Clinical Evaluation of Metal Panel Allergens: Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, Vanadium and Zinc Dose Response Study
Phase: PHASE2
Conditions: Dermatitis, Eczematous
Sponsor: Allerderm

 
 
 
 
 
 
Clinical Evaluation of Metal Panel Allergens:  
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
 
 
Sponsor Study Number: SP 14 8MP 201 
NCT Number: NCT02615249 
IND Number: 16775 
EudraCT Number: 2015-002678-19 
PMDA Number: P3726 
Protocol Version: Amendment V 
 Protocol Date: 27 June 2018 
 
 
 

 
 
 
 
 
 
Clinical Evaluation of Metal Panel Allergens:  
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
 
 
Sponsor Study Number: SP 14 8MP 201 
IND Number: 16775 
EudraCT Number: 2015-002678-19 
PMDA Number: P3726 
Protocol Version: Amendment V 
 Protocol Date: 27 June 2018 
 
 
 
 
 
 
 
 
 
 
CLINICAL PROTOCOL 
CONFIDENTIAL 
 
This protocol contains confidential information belonging to SmartPractice. Except as may be 
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information in confidence and not to disclose it to others (except where required by applicable 
law) nor use it for unauthorized purposes. In the event of actual or suspected breach of this 
obligation, SmartPractice should be promptly notified. 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
SmartPractice 
Page 1 of 82 
27 June 2018 
 
 
1.0 
CONTACT INFORMATION 
 
STUDY SPONSOR: 
SmartPractice 
3400 E. McDowell Rd. 
Phoenix, AZ  85008 USA 
 
SPONSOR MEDICAL 
DIRECTOR: 
Curt Hamann, M.D. 
3400 E. McDowell Rd. 
Phoenix, AZ  85008 USA 
 
Tel: +1 800.365.6868 X7202 
Fax: +1 602-225-0245 
e-mail: hamann@smartpractice.com 
SPONSOR ASSISTANT 
MEDICAL DIRECTOR: 
Dathan Hamann, M.D. 
3400 E. McDowell Rd. 
Phoenix, AZ  85008 USA 
 
PRODUCT 
MANUFACTURER: 
SmartPractice Denmark ApS 
Herredsvejen 2  
DK-3400 Hillerød, Denmark 
Tel: +45 48 20 71 00 
MEDICAL ADVISORS: 
Klaus Andersen, M.D.  
Institute of Clinical Research 
Department of Dermato-Venerology and Allergy Center 
Sdr. Boulevard 29 
DK-5000 Odense C, Denmark 
Tel: +45 65 41 27 00 
 
Kayoko Matsunaga, M.D., Ph.D. 
Professor  
Department of Integrative Medical Science for Allergic Disease  
Fujita Health University School of Medicine 
1-98, Dengakugakubo, Kutsukake-cho 
Toyoake, Aichi 470-1192, Japan  
Tel:  +81 0562 93 9441 (Office)  
Fax:  +81 562 95 2915 (Office) 
 
 
 

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Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
SmartPractice 
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3.0 
TABLE OF CONTENTS  
 
1.0 
CONTACT INFORMATION ...................................................................................... 1 
2.0 
APPROVAL OF THE AMENDED PROTOCOL ...................................................... 2 
3.0 
TABLE OF CONTENTS ............................................................................................. 5 
4.0 
SUMMARY ................................................................................................................. 7 
5.0 
FREQUENTLY USED ABBREVIATIONS AND ACRONYMS............................ 21 
6.0 
BACKGROUND AND RATIONALE ...................................................................... 21 
6.1 METAL ALLERGY .................................................................................................. 21 
6.2 ALUMINUM ............................................................................................................. 21 
6.3 COPPER .................................................................................................................... 22 
6.4 MANGANESE .......................................................................................................... 23 
6.5 MOLYBDENUM ...................................................................................................... 23 
6.6 TIN ............................................................................................................................. 24 
6.7 TITANIUM ................................................................................................................ 24 
6.8 VANADIUM ............................................................................................................. 24 
6.9 ZINC .......................................................................................................................... 24 
6.10 PATCH TESTING WITH METALS ........................................................................ 24 
6.11 T.R.U.E. TEST® ........................................................................................................ 25 
6.12 METAL PANEL T.R.U.E. TEST ............................................................................ 26 
7.0 
OBJECTIVE .............................................................................................................. 27 
7.1 PRIMARY ENDPOINT ............................................................................................ 27 
7.2 SECONDARY ENDPOINT ...................................................................................... 27 
8.0 
STUDY DESIGN ...................................................................................................... 28 
8.1 OVERVIEW .............................................................................................................. 28 
8.2 STUDY CONDUCT .................................................................................................. 28 
8.3  INDEPENDENT IRB/ETHICS COMMITTEE REVIEW ....................................... 28 
8.4 SUBJECT INFORMATION AND CONSENT ......................................................... 29 
8.5 DATA COLLECTION .............................................................................................. 29 
8.6 STUDY DURATION ................................................................................................ 29 
9.0 
SUBJECTS ................................................................................................................ 29 
9.1 OVERVIEW .............................................................................................................. 30 
9.2 ENTRY/ELIGIBILITY CRITERIA ........................................................................... 30 
9.2.1 INCLUSION CRITERIA ..................................................................................... 30 
9.2.2 EXCLUSION CRITERIA .................................................................................... 31 
9.3 SUBJECT WITHDRAWAL AND COMPLIANCE ................................................. 32 
9.4 SUBJECT ACTIVITY RESTRICTIONS .................................................................. 33 
10.0 
MONITORED PARAMETERS ................................................................................ 33 
10.1 VISIT 1: DAY 0......................................................................................................... 34 
10.2 VISIT 2: DAY 2......................................................................................................... 37 
10.3 VISIT 3: DAY 3-4 ..................................................................................................... 40 
10.3.1 TAPE AND POLYESTER CHIP SITES IRRITATION ..................................... 40 
10.3.2 ALLERGIC SKIN RESPONSES......................................................................... 40 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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10.4 VISIT 4: DAY 7-8 AND VISIT 5: DAY 10-14 ........................................................ 42 
10.4.1 TAPE AND POLYESTER CHIP SITES IRRITATION ..................................... 42 
10.4.2 ALLERGIC SKIN RESPONSES......................................................................... 42 
10.5 VISIT 6: DAY 19-23 ................................................................................................. 43 
10.6 POST VISIT 6 ........................................................................................................... 44 
11.0 
INVESTIGATONAL PRODUCT IDENTITY AND USE ....................................... 44 
11.1 INVESTIGATIONAL ALLERGEN PANELS .......................................................... 44 
11.2 REFERENCE ALLERGENS .................................................................................... 49 
12.0 
DATA ANAYLSIS .................................................................................................... 51 
12.1 DESCRIPTIVE STATISTICS AND ANALYSIS ..................................................... 51 
12.2 SAMPLE SIZE AND POWER CALCULATIONS .................................................. 52 
12.3 DATA MONITORING AND QUALITY ASSURANCE ......................................... 52 
13.0 
ADVERSE EVENTS ................................................................................................. 53 
13.1 ADVERSE EVENT DEFINITIONS .......................................................................... 53 
13.2 ADVERSE EVENT REPORTING PERIOD ............................................................ 53 
13.3 SERIOUS ADVERSE EVENTS ............................................................................... 54 
13.4 SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS (SUSARS) .. 54 
13.5 SEVERITY ................................................................................................................ 55 
13.6 RELATIONSHIP ....................................................................................................... 55 
13.7 OUTCOME AND FOLLOW-UP .............................................................................. 57 
14.0 
STUDY DISCONTINUATION ................................................................................ 57 
14.1 CRITERIA FOR DISCONTINUATION ................................................................... 58 
15.0 
DATA AND RECORD KEEPING ........................................................................... 58 
15.1 DATA COLLECTION FORM .................................................................................. 58 
15.2 RECORD RETENTION ............................................................................................ 58 
16.0 
FINANCING AND INSURANCE ............................................................................ 59 
17.0 
DATA PUBLICATION ............................................................................................. 59 
18.0 
AMENDMENT I ....................................................................................................... 59 
19.0 
AMENDMENT II ...................................................................................................... 63 
20.0 
AMENDMENT III ..................................................................................................... 67 
21.0 
AMENDMENT IV .................................................................................................... 80 
22.0 
 AMENDMENT V………………………………………………………… …… ….82 
 
Figure 1: T.R.U.E. TEST Panel ............................................................................................ 25 
Figure 2: Visit Schedule .......................................................................................................... 33 
Figure 3: Qualification Questionnaire ..................................................................................... 35 
Figure 4: Type of Metal Exposure Questionnaire ................................................................... 36 
Figure 5: Tape vs Chip Irritation Illustration .......................................................................... 39 
Figure 6: Reaction Criteria ...................................................................................................... 41 
Figure 7: Illustration of Position Numbering .......................................................................... 45 
Figure 8: Application of Dilution Series Allergens ................................................................ 46 
Figure 9: Panel 6 Configuration and Cutting Instructions ...................................................... 47 
Figure 10: Reference Allergen Preparation ............................................................................. 50 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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4.0 
SUMMARY 
  
4.1  
Clinical Study 
Title 
Clinical Evaluation of Metal Panel Allergens: Aluminum, Copper, 
Manganese, Molybdenum, Tin, Titanium, Vanadium and Zinc Dose 
Response Study 
4.2  
Clinical Study 
Number 
SP 14 8MP 201 
4.3 
Investigators 
Karin Pacheco, MD 
Associate Professor, Preventive Medicine and Allergy/Immunology 
Department of Medicine, School of Medicine 
National Jewish Health, University of Colorado Denver 
1400 Jackson Street 
Denver, CO 80206 USA 
Tel: 303-398-1520 
Fax: 303 398 1452 
e-mail: pachecok@njhealth.org 
 
 
PD Dr. med. Kathrin Scherer Hofmeier 
FMH Dermatology/Venerology and Allergology/Clin. Immunology 
ad interim Head of Allergology 
University Hospital Basel Allergology Unit 
Department of Dermatology 
Petersgraben 4, CH-4031 Basel, Switzerland 
Tel.: +41 (0) 61 265 50 97 
Fax: +41 (0) 61 265 48 85 
e-mail: kathrin.scherer@usb.ch  
 
 
Prof. Paolo Pigatto, M.D. 
Associate Professor of Dermatology 
University of Milano- 
Dipartimento di Scienze Biomediche, Chirurgiche ed 
Odontostomatologiche 
Servizio di Dermatologia/ Servizio di dermatologia allergologica 
IRCCS Istituto Ortopedico Galeazzi 
Via R. Galeazzi 4 
20161 Milano, Italy 
Tel: +39 0266.214761 
e-mail: paolo.pigatto@unimi.it 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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Investigators 
(continued) 
Prof. dr. Thomas Rustemeyer 
Professor of Dermato-Allergology and Occupational Dermatology 
Department of Dermatology, 
VU University Medical Center 
De Boelelaan, 1117 
NL-1081 HV Amsterdam, Netherlands 
Tel: +31.20.444.0111 / 0145 
Fax: +31.20.444.0148 
e-mail: t.rustemeyer@vumc.nl 
 
 
Prof. Dr. med. Peter Thomas 
Institute of Dermatology and Allergy 
Ludwig-Maximilians-Universität München 
Frauenlobstraβe 9-11 
80337 Munich, Germany 
Tel:  +49 (0)89 4400-45178 
Fax: +49 (0)89 4400-56206 
e-mail: peter.thomas@med.uni-muenchen.de 
 
 
Maki Hosoki, DDS, PhD 
Senior Assistant Professor 
Department of Stomatognathic Function and Occlusal Reconstruction 
Institute of Biomedical Sciences 
Tokushima University Graduate School 
3-18-15 Kuramoto-cho 
770-8504 Tokushima, Japan 
Tel: 81-88-633-7350 
Fax: 81-88-633-7391 
e-mail: hosoki@tokushima-u.ac.jp 
 
 
Hiromi Kanto MD, PhD 
Department of Dermatology, School of Medicine 
Faculty of Medicine, Toho University 
Toho University Omori Medical Center 
6-11-1, Omori-Nishi, Ota-ku 
Tokyo 143-8541 Japan 
Tel : +81-3-3762-4151 
Fax: +81-3-3298-6066 
hiromi@med.toho-u.ac.jp 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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Sub-
Investigators 
Gianpaolo Guzzi, D.D.S. 
Italian Association for Metals and Biocompatibility Research 
Via A. Banfi, 4-20122 
Milan, Italy 
Tel : +39 02.782.561 
Fax : +39 02.919.758.53 
e-mail : gianpaolo_guzzi@fastwebnet.it 
 
 
Professor Yoshiaki Kubo 
Head of Dermatological Science  
Tokushima University Hospital 
2-50-1 Kuramoto-cho 
Tokushima City, Tokushima Japan 
7708503 
 
 
Dr. med. Oppel geb. Scharrer 
Institute of Dermatology and Allergy 
Ludwig-Maximilians-Universität München 
Frauenlobstraβe 9-11 
80337 Munich, Germany 
4.4  
Study Sites 
National Jewish Health, University of Colorado Denver 
1400 Jackson Street 
Denver, CO 80206 USA 
 
 
University Hospital Basel Allergology Unit 
Department of Dermatology 
Petersgraben 4, CH-4031 Basel, Switzerland 
 
 
University of Milano- 
Dipartimento di Scienze Biomediche, Chirurgiche ed 
Odontostomatologiche 
Servizio di Dermatologia/ Servizio di dermatologia allergologica 
IRCCS Istituto Ortopedico Galeazzi 
Via R. Galeazzi 4 
20161 Milano, Italy 
 
 
Department of Dermatology, VU University Medical Center 
De Boelelaan, 1117 
NL-1081 HV Amsterdam Netherlands 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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Study Sites 
(continued) 
Institute of Dermatology and Allergy 
Ludwig-Maximilians-Universität München 
Frauenlobstraβe 9-11 
80337 Munich, Germany 
 
 
Department of Stomatognathic Function and Occlusal Reconstruction 
Institute of Biomedical Sciences 
Tokushima University Graduate School 
3-18-15 Kuramoto-cho 
770-8504 Tokushima, Japan 
 
 
Department of Dermatology, School of Medicine 
Faculty of Medicine, Toho University 
Toho University Omori Medical Center 
6-11-1, Omori-Nishi, Ota-ku 
Tokyo 143-8541 Japan 
4.5  
IRB/Ethics 
Committees 
Institutional Review Board 
National Jewish Health 
1400 Jackson St. Room M211 
Denver Colorado,80206 
 
 
Prof. A.P. Perruchoud, Präsident EKNZ 
Ethikkommission Nordwest- und Zentralschweiz  
Hebelstrasse 53 
4056 Basel, Switzerland 
 
 
Comitato Etico 
Ospedale San Raffaele 
Via Olgettina, 60 
20132 Milano, Italy 
 
 
Medisch Ethische Toetsingscommissie VUmc 
Postbus 7057 
1007 MB Amsterdam, Netherlands 
 
 
Ethikkommission der Ludwig-Maximilians-Universität München 
Pettenkoferstr. 8a  
80336 München, Germany 
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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IRB/Ethics 
Committees 
(continued) 
Clinical Trial Center for Developmental Therapeutics 
Tokushima University Hospital 
2-50-1 Kuramoto-cho 
770-8503 Tokushima, Japan 
Tel:  +81-88-633-9294 
Fax: +81-88-633-9295 
 
 
Toho University Omori Medical Center Institutional Review Board 
Toho University Omori Medical Center 
6-11-1, Omori-Nishi, Ota-ku 
Tokyo 143-8541 Japan 
4.6 
Objective 
To determine the optimal test allergen dose of metal allergens proposed 
for inclusion in Metal Panel T.R.U.E. TEST. The study will compare 
the diagnostic performance (primary endpoint) and safety (secondary 
endpoint) of ascending patch test doses of aluminum, copper, 
magnesium, molybdenum, tin, titanium, vanadium and zinc allergens. 
 
 
To determine if subjects who have not had previous patch testing for 
contact metal allergy are allergic to any of the most common metal 
allergens; nickel, cobalt, chromium and gold. 
4.7 
Study Design 
This is a prospective, multi-center, randomized, double-blind design. 
That is, the allergen doses on each panel will be randomized into three 
different configurations, which will be randomly assigned to subjects as 
they enter the study.  Although the investigators and subjects will know 
which allergen is being tested, they will be blinded to the placement of 
the allergen doses within each panel.  A 48-hour application 
(approximate) of investigational allergen panel(s), excipient controls 
and corresponding reference petrolatum (or aqueous) allergen(s) will be 
applied to the skin of human subjects to test for potential positive 
allergic responses. Test sites will be evaluated at 3-4, 7-8, 10-14 and 19-
23 days after application.  
4.8 
Primary and 
Secondary 
Endpoints 
Primary Endpoint 
Determination of optimal test allergen dose as: 
 The lowest concentration of each dilution series allergen eliciting 
positive responses in a minimum of 15 subjects. Positive 
responses are defined as score of 1+, 2+ or 3+ during at least one 
reaction assessment visit. If a significant number of 3+ responses 
are elicited, the dose will be selected based on 1+ and 2+ 
responses. 
 For all sites with the exception of Germany: Concordance will be 
measured using Cohen’s kappa where less than 0% indicates no 
agreement, 0-20% indicates poor agreement, 20-40% indicates fair 
agreement, 40-60% indicates moderate agreement, 60-80% indicates 
good agreement and 80% or higher indicates very good agreement. 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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Concordance will be measured using all subjects who are tested with 
each allergen and corresponding reference allergen. 
Secondary Endpoint 
Determination of allergen safety: 
 Frequency of tape and polyester chip induced irritation or allergic 
reactions at Visits 2 through 6. 
 Frequency of subject reported sensations of itching and/or burning 
for each allergen panel at patch removal.  
 Frequency of positive (1+, 2+, 3+) skin reactions for each 
investigational and reference allergen dose at each post removal visit 
and overall. 
 Frequency of negative, doubtful, irritant, late and persistent skin 
responses for each investigational and reference allergen dose at 
each post removal visit (late and persistent reactions at visits 4, 5 
and 6 only). 
 Frequency of all adverse events. Documentation for all local and 
systemic adverse reactions classified by the investigator as possibly 
or definitely related to the study product (e.g., erythema, hyper-
pigmentation, hypo-pigmentation, skin thinning or dermatitis flare) 
will include grade (mild, moderate or severe) and time point (clinic 
visit). 
 
Positive results from the common allergen testing will be tabulated in 
the final report only. No additional analysis will be performed using this 
data. Comparative data analyses of reactions to these allergens are 
beyond the scope of this study.  
4.9  
Subjects 
The study population will consist of subjects with past positive patch 
test result to at least one of the dilution series metals being tested on this 
study or strong suspicion of metal contact allergy.  
 
A minimum of 15 subjects per dilution series allergen, who exhibit a 
positive skin response (score of 1+, +2 or 3+ during at least one reaction 
assessment visit) to the dilution series allergen and/or at least one of its 
corresponding reference allergens, is needed to complete the study.  
 
Subjects with a past positive patch test response to at least one of the 
dilution series allergens will be tested with the allergen panel and 
corresponding reference allergen(s) to which they have had the previous 
response. Subjects with suspicion of metal contact allergy will be tested 
with all dilution series and reference allergens. All subjects will be 
tested with the excipient controls.  The common allergens will be tested 
at the discretion of the investigator.  
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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The study population should include a reasonable representation of 
patients who have undergone a metal replacement procedure. 
4.10 
Justification of 
Sample Size 
Past dose response study populations have included 20 adult subjects 
(per allergen) with a historical positive patch test to the corresponding 
reference allergen. In these studies, determination of the optimal test 
allergen dose was the lowest concentration eliciting a 1+, 2+ or 3+ 
positive reaction in 70-90% of subjects with the fewest number of 3+ 
reactions; therefore a minimum of 14 subjects with positive reactions 
was needed to determine optimal test allergen dose. 
 
Due to the fact that not all of the metals being tested on this study have a 
large database of patients with past patch-test positive reactions, the 
inclusion criteria was modified to include subjects with a suspicion of 
metal allergy, in addition to those with a historical positive patch test. 
Because it is anticipated that not all subjects will test positive, the study 
will conclude when a total of 400 subjects have been tested whether or 
not the 15 positive response subjects per allergen quota is met. 
 
The option of further testing may be considered for any allergen that 
elicits a minimum of 8 positive responses. In such a case, the protocol 
will be amended 
4.11 
Investigational 
Allergen 
Panels 
Aluminum Dilution Series 
 
0.040 mg/cm² aluminum chloride hexahydrate 
0.12 mg/cm² aluminum chloride hexahydrate 
0.36 mg/cm² aluminum chloride hexahydrate 
0.72 mg/cm² aluminum chloride hexahydrate 
 
0.047 mg/cm² aluminum lactate 
0.14 mg/cm² aluminum lactate 
0.42 mg/cm² aluminum lactate 
0.84 mg/cm² aluminum lactate 
 
 
Copper Dilution Series 
 
 
0.013 mg/cm² copper sulfate anhydrous 
0.040 mg/cm² copper sulfate anhydrous 
0.080 mg/cm² copper sulfate anhydrous 
0.12 mg/cm² copper sulfate anhydrous 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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Investigational 
Allergen 
Panels 
(continued) 
Manganese Dilution Series 
 
 
0.013 mg/cm² manganese chloride tetrahydrate 
0.040 mg/cm² manganese chloride tetrahydrate 
0.080 mg/cm² manganese chloride tetrahydrate 
0.24 mg/cm² manganese chloride tetrahydrate 
 
 
Molybdenum Dilution Series 
 
0.0067 mg/cm² ammonium molybdate 
0.020 mg/cm² ammonium molybdate 
0.040 mg/cm² ammonium molybdate 
0.12 mg/cm² ammonium molybdate 
 
 
Tin Dilution Series  
 
 
0.018 mg/cm² tin chloride dihydrate 
0.037 mg/cm² tin chloride dihydrate 
0.11 mg/cm² tin chloride dihydrate 
0.33 mg/cm² tin chloride dihydrate 
 
 
Titanium Dilution Series 
 
 
Titanium Citrate 
Ammonium titanium peroxo citrate (0.055 mg Ti/cm²) 
Ammonium titanium peroxo citrate (0.11 mg Ti/cm²)  
Ammonium titanium peroxo citrate (0.22 mg Ti/cm²) 
 
Titanium Lactate 
Ammonium titanium lactate (0.070 mg Ti/cm²) 
Ammonium titanium lactate (0.14 mg Ti/cm²) 
Ammonium titanium lactate (0.28 mg Ti/cm²) 
 
Titanium Oxide Oxalate 
Potassium titanium oxide oxalate (0.060 mg Ti/cm²) 
Potassium titanium oxide oxalate (0.12 mg Ti/cm²) 
Potassium titanium oxide oxalate (0.24 mg Ti/cm²) 
Ammonium titanium oxide oxalate (0.055 mg Ti/cm²) 
Ammonium titanium oxide oxalate (0.11 mg Ti/cm²) 
Ammonium titanium oxide oxalate (0.22 mg Ti/cm²) 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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Investigational 
Allergen 
Panels 
(continued) 
Vanadium Dilution Series 
 
 
Vanadium chloride (0.0042 mg V/cm²)  
Vanadium chloride (0.0083 mg V/cm²)  
Vanadium chloride (0.025 mg V/cm²)  
Vanadium chloride (0.050 mg V/cm²)  
 
Vanadium oxide sulfate (0.0042 mg V/cm²)  
Vanadium oxide sulfate (0.0083 mg V/cm²)  
Vanadium oxide sulfate (0.025 mg V/cm²)  
Vanadium oxide sulfate (0.050 mg V/cm²) 
 
 
Zinc Dilution Series 
 
0.013 mg/cm² zinc chloride 
0.040 mg/cm² zinc chloride  
0.080 mg/cm² zinc chloride 
0.24 mg/cm² zinc chloride 
 
 
The dose per unit area of experimental T.R.U.E. Test allergens is 
calculated based on the molecular weight of the compound. Exceptions 
are Titanium and Vanadium allergens as molecular weights are not 
known for all of these, hence the dose per unit area for Titanium and 
Vanadium allergens is based only on the metal part of the compound. 
 
 
Common Allergens/ Excipient Controls 
 
0.2 mg/cm2 nickel sulfate  
0.054 mg/cm2 potassium dichromate  
0.02 mg/cm2 cobalt dichloride  
0.075 mg/cm2 gold sodium thiosulfate (GST)  
Blank patch 
Polyvinylpyrrolidone (PVP) 
Hydroxypropyl cellulose (HPC) 
4.12 
Reference 
Allergens 
 
 The Aluminum Dilution Series will be tested concurrently with 
o Aluminum chloride hexahydrate, 10 % w/w in petrolatum 
o Aluminum lactate, 12 % w/w in petrolatum 
 The Copper Dilution Series will be tested concurrently with copper 
sulfate anhydrous, 2 % w/w in petrolatum 
 The Manganese Dilution Series will be tested concurrently with 
manganese chloride tetrahydrate, 2 % w/w in petrolatum 
 The Molybdenum Dilution Series will be tested concurrently with 
ammonium molybdate, 1% aqueous solution. 
 The Tin Dilution Series will be tested concurrently with tin chloride 
dihydrate, 1% w/w in petrolatum 
 The Titanium Dilution Series will be tested concurrently with 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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o Ammonium titanium peroxo citrate, 17% w/w in petrolatum 
o Ammonium titanium lactate, 34% aqueous solution  
o Potassium titanium oxide oxalate, 22% w/w in petrolatum  
o Ammonium Titanium oxide oxalate 19% w/w in petrolatum 
 The Vanadium Dilution Series will be tested concurrently with 
o Vanadium chloride, 1% w/w in petrolatum  
o Vanadium oxide sulfate, 1.5% w/w in petrolatum 
 The Zinc Dilution Series will be tested concurrently with zinc 
chloride, 2% w/w in petrolatum 
NOTES: 1) The common allergens (Panel 6) will not be tested against 
reference allergens. 2) Subjects enrolled in Germany will not be tested 
with the reference allergens 
The Finn Chamber, polypropylene-coated, supplied by SmartPractice, 
will be used to apply the reference allergens. Reference allergens will 
be dispensed at the rate of 20 μl/chamber using a precision allergen 
dispenser. 
4.13 
Study Outline 
After the subject has consented and all inclusion/exclusion criteria are 
met the subject may be eligible for enrollment.  If enrolled, the 
following timeline will be followed: 
 
Clinic Visit 1 
Day 0 
A. 
Investigational allergen panel(s) and the appropriate reference 
allergen(s) will be applied to the skin on the subject’s back. Patch 
tests are to be worn for approximately 48 hours. 
 
Clinic Visit 2 
Day 2 
B. 
Adhesion of the investigational allergen panel(s) and the reference 
allergen(s) will be evaluated.  Tape and polyester chip induced site 
irritation will be scored. Subject reported itching and burning 
sensations will be captured. Adverse events will be documented. 
 
Clinic Visit 3 
Day 3-4 
C. 
Tape and polyester chip induced site irritation will be scored. Skin 
reactions will be evaluated. Adverse events will be documented. 
De-identified photographs of site reactions may be taken at the 
discretion of the Investigator and will not be reviewed or collected 
by the study sponsor. 
 
Clinic Visit 4 
Day 7-8 
 
D. 
 
Unresolved tape and or polyester chip induced irritation will be 
scored. Skin reactions will be evaluated. Late or persistent 
reactions and adverse events will be documented. De-identified 
photographs of site reactions may be taken at the discretion of the 
Investigator and will not be reviewed or collected by the study 
sponsor. 
 
Clinic Visit 5 
Day 10-14 
E. 
Unresolved tape and or polyester chip induced irritation will be 
scored. Skin reactions will be evaluated. Late or persistent 
reactions and adverse events will be documented. De-identified 
photographs of site reactions may be taken at the discretion of the 
Investigator and will not be reviewed or collected by the study 
sponsor. 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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Clinic Visit 6 
Day 19-23 
F. 
Follow up visit to record unresolved tape or polyester chip induced 
irritation, late or persistent reactions and documentation of adverse 
events. Photographs of site reactions may be taken at the discretion 
of the Investigator. Investigator may elect to perform this 
evaluation via telephone if no reactions are present. 
4.14 
 
Monitored 
Parameters 
 
Visit 1 (Day 0) 
 Informed Consent 
 Documentation of inclusion/exclusion criteria 
 Completion of Qualification and Type of Metal Exposure 
Questionnaires 
 Subject demographics (date of birth, gender and ethnicity) 
 Concomitant medication use and medical history 
 Urine pregnancy test (if needed) 
 Physical examination to record current sites of dermatitis 
 Application of the investigational allergen panel(s) and reference 
allergen(s) to the paraspinal region of the upper back. NOTE:  Upper 
arms may be used if there is not adequate space on the back for all 
panels. 
Visit 2 (Day 2) 
 Documentation of adhesion of investigational allergen panel(s) and 
reference allergen(s) to confirm adequate allergen-to-skin contact 
 Removal of investigational allergen panel(s) and reference allergen 
chamber(s) 
 At least 15-minute wait between patch removal and irritation 
evaluation. 
 Evaluation of tape and polyester chip induced irritation. 
 Documentation of subject self-report of itching and burning 
sensations at test panel sites 
 Documentation of subject-reported adverse events, worsening of a 
pre-existing condition/disease/symptom or changes to concomitant 
medications. 
  Visit 3 (Day 3-4) 
 Evaluation of tape and polyester chip induced irritation. 
 Evaluation of patch site skin reactions 
 Documentation of subject-reported adverse events, worsening of a 
pre-existing condition/disease/symptom or changes to concomitant 
medications. 
 Photographs of site reactions (taken at the discretion of the 
Investigator). 
Visit 4 (Day 7-8) 
 Evaluation of unresolved tape and or polyester chip induced 
irritation.  

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Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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 Evaluation of patch site skin reactions 
 Categorization of positive reactions as late or persistent 
 Documentation of subject-reported adverse events, worsening of a 
pre-existing condition/disease/symptom or changes to concomitant 
medications. 
 Photographs of site reactions (taken at the discretion of the 
Investigator). 
Visit 5 (Day 10-14) 
 Evaluation of unresolved tape and or polyester chip induced 
irritation. 
 Evaluation of patch site skin reactions 
 Categorization of positive reactions as late or persistent;  
 Documentation of subject-reported adverse events, worsening of a 
pre-existing condition/disease/symptom or changes to concomitant 
medications. 
 Photographs of site reactions (taken at the discretion of the 
Investigator). 
Visit 6 (Day 19-23) 
 The investigative site will phone the subject to determine if there are 
any unresolved reactions from the tape, or at the individual test sites. 
If the subject reports no remaining reactions the Investigator may 
choose at this point to complete the visit over the telephone. 
 If the visit is conducted over the telephone all visit related 
paperwork including adverse events and/or changes to concomitant 
medications will be recorded. 
 Should the Investigator elect to see the subject in the office, the 
following procedures will be performed: 
 Evaluation of unresolved tape and or polyester chip induced 
irritation. 
 Evaluation of patch site skin reactions. 
 Categorization of positive reactions as late or persistent. If a 
persistent, escalating reaction is noted at Visit 6, the investigator 
will determine if follow up action is warranted. 
 Subject-reported adverse events, worsening of a pre-existing 
condition/disease/symptom or changes to concomitant medications 
will be recorded. 
 Photographs of site reactions (taken at the discretion of the 
Investigator). 
 Following Visit 6 the Investigator will categorize the skin reactions 
at each site as either negative or positive.  
4.15  Data Analysis 
The frequency of skin responses; positive (1+, 2+, 3+), negative, 
doubtful and irritant, will be calculated for each dilution series 
investigational allergen dose and reference allergen. The optimal 

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Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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allergen dose will be based on the following criteria: 
 The lowest concentration of each dilution series allergen eliciting 
positive responses in a minimum of 15 subjects. Positive 
responses are defined as score of 1+, 2+ or 3+ during at least one 
reaction assessment visit. If a significant number of 3+ responses 
are elicited, the dose will be selected based on 1+ and 2+ 
responses. 
 For all sites with the exception of Germany: Concordance will be 
measured using Cohen’s kappa where less than 0% indicates no 
agreement, 0-20% indicates poor agreement, 20-40% indicates fair 
agreement, 40-60% indicates moderate agreement, 60-80% indicates 
good agreement and 80% or higher indicates very good agreement. 
Concordance will be measured using all subjects who are tested with 
each allergen and corresponding reference allergen. 
Safety evaluations will be tabulated as follows: 
 Frequency of tape and polyester chip induced irritation or allergic 
reactions at Visits 2 through 6 for the T.R.U.E. Test tape and 
polyester chips (Panels 1-6) and Finn Chamber tape (Reference 
allergen panels). 
 Frequency of subject reported sensations of itching and/or burning 
for each allergen panel at patch removal.  
 Frequency of positive (1+, 2+, 3+) skin reactions for each 
investigational and reference allergen dose at each post removal visit 
and overall. 
 Frequency of negative, doubtful, irritant, late and persistent skin 
reactions for each investigational and reference allergen dose at each 
post removal visit (late and persistent reactions at visits 4, 5 and 6 
only). 
 Frequency of all adverse events. Documentation for all local and 
systemic adverse reactions classified by the investigator as possibly 
or definitely related to the study product (e.g., erythema, hyper-
pigmentation, hypo-pigmentation, skin thinning or dermatitis flare) 
will include grade (mild, moderate or severe) and time point (clinic 
visit). 
 
Statistical processing will be performed using SAS® software.  
4.16 
Study 
Duration 
The proposed study is intended to begin in 2016, no later than 6 months 
after approval of the final protocol by the IRB or Ethics Committee. 
Given the rarity of sensitization to these metals, the study may be 
concluded at an individual site if the Investigator believes that the 
patient data base has been exhausted. When this maximum number of 
subjects has been reached the sponsor of the study will inform the 
investigator that the study has been concluded at that site. 
 

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Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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The duration of participation for each enrolled subject will be 
approximately three weeks. 
 
The final report will be submitted to the Principal Investigator within 
120 days of data base lock and to the FDA, European Commission and 
PMDA within 1 year of study completion. 

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Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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5.0 
FREQUENTLY USED ABBREVIATIONS AND ACRONYMS 
 
ACD 
Allergic Contact Dermatitis 
AE 
Adverse Event 
BLA 
Biologics License Application 
CRF 
Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HPC 
Hydroxypropyl cellulose  
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human use 
ICDRG 
International Contact Dermatitis Research Group 
IEC 
International Ethics Committee 
IR 
Irritant Reaction 
IRB 
Institutional Review Board 
MPA 
PVP 
Medical Products Agency 
Polyvinylpyrrolidone, povidone, polyvidone (PVP) 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
T.R.U.E. Test 
Thin-Layer Rapid Use Epicutaneous Test 
UV 
Ultraviolet 
  
6.0 
BACKGROUND AND RATIONALE 
 
6.1 
Metal Allergy 
 
As a group, metals are the most common contact allergens. Contact allergy to metals such as 
nickel, cobalt, and chromium is prevalent in the general population.  It is estimated that up to 
17% of women and 3% of men are nickel allergic, and that about 1 to 2% are allergic to cobalt, 
chromium, or both. Metal-induced allergic contact dermatitis (ACD) is expressed in a wide range 
of cutaneous reactions following prolonged or repeated exposure to personal products such as 
cosmetics, tattoos, detergents, jewelry, piercing studs, leather goods, cell phones, clothing 
buttons, snaps, zippers, partial dentures, dental braces and restorations. Occupational exposure in 
the metal and construction industries is also a significant risk factor for metal allergy reports. 
Apart from the well-known significance of nickel, cobalt, chromium and gold in developing 
ACD, other metals such as aluminum, beryllium, copper, iridium, indium, mercury, palladium, 
platinum, rhodium, molybdenum, manganese, zinc, cadmium and titanium have been reported as 
increasing causes of skin hypersensitivity.  
 
6.2 
Aluminum 
 
The use of aluminum exceeds that of all other metals, except iron, and is used in all segments of 
the world’s economy.  It weighs about one-third as much as steel or copper; is malleable, ductile, 

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Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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and easily machined and cast; and has excellent corrosion resistance and durability.  Some of the 
many uses for aluminum are in transportation (automobiles, airplanes, trucks, railcars, marine 
vessels, etc.), packaging (cans, foil, etc.), construction (windows, doors, siding, etc.), consumer 
durables (appliances, cooking utensils, etc.), electrical transmission lines and machinery. 
 
Aluminum compounds have a wide range of uses in industrial, domestic, consumer and 
medicinal products.  The following summarizes several uses (3): 
 
 Aluminum alkoxides- varnish, cosmetics and pharmaceuticals 
 Aluminum borate- glass and ceramics 
 Aluminum carbonate- antacids 
 Aluminum chloride- (anhydrous) rubber, lubricants and antiperspirants 
 Aluminum chloride- (hexahydrate) deodorants, antiperspirants, cosmetics and astringents 
 Aluminum hydroxide- stomach antacids, antiperspirants, dentifrices and cosmetics  
 Aluminum isopropoxide- soap and paint 
 Aluminum nitrate- antiperspirants 
 Aluminum phosphate- stomach antacids 
 Aluminum silicate- dental cement, antacids and food additives 
 
Typical causes of sensitization to aluminum are injections and vaccines.  Aluminum compounds 
have been widely used as adjuvants in prophylactic and therapeutic vaccines as they prolong the 
period of absorption and increase the immune response.   The two main clinical features of 
aluminum sensitization are persistent granulomas and recurrent eczema.  Aluminum allergies 
seem to be more common in pediatric patients than adults.  Children with aluminum sensitivity 
have been reported to develop subcutaneous nodules at the sites of injection or excoriated 
papules at the sites of hyposensitization therapy. 
 
Prolonged use of antiperspirant and topical medications containing aluminum may also cause 
sensitization to aluminum.  Clinical manifestations of aluminum sensitization are axillary rashes 
and hand dermatitis.    
 
Pruritus due to allergic conditions has been seen after use of toothpaste containing 30-40% of 
aluminum oxide.  
 
Researchers have proposed that tattoo pigments containing aluminum can induce granulomatous 
reactions.  In 87% of tattoo ink studies, the most commonly identified element was aluminum.  
 
6.3 
Copper 
 
Copper is a ductile metal with very high thermal and electrical conductivity. It is used as a 
conductor of heat and electricity, a building material, and a constituent of various metal alloys.  

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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The major applications of copper are in electrical wires (60%), roofing and plumbing (20%) and 
industrial machinery (15%). Copper is mostly used as a pure metal, but when a higher hardness is 
required it is combined with other elements to make an alloy (5% of total use) such 
as brass and bronze.  
 
Numerous copper alloys exist, many with important uses. Brass is an alloy of copper 
and zinc. Bronze usually refers to copper-tin alloys, but can refer to any alloy of copper such 
as aluminum bronze. Copper is one of the most important constituents of carat silver and gold 
alloys and carat solders used in the jewelry industry and the alloy of copper and nickel, is used in 
low-denomination coins. Copper is used in dental alloys and in intrauterine devices. Copper is 
also used in wood preservatives, antimicrobial textile treatments, ceramic glazes, stained glass, 
musical instruments and electroplating. Copper is also found naturally in foods but may also be 
introduced during preparation. 
 
6.4 
Manganese 
 
Manganese is a chemical element found as a free element in nature (often in combination with 
iron), and in many minerals. Manganese is a metal with important industrial metal alloy uses, 
particularly in stainless steels. It is used as a treatment for rust and corrosion prevention on steel 
and as industrial pigments. Manganese dioxide is used as the cathode (electron acceptor) material 
in zinc-carbon and alkaline batteries. The second large application for manganese is as alloying 
agent for aluminum. Corrosion-resistant aluminum/manganese alloys are used for most beverage 
cans. Manganese compounds have been used as pigments and for the coloring of ceramics, glass 
and some paints and as a reagent in organic chemistry. Manganese chloride is used in oral agents 
for an MRI of the abdomen and/or pelvis. Manganese oxide is used in plant food.  
 
6.5 
Molybdenum 
 
Molybdenum, a chemical element, occurs in various oxidation states in minerals. The majority of 
molybdenum produced is used in metallurgical applications such as structural steel, stainless 
steel, tool & high-speed steels, cast iron, molybdenum elemental metal, and super alloys, with the 
remaining portion used as compounds in chemical applications. The ability of molybdenum to 
withstand extreme temperatures without significantly expanding or softening makes it useful in 
applications that involve intense heat, including the manufacture of armor, aircraft parts, 
electrical contacts, pigments, catalysts, industrial motors, and filaments. Molybdenum is also 
used as a fertilizer for some plants, as a solid lubricant, a high-pressure high-temperature anti-
wear agent, an adhesive between enamels and metals, a coloring agent in ceramics and plastics as 
well as in biological staining procedures. 
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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6.6 
Tin 
 
Tin is a silvery, malleable poor metal used to coat other metals to prevent corrosion. Tin is used 
in many alloys, most notably tin/lead soft solders, tin plating, tin chemicals, brass and bronze, 
solder and niche uses. 
Tin is most commonly alloyed with copper and may be found in some coins. Tin is also found in 
some dental amalgams and fluoride treatments. 
 
6.7 
Titanium 
 
Titanium (IV) oxide is used as pigment to color paints, sunscreens, cosmetics, skin care products, 
plastics, papers, inks, medicines, toothpastes, and foods such as milk. It is also a thickener found 
in tattoo pigment and styptic pencils. It has UV resistant properties and is therefore used to act as 
a UV absorber.  
  
6.8 
Vanadium 
  
Vanadium is a hard, silvery gray, ductile and malleable transition metal used in applications for 
bicycle frames, cranks, axles, and gears. It is also found in orthopedic and dental implants, glass 
coatings and jewelry. It is mainly used to produce specialty steel alloys such as high speed tool 
steels. The most important industrial vanadium compound, vanadium pentoxide, is used as a 
catalyst for the production of sulfuric acid. Various vanadium oxides are also used in making 
ceramics, glass coatings and jewelry. 
 
6.9 
Zinc 
 
Zinc is a metallic chemical element used to in the manufacture of cement, paper and textile 
processing it is an accelerator in the production of rubber. It is found as a pigment in paint and as 
a primer for galvanized iron and other metal substrates.  Other applications include batteries, 
small non-structural castings, and alloys, such as brass (copper and zinc). A variety of zinc 
compounds are commonly used, such as zinc carbonate and zinc gluconate (as dietary 
supplements), zinc chloride (in deodorants), zinc pyrithione (antibacterial agent, anti-
dandruff shampoos), zinc sulfide (in luminescent paints), and zinc methyl or zinc diethyl in the 
organic laboratory. 
 
6.10 
Patch Testing with Metals 
 
A broad array of metals is available for patch testing today.  These allergens are manufactured in 
a petrolatum, aqueous or alcohol based excipient and sold in syringes throughout the world 
although none have been submitted to the FDA or to the MPA in conformance with the Biologics 
License Application (BLA) or Medicinal Product Application procedures.   
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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6.11 
T.R.U.E. TEST® 
 
T.R.U.E. TEST, (Thin-layer Rapid Use Epicutaneous Patch Test) was originally granted a 
Biologics License for 23 allergens and a blank patch (control) in 1994 (BL No. 1623).  The 
allergens were selected from substances widely reported to induce Allergic Contact Dermatitis 
(ACD).  As new allergens become clinically relevant in the U.S. population, there is an ever-
growing need to expand the number of allergens included in T.R.U.E. TEST.  The next 5 
allergens were added to a third panel of the T.R.U.E. TEST product in 2007 (BL103738/5019 
and BL 103738/5027).  An additional seven allergens were added in 2012. The current U.S. 
available T.R.U.E. TEST  product includes three panels of 36 allergen polyester patches 
including a blank patch (control).  Each 0.81 cm2 allergen patch is coated with one specific 
allergen or allergen mix.  The allergens/allergen mixes are incorporated in exact dosage in a 
hydrophilic gel. The allergen-gel preparation is coated on an impermeable backing of polyester 
and dried to a thin film.  The coated sheet is then cut into 9 mm x 9 mm squares (test patches), 
which are mounted on tape forming a standard test panel.  The 3 panels together form a standard 
test kit.  All 3 panels are typically applied to the skin of the upper back.  The humidity of the skin 
hydrates the film and transforms to a gel, allowing the allergen to migrate into the skin, thereby 
reaching the cells of the immune system.  The test is removed after 48 hours and read at 72-96 
hours after the application, when the allergic responses are fully developed and mild irritant 
reactions have faded.  Additional readings at 1 week and 21 days after panel placement are also 
advised in some cases. 
 
Figure 1: T.R.U.E. TEST Panel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoallergenic adhesive Surgical 
Tape secures panels to skin. 
Laminated Protective 
Foil protects panels from 
damage during storage 
and handling. 
Melinex (polyester chip) is impermeable 
but flexible, assuring optimal skin 
Allergens are incorporated 
into a thin film 
hydrophilic gel, which is 
hydrated by normal skin 
moisture  

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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6.12 
Metal Panel T.R.U.E. TEST 
 
Today the T.R.U.E. TEST contains the only patch test allergens that have been submitted to the 
FDA and approved for sale in the United States. As such, these allergens require extensive 
developmental and clinical trial work prior to submission for approval. The clinical trials require 
subjects with suspicion of contact allergy (possibly to metals) or local inflammation potentially 
associated with a metal implant to determine both the appropriate dose for the allergen as well as 
the safety & efficacy of the proposed product.  
 
Because metal contact allergy is increasing there is a need to develop a series of standardized 
metal patch test allergens utilizing the same allergen delivery technology as used in the T.R.U.E. 
TEST product.  Metal Panel T.R.U.E. TEST will be indicated for patients exposed to cardiac 
implants (stent, pacemaker, etc.), orthopedic implants (knee, hip or other), gynecological 
implants or devices, surgical hardware (plates, screws, wires, pins, rods, expanders, staples), 
dental metal implants, or dental metal appliances, prosthesis or fillings whose exposure to has 
resulted in: 
 Inflammation associated with an oral metal implant: 
o Burning mouth syndrome 
o Oral lichen planus 
o Oral lichenoid lesion 
o Palmo plantar pustulosis 
o Stomatitis: gingivitis, cheilitis and/or glossitis 
 Itching, papules or nodules at injection site of aluminum containing vaccination 
 Dermatitis over site of metal implant 
 Systemic contact dermatitis 
 Accelerated restenosis of cardiac stent 
 Aseptic loosening 
 Persistent joint pain 
 
Other symptoms may also be associated: 
 Persistent and recalcitrant dermatitis 
 Dorsal or patchy hand dermatitis 
 Leg and foot dermatitis 
 Facial dermatitis (excluding seborrheic) 
 Discoid dermatitis 
 Dermatitis with unusual distribution 
 Atypical allergic symptoms 
 
In addition to the 8 metals on this study, is anticipated that Metal Panel T.R.U.E. Test will 
include metals currently available on T.R.U.E. TEST and additional metals being investigated 
in a separate protocol. 
 
 Nickel sulfate (currently on T.R.U.E. TEST) 

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Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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 Potassium dichromate (currently on T.R.U.E. TEST) 
 Cobalt dichloride (currently on T.R.U.E. TEST) 
 Gold sodium thiosulfate (currently on T.R.U.E. TEST) 
 Ammoniated Mercury (investigated in separate protocol) 
 Sodium tetrachloropalladate (investigated in separate protocol) 
 
The four common allergens (nickel, chromate, cobalt and gold) have been added to this protocol 
for diagnostic purposes only. Subjects with a strong suspicion of metal contact allergy should be 
tested with the most common metal allergens in addition to the 8 experimental (dilution series) 
metal allergens in order to give them a complete diagnosis. The common allergens will be tested 
as approved for T.R.U.E. Test but are considered experimental for this study due to 
reconfiguration of allergen placement on the test panel. Positive results from the common 
allergen testing will be tabulated in the final report only. No additional analysis will be 
performed using this data. 
 
7.0 
OBJECTIVE 
 
To evaluate the diagnostic performance and safety of metal allergens proposed for inclusion in 
Metal Panel T.R.U.E. Test. The study will compare the diagnostic performance (primary) and 
safety (secondary) of ascending patch test doses of aluminum, copper, manganese, molybdenum, 
tin, titanium, vanadium and zinc allergens. 
 
To determine if subjects who have not had previous patch testing are allergic to any of the most 
common metal allergens; nickel, cobalt chromium and gold. 
 
7.1 
Primary Endpoint  
 
Determination of optimal test allergen dose as: 
 The lowest concentration of each dilution series allergen eliciting positive responses in a 
minimum of 15 subjects. Positive responses are defined as score of 1+, 2+ or 3+ during 
at least one reaction assessment visit. If a significant number of 3+ responses are 
elicited, the dose will be selected based on 1+ and 2+ responses. 
 For all sites with the exception of Germany: Concordance will be measured using Cohen’s 
kappa where less than 0% indicates no agreement, 0-20% indicates poor agreement, 20-40% 
indicates fair agreement, 40-60% indicates moderate agreement, 60-80% indicates good 
agreement and 80% or higher indicates very good agreement. Concordance will be measured 
using all subjects who are tested with each allergen and corresponding reference allergen. 
 
7.2 
Secondary Endpoint 
 
Determination of allergen safety 
 Frequency of tape and polyester chip induced irritation or allergic reactions at Visits 2 
through 6. 

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Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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 Frequency of subject reported sensations of itching and/or burning for each allergen panel 
at patch removal.  
 Frequency of positive (1+, 2+, 3+) skin reactions for each investigational and reference 
allergen dose at each post removal visit and overall. 
 Frequency of negative, doubtful, irritant, late and persistent skin reactions for each 
investigational and reference allergen dose at each post removal visit (late and persistent 
reactions at visits 4, 5 and 6 only). 
 Frequency of all adverse events. Documentation for all local and systemic adverse 
reactions classified by the investigator as possibly or definitely related to the study 
product (e.g., erythema, hyper-pigmentation, hypo-pigmentation, skin thinning or 
dermatitis flare) will include grade (mild, moderate or severe) and time point (clinic 
visit). 
 
8.0 
STUDY DESIGN 
 
8.1 
Overview 
 
This is a prospective, multi-center, randomized, double-blind design.  That is, the allergen doses 
on each panel will be randomized into three different configurations, which will be randomly 
assigned to subjects as they enter the study.  Although the investigators and subjects will know 
which allergen is being tested, they will be blinded to the placement of the allergen doses within 
each panel.  A 48-hour application (approximate) of investigational allergen panel(s), an 
excipient control and corresponding reference petrolatum (or aqueous) allergen(s) will be applied 
to the skin of human subjects to test for potential positive allergic responses. Test sites will be 
evaluated at 3-4, 7-8, 10-14 and 19-23 days after application. The chosen evaluation times are 
consistent with generally accepted international patch test guidelines and are designed to prevent 
missed late reactions and false negatives. The final clinic visit (day 21) allows the investigator to 
evaluate any late or persistent localized reactions. The investigator may choose to perform this 
visit via telephone if there are no residual reactions. If there are persistent escalating reactions 
noted at Visit 6, the investigator will determine and record follow up action. 
 
8.2 
Study Conduct 
 
The study will be performed in accordance with the Helsinki Declaration (2013), the GCP-
guidelines and regulatory requirements including Human Subjects and Privacy protection. Study 
subjects may be modestly compensated for their participation. 
 
8.3 
 Independent IRB/ Ethics Committee Review 
 
The study protocol, any amendments and the informed consent will receive favorable approvals 
from all regulatory authorities (US-FDA, Switzerland-Health Authority Swissmedic, Italy-Italian 
Medicines Agency, Netherlands-Medicines Evaluation Board, Germany-Paul Ehrlich Institut, 
Japan- PMDA) and from independent IRB/Ethics committees for each study site prior to study 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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initiation or prior to implementation of protocol changes. This study will not proceed without 
receipt of all written approvals.  
 
8.4 
Subject Information and Consent 
 
Consent, including photograph consent, will be obtained prior to participation in any study 
conduct.  Subjects will be given ample opportunity to read the consent form and have all 
questions regarding the study objective, procedures, possible risks, and the right to withdraw 
answered prior to signing and dating the consent form.  Each subject will be provided with a 
signed and dated copy of the informed consent form to retain for his or her records.  
 
8.5 
Data Collection  
 
Data will be collected using a data collection form, which will capture documented compliance 
with inclusion/exclusion criteria, medical history, current medication use, current dermatitis, 
panel adhesion, tape irritation, subject-reported itching and burning at patch sites, evaluation of 
skin patch site reactions and any changes to the subject’s medical condition or medications used 
during the course of the study. 
 
8.6 
Study Duration  
 
The proposed study is intended to begin in 2016, no later than 6 months after approval of the 
final protocol by the IRB or Ethics Committee. Given the rarity of sensitization to these metals, 
the study may be concluded at an individual site if the Investigator believes that the patient data 
base has been exhausted. When this maximum number of subjects has been reached the sponsor 
of the study will inform the investigator that the study has been concluded at that site. 
 
The duration of participation for each enrolled subject will be approximately three weeks. 
 
The final report will be submitted to the Principal Investigator within 120 days of data base lock 
and to the FDA, European Commission and PMDA within 1 year of study completion. 
 
9.0 
SUBJECTS 
 
The study population will consist of subjects with past positive patch test result to at least one of 
the dilution series metals being tested on this study or strong suspicion of metal contact allergy.  
 
A minimum of 15 subjects per dilution series allergen, who exhibit a positive skin response 
(score of 1+, +2 or 3+ during at least one reaction assessment visit) to the dilution series allergen 
and/or at least one of its corresponding reference allergens, is needed to complete the study.  
 
Subjects with a past positive patch test response to at least one of the dilution series allergens 
will be tested with the allergen panel and corresponding reference allergen(s) (with the exception 
of subjects enrolled in Germany who will not be tested with the reference allergens) to which 
they have had the previous response. Subjects with suspicion of metal contact allergy will be 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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tested with all dilution series and reference allergens. All subjects will be tested with the 
excipient controls.  The common allergens will be tested at the discretion of the investigator.   
 
The study population should include a reasonable representation of patients who have undergone 
a metal replacement procedure.  
 
9.1 
Overview  
 
Subjects will be recruited from patients who are currently visiting or have previously visited 
dermatology, allergy or similar medical practices and clinics for patch testing or evaluation of 
suspicion of metal contact allergy potentially associated with a metal implant. Sensitive subjects 
(those who have had a past positive patch test to at least one of the dilution series allergens) will 
be tested with the allergen panels(s) and corresponding reference allergen(s) (with the exception 
of subjects enrolled in Germany who will not be tested with the reference allergens) to which 
they have had a previous response. Those with suspicion of metal contact allergy potentially 
associated with a metal implant will be tested with all dilution series and reference allergens. All 
subjects will be tested with the excipient controls.  The common allergens will be tested at the 
discretion of the investigator 
 
All subjects (not identified by name) considered for study inclusion who sign the consent form 
must be recorded in the Subject Screening Log. If a subject declines to participate or fails 
inclusion/exclusion entry criteria the reason for the screen fail will be recorded in the Subject 
Screening Log. Subjects enrolled in the study will be assigned a unique subject identification 
code that will also include a site-specific identifier. 
 
9.2 
Entry/Eligibility Criteria  
 
9.2.1 Inclusion Criteria 
 
a. 18 years of age or older. 
b. Past positive patch test result within the past 10 years (to one of the dilution series metals 
being tested on this study) or strong suspicion of metal contact allergy based on results of the 
Qualification Questionnaire. 
c. Unable to become pregnant or willing to use an acceptable method of contraception to 
prevent pregnancy if female of childbearing potential; 
 Inability to become pregnant would include all male subjects and female subjects who are 
postmenopausal for at least 1 year, or surgically sterile- have had a hysterectomy, bilateral 
ovariectomy, uterine ablation or bilateral tubal ligation.   
 Acceptable methods of contraception include: 1) systemic birth control (i.e., oral 
contraceptives, skin patch, vaginal ring, implant, injection, or intrauterine device (IUD), 
which contains either a hormone or copper); 2) double barrier method (i.e., diaphragm, 
cervical cap, sponge, condom with spermicide); 3) IUD; 4) vasectomized partner; or 5) 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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abstinence from sexual intercourse. Subject must agree to use acceptable contraception 
for the duration of the entire study. 
(Notes:   
o Cervical cap and abstinence from sexual intercourse will not be considered as 
acceptable methods of contraception for subjects enrolled in Japan 
o A double-barrier method must be used for all subjects enrolled in Switzerland who 
are practicing non-systemic methods of birth control. 
o Abstinence from sexual intercourse will not be considered an acceptable method of 
contraception for subjects enrolled in Switzerland) 
d. Understands and signs the approved Informed Consent form which is consistent with all 
institutional, local and national regulations.  
 
9.2.2 Exclusion Criteria 
 
a. Breastfeeding or pregnant (as determined by urine pregnancy test) or intending to become 
pregnant during the course of the study. Breastfeeding may be resumed upon completion of 
the study. 
b. Topical treatment with corticosteroids or other immunosuppressive agents on or near the test 
area 14 days prior to inclusion through the end of the subject’s participation in the study. 
c. Systemic treatment with corticosteroids (equivalent to > 10 mg prednisone) or other 
immunosuppressive agents 14 days prior to inclusion through the end of the subject’s 
participation in the study. Inhaled treatments and steroidal nose or eye drops are permitted. 
d. Treatment with ultraviolet (UV) light (including tanning) during the 3 weeks prior to 
inclusion through the end of the subject’s participation in the study. 
e. Acute dermatitis outbreak or dermatitis on or near the test area on the back. 
f. Known or suspected infection of the skin, joints or other site(s) associated with metal 
exposure 
g. Condition such as; fibromyalgia, chronic fatigue, depression, cognitive impairment, flu-like 
symptoms, diarrhea and/or headache without at least one of the symptoms related to metal 
exposure listed in Section 10.1 under physical examination. 
h. Condition such as; psoriasis, dermatitis herpetiformis, mycosis fungoides or cutaneous T-cell 
lymphoma that may confound the evaluation of allergic contact dermatitis. 
i. Inability to comply with patch test study requirements including multiple return visits and 
activity restrictions (e.g., protecting test panels from excess moisture due to showering or 
vigorous activity). 
j. Participation in a clinical trial of an investigational drug, treatment or device during this study 
or 3 weeks prior to inclusion in this study. 
k. An opinion of the Investigator that deems the potential subject to be non-compliant, unable to 
return for study visits or complete the study as detailed in the protocol. 
 
The following exclusion criteria will be required in Germany only: 
l. Alcohol abuse as well as drug and/or medication abuse. 
m. Severe psychiatric, psychological or neurological disorders. 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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n. Patients in any relationship or dependency with the sponsor and/or investigator. 
o. General inflammatory as well severe acute and chronic inflammatory diseases. 
p. Malignancy during the previous 5 years. 
q. Completed or ongoing long-term treatment with tranquilizer or psycho active drug. 
 
9.3 
Subject Withdrawal and Compliance 
 
Subjects may withdraw from the study at any time. However, subjects will not necessarily be 
withdrawn from the study for missing scheduled visits. Subjects will be contacted and outcomes 
documented as described in the clinical protocol and investigator brochure. If a subject misses 
two or more clinic visits he or she may be withdrawn from the study at the discretion of the 
Investigator. Data from withdrawn subjects may be used in the safety analysis and will remain 
anonymous. 
 
The Investigator may withdraw a subject if deemed medically necessary, or if the subject can no 
longer meet study requirements. Any subject who is withdrawn from the trial will continue to 
receive normal standard of care. Subject withdrawal and reasons for withdrawal must be clearly 
described and documented in the subject’s data collection form. Data from withdrawn subjects 
may be used in the safety analysis and will remain anonymous. Withdrawn subjects will be 
replaced.   
 
Additional criteria for subject withdrawal include: 
 
 Overreaction to an allergen.  Defined as a response greater than Extreme Positive (3+). A 
severe reaction to the test tape adhesive or allergen patch that either causes the subject to 
remove the panels prior to the 48 hour return visit or is determined by the investigator to be 
significantly greater in severity than expected or as described in the Investigator’s Brochure. 
Test panels will be immediately removed and reactions treated per standard medical 
guidelines. 
 Unacceptable adverse events.  Defined as development of severe itching and burning, a 
severe dermatitis flare-up or other adverse event that may be considered unacceptable. 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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9.4 
Subject Activity Restrictions 
 
During the first two days of the study subjects must: 
 Keep test panels and test sites dry and protected from UV light. 
 Avoid activities that can hinder patch adherence or interfere with skin reaction evaluations 
such as swimming, sunbathing, tanning, submersion bathing, strenuous activities that may 
cause excessive perspiration and the use of steam rooms or saunas. Subjects may shower but 
should avoid getting the patch sites wet. 
 
During the entire 3-week test period, subjects are restricted from: 
 Sunbathing and tanning to prevent the occurrence of photo-induced skin reactions. 
 Use of new topical or personal care products to prevent a dermatitis flare-up and possible 
confounding of skin reactions.   
 Use of prescription or over-the-counter topical products at patch sites after panel removal 
unless directed and monitored by the Investigator. 
 
The Investigator may withdraw a subject if the subject does not meet the study requirements. 
 
10.0 
MONITORED PARAMETERS 
 
Figure 2: Visit Schedule 
 
 
Day 0 
Day 2 
Day 3-4 
Day 7-8 
Day 10-14 
Day 19-23 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6* 
Read and Sign Consent 
X 
 
 
 
 
 
Study Eligibility 
Questions 
X 
 
 
 
 
 
Urine Pregnancy Test 
X 
 
 
 
 
 
Skin Examination 
X 
 
 
 
 
 
Patch Application 
X 
 
 
 
 
 
Adhesion Evaluation 
 
X 
 
 
 
 
15-minute wait 
 
X 
 
 
 
 
Tape Irritation Evaluation 
 
X 
 
 
 
 
Itching and Burning 
 
X 
 
 
 
 
Skin Reaction Evaluation 
 
 
X 
X 
X 
X 
Possible Photographs of 
Patch Sites 
 
 
X 
X 
X 
X 
Changes to Medications or 
Illness Questions 
 
X 
X 
X 
X 
X 
* May be phone call or office visit. 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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10.1 
Visit 1: Day 0 
 
Documentation of the following must occur prior to application of the investigational panel and 
reference allergen: 
 Informed Consent 
o (Note: Legal representative in addition to subject must sign consent form for subjects 
aged 18-19, enrolled in Japan.) 
 Subject interview including medical history, medication use and documentation of 
inclusion/exclusion criteria 
 Dipstick urine pregnancy test for all females of childbearing potential (mouse anti-beta hCG 
antibody conjugated to colloidal gold and goat anti-alpha hCG antibody coated on the 
membrane)  
 Subject demographics (date of birth, gender, ethnicity) 
 Completion of Qualification Questionnaire and Type of Metal Exposure Questionnaire 
 Physical examination and chart review to record current symptoms of dermatitis related to 
metal exposure. The physical examination will facilitate documentation of the following 
symptoms related to metal exposure: 
o Dermatitis over site of metal implant 
o Systemic contact dermatitis 
o Accelerated restenosis of cardiac stent 
o Aseptic loosening 
o Persistent joint pain, chronic swelling, instability and/or loosening, itching or burning 
o Burning mouth syndrome 
o Oral lichen planus 
o Oral lichenoid lesion 
o Palmo plantar pustulosis 
o Stomatitis: gingivitis, cheilitis and/or glossitis 
o Itching,  papules or nodules at injection site of aluminum containing vaccination 
o Other 
 
Age of diagnosis, distribution, severity and current medication use (including those being 
withheld for the duration of the study) will be captured for subjects who exhibit concurrent atopic 
dermatitis and irritant dermatitis.   
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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Figure 3: Qualification Questionnaire 
 
 Past Positive patch test result(s) within the past 10 years 
 
Name of allergen tested: 
 
 
 
Date of test: 
 
 
 
Results: 
 
 
 
Symptoms at time of patch test: 
 
 
 
Any current symptoms? (Yes, No) 
 
 
 
If yes, list current symptoms: 
 
 
 Suspicion of contact allergy associated with metal exposure 
 
Type of metal exposure 
 
 
 
Cardiac implant (stent, pacemaker, etc.) 
 
 
 
Orthopedic implant (knee, hip or other) 
 
 
 
Gynecological implant or device 
 
 
 
Surgical hardware (plates, screws, wires, pins, rods, expanders, staples) 
 
 
 
Dental metal implant 
 
 
 
Dental metal appliance, prosthesis or filling 
 
 
 
Injection of aluminum containing vaccination 
 
 
 
Other 
 
 
 Other reason Investigator believes the subject qualifies for study inclusion 
 
 
Past positive lymphocyte proliferation (or transformation) test to one of the 
dilution series metals being tested on this study 
 
 
 
Name of metal tested: 
 
 
 
 
Date of test: 
 
 
 
 
Results: 
 
 
 
 
Other 
 
 
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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Figure 4: Type of Metal Exposure Questionnaire 
 
Name of Procedure 
 
 
Date of Procedure 
 
 
Date symptoms first began 
 
 
Patient’s description of symptoms 
 
 
Site(s) of onset 
 
 
Symptoms currently present? 
 Yes 
 No 
 
Duration 
 Continuous 
 Sporadic 
 
If sporadic: 
 
 
How long do symptoms last? 
 
 
 
What is the length of time between episodes? 
 
 
Other symptoms? (itching, burning, pain, etc.) 
 
 
Medication Taken? 
 Yes 
 No 
 
If yes: 
 
 
Name of Medication 
 
 
 
Start Date 
 
 
 
Stop date (or ongoing) 
 
 
 
Dose 
 
 
 
Frequency 
 
 
 
Route 
 
 
 
Subjects who qualify for participation will have the investigational allergen panel(s) and 
reference allergens applied (with the exception of subjects enrolled in Germany who will not be 
tested with the reference allergens) to the paraspinal region of the upper back. Areas of contact 
dermatitis, uneven skin tones, tattoos, scars, moles, excessive hair or other skin disfiguration 
should be avoided. Upper arms may be used if there is not adequate space on the back for all 
panels. In summary, within these parameters, investigators will use their medical expertise to 
determine panel placement based on the features of each subject’s back as they would normally 
do in clinical practice. 
 
Panels may be further secured with medical tape (e.g., Scanpor® or patchProtect™). PatchMap 
may be used to document panel placement. The use of PatchMap will be required in Germany.  
The time of application will be documented. 
 
The panel will be applied to the subject populations per the following: 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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 Sensitive subjects (those who have had a past positive patch test to at least one of the dilution 
series allergens) may be tested with the allergen panels(s) and corresponding reference 
allergen(s) (with the exception of subjects enrolled in Germany who will not be tested with 
the reference allergens) to which they have had a previous response.  
 The Investigator will use his or her experience and medical expertise to determine if a 
subject with a past positive patch result should be tested to all dilution series allergens or 
only to the allergen to which the subject has had the past response.  
 Subjects with a past positive response to copper, zinc, tin, manganese or molybdenum 
will be tested with the panel containing the past positive response allergen plus the other 
allergen(s) located on the same panel.  Specifically, Panel 2 contains copper, zinc and tin, 
and Panel 3 contains manganese and molybdenum.  Hence, subjects with a past positive 
response to one of the allergens on the panel will also be tested with the other allergen(s) 
located on the same panel. It will not be necessary to test the additional reference 
allergens. 
 Subjects with suspicion of metal contact allergy potentially associated with a metal implant 
will be tested with all dilution series and reference allergens. 
 All subjects will be tested with the excipient controls on Panel 6. The Investigator will use 
his or her experience and medical expertise to determine if a subject with a strong suspicion 
of metal contact allergy who has not undergone previous patch testing will benefit from being 
patch tested with the four common allergens (nickel, chromate, cobalt and gold) in order to 
provide the individual with a complete diagnosis of metal contact allergy. Should the 
Investigator decide that testing with the four common allergens will not be of benefit to the 
subject, the Investigator will cut Panel 6 as illustrated in Figure 9, (Section 11.1, 
Investigational Allergen Panels) before applying the panel. 
 
10.2 
Visit 2: Day 2 
 
Prior to removal of the investigational allergen and reference panels, tape adhesion will be 
evaluated and scored according to the following adhesion scale: 
 
Excellent: 
Skin contact good; all tape edges adherent; all allergens in contact with the skin 
Good: 
Skin contact acceptable; some tape edges lifting; all allergens in contact with the skin 
Poor: 
Little to no skin contact with panel; one or more allergens not in contact with the skin 
Detached: 
Panel completely off the skin; none of the allergens in contact with the skin 
 
If adhesion is ‘Poor’ or ‘Detached’ the allergen sites that were not in contact with the skin at the 
time of panel removal will be identified. 
 
Patches that do not remain in place (completely detached) for the intended wear period 
(approximately 48 hours or two days) will not be replaced.  The subject will be asked to return 
for follow-up visits until all patch sites reactions have resolved but data from this subject will not 
be included in the analysis of positive responses necessary to determine optimal dose.  
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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Subjects whose patches are not worn for the intended wear period may return to be retested after 
3 weeks at the discretion of the Investigator providing the skin site remains free of conditions 
that may affect test results. 
 
Factors such as oily skin, excess hair, wet panel, sweat/skin moisture, and activity-associated 
failure, which may potentially contribute to poor adhesion, will also be captured on the data 
collection form.  
 
The patch panels will be removal and time documented. There will be at least a 15-minute wait 
between patch removal and the irritation evaluations. Following the 15-minute wait, tape sites 
(entire panel minus the chip sites) then the polyester chip sites will be evaluated for skin 
irritation.  
 
Skin irritation will be documented as follows: 
 Panels 1-6: Irritation attributed to the adhesive used to adhere the panels to the skin (tape 
irritation) will be documented if the site of the entire panel with the exception of the chip 
sites, as shown below in Figure 5, shows signs of irritation 
 Panels 1-6:  Irritation attributed to the gel chips will be documented if all chip sites show 
signs of irritation.  Note:  To ensure that irritation resulting from skin contact with the 
polyester chip is not confused with an allergic response to a specific allergen, all of the 
polyester chip sites must present the same or nearly the same degree of irritation. 
 Panel 1: Chips on positions 1-4 and 7-10 will be evaluated for irritation 
 Panel 2: Chips on positions 1-12 will be evaluated for irritation 
 Panel 3: Chips on positions 1-4 and 7-10 will be evaluated for irritation 
 Panel 4: Chips on positions 1-12 will be evaluated for irritation 
 Panel 5: Chips on positions 1-4 and 7-10 will be evaluated for irritation 
 Panel 6: Chips on positions 1-4 and 7-9 will be evaluated for irritation. If Panel 6 is cut to 
avoid patch testing with the common allergens chips on the remaining positions will be 
evaluated. 
 Panels 7-8:  Irritation attributed to the adhesive used to adhere the panels to the skin (tape 
irritation) will be documented if the site of the entire panel with the exception of the patch 
test chambers show signs of irritation.  This will be similar to the tape irritation example 
shown below in Figure 5 but the chambers used in the Finn Chamber product are round, not 
square. 
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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Figure 5: Tape vs Chip Irritation Illustration 
 
Tape Irritation:   
Chip Irritation:   
Site of entire panel with exception of chip 
sites shows signs of skin irritation 
Only chip sites show signs of irritation.   
NOTE:  All sites must have the same or nearly 
the same degree of irritation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Position 1  
 
 
Position 7 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Position 2  
 
 
Position 8 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Position 3  
 
 
Position 9 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Position 4  
 
 
Position 10 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Position 5  
 
 
Position 11 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Position 6  
 
 
Position 12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tape irritation will be evaluated according to the following score scale: 
 
None: 
No erythema or other sign of irritation 
Weak: 
Faint to definite pink erythema 
Moderate: 
Moderate erythema, definite redness 
Strong: 
Severe erythema, very intense redness 
 
Polyester chip induced irritation will be evaluated according to the following score scale: 
 
None: 
No erythema or other signs of irritation 
Weak: 
Faint to definite pink erythema at all polyester chip sites* 
Moderate: 
Moderate erythema, definite redness at all polyester chip sites* 
Strong: 
Severe erythema, very intense redness at all polyester chip sites* 
 
*To ensure that irritation resulting from skin contact with the polyester chip is not confused with 
an allergic response to a specific allergen, all of the polyester chip sites on each panel must 
present the same or nearly the same degree of irritation. 
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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Subject self-report of itching and burning sensations for each allergen panel will be documented 
according to the following score scale: 
 
None: 
No discomfort 
Weak: 
Minimal discomfort 
Moderate: 
Definite discomfort 
Strong: 
Significantly bothersome; possible interference with sleep or daily activity 
 
Subject-reported adverse events, worsening of a pre-existing condition/disease/symptom or 
changes to concomitant medications will be recorded. 
 
10.3 
Visit 3: Day 3-4  
 
10.3.1 Tape and Polyester Chip Sites Irritation 
 
Skin irritation due to the patch panel tape or chip will be evaluated and documented per the 
instructions presented in Section 10.2 Irritation that increases in severity or persists beyond visit 
3 will be followed to resolution.  
 
Tape Irritation will be evaluated according to the following score scale: 
 
None: 
No erythema or other sign of irritation 
Weak: 
Faint to definite pink erythema 
Moderate: 
Moderate erythema, definite redness 
Strong: 
Severe erythema, very intense redness 
 
Polyester chip induced irritation will be evaluated according to the following score scale:   
 
None: 
No erythema or other signs of irritation 
Weak: 
Faint to definite pink erythema at all polyester chip sites* 
Moderate: 
Moderate erythema, definite redness at all polyester chip sites* 
Strong: 
Severe erythema, very intense redness at all polyester chip sites* 
 
*To ensure that irritation resulting from skin contact with the polyester chip is not confused with 
an allergic response to a specific allergen, all of the polyester chip sites on each panel must 
present the same or nearly the same degree of irritation. 
 
10.3.2 Allergic Skin Responses 
 
Allergen site reactions will be evaluated for the presence of erythema, infiltration, papules, 
discrete vesicles and bullous reactions. These criteria will be used to score skin reactions 
according to standard patch testing guidelines established by the International Contact Dermatitis 
Research Group as discussed and shown below.  
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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Skin reactions at test sites will be scored as: (Neg) negative; (IR) irritant reaction; (?+) doubtful 
reaction; (1+) weak positive reaction; (2+) strong positive reaction; or (3+) extreme positive 
reaction.  
 
Figure 6: Reaction Criteria 
 
 
 
Notation Description Interpretation 
 
Neg 
Negative, no skin changes in the tested area,  
?+ 
Faint, non-palpable erythema, possibly few papules 
+ (1+) 
Palpable erythema, moderate edema or infiltrate, possibly few papules, no vesicles. 
Weak reaction. 
++ (2+) 
Strong infiltrate, numerous papules, possibly few vesicles present. Strong reaction. 
+++ (3+) 
Coalescing vesicles, bullae or ulceration. Extreme reaction. 
IR 
Inflammation sharply limited to the exposed area, lack of infiltrate, small petechiae, 
pustules, and efflorescences other than papules and vesicles. 
 
Subject-reported adverse events, worsening of a pre-existing condition/disease/symptom or 
changes to concomitant medications will be recorded. 
 
De-identified photographs of site reactions may be taken at the discretion of the Investigator and 
will not be reviewed or collected by the study sponsor. 
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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10.4 
Visit 4: Day 7-8 and Visit 5: Day 10-14 
 
10.4.1 Tape and Polyester Chip Sites Irritation 
 
Unresolved tape and or polyester chip induced irritation will be evaluated. 
 
Tape irritation will be evaluated according to the following score scale: 
 
None: 
No erythema or other sign of irritation 
Weak: 
Faint to definite pink erythema 
Moderate: 
Moderate erythema, definite redness 
Strong: 
Severe erythema, very intense redness 
 
Polyester chip induced irritation will be evaluated according to the following score scale:   
 
None: 
No erythema or other signs of irritation 
Weak: 
Faint to definite pink erythema at all polyester chip sites* 
Moderate: 
Moderate erythema, definite redness at all polyester chip sites* 
Strong: 
Severe erythema, very intense redness at all polyester chip sites* 
 
Any response that is greater in severity than a strong irritation response may be graded as a 
potential allergic response as follows: 
 
1+ Palpable erythema, moderate edema/ infiltrate, few papules, no vesicles. Weak reaction 
2+ Strong infiltrate, numerous papules, possibly few vesicles present. Strong reaction 
3+ Coalescing vesicles, bullae or ulceration. Extreme reaction 
 
*To ensure that response to skin contact with the polyester chip is not confused with an allergic 
response to a specific allergen, all of the polyester chip sites per panel must present with the same 
or nearly the same response score. 
 
 
10.4.2 Allergic Skin Responses 
 
Allergen sites will be examined for the presence of erythema, infiltration, papules, discrete 
vesicles and bullous reactions and scored as follows: (-) negative, (1+) weak positive reaction, 
(2+) strong positive reaction, and (3+) extreme positive reaction.   
 
All reactions (scores of 1+, 2+ or 3+) will be categorized as either late or persistent. Persistent 
reactions will be further clarified as either persistent-healing or persistent-escalating.   
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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Definitions: 
Late Reaction: 
A reaction that initially appears at day 7-14 after application of panels. 
Persistent Reaction:  
A reaction that initially appears at day 2- 4 and persists through day 7-21 
or beyond.   
Persistent-Healing: 
A persistent reaction that has not worsened since the previous 
evaluation, remains the same or appears to be healing.  
Persistent-Escalating: 
A persistent reaction that has worsened since the previous evaluation 
 
Subject-reported adverse events, worsening of a pre-existing condition/disease/symptom or 
changes to concomitant medications will be recorded. 
 
De-identified photographs of site reactions may be taken at the discretion of the Investigator and 
will not be reviewed or collected by the study sponsor. 
 
10.5 
Visit 6: Day 19-23 
 
The investigative site will phone the subject to determine if there are any unresolved tape, 
polyester chip or allergen reactions at the test sites. If the subject reports no remaining reactions, 
the Investigator may choose at this point to complete the visit over the telephone. 
 If the visit is conducted over the telephone all visit related paperwork including adverse 
events and/or changes to concomitant medications will be recorded. 
 
Should the Investigator elect to see the subject in the office, the following procedures will be 
performed: 
 Unresolved tape and or polyester chip induced irritation will be evaluated. 
 Sites will be examined for the presence of erythema, infiltration, papules, discrete vesicles 
and bullous reactions and scored as follows: (-) negative, (1+) weak positive reaction, (2+) 
strong positive reaction, and (3+) extreme positive reaction.  
 All reactions (scores of 1+, 2+ or 3+) will be categorized as either late or persistent. Late 
reactions are defined as reactions that initially occur at 7-10 days after application of the 
panels. Persistent reactions are defined as reactions that appear at day 2-4 and persist through 
day 7-21.  Persistent reactions will be clarified as either persistent-healing or persistent-
escalating. If a persistent-escalating reaction is noted at Visit 6, the investigator will 
determine required follow up action. 
 Subject-reported adverse events, worsening of a pre-existing condition/disease/symptom or 
changes to concomitant medications will be recorded. 
 De-identified photographs of site reactions may be taken at the discretion of the Investigator 
and will not be reviewed or collected by the study sponsor. 
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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Page 44 of 82 
27 June 2018 
 
 
10.6 
Post Visit 6 
 
The Investigator will:  
1. Evaluate tape or polyester chip induced irritation that increased in severity or persisted 
beyond visit 3. A potential allergic response may be considered if the skin response is 
consistent with criteria used to score 1+, 2+ or 3+ positive skin reactions according to 
standard patch testing guidelines established by the International Contact Dermatitis Research 
Group. The skin reaction must present with: 
o Palpable erythema, moderate edema or infiltrate, possibly few papules, no vesicles. Weak 
reaction (Score of 1+). 
o Strong infiltrate, numerous papules, possibly few vesicles present. Strong reaction (Score 
of 2+). 
o Coalescing vesicles, bullae or ulceration. Extreme reaction (Score of 3+). 
2. Categorize the skin reactions at each site as either negative or positive.  No skin reaction 
scores (1+, 2+ or 3+) assigned to during any of the reaction assessment visits, (Visits 3-6) 
would constitute a negative reaction. A positive skin reaction is defined as an assigned score 
of 1+, +2 or 3+ during at least one of the reaction assessment visits (Visits 3-6). 
 
11.0 
INVESTIGATONAL PRODUCT IDENTITY AND USE 
 
11.1 
Investigational Allergen Panels 
 
Investigational T.R.U.E. TEST panels are produced, packed and labeled by the manufacturer 
SmartPractice Denmark, in Hillerød, Denmark. To protect tests against light and air, panels are 
sealed in aluminum foil opaque pouches. Panels are to be stored under refrigeration at 2-8oC (36-
46oF). Products are labeled with allergen batch codes and expiration dating.   
 
Each investigational panel consists of a 5.2 x 13.0 cm piece of surgical tape containing as many 
as 12 allergen patches. Although each allergen patch is assigned a ‘chip number’ for product 
identity, scoring will be by position placement as illustrated below. 
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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27 June 2018 
 
 
Figure 7: Illustration of Position Numbering 
 
 
 
  
 
UP 
 
 
Notch   
Position 1 →  
 
 
  ← 
Position 7 
 
 
Position 2 →  
 
 
  ← 
Position 8 
 
 
Position 3 →  
 
 
  ← 
Position 9 
 
 
Position 4 →  
 
 
  ← 
Position 10 
 
 
Position 5 →  
 
 
  ← 
Position 11 
 
 
Position 6 →  
 
 
 ← 
Position 12 

 
 
  
 
 
Notch 
 
 
An up arrow and two notches indicate the proper product orientation.  The uppermost notch on 
the left side of the panel indicates the top left of the panel, the lower notch indicates the bottom 
of the panel. The patch chip numbering is unmistakable when the panel is removed from its 
pouch. Panels are to be applied with the numbers facing upright. 
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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27 June 2018 
 
 
Figure 8: Application of Dilution Series Allergens 
 
 
 Peel open package and remove 
test panel. 
 Remove plastic covering. 
 Position the panel to the 
paraspinal region of the upper 
back being careful to avoid areas 
of contact dermatitis, uneven 
skin tones, tattoos, scars, moles, 
excessive hair or other skin 
disfiguration.  
 Ensure that each patch is in 
contact with the skin by 
smoothing the panel outward 
from the center 
 Use a skin marker to indicate the 
location of the two notches on 
the panel 
 Panel may be secured with 
additional tape, if needed. 
 
 
In order to differentiate between panels once they are applied the following chip numbers are 
used for each panel. The set of numbers used is unique to each panel so that individual panels 
can easily be identified: 
 
 
Panel 1 
Panel 2 
Panel 3 
Panel 4 
Panel 5 
Panel 6 
Chip 
numbers 
1-4 and  
7-10 
13-24 
25-28 and 
31-34 
25-36 
3-6 and  
9-12 
1, 4, 5, 7, 8, 
12, 28 
 
The lead chemist in the department of pharmaceutical development at SmartPractice Denmark is 
responsible for the randomization of allergens on panels 1-5. The allergens will be randomized 
within each panel into three different configurations, per standard protocol.  The different 
allergen configurations will be randomly assigned to subjects as they enter the study. The 
investigators and subjects will be aware of the allergens and the patch test doses on the test 
panels but will not be aware of the placement of the allergens on the individual panels (the 
different panel configurations).  The key to the randomization scheme will be kept confidential at 
SmartPractice Denmark until it is forwarded to data management for analysis of the study results 
following completion of all study related procedures.  
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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Page 47 of 82 
27 June 2018 
 
 
The allergens on panel 6 will not be randomized into different configurations.  Should the 
Investigator elect to omit the common allergens from an individual’s patch testing, the panel 
should be cut as shown below in Figure 9.   
 
Figure 9: Panel 6 Configuration and Cutting Instructions 
 
 
Position 1 
Nickel →  
 
  
  ← 
Position 7 
Cobalt 
 
Position 2 
Chromate →  
 
  
  ← 
Position 8 
PVP 
 
Position 3 
Gold →  
 
  
  ← 
Position 9 
HPC 
Position 4 
Blank →  
 
  
  ← 
Position 10 
 
Position 5 →  
 
  
  ← 
Position 11 
 
Position 6 →  
 
  
 ← 
Position 12 
 
 
Unused portion of the panel is not to be discarded. 
 
The remaining portion of the panel must be applied as it contains the excipient and blank patch 
controls.  Scores for the blank (Position 4), PVP (Position 8), and HPC (Position 9) patches will 
be recorded in the case report forms as originally intended, in fields for positions 4, 8 and 9.  
Positions 1, 2, 3 and 7 will be documented in the case report form as ‘not applied’. 
 
All investigational products used in this study must be accounted for. Records must show amount 
and date of delivery of all test materials to the investigator. Likewise dates, amount, and 
signatures should document return of unused test panels. Product deliberately and/or accidentally 
destroyed by the investigator must also be documented.  
 
The use of the investigational product for the individual subject, including number and 
identification of specific panels applied, application (or not) of common allergens and date and 
time of application and removal will be documented. 
 
The following investigational panels with ascending doses of allergen and an excipient control 
will be used in this study.  
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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27 June 2018 
 
 
Panel 1 Aluminum Dilution Series 
 
Allergen 
Excipients 
 Ascending Dosages  
(mg salt/cm²) 
Randomized  
Among Positions 
Aluminum chloride 
hexahydrate 
Water, Ethanol 
(99.9%), PVP 
0.040, 0.12, 0.36, 0.72 
1-4 and 7-10 
Aluminum lactate 
Water, Ethanol 
(99.9%), PVP 
0.047, 0.14, 0.42, 0.84 
 
Panel 2 Copper, Zinc and Tin Dilution Series 
 
Allergen 
Excipients 
 Ascending Dosages  
(mg salt/cm²) 
Randomized  
Among Positions 
Copper sulfate 
anhydrous 
HPC, Water 
0.013, 0.040, 0.080, 0.12 
1, 2 and 7, 8 
Zinc chloride 
HPC, Water 
0.013, 0.040, 0.080, 0.24 
3, 4 and 9, 10 
Tin chloride dihydrate 
HPC, Water, 
Ethanol 
0.018, 0.037, 0.11, 0.33 
5, 6 and 11, 12 
 
Panel 3 Manganese and Molybdenum Dilution Series 
 
Allergen 
Excipients 
Ascending Dosages 
(mg salt/cm²) 
Randomized  
Among Positions 
Manganese chloride 
HPC, Water 
0.013, 0.040, 0.080, 0.24 
1-4 
Ammonium 
molybdate 
HPC, Water 
0.0067, 0.020, 0.040, 0.12 
7-10 
  
Panel 4 Titanium Dilution Series 
 
Allergen 
Excipients 
Ascending Dosages  
(mg Ti/cm²) 
Randomized  
Among Positions 
Titanium peroxo 
citrate 
PVP, Water 
0.055, 0.11, 0.22 
1-12 
Titanium lactate 
PVP, Ethanol 
0.070, 0.14, 0.28 
Potassium titanium 
oxide oxalate 
PVP, Ethanol 
0.060, 0.12, 0.24 
Ammonium titanium 
oxide oxalate 
PVP, Water 
0.055, 0.11, 0.22 
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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Page 49 of 82 
27 June 2018 
 
 
Panel 5 Vanadium Dilution Series 
 
Allergen 
Excipient 
Ascending Dosages 
(mg V/cm²) 
Randomized  
Among Positions 
Vanadium chloride 
HPC, Water 
0.0042, 0.0083, 0.025, 0.050 
1-4 and 7-10 
Vanadium oxide 
sulfate 
HPC, Water 
0.0042, 0.0083, 0.025, 0.050 
 
Panel 6 Common Allergens/Excipient Controls 
 
Allergen/Control 
Excipient 
Dose (mg/cm²) 
Position 
Nickel sulfate 
HPC 
0.20 
1 
Potassium dichromate 
PVP 
0.054 
2 
Gold sodium thiosulfate  
HPC 
0.075 
3 
Blank Patch Negative Control 
None 
NA 
4 
Cobalt dichloride 
HPC 
0.020 
7 
PVP Negative Control 
PVP 
NA 
8 
HPC Negative Control 
HPC 
NA 
9 
 
The dose per unit area of experimental T.R.U.E. Test allergens is calculated based on the 
molecular weight of the compound. Exceptions are Titanium and Vanadium allergens as 
molecular weights are not known for all of these, hence the dose per unit area for Titanium and 
Vanadium allergens is based only on the metal part of the compound. 
 
11.2 
Reference Allergens 
 
Commercially available reference allergens may be used or the reference allergen syringes may 
be prepared and labeled by the Department of Occupational and Environmental Dermatology, 
Skåne University Hospital, Malmö, Sweden.  The reference allergens will be stored in individual 
syringes under refrigeration at 2 - 8oC. 
 
The Finn Chamber, polypropylene-coated, supplied by SmartPractice, will be used to apply the 
reference allergens. Reference allergens will be dispensed at the rate of 20 μl/chamber using a 
precision allergen dispenser. 
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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Page 50 of 82 
27 June 2018 
 
 
Figure 10: Reference Allergen Preparation 
 
Petrolatum allergens  
 
  Apply a ribbon of substance across the diagonal of chamber 
 
Petrolatum allergens may be dispensed 24 hours prior to application 
Liquid allergens 
 
 
 Add filter paper to chamber 
Dispense liquid allergen to chamber   
Liquid allergens may not be dispensed 
until immediately prior to patch application 
 
Instructions for precision allergen dispenser: 
1. Fill metering chamber with allergen using syringe plunger.  
2. Wipe excess from tip. 
3. Dispense allergen to chamber by depressing precision allergen dispenser plunger. 
 
 The Aluminum Dilution Series will be tested concurrently with 
o Aluminum chloride hexahydrate, 10 % w/w in petrolatum 
o Aluminum lactate, 12 % w/w in petrolatum 
 The Copper Dilution Series will be tested concurrently with copper sulfate anhydrous, 2 % 
w/w in petrolatum 
 The Manganese Dilution Series will be tested concurrently with manganese chloride 
tetrahydrate, 2 % w/w in petrolatum 
 The Molybdenum Dilution Series will be tested concurrently with ammonium molybdate, 1% 
aqueous solution. 
 The Tin Dilution Series will be tested concurrently with tin chloride dihydrate, 1% w/w in 
petrolatum 
 The Titanium Dilution Series will be tested concurrently with 
o Ammonium titanium peroxo citrate, 17% w/w in petrolatum 
o Ammonium titanium lactate, 34% aqueous solution  
o Potassium titanium oxide oxalate, 22% w/w in petrolatum  
o Ammonium Titanium oxide oxalate 19% w/w in petrolatum 
 The Vanadium Dilution Series will be tested concurrently with 
o Vanadium chloride, 1% w/w in petrolatum  
o Vanadium oxide sulfate, 1.5% w/w in petrolatum 
 The Zinc Dilution Series will be tested concurrently with zinc chloride, 2% w/w in 
petrolatum 
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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27 June 2018 
 
 
NOTES: 1) The common allergens (Panel 6) will not be tested against reference allergens. 2) 
Subjects enrolled in Germany will not be tested with the reference allergens 
 
12.0 
DATA ANAYLSIS 
 
12.1 
Descriptive Statistics and Analysis 
 
True disease status (allergic contact dermatitis to a specific allergen) is rarely definitively known. 
Patch test results, medical history, symptoms and provocation testing (if performed) are used to 
clinically diagnose disease status, and it is not uncommon to observe discordance among these 
diagnostic parameters. Moreover, symptoms and test results can change over time – presumably 
due to skin condition, decreased exposure or overall health. These factors contribute to the 
difficulty of assigning a positive disease status, i.e., sensitive status, to patients. In this clinical 
trial, subjects will be considered sensitive if they’ve had a past positive response even though 
they may not react to the reference allergen at the time of the study.  
  
The frequency of ranked skin responses; positive (1+, 2+, 3+), negative, doubtful and irritant, 
will be calculated for each allergen dose (dilution series and reference) tested. The optimal 
allergen dose will be based on the following criteria: 
 The lowest concentration of each dilution series allergen eliciting positive responses in a 
minimum of 15 subjects. Positive responses are defined as score of 1+, 2+ or 3+ during 
at least one reaction assessment visit. If a significant number of 3+ responses are 
elicited, the dose will be selected based on 1+ and 2+ responses. 
 For all sites with the exception of Germany: Concordance will be measured using Cohen’s 
kappa where less than 0% indicates no agreement, 0-20% indicates poor agreement, 20-40% 
indicates fair agreement, 40-60% indicates moderate agreement, 60-80% indicates good 
agreement and 80% or higher indicates very good agreement. Concordance will be measured 
using all subjects who are tested with each allergen and corresponding reference allergen. 
 
Safety evaluations will be tabulated as follows: 
 Frequency of tape and polyester chip induced irritation or allergic reactions at Visits 2 
through 6 for the T.R.U.E. Test tape and polyester chips (Panels 1-6) and Finn Chamber tape 
(Reference allergen panels). 
 Frequency of subject reported sensations of itching and/or burning for each allergen panel at 
patch removal.  
 Frequency of positive (1+, 2+, 3+) skin reactions for each investigational and reference 
allergen dose at each post removal visit and overall. 
 Frequency of negative, doubtful, irritant, late and persistent skin reactions for each 
investigational and reference allergen dose at each post removal visit (late and persistent 
reactions at visits 4, 5 and 6 only). 
 Frequency of all adverse events. Documentation for all local and systemic adverse reactions 
classified by the investigator as possibly or definitely related to the study product (e.g., 
erythema, hyper-pigmentation, hypo-pigmentation, skin thinning or dermatitis flare) will 
include grade (mild, moderate or severe) and time point (clinic visit). 
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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Statistical processing will be performed using SAS® software. 
 
12.2 
Sample Size and Power Calculations 
 
A minimum of 15 subjects per dilution series allergen, who exhibit a positive skin response 
(score of 1+, +2 or 3+ during at least one reaction assessment visit) to the dilution series allergen 
and/or at least one of its corresponding reference allergens, is needed to complete the study.  
 
Subjects with a past positive patch test response to at least one of the dilution series allergens 
will be tested with the allergen panel and corresponding reference allergen(s) to which they have 
had the previous response. Subjects with suspicion of metal contact allergy will be tested with all 
dilution series and reference allergens. All subjects will be tested with the excipient controls.  
The common allergens will be tested at the discretion of the investigator.  
 
Past dose response study populations have included 20 adult subjects (per allergen) with a 
historical positive patch test to the corresponding reference allergen. In these studies, 
determination of the optimal test allergen dose was the lowest concentration eliciting a 1+, 2+ or 
3+ positive reaction in 70-90% of subjects with the fewest number of 3+ reactions; therefore a 
minimum of 14 subjects with positive reactions was needed to determine optimal test allergen 
dose. 
 
Due to the fact that not all of the metals being tested on this study have a large database of 
patients with past patch-test positive reactions, the inclusion criteria was modified to include 
subjects with a suspicion of metal allergy, in addition to those with a historical positive patch 
test. Because it is anticipated that not all subjects will test positive, the study will conclude when 
a total of 400 subjects have been tested. 
 
The option of further testing may be considered for any allergen that elicits a minimum of 8 
positive responses. In such a case, the protocol will be amended 
 
12.3 
Data Monitoring and Quality Assurance 
 
The study will be performed according to ICH harmonized Tripartite Guidelines for Good 
Clinical Practice, national legislation and SmartPractice internal SOPs for Clinical Studies.  
Study sites will be visited at least once prior to initiation of the study, at approximately 8-12 
week intervals or as needed during the study and at the conclusion of the study.  The sponsor will 
perform all monitoring.  
 
Subject data will be recorded in data collection forms. These data will be entered into SAS, for 
subsequent analysis, and proofread for entry errors. Statistical analysis will be performed 
according to Good Clinical Practice and ICH guidelines using SAS software per the respective 
analytical parameters. 
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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Page 53 of 82 
27 June 2018 
 
 
13.0 
ADVERSE EVENTS 
 
13.1 
Adverse Event Definitions 
 
 Adverse Event (AE):  Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related 
 Adverse Reaction or Adverse Drug Reaction (ADR): Any adverse event caused by a drug. 
 Life-threatening Adverse Event or Life-threatening Suspected Adverse Reaction: An 
adverse event or suspected adverse reaction is considered ‘life-threatening’ if, in the view of 
either the investigator or the sponsor, its occurrence places the subject at immediate risk of 
death.  This does not include an adverse event or suspected adverse reaction that had it 
occurred in a more severe form, might have caused death. 
 Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction (SSAR): An AE or 
SAR is considered serious if, in the view of either the investigator or sponsor it results in any 
of the following outcomes: 
o Death 
o A life-threatening adverse event 
o Inpatient hospitalization or the prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o Is a congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  
 Suspected Adverse Reaction (SAR): Any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event.  ‘Reasonable possibility’ means there is 
evidence to suggest a causal relationship between the drug and the adverse event.  ‘Suspected 
adverse reaction’ implies a lesser degree of certainty about causality than adverse reaction. 
 Suspected Unexpected Serious Adverse Reactions (SUSAR) 
An adverse reaction that is both unexpected (not consistent with the applicable product 
information) and also meets the definition of a Serious Adverse Event/Reaction. 
 Unexpected Adverse Event (UAE) or Unexpected Suspected Adverse Reaction (USAR):  
An AE or SAR is considered ‘unexpected’ if it is 
o not listed in the investigator brochure 
o not listed at the observed specificity 
o not consistent with the risk information described in the general investigational plan or in 
the current application. 
 
13.2 
Adverse Event Reporting Period 
 
The adverse event-reporting period for each study subject begins at panel application and ends 
with the Day 21 visit. All adverse events that occur in study subjects during the adverse event-

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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reporting period specified in the protocol must be reported. In addition, any known adverse event 
that occurs in a study subject after Day 21 that the investigator determines as possibly related to 
the investigational product must also be reported as an adverse event. 
 
13.3 
Serious Adverse Events 
 
Serious adverse events must be documented and reported to the sponsor, SmartPractice, within 
24 hours of the investigator’s learning/awareness of the event. This initial report must be 
followed by submission of more detailed adverse event within 5 working days.  
 
Serious, unexpected reactions that are not fatal or life-threatening will be filed no later than 15 
calendar days after first knowledge by the sponsor.   
 
Determination of expectedness will be based on the contents of the Investigators Brochure.  
 
13.4 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
 
An adverse event will be reported as a SUSAR if the following three criteria are met: 
1. The event is serious, that is to say irrespective of the dose the event: 
 is fatal, and/or 
 is life-threatening for the subject, and/or; 
 makes hospital admission or an extension of the admission necessary, and/or 
 causes persistent or significant invalidity or work disability, and/or 
 manifests itself in a congenital abnormality or malformation 
2. There is a certain degree of probability that the event is harmful, and an undesirable reaction 
to the experimental product being research, regardless of the administered dosage. In other 
words, there is an adverse reaction. 
3. The adverse reaction is unexpected. That is to say, the nature and severity of the adverse 
reaction are not in agreement with the product information as recorded in the Investigator’s 
Brochure. 
 
Fatal or life-threatening unexpected ADRs will be reported to all regulatory agencies and 
IRB/Ethics Committees by telephone, facsimile or in writing as soon as possible but no later than 
7 calendar days after first knowledge by the sponsor followed by as complete a report as possible 
within 8 additional calendar days. 
 
Deciding whether the adverse event meets the definition of a suspected adverse reaction is 
usually the most difficult determination. The sponsor will evaluate the available information and 
decide whether there is a reasonable possibility that the drug caused the adverse event and, 
therefore, that the event meets the definition of a suspected adverse reaction. The suspected 
adverse reaction must then be reported expeditiously in a safety report if it also meets the 
definitions of serious and unexpected.  
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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The only response to a dermatological patch product that would trigger a SUSAR report would 
be anaphylactic reaction.  There may be other reactions which would be categorized as SUSARs 
that are unknown at this time.   
 
13.5 
Severity 
 
The investigator will provide an assessment of the severity of each adverse event by recording a 
severity rating on the appropriate AE reporting page of the subject’s data collection form.  
(Severity, which is a description of the intensity of manifestation of the AE, is distinct from 
seriousness, which implies a subject outcome or AE-required treatment measure associated with 
a threat to life or functionality.)  Severity will be assessed according to the following scale: 
 
Mild: 
Minimal symptoms / annoying / minimal discomfort. Does not interfere with 
subject’s usual function 
Moderate: Definite discomfort / requires medication for relief. Interferes to some extent with 
subject’s usual function 
Severe: 
Symptoms interfere significantly with subject’s usual function (daily activity / sleep). 
 
The Investigator must supervise topical treatment of subject dermatitis and patch test responses. 
 
13.6 
 Relationship 
 
The investigator will provide an assessment of causal relationship to the study product.  The 
causality assessment must be recorded on the appropriate AE reporting page of the subject’s data 
collection form.  Relationship will be classified according to the following criteria: 
 
Not Related 
No association to the test drug.  Related to other etiologies such as 
concomitant medications or conditions or subject’s known clinical state. 
(An unrelated illness, including the worsening of a pre-existing illness, 
injury or accident). 
Possibly Related 
Uncertain association.  Other etiologies are also possible.  
Definitely Related 
Clear-cut association with improvement upon withdrawal of the test drug.  
Not reasonably explained by the subject’s known clinical state but not an 
anticipated event. 
 
Adverse events that are to be reported as having a relationship with the study patch test panels 
include but are not limited to: 
 A severe reaction to the test tape adhesive or allergen patch that either causes the subject 
to remove the panels prior to the 48 hour return visit or is determined by the investigator 
to be significantly greater in severity than expected or as described in the Investigator’s 
Brochure. 
 Any persistent, escalating, positive patch test reaction at the test site lasting beyond the 
day 21 evaluation that the investigator determines is severe. 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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 Any characteristic associated with a late or persistent reaction (i.e. hyper-pigmentation, 
hypo-pigmentation, pruritus or other) at the test site lasting beyond the day 21 evaluation 
that the investigator determines is severe.  
o Hyperpigmentation: The darkening of an area of the skin caused by an excess of 
pigment in a tissue as opposed to an erythematic response. 
o Hypopigmentation: The loss of skin color caused by melanocyte or melanin depletion, 
or a decrease in the amino acid tyrosine, which is used by melanocytes to make melanin. 
o Pruritus: Itching 
 Any of the following reactions: 
o Active Sensitization: A positive reaction initially appearing at approximately 21 days 
after application. Sensitization may be confirmed if a positive reaction were to appear at 
3-4 days after a repeated application of the allergen at a naïve test site. 
o Acute Anaphylactic Reaction: A severe whole body reaction to a chemical. Symptoms 
develop rapidly, often within seconds or minutes and may include, abdominal pain or 
cramping, abnormal (high pitched) breathing sounds, anxiety, confusion, cough, diarrhea, 
difficulty breathing, difficulty swallowing, fainting, lightheadedness, dizziness, hives, 
itchiness, nasal congestion, nausea, vomiting, palpitations, skin redness, slurred speech 
and wheezing. Patch test substances reported to cause immediate contact reactions are 
usually proteins, protein complexes (e.g., milk, latex) or medicinal substances (e.g., 
aminophenazone, ampicillin, bacitracin, neomycin, and bufexamac).  Immediate reactions 
to a few cosmetic ingredients (balsam of Peru, paraben mix and fragrance mix) and 
miscellaneous items (epoxy resin and Formaldehyde) have also been reported but are very 
uncommon.   
Investigator may refer to the Guideline for Acute Therapy and Management of 
Anaphylaxis by Ring, et. al for more information 
o Bacterial or Viral Infections: These adverse reactions are considered exceedingly rare 
but have been reported. 
o Ectopic Flare: A positive patch test reaction accompanied by a flare of an existing or 
pre-existing dermatitis that was caused by the test allergen. 
o Excited Skin Syndrome (Angry Back): A state of skin hyper-reactivity induced by 
dermatitis on other parts of the body or by a strong positive skin-test reaction in which 
other patch test sites become reactive, especially to marginal irritants. 
o Immediate Contact Urticaria (ICU):  An immediate but transient, localized, swelling 
and redness that occurs on the skin after direct contact with an offending substance. 
(Contact urticaria should be distinguished from allergic contact dermatitis where a 
dermatitis reaction develops hours to days after contact with the offending agent). Most 
non-allergic reactions remain local while ICU may produce generalized urticarial lesions.  
ICU reactions, reported in conjunction with patch testing, are due to higher allergen 
concentrations (e.g. 5% pet). 
o Koebner Phenomenon: Psoriasis plaques that form at the site of a skin injury. A positive 
patch test reaction in a subject with active psoriasis or lichen planus may reproduce these 
dermatoses at the patch site during the weeks after testing. Symptoms are cleared with 
topical corticosteroids. 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
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o Necrosis, Scarring and Keloids: Testing with strong irritants (acids, alkalis or chemicals 
of unknown composition) may produce such adverse events but are considered extremely 
rare. 
o Pressure Effect: An edematous area, typically most intense at the margins resulting from 
the application of patch tests.  Dermatographic individuals are more likely to develop this 
reaction. 
o Tape Reaction: Severe reaction to the tape or adhesive used to hold the patches in place 
such that the subject is forced to remove the patch prior to the 48 hour wear time. 
 
13.7 
Outcome and Follow-up  
 
All unrelated adverse events should be followed until they are resolved or the subject’s 
participation in the study ends. All serious, possibly related and definitely related adverse events 
should be followed until they resolve or until the investigator assesses them as chronic or stable 
even after the subject’s participation in the study is over. Follow up of adverse events must be 
documented on the subject’s data collection form. 
 
SmartPractice will review all unexpected serious adverse events to determine if additional risk 
information should be added to the protocol and/or informed consent form.  If it is determined to 
be necessary, the protocol and informed consent form will be revised and submitted according to 
regulatory requirements. 
 
SmartPractice is required to notify each participating investigator informed of new information 
regarding the investigational drug, particularly with respect to adverse effects and safe use. 
 
14.0 
STUDY DISCONTINUATION  
 
SmartPractice reserves the right to discontinue the study prior to inclusion of the intended 
number of subjects, but intends only to exercise this right for valid scientific or administrative 
reasons. 
 
In the event that the study is prematurely terminated or interrupted all regulatory agencies will be 
notified within 15 days. 
 

Clinical Evaluation of Metal Panel Allergens: 
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SP 14 8MP 201 
 
 
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14.1 
Criteria for Discontinuation 
 
If a serious adverse event occurs that is considered associated with an investigational allergen or 
other patch test material, the study will immediately stop entering subjects until the case has been 
reviewed and further action and/or consequences, such as discontinuation of the study, will be 
considered.  
 
If more than 20% of subjects experience an unacceptable adverse event associated with the 
investigational allergen or other patch test material, the cases will be reviewed and further 
action/consequences, i.e., discontinuation of the study, will be considered. 
 
If more than one subject develops an overreaction, the study will immediately stop entering 
subjects until the case has been reviewed and further action and/or consequences, such as 
discontinuation of the study, will be considered. 
 
The study may also be discontinued for the following reasons: 
 Scientific reasons such as invalid study design, inappropriate test methods or subject 
inclusion. 
 Inability to recruit and enroll sufficient subjects within the study period. 
 Internal administrative reasons. 
 
After discontinuation of the study, the investigator must collect all unused study products and 
other study material and complete appropriate data collection forms. The participating subjects 
should be informed and seen for a final visit. 
 
15.0 
DATA AND RECORD KEEPING 
 
15.1 
Data Collection Form  
 
A completed data collection form is required for each subject included in the study. These 
completed original data collection forms are the sole property of SmartPractice.  Data collection 
forms should not be made available in any form to third parties without written permission from 
SmartPractice, except to authorized representatives from regulatory authorities, Data Protection 
Agency and IEC. 
 
15.2 
Record Retention  
 
To enable evaluations and/or audits from Health Authorities and/or SmartPractice, the 
Investigator agrees to keep appropriate records, including original Informed Consent/Assent 
forms, the identification of all participating subjects (sufficient information to link records, e.g., 
collection forms and hospital records) and supporting study documentation. Records will be 
stored, at the investigative site, as written in the ICH guideline section 4.9.5 until 2 years after the 
last approval of a marketing application in ICH region or at least 2 years have elapsed since the 

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Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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formal discontinuation of clinical development of the investigational product. Storage of all 
original data collection forms and detailed records of the investigational product will be 
maintained by SmartPractice or their designated agent according to the current international 
clinical research regulations.   
 
16.0 
FINANCING AND INSURANCE 
 
SmartPractice will supply all investigational panels, patch test chambers and reference allergens 
free of charge to physician-investigators.  
 
Local physician-investigators will also be appropriately compensated for subject evaluation and 
management fees (E/M fees) that would otherwise not be reimbursable through health insurance. 
Study subjects will be nominally compensated per local and institutional clinical research 
guidelines. All compensation (subjects and investigators) will be subject to institutional, 
IRB/IEC, local and federal regulations and stipulations, and may therefore vary by study site. 
For clinical trials conducted in the U.S., SmartPractice assumes responsibility and is covered by 
separate Clinical Trials Liability Insurance (Travelers Property Casualty Co. of America, P # 
ZPP21N3040615I2); $1,000,000 per occurrence and $3,000,000 general aggregate.    
 
17.0 
DATA PUBLICATION  
 
After study closing and/or completion, data analysis will be performed by SmartPractice or a 
designated agent. The results will be presented to the investigator(s). Based on these data a 
Clinical Study Report will be prepared in co-operation with the investigator(s). Clinical Study 
Report will be submitted to the regulatory authorities and/or any other regulatory agency that 
requires this information.  
 
Any proposed oral or written use of study results by local and/or principle investigators must be 
submitted to SmartPractice for review at least 30 days prior to submission for publication, 
presentation, or use. This condition is stated so that SmartPractice will be aware of all written 
and oral presentations of the data and does not imply any editorial review or restriction of the 
contents of the presentation or use. 
 
18.0 
AMENDMENT I 
 
The following changes have been made to the protocol. 
 
The address for Dr. Pigatto  has been changed from: 
To: 
Section 2.0, Page 3, and 
Section 4.0, Page 8 
University of Milano 
Dipartimento di Scienze 
Biomediche, Chirurgiche ed 
Odontostomatologiche 
H Galeazzi Via Galeazzi 4 
University of Milano- 
Dipartimento di Scienze 
Biomediche, Chirurgiche ed 
Odontostomatologiche 
Servizio di Dermatologia/ 

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SP 14 8MP 201 
 
 
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20161 Milano, Italy 
Tel: +39 02.33.14.139 
e-mail: 
pigatto@pigattobersani.it 
Servizio di dermatologia 
allergologica 
IRCCS Istituto Ortopedico 
Galeazzi 
Via R. Galeazzi 4 
20161 Milano, Italy 
Tel: +39 0266.214761 
e-mail: paolo.pigatto@unimi.it 
The site for Dr. Pigatto 
has been changed from: 
To: 
Section 4.4, Page 10 
University of Milano 
Dipartimento di Scienze 
Biomediche, Chirurgiche ed 
Odontostomatologiche 
H Galeazzi Via Galeazzi 4 
20161 Milano, Italy 
University of Milano- 
Dipartimento di Scienze 
Biomediche, Chirurgiche ed 
Odontostomatologiche 
Servizio di Dermatologia/ 
Servizio di dermatologia 
allergologica 
IRCCS Istituto Ortopedico 
Galeazzi 
Via R. Galeazzi 4 
20161 Milano, Italy 
Primary Endpoint 
has been changed from: 
To: 
Section 4.8, Page 12 
Section 4.15, Page 19-20 
Section 7.1, Page 27 and 
Section 12.1, Page 51 
Approximately 50% of the 
positive responses attributed to 
the dilution series allergen; 
At least 50% of the positive 
responses attributed to the 
dilution series allergen; 
Secondary Endpoint 
has been changed from: 
To: 
Section 4.8, Page 12-13 
Section 4.15, Pages 19-20 
Section 7.1, Page 27-28 and 
Section 12.1, Page 51 
Frequency of adverse events. 
Frequency of all adverse 
events. Documentation for all 
local and systemic adverse 
reactions classified by the 
investigator as possibly or 
definitely related to the study 
product (e.g., erythema, hyper-
pigmentation, hypo-
pigmentation, skin thinning or 
dermatitis flare) will include 
grade (mild, moderate or 
severe) and time point (clinic 
visit). 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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Exclusion Criteria b 
has been changed from: 
To: 
Section 9.2.2, Page 31 
Topical treatment with 
corticosteroids or other 
immunosuppressive agents on or 
near the test area during the 14 
days prior to inclusion in this 
study. 
 
Topical treatment with 
corticosteroids or other 
immunosuppressive agents on 
or near the test area 14 days 
prior to inclusion through the 
end of the subject’s 
participation in the study. 
Exclusion criteria c 
has been changed from: 
To: 
Section 9.2.2, Page 31 
Systemic treatment with 
corticosteroids (equivalent to > 
10 mg prednisone) or other 
immunosuppressive agents 
during the 14 days prior to 
inclusion in this study. Inhaled 
treatments are permitted.  NOTE: 
Steroidal nose or eye drops are 
permitted. 
 
Systemic treatment with 
corticosteroids (equivalent to 
> 10 mg prednisone) or other 
immunosuppressive agents 14 
days prior to inclusion through 
the end of the subject’s 
participation in the study. 
Inhaled treatments and 
steroidal nose or eye drops are 
permitted. 
Exclusion Criteria d 
has been changed from: 
To: 
Section 9.2.2, Page 31 
Treatment with ultraviolet (UV) 
light (including tanning) during 
the 3 weeks prior to inclusion in 
this study. 
 
Treatment with ultraviolet 
(UV) light (including tanning) 
during the 3 weeks prior to 
inclusion through the end of 
the subject’s participation in 
the study. 
Exclusion Criteria f 
has been added. 
 
Section 9.2.2, Page 31 
Known or suspected infection of the skin, joints or other site(s) 
associated with metal exposure 
Exclusion Criteria h 
has been added. 
 
Section 9.2.2, Page 31 
A condition such as; psoriasis, dermatitis herpetiformis, mycosis 
fungoides or cutaneous T-cell lymphoma that may confound the 
evaluation of allergic contact dermatitis. 
The following paragraph  
has been added. 
 
Section 10.1, Page 34 
Age of diagnosis, distribution, severity and current medication use 
(including those being withheld for the duration of the study) will 
be captured for subjects who exhibit concurrent atopic dermatitis 
and irritant dermatitis 
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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The following paragraphs have been added 
 
Section 10.2, Pages 37-38 
Patches that do not remain in place (completely detached) for the 
intended wear period (approximately 48 hours or two days) will 
not be replaced.  The subject will be asked to return for follow-up 
visits until all patch sites reactions have resolved but data from this 
subject will not be included in the analysis of positive responses 
necessary to determine optimal dose. 
 
Subjects whose patches are not worn for the intended wear period 
may return to be retested after 3 weeks at the discretion of the 
Investigator providing the skin site remains free of conditions that 
may affect test results 
The following paragraph 
has been changed from: 
To: 
Section 11.1, Pages 46 
Allergens on panels 1-5 will be 
randomized within each panel 
into three different 
configurations, per standard 
protocol. These different allergen 
configurations will be randomly 
assigned to subjects as they enter 
the study. The investigators and 
subjects will be aware of the 
allergens and the patch test doses 
on the test panels but will not be 
aware of the placement of the 
allergens on the individual panels 
(the different panel 
configurations).   
 
The lead chemist in the 
department of pharmaceutical 
development at SmartPractice 
Denmark is responsible for the 
randomization of allergens on 
panels 1-5. The allergens will 
be randomized within each 
panel into three different 
configurations, per standard 
protocol.  The different 
allergen configurations will be 
randomly assigned to subjects 
as they enter the study. The 
investigators and subjects will 
be aware of the allergens and 
the patch test doses on the test 
panels but will not be aware of 
the placement of the allergens 
on the individual panels (the 
different panel 
configurations).  The key to 
the randomization scheme will 
be kept confidential at 
SmartPractice Denmark until 
it is forwarded to data 
management for analysis of 
the study results following 
completion of all study related 
procedures.  
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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19.0 
AMENDMENT II 
 
The following changes have been made to the protocol. 
 
The credentials in: 
have been changed from: 
To: 
Section 2.0, Page 3 and 
Section 4.3, Page 8  
Thomas Rustemeyer, MD, PhD Prof. dr. Thomas Rustemeyer 
The phone number in: 
has been removed. 
 
Section 4.3 
or +31.20.670.4230 
The wording in: 
has been changed from: 
To: 
Section 4.9, Page 13 
Section 9.0, Page 30 
Section 9.1, Page 30 
Section 10.1, Page 37 (bullet 3) 
and Section 12.2, Page 52 
All subjects will be tested with 
the common allergen/excipient 
control panel. 
 
All subjects will be tested 
with the excipient controls.  
The common allergens will 
be tested at the discretion of 
the investigator. 
The wording in: 
has been changed from: 
To: 
Section 6.12, Page 26 
Metal Panel T.R.U.E. TEST 
will be indicated for patients in 
whom the physician suspects 
metal exposure has resulted in: 
 Cardiac implant (stent, 
pacemaker, etc.) 
 Orthopedic implant (knee, 
hip or other) 
 Gynecological implant or 
device 
 Surgical hardware (plates, 
screws, wires, pins, rods, 
expanders, staples) 
 Dental metal implant 
 Dental metal appliance, 
prosthesis or filling 
 Inflammation associated 
with an oral metal implant: 
(no changes to remainder of 
section) 
Metal Panel T.R.U.E. TEST 
will be indicated for patients 
exposed to cardiac implants 
(stent, pacemaker, etc.), 
orthopedic implants (knee, 
hip or other), gynecological 
implants or devices, surgical 
hardware (plates, screws, 
wires, pins, rods, expanders, 
staples), dental metal 
implants, or dental metal 
appliances, prosthesis or 
fillings whose exposure to 
has resulted in: 
 Inflammation associated 
with an oral metal 
implant: 
(no changes to remainder of 
section) 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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The wording in: 
has been added. 
 
Section 9.2.1, c, Page 30 
 
1) systemic birth control (i.e., oral contraceptives, skin patch, 
vaginal ring, implant, injection, or intrauterine device (IUD), 
which contains either a hormone or copper); 2) double barrier 
method (i.e., diaphragm, cervical cap, sponge, condom with 
spermicide);. 
The note in: 
has been added. 
 
Section 9.2.1, Page 31 
(Note:  Cervical cap and abstinence from sexual intercourse 
will not be considered as acceptable methods of 
contraception for subjects enrolled in Japan) 
The wording in: 
has been added. 
 
Section 9.2.2, a, Page 31 
Breastfeeding may be resumed upon completion of the study. 
The visit schedule in: 
has been added. 
 
Section 10.0, Pages 33 
 
 
The note in: 
has been added. 
 
Section 10.1, bullet 1, Page 34  
 (Note: Legal representative in addition to subject must sign 
consent form for subjects aged 18-19, enrolled in Japan.) 
The wording in: 
has been changed from: 
To: 
Section 10.1, Page 34 
Urine pregnancy test (if 
needed)  
Dipstick urine pregnancy test 
for all females of 
childbearing potential (mouse 
anti-beta hCG antibody 
conjugated to colloidal gold 
and goat anti-alpha hCG 
antibody coated on the 
membrane)  
The wording in: 
has been changed from: 
To: 
Section 10.3.2, Page 41  
Skin reactions at test sites 
will be scored as: (Neg) 
negative; (IR) irritant 
reaction; (?+) doubtful 
reaction; (+) weak positive 
reaction; (+) strong positive 
reaction; or (+) extreme 
positive reaction. 
Skin reactions at test sites 
will be scored as: (Neg) 
negative; (IR) irritant 
reaction; (?+) doubtful 
reaction; (1+) weak positive 
reaction; (2+) strong positive 
reaction; or (3+) extreme 
positive reaction. 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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The wording in: 
has been changed from: 
To: 
Section 10.4.2, Pages 42-43 
All reactions (scores of 1+, 
2+ or 3+) will be categorized 
as either late or persistent 
and characterized by the 
presence of hyper/hypo 
pigmentation and/or pruritus 
or other described symptom. 
Late reactions are defined as 
reactions that initially occur 
at 7-10 days after application 
of the panels. Persistent 
reactions are defined as 
reactions that appear at day 
2- 4 and persist through day 
7-21.  Persistent reactions 
will be clarified as either 
persistent-healing or 
persistent-escalating.   
All reactions (scores of 1+, 
2+ or 3+) will be categorized 
as either late or persistent and 
characterized by the presence 
of hyper/hypo pigmentation 
and/or pruritus or other 
described symptom.  
Persistent reactions will be 
further clarified as either 
persistent-healing or 
persistent-escalating.   
 
Definitions: 
Late Reaction: A reaction 
that initially appears at day 
10-14 after application of 
panels. 
Persistent Reaction: A 
reaction that initially appears 
at day 2- 4 and persists 
through day 7-21 or beyond.  
Persistent-Healing:  A 
persistent reaction that has 
not worsened since the 
previous evaluation, remains 
the same or appears to be 
healing. 
Persistent-Escalating: A 
persistent reaction that has 
worsened since the previous 
evaluation. 
Hyperpigmentation: The 
darkening of an area of the 
skin caused by an excess of 
pigment in a tissue as 
opposed to an erythematic 
response. 
Hypopigmentation:  The loss 
of skin color caused by 
melanocyte or melanin 
depletion, or a decrease in the 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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amino acid tyrosine, which is 
used by melanocytes to make 
melanin. 
Pruritus: Itching 
The wording in: 
has been added. 
 
Section 11.1, Page 44 
Panels are to be stored under refrigeration at 2-8oC (36-46oF).  
The wording in: 
has been added. 
 
Section 11.1, Page 47 
The allergens on panel 6 will not be randomized into 
different configurations.  Should the Investigator elect to 
omit the common allergens from an individual’s patch 
testing, the panel should be cut below positions 2 and 8 as 
shown in Figure 5.   
Figure 9, Panel 6 
Configuration and Cutting 
Instructions in: 
has been added. 
 
Section 11.1, Page 47 
 
 
The wording in 
has been added. 
 
Section 11.1, Page 47  
Unused portion of the panel is not to be discarded. 
The wording in: 
has been changed from: 
To: 
Section 11.1, Page 47 
The use of the investigational 
product for the individual 
subject, including the subject 
number, date of application 
of the test panel, and date of 
removal of the test panel will 
be documented. 
The use of the investigational 
product for the individual 
subject, including number 
and identification of specific 
panels applied, application 
(or not) of common allergens 
and date and time of 
application and removal will 
be documented. 
The Dilution Series Tables for 
Panels 1-5 in: 
have been changed from: 
To: 
Section 11.1, Pages 48-49 
3 columns headed: 
(Allergen) Dilution Series 
Excipient 
Dose 
4 columns headed: 
Allergen 
Excipients 
Ascending Dosages 
Randomized Among 
Positions 
The Panel 6 Common 
Allergens/Excipient Control 
Table in: 
has been changed from: 
To: 
Section 11.1, Page 49 
3 columns headed: 
Allergen/Control, Excipient, 
4 columns headed: 
Allergen/Control, Excipient, 

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SP 14 8MP 201 
 
 
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Dose 
Dose, Position 
The wording in: 
has been changed from: 
To: 
Section 16.0, Page 59 
For clinical trials conducted 
in the U.S., SmartPractice 
assumes responsibility and is 
covered by separate Clinical 
Trials Liability Insurance 
(Columbia Casualty 
Company, Policy number: 
ADT2097453381); 
$1,000,000 per occurrence 
and $3,000,000 general 
aggregate.    
For clinical trials conducted 
in the U.S., SmartPractice 
assumes responsibility and is 
covered by separate Clinical 
Trials Liability Insurance 
(Travelers Property Casualty 
Co. of America, P # 
ZPP21N3040615I2); 
$1,000,000 per occurrence 
and $3,000,000 general 
aggregate.    
 
20.0 
AMENDMENT III 
 
The contact information for 
Kayoko Matsunaga, M.D., 
Ph.D. in: 
has been changed from: 
To: 
Section 1.0, Page 1 
Vice-President of Fujita Health 
University 
Professor and Chairperson 
Department of Dermatology 
Professor  
Department of Integrative 
Medical Science for Allergic 
Disease  
The address for Akiko 
Yagami, MD, PhD in: 
has been changed from: 
To: 
Section 2.0, Page 4 
Section 4.4, Page 9 and 
Section 4.4, Page 10  
Associate Professor of 
Department of Dermatology 
Fujita Health University 
School of Medicine 
1-98, Dengakugakubo, 
Kutsukake-cho, Toyake,  
Aichi 470-1192, Japan  
Professor, Department of 
Allergology, 
Fujita Health University 
Second Educational Hospital 
3-6-10, Otobashi,  
Nakagawa-ku,  
Nagoya, 454-8509, Japan 
A new Investigator in: 
has been named. 
 
Section 2.0, Page 4 and 
Section 4.3, Page 9  
Hiromi Kanto MD, PhD 
Department of Dermatology, School of Medicine 
Faculty of Medicine, Toho University 
Toho University Omori Medical Center 
6-11-1, Omori-Nishi, Ota-ku 
Tokyo 143-8541 Japan 
The following Investigator 
has been removed. 
 
Section 2 
Risa Tamagawa-Mineoka MD 

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SP 14 8MP 201 
 
 
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Section 4.3 
Department of Dermatology 
Graduate School of Medical Science 
Kyoto Prefectural University of Medicine 
465 Kajii cho, Kawaramachi Hirokoji, Kamigyo ku 
Kyoto 602-8566, Japan 
A new Sub-Investigator in: 
has been added. 
 
Section 4.3, Page 9  
Professor Yoshiaki Kubo 
Head of Dermatological Science, Tokushima University 
Hospital 2-50-1 Kuramoto-cho 
Tokushima City, Tokushima Japan 7708503 
The site in:  
has been added. 
 
Section 4.4, Page 10 
Department of Dermatology, School of Medicine 
Faculty of Medicine, Toho University 
Toho University Omori Medical Center 
6-11-1, Omori-Nishi, Ota-ku, Tokyo 143-8541 Japan 
The site in:  
has been removed. 
 
Section 4.4 
Department of Dermatology 
Graduate School of Medical Science 
Kyoto Prefectural University of Medicine 
465 Kajii cho, Kawaramachi Hirokoji, Kamigyo ku 
Kyoto 602-8566, Japan 
The IRB in: 
has been added. 
 
Section 4.5, Page 11 
Toho University Omori Medical Center Institutional Review 
Board 
Toho University Omori Medical Center 
6-11-1, Omori-Nishi, Ota-ku 
Tokyo 143-8541 Japan 
The IRB in: 
has been removed. 
 
Section 4.5 
Ethical Review Board, 
Graduate School of Medical Science,  
Kyoto Prefectural University of Medicine, 
465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku,  
Kyoto 602-8566, Japan 
The wording in: 
has been changed from: 
To: 
Section 4.7, Page 12, and 
Section 8.1, Page 28  
This is a prospective, multi-
center, double-blind, 
randomized design 
This is a prospective, multi-
center, randomized, double-
blind design.  
The sentences in: 
have been added. 
 
Section 4.7, Page 12, and 
Section 8.1, Page 29  
That is, the allergen doses on each panel will be randomized 
into three different configurations, which will be randomly 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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27 June 2018 
 
 
assigned to subjects as they enter the study.  Although the 
investigators and subjects will know which allergen is being 
tested, they will be blinded to the placement of the allergen 
doses within each panel.   
The primary endpoint in: 
has been changed from:  
To: 
Section 4.8, Page 12 
Section 4.15,Page 19-20  
Section 7.1 , Page 27, and  
Section 12.1, Page 51  
Determination of optimal test 
allergen dose as: 
 
The lowest dilution series 
dose eliciting a positive 
response (defined as score 
of 1+, 2+ or 3+ during at 
least one reaction 
assessment visit) in a 
minimum of 15 subjects 
who respond positively to 
the dilution series allergen, 
associated reference 
allergen or both.  If a 
significant number of 3+ 
reactions are elicited, the 
optimal allergen dose 
based on 1+ and 2+ 
positive reactions will be 
selected.  
 
At least 50% of the 15 
positive responses 
attributed to a dilution 
series allergen. 
 
Moderate to very good 
concordance (measured 
using Cohen’s kappa, 
includes all subjects who 
test each allergen) between 
the dilution series and 
reference allergens. [less 
than 0% no agreement, 0-
20% poor, 20-40% fair, 
40-60% moderate, 60-80% 
good, 80% or higher very 
good]. 
A positive response to at least 
one of the reference allergens 
associated with each dilution 
Determination of optimal test 
allergen dose as: 
 The lowest concentration 
of each dilution series 
allergen eliciting positive 
responses in a minimum 
of 15 subjects. Positive 
responses are defined as 
score of 1+, 2+ or 3+ 
during at least one 
reaction assessment visit. 
If a significant number of 
3+ responses are elicited, 
the dose will be selected 
based on 1+ and 2+ 
responses. 
 For all sites with the 
exception of Germany: 
Concordance will be 
measured using Cohen’s 
kappa where less than 0% 
indicates no agreement, 0-
20% indicates poor 
agreement, 20-40% 
indicates fair agreement, 
40-60% indicates 
moderate agreement, 60-
80% indicates good 
agreement and 80% or 
higher indicates very good 
agreement. Concordance 
will be measured using all 
subjects who are tested 
with each allergen and 
corresponding reference 
allergen. 
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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27 June 2018 
 
 
series (in the cases where there 
are two or more reference 
allergens) will be considered 
reference positive. 
The sentence in: 
has been added. 
 
Section 4.9, Page 13, and  
Section 9.0, Page 30  
The study population should include a reasonable representation 
of patients who have undergone a metal replacement procedure. 
The paragraphs in: 
have been changed from: 
To: 
Section 4.10 Pages 13 and  
Section 12.2, Page 52 
Because not all subjects will 
have a positive reaction, the 
total number of subjects tested 
will be greater than 15 per 
dilution series allergen. The 
study will conclude when a 
total of 400 subjects have been 
tested.  However, further 
testing may be required on any 
of the dilution series allergens 
that elicit a minimum of 8 
positive responses; in such a 
case, the protocol will be 
amended. 
Past dose response study 
populations have included 20 
adult subjects (per allergen) 
with a historical positive patch 
test to the corresponding 
reference allergen. In these 
studies, determination of the 
optimal test allergen dose was 
the lowest concentration 
eliciting a 1+, 2+ or 3+ 
positive reaction in 70-90% of 
subjects with the fewest 
number of 3+ reactions; 
therefore a minimum of 14 
subjects with positive 
reactions was needed to 
determine optimal test 
allergen dose. 
 
Due to the fact that not all of 
the metals being tested on this 
study have a large database of 
patients with past patch-test 
positive reactions, the 
inclusion criteria was 
modified to include subjects 
with a suspicion of metal 
allergy, in addition to those 
with a historical positive patch 
test. Because it is anticipated 
that not all subjects will test 
positive, the study will 
conclude when a total of 400 
subjects have been tested 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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Page 71 of 82 
27 June 2018 
 
 
whether or not the 15 positive 
response subjects per allergen 
quota is met. 
The option of further testing 
may be considered for any 
allergen that elicits a 
minimum of 8 positive 
responses. In such a case, the 
protocol will be amended. 
The sentence in: 
has been added. 
 
Section 4.12 , Page 16-17 and 
Section 11.2, Page 51  
Subjects enrolled in Germany will not be tested with the 
reference allergens 
The sentences in: 
have been changed from: 
To: 
Section 4.13, Page 17, C, D 
and E, 
Section 10.3.2, Page 41 
Section 10.4.2 , Page 43 and 
Section 10.5, Page 43  
Photographs of site reactions 
may be taken at the discretion 
of the Investigator 
De-identified photographs of 
site reactions may be taken at 
the discretion of the 
Investigator and will not be 
reviewed or collected by the 
study sponsor. 
The sentence in: 
has been changed from: 
To: 
Section 4.14 (Visit 4), Page 18 
Section 4.14 (Visit 5), Page 
18-19 
Categorization of positive 
reactions as late or persistent; 
characterized by the presence 
of hyper/hypo pigmentation 
and/or pruritus or other 
described symptoms 
Categorization of positive 
reactions as late or persistent 
The sentence in: 
has been added. 
 
Section 4.16 , Page 20 and 
Section 8.6, Page 29  
 
When this maximum number of subjects has been reached the 
sponsor of the study will inform the investigator that the study 
has been concluded at that site. 
The sentence in: 
has been changed from: 
To: 
Section 4.16 , Page 20 and 
Section 8.6, Page 29 
 
The final report will be 
submitted to the Principal 
Investigator within 120 days of 
data base lock. 
The final report will be 
submitted to the Principal 
Investigator within 120 days 
of data base lock and to the 
FDA, European Commission 
and PMDA within 1 year of 
study completion. 
The paragraph in: 
has been changed from: 
To: 
Section 8.3, Page 28-29 
Independent IRB/Ethics 
The study protocol, any 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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Page 72 of 82 
27 June 2018 
 
 
committee approval of study 
protocol, any amendments and 
the informed consent form will 
be obtained prior to study 
initiation or prior to 
implementation of protocol 
changes. This study will not 
proceed without receipt of all 
written approvals.  
amendments and the informed 
consent will receive favorable 
approvals from all regulatory 
authorities (US-FDA, 
Switzerland-Health Authority 
Swissmedic, Italy-Italian 
Medicines Agency, 
Netherlands-Medicines 
Evaluation Board, Germany-
Paul Ehrlich Institut, Japan- 
PMDA) and from independent 
IRB/Ethics committees for 
each study site prior to study 
initiation or prior to 
implementation of protocol 
changes. This study will not 
proceed without receipt of all 
written approvals.  
The sentence in: 
has been changed from: 
To: 
Section 9.0, Page 29 
 
Subjects with a past positive 
patch test response to at least 
one of the dilution series 
allergens will be tested with 
the allergen panel and 
corresponding reference 
allergen(s) to which they have 
had the previous response. 
Subjects with a past positive 
patch test response to at least 
one of the dilution series 
allergens will be tested with 
the allergen panel and 
corresponding reference 
allergen(s) (with the exception 
of subjects enrolled in 
Germany who will not be 
tested with the reference 
allergens) to which they have 
had the previous response. 
The sentence in: 
has been changed from: 
To: 
Section 9.1, Page 30 
 
Sensitive subjects (those who 
have had a past positive patch 
test to at least one of the 
dilution series allergens) will 
be tested with the allergen 
panels(s) and corresponding 
reference allergen to which 
they have had a previous 
response. 
Sensitive subjects (those who 
have had a past positive patch 
test to at least one of the 
dilution series allergens) will 
be tested with the allergen 
panels(s) and corresponding 
reference allergen(s) (with the 
exception of subjects enrolled 
in Germany who will not be 
tested with the reference 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
SmartPractice 
Page 73 of 82 
27 June 2018 
 
 
allergens) to which they have 
had a previous response. 
The notes in: 
have been added. 
 
Section 9.2.1, c, Page 31 
(bullets 2 and 3) 
o A double-barrier method must be used for all subjects 
enrolled in Switzerland who are practicing non-systemic 
methods of birth control. 
o Abstinence from sexual intercourse will not be considered 
an acceptable method of contraception for subjects enrolled 
in Switzerland. 
The following exclusion criteria required in Germany only 
have been added to: 
 
Section 9.2.2, Page 31-32 
 Alcohol abuse as well as drug and/or medication abuse 
 Severe psychiatric, psychological or neurological disorders 
 Patients in any relationship or dependency with the sponsor 
and/or investigator 
 General inflammatory as well severe acute and chronic 
inflammatory diseases 
 Malignancy during the previous 5 years 
 Completed or ongoing long-term treatment with tranquilizer 
or psycho active drug 
The sentence in: 
has been changed from: 
To: 
Section 9.3, Page 32 
Data from withdrawn subjects 
may be used in safety analysis. 
 
Data from withdrawn subjects 
may be used in the safety 
analysis and will remain 
anonymous. 
The sentence in: 
has been added. 
 
Section 9.3, Page 32 
(bullet 1) 
Overreaction to an allergen.  Defined as a response greater than 
Extreme Positive (3+). A severe reaction to the test tape 
adhesive or allergen patch that either causes the subject to 
remove the panels prior to the 48 hour return visit or is 
determined by the investigator to be significantly greater in 
severity than expected or as described in the Investigator’s 
Brochure. 
The sentence in: 
has been added. 
 
Section 9.4, Page 33  
The Investigator may withdraw a subject if the subject does not 
meet the study requirements. 
The sentence in: 
has been changed from: 
To: 
Section 10.1, Page 36 
Subjects who qualify for 
participation will have the 
investigational allergen 
panel(s) and reference 
Subjects who qualify for 
participation will have the 
investigational allergen 
panel(s) and reference 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
SmartPractice 
Page 74 of 82 
27 June 2018 
 
 
allergens applied to the 
paraspinal region of the upper 
back 
allergens applied (with the 
exception of subjects enrolled 
in Germany who will not be 
tested with the reference 
allergens) to the paraspinal 
region of the upper back 
The sentences in: 
have been added. 
 
Section 10.1, Page 36 
PatchMap may be used to document panel placement. 
The use of PatchMap will be required in Germany. 
The sentence in: 
has been added. 
 
Section 10.1, Page 36 
In summary, within these parameters, investigators will use 
their medical expertise to determine panel placement based on 
the features of each subject’s back as they would normally do in 
clinical practice. 
The sentence in: 
has been changed from: 
To: 
Section 10.1, Page 37 
Sensitive subjects (those who 
have had a past positive patch 
test to at least one of the 
dilution series allergens) will 
be tested with the allergen 
panels(s) and corresponding 
reference allergen(s) to which 
they have had a previous 
response.  
Sensitive subjects (those who 
have had a past positive patch 
test to at least one of the 
dilution series allergens) may 
be tested with the allergen 
panels(s) and corresponding 
reference allergen(s) (with the 
exception of subjects enrolled 
in Germany who will not be 
tested with the reference 
allergens) to which they have 
had a previous response.  
Two bullets in: 
have been added. 
 
Section 10.1, Page 37 
 The Investigator will use his or her experience and medical 
expertise to determine if a subject with a past positive patch 
result should be tested to all dilution series allergens or only 
to the allergen to which the subject has had the past 
response.  
 Subjects with a past positive response to copper, zinc, tin, 
manganese or molybdenum will be tested with the panel 
containing the past positive response allergen plus the other 
allergen(s) located on the same panel.  Specifically, Panel 2 
contains copper, zinc and tin, and Panel 3 contains 
manganese and molybdenum.  Hence, subjects with a past 
positive response to one of the allergens on the panel will 
also be tested with the other allergen(s) located on the same 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
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Page 75 of 82 
27 June 2018 
 
 
panel. It will not be necessary to test the additional reference 
allergens. 
The final bullet in: 
has been changed from: 
To: 
Section 10.1, Page 37 
 All subjects will be tested 
with the excipient controls 
on Panel 6. The common 
allergens will be tested at 
the discretion of the 
investigator.  
  
 All subjects will be tested 
with the excipient controls 
on Panel 6. The 
Investigator will use his or 
her experience and 
medical expertise to 
determine if a subject with 
a strong suspicion of metal 
contact allergy who has 
not undergone previous 
patch testing will benefit 
from being patch tested 
with the four common 
allergens (nickel, 
chromate, cobalt and gold) 
in order to provide the 
individual with a complete 
diagnosis of metal contact 
allergy. Should the 
Investigator decide that 
testing with the four 
common allergens will not 
be of benefit to the 
subject, the Investigator 
will cut Panel 6 below 
positions 2 and 8 as 
illustrated in Figure 9, 
(Section 11.1, 
Investigational Allergen 
Panels) before applying 
the panel. 
The sentence in: 
has been changed from: 
To: 
Section 10.2, Page 38 
Following the 15 minute wait, 
panel 1-6 tape sites (entire 
panel minus the chip sites) 
then the polyester chip sites 
will be evaluated for skin 
irritation.  
Following the 15 minute wait, 
tape sites (entire panel minus 
the chip sites) then the 
polyester chip sites will be 
evaluated for skin irritation.  
The section on skin irritation has been added. 
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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documentation: 
Section 10.2, Page 38 
Skin irritation will be documented as follows: 
 Panels 1-6: Irritation attributed to the adhesive used to 
adhere the panels to the skin (tape irritation) will be 
documented if the site of the entire panel with the exception 
of the chip sites, as shown below in Figure 5, shows signs of 
irritation 
 Panels 1-6:  Irritation attributed to the gel chips will be 
documented if all chip sites show signs of irritation.  Note:  
To ensure that irritation resulting from skin contact with the 
polyester chip is not confused with an allergic response to a 
specific allergen, all of the polyester chip sites must present 
the same or nearly the same degree of irritation. 
 Panel 1: Chips on positions 1-4 and  7-10 will be 
evaluated for irritation 
 Panel 2: Chips on positions 1-12 will be evaluated for 
irritation 
 Panel 3: Chips on positions 1-4 and 7-10 will be 
evaluated for irritation 
 Panel 4: Chips on positions 1-12 will be evaluated for 
irritation 
 Panel 5: Chips on positions 1-4 and  7-10 will be 
evaluated for irritation 
 Panel 6: Chips on positions 1-4 and 7-9 will be 
evaluated for irritation. If Panel 6 is cut to avoid patch 
testing with the common allergens chips on positions 3-
4 and 9 will be evaluated. 
Panels 7-8:  Irritation attributed to the adhesive used to adhere 
the panels to the skin (tape irritation) will be documented if the 
site of the entire panel with the exception of the patch test 
chambers show signs of irritation.  This will be similar to the 
tape irritation example shown below in Figure 5 but the 
chambers used in the Finn Chamber product are round, not 
square. 
Figure 5: 
has been added. 
 
Section 10.2, Page 40 
 
 
The paragraph in: 
has been changed from: 
To: 
Section 10.3.1, Page 40 
Panel 1-6 tape sites (entire 
panel minus the chip sites) 
then the polyester chip sites 
will be evaluated for skin 
irritation.    
Skin irritation due to the patch 
panel tape or chip will be 
evaluated and documented per 
the instructions presented in 
Section 10.2 Irritation that 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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27 June 2018 
 
 
increases in severity or 
persists beyond visit 3 will be 
followed to resolution.  
The paragraph in: 
has been added. 
 
Section 10.3.1, Page 42 
To ensure that irritation resulting from skin contact with the 
polyester chip is not confused with an allergic response to a 
specific allergen, all of the polyester chip sites on each panel 
must present the same or nearly the same degree of irritation. 
The score scale for polyester chip irritation has been added 
to: 
 
Section 10.4.1, Page 42  
 
 
The sentence in: 
has been changed from: 
To: 
Section 10.4.2, Page 42  
 
Categorization of positive 
reactions as late or persistent; 
characterized by the presence 
of hyper/hypo pigmentation 
and/or pruritus or other 
described symptoms 
All reactions (scores of 1+, 2+ 
or 3+) will be categorized as 
either late or persistent. 
Persistent reactions will be 
further clarified as either 
persistent-healing or 
persistent-escalating.  . 
The definition in: 
has been changed from: 
To: 
Section 10.4.2, Page 43 
Late Reaction: A reaction that 
initially appears at day 10-14 
after application of panels. 
Late Reaction: A reaction that 
initially appears at day 7-14 
after application of panels. 
The sentence in: 
has been changed from: 
To: 
Section 10.5, Page 43  
Categorization of positive 
reactions as late or persistent; 
characterized by the presence 
of hyper/hypo pigmentation 
and/or pruritus or other 
described symptoms 
All reactions (scores of 1+, 2+ 
or 3+) will be categorized as 
either late or persistent. Late 
reactions are defined as 
reactions that initially occur at 
7-10 days after application of 
the panels. Persistent reactions 
are defined as reactions that 
appear at day 2-4 and persist 
through day 7-21.  Persistent 
reactions will be clarified as 
either persistent-healing or 
persistent-escalating. 
The following has been added to the illustration of position 
numbering in: 
 
Figure 7, Page 45 
 
Notations indicating tape notches and an up arrow to indicate 
product orientation. 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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Page 78 of 82 
27 June 2018 
 
 
The paragraph following: 
has been added. 
 
Figure 7, Page 45 
 
An up arrow and two notches indicate the proper product 
orientation.  The uppermost notch on the left side of the panel 
indicates the top left of the panel, the lower notch indicates the 
bottom of the panel. The patch chip numbering is unmistakable 
when the panel is removed from its pouch. Panels are to be 
applied with the numbers facing upright. 
Figure 8 in: 
has been added. 
 
Section 11.1, Page 476  
 
. 
The paragraph and table in: 
has been added. 
 
Section 11.1, Page 46  
 
In order to differentiate between panels once they are applied 
the following chip numbers are used for each panel. The set of 
numbers used is unique to each panel so that individual panels 
can easily be identified: 
Panel 1: 1-4, 7-10 
Panel 2: 13-24 
Panel 3: 25-28, 31-34 
Panel 4: 25-36 
Panel 5: 3-6, 9-12 
Panel 6: 1, 4, 5, 7, 8, 12, 28 
The paragraph in: 
has been added. 
 
Section 11.1, Page 47  
The remaining portion of the panel must be applied as it 
contains the excipient and blank patch controls.  Scores for the 
PVP (Position 3), blank (Position 4) and HPC (Position 9) 
patches will be recorded in the case report forms as originally 
intended, in fields for positions 3, 4 and 9.  Positions 1, 2 and 7, 
8 will be documented in the case report form as ‘not applied’. 
Figure10 in: 
has been added. 
 
Section 11.2, Page 50 
 
 
The definitions for 
hyperpigmentation, 
hypopigmentaton and 
pruritus from: 
have been moved to: 
 
Section 10.4.2 
Section 13.6, Page 56  
 
The sentence from: 
has been removed. 
 
Section 12.2 
Previous studies have indicated that this number is sufficient for 
determining an effective allergen dose. 
The wording in: 
has been added. 
 
Section 13.1, Page 53 
or Adverse Drug Reaction (ADR) 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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27 June 2018 
 
 
The definition in: 
has been added. 
 
Section 13.1, Page 53  
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
An adverse reaction that is both unexpected (not consistent with 
the applicable product information) and also meets the 
definition of a Serious Adverse Event/Reaction. 
The wording in: 
has been added. 
 
Section 13.3, Page 54 
Serious, unexpected reactions that are not fatal or life-
threatening will be filed no later than 15 calendar days after first 
knowledge by the sponsor.   
The wording in: 
has been changed from: 
To: 
Section 13.4, Pages 54 
To comply with worldwide 
serious adverse event 
reporting regulations serious, 
unexpected and related 
adverse events will be 
submitted to regulatory 
authorities according to 
SmartPractice SOPs. 
Fatal or life-threatening 
unexpected ADRs will be 
reported to all regulatory 
agencies and IRB/Ethics 
Committees by telephone, 
facsimile or in writing as soon 
as possible but no later than 7 
calendar days after first 
knowledge by the sponsor 
followed by as complete a 
report as possible within 8 
additional calendar days. 
The definition in: 
has been changed from: 
To: 
Section 13.6, Page 56  
Sensitization: A positive 
reaction observed 7-14 days 
after application, with no 
preceding reaction. The 
positive reaction must meet 
the criteria for an allergic 
reaction (papular or vesicular 
erythema and infiltration), to 
help distinguish between a 
false-positive and 
sensitization. 
Active Sensitization: A 
positive reaction initially 
appearing at approximately 21 
days after application. 
Sensitization may be 
confirmed if a positive 
reaction were to appear at 3-4 
days after a repeated 
application of the allergen at a 
naïve test site 
The title in: 
has been changed from: 
To: 
Section 13.6, Page 56 
Anaphylactic Reaction 
Acute Anaphylactic Reaction 
The sentence in: 
has been changed added. 
 
Section 13.6, Page 56 
Investigator may refer to the Guideline for Acute Therapy and 
Management of Anaphylaxis by Ring, et. al for more 
information 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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Page 80 of 82 
27 June 2018 
 
 
The definition in: 
has been added. 
 
Section 13.6, Page 57 
Tape Reaction: Severe reaction to the tape or adhesive used to 
hold the patches in place such that the subject is forced to 
remove the patch prior to the 48 hour wear time. 
The paragraph in: 
has been added. 
 
Section 14.0, Page 57 
In the event that the study is prematurely terminated or 
interrupted all regulatory agencies will be notified within 15 
days. 
 
21.0 
AMENDMENT IV 
 
The Sponsor Assistant 
Medical Director 
Dathan Hamann, M.D.  
has been added to the study. 
 
The phone for Kayoko 
Matsunaga, M.D., Ph.D. 
in: 
has been changed from: 
To: 
Section 1.0, Page 1 
562 93 2339 
0562 93 9441 
Investigator 
Patricia L Norris, M.D.  
Oregon Health & Science 
University 
Is no longer participating in the 
study.  She has left her position 
at Oregon Health & Science 
University 
The IRB for the Dr. 
Norris site 
Oregon Health & Science 
University IRB  
Will no longer be needed due to 
the departure of Dr. Norris. 
The Title for Maki 
Hosoki, DDS, PhD in: 
has been changed from: 
To: 
Section 2.0, Page 4  
Section 4.0, Page 8 
Assistant 
Associate 
The reference for the 
Helsinki Declaration in 
has been changed from: 
To: 
Section 8.2 
2000 
2013 
The sentence in: 
has been changed from: 
To: 
Section 10.1, Page 37 
Should the Investigator decide 
that testing with the four common 
allergens will not be of benefit to 
the subject, the Investigator will 
cut Panel 6 below positions 2 and 
8 as illustrated in Figure 9, 
(Section 11.1, Investigational 
Allergen Panels) before applying 
Should the Investigator decide 
that testing with the four 
common allergens will not be of 
benefit to the subject, the 
Investigator will cut Panel 6 as 
illustrated in Figure 9, (Section 
11.1, Investigational Allergen 
Panels) before applying the 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
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Page 81 of 82 
27 June 2018 
 
 
the panel. 
panel. 
The bullet on 
has been changed from: 
To: 
Page 38 
Panel 6: Chips on positions 1-4 
and 7-9 will be evaluated for 
irritation. If Panel 6 is cut to 
avoid patch testing with the 
common allergens chips on 
positions 3-4 and 9 will be 
evaluated. 
Panel 6: Chips on positions 1-4 
and 7-9 will be evaluated for 
irritation. If Panel 6 is cut to 
avoid patch testing with the 
common allergens chips on the 
remaining positions will be 
evaluated. 
The Sentence on 
has been changed from: 
To: 
Page 47 
Should the Investigator elect to 
omit the common allergens from 
an individual’s patch testing, the 
panel should be cut below 
positions 2 and 8 as shown in 
Figure 9.   
Should the Investigator elect to 
omit the common allergens from 
an individual’s patch testing, the 
panel should be cut as shown 
below in Figure 9.   
Figure 9 on 
has been changed from: 
To: 
Page 47 
 
Position 1 
Nickel 
 
 
Position 7 
Cobalt 
 
Position 1 
Nickel 
 
 
Position 7 
Cobalt 
 
 
Position 2 
Chromate 
 
 
Position 8 
Gold 
 
Position 2 
Chromate 
 
 
Position 8 
PVP 
 
Position 3 
PVP 
 
 
Position 9 
HPC 
 
Position 3 
Gold 
 
 
Position 9 
HPC 
 
 
Position 4 
Blank 
 
 
Position 10 
Position 4 
Blank 
 
 
Position 10 
 
 
Position 5 
 
 
Position 11 
 
Position 5 
 
 
Position 11 
 
 
Position 6 
 
 
Position 12 
 
Position 6 
 
 
Position 12 
The sentence on 
has been changed from: 
To: 
Page 47 
Scores for the PVP (Position 3), 
blank (Position 4) and HPC 
(Position 9) patches will be 
recorded in the case report forms 
as originally intended, in fields 
for positions 3, 4 and 9.  Positions 
1, 2 and 7, 8 will be documented 
in the case report form as ‘not 
applied’. 
Scores for the blank (Position 
4), PVP (Position 8), and HPC 
(Position 9) patches will be 
recorded in the case report forms 
as originally intended, in fields 
for positions 4, 8 and 9.  
Positions 1, 2, 3 and 7 will be 
documented in the case report 
form as ‘not applied’. 
Panel 6 Common 
Allergens / Excipient 
Controls on  
has been changed from: 
To: 
Page 49 
PVP Position 3 
Gold Position 8 
Gold Position 3 
PVP Position 8 
 

Clinical Evaluation of Metal Panel Allergens: 
Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, 
Vanadium and Zinc Dose Response Study 
SP 14 8MP 201 
 
 
Protocol- Amendment V 
SmartPractice 
Page 82 of 82 
27 June 2018 
 
 
22.0 
AMENDMENT V 
 
Investigator: 
Prof. Dr. med. Andreas Bircher 
FMH in Dermatology/Venereology and Allergology/Clinical Immunology 
Head of Allergology has retired from the University Hospital Basel Allergology 
Unit  
e-mail: andreas.bircher@usb.ch / andreas.bircher@unibas.chand  
is replaced by:  
PD Dr. med. Kathrin Scherer Hofmeier 
FMH Dermatology/Venerology and Allergology/Clin. Immunology 
ad interim Head of Allergology 
e-mail: kathrin.scherer@usb.ch 
The Title for: 
Maki Hosoki, DDS, PhD has been changed from Associate Professor  
to Senior Assistant Professor  
Investigator 
Akiko Yagami, M.D., Ph.D 
Professor, Department of Allergology, 
Fujita Health University Second Educational Hospital 
3-6-10, Otobashi, Nakagawa-ku,  
Nagoya, 454-8509, Japan 
has completed all her obligations on the study. The site was officially closed on 
May 23, 2018. 
Sub-
Investigator: 
Dr. med. Oppel geb. Scharrer, Institute of Dermatology and Allergy has been 
added to the study. 
Clinical Trial 
Site: 
Department of Dermatology  
Fujita Health University Second Educational Hospital 
3-6-10, Otobashi, Nakagawa-ku,  
Nagoya, 454-8509, Japan 
will no longer recruit subjects for this clinical trial.  The site was officially 
closed on May 23, 2018. 
The IRB: 
Institutional Review Board of Fujita Health University Second Educational 
Hospital 
Fujita Health University Second Educational Hospital  
3-6-10, Otobashi, Nakagawa-ku, Nagoya, 454-8509, Japan 
Phone: +81-52-323-5774 
will no longer be used for this clinical trial. The site was officially closed on 
May 23, 2018.