ITN043AD GRASS Protocol v 6 0 (27 OCT 2014)...,ppxqh 7rohudqfh 1hwzrun &21),'(17,$/ 3djh 3urwrfro...

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his clinical study is supported and conducted by the Immune Tolerance Network (ITN), which is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). This document is confidential. It is provided for review only to investigators, potential investigators, consultants, study staff, and applicable independent ethics committees or institutional review boards. It is understood that the contents of this document will not be disclosed to others without written authorization from ITN and NIAID unless it is necessary to obtain informed consent from potential study participants. Downloaded From: https://jamanetwork.com/ by a Non-Human Traffic (NHT) User on 08/19/2020

Transcript of ITN043AD GRASS Protocol v 6 0 (27 OCT 2014)...,ppxqh 7rohudqfh 1hwzrun &21),'(17,$/ 3djh 3urwrfro...

Page 1: ITN043AD GRASS Protocol v 6 0 (27 OCT 2014)...,ppxqh 7rohudqfh 1hwzrun &21),'(17,$/ 3djh 3urwrfro ,71 $' 'xukdp 9huvlrq 2fwrehu /rqj 7hup (iihfwv ri 6xeolqjxdo *udvv 7khuds\

This clinical study is supported and conducted by the Immune Tolerance Network (ITN), which is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID).

This document is confidential. It is provided for review only to investigators, potential investigators, consultants, study staff, and applicable independent ethics committees or institutional review boards. It is understood that the contents of this document will not be disclosed to others without written authorization from ITN and NIAID unless it is necessary to obtain informed consent from potential study participants.

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Guidance for Industry: E6 Good Clinical Practice: Consolidated Guidance

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Phleum pratense

Phleum pratense

Phleum pratense

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Phleum pratense

Phleum pratense

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Alutard SQ® Phleum Pratense ................................................................................................... 18

Grazax® ..................................................................................................................................... 18

Alutard SQ® Grass Pollen ......................................................................................................... 19

Grazax®SQ Standardized Grass Allergy Immunotherapy Tablet .............................................. 20

Intradermal and Skin Prick Tests .............................................................................................. 20

Nasal Allergen Challenge (NAC) .............................................................................................. 20

Nasal Lavage ............................................................................................................................. 21

Venepuncture ............................................................................................................................. 21

Nasal Biopsies ........................................................................................................................... 21

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Up-dosing schedule for Alutard SQ® Grass Pollen ................................................................... 33

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Immunotherapy .......................................................................................................................... 46

Intradermal and skin prick tests: ............................................................................................... 46

Nasal allergen challenge: .......................................................................................................... 47

Nasal biopsy: ............................................................................................................................. 47

Adverse Events .......................................................................................................................... 48

Serious Adverse Events .............................................................................................................. 48

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Adverse Events .......................................................................................................................... 48

Serious Adverse Events .............................................................................................................. 48

Study Medication Adverse Reactions......................................................................................... 48

Selected Study Procedures ........................................................................................................ 49

Grading and Attribution of All Other Adverse Events ............................................................... 50

Comparison of SLIT versus SCIT Treatment Arms ................................................................... 55

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Phleum pratensePhleum pratense

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Alutard SQ® Phleum Pratense

Alutard SQ Phleum pratense

Alutard SQ

Grazax®

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Alutard SQ Phleum pratense

Alutard SQ® Grass Pollen

Alutard SQ

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Alutard SQ

Grazax®SQ Standardized Grass Allergy Immunotherapy Tablet

Intradermal and Skin Prick Tests

Nasal Allergen Challenge (NAC)

Aquagen SQ, Phleum pratense,

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Nasal Lavage

Venepuncture

Nasal Biopsies

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Nasal and skin responses

Pollenseason

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ooo

all

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not

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lost to follow-up

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Phleum pratense

Phleum pratensePhleum pratense

Phleum pratense

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Phleum pratense

Phleum pratense

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Phleum pratense

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Up-dosing schedule for Alutard SQ® Grass Pollen

not

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Phleum pratense

Phleum pratense

Betula verrucosaArtemisia vulgaris Dermatophagoides

pteronyssinus Felis domesticus Canis familiarisEquus caballus Aspergillus fumigatus Cladosporium herbarum Alternaria

alternata

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in situ

P. pratense

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Phleum pratense

Phleum pratense

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: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting

Guidelines for Good Clinical PracticeCommon Terminology Criteria for

Adverse Events, Version 4.0

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Immunotherapy

Intradermal and skin prick tests:

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Nasal allergen challenge:

Nasal biopsy:

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Adverse Events

Serious Adverse Events

Adverse Events

Serious Adverse Events

Study Medication Adverse Reactions

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Common Terminology Criteria for Adverse Events, Version 4.0

Selected Study Procedures

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Grading and Attribution of All Other Adverse Events

CommonTerminology Criteria for Adverse Events, Version 4.0

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oooo

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Comparison of SLIT versus SCIT Treatment Arms

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Phleum

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Trends Mol Med.

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CochraneDatabase Syst Rev.

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Allergy.

J Allergy Clin Immunol.

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oror

Phleum pratense

Phleum pratense

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oror

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oror

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Phleum pratense

Phleum pratense

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before

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Note: Values are mean ± standard deviation.

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No dropout Intraclass correlation0 0.2 0.4 0.6 0.8 0.9

0.4 0.33 0.34 0.38 0.47 0.71 0.93

Standardizedtreatmenteffect

0.6 0.61 0.63 0.69 0.81 0.97 >0.990.8 0.85 0.86 0.91 0.97 >0.99 >0.99

0.95 0.94 0.95 0.98 0.99 >0.99 >0.991.0 0.97 0.97 0.98 >0.99 >0.99 >0.991.2 >0.99 >0.99 >0.99 >0.99 >0.99 >0.99

15% dropoutIntraclass correlation

0 0.2 0.4 0.6 0.8 0.90.4 0.29 0.30 0.34 0.41 0.63 0.89

Standardizedtreatmenteffect

0.6 0.55 0.56 0.62 0.74 0.93 >0.990.8 0.79 0.81 0.85 0.93 >0.99 >0.99

0.95 0.91 0.92 0.95 0.99 >0.99 >0.991.0 0.93 0.94 0.97 0.99 >0.99 >0.991.2 0.99 0.99 0.99 >0.99 >0.99 >0.99

30% dropoutIntraclass correlation

0 0.2 0.4 0.6 0.8 0.90.4 0.24 0.25 0.28 0.35 0.56 0.82

Standardizedtreatmenteffect

0.6 0.47 0.49 0.54 0.65 0.88 0.990.8 0.71 0.73 0.78 0.88 0.99 >0.99

0.95 0.85 0.86 0.90 0.96 >0.99 >0.991.0 0.88 0.89 0.92 0.97 >0.99 >0.991.2 0.97 0.97 0.98 >0.99 >0.99 >0.99

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