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Clinical Trial Results:
Clinical Evaluation of Metal Panel Allergens: Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, Vanadium and Zinc Dose Response Study

Summary
EudraCT number	2015-002678-19
Trial protocol	DE IT
Global end of trial date	15 Jul 2019

Results information
Results version number	v1(current)
This version publication date	15 Aug 2021
First version publication date	15 Aug 2021
Other versions
Summary report(s)	Final Report

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

SP148MP201

ISRCTN number

US NCT number

NCT02615249

WHO universal trial number (UTN)

Sponsor organisation name

SmartPractice

Sponsor organisation address

3400 East McDowell Road, Phoenix, United States, 85008

Public contact

Kathryn Shannon, SmartPractice, 01 602225-05957208, kshannon@smarthealth.com

Scientific contact

Kathryn Shannon, SmartPractice, 01 602225-05957208, kshannon@smarthealth.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

03 Feb 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

15 Jul 2019

Global end of trial reached?

Yes

Global end of trial date

15 Jul 2019

Was the trial ended prematurely?

Main objective of the trial

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.

Protection of trial subjects

Subjects were patched with 6 investigational patch test panels and 2 petrolatum patch test panels. The 2 petrolatum patch test panels were not used in Germany. Patches were to be worn for approximately 48 hours. Subjects for whom the patch test panels were intolerable were at liberty to remove the patches prior to the 48 hour return visit. None of the study subjects removed the patch tests due to intolerable conditions. Skin test sites were evaluated for allergic contact dermatitis at days 4, 7, 14 and 21 following patch test application.

Background therapy

Subjects were patch tested with hydrogel experimental metal allergens and the same metal allergens prepared in petrolatum

Evidence for comparator

Petrolatum allergens were used (in all locations with the exception of Germany) to compare 2 patch test methods. Hydrogel method was used for the investigational product. The same allergens prepared using petrolatum were used as a comparator.

Actual start date of recruitment

03 Oct 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 20

Country: Number of subjects enrolled

Germany: 30

Country: Number of subjects enrolled

Italy: 9

Country: Number of subjects enrolled

Switzerland: 6

Country: Number of subjects enrolled

Japan: 44

Country: Number of subjects enrolled

United States: 13

Worldwide total number of subjects

122

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

122

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects were recruited to the study starting 5 December 2016 through 15 July 2019. Each subject's participation was approximately 3 weeks, 21 +/- 2 days

Screening details

Subjects 18 years of age or older, had a past positive patch test result, or suspected to have metal allergy related to a metal implant, were not pregnant or nursing. Immunosuppressives and corticosteroids were not permitted. There were 2 screen fails

Period 1 title

Visit 1 Patch Test Application

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Blinding implementation details

The investigators and subjects knew which allergens were being tested, but were blinded to the placement of the allergen doses within each panel.

Single Arm Study

Arm description

Qualified subjects were patch tested.

Arm type

Experimental

Investigational medicinal product name

Aluminum chloride

Investigational medicinal product code

Panel 1

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Four doses of aluminum chloride hexahydrate were tested: 0.040 mg/cm², 0.12 mg/cm², 0.36 mg/cm², 0.72 mg/cm²

Investigational medicinal product name

Aluminum lactate

Investigational medicinal product code

Panel 1

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Four doses of aluminum lactate were tested: 0.047 mg/cm², 0.14 mg/cm², 0.42 mg/cm², 0.84 mg/cm²

Investigational medicinal product name

Copper sulfate

Investigational medicinal product code

Panel 2

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Four doses of copper sulfate were tested: 0.013, 0.040, 0.080 and 0.12 mg/cm²

Investigational medicinal product name

Manganese chloride

Investigational medicinal product code

Panel 3

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Four doses of manganese chloride were tested: 0.013, 0.040, 0.080 and 0.24 mg/cm²

Investigational medicinal product name

Ammonium molybdate

Investigational medicinal product code

Panel 3

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Four doses of ammonium molybdate were tested: 0.0067, 0.020, 0.040 and 0.12 mg/cm² ammonium molybdate

Investigational medicinal product name

Tin chloride

Investigational medicinal product code

Panel 2

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Four doses of tin chloride were tested: 0.018, 0.037, 0.11 and 0.33 mg/cm²

Investigational medicinal product name

Titanium citrate

Investigational medicinal product code

Panel 4

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Three doses of titanium citrate were tested: 0.013, 0.040, 0.080 and 0.24 mg/cm²

Investigational medicinal product name

Titanium lactate

Investigational medicinal product code

Panel 4

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Three doses of titanium lactate were tested: 0.070, 0.14 and 0.28 mg Ti/cm²

Investigational medicinal product name

Ammonium titanium oxide oxalate

Investigational medicinal product code

Panel 4

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Three doses of ammonium titanium oxide oxalate were tested: 0.055, 0.11 and 0.22 mg Ti/cm²

Investigational medicinal product name

Potassium titanium oxide oxalate

Investigational medicinal product code

Panel 4

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Three doses of potassium titanium oxide oxalate were tested: 0.060, 0.12 and 0.24 mg Ti/cm²

Investigational medicinal product name

Vanadium chloride

Investigational medicinal product code

Panel 5

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Four doses of vanadium chloride were tested: 0.0042, 0.0083, 0.025 and 0.050 mg V/cm²

Investigational medicinal product name

Vanadium oxide sulfate

Investigational medicinal product code

Panel 5

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Four doses of vanadium oxide sulfate were tested: 0.0042, 0.0083, 0.025 and 0.050 mg V/cm²

Investigational medicinal product name

Zinc chloride

Investigational medicinal product code

Panel 2

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Four doses of zinc chloride were tested: 0.013 mg/cm², 0.040 mg/cm², 0.080 mg/cm², 0.24 mg/cm²

Number of subjects in period 1	Single Arm Study
Started	122
Completed	122

Period 2 title

Visits 2-6 Patch Removal and Evaluations

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Blinding implementation details

The investigators and subjects knew which allergens were tested, but were blinded to the placement of the allergen doses within each panel.

Single Arm Study

Arm description

All subjects who returned for visit 2

Arm type

Experimental

Investigational medicinal product name

Aluminum chloride

Investigational medicinal product code

Panel 1

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Four doses of aluminum chloride hexahydrate were evaluated: 0.040 mg/cm², 0.12 mg/cm², 0.36 mg/cm², 0.72 mg/cm²

Investigational medicinal product name

Aluminum lactate

Investigational medicinal product code

Panel 1

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Four doses of aluminum lactate were evaluated: 0.047 mg/cm², 0.14 mg/cm², 0.42 mg/cm², 0.84 mg/cm²

Investigational medicinal product name

Copper sulfate

Investigational medicinal product code

Panel 2

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Four doses of copper sulfate were evaluated: 0.013, 0.040, 0.080 and 0.12 mg/cm²

Investigational medicinal product name

Manganese chloride

Investigational medicinal product code

Panel 3

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Four doses of manganese chloride were evaluated: 0.013, 0.040, 0.080 and 0.24 mg/cm²

Investigational medicinal product name

Ammonium molybdate

Investigational medicinal product code

Panel 3

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Four doses of ammonium molybdate were evaluated: 0.0067, 0.020, 0.040 and 0.12 mg/cm²

Investigational medicinal product name

Tin chloride

Investigational medicinal product code

Panel 2

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Four doses of tin chloride were evaluated: 0.018, 0.037, 0.11 and 0.33 mg/cm²

Investigational medicinal product name

Titanium citrate

Investigational medicinal product code

Panel 4

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Three doses of titanium citrate were evaluated: 0.013, 0.040, 0.080 and 0.24 mg/cm²

Investigational medicinal product name

Titanium lactate

Investigational medicinal product code

Panel 4

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Three doses of titanium lactate were evaluated: 0.070, 0.14 and 0.28 mg Ti/cm²

Investigational medicinal product name

Ammonium titanium oxide oxalate

Investigational medicinal product code

Panel 4

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Three doses of ammonium titanium oxide oxalate were evaluated: 0.055, 0.11 and 0.22 mg Ti/cm²

Investigational medicinal product name

Potassium titanium oxide oxalate

Investigational medicinal product code

Panel 4

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Three doses of potassium titanium oxide oxalate were evaluated: 0.060, 0.12 and 0.24 mg Ti/cm²

Investigational medicinal product name

Vanadium chloride

Investigational medicinal product code

Panel 5

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Four doses of vanadium chloride were evaluated: 0.0042, 0.0083, 0.025 and 0.050 mg V/cm²

Investigational medicinal product name

Vanadium oxide sulfate

Investigational medicinal product code

Panel 5

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Four doses of vanadium oxide sulfate were evaluated: 0.0042, 0.0083, 0.025 and 0.050 mg V/cm²

Investigational medicinal product name

Zinc chloride

Investigational medicinal product code

Panel 2

Other name

Pharmaceutical forms

Cutaneous patch

Routes of administration

Cutaneous use

Dosage and administration details

Four doses of zinc chloride were evaluated: 0.013 mg/cm², 0.040 mg/cm², 0.080 mg/cm², 0.24 mg/cm²

Number of subjects in period 2	Single Arm Study
Started	122
Completed	122

Baseline characteristics

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Reporting group title

Visit 1 Patch Test Application

Reporting group description

Reporting group values	Visit 1 Patch Test Application	Total
Number of subjects	122	122
Age categorical
Units: Subjects
In utero		0
Preterm newborn infants (gestational age < 37 wks)		0
Newborns (0-27 days)		0
Infants and toddlers (28 days-23 months)		0
Children (2-11 years)		0
Adolescents (12-17 years)		0
Adults (18-64 years)		0
From 65-84 years		0
85 years and over		0
Age continuous
122 subjects ages 26 to 84 years old were enrolled
Units: years
median (full range (min-max))	60.0 (26 to 84)	-
Gender categorical
Units: Subjects
Female	93	93
Male	29	29

Subject analysis set title

Allergens with 15 or more positive responses

Subject analysis set type

Per protocol

Subject analysis set description

In this single arm study subjects with a past positive patch test were tested with the allergen responsible for the past positive patch test and any other relevant allergen. Those enrolled based on suspicion of metal allergy were tested with all investigational allergens. The primary endpoint was the lowest concentration of each allergen that elicited positive responses in at least 15 subjects. this section will be used to report the number of allergens for which there were at least 15 positive reactions. The attachment will itemize each allergen dose and the corresponding number of positive responses.

Subject analysis set title

Subjects Positive to Investigationall and Reference Allergen

Subject analysis set type

Per protocol

Subject analysis set description

Subjects were patch tested with the investigational and reference allergens (with the exception of subjects enrolled in Germany who were not tested with the reference allergens).

Subject analysis set title

Subjects Negative to Investigational and Reference Allergen

Subject analysis set type

Per protocol

Subject analysis set description

Subjects were patch tested with the investigational allergen and corresponding reference allergen. Percent agreement is measured by the number of subjects with positive or negative reactions to each allergen.

Subject analysis set title

Subjects Positive to Investigational and Negative to Reference

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Subjects Negative to Investigational and Positive to Reference

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Panel 1

Subject analysis set type

Per protocol

Subject analysis set description

Panel 1 contained aluminum allergens: 0.040, 0.12, 0.36 and 0.72 mg/cm² aluminum chloride hexahydrate and 047, 0.14, 0.42 and 0.84 mg/cm² aluminum lactate

Subject analysis set title

Panel 2

Subject analysis set type

Per protocol

Subject analysis set description

Panel 2 contained copper, zinc and tin allergens, 0.013, 0.040, 0.080 and 0.12 mg/cm² copper sulfate, 0.013, 0.040, 0.080 and 0.24 mg/cm² zinc chloride and 0.018, 0.037, 0.11 and 0.33 mg/cm² tin chloride

Subject analysis set title

Panel 3

Subject analysis set type

Per protocol

Subject analysis set description

Panel 3 contained manganese and molybdenum allergens: 0.013, 0.040, 0.080 and 0.24 mg/cm² manganese chloride tetrahydrate and 0.0067, 0.020, 0.040 and 0.12 mg/cm² ammonium molybdate

Subject analysis set title

Panel 4

Subject analysis set type

Per protocol

Subject analysis set description

Panel 4 contained titanium allergens, Ammonium titanium peroxo citrate: 0.055, 0.11 and 0.22 mg Ti/cm², Ammonium titanium lactate: 0.070, 0.14 and 0.28 mg Ti/cm², Potassium titanium oxide oxalate: 0.060, 0.12 and 0.24 mg Ti/cm² and Ammonium titanium oxide oxalate: 0.055, 0.11 and 0.22 mg Ti/cm²*

Subject analysis set title

Panel 5

Subject analysis set type

Per protocol

Subject analysis set description

Panel 5 contained vanadium allergens: Vanadium chloride: 0.0042, 0.0083, 0.025 and 0.050 mg V/cm² and Vanadium oxide sulfate: 0.0042, 0.0083, 0.025 and 0.050 mg V/cm²

Subject analysis set title

Panel 6

Subject analysis set type

Per protocol

Subject analysis set description

Panel 6 contained already approved allergens and negative 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) and Hydroxypropyl cellulose (HPC)

Subject analysis set title

0.12 mg/cm2 Copper sulfate

Subject analysis set type

Per protocol

Subject analysis set description

One hundred eleven (111) subjects were tested with all doses of the copper sulfate investigational allergen. There were 16 subjects with positive responses to the 0.12 mg/cm2 dose which was the only dose that met the minimum criteria of at least 15 subjects with positive responses

Subject analysis set title

0.24 mg/cm2 Manganese chloride

Subject analysis set type

Per protocol

Subject analysis set description

One hundred four (104) subjects were tested with all doses of the manganese chloride investigational allergen however the 0.040 mg/cm2, 0.080 mg/cm2 and 0.24 mg/cm2 doses (positions 3, 2 and 1 respectively) for a single subject were not scored due to poor adhesion at patch removal. Of the 103 subjects with study results, there were 29 subjects with positive responses to the 0.24 mg/cm2 dose which was the only dose that met the minimum criteria of at least 15 subjects with positive responses.

Subject analysis set title

0.11 mg/cm2 Tin chloride

Subject analysis set type

Per protocol

Subject analysis set description

One hundred eleven (111) subjects were tested with all doses of the tin chloride investigational allergen. There were 25 subjects with positive responses to the 0.11 mg/cm2 dose

Subject analysis set title

0.33 mg/cm2 Tin chloride

Subject analysis set type

Per protocol

Subject analysis set description

One hundred eleven (111) subjects were tested with all doses of the tin chloride investigational allergen however the 0.33 mg/cm2 dose (position 6) for a single subject was not scored due to poor adhesion at patch removal. Of the subjects with study results there were 65 subjects with positive responses to the 0.33 mg/cm2 dose.

Subject analysis set title

0.11 mg Ti/cm2 Ammonium titanium oxide oxalate

Subject analysis set type

Per protocol

Subject analysis set description

One hundred nine (109) subjects were tested with all doses of the titanium investigational allergens. Ammonium titanium oxide oxalate was the only titanium salt that met the minimum criteria of at least 15 subjects with positive responses. There were 21 subjects with positive responses to the 0.11 mg Ti/cm2 dose /

Subject analysis set title

0.22 mg Ti/cm2 Ammonium titanium oxide oxalate

Subject analysis set type

Per protocol

Subject analysis set description

One hundred nine (109) subjects were tested with all doses of the titanium investigational allergens. Ammonium titanium oxide oxalate was the only titanium salt that met the minimum criteria of at least 15 subjects with positive responses. There were 18 subjects with positive responses to the 0.22 mg Ti/cm2 dose.

Subject analysis set title

0.025 mg V/cm2 Vanadium chloride

Subject analysis set type

Per protocol

Subject analysis set description

One hundred six (106) were tested with all doses of the vanadium investigational allergens. There were 2 doses of vanadium chloride and one of vanadium sulfate which met the minimum criteria of at least 15 subjects with positive responses. Vanadium chloride: There were 25 subjects with positive responses to the 0.025 mg V/cm2 dose.

Subject analysis set title

0.050 mg V/cm2 Vanadium chloride

Subject analysis set type

Per protocol

Subject analysis set description

One hundred six (106) were tested with all doses of the vanadium investigational allergens. There were 2 doses of vanadium chloride and one of vanadium sulfate which met the minimum criteria of at least 15 subjects with positive responses. Vanadium chloride: There were 46 subjects with positive responses to the 0.050 mg V/cm2 dose.

Subject analysis set title

0.050 mg V/cm2 Vanadium sulfate

Subject analysis set type

Per protocol

Subject analysis set description

One hundred six (106) were tested with all doses of the vanadium investigational allergens. There were 2 doses of vanadium chloride and one of vanadium sulfate which met the minimum criteria of at least 15 subjects with positive responses. Vanadium sulfate: There were 30 subjects with positive responses to the 0.050 mg V/cm2 dose of vanadium sulfate

Subject analysis set title

0.24 mg/cm2 Zinc chloride

Subject analysis set type

Per protocol

Subject analysis set description

One hundred eleven (111) subjects were tested with all doses of the zinc chloride investigational allergen. There were 69 subjects with positive responses to the 0.24 mg/cm2 dose which was the only dose that met the minimum criteria of at least 15 subjects with positive responses

Allergens with 15 or more positive responses

Subjects Positive to Investigationall and Reference Allergen

Subjects Negative to Investigational and Reference Allergen

Subjects Positive to Investigational and Negative to Reference

Subjects Negative to Investigational and Positive to Reference

Panel 1

Panel 2

Panel 3

Panel 4

Panel 5

Panel 6

0.12 mg/cm2 Copper sulfate

0.24 mg/cm2 Manganese chloride

0.11 mg/cm2 Tin chloride

0.33 mg/cm2 Tin chloride

0.11 mg Ti/cm2 Ammonium titanium oxide oxalate

0.22 mg Ti/cm2 Ammonium titanium oxide oxalate

0.025 mg V/cm2 Vanadium chloride

0.050 mg V/cm2 Vanadium chloride

0.050 mg V/cm2 Vanadium sulfate

0.24 mg/cm2 Zinc chloride

Number of subjects

121

105

111

104

109

106

120

111

104

111

110

109

106

111

Units: Subjects

In utero

Preterm newborn infants (gestational age < 37 wks)

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65-84 years

85 years and over

122 subjects ages 26 to 84 years old were enrolled

Units: years

median (full range (min-max))

60.0 (26 to 84)

Units: Subjects

Female

Male

End points

Top of page

Reporting group title

Single Arm Study

Reporting group description

Qualified subjects were patch tested.

Reporting group title

Single Arm Study

Reporting group description

All subjects who returned for visit 2

Subject analysis set title

Allergens with 15 or more positive responses

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Subjects Positive to Investigationall and Reference Allergen

Subject analysis set type

Per protocol

Subject analysis set description

Subjects were patch tested with the investigational and reference allergens (with the exception of subjects enrolled in Germany who were not tested with the reference allergens).

Subject analysis set title

Subjects Negative to Investigational and Reference Allergen

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Subjects Positive to Investigational and Negative to Reference

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Subjects Negative to Investigational and Positive to Reference

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Panel 1

Subject analysis set type

Per protocol

Subject analysis set description

Panel 1 contained aluminum allergens: 0.040, 0.12, 0.36 and 0.72 mg/cm² aluminum chloride hexahydrate and 047, 0.14, 0.42 and 0.84 mg/cm² aluminum lactate

Subject analysis set title

Panel 2

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Panel 3

Subject analysis set type

Per protocol

Subject analysis set description

Panel 3 contained manganese and molybdenum allergens: 0.013, 0.040, 0.080 and 0.24 mg/cm² manganese chloride tetrahydrate and 0.0067, 0.020, 0.040 and 0.12 mg/cm² ammonium molybdate

Subject analysis set title

Panel 4

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Panel 5

Subject analysis set type

Per protocol

Subject analysis set description

Panel 5 contained vanadium allergens: Vanadium chloride: 0.0042, 0.0083, 0.025 and 0.050 mg V/cm² and Vanadium oxide sulfate: 0.0042, 0.0083, 0.025 and 0.050 mg V/cm²

Subject analysis set title

Panel 6

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

0.12 mg/cm2 Copper sulfate

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

0.24 mg/cm2 Manganese chloride

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

0.11 mg/cm2 Tin chloride

Subject analysis set type

Per protocol

Subject analysis set description

One hundred eleven (111) subjects were tested with all doses of the tin chloride investigational allergen. There were 25 subjects with positive responses to the 0.11 mg/cm2 dose

Subject analysis set title

0.33 mg/cm2 Tin chloride

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

0.11 mg Ti/cm2 Ammonium titanium oxide oxalate

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

0.22 mg Ti/cm2 Ammonium titanium oxide oxalate

Subject analysis set type

Per protocol

Subject analysis set description

One hundred nine (109) subjects were tested with all doses of the titanium investigational allergens. Ammonium titanium oxide oxalate was the only titanium salt that met the minimum criteria of at least 15 subjects with positive responses. There were 18 subjects with positive responses to the 0.22 mg Ti/cm2 dose.

Subject analysis set title

0.025 mg V/cm2 Vanadium chloride

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

0.050 mg V/cm2 Vanadium chloride

Subject analysis set type

Per protocol

Subject analysis set description

One hundred six (106) were tested with all doses of the vanadium investigational allergens. There were 2 doses of vanadium chloride and one of vanadium sulfate which met the minimum criteria of at least 15 subjects with positive responses. Vanadium chloride: There were 46 subjects with positive responses to the 0.050 mg V/cm2 dose.

Subject analysis set title

0.050 mg V/cm2 Vanadium sulfate

Subject analysis set type

Per protocol

Subject analysis set description

One hundred six (106) were tested with all doses of the vanadium investigational allergens. There were 2 doses of vanadium chloride and one of vanadium sulfate which met the minimum criteria of at least 15 subjects with positive responses. Vanadium sulfate: There were 30 subjects with positive responses to the 0.050 mg V/cm2 dose of vanadium sulfate

Subject analysis set title

0.24 mg/cm2 Zinc chloride

Subject analysis set type

Per protocol

Subject analysis set description

Primary: Allergens with at least 15 positive Responses

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End point title

Allergens with at least 15 positive Responses ^[1]

End point description

Patch test sites were evaluated at days 3(+1), 7(+1), 10(+/-2) and 21(+/-2). Following all evaluations the Investigator categorized each patch test site as either negative (no 1+, 2+ or 3+ reactions) or positive (1+, 2+ or 3+ during at least one evaluation visit). A minimum of 15 positive (+) reactions were needed to be considered for the final metal panel. Results are posted for the number subjects with + responses. The posted results are only for the allergens/allergen doses for which there were a minimum of 15 positive responses. None of the other allergen doses met the criteria of at least 15 positive responses. The allergens/allergen doses chosen for the final panel are: 0.12mg/cm2 copper sulfate, 0.24 mg/cm2 manganese chloride, 0.33 mg/cm2 tin chloride, 0.22 mg Ti/cm2 ammonium titanium oxide oxalate, 0.050 mg V/cm2 vanadium sulfate and 0.24 mg/cm2 tin chloride

End point type

Primary

End point timeframe

Post Visit 6 (at study completion).

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analysis not performed. Endpoint is defined as a minimum threshold

End point values	0.12 mg/cm2 Copper sulfate	0.24 mg/cm2 Manganese chloride	0.11 mg/cm2 Tin chloride	0.33 mg/cm2 Tin chloride	0.11 mg Ti/cm2 Ammonium titanium oxide oxalate	0.22 mg Ti/cm2 Ammonium titanium oxide oxalate	0.025 mg V/cm2 Vanadium chloride	0.050 mg V/cm2 Vanadium chloride	0.050 mg V/cm2 Vanadium sulfate	0.24 mg/cm2 Zinc chloride
Number of subjects analysed	111	104	111	110	109	109	106	106	106	111
Units: Positive Responses
Positive Reaction	16	29	25	65	21	18	25	46	30	69
Negative Reaction	69	48	68	17	55	56	57	28	53	17
Doubtful Reaction	16	17	12	12	24	27	18	14	15	16
Irritant Reaction	10	10	6	16	9	8	6	18	8	9

Attachments

Untitled (Filename: Table 14.2.8 Summary of No of Positive Responses to Each Allergen.rtf)

No statistical analyses for this end point

Primary: Concordance Copper Sulfate 0.12mg/cm2 and 2% pet

Top of page

End point title

Concordance Copper Sulfate 0.12mg/cm2 and 2% pet

End point description

Percent agreement= [observed agreement /N1] x 100, based on total number of subjects having responses for investigational and reference allergen.

End point type

Primary

End point timeframe

Day 21

End point values	Subjects Positive to Investigationall and Reference Allergen	Subjects Negative to Investigational and Reference Allergen	Subjects Positive to Investigational and Negative to Reference	Subjects Negative to Investigational and Positive to Reference
Number of subjects analysed	4	61	6	7
Units: Agreement
Agreement	4	61	6	7

Attachments

Concordance Copper Sulfate

Kappa Statistic

Statistical analysis description

Concordance was 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 pair.

Comparison groups

Subjects Positive to Investigationall and Reference Allergen v Subjects Negative to Investigational and Reference Allergen v Subjects Positive to Investigational and Negative to Reference v Subjects Negative to Investigational and Positive to Reference

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

equivalence

Method

Fisher exact

Parameter type

Cohen's Kappa Coefficient

Point estimate

0.28

Confidence interval

level

95%

sides

2-sided

lower limit

-0.01

upper limit

0.58

Kappa Statistic

Statistical analysis description

Comparison groups

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[2]

P-value

= 0.0117

Method

Fisher exact

Parameter type

Cohen's Kappa Coefficient

Point estimate

0.28

Confidence interval

level

95%

sides

2-sided

lower limit

-0.01

upper limit

0.58

Notes
[2] - Subjects were patch tested with the investigational and reference allergens (with the exception of subjects enrolled in Germany who were not tested with the reference allergens). Patch test sites were evaluated at days 4(-1), 7(+1), 12(+/-2), and 21(+/-2). Following the completion of all visits (day 21), the investigator categorized the skin reactions as either negative (no 1+, 2+ or 3+ scores ) or positive (at least one 1+, +2 or 3+ score). Concordance was measured using Cohen’s kappa.

Kappa Statistic

Statistical analysis description

Comparison groups

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[3]

P-value

= 0.0117

Method

Fisher exact

Parameter type

Kappa Statistic

Point estimate

0.28

Confidence interval

level

95%

sides

2-sided

lower limit

-0.01

upper limit

0.58

Notes
[3] - Subjects were patch tested with the investigational and reference allergens (with the exception of subjects enrolled in Germany who were not tested with the reference allergens). Patch test sites were evaluated at days 4(-1), 7(+1), 12(+/-2), and 21(+/-2). Following the completion of all visits (day 21), the investigator categorized the skin reactions as either negative (no 1+, 2+ or 3+ scores ) or positive (at least one 1+, +2 or 3+ score). Concordance was measured using Cohen’s kappa

Primary: Concordance Manganese 0.24mg/cm2 vs 2% pet

Top of page

End point title

Concordance Manganese 0.24mg/cm2 vs 2% pet

End point description

Percent agreement= [observed agreement /N1] x 100, based on total number of subjects having responses for investigational and reference allergen.

End point type

Primary

End point timeframe

Day 21

End point values	Subjects Positive to Investigationall and Reference Allergen	Subjects Negative to Investigational and Reference Allergen	Subjects Positive to Investigational and Negative to Reference	Subjects Negative to Investigational and Positive to Reference
Number of subjects analysed	10	44	14	1
Units: Agreement
Agreement	10	44	14	1

Attachments

Concordance Manganese chloride

Kappa Statistic

Statistical analysis description

Comparison groups

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[4]

P-value

< 0.0001

Method

Fisher exact

Parameter type

Kappa Statistic

Point estimate

0.45

Confidence interval

level

95%

sides

2-sided

lower limit

0.24

upper limit

0.66

Notes
[4] - Subjects were patch tested with the investigational and reference allergens (with the exception of subjects enrolled in Germany who were not tested with the reference allergens). Patch test sites were evaluated at days 4(-1), 7(+1), 12(+/-2), and 21(+/-2). Following the completion of all visits (day 21), the investigator categorized the skin reactions as either negative (no 1+, 2+ or 3+ scores ) or positive (at least one 1+, +2 or 3+ score). Concordance was measured using Cohen’s kappa

Primary: Concordance Tin Chloride 0.11 mg/cm2 vs 1% pet

Top of page

End point title

Concordance Tin Chloride 0.11 mg/cm2 vs 1% pet

End point description

Percent agreement= [observed agreement /N1] x 100, based on total number of subjects having responses for investigational and reference allergen.

End point type

Primary

End point timeframe

Day 21

End point values	Subjects Positive to Investigationall and Reference Allergen	Subjects Negative to Investigational and Reference Allergen	Subjects Positive to Investigational and Negative to Reference	Subjects Negative to Investigational and Positive to Reference
Number of subjects analysed	9	45	8	11
Units: Agreement
Agreement	9	45	8	11

Attachments

Concordance Tin chloride

Kappa Statistic

Statistical analysis description

Comparison groups

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[5]

P-value

= 0.007

Method

Fisher exact

Parameter type

Kappa Statistic

Point estimate

0.31

Confidence interval

level

95%

sides

2-sided

lower limit

0.07

upper limit

0.56

Notes
[5] - Subjects were patch tested with the investigational and reference allergens (with the exception of subjects enrolled in Germany who were not tested with the reference allergens). Patch test sites were evaluated at days 4(-1), 7(+1), 12(+/-2), and 21(+/-2). Following the completion of all visits (day 21), the investigator categorized the skin reactions as either negative (no 1+, 2+ or 3+ scores ) or positive (at least one 1+, +2 or 3+ score). Concordance was measured using Cohen’s kappa

Primary: Concordance Tin Chloride 0.33 mg/cm2 vs 1% pet

Top of page

End point title

Concordance Tin Chloride 0.33 mg/cm2 vs 1% pet

End point description

Percent agreement= [observed agreement /N1] x 100, based on total number of subjects having responses for investigational and reference allergen.

End point type

Primary

End point timeframe

Day 21

End point values	Subjects Positive to Investigationall and Reference Allergen	Subjects Negative to Investigational and Reference Allergen	Subjects Positive to Investigational and Negative to Reference	Subjects Negative to Investigational and Positive to Reference
Number of subjects analysed	18	22	30	2
Units: Agreement
Agreement	18	22	30	2

Attachments

Concordance Tin chloride

Kappa Statistic

Statistical analysis description

Comparison groups

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[6]

P-value

= 0.0092

Method

Fisher exact

Parameter type

Kappa Statistic

Point estimate

0.23

Confidence interval

level

95%

sides

2-sided

lower limit

0.07

upper limit

0.38

Notes
[6] - Subjects were patch tested with the investigational and reference allergens (with the exception of subjects enrolled in Germany who were not tested with the reference allergens). Patch test sites were evaluated at days 4(-1), 7(+1), 12(+/-2), and 21(+/-2). Following the completion of all visits (day 21), the investigator categorized the skin reactions as either negative (no 1+, 2+ or 3+ scores ) or positive (at least one 1+, +2 or 3+ score). Concordance was measured using Cohen’s kappa.

Primary: Concordance Ammonium titanium oxide oxalate 0.11mgTi/cm2 vs 19% pet

Top of page

End point title

Concordance Ammonium titanium oxide oxalate 0.11mgTi/cm2 vs 19% pet

End point description

Percent agreement= [observed agreement /N1] x 100, based on total number of subjects having responses for investigational and reference allergen.

End point type

Primary

End point timeframe

Day 21

End point values	Subjects Positive to Investigationall and Reference Allergen	Subjects Negative to Investigational and Reference Allergen	Subjects Positive to Investigational and Negative to Reference	Subjects Negative to Investigational and Positive to Reference
Number of subjects analysed	7	52	14	3
Units: Agreement
Agreement	7	52	14	3

Attachments

Concordance Titanium Allergens

Kappa Statistic

Statistical analysis description

Comparison groups

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[7]

P-value

= 0.0013

Method

Fisher exact

Parameter type

Kappa Statistic

Point estimate

0.33

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

0.57

Notes
[7] - Subjects were patch tested with the investigational and reference allergens (with the exception of subjects enrolled in Germany who were not tested with the reference allergens). Patch test sites were evaluated at days 4(-1), 7(+1), 12(+/-2), and 21(+/-2). Following the completion of all visits (day 21), the investigator categorized the skin reactions as either negative (no 1+, 2+ or 3+ scores ) or positive (at least one 1+, +2 or 3+ score). Concordance was measured using Cohen’s kappa

Primary: Concordance Ammonium titanium oxide oxalate 0.22mgTi/cm2 vs 19% pet

Top of page

End point title

Concordance Ammonium titanium oxide oxalate 0.22mgTi/cm2 vs 19% pet

End point description

Percent agreement= [observed agreement /N1] x 100, based on total number of subjects having responses for investigational and reference allergen.

End point type

Primary

End point timeframe

Day 21

End point values	Subjects Positive to Investigationall and Reference Allergen	Subjects Negative to Investigational and Reference Allergen	Subjects Positive to Investigational and Negative to Reference	Subjects Negative to Investigational and Positive to Reference
Number of subjects analysed	7	55	11	3
Units: Agreement
Agreement	7	55	11	3

Attachments

Concordance Titanium Allergens

Kappa Statistic

Statistical analysis description

Comparison groups

Subjects Positive to Investigationall and Reference Allergen v Subjects Negative to Investigational and Positive to Reference v Subjects Positive to Investigational and Negative to Reference v Subjects Negative to Investigational and Reference Allergen

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[8]

P-value

= 0.0002

Method

Fisher exact

Parameter type

Kappa Statistic

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.15

upper limit

0.65

Notes
[8] - Subjects were patch tested with the investigational and reference allergens (with the exception of subjects enrolled in Germany who were not tested with the reference allergens). Patch test sites were evaluated at days 4(-1), 7(+1), 12(+/-2), and 21(+/-2). Following the completion of all visits (day 21), the investigator categorized the skin reactions as either negative (no 1+, 2+ or 3+ scores ) or positive (at least one 1+, +2 or 3+ score). Concordance was measured using Cohen’s kappa

Primary: Concordance Vanadium chloride 0.050 mgV/cm2 vs 1% pet

Top of page

End point title

Concordance Vanadium chloride 0.050 mgV/cm2 vs 1% pet

End point description

Percent agreement= [observed agreement /N1] x 100, based on total number of subjects having responses for investigational and reference allergen.

End point type

Primary

End point timeframe

Day 21

End point values	Subjects Positive to Investigationall and Reference Allergen	Subjects Negative to Investigational and Reference Allergen	Subjects Positive to Investigational and Negative to Reference
Number of subjects analysed	3	44	25
Units: Agreement
Agreement	3	44	25

Attachments

Concordance Vanadium Allergens

Kappa Statistic

Statistical analysis description

Comparison groups

Subjects Negative to Investigational and Reference Allergen v Subjects Positive to Investigational and Negative to Reference v Subjects Positive to Investigationall and Reference Allergen

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[9]

P-value

= 0.0266

Method

Fisher exact

Parameter type

Kappa Statistic

Point estimate

0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.01

upper limit

0.26

Notes
[9] - Subjects were patch tested with the investigational and reference allergens (with the exception of subjects enrolled in Germany who were not tested with the reference allergens). Patch test sites were evaluated at days 4(-1), 7(+1), 12(+/-2), and 21(+/-2). Following the completion of all visits (day 21), the investigator categorized the skin reactions as either negative (no 1+, 2+ or 3+ scores ) or positive (at least one 1+, +2 or 3+ score). Concordance was measured using Cohen’s kappa

Primary: Concordance Vanadium chloride 0.025 mgV/cm2 vs 1% pet

Top of page

End point title

Concordance Vanadium chloride 0.025 mgV/cm2 vs 1% pet

End point description

Percent agreement= [observed agreement /N1] x 100, based on total number of subjects having responses for investigational and reference allergen.

End point type

Primary

End point timeframe

Day 21

End point values	Subjects Positive to Investigationall and Reference Allergen	Subjects Negative to Investigational and Reference Allergen	Subjects Positive to Investigational and Negative to Reference	Subjects Negative to Investigational and Positive to Reference
Number of subjects analysed	2	56	13	1
Units: Agreement
Agreement	2	56	13	1

Attachments

Concordance Vanadium Allergens

Kappa Statistic

Statistical analysis description

Comparison groups

Subjects Negative to Investigational and Reference Allergen v Subjects Positive to Investigationall and Reference Allergen v Subjects Positive to Investigational and Negative to Reference v Subjects Negative to Investigational and Positive to Reference

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[10]

P-value

= 0.0458

Method

Fisher exact

Parameter type

Kappa Statistic

Point estimate

0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-0.07

upper limit

0.4

Notes
[10] - Subjects were patch tested with the investigational and reference allergens (with the exception of subjects enrolled in Germany who were not tested with the reference allergens). Patch test sites were evaluated at days 4(-1), 7(+1), 12(+/-2), and 21(+/-2). Following the completion of all visits (day 21), the investigator categorized the skin reactions as either negative (no 1+, 2+ or 3+ scores ) or positive (at least one 1+, +2 or 3+ score). Concordance was measured using Cohen’s kappa

Primary: Concordance Vanadium sulfate 0.050 mgV/cm2 vs 1.5% pet

Top of page

End point title

Concordance Vanadium sulfate 0.050 mgV/cm2 vs 1.5% pet

End point description

Percent agreement= [observed agreement /N1] x 100, based on total number of subjects having responses for investigational and reference allergen.

End point type

Primary

End point timeframe

Day 21

End point values	Subjects Positive to Investigationall and Reference Allergen	Subjects Negative to Investigational and Reference Allergen	Subjects Positive to Investigational and Negative to Reference
Number of subjects analysed	9	51	12
Units: Agreement
Agreement	9	51	12

Attachments

Concordance Vanadium Allergens

Kappa Statistic

Statistical analysis description

Comparison groups

Subjects Positive to Investigationall and Reference Allergen v Subjects Negative to Investigational and Reference Allergen v Subjects Positive to Investigational and Negative to Reference

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[11]

P-value

< 0.0001

Method

Fisher exact

Parameter type

Kappa Statistic

Point estimate

0.52

Confidence interval

level

95%

sides

2-sided

lower limit

0.3

upper limit

0.73

Notes
[11] - Subjects were patch tested with the investigational and reference allergens (with the exception of subjects enrolled in Germany who were not tested with the reference allergens). Patch test sites were evaluated at days 4(-1), 7(+1), 12(+/-2), and 21(+/-2). Following the completion of all visits (day 21), the investigator categorized the skin reactions as either negative (no 1+, 2+ or 3+ scores ) or positive (at least one 1+, +2 or 3+ score). Concordance was measured using Cohen’s kappa

Primary: Concordance Zinc 0.24 mg/cm2 vs 2% pet

Top of page

End point title

Concordance Zinc 0.24 mg/cm2 vs 2% pet

End point description

Percent agreement= [observed agreement /N1] x 100, based on total number of subjects having responses for investigational and reference allergen.

End point type

Primary

End point timeframe

Day 21

End point values	Subjects Positive to Investigationall and Reference Allergen	Subjects Negative to Investigational and Reference Allergen	Subjects Positive to Investigational and Negative to Reference	Subjects Negative to Investigational and Positive to Reference
Number of subjects analysed	27	22	22	3
Units: Agreement
Agreement	27	22	22	3

Attachments

Concordance Tin chloride

Kappa Statistic

Statistical analysis description

Comparison groups

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[12]

P-value

= 0.0004

Method

Fisher exact

Parameter type

Kappa Statistic

Point estimate

0.36

Confidence interval

level

95%

sides

2-sided

lower limit

0.18

upper limit

0.54

Notes
[12] - Subjects were patch tested with the investigational and reference allergens (with the exception of subjects enrolled in Germany who were not tested with the reference allergens). Patch test sites were evaluated at days 4(-1), 7(+1), 12(+/-2), and 21(+/-2). Following the completion of all visits (day 21), the investigator categorized the skin reactions as either negative (no 1+, 2+ or 3+ scores ) or positive (at least one 1+, +2 or 3+ score). Concordance was measured using Cohen’s kappa

Secondary: Tape Irritation

Top of page

End point title

Tape Irritation

End point description

Tape irritation was evaluated at visits 2-6 Following visit 6, the Investigator summarized the rape irritation as none, irritant response or allergic response.

End point type

Secondary

End point timeframe

Days 2, 3 (+1), 7 (+1), 12 (+/-2) and 21 (+/- 2)

End point values	Panel 1	Panel 2	Panel 3	Panel 4	Panel 5	Panel 6
Number of subjects analysed	105	111	104	109	106	120
Units: Subjects
No Irritation	103	109	103	108	105	120
Irritant Response	2	2	1	1	1	0

Attachments

Tape Irritation

No statistical analyses for this end point

Secondary: Chip Irritation

Top of page

End point title

Chip Irritation

End point description

Chip irritation was evaluated at visits 2-6 Following visit 6, the Investigator summarized the rape irritation as none, irritant response or allergic response.

End point type

Secondary

End point timeframe

Days 2, 3(+1), 7(+1), 10 (+/-2), 21(+/-2)

End point values	Panel 1	Panel 2	Panel 3	Panel 4	Panel 5	Panel 6
Number of subjects analysed	105	111	104	109	106	120
Units: Subjects
No Chip Irritation	105	111	104	109	106	120

Attachments

Chip Irritation

No statistical analyses for this end point

Secondary: Itching and Burning

Top of page

End point title

Itching and Burning

End point description

Subjects were asked to report any itching or burning sensations they experienced while wearing the patch test panels.

End point type

Secondary

End point timeframe

Day 2, following panel removal

End point values	Panel 1	Panel 2	Panel 3	Panel 4	Panel 5	Panel 6
Number of subjects analysed	105	111	104	109	106	120
Units: Subjects
Itching-None	77	62	77	73	71	82
Itching-Weak	16	32	17	20	20	21
Itching-Moderate	9	12	7	12	13	11
Itching-Strong	3	5	3	4	2	6
Burning-None	96	99	93	94	98	108
Burning-Weak	5	8	10	11	4	9
Burning-Moderate	4	4	1	3	4	3
Burning-Severe	0	0	0	1	0	0

Attachments

Itching and Burning

No statistical analyses for this end point

Secondary: Late and Persistent Reactions

Top of page

End point title

Late and Persistent Reactions

End point description

A late reaction is defined as a reaction that initially appears at visit 4 or later. A persistent reaction is defined as a reaction that initially appears at one visit then persists through to the next visit.

End point type

Secondary

End point timeframe

Late and persistent reactions are evaluated at visits 4 (day 7(+1), 5 (day 10+/- 2) and 6 (day 21+/-2)

End point values	0.12 mg/cm2 Copper sulfate	0.24 mg/cm2 Manganese chloride	0.11 mg/cm2 Tin chloride	0.33 mg/cm2 Tin chloride	0.11 mg Ti/cm2 Ammonium titanium oxide oxalate	0.22 mg Ti/cm2 Ammonium titanium oxide oxalate	0.025 mg V/cm2 Vanadium chloride	0.050 mg V/cm2 Vanadium chloride	0.050 mg V/cm2 Vanadium sulfate	0.24 mg/cm2 Zinc chloride
Number of subjects analysed	111	103	111	110	109	109	106	106	106	111
Units: Subjects
Late Reactions	3	1	5	6	1	0	4	9	7	10
Persistent Reactions	4	10	5	39	1	4	11	24	15	44

Attachments

Late Reactions
Persistent Reactions

No statistical analyses for this end point

Secondary: Adhesion

Top of page

End point title

Adhesion

End point description

Adhesion of the panels was evaluated at visit 2 prior to panel removal according to the following 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. The purpose of evaluating panel adhesion was to document allergen-to-skin contact during the 48-hour panel application period.

End point type

Secondary

End point timeframe

Adhesion was measured at Visit 2 prior to removal of patch test panels

End point values	Panel 1	Panel 2	Panel 3	Panel 4	Panel 5	Panel 6
Number of subjects analysed	105	111	105	110	107	121
Units: Number of Subjects
Adhesion: Excellennt	102	103	98	105	100	113
Adhesion: Good	1	3	3	1	6	5
Adhesion Poor	2	5	3	3	0	2
Adhesion: Detached	0	0	0	0	0	0
Adhesion: Missing Score	0	0	1	1	1	1

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Day 1-21

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Adverse Events

Reporting group description

Subjects were asked at visits 2-6 if they had any changes to their health or medications

Serious adverse events	Adverse Events
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 122 (0.82%)
number of deaths (all causes)	0
number of deaths resulting from adverse events	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Intraductal proliferative breast lesion
subjects affected / exposed	1 / 122 (0.82%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0

Frequency threshold for reporting non-serious adverse events: 0.2%

Non-serious adverse events	Adverse Events
Total subjects affected by non serious adverse events
subjects affected / exposed	30 / 122 (24.59%)
Surgical and medical procedures
Endodontic procedure
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Therapeutic nerve ablation
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Nervous system disorders
Dizziness
subjects affected / exposed	2 / 122 (1.64%)
occurrences all number	2
Headache
subjects affected / exposed	3 / 122 (2.46%)
occurrences all number	3
Tension headache
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
General disorders and administration site conditions
Abdominal pain upper
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Application site erythema
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Fatigue
subjects affected / exposed	3 / 122 (2.46%)
occurrences all number	3
Inflammation
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Influenza type illness
subjects affected / exposed	2 / 122 (1.64%)
occurrences all number	2
Malaise
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Pyrexia
subjects affected / exposed	2 / 122 (1.64%)
occurrences all number	2
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Eye disorders
Dry eye
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Hordeolum
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Gastrointestinal disorders
Glossitis
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Nausea
subjects affected / exposed	2 / 122 (1.64%)
occurrences all number	2
Periodontal inflammation
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Toothache
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Vomiting
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea exertional
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Skin and subcutaneous tissue disorders
Dermatitis
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Dermatitis atopic
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Dry skin
subjects affected / exposed	2 / 122 (1.64%)
occurrences all number	2
Dyshidrotic eczema
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Pruritus
subjects affected / exposed	2 / 122 (1.64%)
occurrences all number	2
Pustular psoriasis
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Urticaria
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Groin pain
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Musculoskeletal pain
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Pain in extremity
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Infections and infestations
Cystitis
subjects affected / exposed	1 / 122 (0.82%)
occurrences all number	1
Viral upper respiratory tract infection
subjects affected / exposed	3 / 122 (2.46%)
occurrences all number	3

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

03 Mar 2016

1. Address change for Dr. Pigatto in Milan, Italy 2. Primary endpoint wording changed from approximately 50% of positive responses to at least 50% of positive responses 3. Adverse event wording was enhanced 4. Use of systemic and topical corticosteroids and immunosuppressive agents was changed from 14 days prior to inclusion to 14 days prior to inclusion through the end of the subject’s participation. 5. Treatment with UV light was changed from 3 weeks prior to inclusion to 3 weeks prior to inclusion through the end of the subject’s participation. 6. Exclusion criteria f was added: Known or suspected infection of the skin, joints or other site(s) associated with metal exposure 7. Inclusion criteria h was added: A condition such as, psoriasis, dermatitis herpetiformis, mycosis fungoides or cutaneous T-cell lymphoma that may confound the evaluation of allergic contact dermatitis. 8. 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 was added. 9. Two paragraphs: 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 were added. 10.The section on randomization of dosages was enhanced.

18 Aug 2016

1. Prof. Rustemeyer’s credentials updated 2. Dr. Pigatto’s phone numbers updated 3. The common allergens will be tested at the discretion of the Investigator’ added 4. Wording updated ‘ 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, prostheses or fillings whose exposure to has resulted in: (remainder of list unchanged) 5. Systemic birth control were listed 6. Cervical cap and abstinence from sexual intercourse not acceptable in Japan 7. Breastfeeding may be resumed upon completion of the study 8. Visit schedule added 9. Legal representative must sign consent for subjects aged 18-19 in Japan added 10. Description of dipstick pregnancy test added 11. Numeric descriptors for positive skin reactions were added 12. Definitions for late, persistent hyperpigmentation, hypopigmentation and pruritus added. 13. Panels to be stored under refrigeration at 2-8oC added. 14. The allergens on panel 6 will not be randomized into different configurations. 15. Unused portion of the panel is not to be discarded added. 16. Number and identification of specific panels applied, application (or not) of common allergens added 17 The column headings in the dilution series tables were changed from ‘Dose’ to ‘Ascending Dosages’ and ‘Randomized Among Positions’ 18. The column heading Position was added to the Common Allergens Excipient Control Table 19. Insurance information was updated.

29 Mar 2017

1. Contact info for Kayoko Matsunaga updated 2. Address for Akiko Yagami updated 3. Info for Hiromi Kanto MD, PhD added 4. Info for Risa Tamagawa-Mineoka deleted 5. Yoshiaki Kubo added as Sub-I 6. Study population include patients with metal replacement procedure added 7. Justification of sample size updated 8. Subjects enrolled in Germany not be tested with the reference allergens 9. Symptoms removed from late and persistent reactions 10. Double-barrier method to be used for subjects enrolled in Switzerland who are practicing non-systemic methods of birth control. 11. Abstinence from sexual intercourse not be considered an acceptable method of contraception for subjects enrolled in Switzerland 12. Exclusion criteria l through q were added for subjects enrolled in Germany 13. The definition of overreaction to an allergen added 14. Investigator may withdraw a subject if the subject does not meet the study requirements added 15. Use of PatchMap will required in Germany added 16. Investigators will use medical expertise to determine panel placement added 17. Investigator will use experience and medical expertise to determine if a subject with a past positive patch result should be tested to all allergens or only to the allergen to which the subject has had the past response 18. Subjects with 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 19. Direction for cutting panels to avoid testing nickel, chromium, cobalt and gold added 20. Late and persistent reactions redefined 21. Definitions and reporting procedures for adverse drug reactions and SUSAR updated 22. Definition of active sensitization updated 23. Anaphylactic reaction changed to acute anaphylactic reaction 24. Definition of tape reaction updated 25. Regulatory agencies notified within 15 days if study is prematurely discontinued

06 Feb 2018

1. Assistant Medical Director, Dathan Hamann, MD. was added to the study. 2. The phone number for Kayoko Matsunaga, MD., PhD. was changed. 3. Investigator, Patricia Norris, MD, left OHSU therefore would no longer be participating in the study. The investigative site and IRB were also removed from the protocol. 4. The title for Maki Hosoki, DDS, PhD was updated. 5. The reference for the Declaration of Helsinki was updated. 6. The direction and illustration for cutting the nickel, chromium, cobalt and gold patches from panel 6 was updated. 7. The location of PVP and gold on panel 6 was clarified

17 Jun 2018

1. Investigator, Prof Dr. med. Andreas Bircher who retired from the University Hospital, Basel was replaced by PD Dr. med. Kathrin Scherer Hofmeier 2. The title for Maki Hosoki, DDS, PhD was updated. 3. Investigator Akiko Yagami, M.D., Ph.D completed all her study obligations therefore was removed from the protocol.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

The number of positive responses per allergen could not be included within body of online form. Reference needs to be made to the attachment.

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Clinical trials

Clinical Trial Results: Clinical Evaluation of Metal Panel Allergens: Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, Vanadium and Zinc Dose Response Study

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Allergens with at least 15 positive Responses

Primary: Allergens with at least 15 positive Responses

Primary: Concordance Copper Sulfate 0.12mg/cm2 and 2% pet

Primary: Concordance Copper Sulfate 0.12mg/cm2 and 2% pet

Primary: Concordance Manganese 0.24mg/cm2 vs 2% pet

Primary: Concordance Manganese 0.24mg/cm2 vs 2% pet

Primary: Concordance Tin Chloride 0.11 mg/cm2 vs 1% pet

Primary: Concordance Tin Chloride 0.11 mg/cm2 vs 1% pet

Primary: Concordance Tin Chloride 0.33 mg/cm2 vs 1% pet

Primary: Concordance Tin Chloride 0.33 mg/cm2 vs 1% pet

Primary: Concordance Ammonium titanium oxide oxalate 0.11mgTi/cm2 vs 19% pet

Primary: Concordance Ammonium titanium oxide oxalate 0.11mgTi/cm2 vs 19% pet

Primary: Concordance Ammonium titanium oxide oxalate 0.22mgTi/cm2 vs 19% pet

Primary: Concordance Ammonium titanium oxide oxalate 0.22mgTi/cm2 vs 19% pet

Primary: Concordance Vanadium chloride 0.050 mgV/cm2 vs 1% pet

Primary: Concordance Vanadium chloride 0.050 mgV/cm2 vs 1% pet

Primary: Concordance Vanadium chloride 0.025 mgV/cm2 vs 1% pet

Primary: Concordance Vanadium chloride 0.025 mgV/cm2 vs 1% pet

Primary: Concordance Vanadium sulfate 0.050 mgV/cm2 vs 1.5% pet

Primary: Concordance Vanadium sulfate 0.050 mgV/cm2 vs 1.5% pet

Primary: Concordance Zinc 0.24 mg/cm2 vs 2% pet

Primary: Concordance Zinc 0.24 mg/cm2 vs 2% pet

Secondary: Tape Irritation

Secondary: Tape Irritation

Secondary: Chip Irritation

Secondary: Chip Irritation

Secondary: Itching and Burning

Secondary: Itching and Burning

Secondary: Late and Persistent Reactions

Secondary: Late and Persistent Reactions

Secondary: Adhesion

Secondary: Adhesion

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Clinical Evaluation of Metal Panel Allergens: Aluminum, Copper, Manganese, Molybdenum, Tin, Titanium, Vanadium and Zinc Dose Response Study