 
of HA in the spongiotic epidermis by immunohistochemical staining using HABP and 
augmented hylauronan synthase 3 (HAS3) mRNA expression by spongiotic keratinocytes. 
Secondly, they showed that the epidermis where the intercellular space was strongly stained with 
HABP showed weaker expression of membrane E-cadherin. Thirdly, IL-4, IL-13, and IFN-γ 
increased HA production, enhanced HAS3 mRNA expression, and decreased membrane E- 
cahedrin expression by normal human epidermal keratinocytes in both low- and high Ca+ media. 
Lastly, they demonstrated that IL-4, IL-13, their combination, and IFN-γ could induce 
intercellular space widening in the epidermis with increased HA accumulation and decreased E- 
cadherin expression. These results suggest that the augmented production of HA and the 
decreased E-cadherin expression by keratinocytes stimulated with IL-4/IL-13 or IFN γ cause 
spongiosis in acute eczema. 
Based on these recent preclinical studies, HA appears to be directly involved in the pathogenesis 
of spongiosis. Further investigation is merited to better understand the role of hyaluronidase, 
more specifically, rHuPH20 in the prevention and treatment of spongiosis. 


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1.3. 
Rationale for Intra-dermal Injection of rHuPH20 in Subjects with 
Nickel Allergic Contact Dermatitis 
As discussed in the previous section, HA plays an important role in the pathogenesis of 
spongiosis, the characteristic histopathological feature in acute eczema. However, there are no 
clinical data in the current medical literature that demonstrate the safety and efficacy of 
hyaluronidase for the treatment of eczema. Eczema is one of the most common skin diseases 
affecting up to 20% of children and up to 3 % of adults8,9. While mild cases can be treated with 
emollients alone, most cases require the use of pharmacologic interventions. Topical 
corticosteroids have been the mainstay of pharmacologic treatment for eczema. However due to 
potential side effects including both local effects (skin atrophy and pigmentary changes) and 
systemic effects (adrenal suppression) new topical modalities have been developed. The most 
efficacious of theses topical agents have been the topical calcinerin inhibitors (TCIs), tacrolimus 
ointment and pimecrolimus cream10. These were widely used until 2006 when the FDA issued a 
boxed warning due to rare cases of cutaneous and systemic malignancy. Thus there is a 
significant need for novel safe and effective topical therapies. 
The dose of rHuPH20 selected for this proof of concept study (3,000 U/dose) is intended to 
model a future topical formulation of rHuPH20 that will provide controlled release of rHuPH20 
into the epidermis through the stratum corneum. The intradermal administration of rHuPH20 in 
this study will not require diffusion through the stratum corneum, and it is therefore considered a 
more direct route of administration for this proof of concept study. While daily intradermal 
injection of 3,000 U of rHuPH20 in 0.25mL is not likely to provide sustained release of enzyme 
at the injection site, it is anticipated that this dose will be sufficient to temporarily depolymerize 
the hyaluronan present in the dermis and epithelium. 
Doses of rHuPH20 in non-human primates up to approximately 3.6 million U/kg were well 
tolerated, and daily repeat subcutaneous dosing of 600,000 U/kg showed no histologic findings 
at the injection site. Additionally, in a Halozyme sponsored clinical study, 6 subjects received a 
single dose of rHuPH20 at a dose of 96,000 U which is greater than the expected cumulative 
dose in this clinical study. 
rHuPH20 may prevent and treat acute contact dermatitis/eczema. Therefore, we propose to 
conduct this Phase II pilot study in subjects who have a + or ++ reaction (see Appendix B) to 
nickel sulfate as a model of spongiosis. 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
• Determine the treatment effect of rHuPH20 or placebo control injection on the 
exposure to topical nickel allergen (Treatment Regimens 1 and 2) 
• Determine the time to onset and severity of the cutaneous reaction to nickel allergen 
after pre-treatment with rHuPH20 or placebo control (Treatment Regimen 2) 
• Assess the safety and tolerability of the rHuPH20 injection 
2.2. 
Secondary Objectives 
• Proportion (%) of subjects who, with pre-treatment, have a ≥1 grade reduction of the 
cutaneous reaction to nickel sulfate in at least one patch region at 48 hours 
• Proportion (%) of subjects with a ≥1 grade reduction of the cutaneous reaction to 
nickel sulfate in at least one patch region after treatment 
• Proportion (%) of subjects that have a ≥1 grade reduction of the cutaneous reaction to 
nickel sulfate in at least one patch region at Days 2, 3, 4, or 5 
• Safety and tolerability of the injection based on AEs, physical examinations, and vital 
signs 
 
2.3. 
Descriptive-Only Parameters 
• Digital photographic images of the allergen test sites at Baseline (Day 1), 48, 72, and 
96 hours after the placement of the patches 
• Chromometer images of the allergen test sites at Baseline (Day 1), 48, 72, and 96 
hours after the placement of the patches 
• TEWL (Trans-epidermal water loss) assessments at Baseline (Day 1), 48, 72, and 96 
hours after the placement of the patches 


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3. 
STUDY DESIGN 
3.1. 
Overview of Study Design 
This is a pilot Phase II, prospective, double-blind, placebo-controlled study to compare the 
efficacy, safety and tolerability of rHuPH20 or placebo control administered intradermally (ID) 
in the prevention and treatment of subjects with contact allergy to nickel. This study will involve 
two treatment regimens, which will run in parallel (Treatment Regimens 1 and 2). A maximum 
of 30 subjects will be enrolled to achieve a likely estimate of 20 evaluable adult subjects. This 
study will be conducted at a dermatology unit. 
Subjects with a known history of contact allergy to nickel will be recruited for the Screening 
period. During the Screening period, subjects will be tested to confirm the presence of cutaneous 
nickel sensitivity using the 1, 2.5, and 5% nickel sulfate patch. The concentration of nickel 
sulfate for each subject that causes no greater than a ++ cutaneous reaction (2 out of 4), 
International Contact Dermatitis Research Group [ICDRG11] scoring scale will be the 
concentration administered at Baseline. 
After re-confirmation of the subject meeting all inclusion/exclusion criteria and prior to dosing, 
each subject will have the upper half of the posterior aspect of the torso divided into two equal 
spaces using a template and marking the edges with a medical marking pen. 
There will be two treatment regimens in this study (1 and 2), which will be conducted in parallel. 
Within each regimen, the four patch areas will be randomized to rHuPH20 or placebo control for 
each subject. The randomization for Treatment Regimen 1 will be independent of the 
randomization for Treatment Regimen 2; thus, two randomization schemes (one for each 
Treatment Regimen) will be used. Specifically, for each subject, two random patch areas in 
Treatment Regimen 1 will be assigned rHuPH20; the other two patch areas in Treatment 
Regimen 1 will receive Placebo control. This same randomization concept will be used in 
Treatment Regimen 2. 
Treatment Regimen 1: 
This regimen will assess the treatment of contact allergy to nickel: At baseline, a single row of 
four patches (1, 2.5, or 5% nickel sulfate patches; determined for each subject during the 
Screening period) will be placed on the upper space on the upper back. After 48 hours, the 
patches will be removed and an assessment will be made of the reaction site as per the ICDRG 
scoring system. Each subject will receive in the center of the cutaneous reaction an ID syringe 
push bolus injection of either rHuPH20 or placebo control. Each injection will be administered 
once daily for 5 days. Prior to each daily injection, subjects will be evaluated for efficacy, 
safety, and tolerability. A final evaluation will be conducted 7 days after the last dose of study 
treatment. 
Treatment Regimen 2: 
This regimen will assess the prevention and treatment of contact allergy to nickel sulfate. Each 
subject will receive in the center of each lower space on the back, either an ID syringe push 
bolus injection of rHuPH20 or placebo control. Exactly 10 minutes after the injection, a single 


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row of four patches (1, 2.5, or 5% nickel sulfate patches; determined for each subject during the 
Screening period) will be placed over the center of the ID injection. After 48 hours, the patches 
will be removed and an assessment will be made of the reaction site as per the ICDRG scoring 
system. The subject will receive an ID injection of the same study drug from pre-treatment in 
the center of the cutaneous reaction once daily for 5 days. Subjects will be evaluated for 
efficacy, safety, and tolerability, on a daily basis. A final evaluation will be conducted 7 days 
after the last dose of study treatment. 
Each of the injections will consist of 0.25 mL of rHuPH20 (3,000 U) or 0.25 mL of placebo 
control. 
Safety, tolerability, and efficacy will be assessed through physical examinations, signs and 
symptoms at injection sites, vital signs, and adverse events. 
 
3.2. 
Duration Of Time On Study 
Study subjects will be screened (Visit 1) for eligibility within 21 days prior to receiving study 
drug. The baseline nickel allergy patch test must be administered no less than 14 days after the 
screening nickel allergy test. 
• Visit 2 (Day 1) will consist of the nickel patch test (Treatment regimen 1) and pre- 
treatment and then the nickel patch test (Treatment regimen 2) 
• Visit 3 (Day 3) is the day of first treatment dose and conducted 2 days (no less than 
48 hours) after V2 
• Visits 4-7 (Days 4-7) are dose days 
• Visit 8 will be conducted seven days after the last dose 
Therefore, the anticipated duration of time on study for a given subject, from Screening to 
completion of the study is up to 35 days. 
 
3.3. 
Planned Total Sample Size 
At enrollment, subjects will be assigned a unique identifier according to the randomization 
schedule. A maximum of 30 subjects may be enrolled to ensure that at least approximately 20 
evaluable subjects complete the study. The sample size of 20 evaluable subjects is intended to 
provide a sufficient sample size to allow for a meaningful comparison between rHuPH20 and 
placebo control. 
For Treatment Regimens 1 and 2, an evaluable subject is one who has completed dosing (or 
prematurely discontinued the administration due to a toxicity) and has undergone sufficient 
assessments to allow an assessment of the tolerability of the administration. Each subject not 
meeting the criteria for evaluability will be replaced with the enrollment of another subject. All 
subjects who receive at least one injection will be included in the safety analysis. 


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3.4. 
Stopping Rules 
Subjects may withdraw from the study at any time and for any reason. Should any subject 
withdraw, the Investigator should be informed immediately. The Investigator may decide to 
terminate the participation of any subject for reasons not limited to the following criteria: 
• The occurrence of serious or unexpected unwanted effects attributable to the study 
drug(s) or study procedure(s) 
• In the event of abnormal laboratory results judged to be related to study drug(s) or 
study procedure(s) and of clinical significance 
• Any significant protocol violation (including demonstrated lack of compliance) 
• Serious difficulty in obtaining blood samples 
• Enrolled subject withdraws consent 
• Intercurrent illness requiring medication that might interfere with the study 
• Other reasons as determined by the Investigator 


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following inclusion criteria in order to be enrolled in the study. 
1. Females 18-60 years of age. Females of child-bearing potential must use a standard and 
effective means of birth control for the duration of the study. 
2. Known contact dermatitis to nickel with a confirmed positive patch-test result to nickel 
sulfate. 
3. Intact normal skin without potentially obscuring tattoos, acne, dermatitis, pigmentation or 
lesions on the posterior aspect of the torso (back) in the area intended for allergen testing 
and dose administration. 
4. Vital signs (BP, HR, temperature, respiratory rate) within normal range or, if out of 
range, assessed by the Investigator as not clinically significant and it is mutually agreed 
by both Investigator and Sponsor Medical Monitor that the subject need not be excluded 
from the study for this reason. 
5. A negative serum or urine pregnancy test (if female of child-bearing potential) within 14 
days of initial study drug administration. 
6. Subject should be in good general health based on medical history and physical 
examination, without medical conditions that might prevent the completion of study drug 
injections and assessments required in this protocol. 
7. Decision-making capacity and willingness and ability to comply with the requirements 
for full completion of the study. 
8. Signed, written Institutional Review Board (IRB)/EC-approved informed consent. 
 
4.2. 
Exclusion Criteria 
Subjects satisfying any one or more of the following exclusion criteria are not allowed in this 
study. 
1. Nickel allergen patch test greater than a ++ reaction. 
2. Subjects who were treated with chemotherapy agents or systemic corticosteroids within 
the past 3 months. 
3. Use of topical steroids, antihistamines, or immunosuppressants used near the site of 
allergen testing/injection within 14 days. 
4. Use of oral antihistamines within 14 days of study conduct. 
5. Extensive ongoing outbreaks of contact dermatitis anywhere on the body. 
6. Pregnant or women who are breast-feeding. 


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7. Subjects with a current disease state that can affect immune response (e.g., flu, cancer, 
HIV). 
8. Known allergy to any hyaluronidase or the ingredients in the dose preparation. 
9. History of autoimmune disorder. 
10. Subjects with any other medical condition that, in the opinion of the investigator, might 
significantly affect their ability to safely participate in the study or affect the conduct of 
this study. Examples might include asthma, diabetes, heart disease, epilepsy, cancer, etc. 
 
4.3. 
Prohibitions and Restrictions During the Study 
The following medications / conditions are prohibited during the subject’s time on study: 
• Oral antihistamines within 14 days of study conduct 
• Topical steroids, antihistamines, or immunosuppressants used near the site of allergen 
testing/injection within 14 days of study conduct 
• A current disease state that can affect immune response (e.g., flu, cancer, HIV) 
4.4. 
Assessments 
• Complete medical history at screening 
• Complete physical exam at screening 
• A physical exam including visual inspection of the injection site at baseline, treatment 
days 3 – 7, and at follow-up visit 
• A complete blood count (WBC with differential, Hgb, Hct, and platelets) at screening 
• Vital signs Body Temperature (screening), BP, Heart Rate, Respiration Rate at 
screening, baseline, before each injection on treatment days 3 - 7, and within 10 
minutes following each injection 
• Pregnancy test at screening and baseline 
• Targeted physical exam (positive findings on a review of systems and follow-up of 
findings from previous physical examinations) at baseline and treatment days 3 - 7 
• Concomitant medications from 21 days before screening through the follow-up 
evaluation at 7-10 days after final injection 
• TEWL (Trans-epidermal water loss) assessment at Baseline (Day 1)and treatment 
days 3 – 5 
• Digital photographs of each allergen test site at Baseline (Day 1) and treatment days 3 
– 5 
• Chromometer images of each allergen test site at Baseline (Day 1) and treatment days 
3 – 5 
• Subject questionnaire at treatment days 3 - 5 
• Adverse events / toxicity assessment at baseline through follow-up visit 


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5. 
STUDY METHODS AND PROCEDURES 
5.1. 
Study Procedures by Visit 
5.1.1. 
Screening Visit (Visit 1; Day -21 to Day -14) 
Before the screening takes place, potential subjects for the study will be provided with written 
and oral information about the study and the procedures involved. 
Subjects will be fully informed of all the procedures involved in the study, the possible risks and 
disadvantages of the study drugs and study procedures, and their rights and responsibilities while 
participating in the study. They will be allowed enough time to consider their participation in the 
study and will have the opportunity to ask questions. If the patient wishes to participate in the 
study, the patient will sign and date the IRB approved Informed Consent Form (ICF) prior to any 
screening procedures. Screening will be performed within 21 days prior to the first dosing visit, 
Visit 2. 
As shown in Appendix A, Study Schedule of Events, the following activities are to be completed 
during this visit. 
• Obtain signed informed consent 
• Review subject eligibility based on Inclusion/Exclusion Criteria 
• See Section 4.1 and Section 4.2. 
• Review demographic information and perform a complete medical history 
• Review prior and concomitant medication taken within 21 days of enrollment 
• Perform a complete physical exam 
• Vital signs collection (BP, heart rate, respiration rate and body temperature) 
• Collect blood samples for hematology 
• Sample collection for pregnancy testing 
• Apply the nickel sulfate and vehicle control patches 
Nickel Sulfate and Vehicle Control Patches 
Follow the instructions in Appendix C. Follow the manufacturer’s instructions for filling the 
unit chambers. Concentrations of 1%, 2.5% and 5% nickel sulfate solution will be used to 
determine the subject’s allergic reaction to nickel. Apply the test patches to a clean surface on 
the upper back (at least 2 cm above the area to be used for the post-screening visits). Have the 
subject return to the study site after 48 hours to have the test results interpreted. 
The concentration of nickel sulfate that causes no greater than + + cutaneous reaction 
(International Contact Dermatitis Research Group [ICDRG11] scoring scale, see Appendix B) 
will be the assigned dose for use per subject for the study. One half (50%) of study subjects will 


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be treated using the nickel concentration that elicits a + cutaneous reaction and the other half 
(50%) of study subjects will be treated with the nickel concentration that elicits a ++ cutaneous 
reaction. Any subjects not meeting the cutaneous reaction scale will be a screen failure. 
Record the nickel sulfate concentration to be used for the subject in the subject’s source 
documentation. 
 
5.1.2. 
Baseline (Visit 2; Day 1) 
Subject Arrival at Site: 
As shown in Appendix A, Study Schedule of Events, the following activities are to be completed 
during this visit. 
• Confirm subject meets inclusion and exclusion criteria 
• Assign Randomization Number (at Baseline visit only) 
• Review concomitant medication use 
• Vital signs collection (BP, heart rate, respiration rate) 
• Pregnancy test (only for females of child bearing potential) 
• Targeted physical exam 
• Physical examination of the administration site 
• Perform baseline TEWL, Chromometer, digital photography assessments 
• Mark the upper back into 2 rows of 4 areas each (see Figure 1) 
• Treatment Regimen 1 - Apply the nickel sulfate patches (see Appendix C) at the 
concentration that caused no greater than a ++ cutaneous reaction (ICDRG11 scoring 
scale, see Appendix B) 
• Treatment Regimen 2 - Administer the intra-dermal injection of rHuPH20 or placebo. 
Exactly 10 minutes after the injection, apply a single row of four patches (1%, 2.5%, 
or 5% nickel sulfate patches; determined for each subject during the Screening 
period) over the center of the intra-dermal injection 
• Assess Adverse Events (AE’s) 
• Assess injection site 
After Study Patch Placement: 
• Vital signs collection (BP, heart rate, respiration rate) within 10 minutes post- 
injection 
• Physical examination of the administration injection site 
• Review for adverse events (After 30 minutes post-injection if no safety issues are 
observed, the subject will be allowed to leave) 


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5.1.3. 
Visit 3: Treatment Day 3 
As shown in Appendix A, Study Schedule of Events, the following activities are to be completed 
during this visit. 
• Review concomitant medication use 
• Targeted physical exam 
• Vital signs collection (BP, heart rate, respiration rate) 
• Physical examination of the administration injection sites immediately after patch 
removal (Treatment regimen 2) 
• Administer/review the subject questionnaire 
• Perform the TEWL, Chromometer, digital photography assessments 
• Administer the intra-dermal injection of rHuPH20 or placebo (Treatment regimens 1 
and 2). 
• Review for adverse events / toxicity 
After Study Drug Administration: 
• Vital signs collection (BP, heart rate, respiration rate) within 10 minutes post- 
injection 
• Physical examination of the administration site 
• Review for adverse events (After 30 minutes post-injection if no safety issues are 
observed, the subject will be allowed to leave) 
 
5.1.4. 
Visit 4 - 5: Treatment Days 4 - 5 
As shown in Appendix A, Study Schedule of Events, the following activities are to be completed 
during this visit. 
• Review concomitant medication use 
• Vital signs collection (BP, heart rate, respiration rate) 
• Targeted physical exam 
• Physical examination of the administration injection site 
• Administer/review the subject questionnaire 
• Perform the TEWL, Chromometer, digital photography assessments 
• Administer the intra-dermal injection of rHuPH20 or placebo (Treatment regimen 1 
and 2). 
• Review for adverse events / toxicity 


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After Study Drug Administration: 
• Vital signs collection (BP, heart rate, respiration rate) within 10 minutes post- 
injection 
• Physical examination of the administration site 
• Review for adverse events (After 30 minutes post-injection if no safety issues are 
observed, the subject will be allowed to leave) 
 
5.1.5. 
Visit 6 - 7: Treatment Days 6 - 7 
As shown in Appendix A, Study Schedule of Events, the following activities are to be completed 
during this visit. 
• Review concomitant medication use 
• Vital signs collection (BP, heart rate, respiration rate) 
• Targeted physical exam 
• Physical examination of the administration injection site 
• Administer the intra-dermal injection of rHuPH20 or placebo (Treatment regimen 1 
and 2). 
• Review for adverse events / toxicity 
After Study Drug Administration: 
• Vital signs collection (BP, heart rate, respiration rate) within 10 minutes post- 
injection 
• Physical examination of the administration site 
• Review for adverse events (After 30 minutes post-injection if no safety issues are 
observed, the subject will be allowed to leave) 
 
5.1.6. 
Follow-up Visit: Day 14 
As shown in Appendix A, Study Schedule of Events, the following activities are to be completed 
during this visit. 
• Review concomitant medication use 
• Vital signs collection (BP, heart rate, respiration rate) 
• Targeted physical exam 
• Physical examination of the administration site 
• Review adverse events / toxicity 


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5.2. 
Subject Replacement/Completion Criteria 
Subjects who are not evaluable will be replaced. An evaluable subject is one who has completed 
dosing (or prematurely discontinued the administration due to a toxicity) and has undergone 
sufficient assessments to allow an assessment of the tolerability of the administration. 
As this study is being conducted at a single site, the site personnel, in conjunction with the 
Sponsor, will make the determination when a subject will need to be replaced in the study. This 
information will be collected on the Enrollment Log. Each subject not meeting the completion 
criteria will be replaced by the enrollment of an additional subject. In the event that a subject 
withdraws from the study prematurely or does not meet the completion criteria, every effort will 
be made to document the reason for termination and obtain follow-up safety data. 
 
5.3. 
Study Methods and Procedures 
5.3.1. 
Informed Consent 
The Investigator or designee must present and explain the study protocol to prospective study 
subjects prior to any screening procedures. Once the subject has had an opportunity to read the 
IRB-approved ICF, the Investigator (or designee) must be available to answer any questions the 
subject may have regarding the study protocol and procedures. 
 
5.3.2. 
Inclusion/Exclusion Criteria Review 
Review the inclusion/exclusion criteria (Section 4.1 and Section 4.2) to ensure the subject 
qualifies for this study at the screening visit. 
 
5.3.3. 
Demographics 
Collect demographic information, including the subject’s initials, date of birth, gender, race and 
ethnic origin at the screening visit. 
 
5.3.4. 
Medical History 
A complete medical history will be collected at the screening visit. 
 
5.3.5. 
Complete Physical Exam 
Physical examination, including ears/eyes/nose/throat/neck, respiratory, cardiovascular, 
gastrointestinal including mouth, musculo-skeletal, central and peripheral nervous system and 
dermatological assessments will be performed by the Investigator at the screening visit. 
 
5.3.6. 
Targeted Physical Exam 
An abbreviated physical exam, reviewing only those body systems for which an abnormality was 
noted during the complete review of systems or a follow up of previous physical exam(s), will be 
performed by the Investigator prior to study drug injection at Visits 1-7, and at the Follow-up 
Visit. 


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5.3.7. 
Vital Signs 
Assessment of vital signs includes the measurement of blood pressure (systolic and diastolic), 
heart rate, and respiration rate and body temperature (at screening). Blood pressure and heart 
rate will be measured with the subject at rest and in supine position for at least 5 minutes prior to 
recording. Vital signs will be recorded at screening, baseline, prior to injection, immediately 
after each injection, and before discharge. 
 
5.3.8. 
Pregnancy Testing 
For females of childbearing potential, serum or urine pregnancy testing will be performed at the 
screening and baseline visits. 
 
5.3.9. 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count (differential), and platelet 
count will be determined at the screening visit. 
 
5.3.10. 
Study Drug Administration 
There will be two treatment regimens in this study (1 and 2), which will be conducted in parallel. 
Within each regimen, the four patch areas will be randomized to rHuPH20 or placebo control for 
each subject (Figure 1). The randomization for Treatment Regimen 1 will be independent of the 
randomization for Treatment Regimen 2; thus, two randomization schemes (one for each 
Treatment Regimen) will be used. Specifically, for each subject, two random patch areas in 
Treatment Regimen 1 will be assigned rHuPH20; the other two patch areas in Treatment 
Regimen 1 will receive Placebo control. This same randomization concept will be used in 
Treatment Regimen 2. 
 
Figure 1: 
Study Treatment Arm Randomization 
 
Allergen 
Allergen 
Allergen 
Allergen 
Placebo 
rHuPH20 
Placebo 
rHuPH20 
or 
or 
or 
or 
rHuPH20 
Placebo 
rHuPH20 
Placebo 
(1) 
(2) 
(3) 
(4) 
Allergen 
Allergen 
Allergen 
Allergen 
Placebo 
rHuPH20 
Placebo 
rHuPH20 
or 
or 
or 
or 
rHuPH20 
Placebo 
rHuPH20 
Placebo 
(5) 
(6) 
(7) 
(8) 
Treatment Regimen 2 
Treatment Regimen 1 


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Treatment Regimen 1 (Spaces 1-4): 
This regimen will assess the treatment of contact allergy to nickel: At baseline, a single row of 
four patches (1, 2.5, or 5% nickel sulfate patches; determined for each subject during the 
Screening period) will be placed on the upper space on the upper back. After 48 hours, the 
patches will be removed and an assessment will be made of the reaction site as per the ICDRG 
scoring system, Appendix B. Each subject will receive in the center of the cutaneous reaction an 
ID syringe push bolus injection of either rHuPH20 or placebo control. Each injection will be 
administered once daily for 5 days. Prior to each daily injection, subjects will be evaluated for 
efficacy, safety, and tolerability. A final evaluation will be conducted 7 days after the last dose 
of study treatment. 
Treatment Regimen 2 (Spaces 5-8): 
This regimen will assess the prevention and treatment of contact allergy to nickel sulfate. Each 
subject will receive in the center of each lower space on the back, either an ID syringe push 
bolus injection of rHuPH20 or placebo control. Exactly 10 minutes after the injection, a single 
row of four patches (1, 2.5, or 5% nickel sulfate patches; determined for each subject during the 
Screening period) will be placed over the center of the ID injection. After 48 hours, the patches 
will be removed and an assessment will be made of the reaction site as per the ICDRG scoring 
system. The subject will receive an ID injection of the same study drug from pre-treatment in 
the center of the cutaneous reaction once daily for 5 days. Subjects will be evaluated for 
efficacy, safety, and tolerability, on a daily basis. A final evaluation will be conducted 7 days 
after the last dose of study treatment. 
Each of the injections will consist of 0.25 mL of rHuPH20 (3,000 U) or 0.25 mL of placebo 
control. 
 
5.3.11. 
Determination of Nickel Sulfate Sensitivity 
During the Screening period, subjects will be tested to confirm the presence of cutaneous nickel 
sensitivity using the 1, 2.5, and 5% nickel sulfate patch. The test site will not be in the same area 
where patches will be placed at Baseline. The concentration of nickel sulfate for each subject 
that causes no greater than a ++ cutaneous reaction (2 out of 4, International Contact Dermatitis 
Research Group [ICDRG11] scoring scale will be the concentration administered at Baseline 
(Day 1). 
 
5.3.12. 
Nickel Sulfate Patch 
At baseline the nickel sulfate patch will be applied. For Treatment regimen 1, the nickel sulfate 
patches will be applied and the subject will return within 48 hours for removal and to begin 
treatment intra-dermal injections. For Treatment regimen 2, the nickel sulfate patches will be 
applied at baseline after 10 minutes post-injection of either rHuPH20 or placebo. 
The concentration of nickel sulfate (1, 2.5, or 5%) will be determined during the Screening 
period. Once the concentration is confirmed, this will be the concentration applied on the subject 
at the baseline visit. 


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At the baseline visit, the patches will be inoculated with the correct nickel sulfate concentration. 
The procedure for using the allergy patch system is found in Appendix C. 
 
5.3.13. 
Trans-Epidermal Water Loss (TEWL) 
All measurements should be conducted in an enclosed room in which air movement is 
minimized. Subjects must equilibrate for 30 minutes prior to testing in the controlled 
environment of 72 plus/minus 2 degrees F and a relative humidity (RH) of less than 50% prior to 
measurement reading. Make sure the skin area to be read is dry and clean. Press and securely 
hold the evaporimeter probe to the skin surface for 45 seconds. A validated Evaporimeter 
Operator should only be used to collect data. 
 
5.3.14. 
Digital Photographs 
In these clinical photographs, for the duration of the study, the only variable allowed to change is 
the skin condition itself. Therefore, anything extraneous to the condition (jewelry, clothing, 
furniture, walls, etc.) is to be eliminated from the fields to be photographed, from the baseline 
through the final photographs. The necessity of good end-of-study photos should be stressed to 
the subjects to ensure their cooperation. Lighting, framing, exposure and reproduction ratios 
must be held constant. In the end, the pictures should read like a time-lapse movie. Detailed 
instructions are found in Appendix D. 
 
5.3.15. 
Chromometer 
Make sure the skin area to be read is dry and clean. To collect data, position the device directly 
over the skin area without applying pressure to the skin surface. Ensure the position of the 
device on the skin is level or parallel with the surface of the skin. Press the trigger once on the 
chromometer. A reading will be recorded on the program. Data collection should be done by a 
validated Chromometer Operator only. 
 
5.3.16. 
Adverse Events 
Each study participant will be carefully monitored for the development of adverse events 
(Section 7). 
 
5.3.17. 
Injection Site Assessment 
An assessment of local tolerability at the injection site will be performed prior to and 10 minutes 
after the injection for site reactions such as erythema, pruritus, and edema. If an injection site 
reaction is observed, it must be recorded as an adverse event. Local tolerability will be assessed 
by a qualified person. 
 
5.3.18. 
Prior/Concomitant Medications 
Review any concomitant medications the subject is taking at each study visit, beginning 21 days 
prior to Visit 1. See Section 4.3 for a list of prohibited medications. 


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5.4. 
Premature Termination of Treatment/Withdrawal of Subjects 
The Investigator must guard the subject’s welfare and should discontinue study drug treatment at 
any time that this action appears to be in the subject’s best interest. Subjects may discontinue 
study drug treatment and may withdraw or be removed from the study at any time. Possible 
reasons for such actions may include, but are not limited to, the following: 
• The occurrence of serious or unexpected unwanted effects attributable to the study 
drug(s) or study procedure(s) 
• In the event of abnormal laboratory results judged to be related to study drug(s) or 
study procedure(s) and of clinical significance 
• Any significant protocol violation (including demonstrated lack of compliance) 
• Serious difficulty in obtaining blood samples 
• Enrolled subject withdraws consent 
• Intercurrent illness requiring medication that might interfere with the study 
• Other reasons as determined by the Investigator 
It is the right and duty of the Investigator to interrupt the treatment of any study subject whose 
health or well-being may be threatened by continuation in this study. 
Once a study subject has received study drug under this protocol, the subject must be followed 
for safety as required in the protocol (see Section 7). In the event that a study subject 
discontinues treatment prematurely, every effort will be made to document the reason for 
premature termination and obtain follow-up safety data. 
Should the enrollment rate lag or significant numbers of clearly non-eligible and/or 
non-evaluable subjects be entered in the study, Halozyme may elect to terminate the study at any 
and all investigational sites. Halozyme also has the right to terminate the study at any time for 
non-adherence to protocol, unavailability of the Investigator or his or her study staff for 
Halozyme or its designated monitoring personnel, or for administrative reasons, at any time. 


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6. 
STUDY MEDICATIONS AND ADMINISTRATION 
6.1. 
Study Medication 
rHuPH20 (recombinant hyaluronidase human injection), also designated as Study Drug, will be 
provided as 12,000 USP units/mL in 1 mL vial. This Study Drug is a concentrated formulation 
of the FDA-approved rHuPH20 drug product known as HYLENEX (150 USP units/mL), with 
the exception that Study Drug does not contain calcium chloride and disodium edentate. 
Clinical Study Drug placebo will consist of the same formulation of rHuPH20 Clinical Study 
Drug without active drug substance. 
The manufacturing and packaging of the study products will be in accordance with GMP. 
 
6.2. 
Packaging and Labeling of Study Products 
Labeling of study products will be in accordance with local law and study requirements. 
Blinding of the study products will be done at the investigational site. Before dosing, the 
unblinded person at the investigational site, the pharmacist or designee, will prepare the dosing 
syringe containing the study products. The pharmacist or designee will give the dosing syringe 
to the physician for dose administration, making sure that the content of the syringe is not 
revealed to the subject or the study staff. 
 
6.3. 
Storage and Drug Accountability of Study Products 
All study drug products will be stored refrigerated (2ºC to 8ºC) at the Investigator’s site and 
should not be exposed to excessive heat, direct sunlight and never be frozen. 
All used and unused vials must be kept by the Investigator and stored between 2ºC and 8ºC. 
Used and unused vials must be stored separately. 
All study-specific supplies must be kept in a secure area with access limited to only authorized 
clinical investigation personnel. 
No study products may be dispensed to any person not enrolled in the study. 
In order to ensure that the vials reach room temperature prior to performing the study drug 
preparation procedure, they will be removed from the refrigerator / storage approximately 
1-2 hours prior to dose administration. The study drug preparation procedure must take place 
within 2 hours of dosing. 
The Investigator must keep an accurate record of all study products received and the products 
used for each subject. 
The Monitor will check the drug accountability periodically and after completion of the study. 
The Sponsor will maintain a record of supplies dispatched to and returned from the site. Study 
drug will only be destroyed on the authorization of the Sponsor. The destruction of study 
products will be recorded on a Destruction Form signed by the person responsible for the 
destruction. 


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The drug supplies will be stored at the site as noted on the Form FDA 1572. These samples will 
be stored under conditions consistent with the product labeling, in an area segregated from the 
area where testing is conducted. Access will be limited to authorized personnel only. Retained 
clinical supplies will be kept at the site until the completion of the study. Once the study is 
completed, the Sponsor will inform the site of any final disposition or shipment of retained study 
materials. None of the retained clinical supplies may be destroyed by the site without the written 
permission of Halozyme Therapeutics. 
 
6.4. 
Randomization and Blinding 
This is a double-blind randomized study. Subjects and the investigative staff will be blinded to 
the contents of each study drug injection. The pharmacist or designee at the investigative site 
preparing syringes for injection will not be blinded. The randomization list will be provided by 
the designated data management team. When a subject is randomized in the study, they must 
always be assigned to the lowest randomization number (e.g., subject number) available at the 
time of randomization. 
Replacement subjects will be added if a subject discontinues prior to fulfilling the evaluability 
criteria (Section 5.2). Replacement subjects must always be assigned to the lowest available 
subject ID number available from the replacement randomization code. 
 
6.5. 
Unblinding Procedures 
The randomization code will be kept in a secure, limited-access area, so that no one other than 
the pharmacist or designee preparing the syringes has access. The rest of the investigational 
staff, the study subjects, and the Sponsor and representatives of the Sponsor will not have access 
to the randomization code until the study as a whole has been unblinded, after the last data have 
been collected for the last subject in the study. 


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7. 
ADVERSE EVENTS AND SAFETY MONITORING 
The safety parameters collected and monitored during this study include AEs, concomitant 
medications, laboratory determinations, physical examination, vital signs, and local tolerability at 
injection sites. 
All AEs that occur during the study should be treated appropriately to protect and ensure the 
patient’s well-being. If such treatment constitutes a deviation from this protocol, Halozyme must 
be notified and the Investigator should comply with applicable IRB reporting requirements. If 
the patient is withdrawn from the study as a result of this AE, the reason will be appropriately 
documented. 
7.1. 
Adverse Event Definitions 
The following definitions of terms are guided by the International Conference on Harmonization 
and the U.S. Code of Federal Regulations (21 CFR 1998) and are included herein. The terms 
"serious adverse event" and "adverse event," inserted in parentheses, are commonly used 
terminology. 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product which does not necessarily have a causal 
relationship with this treatment. 
Serious adverse drug experience (serious adverse event, SAE) is any adverse drug experience 
(AE) occurring at any dose that results in any of the following outcomes: 
• Is fatal or immediately life-threatening (life-threatening is defined as a medical event 
during which the patient is at immediate risk of death from the reaction as it occurred; 
it does not include an event that, had it occurred in a more serious form, might have 
caused death); 
• Requires hospitalization, or prolongs existing hospitalization. Any in-patient hospital 
admission, regardless of duration of hospital stay, will be considered as in-patient 
hospitalization. Hospitalizations for procedures scheduled prior to enrollment into 
the study and emergency room visits do not constitute a serious AE. 
• Results in persistent or significant disability/incapacity; 
• Results in a congenital anomaly or birth defect; or 
• Is any other Important Medical Event. Important Medical Events that may not result 
in death, be life-threatening, or require hospitalization may be considered SAEs 
when, based upon appropriate medical judgment, they may jeopardize the patient or 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias, or 
convulsions that do not result in hospitalization of the patient, or the development of 
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Life-threatening is any adverse drug experience (adverse event) that places the patient or subject, 
in the view of the Investigator, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that, had it occurred in a more severe form, might have caused death. 
Associated with the use of the drug means that there is a reasonable possibility that the 
experience (adverse event) may have been caused by the drug. 
Unexpected adverse drug experience means any adverse drug experience (adverse event), the 
specificity or severity of which is not consistent with the current IB. 
 
7.2. 
Pre-Treatment-Emergent Adverse Events 
Halozyme considers AEs that occur between the time the subject signs the informed consent 
document for the study to the time leading up to when that subject is first exposed to study drug 
as “pre-treatment-emergent” events.  All known pre-treatment-emergent AEs that are serious 
(see Section 7.1) should be immediately reported to Halozyme. The reason for collection of 
serious pre-treatment-emergent AEs is to allow for an assessment of whether or not the SAE was 
causally associated with any protocol-related activities. Halozyme does not intend to collect 
information on pre-treatment-emergent AEs that do not meet at least one accepted criterion for a 
serious classification under the most rigid and comprehensive of the applicable regulatory 
agency criteria for this study, unless the event was related to a study procedure. Events 
occurring during or immediately after first administration of study drug will be considered 
treatment-emergent AEs and will be captured on the AE CRF. 
 
7.3. 
Laboratory Abnormalities as Adverse Events 
It is anticipated that many laboratory abnormalities observed during the course of a study will be 
encompassed under a reported AE describing a clinical syndrome (e.g., elevated BUN and 
creatinine in the setting of an AE of renal failure, or elevated SGOT/SGPT in the setting of an 
AE of hepatitis). In these cases (e.g., an AE of renal failure), the laboratory abnormality itself 
(e.g., elevated creatinine) does not need to be recorded as an AE. 
In the absence of a reported AE identifying a clinical syndrome that encompasses the observed 
laboratory abnormality that isolated laboratory abnormality itself should be reported as an AE if 
it is judged by the Investigator to be clinically significant for that patient. 
For the purposes of this study, criteria defining a "clinically significant" laboratory abnormality 
are: 
a. Laboratory abnormality leads to a dose-limiting toxicity (e.g., judged to be associated 
with study drug administration and resulting in study drug dose reduction, suspension 
or discontinuation), or 
b. Laboratory abnormality results in any therapeutic intervention (i.e., concomitant 
medication or therapy), or 
c. Other laboratory abnormality judged by the Investigator to be of other particular 
clinical relevance. 


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7.4. 
Classification of Adverse Events by Severity 
The Investigator must categorize the severity of each AE according to the following guidelines. 
The level of severity is guided by the National Cancer Institute (NCI) Common Terminology 
Criteria (CTC) for adverse events, which will be provided to each study center and is available 
on line at http://ctep.cancer.gov/reporting/ctc.html (CTCAE, National Cancer Institute). 
Mild: 
Grade 1 NCI Common Terminology Criteria AE; if not found in the Common Terminology 
tables, an AE that is asymptomatic or barely noticeable to the patient; not interfering with 
patient’s daily activity performance or functioning; generally not requiring alteration or 
cessation of study drug administration; and/or ordinarily not needing therapeutic 
intervention. 
Moderate: 
Grade 2 NCI Common Terminology Criteria AE; if not found in the Common Terminology 
tables, an AE of sufficient severity as to possibly make the patient moderately 
uncomfortable; possibly influencing the patient’s daily activity performance or functioning; 
generally not impairing the patient’s ability to continue in the study; and/or possibly needing 
therapeutic intervention. 
Severe: 
Grade 3 or 4 NCI Common Terminology Criteria AE; if not found in the Common 
Terminology tables, an AE generally causing severe discomfort; significantly influencing the 
patient’s daily activity performance or functioning; generally requiring alteration or cessation 
of study drug administration; life-threatening; resulting in significant disability or incapacity; 
and/or generally requiring therapeutic intervention. 
 
7.5. 
Classification of Adverse Events by Relationship to Study Drug 
Administration 
The relationship of each AE to the study drug administration will be assessed by the Investigator 
after careful consideration and according to the following guidelines. Investigators will consider 
AEs to be either causally related to the therapy or to be not causally related; the following 
definitions apply: 
Causally Related: 
The event follows a reasonable temporal sequence from administration of the study drug or 
in which the drug level has been established in body fluid or tissue; it follows a known or 
expected pattern of response to the study drug; or it can not be readily explained by well- 
documented concurrent or co-existent pathological processes, environmental or toxic factors, 
or other therapy administered to the subject. A causal relationship may be confirmed by 
improvement following cessation of the study drug or dose reduction, especially if the 


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reaction reappears following subsequent study drug exposure. The Investigator should refer 
to the SAE sections in the protocol and to the IB for additional guidance. 
If the clinical data are not clear, the Investigator must use his or her best judgment. The AE 
should be recorded as causally related if the Investigator considers the balance of the 
available data to be consistent with a study drug effect. 
Not Causally Related: 
The event does not meet the “causally related” criteria. The Investigator should record an 
AE as not causally related if the Investigator concludes that the balance of all available data 
is in keeping with an effect unrelated to the study drug. 
 
7.6. 
Known Toxicity Profiles of Study Drugs 
As noted in Section 7.5 the Investigator is expected to make his/her best assessment of the causal 
relationship of each AE in this clinical study. The Investigator should base the assessment on all 
available information including, but not limited to, the Investigator’s Brochure. 
 
7.7. 
Reporting of Adverse Events 
For the purpose of this study, all AEs, regardless of seriousness, severity, expectedness, or 
relationship to the study drug, will be collected if the date and time of onset of the AE was after 
the subject’s first exposure to any study drug and through Visit 8 (Day 14 follow up visit). There 
is no time limitation on the reporting of AEs that are treatment-emergent and assessed as 
reasonably associated with study drug (i.e., a drug-associated AE should be reported even if after 
Visit 8). 
Events that occur prior to first study drug administration will be considered pre-treatment- 
emergent because the time of onset preceded the first exposure to study drug (see Section 7.2), 
and these observations will be captured on the patient’s Medical History CRF. Events occurring 
during or after first administration of study drug will be considered treatment-emergent AEs and 
will be captured on the AE CRF. 
Subjects will be questioned and/or examined by the Investigator and his/her designee for 
evidence of AEs. The questioning of study subjects with regard to the possible occurrence of 
AEs will be generalized such as, “How have you been feeling since your last visit?” Information 
gathering for AEs should generally not begin with direct solicitation from subjects regarding the 
presence or absence of specific AEs. 
All serious AEs (SAEs) occurring with any patient participating in this clinical study must be 
immediately reported to Halozyme as described in Section 7.7.1. 
 
7.7.1. 
Reporting of Serious Adverse Events 
All SAEs must be reported to Halozyme or designee WITHIN 1 BUSINESS DAY of discovery 
or notification of the event. Initial SAE information and all amendments or additions must be 
recorded on a Serious Adverse Event Form and faxed along with all available pertinent 
information to: 


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Halozyme Safety Department 
Fax: 
 
The minimum required information for an initial report of an SAE is: 
1. Reporter’s name and contact information, 
2. Protocol number, 
3. Site and patient identification information, and 
4. The SAE term(s) with a brief summary of the event(s) including the causality assessment, 
if possible. 
 
7.7.2. 
Duration of Follow-Up of Adverse Events 
Ongoing AEs and laboratory abnormalities that are considered by the Investigator to be 
CAUSALLY RELATED to the study drug will be followed until resolved, returned to pre-study 
drug exposure level, stabilized at a level acceptable to the Investigator, or later determined by the 
Investigator to be Not causally related to the study drug. Ongoing events and laboratory 
abnormalities that are considered Not Causally Related to the study drug need only be followed 
until the patient’s final study visit (i.e., Visit 8, or earlier if the patient is withdrawn from study). 
 
7.7.3. 
Other Information on the Reporting of Adverse Events 
Follow-up information regarding serious AEs must be provided to Halozyme promptly as it 
becomes known to the Investigator. 
The Institutional Review Board (IRB) that approved the clinical investigation must be notified of 
any fatal, life-threatening and/or serious AEs regardless of cause on a timely basis, according to 
the IRB’s established procedures (see Section 7.7.4). 
A written report of all serious AEs and deaths will be submitted by the Investigator to the IRB 
and to Halozyme. In this report, the Investigator will advise whether or not the AE is judged to 
be related to the study drug administration. All such subjects with AEs should be followed 
clinically and by the appropriate diagnostic evaluations. 
All AEs, regardless of severity, and whether or not ascribed to the study drug administration, will 
be recorded in the appropriate section of the CRF. 
 
7.7.4. 
Reporting of Safety Information to the Institutional Review Board 
It is the responsibility of the Investigator to inform the study center’s Institutional Review Board 
(IRB) of all SAEs and other safety information in accordance with applicable IRB’s 
requirements. At the completion or early termination of the study, a final report should be made 
to the IRB by the Investigator within the applicable IRB time frames. 
 
7.7.5. 
Pregnancy 
A negative pregnancy test during screening for women of childbearing potential and the use of 
effective contraceptive methods for the duration of the study are required. 


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Any pregnancy in a study patient must be immediately reported to the Investigator and in turn to 
Halozyme (see Section 7.7.1 for contact information). Pregnancy during the study period will be 
reported and followed until final resolution (i.e., delivery or early termination). Any birth defect 
or congenital anomaly will be reported to Halozyme immediately as an SAE. 
 
7.8. 
Precautions/Over-Dosage 
Normal precautions taken for a human study, including the provision of emergency equipment, 
will be taken during this study. Qualified and well trained physicians and medical staff will 
instruct the subjects. 
 
7.9. 
Prior/Concomitant Medications and Procedures 
Any medication taken during the study other than study drug is regarded as concomitant 
medication. A history of current medications will be obtained from each subject during 
screening and recorded in the CRF under Prior/Concomitant medications. Subjects must be 
queried regarding both prescription and over-the-counter medications that they take. 
Prior/Concomitant medications taken during the time period beginning 21 days prior to initial 
dosing, Visit 1, through the last visit on study, anticipated to the be the follow-up visit, Visit 8, 
will be collected for all subjects. 
Concomitant medications will be updated at each subsequent visit according to the Study 
Schedule of Activities (see Appendix A), including any medication taken to treat an AE. At each 
study visit, subjects will be asked if there has been any change in the medications they have 
taken since their last study visit. Changes will be recorded on the Prior/Concomitant 
Medications CRF. 
Recording of concomitant medications will include the name of the drug, dosage, route, 
frequency, date of treatment, and the clinical indication for which the medication was taken. 
Subjects may receive medical care during the study including but not limited to antibiotics, 
analgesics, antipyretics, etc., when clinically indicated. Whenever possible, the subject should 
avoid starting any new medications during the treatment period of this study (including over-the- 
counter medications) unless the Investigator deems such medication medically necessary. A list 
of medications prohibited during the study is provided in Section 4.3 of this protocol. 


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8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
Primary and Secondary Analysis 
The primary analysis is the pair-wise intra-subject comparison of endpoint parameters for the 
injections with and without rHuPH20. The primary analysis is the observer’s assessment of the 
nickel sulfate allergen reaction site. The ICDRG scoring system will be used to conduct this 
assessment, which is either + (Weak [non-vesicular] positive reaction: Erythema, infiltration, 
possibly papules) or ++ (Strong [vesicular] positive reaction: Erythema, infiltration, papules, 
vesicles). Secondary analysis of the study is the comparison of safety and other endpoint 
parameters for the SC administration between rHuPH20 and placebo control. 
Dataset for Analysis 
The primary analysis data set for this study will consist of all evaluable subjects. An evaluable 
subject is one who has completed dosing (or prematurely discontinued the administration due to 
a toxicity) and has undergone sufficient assessments to allow an assessment of the tolerability of 
the administration. A secondary analysis data set will consist of all intent-to treat subjects (ITT) 
(i.e., all subjects enrolled, defined as subjects assigned a subject identification number at the time 
of study enrollment in anticipation of receiving a dose of study drug). The safety analysis data 
set is all subjects exposed to rHuPH20 or placebo control. 
The hypothesis is that 1) pre-treatment of rHuPH20 prior to nickel allergy testing will decrease 
the severity of the allergic skin reaction as compared to placebo control and 2) rHuPH20 will 
decrease the severity of nickel contact dermatitis as compared to control. The null hypothesis for 
this study is that rHuPH20 will not be different than what will be observed from placebo control. 
The alternative hypothesis is that rHuPH20 will be better than placebo control. 
The sample size of 20 evaluable subjects is intended to provide a sufficient sample size to allow 
for a meaningful comparison between rHuPH20 and placebo control. 
All data collected, including demographics, baseline information, contact dermatitis scoring, 
safety data, will be summarized by treatment group. Descriptive statistics including the number 
of observations (N), mean, standard deviation, median, and range will be presented for the 
continuous variables. Frequency and percentage will be presented for categorical variables. 
Figures of the individual measurements over time by subject and means by treatment group may 
also be provided. 
Descriptive statistics will be used to summarize all efficacy variables. No formal statistical 
comparisons between treatments are planned. 
All safety data will be examined, including AEs, physical examination findings, and vital signs. 
The incidence of subjects with AEs will be tabulated by MedDRA System Organ Class (SOC) 
and Preferred Term, seriousness, severity grade, relatedness to study drug, and localization to 
infusion site. Descriptive statistics will be used to summarize all safety variables. 


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9. 
REGULATORY/ADMINISTRATIVE PROCEDURES AND 
DOCUMENTATION 
9.1. 
Ethics 
This study will be conducted under a U.S. Investigational New Drug (IND) Application. All 
applicable U.S. regulations governing human subject protection must be followed. All ethical 
and regulatory requirements are necessary to comply with the principals of Good Clinical 
Practice (GCP). 
To ensure ethical conduct of this clinical study, Investigators will be expected to adhere to basic 
principles provided from generally recognized guidelines such the Belmont Report and the 
International Ethical Guidelines for Biomedical Research Involving Human Subjects. The study 
has been designed to involve the participation of representative subjects affected by the disease 
under investigation. Participants must have provided written informed consent to document their 
voluntary participation in this study. Updated safety information will be provided to the 
Investigators, Institutional Review Boards (IRBs) and subjects as necessary in order that they 
may consider relevant and emerging information that could affect their willingness to continue 
participation in this study. 
 
9.2. 
Institutional Review Board and Approval 
In accordance with 21 CFR Parts 50 and 56, the Investigator agrees to provide the appropriate 
Institutional Review Board (IRB) with all appropriate material, including a copy of the protocol, 
ICF, IB, and any proposed advertisement for the study prior to the start of the study. 
The proposed ICF and any proposed advertisement must also be agreed to by the Sponsor 
(Halozyme). A copy of the IRB approval letter of the protocol and the ICF must be supplied to 
Halozyme prior to consent of any subjects for the study. A copy of the IRB approval letter of 
any protocol amendments and any advertisements must be supplied to Halozyme prior to 
implementing these documents. The study may not begin screening or enrolling subjects until 
the Investigator has obtained IRB approval of the protocol and ICF and Halozyme has received a 
hardcopy documentation of each. 
The Investigator will supply to Halozyme a list of the names, professions, and affiliations of IRB 
members to demonstrate compliance with membership requirements. If the Investigator or a 
sub-investigator is a routine voting member of the IRB, Halozyme will be provided with a 
statement from the IRB that the Investigator/sub-investigator did not and will not vote on the 
subject of this investigation. 
During the course of the study, the Investigator shall make timely and accurate reports to the IRB 
on the progress of the study, at intervals not exceeding one year, as well as satisfying any other 
local IRB regulations regarding reporting. Copies of all reports to and correspondence with and 
from the IRB must be provided to Halozyme. Furthermore, at the completion or early 
termination of the study, a final report should be made to the IRB by the Investigator within the 
applicable IRB time frames.  A copy of this report will be provided to Halozyme. 


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Any significant changes or revisions in the study protocol or any changes that may alter subject 
risk must be approved by Halozyme (and may require FDA/other regulatory agency review 
and/or approval) and must be approved in writing by the IRB prior to implementation 
(see Section 9.7 for protocol amendments). The Investigator must also receive a written notice 
of approval from Halozyme prior to initiating the revised changes to the study protocol. A 
protocol change intended to eliminate an apparent immediate hazard may be implemented 
immediately, provided that Halozyme is immediately notified and an amendment is subsequently 
provided by Halozyme and approved by the IRB. 
It is the Investigator's obligation to maintain an IRB correspondence file, and to make this 
available for review by Halozyme or its designated representatives as part of the study 
monitoring process. 
 
9.3. 
Informed Consent 
A copy of the proposed ICF document must be submitted to Halozyme for review and comment 
prior to submission to the reviewing IRB. The ICF must be approved by the IRB and contain all 
elements required by all applicable federal, state, local, and institutional regulations or 
requirements prior to consenting a subject. Authorization to use or disclose Personal Health 
Information (PHI) in accordance with requirements of the Health Insurance Portability Act of 
1996 (HIPAA) should be covered in the ICF or in a separate document to be signed by the 
subject. 
The proposed ICF must contain a full explanation of the purpose and nature of the study, a 
description of the procedures, the possible advantages, risks, alternate treatment options, and a 
statement of confidentiality of subject study records, a statement regarding voluntary 
compensation and availability of treatment in the case of injury, an explanation of whom to 
contact about the research, the subject’s rights, and notification that participation is voluntary 
and refusal will involve no penalty or loss of medical benefits. These requirements are in 
accordance with the U.S. Federal Regulations as detailed in the 21CFR50.25 and the Declaration 
of Helsinki. The ICF should also indicate by signature that the subject, or where appropriate, 
legal guardian/representative, permits access to relevant medical records by the Sponsor 
(Halozyme) and/or the Sponsor's duly appointed agent and by representatives of the U.S. Food 
and Drug Administration (FDA) or other applicable regulatory agency and permits their data to 
be used in publications. 
The Investigator will be responsible for obtaining written informed consent from potential 
subjects prior to any study specific screening and entry into the study. The research study will be 
completely explained to each prospective study subject. The Investigator or designee must 
explain that the subject is free to refuse to enter the study, and free to withdraw from it at any 
time for any reason. If new safety information becomes available and results in significant 
changes in the risk/benefit assessment, the ICF should be reviewed and updated if necessary. 
Under this circumstance, all subjects (including those already being treated) should be informed 
of the new information, given a copy of the revised ICF, and be allowed to re-evaluate their 
consent to continue in the study. 


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Each subject (and/or legally authorized representative if the subject is a minor, mentally 
incompetent or physically incapacitated) found to be eligible for the study must have voluntarily 
provided written informed consent using the IRB-approved ICF prior to screening procedures or 
enrollment in the study (i.e., before performing any protocol-dictated procedures that are not part 
of normal subject care). A copy of the signed and dated ICF document will be provided to the 
subject, and a copy will be maintained with the subject's CRFs, or in the study documentation. 
The original will be retained by the Investigator along with the CRFs. The ICF must be in a 
language that the subject can read and understand. 
 
9.4. 
Laboratory Accreditation 
Any laboratory facility intended to be used for analysis of clinical laboratory samples required by 
this protocol must provide evidence of adequate licensure or accreditation. Reference values 
and/or normal ranges for the test results must be provided to Halozyme. Halozyme must be 
notified immediately in writing of any changes occurring in reference values during the course of 
the study. 
All local and central laboratories used in the study must have, as necessary, the following. 
• College of American Pathologists (CAP) accreditation, and/or 
• Clinical Laboratory Improvement Amendments (CLIA) accreditation 
• Listing of laboratory normal reference values (for all protocol required tests) 
• Laboratory license 
• Curriculum vitae of laboratory director may also be requested 
9.5. 
Drug Accountability 
Upon receipt of study drug(s), the Investigator, pharmacist or qualified designee is responsible 
for taking an inventory of the study drug(s). A record of this inventory must be kept and all 
usage of study drugs must be documented. All vials of study drug, both used and unused, must 
be retained as discussed in Section 6. The investigational drug is to be administered/ prescribed 
only by the Principal Investigator or appropriately qualified physician sub-investigators named 
on the Form FDA 1572. Under no circumstances will the Investigator(s) allow the 
investigational drug to be used other than as directed by this protocol. Although appropriate 
personnel may be designated to administer/dispense drug and maintain drug accountability 
records, the Principal Investigator is ultimately responsible for all drug accountability. 
The Investigator or their designee must maintain accurate records accounting for the receipt of 
the investigational drug supplies and for the disposition of the drug. Documentation of the 
disposition of the drug should consist of a dosing record including the identification of the 
person to whom the drug is dosed, the quantity and the date of dosing, and any unused drug. 
This record is in addition to any drug accountability information recorded on the CRFs. At study 
end, unused drug will be reconciled with dosing records. All unused investigational drug shall 
be returned to Halozyme upon request unless otherwise instructed.  A copy of the reconciled 


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drug inventory record will be provided to Halozyme or its designee, and the original will be 
retained at the site. 
 
9.6. 
Protocol Compliance and Protocol Deviations 
Except for a change that is intended to eliminate an apparent immediate hazard to a study 
subject, the protocol shall be conducted as specified. Any such change must be reported 
immediately to Halozyme and to the IRB. 
From time to time, it is possible that Halozyme may prospectively authorize protocol deviations 
if the deviation is minor, and does not place subject at increased risk or the anticipated risk of 
potential benefit outweighs the anticipated risk of potential harm. All such protocol “waivers” 
must be provided in advance and in writing by Halozyme, and will be forwarded to the 
Investigator for filing with the subject’s study records. The Investigator must notify the IRB of 
any and all protocol deviations according to the applicable IRB policy. 
Written documentation of all major protocol deviations must be kept in the study center file and 
provided to Halozyme. Examples of possible major protocol deviations include, but are not 
limited to: 
• failure to obtain/maintain approval for research 
• failure to obtain required informed consent 
• failure to collect, report or file AE reports 
• performance of an unapproved study procedure 
• performance of research at an unapproved location 
• failure to file protocol modifications, and failure to adhere to an approved protocol 
9.7. 
Protocol Amendments 
If the protocol is revised, protocol amendments will be prepared and must be approved by 
Halozyme. All protocol amendments must be submitted to the IRB for review and approval 
prior to implementation. However, as discussed in Section 9.2, immediate implementation of a 
protocol amendment may be necessary if the nature of the amendment concerns the safety of 
subjects and is required to be implemented on an urgent basis to protect the safety of subjects. 
Any such immediate implementation of protocol amendments must be agreed to in advance and 
in writing by Halozyme. Hard copy documentation of IRB approval must be forwarded to 
Halozyme. 
If an amendment significantly alters the study design, increases potential risk to the subject or 
otherwise affects statements in the ICF, the ICF must be revised accordingly and submitted to the 
IRB for review and approval (see Section 9.3). The approved ICF must be used to obtain 
informed consent from new subjects prior to enrollment and must be used to obtain informed 
consent from subjects already enrolled if they are potentially affected by the amendment and 
wish to continue participation. 


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9.8. 
Data Collection and Case Report Forms 
In accordance with 21 CFR 312.62, a case report form (CRF) must be completed for each subject 
enrolled in the study. CRFs are an integral part of the study and subsequent reports. All data 
collected for each study subject will be recorded on CRFs provided or approved by Halozyme. 
CRFs need not be completed by the Investigator, but all entries in CRFs are the responsibility of 
the Investigator and entry of CRF data must be made under the supervision of the Investigator. 
CRF completion may be formally delegated to other study personnel. However, the Sponsor 
(Halozyme) must be informed in writing of the name of such persons and the scope of their 
authority. The Investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of all data reported in the CRFs and all required reports for each study subject. It is 
the obligation of the Investigator to review each page of the CRFs and to sign the designated and 
appropriate CRFs as the study's authority. The Investigator is also responsible for maintaining 
any source documentation related to the study, including, but not limited to, any operative 
reports, laboratory results, radiographic films, tracings, and computer discs, files or tapes. 
CRFs must be completed legibly, preferably with black ballpoint pen. A correction should be 
made by striking through the incorrect entry with a single line and entering the correct 
information adjacent to the incorrect entry. The correction must be initialed and dated by the 
person making the correction.  Erasure or the use of correction fluid or film is unacceptable. 
Entries to the CRFs should be made only in the spaces provided, and not in the margins. 
Information that cannot be accommodated by the spaces provided should be entered on the 
comments CRF page. 
For each study subject, the completed CRFs must be promptly reviewed, and required pages 
signed and dated by the Investigator. The original copy of all CRFs will be reviewed and 
retrieved by the Study Monitor representing Halozyme. The Investigator must retain a copy of 
all CRFs. 
 
9.9. 
Study Initiation, Monitoring and Closeout Visits and Reports 
Representatives of Halozyme, in conjunction with Study Monitor(s) representing Halozyme, will 
perform a number of on-site visits to the study center. Prior to commencement of the study, 
representatives of Halozyme will visit the study center to ensure adequacy of facilities to conduct 
the protocol, and to discuss with the Investigator the general obligations regarding studies with 
investigational new drugs. This visit will be documented in a report. If the study center has 
participated in a clinical study in conjunction with Halozyme within one year, this Pre-Study 
Qualification visit may be waived. 
Upon satisfactory receipt of all necessary documentation (including, but not limited to, an 
allowed IND, the Form FDA 1572, an executed Clinical Trials Agreement, and IRB approval of 
the protocol and informed consent form), Halozyme or its designee monitor(s) will arrange for 
all study material to be delivered to the study center and for the scheduling of a mutually 
convenient appointment for a Study Initiation visit. Subject entry must not begin until this 
initiation visit by Halozyme or its designee personnel has been made. At this meeting, all 
personnel expected to be involved in the conduct of the study should undergo an orientation to 
include review of the study protocol, instruction for CRF completion, and overall responsibilities 


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including those for drug accountability and study file maintenance. This visit will be 
documented in a report. 
Throughout the course of the study, the Halozyme or its designee monitor(s) will make frequent 
contacts with the Investigator. Study Monitors representing Halozyme will visit study centers 
periodically throughout the study for Routine Monitoring visits. The Study Monitor will review 
CRFs to verify that they are accurate, complete and verifiable from source documents. They will 
also verify the rights and well-being of the study subjects are protected and that the study 
conduct is in compliance with the currently approved protocol/amendment(s), with GCP, and 
with the applicable regulatory requirements. As part of the data review it is expected that source 
documents (e.g., hospital records, office records) will be made available for review by Halozyme 
or its designee monitor(s). The study and its monitors may also be similarly evaluated by 
auditors representing Halozyme. For these purposes, the Investigator will make CRFs, source 
documents and study files available when requested. A report will be generated for each 
monitoring visit. 
At fulfillment of subject enrollment, each Investigator will be notified in writing by Halozyme. 
The study will be terminated and the study center closed when all completed original CRFs have 
been collected, all data discrepancies resolved, and drug accountability has been reconciled. A 
Closeout visit will be scheduled for study centers that enrolled at least one subject, during which 
Halozyme or its representative will review all informed consents, CRFs, drug accountability 
records, and other study-related documents. Halozyme or its representative will hold a final 
meeting with the Investigator and study staff to explain procedures for record retention, 
publication policy, site audit notification, and financial disclosure. A final letter to the site will 
record the events of this closeout visit. Study-closure activities will be documented in a report. 
It will be the responsibility of the Investigator to notify the IRB that the study has been 
completed (see Section 9.11). 
The Sponsor (Halozyme) has the right to terminate the study for non-adherence to protocol, 
unavailability of the Investigator or his or her study staff for Halozyme or its designee 
monitoring personnel, or for administrative reasons, at any time. In that event, Halozyme will 
notify each Investigator in writing that the study is to be discontinued. The Investigator will 
comply with Halozyme’s written instructions for study discontinuation, which will include the 
following: 
• Date discontinuation will occur 
• Rationale for discontinuation 
• Instructions on how discontinuation is to be performed 
• Instructions for subjects participating in the study 
• Instructions for retention of study documents 
In addition to monitoring by Halozyme or its designees, the study may be audited by 
representatives of the Food and Drug Administration (FDA), who will also be allowed access to 
study documents. The Investigator should immediately notify the Clinical Research Department 
at Halozyme of any proposed or scheduled audits with any regulatory authorities. 


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9.10. 
Study Documentation and Retention of Records 
All records of this clinical study must be retained by the Investigator, including but not limited 
to, the following. 
• Protocol and all protocol amendments 
• All signed versions of the Statement of Investigator, Form FDA 1572 
• All drug accountability records 
• All IRB approvals, correspondence and reports 
• Signed and dated informed consent forms for each subject 
• Completed CRFs for each subject 
• Copies of any other material distributed to subjects 
• Any advertisements for this study 
• The Investigator’s final report to the IRB 
• Source documents pertaining to the study, including, but not limited to, any operative 
reports, laboratory results, radiographic films, tracings, and computer discs, files or 
tapes 
The period of time these documents must be maintained is governed by U.S. law and, when 
applicable, non-U.S., regulations. Some countries require these documents to be maintained for 
15 years or longer. All records are to be retained by the Investigator for a minimum of fifteen 
(15) years after the FDA has approved the new drug application, or after the Sponsor (Halozyme) 
has notified the Investigator in writing that all investigations of the drug have been discontinued. 
However, because of international regulatory requirements, Halozyme may request retention for 
a longer period of time. Therefore, Halozyme or its designee will inform the Investigator when 
these documents may be destroyed. The Investigator must obtain written approval from the 
Halozyme prior to destruction of any records. 
The Investigator must advise Halozyme in writing if the records are to be moved to a location 
other than the Investigator’s archives. If the Investigator leaves the institution or study center, 
the records shall be transferred to an appropriate designee, at the study center, who assumes the 
responsibility for record retention. Notice of such transfer shall be documented in writing and 
provided to Halozyme. 
In the event of accidental loss or destruction of any study records, the Investigator will 
immediately notify Halozyme in writing. Halozyme or its designee must be notified in writing at 
least 30 days prior to the intended date of disposal of any study records related to this protocol. 
 
9.11. 
Investigator’s Final Report 
Shortly after completion of the Investigator’s participation in the study, the Investigator will 
submit a written report to Halozyme. This report may be a copy of the Investigator’s end-of- 
study report to their IRB, which will include, but not be limited to; notification that the study has 


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concluded, the number of subjects enrolled/ treated, and the number of adverse and serious AEs 
that occurred during the study. The report to the IRB will be consistent with the applicable IRB 
regulations and time frames. 
 
9.12. 
Financial Disclosure 
Each investigator is required to provide financial disclosure statements or certifications to 
Halozyme prior to study initiation. In accordance with 21 CFR 54, Investigators and all 
subinvestigators are required to disclose all financial interests in the Sponsor (Halozyme) in 
order to permit complete and accurate certification statements in an application for marketing 
authorization. This includes compensation affected by the outcome of a clinical study, 
significant equity interest in the Sponsor (Halozyme), and proprietary interest in the tested 
product. The investigators must promptly update this information if any relevant changes occur 
during the course of the investigation and over the period of one year following completion of 
the investigation (21 CFR 312.64(d)). 
 
9.13. 
Disclosure of Data and Publication 
All information obtained as a result of this study or during the conduct of this study will be 
regarded as confidential. All unpublished information relating to this drug or to the operations of 
the Sponsor (Halozyme), including clinical indications, formula, methods of manufacture, and 
any other related scientific data provided to or developed by the Investigator, is confidential and 
shall remain the sole property of the Sponsor (Halozyme). The Investigator agrees to use the 
information for the purpose of carrying out this study and for no other purpose, unless prior 
written permission from the Sponsor (Halozyme) is obtained. The Sponsor has full ownership of 
the CRFs and database resulting from this study. 
Disclosures (i.e., any release of information to any third party not noted herein) of any not 
previously known to be public information and/or results of the investigation for publication or 
by oral or poster presentation shall not be made earlier than 45 days after submission of the 
proposed material to the Sponsor (Halozyme) for inspection, unless the Sponsor consents to 
earlier disclosure. Any proposed publication must be submitted to the Sponsor at least 40 days 
prior to intended submission for publication. Publication or presentation of any study 
information, whether presented orally or in writing, may not be undertaken either during or after 
the study without Sponsor’s (Halozyme’s) express written approval. The Sponsor (Halozyme) 
may, for appropriate reason, withhold approval for publication or presentation. If the 
Investigator is to be listed as an author of a publication prepared by the Sponsor (Halozyme), the 
Investigator will be given 40 days for review of the manuscript prior to publication. The 
Investigator expressly agrees that no publication of interim, non-final, data will occur without the 
written authorization of the Sponsor (Halozyme). The Investigator will take appropriate 
cognizance of the Sponsor’s (Halozyme’s) suggestions before disclosure for publication or 
presentation consistent with protection of the Sponsor's right to its confidential data. 
The Investigator agrees that if the Study is part of a multi-center study, any publication of 
Results by Investigator shall not be made prior to a first multi-center publication, unless the 
Sponsor has provided prior written consent to do so. The Investigator also agrees that 
publication by Investigator of interim, non-final Results from any study shall not be made prior 


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to publication of the Final Results, unless the Sponsor has provided prior written consent to do 
so. 
The Investigator agrees that results from this study may be used by the Sponsor (Halozyme) for 
purposes of domestic and international new drug registration, for publication, and to inform 
medical and pharmaceutical professionals. Regulatory authorities will be notified of the 
Investigator’s name, address, qualifications, and extent of involvement. 


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10. 
REFERENCES 
1. 
Holden CA, Berth-Jones J (2004) Eczema, lichenification, prurigo and erythroderma. In: 
Rook’s Textbook of Dermatology. (Burns T, Breathnach S, Cox N, Griffiths C, eds), 7th 
edn, vol. 1. Blackwell Science Ltd: Oxford, 17.1. 
2. 
Wolff K, Kibbi AG, Mihm MC (2003). Basic pathologic reaction of the skin. In: 
Frredberg IM, Eizen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI. Dermatology in 
General Medicine. 6th ed, vol. 1. McGraw-Hill: New York, 30-43. 
3. 
Tammi R, Ripellino JA, Margolis RU, Tammi M (1988) Localization of epidermal 
hyaluronic acid using the hyaluronate binding region of cartilage proteoglycan as a 
specific probe. J Invest Dermatol 90:412–4. 
4. 
Wells AF, Lundin A, Michae¨lsson G (1991) Histochemical localization of hyaluronan in 
psoriasis, allergic contact dermatitis and normal skin. Acta Derm Venereol 71:232–8. 
5. 
Sakai S, Yasuda R, Sayo T, Ishikawa O, Inoue S (2000) Hyaluronan exists in the normal 
stratum corneum. J Invest Dermatol 114:1184–7. 
6. 
Maytin EV, Chung HH, Seetharaman VM. Hyaluronan participates in the Epidermal 
Response to Disruption of the Permeability Barrier in vivo. Am J Pathology. 165(4). Oct 
2004 p.p. 1331-1341. 
7. 
Ohtani T, Memezawa A, Okuyama R, Sayo T, Sugiyama Y, Inoue S, and Aiba S. 
Increased Hyaluronan Production and Decreased E-Cadherin Expression by Cytokine- 
Stimulated Keratinocytes Lead to Spongiosis Formation. Journal of Investigative 
Dermatology advance online publication 1 January 2009. Available at: 
http://www.nature.com/jid/journal/vaop/ncurrent/abs/jid2008394a.html. 
8. 
Williams H, Roberston C, Stewart A et al. Worldwide variations in the prevalence of 
symptoms of atopic eczema in the international study of asthma and allergies in 
childhood. J Allergy Clinic Immunol 1999; 103:125-138. 
9. 
Orlow Seth J Topical Calcinerin Inhibitors in Pediatric Atopic Dermatitis Pediatr Drugs 
2007; 9 (5) 289-299. 
10. 
US Food and Drug Administration. FDA Public Advisory: Elidel (pimecrolimus) cream 
and Protopic (tacrolimus) ointment (online) Available from 
URL:http://www.fda.gov/cder/drug/advisory/elidel_protopic.htm. 
11. 
Rietschel RL and Fowler, Jr. JF. In: Fisher’s Contact Dermatitis. 4th edition Baltimore, 
Williams and Wilkins, 1995:29. 


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11. 
APPENDICES 


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APPENDIX A. STUDY SCHEDULE OF EVENTS 
 
Event 
Screening 
Baseline 
Treatment 
Follow- 
up 
Day -21 to 
Day -14 
Day 1 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 14 
VISIT 1 
VISIT 2 
VISIT 3 
VISIT 4 
VISIT 5 
VISIT 6 
VISIT 7 
VISIT 8 
Signed and Dated Informed Consent 
X 
Inclusion/Exclusion Criteria 
X 
X 
Medical History 
X 
Concomitant Medicationsa 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Physical Exam 
X 
Vital Signs (Body temperature, BP, HR, 
Resp. rate) 
Xb 
X 
X 
X 
X 
X 
X 
X 
CBCc 
X 
Pregnancy Test, Serum or Urine 
X 
X 
Targeted Physical Examd 
X 
X 
X 
X 
X 
X 
X 
Physical Examination of the Administration 
Sitee 
X 
X 
X 
X 
X 
X 
X 
Nickel Sulfate and Vehicle Control Patch 
Placement and Interpretation 
X 
X 
Dose Administration 
X 
X 
X 
X 
X 
X 
Test Area Assessment 
X 
X 
X 
X 
X 
X 
Trans-epidermal Water Loss Assessmentf 
X 
X 
X 
X 


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Event 
Screening 
Baseline 
Treatment 
Follow- 
up 
Day -21 to 
Day -14 
Day 1 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 14 
VISIT 1 
VISIT 2 
VISIT 3 
VISIT 4 
VISIT 5 
VISIT 6 
VISIT 7 
VISIT 8 
Digital Photographs of the Allergen Test 
Sitesf 
X 
X 
X 
X 
Chromometer Images of the Allergen Test 
Sitesf 
X 
X 
X 
X 
AE/Toxicity Assessment 
X 
X 
X 
X 
X 
X 
X 
a Con meds within 21 days prior to dosing and through the follow-up assessment on Visit 8/Day 14 to be recorded. 
b Include body temperature at screening visit. 
c WBC (with differential), Hgb, Hct, and platelets. 
d Includes positives on a review of systems and follow-up of findings from previous physical examinations. 
e Conducted immediately before patch administration, after dose administration (Treatment Regimen 2), immediately after patch removal, and prior to and 
10 minutes post-dose on Study Days 3-7, and Day 14. 
f To be conducted at Baseline and on Days 3-5 and includes subject questionnaire (Days 3-5). 


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APPENDIX B. INTERNATIONAL CONTACT DERMATITIS RESEARCH 
GROUP [ICDRG] SCORING SCALE11 
 
International Contact Dermatitis Research Group Scoring Scale 
 
Score 
Interpretation 
? 
Doubtful reaction; faint macular 
erythema only 
+ 
Weak (nonvesicular) positive reaction; 
erythema infiltration, possibly papules 
++ 
Strong (vesicular) positive reaction; 
erythema, infiltration, papules, vesicles 
+++ 
Extreme positive reaction; bullous 
reaction 
- 
Negative reaction 
IR 
Irritant reaction of different types 


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APPENDIX C. NICKEL SULFATE ALLERGY SYSTEM 
Application for Nickel Sulfate Concentration Determination: 
 
Preparing Patch: 
Place a filter paper disc in the chamber and moisten thoroughly with the 1%, 2.5% or 5% nickel 
sulfate solution. 
Applying Patch: 
1. Skin should be clean, healthy, and free of ointments, lotions, powders, acne, dermatitis, 
scars, hair or any other condition that might interfere with the application of the chamber or 
interpretation of the results. 
2. The subject should stand or sit in a relaxed position. Apply prepared patches to the back. 
3. Affix tape to the skin at the lower end and slowly roll patches up the back, pushing out air. 
Gently press patch to skin to ensure an even distribution of allergens. Rub the tape gently but 
firmly to ensure good adherence. 
4. Mark the four corners of each unit with Chemotechnique Skin Markers to indicate each 
unit’s location on the subject’s skin. 
5. Subjects should refrain from exposing patch tests to excess moisture or sweat and should 
return for patch test removal in 48 hours. 
6. Record in the source documentation the location of the patch and the nickel sulfate 
concentration for each location. 
Removing Patch: 
After 48 hours, remove the patch. The initial visual patch imprint on the patient's back indicates 
excellent occlusion. 
Reading the Results: 
1. Allow about 20 to 30 minutes for the transient skin irritation and visual patch imprints to 
subside before interpreting the test results. 
2. Reading will be done at approximately48 hours post application. 
3. Use the Reading Plate to facilitate the reading. 
4. Use the International Contact Dermatitis Research Group Scoring Scale to interpret the test 
results (Appendix B). 


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APPENDIX D. PHOTOGRAPHIC PROCEDURE 
Serial Photography for Contact Dermatitis 
Locations: ID card/color card view: 2 each Close-up view of target area(s): 2 each Anatomical 
location view of target area(s): 2 each 
Digital Format Photography Equipment: Media: SD Memory card, 1GB 
Camera: Nikon D80 (10.2MP) Lens: Nikkor 60mm f2.8 Flash: Canfield TwinFlash system 
Other: Canfield MM scale arm attachment Blue deluxe felt backdrop (3’x8’) Color card/Patient 
ID card holder 
Digital Format Photographic Considerations: Each memory card will contain one patient 
photo session. 
Procedure: 
In these clinical photographs, for the duration of the study, the only variable allowed to change is 
the skin condition itself. Therefore, anything extraneous to the condition (jewelry, clothing, 
furniture, walls, etc.) is to be eliminated from the fields to be photographed, from the baseline 
through the final photographs. The necessity of good end-of-study photos should be stressed to 
the patients to ensure their cooperation. Lighting, framing, exposure and reproduction ratios must 
be held constant. In the end, the pictures should read like a time-lapse movie. 
1. The supplied equipment is to be used exclusively for this study. Modifications, adjustments 
or repairs of the camera equipment are not to be undertaken without the expressed instruction 
of Canfield Scientific, Inc. 
2. After obtaining informed consent, the patients are prepped for photography. All jewelry, 
makeup and clothing are to be removed from the photographic field prior to photography. 
Target area(s) are identified for photos. The supplied standardized blue deluxe felt 
background is to be used for the photographs. Do not use folded or crimped material. 
3. Magnifications for digital camera: A standardized reproduction ratio (35MM film equivalent) 
of 1:3 (red index on lens focusing barrel) is used for the target area close-up views. Focusing 
at 1:3 is accomplished with the use of the mm scale arm attachment dictating distance. A 
standardized reproduction ratio of 1:9 (green index on lens focusing barrel) is used for the 
target area anatomical views. Focusing at 1:9 is accomplished by moving the camera/lens 
close to/away from the target area until it is in focus. 
4. Apertures for digital camera: Each and every target area close-up view is taken at f/22. Each 
and every target area anatomical location view is taken at f/16. 
5. SD is the media format used to capture images. If there is any doubt as to the correctness of 
technique or data, re-shoots are strongly urged. 


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6. Each SD memory card at every photographic session includes an exposure series of: 
a. Two exposures of patient’s ID card which includes the following legible information in 
black indelible ink: Protocol No. Date Investigator Number Visit Week Number Patient's 
Initials Patient's ID Number Photographer's Initials Color card 
b. Two exposures of close-up view of target area(s) 
c. Two exposures of anatomical location view of target area(s) 
7. Upon completion of the photographic session, the contents of the SD memory card are 
uploaded to the Canfield Clinical Website once a patient’s photographic session has been 
recorded on it. A secure, validated, compliant web server set up at Canfield is used for this 
secure transfer of study images by study sites. Images are transferred the day recorded. 
Remote access to all images by the sponsor is also provided. Only approved individuals by 
sponsor have access to the website. 
8. Upon a successful upload of all images contained on the SD memory card, the memory 
card’s images are deleted and the memory card re-used for the next photographic session. 
These memory cards are reserved for use on this project only. Any doubt as to the 
correctness of technique or data warrants a re-shoot then and there. 
9. All images are monitored for technical adherence according to Canfield’s internal SOPs. The 
study site is contacted if errors or deviation from photographic guidelines are observed. All 
communication to the study site relating to the photography is the responsibility of Canfield. 
10. All supplied photographic equipment and photographic originals remain the property of the 
sponsor. One set of photography result report forms for all photographic time-points is 
supplied for the Investigators' study records. 
11. Questions or problems regarding the photographic portion of this study protocol should be 
directed to the respective Canfield Project Manager assigned to the study. 
 
Canfield Scientific, Inc. 253 Passaic Ave. Fairfield, NJ 07004 Telephone: 
Toll- 
Free:
 Facsimile:
 E-mail:
 


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APPENDIX E. ABBREVIATIONS 
 
ABBREVIATION 
TERM 
AE 
Adverse event 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
ºC 
Degrees Celsius 
CAP 
College of American Pathologists 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DESI 
Drug Efficacy Study Implementation 
EC 
Ethics Committee 
FDA 
U.S. Food and Drug Administration 
GCP 
Good Clinical Practice 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
HIPAA 
Health Insurance Portability Act of 1996 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICDRG 
International Contact Dermatitis Research Group 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
ID 
Intradermally 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
NCI 
National Cancer Institute 
PHI 
Personal Health Information 
RH 
Relative humidity 
rHuPH20 
Recombinant human hyaluronidase enzyme PH20 
SAE 
Serious adverse event 


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ABBREVIATION 
TERM 
SC 
Subcutaneous 
SD 
Secure digital 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamate pyruvate transaminase 
SOPs 
Standard operating procedures 
TEWL 
Trans-epidermal water loss 
USP 
United States Pharmacopoeia 
VAS 
Visual analog scale 
WBC 
White blood cells 
 

SAP_001.pdf: 
Statistical Analysis Plan 
Halozyme Therapeutics, Inc. 
Protocol Number: HALO-114-201 
A Prospective, Randomized, Double-blind, Placebo-controlled, Single-center Study 
of the Intradermal Injection of rHuPH20 or Placebo in Subjects with Nickel Allergic 
Contact Dermatitis 
Protocol Version 1.0 (27May2008) 
Sponsor: 
Halozyme Therapeutics, Inc. (Halozyme) 
11388 Sorrento Valley Road 
San Diego, California 92121 
Prepared by: 
 
Synteract, Inc. 
5759 Fleet Street, Suite 100 
Carlsbad, CA 92008 
Version: 
Final 
Date of Creation: 
28 July 2009 
Last Updated: 
9 October 2009 
NCT# 00928447


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Protocol HALO-114-201 
Statistical Analysis Plan 
9 October 2009 
Page 2 of 64 
 
 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ....................................................................................................... 3 
DEFINITIONS ............................................................................................................................... 4 
1. 
INTRODUCTION .................................................................................................................. 5 
2. 
OBJECTIVES ........................................................................................................................ 5 
3. 
STUDY OVERVIEW ............................................................................................................ 5 
TREATMENT REGIMEN 1 (TR1-1 – TR1-4): ............................................................................. 6 
TREATMENT REGIMEN 2 (TR2-5 – TR2-8): ............................................................................. 7 
4. 
GENERAL ANALYSIS CONSIDERATIONS ................................................................... 7 
5. 
ANALYSIS POPULATIONS ................................................................................................ 8 
6. 
SUBJECT DISPOSITION..................................................................................................... 9 
7. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ............................................ 9 
8. EFFICACY ANALYSES ........................................................................................................... 9 
8.1 
PRIMARY VARIABLES .......................................................................................................................... 9 
8.2 
SECONDARY VARIABLES ..................................................................................................................10 
8.3 
DESCRIPTIVE PARAMETERS .............................................................................................................10 
8.4 
BASELINE VALUES .............................................................................................................................10 
8.5 
HANDLING MISSING DATA ..............................................................................................................11 
8.6 
INTERIM ANALYSES ...........................................................................................................................11 
9. 
STUDY ANALYSIS ............................................................................................................. 11 
9.1 
STATISTICAL ANALYSES ..................................................................................................................11 
9.2 
EXPLORATORY ANALYSES ..............................................................................................................12 
10. SAFETY ANALYSES .......................................................................................................... 12 
10.1 ADVERSE EVENTS ...............................................................................................................................12 
10.2 VITAL SIGNS .........................................................................................................................................13 
10.3 PHYSICAL EXAMINATION .................................................................................................................13 
10.4 PRIOR AND CONCOMITANT MEDICATIONS .................................................................................13 
11. SAMPLE SIZE CALCULATION ...................................................................................... 14 
APPENDIX A:  LIST OF TABLES, LISTINGS AND FIGURES .......................................... 15 
APPENDIX B:  TABLE LAYOUTS .......................................................................................... 18 
APPENDIX C:  LISTING LAYOUTS ....................................................................................... 34 
APPENDIX D:  FIGURE LAYOUTS ........................................................................................ 61 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Statistical Analysis Plan 
9 October 2009 
Page 3 of 64 
 
 
 
 
LIST OF ABBREVIATIONS 
 
AEs 
Adverse Events 
ATC 
Anatomical/Therapeutic/Chemical 
BP 
Blood Pressure 
CBC 
Complete Blood Count 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CSR 
Clinical Study Report 
ET 
Early Termination 
ICDRG 
International Contact Dermatitis Research Group 
ID 
Intradermally 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
RBC 
Red Blood Cell Count 
rHuPH20 
Recombinant Human Hyaluronidase enzyme PH20 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
TEWL 
Trans-Epidermal Water Loss 
TEAE 
Treatment-Emergent Adverse Event 
WBC 
White Blood Cells 
WHO 
World Health Organization 


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Protocol HALO-114-201 
Statistical Analysis Plan 
9 October 2009 
Page 4 of 64 
 
 
 
 
DEFINITIONS 
 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence 
in a subject or clinical investigation subject administered a 
pharmaceutical product which does not necessarily have a 
causal relationship with this treatment. 
 
Injection Type 
rHuPH20 or Placebo 
 
Pre-Treatment-emergent 
AE 
AEs occur between the time the subject signs the informed 
consent document for the study to the time leading up to 
when that subject is first exposed to study drug. 
 
Serious AE 
An AE occurring at any dose that: results in death; is a 
life-threatening event; requires in-subject hospitalization or 
prolongation of an existing hospitalization; results in a 
persistent or significant disability/incapacity; results in a 
congenital anomaly/birth defect in the offspring of a 
subject who received study drug, or is any other important 
medical event. 
 
Treatment-emergent AE 
AEs with an onset time during or after the initial 
administration of study drug. 
 
Treatment Regimens 
Treatment Regimen 1 and Treatment Regimen 2 


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Statistical Analysis Plan 
9 October 2009 
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1. INTRODUCTION 
 
This document outlines the statistical methods to be implemented during the analyses of 
data collected within the scope of Halozyme Therapeutics, Inc. Protocol HALO-114-201 
[A prospective, randomized, double-blind, placebo-controlled, single-center study of the 
intradermal injection of rHuPH20 or placebo in subjects with nickel allergic contact 
dermatitis]. The purpose of this plan is to provide specific guidelines from which the 
analysis will proceed. Any deviations from these guidelines will be documented in the 
clinical study report (CSR). 
 
2. OBJECTIVES 
 
The primary objectives of the study are: 
• Determine the treatment effect of rHuPH20 or placebo control injection on the 
exposure to topical nickel allergen (Treatment Regimens 1 and 2) 
• Determine the time to onset and severity of cutaneous reaction to nickel allergen 
after pre-treatment with rHuPH20 or placebo control (Treatment Regimen 2) 
• Assess the safety and tolerability of the rHuPH20 injection 
 
Secondary objectives include: 
• Proportion (%) of subjects who, with pre-treatment, have a ≥ 1 grade reduction of 
the cutaneous reaction to nickel sulfate in at least one patch region at 48 hours 
• Proportion (%) of subjects with a ≥ 1 grade reduction of the cutaneous reaction to 
nickel sulfate in at least one patch region after treatment 
• Proportion (%) of subjects that have a ≥ 1 grade reduction of the cutaneous 
reaction to nickel sulfate in at least one patch region at Days 4, 5, 6, 7 and 14. 
• Safety and tolerability of the injection based on AEs, physical examinations, and 
vital signs 
 
Descriptive-Only parameters include: 
• Chromometer readings of the allergen test sites on Day 1, Day 3 (48 hrs), Day 4 
(72 hrs) and Day 5 (96 hrs) after the placement of the patches 
• TEWL (Trans-epidermal water loss) assessment on Day 1, Day 3 (48 hrs), Day 4 
(72 hrs) and Day 5 (96 hrs) after the placement of the patches 
 
3. STUDY OVERVIEW 
 
This is a pilot Phase II, prospective, double-blind, placebo-controlled study to compare 
the efficacy, safety, and tolerability of rHuPH20 or placebo control administered 


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Statistical Analysis Plan 
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Page 6 of 64 
 
 
 
intradermally (ID) in the prevention and treatment of subjects with contact allergy to 
nickel. A maximum of 30 subjects may be enrolled to ensure that at least approximately 
20 evaluable subjects complete the study. This study will be conducted at a dermatology 
unit. 
 
There are two treatment regimens (Treatment Regimens 1 and 2) in this study, which will 
run in parallel. Within each regimen, four nickel sulfate patches will be used. The four 
patch areas will be randomized to rHuPH20 or placebo for each subject with 1:1 ratio. 
The randomization for Treatment Regimen 1 will be independent of the randomization 
for Treatment Regimen 2. 
 
Figure 1: Study Treatment Arm Randomization 
 
rHuPH20 
or Placebo 
(TR1-1) 
rHuPH20 
or Placebo 
(TR1-2) 
rHuPH20 
or Placebo 
(TR1-3) 
rHuPH20 
or Placebo 
(TR1-4) 
rHuPH20 
or Placebo 
(TR2-5) 
rHuPH20 
or Placebo 
(TR2-6) 
rHuPH20 
or Placebo 
(TR2-7) 
rHuPH20 
or Placebo 
(TR2-8) 
 
 
Subjects with a known history of contact allergy to nickel will be recruited. During the 
screening period, subjects will be tested to confirm the presence of cutaneous nickel 
sensitivity using 1, 2.5 and 5% nickel sulfate patches. The concentration of nickel sulfate 
for each subject that causes no greater than a ++ cutaneous reaction using the 
International Contact Dermatitis Research Group (ICDRG) scoring scale will be the 
concentration administered on Day 1. Once the concentration is determined for the 
subject, the patches in Treatment Regimen 1 and Treatment Regimen 2 will use the same 
concentration patches. 
 
Treatment Regimen 1 (TR1-1 – TR1-4): 
 
This regimen will assess the treatment of contact allergy to nickel: On Day 1, a single 
row of four patches (1, 2.5, or 5% nickel sulfate patches; determined for each subject 
during the Screening period) will be placed on the upper space on the upper back. After 
48 hours, the patches will be removed and an assessment will be made of the reaction site 
as per the ICDRG scoring system. Each subject will receive in the center of the 
Treatment 
Regimen 2 
Treatment 
Regimen 1 


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9 October 2009 
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cutaneous reaction an ID syringe push bolus injection of either rHuPH20 or placebo 
control. Each injection will be administered once daily for 5 days. Prior to each daily 
injection, subjects will be evaluated for efficacy, safety, and tolerability. A final 
evaluation will be conducted 7 days after the last dose of study treatment. 
 
Treatment Regimen 2 (TR2-5 – TR2-8): 
 
This regimen will assess the prevention and treatment of contact allergy to nickel sulfate. 
Each subject will receive in the center of each lower space on the back, either an ID 
syringe push bolus injection of rHuPH20 or placebo control. Exactly 10 minutes after the 
injection, a single row of four patches (1, 2.5, or 5% nickel sulfate patches; determined 
for each subject during the Screening period) will be placed over the center of the ID 
injection. After 48 hours, the patches will be removed and an assessment will be made of 
the reaction site as per the ICDRG scoring system. The subject will receive an ID 
injection of the same study drug from pre-treatment in the center of the cutaneous 
reaction once daily for 5 days. Subjects will be evaluated for efficacy, safety, and 
tolerability, on a daily basis. A final evaluation will be conducted 7 days after the last 
dose of study treatment. 
 
For a given subject, the anticipated duration of time on study is up to 35 days, which 
include Visit 1 (screening, within 21 days prior to receiving study drug), Visit 2 (Day 1), 
Visit 3 (Day 3), Visits 4 – 7 (Day 4 – 7) and Visit 8 (Day 14). 
 
4. GENERAL ANALYSIS CONSIDERATIONS 
 
The statistical analyses will be reported using summary tables, figures, and data listings. 
Descriptive statistics will be used to summarize all efficacy variables. No formal 
statistical comparisons between treatments are planned. Continuous variables will be 
summarized with means, standard deviations, medians, minimums, and maximums. 
Categorical variables will be summarized by counts and by percentage of subjects in 
corresponding categories. 
 
Individual subject data obtained from the case report forms (CRFs), local lab and any 
derived data will be presented by subject in data listings. 
 
The analyses described in this plan are considered a priori, in that they have been defined 
prior to database lock and prior to breaking the blind. Any analyses performed 
subsequent to breaking the blind will be considered post-hoc. Post-hoc analyses will be 
identified in the CSR. 


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Statistical Analysis Plan 
9 October 2009 
Page 8 of 64 
 
 
 
All analyses and tabulations will be performed using SAS Version 9.1 on a PC platform. 
Tables and listings will be presented in RTF format. Figures will be presented in PDF 
format. Upon completion, all SAS programs will be validated by an independent 
programmer. In addition, all program output will undergo a senior level statistical 
review. The validation process will be used to confirm that statistically valid methods 
have been implemented and that all data manipulations and calculations are accurate. 
Checks will be made to ensure accuracy, consistency with this plan, consistency within 
tables, and consistency between tables and corresponding data listings. Upon completion 
of validation and quality review procedures, all documentation will be collected and filed 
by the project statistician or designee. 
 
5. ANALYSIS POPULATIONS 
 
The ITT population will include all enrolled subjects (all subjects who got a subject 
identification number assigned at the time of study enrollment in anticipation of receiving 
a dose of study drug). 
 
The Safety population will include all subjects who receive at least one dose of study 
drug. 
 
The Evaluable population will include all evaluable subjects. An evaluable subject is one 
who has completed dosing (or prematurely discontinued the administration due to a 
toxicity) and has undergone sufficient assessments to allow an assessment of the 
tolerability of the administration. 
 
A subject is considered to have undergone sufficient assessments to allow an assessment 
of the tolerability of the administration if the subject has at least one ICDRG score 
reported on Day 4 or later. 
 
A subject is considered to have prematurely discontinued the administration due to 
toxicity if the subject has Adverse Event checked as the reason for not completing the 
study on the Study Completion/Termination CRF page, and has Drug Withdrawn as the 
action taken with study drug checked on the Adverse Event CRF page. 
 
Efficacy analyses will be run on the Evaluable population and the ITT (Intent-to-Treat) 
population. Analyses run on the Evaluable population will be considered the primary 
analyses. 
 
Safety analyses will be run on the Safety population. 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Statistical Analysis Plan 
9 October 2009 
Page 9 of 64 
 
 
 
6. SUBJECT DISPOSITION 
 
Subject disposition information will be summarized for all subjects. Summaries will 
include: the number of subjects in each analysis (ITT, Safety, Evaluable) population, the 
number of subjects replaced, the number of subjects completing the study and the 
primary reason for discontinuation. 
 
7. DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
 
Demographic and baseline characteristics variables include: age, sex, ethnicity, race and 
the concentration of nickel sulfate assigned. Other baseline characteristics include: 
medical history and hematology and CBC with differential, including incidence rates of 
clinically significant abnormalities at screening. Demographic and baseline 
characteristics will be summarized for the Safety, ITT and Evaluable analysis 
populations. 
 
8. EFFICACY ANALYSES 
 
Efficacy analyses will be carried out on both the Evaluable and the ITT analysis 
populations. 
 
8.1 Primary Variables 
 
The primary efficacy endpoint will be based on the International Contact Dermatitis 
Research Group (ICDRG) Scoring Scale. Using the ICDRG Scoring Scale, each score 
will be assigned a Sponsor-defined “grade”. Scores with stronger reactions will be 
assigned grades with higher values with a maximum grade of 3; scores with weaker 
reactions will receive lower values with a minimum grade of 0. Grade assignments based 
on the ICDRG Scoring Scale are shown in the table below. 
 
International Contact Dermatitis Research Group (ICDRG) Scoring Scale 
 
Grade 
Score 
Interpretation 
0 
- 
Negative reaction 
1/2 
? 
Doubtful reaction; faint macular erythema only 
1 
+ 
Weak (nonvesicular) positive reaction; erythema, infiltration, 
papules, vesicles 
2 
++ 
Strong (vesicular) positive reaction; erythema, infiltration, 
papules, vesicles 
3 
+++ 
Extreme positive reaction; bullous reaction 
NA 
IR 
Irritant reaction of different types 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Statistical Analysis Plan 
9 October 2009 
Page 10 of 64 
 
 
 
 
Treatment effect of rHuPH20 or placebo control injection on the exposure to topical 
nickel allergen will be assessed using ICDRG grades for Treatment Regimens 1 and 2 at 
Day 3 through Day 7 and Day 14. 
 
Regimen 2 only: For each subject, the day of maximal ICDRG score will be determined 
for each injection type (rHuPH20 and Placebo). The maximal ICDRG score will be the 
highest score reported for each subject. If the maximal ICDRG score for a particular 
subject is reported more than one time, the first instance will be used to determine the day 
when the maximal ICDRG score was reached. 
 
8.2 Secondary Variables 
 
Analyses of the secondary endpoints will be based on the grades shown in ICDRG table 
in Section 8.1. 
 
For Treatment Regimen 1 and 2, proportion of subjects that have a ≥ 1 grade reduction of 
the cutaneous reaction to nickel sulfate in at least one patch region after treatment. 
 
For Treatment Regimen 2, proportion of subjects that have a ≥ 1 grade reduction of the 
cutaneous reaction to nickel sulfate in at least one patch region at 48 hours (Day 3) will 
be assessed. 
 
8.3 Descriptive Parameters 
 
TEWL (Trans-epidermal water loss) measurements and Chromometer readings will be 
carried out at Day 1, Day 3, Day 4 and Day 5. On each day, TEWL (Trans-epidermal 
water loss) measurements and Chromometer readings will be collected for each treatment 
region. 
 
8.4 Baseline Values 
 
For analyses based on grades, each treatment region will be assigned its own baseline 
value. The baseline values for regions under Treatment Regimen 1 and 2 will be the 
values collected at Day 3. 
 
The baseline values for TEWL measurements and Chromometer readings will be the 
assessments collected on Day 1. 


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Statistical Analysis Plan 
9 October 2009 
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8.5 Handling Missing Data 
 
No missing values will be imputed. 
 
8.6 Interim Analyses 
 
No interim analyses are planned for this study. 
 
9. STUDY ANALYSIS 
 
The hypothesis for this study is that 1) pre-treatment or rHuPH20 prior to nickel allergy 
testing will decrease the severity of the allergic skin reaction as compared to placebo 
control and 2) rHuPH20 will decrease the severity of nickel contact dermatitis as 
compared to control. The null hypothesis is that rHuPH20 will not be different than what 
will be observed from placebo control. 
 
Figures, listings and descriptive statistics will be used to summarize all efficacy variables. 
No formal statistical comparisons between treatments are planned. 
 
9.1 Statistical Analyses 
 
The primary analysis is the pair-wise intra-subject comparison of endpoint parameters for 
the injections with and without rHuPH20. The secondary analysis covers safety and 
other endpoint parameters (see Section 10). 
 
ICDRG scores will be shown for Treatment Regimen 1 and Treatment Regimen 2 by 
injection types (rHuPH20 or Placebo) at Baseline, Day 4, Day 5, Day 6, Day 7 and Day 
14. ICDRG scores will be reported by subject using figures (Figure 1) and listings 
(Listing 8). 
 
A qualitative medical review of the ICDRG scores will be used to investigate: 
• Possible treatment effect of rHuPH20 or placebo control injection on the 
exposure to topical nickel allergen. 
• Proportion of subjects that have a ≥ 1 grade reduction in at least one patch region. 
At the conclusion of the study, findings from the medical review will be summarized in 
the clinical study report. 
 
For Treatment Regimen 2, the day of maximal ICDRG Score will be used to assess the 
possible effect each injection type has on the onset of reaction to topical nickel allergen. 
The day of maximal ICDRG Score will be summarized for each injection type using 
counts and percentages (Table 6.1/6.2). Possible days of maximal ICDRG Score include 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Statistical Analysis Plan 
9 October 2009 
Page 12 of 64 
 
 
 
the following: Day 4, Day 5, Day 6, Day 7, and Day 14. If the maximal ICDRG Score 
for an injection type occurred prior to treatment, the subject will be reported as never 
having had an ICDRG Score more severe than Day 3 for summary purposes. 
 
9.2 Exploratory Analyses 
 
TEWL (Trans-epidermal water loss) assessments at Baseline (Day 1), Day 3, Day 4 and 
Day 5 will be summarized for Treatment Regimen 1 and Treatment Regimen 2 by 
injections type (rHuPH20 or Placebo). Summaries of TEWL assessments will be 
generated by subject using figures (Figure 2) and listings (Listing 9). A review of the 
TEWL assessments summaries will be used to investigate possible treatment effect of 
rHuPH20 or placebo control injection on the exposure to topical nickel allergen. 
 
Analysis of Chromometer readings will be carried in the same manner as the analysis for 
TEWL assessments (Figure 3, Listing 11). All Chromometers readings reported will be 
presented in listings; however, only reported “a” scale readings will be considered for 
figures. 
 
10. SAFETY ANALYSES 
 
All subjects who received study drug will be included in the safety analyses, analyzed 
according to the study treatment actually received. 
 
10.1 Adverse Events 
 
All adverse event summaries will be restricted to Treatment Emergent Adverse Events 
(TEAE), which are defined as those AEs that occurred after dosing and those existing 
AEs that worsened during the study. Verbatim terms on case report forms will be 
mapped to preferred terms and system organ classes using the MedDRA dictionary 
(version 12.0). 
 
Each adverse event summary will be displayed for the Safety population. Summaries that 
are displayed by system organ class and preferred terms will be ordered by descending 
order of incidence of system organ class and preferred term within each system organ 
class. Summaries of the following types will be presented: 
 
• Subject incidence of TEAEs and total number of unique TEAEs by MedDRA 
system organ class and preferred term. 
• Subject incidence of TEAEs by MedDRA system organ class, preferred term, and 
highest severity. At each level of subject summarization a subject is classified 
according to the highest severity if the subject reported one or more events. A 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Statistical Analysis Plan 
9 October 2009 
Page 13 of 64 
 
 
 
missing column will be added to the summary table if any TEAEs are reported 
with missing severity. 
• Subject incidence of TEAEs by MedDRA system organ class, preferred term, and 
closest relationship to study drug (Related/Not Related). At each level of subject 
summarization a subject is classified according to the closest relationship if the 
subject reported one or more events. AEs with a missing relationship will be 
considered related for this summary. 
• Subject incidence of serious TEAEs and total number of unique serious TEAEs 
by MedDRA system organ class and preferred term. 
• Subject incidence of TEAEs and total number of unique serious TEAEs leading to 
discontinuation of study drug or premature withdrawal from study. 
• Subject incidence of TEAEs reported after physical examination of injection site 
and safety review on Day 1 (for Treatment Regimen 2 only), Day 3 through Day 7 
and Day 14 will be presented by injection type. 
 
10.2 Vital Signs 
 
Assessment of vital signs includes the measurement of blood pressure (systolic and 
diastolic), heart rate, and respiration rate and body temperature (at screening). Vital signs 
will be recorded one time at Screening; pre- and post injection vital sign results will be 
collected on the following days: Day 1, Day 3, Day 4, Day 5, Day 6, Day 7, Day 14. 
 
Vital signs will be summarized using descriptive statistics at each visit time point. 
Changes from baseline will also be summarized. Baseline is defined as the pre-dose 
result for the visit under consideration. 
 
10.3 Physical Examination 
 
Physical examination results will be summarized with shift tables comparing baseline to 
the most abnormal post baseline assessment. Possible assessments for each body system 
include: Normal/Return to Normal and Abnormal. 
 
Baseline will be defined as the last non-missing result recorded before injection. 
 
10.4 Prior and Concomitant Medications 
 
Verbatim terms on case report forms will be mapped to 
Anatomical/Therapeutic/Chemical (ATC) Level 4 categories and Drug Reference Names 
using the World Health Organization (WHO) dictionary (March 1, 2009). 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Statistical Analysis Plan 
9 October 2009 
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Prior medications are those medications taken within 21 days prior to the initial dose of 
study drug. Concomitant medications are those medications taken after the initial dose of 
study drug. Prior and concomitant medications will be summarized for each treatment by 
WHO ATC class and medication name. These summaries will present the number and 
percentage of subjects using each medication. Subjects may have more than one 
medication per ATC category and medication. At each level of subject summarization, a 
subject is counted once if he/she reported one or more medications at that level. Each 
summary will be ordered by descending order of incidence of ATC class and medication 
within each ATC class. 
 
11. SAMPLE SIZE CALCULATION 
 
The sample size of 20 evaluable subjects is intended to provide a sufficient sample size to 
allow for a meaningful comparison between rHuPH20 and placebo control. 


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Statistical Analysis Plan 
9 October 2009 
Page 15 of 64 
 
 
 
 
APPENDIX A: LIST OF TABLES, LISTINGS AND FIGURES 
 
List of Tables 
 
Table 
Number 
Table Description 
1 
Subject Disposition 
2 
Demographic and Baseline Characteristics 
3 
Abnormal Medical History 
4 
Hematology and CBC with Differential at Screening 
5 
Incidence of Clinically Significant Laboratory Abnormalities at Screening 
6 
Day of Maximal ICDRG Score 
7 
Adverse Events by System Organ Class (Safety Population) 
8 
Adverse Events by System Organ Class and Severity [1] (Safety 
Population) 
9 
Adverse Events by System Organ Class and Relationship to Study Drug 
[1] (Safety Population) 
10 
Serious Adverse Events by System Organ Class (Safety Population) 
11 
Adverse Events Leading to Discontinuation of Study Drug or Premature 
Withdrawal of From Study 
12 
Adverse Events by System Organ Class and Injection Type (Safety 
Population) 
13 
Vital Signs (Safety Population) 
14 
Physical Examination (Safety Population) 
15 
Concomitant Medications (Safety Population) 


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Statistical Analysis Plan 
9 October 2009 
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List of Data Listings 
 
Listing 
Number Listing Description 
CRF 
Plate(s) 
1 
Subject Disposition 
Derived 
2 
Inclusion/Exclusion Criteria 
2,3,4 
3 
Demographics 
1 
4 
Medical History 
5 
5 
Hematology and CBC with Differential 
8 
6 
Lab Normal - Hematology 
350 
7 
Pregnancy Test 
9 
8 
ICDRG Score 
13,15 
9 
TEWL (Trans-Epidermal Water Loss) Assessment 
17 
10 
Digital Photographs 
17 
11 
Chromometer 
18 
12 
Subject Diary 
19 
13 
Screening Nickel Sulfate and Vehicle Control Patches 
11 
14 
Study Drug Administration – Treatment Regimen 1 
12,13,14 
15 
Study Drug Administration – Treatment Regimen 2 
15,16 
16 
Adverse Events 
97 
17 
Serious Adverse Events 
97 
18 
Vital Signs 
7 
19 
Physical Examination 
6,10 
20 
Comments 
96 
21 
Prior and Concomitant Medications 
98 
22 
Deaths 
101 
23 
Subject Visit 
Derived 


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Protocol HALO-114-201 
Statistical Analysis Plan 
9 October 2009 
Page 17 of 64 
 
 
 
List of Figures 
 
Figure 
Number 
Figure Description 
1 
ICDRG Scores by Day 
2 
Individual TEWL Scores by Day and Injection Site 
3 
Individual a-Scale Chromometer Baseline Corrected Scores by Day and 
Injection Site 


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Statistical Analysis Plan 
9 October 2009 
Page 18 of 64 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX B: TABLE LAYOUTS 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Table 1 
Page 19 of 64 
 
 
Subject Disposition 
All Subjects 
 
  
Total 
 
 
ITT Population[1] 
N 
 
Safety Population [2] 
n (%) 
Evaluable Population [3] 
n (%) 
Number of Subjects Replaced [4] 
n (%) 
 
Completed Study 
Yes 
n (%) 
No 
n (%) 
 
Primary Reason for Discontinuation 
Protocol Violation 
n (%) 
Lost to Follow-up 
n (%) 
Adverse Event 
n (%) 
Non-compliance 
n (%) 
Subject Decision 
n (%) 
Investigator Decision 
n (%) 
Other 
n (%) 
 
[1] Intent to Treat (ITT): Enrolled subjects who signed informed consent. 
[2] Received at least one dose of study drug. 
[3] An evaluable subject is one who has completed dosing (or prematurely discontinued the administration due to a toxicity) and has undergone sufficient assessments to allow an assessment of the 
tolerability of the administration. 
[4] Enrolled subjects but not meeting the criteria of evaluability. 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Table 2 
Page 20 of 64 
 
 
Demographic and Baseline Characteristics 
All Subjects 
 
ITT 
Safety 
Evaluable 
(N= ) 
(N= ) 
(N= ) 
Age (years) [1] 
N 
n 
n 
n 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
Sex 
Male 
n (%) 
n (%) 
n (%) 
Female 
n (%) 
n (%) 
n (%) 
Ethnicity 
Hispanic or Latino 
n (%) 
n (%) 
n (%) 
Not Hispanic or Latino 
n (%) 
n (%) 
n (%) 
Race 
American Indian or Alaska Native 
n (%) 
n (%) 
n (%) 
Asian 
n (%) 
n (%) 
n (%) 
Black or African American 
n (%) 
n (%) 
n (%) 
Native Hawaiian or Other Pacific Islander 
n (%) 
n (%) 
n (%) 
White 
n (%) 
n (%) 
n (%) 
Other 
n (%) 
n (%) 
n (%) 
More than one race marked 
n (%) 
n (%) 
n (%) 
Concentration of nickel sulfate (%) 
1 
n (%) 
n (%) 
n (%) 
2.5 
n (%) 
n (%) 
n (%) 
5 
n (%) 
n (%) 
n (%) 
 
[1] Age at the date of informed consent signed. 
path\t_program.sas 
date 
time 


Page 1 of x 
Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Table 
Page 21 of 64 
 
 
Abnormal Medical History 
All Subjects 
ITT 
Safety 
Evaluable 
Body System 
(N= ) 
(N= ) 
(N= ) 
Respiratory 
n (%) 
n (%) 
n (%) 
Cardiovascular 
n (%) 
n (%) 
n (%) 
Gastrointestinal 
n (%) 
n (%) 
n (%) 
Hepatic 
n (%) 
n (%) 
n (%) 
Endocrine/Metabolic 
n (%) 
n (%) 
n (%) 
Central and Peripheral Nervous System 
n (%) 
n (%) 
n (%) 
Hematopoietic/Lymphatic 
n (%) 
n (%) 
n (%) 
Dermatological 
n (%) 
n (%) 
n (%) 
Musculoskeletal 
n (%) 
n (%) 
n (%) 
Genitourinary/Reproductive 
n (%) 
n (%) 
n (%) 
Psychiatric 
n (%) 
n (%) 
n (%) 
Alcohol/Drug Abuse 
n (%) 
n (%) 
n (%) 
Drug Allergy 
n (%) 
n (%) 
n (%) 
Non-Drug Allergy 
n (%) 
n (%) 
n (%) 
HEENT 
n (%) 
n (%) 
n (%) 
Other 
n (%) 
n (%) 
n (%) 
 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Table 
Page 22 of 64 
 
 
Hematology and CBC with Differential at Screening 
All Subjects 
 
ITT 
 
Safety 
 
Evaluable 
  Laboratory Parameter 
(N= ) 
(N= ) 
(N= ) 
 
 
WBC (X 1000/uL) 
N 
n 
n 
n 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
RBC (X Mil/uL) 
N 
n 
n 
n 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
.. 
path\t_program.sas 
date 
time 
 
 
Programmer note: Table will include the following hematology parameters: Hemoglobin (g/dL), Hematocrit (%), Platelets (X 1000/uL), Neutrophils (segs) (%), Neutrophils (bands) (%), Lymphocytes 
(%), Monocytes (%), Eosinophils (%) and Basophils (%). 


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Protocol HALO-114-201 
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Table 
Page 23 of 64 
 
 
Incidence of Clinically Significant Laboratory Abnormalities at Screening 
All Subjects 
 
Any Clinically Significant Abnormalities? 
ITT 
(N= ) 
Safety 
(N= ) 
Evaluable 
(N= ) 
WBC 
n (%) 
n (%) 
n (%) 
RBC 
n (%) 
n (%) 
n (%) 
Hemoglobin 
n (%) 
n (%) 
n (%) 
Hematocrit 
n (%) 
n (%) 
n (%) 
Platelets 
n (%) 
n (%) 
n (%) 
Neutrophils (segs) 
n (%) 
n (%) 
n (%) 
Neutrophils (bands) 
n (%) 
n (%) 
n (%) 
Lymphocytes 
n (%) 
n (%) 
n (%) 
Monocytes 
n (%) 
n (%) 
n (%) 
Eosinophils 
n (%) 
n (%) 
n (%) 
Basophils 
n (%) 
n (%) 
n (%) 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Table 6.1 
Page 24 of 64 
 
 
Day of Maximal ICDRG Score 
Evaluable Population 
 
Treatment Regimen 2 
  
(N=) 
 
  Day of ICDRG Maximal Severity Score 
rHuPH20 
Placebo 
 
 
Never had an ICDRG Score More Severe than Day 3 
n (%) 
n (%) 
Day 4 
n (%) 
n (%) 
Day 5 
n (%) 
n (%) 
Day 6 
n (%) 
n (%) 
Day 7 
n (%) 
n (%) 
Day 14 
n (%) 
n (%) 
 
 
Note: For both injection types (rHuPH20 and Placebo), each subject will contribute one result based on the single most severe patch assessment reported. 
path\t_program.sas 
date 
time 
 
Programmer Note: Table 6.2 will contain the same information for the ITT population. 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Table 
Page 25 of 64 
 
 
Treatment Emergent Adverse Events by System Organ Class 
Safety Population 
 
Safety Population 
  
(N= ) 
 
Number of 
Number of 
  System Organ Class / Preferred Term 
Subjects [1] 
Events 
 
 
Subjects Reporting at Least One Adverse Event 
n (%) 
n 
System Organ Class 1 
n (%) 
n 
Preferred Term 1 
n (%) 
n 
Preferred Term 2 
. 
. 
n (%) 
n 
System Organ Class 2 
n (%) 
n 
Preferred Term 1 
n (%) 
n 
Preferred Term 2 
n (%) 
n 
 
 
 
[1] At each level of summation (overall, system organ class, preferred term), subjects reporting more than one adverse event are counted only once. 
path\t_program.sas 
date 
time 


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Protocol HALO-114-201 
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Table 
Page 26 of 64 
 
 
Treatment Emergent Adverse Events by System Organ Class and Severity 
Safety Population 
 
Safety Population 
  
(N= ) 
 
System Organ Class / Preferred Term [1] 
Mild 
Moderate 
Severe 
Life 
Threatening 
Fatal 
Subjects Reporting at Least One Adverse Event 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
System Organ Class 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 2 
. 
. 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
System Organ Class 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 2 
. 
. 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
[1] At each level of summation (overall, system organ class, preferred term), subjects reporting more than one adverse event are counted only once using the highest severity. 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Table 
Page 27 of 64 
 
 
Treatment Emergent Adverse Events by System Organ Class and Relationship to Study Drug 
Safety Population 
 
Safety Population 
  
(N= ) 
 
  System Organ Class / Preferred Term [1] 
Related 
Not Related 
 
 
Subjects Reporting at Least One Adverse Event 
n (%) 
n (%) 
System Organ Class 1 
n (%) 
n (%) 
Preferred Term 1 
n (%) 
n (%) 
Preferred Term 2 
. 
. 
n (%) 
n (%) 
System Organ Class 2 
n (%) 
n (%) 
Preferred Term 1 
n (%) 
n (%) 
Preferred Term 2 
n (%) 
n (%) 
 
 
 
[1] At each level of summation (overall, system organ class, preferred term), subjects reporting more than one adverse event are counted only once using the closest relationship to study drug. 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Table 28 
Page 28 of 64 
 
 
Treatment Emergent Serious Adverse Events by System Organ Class 
Safety Population 
 
Safety Population 
  
(N= ) 
 
Number of 
Number of 
  System Organ Class / Preferred Term 
Subjects [1] 
Events 
 
 
Subjects Reporting at Least One Serious Adverse Event 
n (%) 
n 
System Organ Class 1 
n (%) 
n 
Preferred Term 1 
n (%) 
n 
Preferred Term 2 
. 
. 
n (%) 
n 
System Organ Class 2 
n (%) 
n 
Preferred Term 1 
n (%) 
n 
Preferred Term 2 
n (%) 
n 
 
 
 
[1] At each level of summation (overall, system organ class, preferred term), subjects reporting more than one serious adverse event are counted only once. 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Table 29 
Page 29 of 64 
 
 
Treatment Emergent Adverse Events Leading to Discontinuation of Study Drug or Premature Withdrawal of From Study 
Safety Population 
 
Safety Population 
  
(N= ) 
 
Number of 
Number of 
  System Organ Class / Preferred Term 
Subjects [1] 
Events 
 
 
Subjects Reporting at Least One Serious Adverse Event 
n (%) 
n 
System Organ Class 1 
n (%) 
n 
Preferred Term 1 
n (%) 
n 
Preferred Term 2 
. 
. 
n (%) 
n 
System Organ Class 2 
n (%) 
n 
Preferred Term 1 
n (%) 
n 
Preferred Term 2 
n (%) 
n 
 
 
 
[1] At each level of summation (overall, system organ class, preferred term), subjects reporting more than one adverse event are counted only once. 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Page 30 of 64 
 
 
Table 12 
Treatment Emergent Adverse Events by System Organ Class and Injection Type 
Safety Population 
 
Treatment Regimen 1 
(N= ) 
 
Treatment Regimen 2 
(N= ) 
 
rHuPH20 
Placebo 
  
rHuPH20 
Placebo 
 
System Organ Class / Preferred Term 
Number of 
Subjects [1] 
Number of 
Events 
Number of 
Subjects [1] 
Number of 
Events 
Number of 
Subjects [1] 
Number of 
Events 
Number of 
Subjects [1] 
Number of 
Events 
Subjects Reporting at Least One Serious 
Adverse Event 
n (%) 
n 
n (%) 
n 
n (%) 
n 
n (%) 
n 
System Organ Class 1 
n (%) 
n 
n (%) 
n 
n (%) 
n 
n (%) 
n 
Preferred Term 1 
n (%) 
n 
n (%) 
n 
n (%) 
n 
n (%) 
n 
Preferred Term 2 
. 
. 
n (%) 
n 
n (%) 
n 
n (%) 
n 
n (%) 
n 
System Organ Class 2 
n (%) 
n 
n (%) 
n 
n (%) 
n 
n (%) 
n 
Preferred Term 1 
n (%) 
n 
n (%) 
n 
n (%) 
n 
n (%) 
n 
Preferred Term 2 
n (%) 
n 
n (%) 
n 
n (%) 
n 
n (%) 
n 
 
 
 
Note: For this summary, only Adverse Events reported during the physical examinations/safety reviews at Day 1 (TR 2 only), Day 3 through Day 7, and Day 14 are considered. 
[1] At each level of summation (overall, system organ class, preferred term), subjects reporting more than one adverse event are counted only once. 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Table 31 
Page 31 of 64 
 
 
Vital Signs 
Safety Population 
 
Safety Population 
  Vital Sign 
Time Point 
(N= ) 
 
 
Systolic BP (mmHg) 
Screening 
N 
n 
Mean (SD) 
xx.x (xx.xx) 
Median 
xx.x 
Min, Max 
xx, xx 
 
Day 1 Pre-Injection 
N 
n 
Mean (SD) 
xx.x (xx.xx) 
Median 
xx.x 
Min, Max 
xx, xx 
 
Day 1 Post-Injection 
N 
n 
Mean (SD) 
xx.x (xx.xx) 
Median 
xx.x 
Min, Max 
xx, xx 
 
Day 1 Change from Baseline [1] 
N 
n 
Mean (SD) 
xx.x (xx.xx) 
Median 
xx.x 
Min, Max 
xx, xx 
 
… 
Diastolic BP (mmHg) 
 
[1] Baseline is defined as pre-injection assessment for the visit under consideration. 
path\t_program.sas 
date 
time 
 
Programmer note: Table will include the following vital signs: systolic BP (mmHg), diastolic BP (mmHg),Heart Rate (bpm) and Respiration (breaths/min). for each vital sign, time points will include: 
Screening, Day 1 Pre-Injection, Day 1 Post-Injection, Day 1 Change from Baseline, Day 3 Pre-Injection, Day 3 Post-Injection, Day 3 Change from Baseline, Day 4 Pre-Injection, Day 4 Post-Injection, 
Day 4 Change from Baseline, Day 5 Pre-Injection, Day 5 Post-Injection, Day 5 Change from Baseline, Day 6 Pre-Injection, Day 6 Post-Injection, Day 6 Change from Baseline, Day 7 Pre-Injection, 
Day 7 Post-Injection, Day 7 Change from Baseline, Day 14. 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Table 32 
Page 32 of 64 
 
 
Physical Examination 
Safety Population 
 
Safety Population 
(N= ) 
  
Baseline Assessment 
 
  Most Abnormal Post-Baseline Assessment 
Normal 
Abnormal 
 
 
HEENT 
Normal 
(N= ) 
n (%) 
n (%) 
Abnormal 
n (%) 
n (%) 
Respiratory 
Normal 
(N= ) 
n (%) 
n (%) 
Abnormal 
n (%) 
n (%) 
Cardiovascular 
. 
. 
 
 
path\t_program.sas 
date 
time 
 
Programmer note: Table will include all physical examination body systems. 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Table 15 
Concomitant Medications [1] 
Safety Population 
Page 33 of 64 
 
 
 
Safety Population 
  ATC Drug Class / Medication Term 
(N= ) 
 
 
Subjects Receiving any Concomitant Medications 
n (%) 
Drug Class 1 
n (%) 
Medication Term 1 
n (%) 
Medication Term 2 
. 
. 
n (%) 
Drug Class 2 
n (%) 
Medication Term 1 
n (%) 
Medication Term 2 
. 
. 
n (%) 
 
[1] At each level of summation (overall, ATC drug class, medication term), subjects reporting more than one medication are counted only once. 
path\t_program.sas 
date 
time 


Page 34 of 64 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX C: LISTING LAYOUTS 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 
Page 35 of 64 
 
 
Subject Disposition 
 
 
Concentration of Nickel 
First Injection 
Last Injection 
Total # 
Primary Reason for 
Subject 
ITT[1] 
Safety[2] 
Evaluable[3] 
Replaced[4] 
Sulfate Used 
Date 
Date 
of Injection(s) 
Complete? 
Not Completing 
 
[1] Intent to Treat (ITT): Enrolled subjects who signed informed consent. 
[2] Received at least one dose of study drug. 
[3] An evaluable subject is one who has completed dosing (or prematurely discontinued the administration due to a toxicity) and has undergone sufficient assessments to allow an assessment of the 
tolerability of the administration. 
[4] Enrolled subjects but not meeting the criteria of evaluability. 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 
Page 36 of 64 
 
 
Inclusion/Exclusion Criteria 
Part 1 of 4 
Inclusion Criteria: 
1: 
2: 
3: 
4: 
5: 
6: 
7: 
8: 
Exclusion Criteria: 
1: 
2: 
3: 
4: 
5: 
6: 
7: 
8: 
9: 
10: 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 2(cont.) 
Inclusion/Exclusion Criteria 
Page 37 of 64 
 
 
Part 2 of 4: Inclusion Criteria 
 
Date Informed 
  
Inclusion Criteria 
 
Subject 
Consent Signed 
1 
2 
3 
4 
5 
6 
7 
8 
 
 
 
path\t_program.sas 
date 
time 
 
 
Halozyme Therapeutics, Inc. 
Page 1 of x 
Protocol HALO-114-201 
 
 
 
 
Date Informed 
 
Listing 2(cont.) 
Inclusion/Exclusion Criteria 
Part 3 of 4: Exclusion Criteria 
  
Exclusion Criteria 
 
Subject 
Consent Signed 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
path\t_program.sas 
date 
time 
 
 
Halozyme Therapeutics, Inc. 
Page 1 of x 
Protocol HALO-114-201 
 
 
 
 
Comply with ALL 
 
 
 
 
Entry Criteria 
 
Listing 2(cont.) 
Inclusion/Exclusion Criteria 
Part 4 of 4: Waiver 
Subject 
Entry Criteria 
Not Met 
Exemption Explanation 
Exemption Granted By 
Date 
Inclusion:1 
 
 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 3 
Demographics 
Page 38 of 64 
 
 
 
    Subject 
Date of Birth 
Age 
Sex 
Ethnicity 
Race 
 
 
[1] Age is calculated by comparing the date of birth and the informed consent date. 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 4 
Medical History 
Page 39 of 64 
 
 
 
Subject 
Mark if None 
MH # 
Body System 
Description 
Diagnosis/Onset 
Mark if Ongoing 
 
 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 5 
Hematology and CBC with Differential 
Page 40 of 64 
 
 
Part 1 of 2 
 
Mark if 
Not Done 
WBC 
RBC 
Hemoglobin 
Hematocrit 
Platelets 
Neutrophils 
Neutrophils 
Subject 
Visit 
Not Done 
Reason 
Collection Date/Time 
(X1000/uL) 
(XMil/uL) 
(g/dL) 
(%) 
(X1000/uL) 
(segs) (%) 
(bands) (%) 
 
 
 
Note: A result marked with “*” indicates a result that is abnormal and clinically significant. 
path\t_program.sas 
date 
time 
 
 
Halozyme Therapeutics, Inc. 
Page 1 of x 
Protocol HALO-114-201 
 
Listing 5 (cont.) 
Hematology and CBC with Differential 
Part 2 of 2 
 
Mark if 
Not Done 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Subject 
Visit 
Not Done 
Reason 
Collection Date/Time 
(%) 
(%) 
(%) 
(%) 
Other 
 
Note: A result marked with “*” indicates a result that is abnormal and clinically significant. 
path\t_program.sas 
date 
time 
 
Programmer note: for “other”, put test name instead of “other” in the column name. 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 6 
Lab Normal - Hematology 
Page 41 of 64 
 
 
 
  
Lab 
 
Lab Test 
Sex 
Low 
High 
 
Lab Units 
If Other, Specify 
WBC 
 
 
 
X1000/uL 
 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 7 
Pregnancy Test 
Page 42 of 64 
 
 
 
Mark if 
Not Done 
    Subject 
Visit 
Not Done 
Reason 
Collection Date 
Sample Type 
Result 
 
 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 
Page 43 of 64 
 
 
ICDRG Score [1] 
 
Treatment 
  
Treatment Regimen 1 
Treatment Regimen 2 
 
Subject 
Visit 
Date 
TR 1-1 
TR 1-2 
TR 1-3 
TR 1-4 
TR 2-5 
TR 2-6 
TR 2-7 
TR 2-8 
 
Day 3 
? (A) 
+ (P) * 
Day 4 
 
Note: A= rHuPH20; P= Placebo 
Note: Results marked with “*” indicate Maximal Severity Score. 
[1] ICDRG Score: 
Score (Grade) 
Score Interpretation 
? 
(1/2) 
Doubtful reaction; faint macular erythema only 
+ 
(1) 
Weak (nonvesicular) positive reaction; erythema infiltration, possibly papules 
++ 
(2) 
Strong (vesicular) positive reaction; erythema, infiltration, papules, vesicles 
+++ 
(3) 
Extreme Positive reaction; bullous reaction 
- 
(0) 
Negative reaction 
IR 
(NA) 
Irritant reaction of different types 
 
 
path\t_program.sas 
date 
time 
 
Programmer Note: Each subject will have one Maximal Severity Score marked for each injection type (for a total of 2 scores marked per subject). 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 
Page 44 of 64 
 
 
TEWL (Trans-Epidermal Water Loss) Assessment (g/m2h) 
 
Was TEWL 
Collection 
  
Result 
 
Subject 
 
Visit 
Day 1 
Day 3 
.. 
path\t_program.sas 
date 
time 
Completed? 
Date/Time 
TR 1-1 
TR 1-2 
TR 1-3 
TR 1-4 
TR 2-5 
TR 2-6 
TR 2-7 
TR 2-8 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 45 
Page 45 of 64 
 
 
 
 
 
 
 
 
 
path\t_program.sas 
date 
time 
Digital Photographs 
 
Subject 
Visit 
Were Digital 
Photos Taken? 
Collection 
Date 
Collection 
Time 
Uploaded to 
Website? 
No:reason 
No:reason 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 46 
Page 46 of 64 
 
 
Chromometer 
Part 1 of 3: a-Scale 
 
 
Subject 
Visit 
Was a Chromometer 
Reading Completed? 
Collection 
Date 
Collection 
Time 
Category 
TR 1-1 
TR 1-2 
TR 1-3 
TR 1-4 
TR 2-5 
TR 2-6 
TR 2-7 
TR 2-8 
 
Day 1 
No:reason 
Day 3 
Result 
Change from Day 1 
 
path\t_program.sas 
date 
time 
 
Halozyme Therapeutics, Inc. 
Page 1 of x 
Protocol HALO-114-201 
 
Listing 11 
Chromometer 
Part 2 of 3: b-Scale 
 
 
Subject 
Visit 
Was a Chromometer 
Reading Completed? 
Collection 
Date 
Collection 
Time 
Category 
TR 1-1 
TR 1-2 
TR 1-3 
TR 1-4 
TR 2-5 
TR 2-6 
TR 2-7 
TR 2-8 
 
Day 1 
No:reason 
Day 3 
Result 
Change from Day 1 
 
path\t_program.sas 
date 
time 
Halozyme Therapeutics, Inc. 
Page 1 of x 
Protocol HALO-114-201 
 
Listing 11 
Chromometer 
Part 3 of 3: l-Scale 
 
 
Subject 
Visit 
Was a Chromometer 
Reading Completed? 
Collection 
Date 
Collection 
Time 
Category 
TR 1-1 
TR 1-2 
TR 1-3 
TR 1-4 
TR 2-5 
TR 2-6 
TR 2-7 
TR 2-8 
 
Day 1 
No:reason 
Day 3 
Result 
Change from Day 1 
 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 47 
Page 47 of 64 
 
 
Subject Diary 
 
 
Subject 
Visit 
Mark if Not 
Done 
Not Done 
Reason 
Date 
Start 
Time 
End 
Time 
Symptom 
Severity[1] 
Comments 
ongoing 
Dispense next 
Diary to subject? 
 
[1] 1 – Least Discomfort, 5 – Most Discomfort. 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 48 
Page 48 of 64 
 
 
Screening Nickel Sulfate and Vehicle Control Patches 
 
  
Application of Patches 
 
  
Test Results (48 Hours After Application) 
 
Patches 
48 hours 
ICDRG 
Subject 
Applied? 
Date 
Time 
Date 
Time 
After App.? 
1% 
2.5% 
5% 
Dose Assigned? 
Assigned Dose 
 
No:reason 
No:reason 
No:reason 
 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 49 
Page 49 of 64 
 
 
Study Drug Administration – Treatment Regimen 1 
Part 1 of 4: Application of Nickel Sulfate Patches 
 
 
Subject 
Visit 
Treatment 
Date 
8 Areas 
Normal? 
No:reason 
Application 
Time 
4 Patches 
applied? 
Concentrations of 
Nickel Sulfate 
 
path\t_program.sas 
date 
time 
 
 
Halozyme Therapeutics, Inc. 
Page 1 of x 
Protocol HALO-114-201 
 
Listing 14 (cont.) 
Study Drug Administration – Treatment Regimen 1 
Part 2 of 4: Physical Examination Prior to Injection 
 
 
 
Subject 
Visit 
 
Subject 
Randomized? 
 
Treatment 
Date 
 
Asse. 
Time 
ICDRG Score 
AE # 
 
TR 1-1 
TR 1-2 
TR 1-3 
TR 1-4 
TR 1-1 
TR 1-2 
TR 1-3 
TR 1-4 
None 
None 
None 
None 
 
 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 14 (cont.) 
Study Drug Administration – Treatment Regimen 1 
Page 50 of 64 
 
 
Part 3 of 4: Study Drug Administration 
 
 
 
Subject 
Visit 
 
Treatment 
Date 
TR 1-1 
TR 1-2 
TR 1-3 
TR 1-4 
 
Drug Injected? 
Time 
Drug Injected? 
Time 
Drug Injected? 
Time 
Drug Injected? 
Time 
No:reason 
 
 
path\t_program.sas 
date 
time 
 
 
 
Halozyme Therapeutics, Inc. 
Page 1 of x 
Protocol HALO-114-201 
 
Listing 14 (cont.) 
Study Drug Administration – Treatment Regimen 1 
Part 4 of 4: Physical Examination and Safety Review after Injection 
 
Treatment 
Asse. 
  
AE # 
 
Subject 
Visit 
Date 
Test Category 
Time 
TR 1-1 
TR 1-2 
TR 1-3 
TR 1-4 
 
Physical Exam. (10 mins. Post) 
None 
None 
None 
None 
Safety Review (30 mins Post) 
 
 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 15 
Study Drug Administration – Treatment Regimen 2 
Page 51 of 64 
 
 
Part 1 of 4: Physical Examination Prior to Injection 
 
 
Subject 
 
Treatment 
 
Asse. 
ICDRG Score 
AE # 
 
 
 
 
path\t_program.sas 
date 
time 
 
 
 
Halozyme Therapeutics, Inc. 
Page 1 of x 
Protocol HALO-114-201 
 
Listing 15 (cont.) 
Study Drug Administration – Treatment Regimen 2 
Part 2 of 4: Study Drug Administration 
 
 
 
Subject 
Visit 
 
Treatment 
Date 
TR 2-5 
TR 2-6 
TR 2-7 
TR 2-8 
 
Drug Injected? 
Time 
Drug Injected? 
Time 
Drug Injected? 
Time 
Drug Injected? 
Time 
No:reason 
 
 
path\t_program.sas 
date 
time 
Subject 
Visit 
Randomized? 
Date 
Time 
TR 2-5 
TR 2-6 
TR 2-7 
TR 2-8 
TR 2-5 
TR 2-6 
TR 2-7 
TR 2-8 
None 
None 
None 
None 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 15 (cont.) 
Study Drug Administration – Treatment Regimen 2 
Page 52 of 64 
 
 
Part 3 of 4: Physical Examination and Safety Review after Injection 
 
Treatment 
Asse. 
  
AE # 
 
Subject 
Visit 
Date 
Test Category 
Time 
TR 2-5 
TR 2-6 
TR 2-7 
TR 2-8 
 
Physical Exam. (10 mins. Post) 
None 
None 
None 
None 
Safety Review (30 mins Post) 
 
 
path\t_program.sas 
date 
time 
 
 
 
Halozyme Therapeutics, Inc. 
Page 1 of x 
Protocol HALO-114-201 
 
Listing 15 (cont.) 
Study Drug Administration – Treatment Regimen 2 
Part 4 of 4: Application of Nickel Sulfate Patches 
 
Treatment 
Application 
Mark if Not 
4 Patches Not applied 
Concentrations of 
Subject 
Visit 
Date 
Time 
Done 
Reason 
Nickel Sulfate 
 
 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 16 
Adverse Events 
Page 53 of 64 
 
 
 
Mark if 
Start 
Resolved 
Severity 
Action Taken with 
Relationship to 
Other Action 
Subject 
None 
AE Term 
Date/Time 
Date/Time 
Serious 
(CTCAE3) 
Study Drug 
Study Drug 
Taken 
Outcome 
 
 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 17 
Serious Adverse Events 
Page 54 of 64 
 
 
 
Mark if 
Start 
Resolved 
Severity 
Action Taken with 
Relationship to 
Other Action 
Subject 
None 
AE Term 
Date/Time 
Date/Time 
(CTCAE3) 
Study Drug 
Study Drug 
Taken 
Outcome 
 
 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 18 
Vital Signs 
Page 55 of 64 
 
 
 
 
Subject 
Visit 
Mark if 
Not Done 
Not Done 
Reason 
Visit 
Date 
Category 
Visit 
Time 
Heart Rate 
(bpm) 
Blood Pressure 
(mmHg) 
Respiration 
(breaths/min) 
Body Temperature 
(oF) 
 
Screening 
Sys/Dia 
 
Day 1 
Pre-injection 
Post-injection 
 
… 
Day 14 
 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 19 
Physical Examination 
Page 56 of 64 
 
 
 
 
Subject 
Visit 
 
 
 
 
path\t_program.sas 
date 
time 
Mark if 
Not Done 
Not Done 
Reason 
Date of 
Exam 
Any Change from 
Previous Exam 
Body System 
 
Result 
Normal 
Abnormal 
Abnormal, Clinically 
Significant 
Description of 
Abnormality 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 20 
Comments 
Page 57 of 64 
 
 
 
 
Subject 
Mark if 
None 
Comment # 
Pertains to 
Visit Date 
CRF Page 
Comment 
 
 
 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 21 
Prior and Concomitant Medications 
Page 58 of 64 
 
 
 
 
Subject 
Mark if 
None 
CM # 
Medication 
Indication 
Start 
Date 
Stop 
Date 
Dose 
Unit 
Route 
Frequency 
onging 
Taken for 
AE? 
AE # 
 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 22 
Deaths 
Page 59 of 64 
 
 
 
Date of 
Date Death 
Was Autopsy 
Signature of 
Signature 
Subject 
Death 
Reported to Site 
Primary Cause of Death 
Performed? 
Comment 
Investigator 
Date 
 
 
 
path\t_program.sas 
date 
time 


Halozyme Therapeutics, Inc. 
Protocol HALO-114-201 
Page 1 of x 
Listing 23 
Subject Visit 
Page 60 of 64 
 
 
 
     Subject 
Initials 
Visit 
Visit Date 
 
 
path\t_program.sas 
date 
time 


Page 61 of 64 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX D: FIGURE LAYOUTS 


Page 62 of 64 
 
 
 
Halzoyme Therapeutics, Inc 
Protocol HALO-114-201 
 
 
Figure 1 
ICDRG Scores- Subject 001XXX 
 
 
 
 
Day 3 
Day 4 
Day 5 
 
 
 
Regimen 1 
+ 
P 
++ 
A 
+ 
P 
++ 
A 
Regimen 2 
+ 
P 
++ 
A 
++ 
P 
+ 
A 
Day 6 
 
Note: A= rHuPH20, P= Placebo, NR= Not Reported. 
Only subjects reported in both the Demographic and ICDRG datasets are considered. 
Regimen 1 from left to right- TR1-1, TR1-2, TR1-3, TR1-4 and Regimen 2 from left to right- TR2-5, TR2-6, TR2-7, TR2-8 
path\program.sas date time 
Regimen 1 
++ 
P 
++ 
A 
++ 
P 
++ 
A 
Regimen 2 
++ 
P 
++ 
A 
++ 
P 
++ 
A 
Regimen 1 
++ 
P 
++ 
A 
++ 
P 
++ 
A 
Regimen 2 
++ 
P 
++ 
A 
++ 
P 
++ 
A 
Regimen 1 
 
++ 
P 
++ 
A 
++ 
P 
++ 
A 
Regimen 2 
 
++ 
P 
++ 
A 
+++ 
P 
++ 
A 
Regimen 1 
Regimen 1 
+ 
P 
++ 
A 
+ 
P 
+ 
A 
? 
P 
+ 
A 
? 
P 
+ 
A 
Regimen 2 
Regimen 2 
+ 
+ 
? 
+ 
+ 
+ 
+ 
? 
P 
A 
P 
A 
P 
A 
P 
A 
Day 7 
Day 14 


Halozyme Therapeutics, Inc 
Protocol HALO-114-201 
Figure 2 
Page 63 of 64 
 
 
Individual TEWL Scores by Day and Injection Site 
Subject 001XXX- Regimen 1 
 
20 
 
 
 
 
15 
 
 
 
 
10 
 
 
 
 
5 
 
 
 
 
0 
Day 1 
 
 
Day 3 
 
 
Day 4 
 
Day 5 
Regimen 1 
TR1-1(P) 
TR1-2(P) 
TR1-3(A) 
TR1-4(A) 
Note: A= rHuPH20, P= Placebo. 
path/program.sas date time 
TEWL (unit) 


Halozyme Therapeutics, Inc 
Protocol HALO-114-201 
Figure 3 
Page 64 of 64 
 
 
Individual a-Scale Chromometer Baseline Corrected Scores by Day and Injection Site 
Subject 001XXX- Regimen 1 
 
10 
 
 
 
 
5 
 
 
 
 
0 
 
 
 
 
-5 
 
 
 
 
-10  
 
Day 1 
 
 
Day 3 
 
 
Day 4 
 
Day 5 
Regimen 1 
TR1-1(P) 
TR1-2(P) 
TR1-3(A) 
TR1-4(A) 
Note: A= rHuPH20, P= Placebo. 
path/program.sas date time 
a-scale (unit)