(YDOXDWLRQGHO¶HIILFDFLWpGHO¶D]LWKURP\FLQHGDQVODSUpYHQWLRQGXV\QGURPHGH EURQFKLROLWHREOLWpUDQWHDXGpFRXUVGHO¶DOORJUHIIHGHFHOOXOHVVRXFKHV KpPDWRSRwpWLTXHV
(YDOXDWLRQRIWKHHIILFDF\RID]LWKURP\FLQWRSUHYHQWEURQFKLROLWLVREOLWHUDQV V\QGURPHDIWHUDOORJHQHLFKHPDWRSRLHWLFVWHPFHOOWUDQVSODQWDWLRQ $//2=,7+52
P120110/ EudraCT 2013-000499-14
version 1.2 du 28/08/2013
Principal Investigator (IP) Pr Anne Bergeron-Lafaurie Service de Pneumologie Hôpital Saint Louis Paris Tel sec. +33 (0) 1 42 49 41 66 ou +33 (0) 1 42 49 96 18 Fax : +33 (0)1 42 49 93 95 E-mail : [email protected]
Sponsor Clinical Research and Data Center Assistance Publique – Hôpitaux de URC du GH Saint Louis Lariboisière Paris (AP- HP) Direction de la Politique Médicale Professeur Sylvie CHEVRET Département de la Recherche Clinique URC du GH Saint Louis Lariboisière et du Développement Site Saint Louis 1, avenue Claude Vellefaux - 75010 Paris Tel. : +33 (0) 1 42 49 97 42 Fadila Amerali Fax : +33 (0) 1 42 49 97 45 Chef de projet DRCD DRCD - Hôpital Saint Louis E-mail : [email protected] 1, avenue Claude Vellefaux - 75010 Paris Tel. : +33 (0) 1 44 84 17 48 Fax : +33 (0) 1 44 84 17 01 E-mail : ĨĂĚŝůĂ͘ĂŵĞƌĂůŝΛƐůƐ͘ĂƉŚƉ͘Ĩƌ
Pharmacy and manufacturer Clinical Trial Departement EPHP- AGEPS Dr Florence EMPANA-BARAT Département Essais Cliniques Etablissement Pharmaceutique des Hôpitaux de Paris AGEPS 7, rue du Fer à Moulin – 75005 Paris Tel. : +33 (0) 1 46 69 90 84 Fax : +33 (0) 1 42 14 09 E-mail : [email protected]
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϭͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 >>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ Ϯͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 Contact List Chief Investigator
Pr Anne Bergeron-Lafaurie Tel : +33 (0) 1 42 49 96 18 HOPITAL Saint LOUIS Tel sec. +33 (0) 1 42 49 41 66 1, avenue Claude Vellefaux ou +33 (0) 1 42 49 96 18 75475 Paris Cedex 10 Fax : +33 (0)1 42 49 93 95 E-mail : [email protected]
Trial Sponsor
Monsieur Christophe Misse, directeur Fadila Amerali, Chef de projet Assistance publique – hôpitaux de Paris Tel. : +33 (0) 1 44 84 17 48 Délégation Interrégionale à la Recherche Fax : +33 (0) 1 44 84 17 01 Clinique E-mail : ĨĂĚŝůĂ͘ĂŵĞƌĂůŝΛƐůƐ͘ĂƉŚƉ͘Ĩƌ Hôpital Saint Louis 75010 PARIS
Trial Statistician Tel. : +33 (0) 1 42 49 97 42 Professeur Sylvie Chevret Fax : +33 (0) 1 42 49 97 45 URC du GH Saint Louis Lariboisière E-mail : [email protected] Site Saint Louis 1, avenue Claude Vellefaux 75010 Paris
SUSAR Reporting Pharmacovigilance DRCD Assistance publique – hôpitaux de Paris Délégation Interrégionale à la Recherche Clinique Hôpital Saint Louis 75010 PARIS
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϯͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 Sites involved in recruiting patients:
Nom Téléphone Discipline Etablissement de santé Prénom E-mail
Investigateur 01.42.49.41.66 Team 1 Coordonnateur Pneumologie Hôpital Saint Louis, APHP Pr BERGERON- [email protected] LAFAURIE
01.42.49.96.45 Team 2 Pr SOCIE Hématologie Hôpital Saint Louis, APHP [email protected]
Hôpital Haut Lévêque, 05.57.65.65.11 Team 3 Pr MILPIED Hématologie Bordeaux [email protected]
04.78.86.22.33 Team 4 Pr MICHALLET Hématologie CHU Lyon-Sud, Lyon [email protected]
04.91.22.37.54 Team 5 Dr Patrice CHEVALLIER Hématologie CHU Nantes [email protected]
Dr GRANATA Angela Institut Paoli Calmette, 04.91.22.37.54 Team 6 Hématologie (Service du Pr BLAISE) Marseille [email protected]
Dr HERMET CHU Estaing, Clermont- 04.73.75.00.66 Team 7 Hématologie (Service du Pr BAY) Ferrand [email protected]
Hôpital Saint Antoine, 01.49.28.26.20 Team 8 Dr RUBIO Hématologie APHP, Paris [email protected] 04 76 76 57 55 Team 9 Dr THIEBAUT Hématologie CHU Grenoble AThiebautbertrand@chu- grenoble.fr 05 61 77 76 05 Team 10 Dr HUYNH Hématologie CHU Toulouse [email protected]
Team 11 Dr VINCENTLaure Hématologie CHU Montpellier [email protected]
Dr Ibrahim 03 20 44 55 51 Team 12 Hématologie CHU de Lille YAKOUB-AGHA [email protected]
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϰͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 Plan
CONTACT LIST͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯ ϭ ^dZd͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳ Ϯ ^zEKW^/^͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϵ ϯ >Kd/KEK&d, tKZ</Ed, hZZ Ed
ϯ͘ϭ hZZ Ed^ddh^K&>>K' E /, DdKWK/ d/^d D >>dZE^W>Edd/KE/E&ZE ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϬ ϯ͘ϭ͘ϭ ŽŵƉůŝĐĂƚŝŽŶƐŽĨĂůůŽŐĞŶĞŝĐ,^d͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϭ ϯ͘Ϯ >KtͲK^ DZK>/ ^/E,ZKE//Ztz/^ ^ ^͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϲ ϯ͘Ϯ͘ϭ DĂĐƌŽůŝĚĞƐŝŶK͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϴ ϯ͘Ϯ͘Ϯ džƉĞƌŝĞŶĐĞĨƌŽŵůƵŶŐƚƌĂŶƐƉůĂŶƚĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϵ ϯ͘Ϯ͘ϯ ƌŐƵŵĞŶƚƐĨŽƌ^KƉƌŽƉŚLJůĂdžŝƐŝŶĂůůŽŐĞŶĞŝĐ,^ƌĞĐŝƉŝĞŶƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϵ ϯ͘Ϯ͘ϰ dŽůĞƌĂŶĐĞŽĨĂnjŝƚŚƌŽŵLJĐŝŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϮϬ ϯ͘Ϯ͘ϱ ƌƵŐŝŶƚĞƌĂĐƚŝŽŶƐǁŝƚŚnjŝƚŚƌŽŵLJĐŝŶ;ĂĐĐŽƌĚŝŶŐƚŽƚŚĞ^ƵŵŵĂƌLJŽĨWƌŽĚƵĐƚŚĂƌĂĐƚĞƌŝƐƚŝĐƐ͕ ƉƉĞŶĚŝdžŶΣϭͿ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϰ ϰ K: d/s ^K&d, >/E/>Z ^ Z,͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϱ ϱ yW Z/D Ed>W>E͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϱ ϲ ^dhz EWK/Ed^͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϱ
ϲ͘ϭ WZ/DZz EWK/Ed͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϱ ϲ͘Ϯ ^ KEZz EWK/Ed^͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϱ ϳ ^dhzWKWh>d/KE͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϲ
ϳ͘ϭ /E>h^/KEZ/d Z/͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϲ ϳ͘Ϯ y>h^/KEZ/d Z/͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϲ ϳ͘ϯ ^DW> ^/ KDWhdd/KE͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϲ ϴ dZ dD Ed͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϴ
ϴ͘ϭ ZEKD/d/KEEdZ dD Ed>>Kd/KE͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϴ ϴ͘ϭ͘ϭ dƌĞĂƚŵĞŶƚƵŶŝƚƐĂŶĚƉůĂĐĞďŽ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϴ ϴ͘ϭ͘Ϯ ZĂŶĚŽŵŝnjĂƚŝŽŶůŝƐƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϴ ϴ͘ϭ͘ϯ ƵƌĂƚŝŽŶŽĨƉĂƚŝĞŶƚƐƉĂƌƚŝĐŝƉĂƚŝŽŶĂŶĚĚĞƐĐƌŝƉƚŝŽŶŽĨƚŚĞƚŝŵŝŶŐĂŶĚĚƵƌĂƚŝŽŶŽĨĂůůŽĨƚŚĞƚĞƐƚ ƉĞƌŝŽĚƐϮϴ ϴ͘Ϯ KhEdK& yW Z/D Ed>dZ dD Ed^͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϵ ϵ s>hd/KE͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϵ
ϵ͘ϭ d/D/E'EKEd EdK&s/^/d^͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϵ ϵ͘Ϯ WZK hZ K&>/E/E'Z <͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϮ ϵ͘ϯ h^ ^K&W ZDE Ed ^^d/KEK&d, WZKdKK>Wd/ EdWZd//Wd/KE͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϮ ϵ͘ϰ h^ ^K&WZ DdhZ ^^d/KEK& yW Z/D Ed>dZ dD Ed͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϮ ϭϬ ^dd/^d/^͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϰ
ϭϬ͘ϭ D/EWZ/E/W> ^͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϰ ϭϬ͘Ϯ ^dd/^d/>d ^d^͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϰ ϭϭ ^& dz^^ ^^D Ed͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϲ
11.1 &/E/d/KE^͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϲ ϭϭ͘Ϯ d, /Es ^d/'dKZΖ^ZK> ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϳ >>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϱͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 ϭϮ ZK> K& s Zzd DEKKZ/Ed/KE͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϬ ϭϯ dK>> d/KED d,K^͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϭ
• RIGHT TO ACCESS SOURCE DATA AND DOCUMENTS͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϭ Data access͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϭ Source documents͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϭ Data confidentiality͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϮ ϭϰ dWZK ^^/E'EWZ ^ Zsd/KEK&KhD Ed^Ed͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϮ
• DATA PROCESSING (CNIL [FRENCH NATIONAL COMMISSION ON INFORMATION TECHNOLOGY AND DATA PRIVACY])͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϮ • Archiving͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϮ • DATA OWNERSHIP͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϯ ϭϱ KEdZK>EYh>/dz^^hZE ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϯ
• GENERAL ORGANISATION͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϯ • STRATEGY FOR OPENING CENTERS͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϰ • QUALITY CONTROL͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϰ • CASE REPORT FORM͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϰ • MANAGEMENT OF BREACHES͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϱ • AUDIT/INSPECTIONS͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϱ ϭϲ > '>E d,/>^W d^͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϲ
• METHODS OF INFORMING AND OBTAINING CONSENT FROM TRIAL SUBJECTS͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϲ • LEGAL REQUIREMENTS͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϴ The sponsor's role͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϴ Request for the opinion of the French Institutional Review Board (CPP)͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϴ Request for authorisation from the ANSM͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϴ COMMITMENT TO CONFORMANCE WITH THE "REFERENCE METHODOLOGY", MR 001͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϴ RESEARCH MODIFICATIONS͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϵ THE FINAL RESEARCH REPORT͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϵ INSURANCE͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϵ ϭϳ Z & Z E ^͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϬ ϭϴ WW E/y͗͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϯ
ϭϴ͘ϭ ZW͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϯ ϭϴ͘Ϯ &KZDh>dK>h>d Yd&;KZZ d KZ/E'&Z Z//Ϳ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϮ ϭϴ͘ϯ ^ Z WKZd&KZD͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϮ
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϲͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 ͳ
%DFNJURXQG 7KH RFFXUUHQFH RI EURQFKLROLWLVREOLWHUDQVV\QGURPH 6%2 DIWHU DOORJHQHLF KHPDWRSRLHWLFVWHPFHOOWUDQVSODQWDWLRQ +6&7 LVFRQVLGHUHGWREHDFKURQLFSXOPRQDU\JUDIW YHUVXVKRVWGLVHDVH *9+' WKDWLVDVVRFLDWHGZLWKVLJQLILFDQWPRUWDOLW\DQGPRUELGLW\7KH UHSRUWHGLQFLGHQFHRI6%2YDULHVIURPWRRIDOORJHQHLF+6&UHFLSLHQWVDQGLVXVXDOO\ GLDJQRVHGZLWKLQ\HDUVDIWHUWUDQVSODQWDWLRQ7KHGLDJQRVLVRI6%2UHOLHVRQWKHRFFXUUHQFH RIDQHZDLUIORZREVWUXFWLRQLGHQWLILHGGXULQJSXOPRQDU\IXQFWLRQWHVWLQJDQGWKHGHILQLWLRQ GLIIHUV EHWZHHQ VWXGLHV &XUUHQWO\ QR FXUDWLYH LPPXQRVXSSUHVVLYH WUHDWPHQW LV DYDLODEOH DQGUHFHQWGDWDVXJJHVWWKDWWKHXVHRIWKHVHWUHDWPHQWVHVSHFLDOO\FRUWLFRVWHURLGVVKRXOG EH OLPLWHG EHFDXVH RI WKHLU WR[LFLW\ 7KH LPSDLUPHQW RI OXQJ IXQFWLRQ SDUDPHWHUV LV OLNHO\ FDXVHGE\ILEURXVVPDOODLUZD\OHVLRQV)HZGDWDRQWKHSDWKRJHQHVLVRI6%2DIWHUDOORJHQHLF +6&7DUHDYDLODEOH6HYHUDOK\SRWKHVHVDUHEDVHGRQWKHRFFXUUHQFHRI6%2GXULQJFKURQLF JUDIW UHMHFWLRQ DIWHU OXQJ WUDQVSODQWDWLRQ ZKLFK VKDUHV PDQ\ FOLQLFDO DQG KLVWRSDWKRORJLFDO VLPLODULWLHVZLWK6%2DIWHUDOORJHQHLF+6&72QHK\SRWKHVLVLVWKDWWKHILUVWVWHSOHDGLQJWR 6%2LVOXQJHSLWKHOLXPLQMXU\6%2LVWKHQLGHQWLILHGDVDQDOORLPPXQHUHDFWLRQZLWKRQO\RQH FOHDUO\LGHQWLILHGULVNIDFWRU H[WUDWKRUDFLFFKURQLF*9+''XHWRWKHLUDQWLLQIODPPDWRU\DQG LPPXQRPRGXODWRU\ SURSHUWLHV UHFHQW GDWD VXJJHVW WKDW ORZGRVH PDFUROLGHVPD\EH HIIHFWLYH DW SUHYHQWLQJ 6%2 DIWHU OXQJ WUDQVSODQWV 7KLV ZHOOWROHUDWHG WUHDWPHQW PD\ EH XVHIXOIRUSUHYHQWLQJ6%2DIWHUDOORJHQHLF+6&7 2EMHFWLYHV 7R HYDOXDWH WKH HIILFDF\ RI D]LWKURP\FLQ LQ SUHYHQWLQJ %2 V\QGURPH DIWHU DOORJHQHLF+6&7LQSDWLHQWVZLWKPDOLJQDQWKHPDWRORJLFDOGLVHDVHV 'HVLJQ 3KDVHPXOWLFHQWUHUDQGRPL]HGGRXEOHEOLQGHGFOLQLFDOWULDOZLWKSDUDOOHODUPV RUDOD]LWKURP\FLQPJ[ZHHN SODFHER ,QFOXVLRQFULWHULD 3DWLHQWV!\HDUVROG ([SHULPHQWLQJDQDOORJHQHLF+6&7IRUDKHPDWRORJLFPDOLJQDQF\ 3UHWUDQVSODQWDWLRQ3XOPRQDU\)XQFWLRQ7HVWLQJ :LWKZULWWHQLQIRUPHGFRQVHQW ([FOXVLRQFULWHULD $OOHUJ\RU,QWROHUDQFHWRD]LWKURP\FLQPDFUROLGHVRUNHWROLGHRUH[FLSLHQW 3URORQJHGFRUUHFWHG47 47F LQWHUYDO !PVHF 7DNLQJPHGLFDWLRQVWKDWSURORQJWKH47FLQWHUYDO &LVDSULGHHUJRWDPLQH G\K\GURHUJRWDPLQH 7DNLQJHUJRWDPLQHDQGG\K\GURHUJRWDPLQHGXHWRWKHULVNRIHUJRWLVP )DPLO\KLVWRU\RIDSURORQJHG47FLQWHUYDO +LVWRU\RIFRQJHVWLYHKHDUWIDLOXUH 7DNLQJFROFKLFLQH 6HYHUHOLYHULQVXIILFLHQF\
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϳͬϲϯ
Downloaded From: https://jamanetwork.com/ on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
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϴͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 ʹ
3ODQRIUHVHDUFK (YDOXDWLRQRIWKHHIILFDF\RID]LWKURP\FLQWRSUHYHQWEURQFKLROLWLVREOLWHUDQV 7LWOH V\QGURPHDIWHUDOORJHQHLFKHPDWRSRLHWLFVWHPFHOOVWUDQVSODQWDWLRQ +6&7 $//2=,7+52 3KDVHPXOWLFHQWHUUDQGRPL]HGGRXEOHEOLQGFOLQLFDOWULDOZLWKSDUDOOHO DUPV
([SHULPHQWDOSODQ RUDOD]LWKURP\FLQPJ[ZHHNGXUDQWDQV
SODFHERPJ[ZHHNGXUDQWDQV SDWLHQWVLQHDFKDUP $]LWKURP\FLQDQGSODFHER 6DPSOHVL]H 7RWDORISDWLHQWV ,QFOXVLRQ \HDU
6WXG\GXUDWLRQ /HQJWKRIIROORZXSRIHDFKSDWLHQW \HDUV
2YHUDOOVWXG\GXUDWLRQ \HDUV 3DWLHQWV¶YLVLWV '0000 2EMHFWLYHRIWKHUHVHDUFK 7RHYDOXDWHWKHHIILFDF\RID]LWKURP\FLQLQSUHYHQWLQJEURQFKLROLWLVREOLWHUDQVV\QGURPHDIWHUDOORJHQHLF+6&7 LQSDWLHQWVZLWKPDOLJQDQWKHPDWRORJLFDOGLVHDVHV 6SHFLILFH[SORUDWLRQVIRUUHVHDUFK $OOSODQHGH[SORUDWLRQVDUHURXWLQHO\SDUWRIDQ\+6&7UHFLSLHQW¶VIROORZXS
2QO\WKHH[SHULPHQWDOGUXJLVVSHFLILFIRUUHVHDUFK
(QGSRLQWV $)2IUHHVXUYLYDODW\HDUVDIWHUDOORJHQHLF+6&7 7KHDLUIORZREVWUXFWLRQ $)2 LVGHILQHGRQWKHFULWHULDIURP&KLHQ-:HWDO $P- 0DLQ 5HVSLU&ULW&DUH0HG E\DQDQQXDOL]HGGHFOLQHRI)(9RIDW OHDVWDQGWKHORZHVWGRFXPHQWHGSRVWWUDQVSODQW)(9)9&UDWLR
• 2YHUDOOVXUYLYDO • 2FFXUUHQFH RI ODWHRQVHW SXOPRQDU\ QRQLQIHFWLRXV FRPSOLFDWLRQV ERWK6%2 DQGLQWHUVWLWLDOOXQJGLVHDVH • 9DULDWLRQRISXOPRQDU\IXQFWLRQWHVWLQJSDUDPHWHUV )9&59)() • 2FFXUUHQFHRIDFXWHDQGFKURQLF*9+' 6HFRQGDU\ • 4XDOLW\RIOLIH • 7ROHUDQFHRID]LWKURP\FLQ • &XPXODWLYHGRVHRILPPXQRVXSSUHVVLYHVWHURLGVWUHDWPHQWIRUWKHGXUDWLRQRI WKHVWXG\
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϵͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 6HOHFWLRQFULWHULD $OOFRQVHFXWLYHSDWLHQWVZKRDUHJRLQJWRH[SHULPHQWDQDOORJHQHLF+6&7LQWKH GLIIHUHQWSDUWLFLSDWLQJFHQWUHVDQGZKRIXOILOWKHLQFOXVLRQFULWHULDRIWKHVWXG\ZLOO EHLQFOXGHG
,QFOXVLRQFULWHULD • 2OGHU\HDUVRIDJH • 5HFHLYHDQDOORJHQHLF+6&7IRUDKHPDWRORJLFPDOLJQDQF\ • 8QGHUJRSUHWUDQVSODQWDWLRQ3)7 • 3URYLGHZULWWHQLQIRUPHGFRQVHQW
$OOHUJ\RULQWROHUDQFHWRD]LWKURP\FLQPDFUROLGHVNHWROLGHRUH[FLSLHQW 3URORQJHGFRUUHFWHG47 47F LQWHUYDO !PVHF • 7DNLQJPHGLFDWLRQVWKDWSURORQJWKH47FLQWHUYDO • )DPLO\KLVWRU\RIDSURORQJHG47FLQWHUYDO ([FOXVLRQFULWHULD • +LVWRU\RIFRQJHVWLYHKHDUWIDLOXUH • 7DNLQJFROFKLFLQH • 7DNLQJHUJRWDPLQHDQGG\K\GURHUJRWDPLQHGXHWRWKHULVNRIHUJRWLVP • 6HYHUHOLYHULQVXIILFLHQF\ +LVWRU\RILQIHFWLRQGXHWRDW\SLFDOP\FREDFWHULD
͵
Ǥͷ
$OORJHQHLFKHPDWRSRLHWLFVWHPFHOOWUDQVSODQWDWLRQ +6&7 LVDFXUHIRUYDULRXVGLVHDVHVLQ ERWK PDOLJQDQW DQG QRQPDOLJQDQW VHWWLQJV 2YHU WKH ODVW WHQ \HDUV WKH QXPEHU RI DOORJHQHLF +&67 SURFHGXUHV SHUIRUPHG LQFUHDVHG E\ LQ )UDQFH EHWZHHQ DQG 7KXV LQ WUDQVSODQWV ZHUH SHUIRUPHG LQ )UHQFK FHQWUHV %LRPHGLFLQH $JHQF\ZZZDJHQFHELRPHGHFLQHIU 0RUHWKDQ RIWKHVHSURFHGXUHVZHUHSHUIRUPHG WRWUHDWKHPDWRORJLFPDOLJQDQFLHV
7KHLQFUHDVHLQWKHQXPEHURIDOORJHQHLF+6&7SURFHGXUHVZDVFDXVHGE\WZRPDLQIDFWRUV
D $QLQFUHDVHGQXPEHURIXQUHODWHGWUDQVSODQWV LQYVLQ
E 7KHGHYHORSPHQWRIQRQP\HORDEODWLYHFRQGLWLRQLQJWUDQVSODQWVZKLFKH[WHQGVWKLV WKHUDSHXWLFDSSURDFKWRROGHUDQGOHVVKHDOWK\SDWLHQWV
7KXV DOORJHQHLF +6&7 SURFHGXUHV KDYH HYROYHG LQ WHUPV RI FRQGLWLRQLQJ DQG WKH W\SH RI JUDIW DGPLQLVWHUHG %RQH PDUURZ WUDQVSODQWV ZHUH WKH PDLQ VRXUFH IRU DOORJHQHLF JUDIWV EHIRUH KRZHYHUVLQFHSHULSKHUDOEORRGVWHPFHOOVKDYHEHHQWKHSULPDU\VRXUFH IRUDOORJHQHLFJUDIWV LQ
,QRYHUDOOVXUYLYDOZDVRIDIWHU\HDUDQGDIWHU\HDUVRIWUDQVSODQWDWLRQ
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϭϬͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 XSGDWH %LRPHGLFLQH$JHQF\ZZZDJHQFHELRPHGHFLQHIU ,Q DOORJHQHLF KHPDWRSRLHWLFVWHPFHOOWUDQVSODQWDWLRQVZHUHSHUIRUPHGLQ)UDQFH YV ZLWK QRQP\HORDEODWLYHFRQGLWLRQLQJVDQGSHULSKHUDOEORRGVWHPFHOOVJUDIWV$ERXW ZHUHSHUIRUPHGIRUDKDHPDWRORJLFDOPDOLJQDQF\$WRWDORI DOORJHQHLF KHPDWRSRLHWLFVWHPFHOOWUDQVSODQWDWLRQVZHUHSHUIRUPHGLQWKHFHQWUHVSDUWLFLSDWLQJLQ RXUWULDO
͵ǤͳǤͳ
7KH PDLQ FRPSOLFDWLRQV RI DOORJHQHLF +6&7 DUH LQIHFWLRXV RU LPPXQRORJLFDO FRPSOLFDWLRQV $OWKRXJKDGYDQFHVLQWKHSURSK\OD[LVDQGWUHDWPHQWRILQIHFWLRXVFRPSOLFDWLRQVRYHUWKDWODVW \HDUV KDYH FRQWULEXWHG WR WKH UHGXFHG PRUELGLW\ DQG SUHPDWXUH PRUWDOLW\ UHODWHG WR LQIHFWLRQV RFFXUULQJ DIWHU DOORJHQHLF +6&7 LQIHFWLRXV FRPSOLFDWLRQV DOWHU WKH SURJQRVLV RI ORQJWHUPLPPXQHFRPSURPLVHGSDWLHQWV
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
7KHLQFLGHQFHRI*9+'GHSHQGVRQYDULRXVIDFWRUVDQGPRVWFRPPRQO\ RFFXUV GXULQJ XQUHODWHGWUDQVSODQWDWLRQVDQGSHULSKHUDOVWHPFHOOWUDQVSODQWDWLRQV7KHLQFLGHQFHRI*9+' ZLOOOLNHO\LQFUHDVHDVDUHVXOWRIWKHFKDQJLQJWUDQVSODQWDWLRQSURILOHLQ)UDQFH VHHSUHYLRXV VHFWLRQ
*9+'WUHDWPHQWUHTXLUHVWKHPDLQWHQDQFHRUHQKDQFHPHQWRILPPXQRVXSSUHVVLYHWKHUDS\ 7KH SURJQRVLV RI *9+' LV SULPDULO\ UHODWHG WR WKH VHYHULW\ RI WKH LQLWLDO UHVSRQVH WR FRUWLFRVWHURLGV 7KH RFFXUUHQFH RIFKURQLF*9+'DIIHFWVWKHPRUELGLW\ DQG PRUWDOLW\ WKDW UHVXOW IURP WKH JUDIW HVSHFLDOO\ IRU ROGHU SDWLHQWV DQG SDWLHQWVZKRGHYHORSH[WHQVLYH FKURQLF*9+' DVZHOODVWKHTXDOLW\RIOLIHRIWKHSDWLHQWV
ǤͷǤͷǤͷ Ǧ
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϭϭͬϲϯ
Downloaded From: https://jamanetwork.com/ on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
ǤͷǤͷǤ
D (SLGHPLRORJ\DQGULVNIDFWRUV
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
1XPHURXVULVNIDFWRUVIRU%2KDYHEHHQSURSRVHGLQYDULRXVUHWURVSHFWLYH VWXGLHV ZLWK FRQIOLFWLQJ UHVXOWV 7KH RQO\ DVVRFLDWLRQ UHSRUWHG LQ DOO RI WKH VWXGLHV ZDV WKH RFFXUUHQFHRIH[WUDWKRUDFLFFKURQLF*9+'DWWKHWLPHRI%2GLDJQRVLV2QHREMHFWLYHRIRXU $//238/0 VWXG\ ZDV WR SURVSHFWLYHO\ LGHQWLI\ WKH HYHQWV RFFXUULQJ ZLWKLQ PRQWKV DIWHU WUDQVSODQWDWLRQWKDWDUHDVVRFLDWHGZLWKWKHVXEVHTXHQWRFFXUUHQFHRI%28VLQJPXOWLYDULDWH DQDO\VLVZHVKRZHGWKDWDKLVWRU\RIVPRNLQJWKHRFFXUUHQFHRISXOPRQDU\LQIHFWLRQDQG
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϭϮͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 SUHH[LVWLQJ DEQRUPDO SUHWUDQVSODQW SXOPRQDU\ IXQFWLRQ ZHUH DVVRFLDWHG ZLWK %2 GHYHORSPHQW
E 3K\VLRSDWKRORJ\RI6%2
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
7KHUHFHQWGHYHORSPHQWRID%2DQLPDOPRGHOFDXVHGE\DOORJHQHLF+6&7KDVSURYLGHGQHZ SDWKRSK\VLRORJLFDOSDWKZD\V7KXVWKHIROORZLQJSDWKZD\VDUHLQYROYHGLQWKLVPRGHO WKH SHULEURQFKLRODULQIODPPDWRU\LQILOWUDWHLVPDLQO\FRPSRVHGRI&'O\PSKRF\WHV &ODUDFHOOV WKDWUHJHQHUDWHEURQFKLRODUHSLWKHOLXPPD\EHWDUJHWV DQGDODUJHQXPEHURIF\WRNLQHVDUH SURGXFHG GXULQJ WKH SURFHVV 0RVW UHFHQWO\ WKH SHULEURQFKLRODU GHSRVLWLRQ RI DOORDQWLERGLHVZDVGHPRQVWUDWHGLQWKHVDPHDQLPDOPRGHODVZHOODVWKHUROHRIPDWXUH% FHOOVIURPWKHGRQRULQ%2GHYHORSPHQW
F 'LDJQRVWLFFULWHULDRI%2
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
&OLQLFDOVLJQVDUHQRQVSHFLILFDQGYDULDEOHDPRQJSDWLHQWV,IDFRXJKDQGG\VSQHDDUHWKH PRVWFRPPRQV\PSWRPVVRPHSDWLHQWVPD\H[SHULHQFHZKHH]LQJUHSHDWHGOXQJLQIHFWLRQV RU EURQFKRVSDVPV 7KH DXVFXOWDWLRQPD\EHQRUPDORUVXJJHVWLYHRI VPDOO DLUZD\ REVWUXFWLRQE\UHYHDOLQJZKHH]LQJVXEFUHSLWDQWVRXQGVRUVTXHDNLQJVRXQGV
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϭϯͬϲϯ
Downloaded From: https://jamanetwork.com/ on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
7RFRQVLGHUDOORIWKHVHSDWLHQWVDPRGLILFDWLRQRIWKH1,+FULWHULDZDVUHFHQWO\SURSRVHG )(9 RISUHGLFWHGRUDGHFUHDVHLQWKH)(9)(969&UDWLR RU59RU 59&37UDWLR!+RZHYHULWLVOLNHO\WKDWWKLVGHILQLWLRQVWLOOGRHVQRWDSSO\ WRHDUOLHVWIRUPVRI%2$IHZ\HDUVDJR&KLHQHWDOFRQGXFWHGDVWXG\XVLQJD GLIIHUHQW GHILQLWLRQ RI DLUIORZ REVWUXFWLRQ LQ WKH VHWWLQJ RI DOORJHQHLF +6&7 VKRZLQJWKDWVWDQGDUGGHILQLWLRQVSUREDEO\XQGHUHVWLPDWHWKHLQFLGHQFHRI$)2 8VLQJWKHUDWHRISHUFHQWSUHGLFWHG)(9GHFOLQHDIWHUWUDQVSODQWWKH\GHILQHG $)2DVDPRUHWKDQSHU\HDUGHFOLQHLQSHUFHQWSUHGLFWHG)(9 ZLWK WKH ORZHVWSRVWWUDQVSODQW)(9)9&UDWLROHVVWKDQ2IQRWHWKH PHDQ UDWH RI >>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϭϰͬϲϯ
Downloaded From: https://jamanetwork.com/ on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
G 2XWFRPH
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
7KHQDWXUDOFRXUVHRI6%2LVXQFOHDU6RPHSDWLHQWVH[SHULHQFHSURIRXQGO\ZRUVHUHVSLUDWRU\ IXQFWLRQDQGGLHZLWKLQPRQWKVZKLOHWKHUHVSLUDWRU\IXQFWLRQRIRWKHUSDWLHQWVVWDELOL]HVWRD YDU\LQJGHJUHH7KHOXQJIXQFWLRQRIVRPHSDWLHQWVHYHQVSRQWDQHRXVO\UHWXUQVWRQRUPDO 7KHUH DUH FXUUHQWO\ QR SUHGLFWLYH PDUNHUV RI WKH HYROXWLRQ RI WKH SXOPRQDU\ IXQFWLRQ DQG SURJQRVLVRI6%2+RZHYHU&KLHQHWDOKDYHVKRZQWKDWWKHSDWLHQWV¶RXWFRPHZDV DOWHUHGDVVRRQDVDQDQQXDOGHFOLQHLQ)(9RIRYHU
H &XUUHQWWKHUDSHXWLFDSSURDFK
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϭϱͬϲϯ
Downloaded From: https://jamanetwork.com/ on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
+RZHYHU WKHVH WKHUDSHXWLF VWUDWHJLHV DUH FXUUHQWO\ HQFRXUDJHGDQGVRPHSURVSHFWLYH HYDOXDWLRQV DUH RQJRLQJ &OLQLFDO7ULDOVJRY )RUPRWHURO%XGHVRQLGH )UDQFH 3U %HUJHURQ 1&7 0RQWHOXNDVW86$1&7 )OXWLFDVRQHD]LWKURP\FLQPRQWHOXNDVW86$ 1&7
Ǥ Ǧ
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
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϭϲͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 WKH PRGXODWLRQ RI KRVWSDWKRJHQ LQWHUDFWLRQV VLJQDOOLQJ SDWKZD\V EORFNLQJ H[WUDFHOOXODU VLJQDOUHJXODWHG NLQDVH (5. SKRVSKRU\ODWLRQ LQ WKH PLWRJHQDFWLYDWHG SURWHLQ NLQDVH SDWKZD\DQGLQKLELWLQJN% ,N% SKRVSKRU\ODWLRQ F\WRNLQHUHVSRQVHV GHFUHDVHVLQ71)Į ,/,/ǃDQG*0&6) R[LGDWLYHVWUHVVDQGLQQDWHLPPXQLW\$OWKRXJKDGGLWLRQDOVWXGLHV DUHQHHGHGFKURQLFPDFUROLGHWKHUDS\PD\PRGLI\WKHPRUELGLW\DQGPRUWDOLW\RISDWLHQWV ZLWK VRPH RI WKHVH FRQGLWLRQV 0DFUROLGH DQWLELRWLFV EHORQJ WR DQ H[SDQVLYH IDPLO\ RI FRPSRXQGVWKDWDUHFKDUDFWHUL]HGE\WKHSUHVHQFHRIDPDFURF\FOLFODFWRQHULQJ7KLVIDPLO\ LQFOXGHVFRPSRXQGVWKDWPDLQO\GHPRQVWUDWHLPPXQRVXSSUHVVDQWDFWLYLW\ HJ).DQG UDSDP\FLQ RUDQWLIXQJDODFWLYLW\ZLWKDQWLQHRSODVWLFSURSHUWLHV HJEDILORP\FLQV 6RPHRI WKH EHQHILFLDO SURSHUWLHV RI PDFUROLGH DQWLELRWLFV LQFOXGH JRRG RUDO ELRDYDLODELOLW\ H[FHOOHQW WLVVXHSHQHWUDWLRQDQGEURDGHIILFDF\DJDLQVWPDQ\RUJDQLVPVDIIHFWLQJWKHOXQJV
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
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϭϳͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 ͵ǤʹǤͳ
%URQFKLROLWLVREOLWHUDQVV\QGURPHLVDOVRDPDQLIHVWDWLRQRIOXQJFKURQLFUHMHFWLRQZKLFKLV UHVSRQVLEOH IRU PRVW RI WKH GHDWKV IROORZLQJ OXQJ WUDQVSODQWDWLRQ8SWRRIOXQJ WUDQVSODQWUHFLSLHQWVVXUYLYLQJDWOHDVWPRQWKVZLOOGHYHORS6%27KHVXEVWDQWLDOPRUELGLW\ DQG PRUWDOLW\ DVVRFLDWHG ZLWK 6%2 FRPELQHG ZLWK WKH OLPLWHG HIIHFWLYHQHVV DQG FRPPRQ VLGHHIIHFWVRIWUDGLWLRQDOLPPXQRVXSSUHVVLYHWKHUDSLHVKDYHJHQHUDWHGLQWHUHVWLQDVVHVVLQJ WKHXVHIXOQHVVRIPDFUROLGHVSULPDULO\LQWKHVHWWLQJRIOXQJWUDQVSODQWDWLRQ
D 0DFUROLGHVIRU6%2DIWHUOXQJWUDQVSODQWDWLRQ
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
6HYHUDO VPDOO RSHQODEHO UHWURVSHFWLYH DQG SURVSHFWLYH QRQSODFHER FRQWUROOHG VWXGLHV LQYROYLQJOXQJWUDQVSODQWUHFLSLHQWVZLWK6%2XVLQJD]LWKURP\FLQ PJ[ZHHN IRU ZHHNV UHSRUWHG WKDW ± RI WKH WUHDWHG SDWLHQWV GHPRQVWUDWHG D VLJQLILFDQW LPSURYHPHQW LQ OXQJ IXQFWLRQ E\ D PHDQ RI ± DFURVV WKH VWXG\ JURXSV7KH LPSURYHPHQW LQ )(9 LQ WKH UHVSRQGHUV ZDV KLJKO\ FOLQLFDOO\ DQG VWDWLVWLFDOO\ VLJQLILFDQW UDQJLQJIURPWR,QDUHFHQWVWXG\-DLQHWDOUHSRUWHGWKDWD]LWKURP\FLQWUHDWPHQW LQLWLDWHG DW DQ HDUO\ VWDJH RI 6%2 ZDV LQGHSHQGHQWO\ DVVRFLDWHG ZLWK D GHFUHDVHG ULVN RI GHDWK)URPWKHVHREVHUYDWLRQVLWZDVFRQFOXGHGWKDWWKHDGGLWLRQRIDPDFUROLGHDQWLELRWLF RIIHUHG D QHZ DQG H[FLWLQJ WUHDWPHQW RSWLRQ IRU 6%2 $]LWKURP\FLQDUUHVWHGIXUWKHUOXQJ IXQFWLRQGHFOLQHZKLFKFRXOGEHREWDLQHGZLWKRWKHUWKHUDSLHVEXWDOVRDSSHDUHGWRUHYHUVH WKH GHFOLQH LQ OXQJ IXQFWLRQ LQ VRPH SDWLHQWV 2XW RI WKH SDWLHQWV SXEOLVKHG LQ WKH SUHYLRXVO\ PHQWLRQHG VWXGLHV UHVSRQGHG WR WKH WKHUDS\ $OWKRXJK WKH UROH RI D]LWKURP\FLQDVDSRWHQWLDOWKHUDS\LQ6%2DSSHDUHGWREHSURPLVLQJDIWHUWKHVHUHSRUWVWKH ODFN RI D UDQGRPL]HG SODFHERFRQWUROOHG WULDO SUHYHQWV D]LWKURP\FLQ IURP EHFRPLQJ D QHZ VWDQGDUGLQWHUYHQWLRQIRU6%2
E 0DFUROLGHVIRU6%2DIWHUDOORJHQHLF+6&7
%URQFKLROLWLVREOLWHUDQVV\QGURPHRFFXUULQJDIWHUOXQJWUDQVSODQWDWLRQ DQG 6%2 RFFXUULQJ DIWHU DOORJHQHLF +6&7 KDYH PDQ\ VLPLODULWLHV)LUVWERWKDUHXVXDOO\UHODWHGWRDQDOOR LPPXQHUHDFWLRQDOWKRXJKRWKHUIDFWRUVKDYHEHHQLPSOLFDWHGLQWKHSK\VLRSDWKRORJ\DQG VRPHIDFWRUVDUHVSHFLILFWRHDFKVLWXDWLRQ IRUH[DPSOHFKHPRWKHUDS\ RU LUUDGLDWLRQ IRU
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϭϴͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 DOORJHQHLF+6&7RUSULPDU\JUDIW G\VIXQFWLRQ IRU OXQJ WUDQVSODQWDWLRQ )XUWKHUPRUH ERWK GLVSOD\VLPLODUKLVWRORJLFDOFOLQLFDOIXQFWLRQDODQGSURJQRVWLFFKDUDFWHULVWLFV LQSDUWLFXODU ERWK6%2VDUHXVXDOO\UHIUDFWRU\WRWUDGLWLRQDOLPPXQRVXSSUHVVLYHWUHDWPHQWV
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¶V VWXG\
F $UJXPHQWVIRU6%2SURSK\OD[LV K\SRWKHVLVDQGREMHFWLYHRIWKHZRUN
*LYHQWKHFXUUHQWSRRUSURJQRVLVRI6%2GDWDVXJJHVWLQJWKHHIILFDF\RID]LWKURP\FLQRQO\ DWWKHHDUO\VWDJHVRI6%2DQGWKHGLIILFXOWLHVLQWKHHDUO\GLDJQRVLVRI6%2WKHHYDOXDWLRQRI DSURSK\ODFWLFVWUDWHJ\ZLWKD]LWKURP\FLQLVIXOO\MXVWLILHG
͵ǤʹǤʹ
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±
͵ǤʹǤ͵
:HK\SRWKHVL]HWKDWWKHDGPLQLVWUDWLRQRID]LWKURP\FLQSURPSWO\DIWHUDOORJHQHLF+6&7 ZRXOGSUHYHQWOXQJIXQFWLRQLPSDLUPHQWIRUVHYHUDOUHDVRQVGHWDLOHGDERYHDQGVXPPDUL]HG EHORZ
6%2 GHILQHGDVDQDLUIORZREVWUXFWLRQLQSXOPRQDU\IXQFWLRQWHVWLQJ LVDVHULRXV FRPSOLFDWLRQRIDOORJHQHLF+6&7WKDWLVDVVRFLDWHGZLWKVLJQLILFDQWPRUELGLW\DQGPRUWDOLW\
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϭϵͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 7KHUHLVFXUUHQWO\QRPDUNHUWRSUHGLFWWKHRFFXUUHQFHDQGVHYHULW\RI6%2GXULQJWKH DOORJHQHLF+6&7UHFLSLHQWV¶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
͵ǤʹǤͶ
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
^LJƐƚĞŵŽƌŐĂŶ ^ŝĚĞĞĨĨĞĐƚƐ ĐůĂƐƐĞƐͲ&ƌĠƋƵĞŶĐLJ /ŶĨĞĐƚŝŽŶƐĞƚ/ŶĨĞƐƚĂƚŝŽŶƐ ͲhŶĐŽŵŵŽŶ ĐĂŶĚŝĚŝĂƐŝƐ͕ŽƌĂůĐĂŶĚŝĚŝĂƐŝƐ͕ǀĂŐŝŶŝƚŝƐ Ͳ/ŶĚĞƚĞƌŵŝŶĞĚ ƉƐĞƵĚŽŵĞŵďƌĂŶŽƵƐĐŽůŝƚŝƐ ůŽŽĚĂŶĚůLJŵƉŚĂƚŝĐƐLJƐƚĞŵ ͲhŶĐŽŵŵŽŶ ůĞƵĐŽƉĞŶŝĂ͕ŶĞƵƚƌŽƉĞŶŝĂ Ͳ/ŶĚĞƚĞƌŵŝŶĞĚ ƚŚƌŽŵďŽĐLJƚŽƉĞŶŝĂ͕ŚĞŵŽůLJƚŝĐĂŶĞŵŝĂ /ŵŵƵŶĞƐLJƐƚĞŵ ͲhŶĐŽŵŵŽŶ ĂŶŐŝŽĞĚĞŵĂ͕ŚLJƉĞƌƐĞŶƐŝƚŝǀŝƚLJ Ͳ/ŶĚĞƚĞƌŵŝŶĞĚ ĂŶĂƉŚLJůĂĐƚŝĐƌĞĂĐƚŝŽŶƐ DĞƚĂďŽůŝƐŵĂŶĚŶƵƚƌŝƚŝŽŶ ͲŽŵŵŽŶ ĂŶŽƌĞdžŝĂ WƐLJĐŚŝĂƚƌŝĐĚŝƐŽƌĚĞƌƐ
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϮϬͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 ͲhŶĐŽŵŵŽŶ ŶĞƌǀŽƵƐŶĞƐƐ ͲZĂƌĞ ĂŐŝƚĂƚŝŽŶ Ͳ/ŶĚĞƚĞƌŵŝŶĞĚ ĂŐŐƌĞƐƐŝŽŶ͕ĂŶdžŝĞƚLJ EĞƌǀŽƵƐƐLJƐƚĞŵĚŝƐŽƌĚĞƌƐ ͲŽŵŵŽŶ ĚŝnjnjŝŶĞƐƐ͕ŚĞĂĚĂĐŚĞ͕ƉĂƌĞƐƚŚĞƐŝĂ͕ĚLJƐŐĞƵƐŝĂ ͲhŶĐŽŵŵŽŶ ŚLJƉŽĂĞƐƚŚĞƐŝĂ͕ƐŽŵŶŽůĞŶĐĞ͕ŝŶƐŽŵŶŝĂ Ͳ/ŶĚĞƚĞƌŵŝŶĞĚ ƐLJŶĐŽƉĞ͕ƐĞŝnjƵƌĞƐ͕ƉƐLJĐŚŽŵŽƚŽƌŚLJƉĞƌĂĐƚŝǀŝƚLJ͕ĂŶŽƐŵŝĂ͕ƚĂƐƚĞůŽƐƐ͕ƉĂƌŽƐŵŝĂ͕ ŵLJĂƐƚŚĞŶŝĂŐƌĂǀŝƐ LJĞĚŝƐŽƌĚĞƌƐ ͲŽŵŵŽŶ ǀŝƐƵĂůĚŝƐƚƵƌďĂŶĐĞƐ Ăƌ ͲŽŵŵŽŶ ĚĞĂĨŶĞƐƐ ͲhŶĐŽŵŵŽŶ ŚĞĂƌŝŶŐĚŝƐŽƌĚĞƌƐ ͲZĂƌĞ ĚŝnjnjŝŶĞƐƐ ĂƌĚŝĂĐ ͲhŶĐŽŵŵŽŶ ƉĂůƉŝƚĂƚŝŽŶƐ Ͳ/ŶĚĞƚĞƌŵŝŶĞĚ ƚŽƌƐĂĚĞƐĚĞƉŽŝŶƚĞƐ͕ĂƌƌŚLJƚŚŵŝĂǁŝƚŚǀĞŶƚƌŝĐƵůĂƌƚĂĐŚLJĐĂƌĚŝĂ sĂƐĐƵůĂƌ Ͳ/ŶĚĞƚĞƌŵŝŶĞĚ ŚLJƉŽƚĞŶƐŝŽŶ 'ĂƐƚƌŽŝŶƚĞƐƚŝŶĂůĚŝƐŽƌĚĞƌƐ ͲsĞƌLJĐŽŵŵŽŶ ĚŝĂƌƌŚĞĂ͕ĂďĚŽŵŝŶĂůƉĂŝŶ͕ŶĂƵƐĞĂ͕ĨůĂƚƵůĞŶĐĞ ͲŽŵŵŽŶ ǀŽŵŝƚŝŶŐ͕ĚLJƐƉĞƉƐŝĂ ͲhŶĐŽŵŵŽŶ ŐĂƐƚƌŝƚŝƐ͕ĐŽŶƐƚŝƉĂƚŝŽŶ Ͳ/ŶĚĞƚĞƌŵŝŶĞĚ ƉĂŶĐƌĞĂƚŝƚŝƐ͕ƚŽŶŐƵĞĚŝƐĐŽůŽƌĂƚŝŽŶ ,ĞƉĂƚŽďŝůŝĂƌLJĚŽƐŽƌĚĞƌƐ ͲhŶĐŽŵŵŽŶ ŚĞƉĂƚŝƚŝƐ ͲZĂƌĞ ĚŝƐŽƌĚĞƌƐŽĨůŝǀĞƌĨƵŶĐƚŝŽŶ Ͳ/ŶĚĞƚĞƌŵŝŶĞĚ ŚĞƉĂƚŝĐŝŵƉĂŝƌŵĞŶƚ͕ĨƵůŵŝŶĂŶƚŚĞƉĂƚŝƚŝƐ͕ŚĞƉĂƚŝĐŶĞĐƌŽƐŝƐ͕ĐŚŽůĞƐƚĂƚŝĐũĂƵŶĚŝĐĞ ^ŬŝŶĂŶĚƐƵďĐƵƚĂŶĞŽƵƐƚŝƐƐƵĞĚŝƐŽƌĚĞƌƐ ͲŽŵŵŽŶ ƌĂƐŚ͕ƉƌƵƌŝƚƵƐ ͲhŶĐŽŵŵŽŶ ƐƚĞǀĞŶƐͲ:ŽŚŶƐŽŶƐLJŶĚƌŽŵĞ͕ƉŚŽƚŽƐĞŶƐŝƚŝǀŝƚLJ͕ƵƌƚŝĐĂƌŝĂ Ͳ/ŶĚĞƚĞƌŵŝŶĞĚ ƚŽdžŝĐĞƉŝĚĞƌŵĂůŶĞĐƌŽůLJƐŝƐ͕ĞƌLJƚŚĞŵĂŵƵůƚŝĨŽƌŵĞ DƵƐĐƵůŽƐŬĞůĞƚĂůĂŶĚƐLJƐƚĞŵŝĐ ͲŽŵŵŽŶ ĂƌƚŚƌĂůŐŝĂ ZĞŶĂůĂŶĚƵƌŝŶĂƌLJƚƌĂĐƚ Ͳ/ŶĚĞƚĞƌŵŝŶĞĚ ĂĐƵƚĞƌĞŶĂůĨĂŝůƵƌĞ͕ŝŶƚĞƌƐƚŝƚŝĂůŶĞƉŚƌŝƚŝƐ 'ĞŶĞƌĂůƐLJŵƉƚŽŵƐ ͲŽŵŵŽŶ ĨĂƚŝŐƵĞ ͲhŶĐŽŵŵŽŶ ĐŚĞƐƚƉĂŝŶ͕ĞĚĞŵĂ͕ŵĂůĂŝƐĞ͕ĂƐƚŚĞŶŝĂ /ŶǀĞƐƚŝŐĂƚŝŽŶƐ
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ Ϯϭͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 ͲŽŵŵŽŶ ĚĞĐƌĞĂƐĞŝŶůLJŵƉŚŽĐLJƚĞĐŽƵŶƚ͕ŝŶĐƌĞĂƐĞĚĞŽƐŝŶŽƉŚŝůĐŽƵŶƚ͕ĚĞĐƌĞĂƐĞŝŶďŝĐĂƌďŽŶĂƚĞ ĐŽŶĐĞŶƚƌĂƚŝŽŶŝŶƚŚĞďůŽŽĚ ͲhŶĐŽŵŵŽŶ ŝŶĐƌĞĂƐĞĚĂƐƉĂƌƚĂƚĞĂŵŝŶŽƚƌĂŶƐĨĞƌĂƐĞ͕ŝŶĐƌĞĂƐĞĚĂůĂŶŝŶĞĂŵŝŶŽƚƌĂŶƐĨĞƌĂƐĞ͕ ŝŶĐƌĞĂƐĞĚďŝůŝƌƵďŝŶ͕ŝŶĐƌĞĂƐĞĚďůŽŽĚƵƌĞĂ͕ĐƌĞĂƚŝŶŝŶĞŝŶĐƌĞĂƐĞ͕ĂďŶŽƌŵĂů ĐŽŶĐĞŶƚƌĂƚŝŽŶŽĨƉŽƚĂƐƐŝƵŵŝŶƚŚĞďůŽŽĚ Ͳ/ŶĚĞƚĞƌŵŝŶĞĚ ƉƌŽůŽŶŐĂƚŝŽŶŽĨƚŚĞYdŝŶƚĞƌǀĂůŽŶƚŚĞĞůĞĐƚƌŽĐĂƌĚŝŽŐƌĂŵ
$ UHFHQW ODUJH UHWURVSHFWLYH REVHUYDWLRQDO VWXG\ FRKRUW IRXQG WKDW GXULQJ GD\V RI D]LWKURP\FLQWKHUDS\ LHSUHVFULEHGZLWKGRVHVDGDSWHGWRDQDQWLELRWLFHIIHFW WKHUHZDVD VPDOODEVROXWHLQFUHDVHLQFDUGLRYDVFXODUGHDWKV+RZHYHUWKLVVWXG\KDGWKHOLPLWDWLRQVRI DQREVHUYDWLRQDOUHWURVSHFWLYHVWXG\$FWXDOO\WKLVFDUGLRYDVFXODUULVNKDGQHYHUEHHQIRXQG LQ SUHYLRXV SURVSHFWLYH VWXGLHV LQ SDUWLFXODU LQ WKH UHFHQW $OEHUW¶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
7KHDGPLQLVWUDWLRQRIORZGRVHD]LWKURP\FLQLVH[SHFWHGWRSURYLGHVLJQLILFDQWO\IHZHUVLGH HIIHFWVWKDQWKHDQWLPLFURELDOGRVHVRID]LWKURP\FLQDQGLPPXQRVXSSUHVVLYH WUHDWPHQWV FXUUHQWO\DGPLQLVWHUHGIRU6%2
,Q D VWXG\ E\ 9RV WKDW SURVSHFWLYHO\ HYDOXDWHG ORZGRVH D]LWKURP\FLQ PJ [ ZHHN Q YHUVXVDSODFHERIRU\HDUVLQOXQJWUDQVSODQWUHFLSLHQWVWKHWUHDWPHQWZDVJHQHUDOO\ ZHOOWROHUDWHGDOWKRXJKWKHJDVWURLQWHVWLQDOVLGHHIIHFWVRIQDXVHDDQGGLDUUKHDZHUHKLJKHU EXWQRWVWDWLVWLFDOO\VLJQLILFDQWLQWKHWUHDWPHQWJURXS7KHVHVLGHHIIHFWVDUHOLNHO\GXHWR WKH HIIHFW RI D]LWKURP\FLQ RQ JXW PRWLOLW\ *DVWURLQWHVWLQDO GLVRUGHUV ZHUH REVHUYHG LQ RQH SDWLHQW UHFHLYLQJWKHSODFHERZKRXQGHUZHQWDPLOGHSLVRGHRISVHXGRPHPEUDQRXV FROLWLVDQGLQWKUHH SDWLHQWVUHFHLYLQJD]LWKURP\FLQ7KHODWWHUJURXSUHSRUWHGQDXVHD DQGGLDUUKHDDIWHUWDNLQJD]LWKURP\FLQDQGWKHGUXJZDVGLVFRQWLQXHGLQWZRRIWKHSDWLHQWV RQHRIZKLFKDOVRH[SHULHQFHGDQHSLVRGHRISVHXGRPHPEUDQRXVFROLWLV1RDOOHUJLFUHDFWLRQV RU QHXURORJLFDO GLVRUGHUV ZHUH REVHUYHG &DUGLDF DUUK\WKPLDV DOORIZKLFKZHUHDWULDORU VXSUDYHQWULFXODU WDFK\DUU\WKPLDV ZHUH REVHUYHG LQ IRXU SDWLHQWV UHFHLYLQJ WKH SODFHERDQGRQH SDWLHQWUHFHLYLQJD]LWKURP\FLQ1RYHQWULFXODUWDFK\DUU\WKPLDVZHUH REVHUYHG1RWDEO\WKHH[FOXVLRQFULWHULDRIWKLVVWXG\GLGQRWLQFOXGHDQ\FDUGLDFGLVHDVHRU DEQRUPDOLWLHV LQ HOHFWURFDUGLRJUDPV 7KXV FRQFHUQV DERXW VLGH HIIHFWV VXFK DV FDUGLDF DUUK\WKPLDV RU VHYHUH JDVWURLQWHVWLQDO SUREOHPV GLG QRW PDWHULDOL]H ZLWKLQ WKH VWXG\ WLPHIUDPH7KLVUHVXOWPD\EHGXHWRWKHXVHRIDORZGRVHRID]LWKURP\FLQDVWKHPDFUROLGH RIFKRLFH D]LWKURP\FLQKDVEHHQDVVRFLDWHGZLWKDUHGXFHGULVNRIFDUGLDFDUUK\WKPLDVDQG LPSURYHGJDVWURLQWHVWLQDOWROHUDELOLW\FRPSDUHGZLWKROGHUDJHQWVVXFKDVHU\WKURP\FLQ
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϮϮͬϲϯ
Downloaded From: https://jamanetwork.com/ on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¶V VWXG\ PRUH SDUWLFLSDQWV UHFHLYLQJ D]LWKURP\FLQ PHW WKH FULWHULD IRU WKH GHYHORSPHQW RI D KHDULQJGHFUHPHQWWKDQWKRVHUHFHLYLQJWKHSODFHER+RZHYHUWKHLPSURYHPHQWVLQKHDULQJ WKDWRFFXUUHGDIWHUUHSHDWHGWHVWLQJUHJDUGOHVVRIZKHWKHUWKHVWXG\GUXJZDVGLVFRQWLQXHG VXJJHVWWKDWWKHFULWHULDRIWKLVVWXG\ZHUHSUREDEO\WRRVWULQJHQWDQGWKDWWKHLQFLGHQFHRI KHDULQJGHFUHPHQWVZDVRYHUHVWLPDWHGLQERWKJURXSV
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
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ Ϯϯͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 ͵ǤʹǤͷ ȋ ǡιͳȌ • )RUELGGHQ DVVRFLDWHG WUHDWPHQWV &LVDSULGH HUJRWDPLQH G\K\GURHUJRWDPLQH FROFKLFLQH
(UJRWDPLQH DQG G\K\GURHUJRWDPLQH DUH IRUELGGHQ GXH WR ULVN RI ERWK 47 SURORQJDWLRQDQGHUJRWLVP
• 1RW UHFRPPHQGHG DVVRFLDWHG WUHDWPHQWV EURPRFULSWLQH FDEHUJROLQH OLVXULGH SHUJROLGH
• $VVRFLDWHGWUHDWPHQWVWKDWQHHGVSHFLDOFDXWLRQIURPWKHLQYHVWLJDWRUV
•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pQRWKLD]LQHV SLPR]LGH@ WULF\FOLF DQWLGHSUHVVDQWV >H[ FLWDORSUDP@ VRPH IOXRURTXLQRORQHV >H[ PR[LIOR[DFLQHOHYRIOR[DFLQH@K\SRNDOHPLDQWGUXJVEUDG\FDUGLDGUXJV
• $FORVHFOLQLFDODQG(&*PRQLWRULQJVKRXOGEHSHUIRUPHGGXULQJWKHGXUDWLRQRIWKH DVVRFLDWLRQGXHWRDQLQFUHDVHGULVNRIYHQWULFXODUDUUK\WKPLDVLQFOXGLQJWRUVDGHVGH SRLQWHV
,WLVLPSRUWDQWWRQRWHWKDWYHU\IHZSDWLHQWVZKRXQGHUJRDQDOORJHQHLFKHPDWRSRLHWLFVWHP FHOOWUDQVSODQWDWLRQDUHDIIHFWHGE\WKHIRUELGGHQDQGQRWUHFRPPHQGHGPHGLFDWLRQV
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ Ϯϰͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 Ͷ
7RHYDOXDWHWKHHIILFDF\RID]LWKURP\FLQLQSUHYHQWLQJ%2V\QGURPHDIWHUDOORJHQHLF+6&7LQ SDWLHQWVZLWKPDOLJQDQWKHPDWRORJLFDOGLVHDVHV
ͷ 7KLVLVD3KDVHPXOWLFHQWUHUDQGRPL]HGGRXEOHEOLQGHGFOLQLFDOWULDOZLWKSDUDOOHOGRVLQJ JURXSV
2UDOD]LWKURP\FLQ PJ[ZHHN
3ODFHER
Ǥͳ $LUIORZREVWUXFWLRQIUHHVXUYLYDODW\HDUVDIWHUDOORJHQHLF+6&7
7KHDLUIORZREVWUXFWLRQ $)2 LVGHILQHGRQWKHFULWHULDSURSRVHGE\&KLHQ-:HWDOZKLFK LQFOXGHDQDQQXDOL]HGGHFOLQHRI)(9RIDWOHDVWDQGWKHORZHVWGRFXPHQWHGSRVW WUDQVSODQW)(9)9&UDWLRRI 7KH3)7REWDLQHGLPPHGLDWHO\EHIRUH+6&7ZLOOEH FRQVLGHUHGWKHEDVHOLQHOXQJIXQFWLRQ3)7VREWDLQHGZLWKLQWKHILUVWPRQWKVDIWHU+6&7 DUHQRWFRQVLGHUHGEHFDXVHFKDQJHVLQSXOPRQDU\IXQFWLRQGXULQJWKHILUVWPRQWKVDIWHU WUDQVSODQWPD\EHUHYHUVLEOHDQGUHIOHFWWHPSRUDU\IXQFWLRQDOFKDQJHVUHODWHGWR SHULWUDQVSODQWHYHQWV$OO3)7VREWDLQHGDIWHUWKHLQLWLDOPRQWKVZLOOEHXVHGWRFDOFXODWH DQDQQXDOL]HGUDWHRIGHFOLQHIRUWKHSUHGLFWHG)(9
Ǥʹ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
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ Ϯϱͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021
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
Ǥͳ 2OGHU\HDUVRIDJH 5HFHLYHDQDOORJHQHLF+6&7IRUDKHPDWRORJLFPDOLJQDQF\ 8QGHUJRSUHWUDQVSODQWDWLRQ3)7 3URYLGHZULWWHQLQIRUPHGFRQVHQW
Ǥʹ • $OOHUJ\RULQWROHUDQFHWRD]LWKURP\FLQPDFUROLGHVRUNHWROLGHVRUH[FLSLHQW • 3URORQJHGFRUUHFWHG47 47F LQWHUYDO !PVHF • 7DNLQJPHGLFDWLRQVWKDWSURORQJWKH47FLQWHUYDO &LVDSULGHHUJRWDPLQH G\K\GURHUJRWDPLQH • )DPLO\KLVWRU\RIDSURORQJHG47FLQWHUYDO • +LVWRU\RIFRQJHVWLYHKHDUWIDLOXUH 7DNLQJFROFKLFLQH 7DNLQJHUJRWDPLQHDQGG\K\GURHUJRWDPLQHGXHWRWKHULVNRIHUJRWLVP 6HYHUHOLYHULQVXIILFLHQF\ • +LVWRU\RIQRQWXEHUFXORXVP\FREDFWHULDOLQIHFWLRQ
7KHUHLVQRULVNRISUHJQDQF\IRUZRPHQZKRDUHLQFOXGHGHQWKHVWXG\ EHFDXVH RISDWKRORJ\WUHDWPHQW
Ǥ͵ %DVHGRQD\HDUHVWLPDWHG$)2IUHHVXUYLYDORILQWKHFRQWURODUPLWKDVEHHQ FRPSXWHG WKDW DWRWDORIHYHQWVDQGSDWLHQWV LQHDFKDUP DUH UHTXLUHGLQHDFKDUP WR GHPRQVWUDWH D EHQHILW LQ WKH H[SHULPHQWDO DUP ZLWK DQ RYHUDOOW\SH,HUURURIDQGDVWDWLVWLFDOSRZHURI EDVHGRQDWZRVLGHGORJUDQNWHVW 7KLVHVWLPDWLRQWDNHVLQWRDFFRXQWERWKWKHLQFLGHQFHRI$)2SRVWDOORJHQHLF+6&7DQG WKHVXUYLYDODIWHUWUDQVSODQWDWLRQ DIWHURQH\HDUDQGDIWHU\HDUV
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ Ϯϲͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 7KHFDOFXODWHGVDPSOHVL]HWRWHVWRXUK\SRWKHVLVLVSDWLHQWV)UHQFKFHQWUHVZLOO SDUWLFLSDWHLQWKHVWXG\
7KHQXPEHURIUHTXLUHGSDWLHQWVDQGFKRLFHRIWKHFHQWUHVFRQVLGHUHGWKHIROORZLQJ
7KHODWHVWGDWDIURPWKH$JHQF\IRU%LRPHGLFLQHUHJDUGLQJDOORJHQHLF+6&7LQ)UDQFH KWWS ZZZDJHQFHELRPHGHFLQHIUDQQH[HVELODQGRQQHHVFHOOXOHV JUHIIHV\QWKHVHKWP ZKLFKUHSRUWVWKHQXPEHURIWUDQVSODQWDWLRQVLQHDFKFHQWUHDV IROORZV WUDQVSODQWUHFLSLHQWVZHUHUHSRUWHGLQLQWKHSDUWLFLSDWLQJFHQWUHV 6DLQW /RXLV%RUGHDX[/\RQ0DUVHLOOH1DQWHV7RXORXVH*UHQREOH6DLQW$QWRLQH&OHUPRQW )HUUDQG0RQWSHOOLHUDQG/LOOH ZLWKDQLQFUHDVHRILQDQGRYHUDOOVXUYLYDORI DIWHU\HDUDQGDIWHU\HDUV
7KHSUHYDOHQFHRI$)2LQDOORJHQHLF+6&7UHFLSLHQWVDFFRUGLQJWRWKHVWXG\E\&KLHQ-: ZKLFKLVWKHVRXUFHRIRXUGHILQLWLRQRI$)2ZDVLQWKHSRSXODWLRQRISDWLHQWVDOLYHDW GD\DIWHUDOORJHQHLF+6&7
:HSUHGLFWHGWKDW$)2IUHHVXUYLYDOZRXOGEHLQWKHSODFHERJURXSDQGLQWKH JURXSRISDWLHQWVWUHDWHGZLWKD]LWKURP\FLQ7KLVHVWLPDWLRQWDNHVLQWRDFFRXQWERWKWKH LQFLGHQFHRI$)2DQGWKHVXUYLYDODIWHUWUDQVSODQWDWLRQ DIWHU\HDUDIWHU \HDUV
7KHSUHOLPLQDU\VWXG\RIWKH$//238/0FRKRUWZDVIXQGHGE\&,5& DQGFRQGXFWHG E\WKHDSSOLFDQW 3U%HUJHURQ 7KLVFRKRUWSURVSHFWLYHO\DGGUHVVHVWKHHSLGHPLRORJ\RI ODWHRQVHWQRQLQIHFWLRXVSXOPRQDU\FRPSOLFDWLRQVDIWHUDOORJHQHLF+6&7
7KHSULQFLSDOLQYHVWLJDWRULVDQDWLRQDOUHIHUHQFHLQSXOPRQDU\FRPSOLFDWLRQVDIWHU DOORJHQHLF+6&7 FRRUGLQDWHVVWXGLHVDQGURXWLQHO\SHUIRUPVFOLQLFDOZRUNZLWKWKH SDUWLFLSDWLQJFHQWUHV
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ Ϯϳͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 ͺ
(DFKSDWLHQWZLOOUHFHLYHHLWKHUPJRID]LWKURP\FLQRUDSODFHERRUDOO\WLPHVDZHHNIRU WZR\HDUV7KHILUVWGD\RIWUHDWPHQWZLOOEHWKHILUVWGD\RIFRQGLWLRQLQJ3DWLHQWVZLOOEHWROG WRWDNHWKHLUWUHDWPHQWGXULQJDPHDO7KHWUHDWPHQWEDWFKHVZLOOEHSDFNDJHGLQDQLGHQWLFDO PDQQHUWRHQVXUHGRXEOHEOLQGFRQGLWLRQVWKURXJKRXWWKHWULDO
ͺǤͳ
ͺǤͳǤͳ $]LWKURP\FLQRUSODFHERZLOOEHDGPLQLVWHUHGDWDGRVHRIPJ[ZHHNGXULQJDPHDOIRU DSHULRGRI\HDUV
Treatments will be sent to the hospital pharmacies by the DEC (Département Essais Cliniques) EP-HP AGEPS (Agence Générale des Equipements et Produits de Santé).
7KHWDEOHWVZLOOEHILOPFRDWHGDQGFRQWDLQPJRID]LWKURP\FLQ7KHSODFHERZLOOKDYH WKHVDPHDVSHFWWKDQWKHD]LWKURP\FLQThe two will be provided, conditioned and labelled according to clinical trial regulation by the EP-HP AGEPS. All tablets and outer packaging will be numbered. Treatment numbers will be attributed to the patients every three month following the randomization list. They will be provided with a complete leaflet including data about the drug and treatment instructions.
7KH FRQFHDOPHQW RI DOORFDWLRQ ZKLFK LV WKH SURFHVV IRU DFWXDOO\ DVVLJQLQJ D SDWLHQW WR D JURXS ZLWKRXW EUHDNLQJ EOLQGLQJ ZLOO EH SHUIRUPHG E\ WKH LQWHUQHW VRIWZDUH QDPHG &OHDQZHE&706 5DQGRPL]DWLRQ RI WKH WZR SDUDOOHO JURXSV ZLOO EH SHUIRUPHG DIWHU WKH HOLJLELOLW\FULWHULDDUHYHULILHG FRPSOLDQFHZLWKLQFOXVLRQDQGH[FOXVLRQFULWHULD RQ&OHDQZHE
7KH SK\VLFLDQ UHVSRQVLEOH IRU WKH SDWLHQW ZLOO EH SURYLGHG DQ DQRQ\PRXV LGHQWLILFDWLRQ QXPEHUIRUHDFKLQFOXGHGSDWLHQW
ͺǤͳǤʹ The randomization list stratified by center, FEV1/FVC ratio (( ou > 85%) and age (( ou > à 50 yrs old) will be established by the Clinical and Biostatistics research unit of Saint-Louis Hospital before the beginning of the study according to a method based on permutation block whose size will be kept confidential. Randomization of patients will be centralized and carried out using a computerized system. Distribution in the two groups (azothomycine versus placebo) is made in a 1/1 ratio. Inclusion criteria will be checked before randomization.
ͺǤͳǤ͵ 7KHUHFUXLWPHQWSHULRGZLOOODVWIRU\HDU7KHGXUDWLRQRISDUWLFLSDWLRQIRUDSDWLHQWZLOOEH \HDUV7KHGXUDWLRQRIWKHVWXG\ZLOOEH\HDUV
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ Ϯϴͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 ͺǤʹ 7KHWUHDWPHQWXQLWVZLOOEHSDFNDJHGVWRUHGDQGVKLSSHGWRWKHSKDUPDFLHVDWHDFKFHQWHU
$WHDFKYLVLWWKHSDWLHQWZLOOUHWXUQWKHHPSW\FDSVXOHVWRWKHSKDUPDF\RIWKHDSSURSULDWH KRVSLWDO7KHQXPEHURIWDEOHWVWDNHQZLOOEHUHFRUGHGDQGUHSRUWHGLQWKHH&5)E\WKH LQYHVWLJDWRU
ͻ
,QDGGLWLRQWRFOLQLFDOYLVLWVZKLFKDUHURXWLQHO\SHUIRUPHGLQWKHVHSDWLHQWV7KHUHVSLUDWRU\ 6DLQW*HRUJH¶VKRVSLWDOTXDOLW\RIOLIHTXHVWLRQQDLUHZLOOEHVXEPLWWHGE\HDFKSDWLHQWEHIRUH WUDQVSODQWDWLRQDW0DQG0,ISDWLHQWVKDYHGHYHORSHGDQLQIHFWLRXVUHVSLUDWRU\GLVHDVH RUDQ\V\PSWRPOHDGLQJWRGLIILFXOWLHVLQSHUIRUPLQJWKH3)7DWWKHVFKHGXOHGWLPHWKH3)7 ZLOOEHSHUIRUPHGRQHPRQWKODWHU(U\WKURP\FLQWROHUDQFHZLOOEHDVVHVVHGDWHDFKYLVLW
ͻǤͳ
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¶ TXDOLW\ RI OLIH TXHVWLRQQDLUH SURYLGHG E\ 6DLQW *HRUJH¶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
$IWHU WUHDWPHQW LQLWLDWLRQ WKHSDWLHQWV ZLOO EH DVVHVVHG DW PRQWKV DIWHU WUHDWPHQW 0 00DQG0
'HWDLOHG PRQLWRULQJ DIWHU WUDQVSODQWDWLRQ ZLOO EH URXWLQHO\ SHUIRUPHG LQ DOO FHQWUHV DW DQG EHWZHHQWKHSUHYLRXVO\OLVWHGGDWHV7KHVDIHW\RIWKHVWXG\WUHDWPHQWZLOOEHDVVHVVHGDW HDFKYLVLWE\WKHKDHPDWRORJLVWDVVLJQHGWRWKHSDWLHQW7KHSDWLHQWZLOOEHDVNHGVSHFLILFDOO\
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ Ϯϵͬϲϯ
Downloaded From: https://jamanetwork.com/ on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
7KHSXOPRQDU\IXQFWLRQWHVWVDUHLQFOXGHGLQWKHQRUPDOIROORZXSIRUUHFLSLHQWVRIDOORJHQHLF +6&7 EXW DW D IUHTXHQF\ WKDW YDULHV DPRQJ GLIIHUHQW FHQWUHV )RU WKH SURWRFRO SOHWK\VPRJUDSK\ZLOOEHFRQGXFWHGGXULQJWKHVFKHGXOHGYLVLWV,ISDWLHQWVKDYHGHYHORSHG DQLQIHFWLRXVUHVSLUDWRU\GLVHDVHRUDQ\V\PSWRPOHDGLQJWRGLIILFXOWLHVLQSHUIRUPLQJWKH3)7 DWWKHVFKHGXOHGWLPHWKH3)7ZLOOEHSHUIRUPHGRQHPRQWKODWHU
7KH H&5) ZLOO EH IXOILOOHG E\ WKH FOLQLFDO UHVHDUFK DVVLVWDQW DIWHU HDFK YLVLW LQ HDFK FHQWHU LQFOXGLQJWKHUHVXOWVRIWKHSXOPRQDU\IXQFWLRQWHVWV7KHFDOFXODWLRQRIWKHGHFOLQHLQ)(9 ZLOOEHGRQHV\VWHPDWLFDOO\LQWKHZHHNVIROORZLQJWKHYLVLWE\WKHPHWKRGRORJLVWYDOLGDWHG E\WKHFRRUGLQDWRU,QWKHHYHQWRI$)2 SULPDU\HQGSRLQW WKHLQYHVWLJDWRUZLOOEHQRWLILHG E\ WKH FRRUGLQDWRU ERWK EOLQGO\ RI WKH UDQGRPL]DWLRQ DUP &RQWURO RI SXOPRQDU\ IXQFWLRQ WHVWLQJZLOOEHSHUIRUPHGZHHNVODWHUWRUHPRYHWKHUROHRIDQLQWHUFXUUHQWHYHQWVXFKDV DQLQIHFWLRXVRQH$)2ZLOOEHYDOLGDWHGRQO\LI$)2LVSHUVLVWHQW
3XOPRQDU\ IXQFWLRQ WHVWLQJ ZLOO DOVR EHHQ SHUIRUPHG ZKHQ SDWLHQWV GHYHORS VSHFLILF UHVSLUDWRU\V\PSWRPV
6W*HRUJH¶VTXDOLW\RIOLIHTXHVWLRQQDLUHZLOOEHSUHVHQWHGWRSDWLHQWVDW0DQG0$W HDFKYLVLWWKHSUHVHQFHRILQWHUFXUUHQWLQIHFWLRXVRUQRQLQIHFWLRXVUHVSLUDWRU\HYHQWVZLOOEH UHFRUGHGZLWKWKHRFFXUUHQFHDQGVHYHULW\RIDFXWHRUFKURQLF*9+'DFFRUGLQJWRWKH1,+ FULWHULD
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
,WLVH[SHFWHGWKDWVRPHSDWLHQWVZLOOEHXQDEOHWRWROHUDWHDWHPSRUDU\HQWHUDOWKHUDS\GXH WR GLJHVWLYH SUREOHPV FDXVHG E\ FRQGLWLRQLQJ RU JDVWURLQWHVWLQDO *9+' )RU WKH ORQJWHUP
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϯϬͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 SURSK\ODFWLF WUHDWPHQW DVVHVVPHQW SDWLHQWV ZLOO UHPDLQ LQ WKH VWXG\ LI WUHDWPHQW GLVFRQWLQXDWLRQGRHVQRWH[FHHGFRQVHFXWLYHPRQWK
,QFDVHRILQFUHDVHLQOLYHUHQ]\PHV $6$7$/$7 GXULQJWKHIROORZXSPRUHWKDQWLPHV QRUPDOUDQJH 1 DQGRUELOLUXELQPRUHWKDQWLPHVQRUPDOUDQJH 1 WUHDWPHQWZLOOEH VWRSSHG 7KH WUHDWPHQW ZLOO EH UHLQWURGXFHG LI $6$7$/$7 < 4N and bilirubin 2N.7KH SDWLHQWZLOOUHPDLQLQWKHVWXG\LIGLVFRQWLQXDWLRQPRQWK
,QWKHFDVHRIDQLQWHUFXUUHQWHYHQW UHTXLULQJ WKH DGPLQLVWUDWLRQ RI D FXUDWLYH PDFUROLGH SURSK\ODFWLFWUHDWPHQWZLWKD]LWKURP\FLQZLOOEHVXVSHQGHGDQGUHLQWURGXFHGDWWKHHQGRI FXUDWLYHWUHDWPHQW7KHSDWLHQWZLOOUHPDLQLQWKHVWXG\
7KHVHWUHDWPHQWLQWHUUXSWLRQVVKRXOGEHVSHFLILHGLQWKHH&5)
7KHHIILFDF\DVVHVVPHQWZLOOEHHYDOXDWHGDIWHUWZR\HDUVRIWUHDWPHQW%HFDXVH DQLQWHUFXUUHQWUHVSLUDWRU\LQIHFWLRQUHFRUGHGDWWKHWLPHRIWKHYLVLWZRXOGDOWHU WKHUHVXOWVRIWKHSXOPRQDU\IXQFWLRQWHVWVWKHYLVLWZLOOEHSRVWSRQHGIRUWR ZHHNV
6XPPDU\WDEOHRIWKHH[DPLQDWLRQVWREHSHUIRUPHGDWHDFKYLVLW
' 0 0 0 0 0 0 0 0
,QIRUPHGFRQVHQW ;
&OLQLFDOH[DP ; ; ;;;
3OHWK\VPRJUDSK\ ; ; ;;;
(OHFWURFDUGLRJUDP ; ; ;;;
%ORRGFRXQWXUHDFUHDWLQLQHOLYHU ; ; ;;; HQ]\PHVELOLUXELQELFDUERQDWHV SRWDVVLXPFRQFHQWUDWLRQVDQG 0DJQHVLXPFRQFHQWUDWLRQV %ORRG YROXPH P/
/XQJ&7VFDQ ;
6W*HRUJH¶V+RVSLWDOTXHVWLRQQDLUH ;; ;
7UHDWPHQWSUHVFULSWLRQDQG ; ; ; ; ; ; ; ; GHOLYHU\
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϯϭͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 7KH LQYHVWLJDWRU VKDOO UHSRUW DOO VHULRXV DGYHUVH HYHQWV ZKLFK DUH NQRZQ WKURXJKRXW WKH GXUDWLRQRISDWLHQWSDUWLFLSDWLRQ
ͻǤʹ
7KH LQYHVWLJDWRU FDQ DVN WKH VSRQVRU WR DOORZ HDUO\ XQEOLQGLQJ GXULQJ ZRUNLQJ GD\V DQG KRXUVH[FHSWLQDQHPHUJHQF\E\WHOHSKRQHID[ RUHPDLOWRWKH VSRQVRU VSURMHFWFRQVXOWDQWV$OOUHTXHVWVVKRXOGEHMXVWLILHG,QFDVHWKHVSRQVRUDJUHHV WKHUHVXOWRIXQEOLQGLQJWUHDWPHQWDOORFDWLRQLVVHQWWRWKHUHTXHVWLQJLQYHVWLJDWRUE\ID[RU HPDLO
,QFDVHRIDQHPHUJHQF\WKDWDIIHFWVWKHLPPHGLDWHVDIHW\RIWKHVXEMHFWWKHLQYHVWLJDWRURU WKHSK\VLFLDQZKRLVLQFKDUJHVKDOOPDNHDQXQEOLQGLQJUHTXHVWDWWKH)HUQDQG:LGDOSRLVRQ FRQWUROFHQWUHLQ3DULVE\SKRQH
ͻǤ͵
7KHSDWLHQWZLOOEHLQIRUPHGZKHQKHRUVKHVLJQVWKHLQIRUPHGFRQVHQWWKDWKHRUVKHZLOO EHIUHHWRZLWKGUDZKLVRUKHURZQFRQVHQWWRSDUWLFLSDWHWRWKHVWXG\DWDOOWLPHVUHJDUGOHVV RI KLV RU KHU UHDVRQV DQG ZLWKRXW VXEVHTXHQW SUHMXGLFH WR KLV RU KHU VXEVHTXHQW PHGLFDO FDUH
2WKHUZLVHDOOWUHDWPHQWGLVFRQWLQXDWLRQVZLOOQRWEHFRQVLGHUHGWREHDSHUPDQHQWFHVVDWLRQ RISDWLHQWSDUWLFLSDWLRQGXHWRWKHLQWHQWWRWUHDWVFKHGXOHGDQDO\VLV
ͻǤͶ
7KHRFFXUUHQFHRIGUXJWR[LFLW\PD\LQWHUUXSWWUHDWPHQWLIWKHIROORZLQJRFFXU
8QPDQDJHDEOHGUXJLQWHUDFWLRQVDFFRUGLQJWRWKHLQYHVWLJDWRU
'HFLVLRQRIWKHLQYHVWLJDWRULQWKHFDVHRIIRUH[DPSOHDVHULRXVDGYHUVHHYHQW
2FFXUUHQFHRIDSURORQJHG47FLQWHUYDO !PVHF GXULQJWKHIROORZXS
7UDQVLHQWLQWHUUXSWLRQRIWUHDWPHQWIRUDSHULRGQRWH[FHHGLQJRQHPRQWKLVWROHUDWHGDQG GRHVQRWMXVWLI\H[FOXVLRQIURPWKHVWXG\
,QDOOWKHVHFDVHVDVPHQWLRQHGDERYHWKHSDUWLFLSDWLRQRIWKHSDWLHQWWRWKHSURWRFROZLOOEH SXUVXHGWRFRPSOHWHVFKHGXOHGDVVHVVPHQWVXQOHVVH[SOLFLWFRQVHQWZLWKGUDZDO5HVHDUFK VWDII VKRXOG PDNH HYHU\ HIIRUW WR FRPSOHWH RXWFRPH DVVHVVPHQWV ZLWK DOO
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϯϮͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 UDQGRPL]HGVWXG\SDUWLFLSDQWVLQFOXGLQJDQ\ZKRKDYHVWRSSHGSDUWLFLSDWLQJ LQ WUHDWPHQW
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϯϯͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 ͳͲ
ͳͲǤͳ
$Q DQDO\VLV ZLOO EH SHUIRUPHG EDVHG RQ DQ LQWHQWWRWUHDW SULQFLSOH RQFH SDWLHQWV DUH UDQGRPL]HG DOO ZLOO EH DQDO\VHG 7KLV SROLF\ NQRZQ DV WKH LQWHQWWRWUHDW ,77 DQDO\VLV SULQFLSOH LV D FRUQHUVWRQH RI JRRG FOLQLFDO WULDO SUDFWLFH $OO SDUWLFLSDQWV UDQGRPL]HG DQG HQWHUHG LQWR WKH WULDO VKRXOG EH LQFOXGHG LQ WKH DQDO\VLV RI WKH JURXS WR ZKLFK WKH\ ZHUH DVVLJQHG UHJDUGOHVV RI ZKHWKHU WKH\ FRPSOHWHG WKH WULDO RU VZLWFKHG WR UHFHLYH GLIIHUHQW WUHDWPHQW
7KH VWXG\ V SULPDU\ DLP WHVWV D K\SRWKHVLV DQG FRUUHVSRQGV ZLWK DQ DQDO\WLFDO SODQ VHH DERYH 7KH VWDWLVWLFDO SRZHU KDV EHHQ FRPSXWHG WR FKRRVH D VDPSOH VL]H DGHTXDWH IRU GHWHFWLQJWKHSUHGLFWHGHIIHFWVLISUHVHQW VHHEHORZVHFWLRQ
1RQH LQWHULP DQDO\VLV ZLOO EH SHUIRUPHG 7KH DQDO\VLV ZLOO EH WHUPLQDO EDVHG RQ WKH SUHYLRXVO\FDOFXODWHGUHTXLUHGVDPSOHVL]H
7KH VWDWLVWLFDO UHSRUW ZLOO EH EDVHG RQ WKH &RQVROLGDWHG 6WDQGDUGV RI 5HSRUWLQJ 7ULDOV &216257
ͳͲǤʹ
7KH EDVHOLQH LH DW UDQGRPL]DWLRQ FKDUDFWHULVWLFV RI WKH UDQGRPL]HG JURXSV ZLOO EH FRPSDUHG URXJKO\ EDVHG RQ HVWLPDWLRQV ZLWK FRQILGHQFH LQWHUYDOV DQG ZLWKRXW DQ\ VWDWLVWLFDO WHVWV RI VLJQLILFDQFH 5DQGRPL]DWLRQ LV WKH EHVW PHDQV IRU FUHDWLQJ EDODQFHG JURXSV
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
7KH ULJKWFHQVRUHG HQGSRLQWV $)2IUHH VXUYLYDO DQG RYHUDOO VXUYLYDO ZLOO EH HVWLPDWHG E\ WKHQRQSDUDPHWULF.DSODQ0HLHUPHWKRGDQGFRPSDUHGEHWZHHQUDQGRPL]HGJURXSVE\WKH ORJUDQN WHVW DIWHU FKHFNLQJ IRU WKH SURSRUWLRQDOLW\ RI KD]DUG IXQFWLRQV 7KH WUHDWPHQW FRPSDULVRQV ZLOO EH DGMXVWHG IRU LPEDODQFHV RU SURJQRVWLF FRYDULDWHV XVLQJ D PXOWLYDULDEOH &R[ PRGHO 7KH PRGHOV ZLOO EH HYDOXDWHG EDVHG RQ WKH WHVWLQJ DVVXPSWLRQV RI WKH
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϯϰͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 SURSRUWLRQDOLW\ RI KD]DUG IXQFWLRQV DQG ORJOLQHDU UHODWLRQVKLSV EHWZHHQ WKH SUHGLFWRUV DQG KD]DUG
&RPSHWLQJ ULVNV HQGSRLQWV WKH RFFXUUHQFH RI ODWHRQVHW SXOPRQDU\ QRQLQIHFWLRXV FRPSOLFDWLRQVRUDFXWHDQGFKURQLFH[WUDWKRUDFLF*9+' ZLOOEHDQDO\VHGXVLQJFRPSHWLQJ ULVNV PHWKRGV 6SHFLILFDOO\ WKH FXPXODWLYH LQFLGHQFHV RI ODWHRQVHW SXOPRQDU\ QRQ LQIHFWLRXVFRPSOLFDWLRQVDQGDFXWHDQGFKURQLFH[WUDWKRUDFLF*9+' ZLOO EH HVWLPDWHG FRQVLGHULQJGHDWKVSULRUWRWKHHYHQWRILQWHUHVWDVFRPSHWLQJULVNRXWFRPHVDQGFRPSDUHG XVLQJWKH*UD\WHVW7KHDGMXVWPHQWVIRUSRWHQWLDOFRQIRXQGHUVZLOOEHEDVHGRQWKH)LQHDQG *UD\PRGHO
9DULDWLRQVLQSXOPRQDU\IXQFWLRQWHVWLQJSDUDPHWHUV )9&59)() ZLOOEHFRPSDUHG EHWZHHQUDQGRPL]HGJURXSVE\JHQHUDOL]HGOLQHDUPRGHOV
$OOWHVWVZLOOEHWZRVLGHGZLWKSYDOXHVRIRUOHVVGHQRWLQJVWDWLVWLFDOVLJQLILFDQFH$OO DQDO\VHV ZLOO EH SHUIRUPHG XVLQJ WKH 6$6 6$6 ,QF &DU\ 1& DQG 5 KWWS ZZZ5 SURMHFWRUJ VRIWZDUHSDFNDJHV
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϯϱͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 ͳͳ
7KHVDIHW\DVVHVVPHQWVKDOOEHGRQHE\FROOHFWLQJDOODGYHUVHHYHQWVWKDWRFFXUGXULQJWKH UHVHDUFK$OOHYHQWVVKDOOEHJUDGHGDFFRUGLQJWRWKH&7&$( &RPPRQ7HUPLQRORJ\&ULWHULD IRU$GYHUVH(YHQWV GRFXPHQW
11.1 • Adverse event DQ\ XQWRZDUG PHGLFDO RFFXUUHQFH LQ D SDWLHQW RU FOLQLFDO WULDO VXEMHFW DGPLQLVWHUHG D PHGLFLQDO SURGXFW DQG ZKLFK GRHV QRW QHFHVVDULO\ KDYH D FDXVDO UHODWLRQVKLS ZLWK WKLV WUHDWPHQW • Adverse reaction DOOXQWRZDUGDQGXQLWHQGHGUHVSRQVHVWRDQLQYHVWLJDWLRQDOPHGLFLQDOSURGXFWUHODWHGWRDQ\ GRVHDGPLQLVWHUHG • Serious Adverse Event or Serious Adverse reaction DQ\ XQWRZDUG PHGLFDO RFFXUUHQFH RU HIIHFW WKDW DW DQ\ GRVH UHVXOW LQ GHDWK LV OLIH WKUHDWHQLQJ UHTXLUHV KRVSLWDOLVDWLRQ RU SURORQJDWLRQ RI H[LVWLQJ KRVSLWDOLVDWLRQ UHVXOWV LQ SHUVLVWHQWRUVLJQLILFDQWGLVDELOLW\RULQFDSDFLW\RULVDFRQJHQLWDODQRPDO\RUELUWKGHIHFW +RVSLWDOL]DWLRQV PHHWLQJ WKH UHJXODWRU\ UHTXLUHPHQW IRU WKH ³VHULRXV´ FULWHULD LQFOXGH DQ\ LQSDWLHQW KRVSLWDO DGPLVVLRQ WKDW LQYROYHV D PLQLPXP RI DQ RYHUQLJKW VWD\ LQ D KHDOWKFDUH IDFLOLW\
• Unexpected adverse reaction due to an experimental medicine
$QDGYHUVHUHDFWLRQWKHQDWXUHRUVHYHULW\RIZKLFKLVQRWFRQVLVWHQWZLWKWKHDSSOLFDEOH SURGXFWLQIRUPDWLRQ HJ,QYHVWLJDWRU V%URFKXUHIRUDQXQDSSURYHGLQYHVWLJDWLRQDOSURGXFW RUSDFNDJHLQVHUWVXPPDU\RISURGXFWFKDUDFWHULVWLFVIRUDQDSSURYHGSURGXFW
1HZVDIHW\LVVXHDQ\QHZVDIHW\LVVXHVWKDWPLJKWPDWHULDOO\DOWHUWKHFXUUHQWEHQHILWULVN DVVHVVPHQWRIDQLQYHVWLJDWLRQDOPHGLFLQDOSURGXFWRUWKDWZRXOGEHVXIILFLHQWWRFRQVLGHU FKDQJHVLQWKHLQYHVWLJDWLRQDOPHGLFLQDOSURGXFWVDGPLQLVWUDWLRQRULQWKHRYHUDOOFRQGXFWRI WKHWULDO Example: - a serious adverse event which could be associated with the trial procedures and which could modify the conduct of the trial, - a significant hazard to the subject population such as lack of efficacy of an investigational medicinal product used for the treatment of a life-threatening disease, - a major safety finding from a newly completed animal study (such as carcinogenicity, -a temporary halt of a trial for safety reasons if the trial is conducted with the same investigational medicinal products in another country by the same sponsor, - an unexpected serious adverse reaction to a non-experimental medicine required for conducting the trial (ex: "challenge agents", emergency treatment).
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϯϲͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 ͳͳǤʹ ̵ 11.2.1 Immediate reporting of adverse events to the sponsor
7KHLQYHVWLJDWRUVKDOOUHSRUWDOOVHULRXVDGYHUVHHYHQWVLPPHGLDWHO\WRWKHVSRQVRUH[FHSWIRU WKRVHWKDWWKHSURWRFRO FI RULQYHVWLJDWRU¶VEURFKXUHLGHQWLILHVDVQRWUHTXLULQJ LPPHGLDWHUHSRUWLQJ
5HVXOWVLQGHDWK
LVOLIHWKUHDWHQLQJ
UHTXLUHVLQSDWLHQWKRVSLWDOL]DWLRQRUSURORQJDWLRQRIH[LVWLQJKRVSLWDOL]DWLRQ
5HVXOWVLQSHUVLVWHQWRUVLJQLILFDQWGLVDELOLW\LQFDSDFLW\,
7KHLQYHVWLJDWRUVKDOOUHSRUWDOOVHULRXVDGYHUVHHYHQWVDVVRFLDWHGZLWKD]\WKURP\FLQ LPPHGLDWHO\WRWKHVSRQVRU FI5&3$SSHQGL[
,QLWLDOUHSRUWLQJLVLQWKHIRUPRIDUHSRUWZULWWHQDQGVLJQHGE\WKHLQYHVWLJDWRUXVLQJD VSHFLILF6$(UHSRUWIRUPLQWHQGHGIRUWKLVSXUSRVH
7KLVLQLWLDOUHSRUWLQJVKRXOGEHIROORZHGE\GHWDLOHGZULWWHQDQGVLJQHGIROORZXSUHSRUW V ZLWKLQDPD[LPXPGHDGOLQHRIGD\V
,IWKHLQYHVWLJDWRUEHOLHYHVWKDWWKHVHULRXVDGYHUVHHYHQWLVUHODWHGWRWKHUHVHDUFKRUWR LQYHVWLJDWLRQDOPHGLFLQDOSURGXFW V HYHU\HIIRUWVKRXOGEHPDGHWRWUDQVPLWDQ\GRFXPHQW WKDWPLJKWEHXVHIXOWRWKHVSRQVRU PHGLFDOKRVSLWDOLVDWLRQUHSRUWVELRORJLFDOUHVXOWV FRPSOHPHQWDU\WHVWUHVXOWVHWF 7KHVHGRFXPHQWVVKRXOGEHDQRQ\PLVHG,QDGGLWLRQWKH\ VKRXOGEHFRPSOHWHGE\WKHIROORZLQJPHQWLRQV UHVHDUFKDFURQ\PQXPEHUDQGLQLWLDOVRI WKHSDWLHQWGHVFULSWLRQDQGGDWHRIRQVHWRIWKHVHULRXVDGYHUVHHYHQW
7KHLQYHVWLJDWRUVKRXOGDGGUHVVDOOTXHULHVIURPWKHVSRQVRUIRUDQ\IROORZXSLQIRUPDWLRQ.
,PPHGLDWHUHSRUWLQJIROORZXSUHSRUWVDQGDQ\XVHIXOGRFXPHQW PHGLFDOKRVSLWDOLVDWLRQ UHSRUWVIRUH[DPSOH VKDOOEHWUDQVPLWWHGWRWKH9LJLODQFH'HSDUWPHQWRIWKH'5&' H[FOXVLYHO\E\ID[DW
)RUDQ\TXHVWLRQFRQFHUQLQJWKHUHSRUWLQJRIDQDGYHUVHHYHQWWKH9LJLODQFH'HSDUWPHQWRI WKH'5&' )UHQFK&OLQLFDO5HVHDUFKDQG'HYHORSPHQW'HSDUWPHQW FDQEHFRQWDFWHGE\H PDLODW YLJLODQFHGUFG#VOVDSKSIU
,QFDVHRISUHPDWXUHWHUPLQDWLRQRIWKHWUHDWPHQWGXHWRWR[LFLW\DVHULRXVDGYHUVHHYHQW UHSRUWLVWUDQVPLWWHGWRWKHVSRQVRU7KHVHULRXVDGYHUVHHYHQWLVPRQLWRUHGXQWLOLWLV UHVROYHG
$OODGYHUVHHYHQWVDUHPRQLWRUHGXQWLOWKH\DUHFRPSOHWHO\UHVROYHG VWDELOLVDWLRQDWDOHYHO FRQVLGHUHGWREHDFFHSWDEOHE\WKHLQYHVWLJDWRURUUHWXUQWRWKHSULRUVWDWXV HYHQLIWKH SDWLHQWLVUHPRYHGIURPWKHWULDO 11.2.2 Adverse events that do not require immediate reporting to the sponsor
$GYHUVHHYHQWVWKDWGRQRWUHTXLUHLPPHGLDWHUHSRUWLQJ
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϯϳͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 Everything that is related to the known complications that can occur after allogeneic hematopoietic stem cell transplantation: Graft versus host disease Relapse of the haematological disease Intercurrent infection Adverse side effects of treatments other than azithromycin Scheduled hospitalization Do not report the non-serious adverse events associated with azythromycin (cf. RCP Appendix 1)
The sponsor's role
• Assessment and declaration of serious adverse events
7KHVSRQVRULVUHVSRQVLEOHIRUWKHFRQWLQXRXVVDIHW\HYDOXDWLRQRIWKHLQYHVWLJDWLRQDO PHGLFLQDOSURGXFW V
+HDVVHVVHVWKHVHULRXVQHVVRIDOODGYHUVHHYHQWVWKDWDUHUHSRUWHGE\WKHLQYHVWLJDWRUVWKH FDXVDOUHODWLRQVKLSZLWKHDFKLQYHVWLJDWLRQDOPHGLFLQDOSURGXFWDQGZLWKRWKHUWUHDWPHQWVLI DQ\DVZHOODVWKHH[SHFWHGQHVVRIDGYHUVHUHDFWLRQV
$OODGYHUVHHYHQWVIRUZKLFKWKHLQYHVWLJDWRURUWKHVSRQVRUFRQVLGHUVWKDWDFDXVDO UHODWLRQVKLSZLWKWKHLQYHVWLJDWLRQDOPHGLFLQDOSURGXFWPLJKWEHUHDVRQDEO\H[SHFWHGDUH FRQVLGHUHGDVVXVSHFWHGDGYHUVHUHDFWLRQV
$OOVXVSHFWHGXQH[SHFWHGVHULRXVDGYHUVHUHDFWLRQRUQHZVDIHW\LVVXHDUHGHFODUHGE\WKH VSRQVRUWR$160 )UHQFK1DWLRQDO0HGLFLQDODQG+HDOWKFDUH3URGXFWV6DIHW\$JHQF\ DQG WKHFRQFHUQHGHWKLFFRPPLWWHHZLWKLQWKHOHJDOGHDGOLQH
7KHLQLWLDOGHFODUDWLRQVKRXOGEHPDGHZLWKLQFDOHQGDUGD\VVWDUWLQJIURPWKHPRPHQWWKH VSRQVRULVLQIRUPHGRIWKHVHULRXVDGYHUVHUHDFWLRQLQFDVHRIGHDWKRUOLIHWKUHDWHQLQJ
7KHLQLWLDOGHFODUDWLRQVKRXOGEHPDGHZLWKLQFDOHQGDUGD\VVWDUWLQJIURPWKHPRPHQW WKHVSRQVRULVLQIRUPHGRIWKHVHULRXVDGYHUVHUHDFWLRQLQFDVHRIDQ\RWKHUVHULRXV VLWXDWLRQ
7KHIROORZXSGHFODUDWLRQVKRXOGEHPDGHZLWKLQGD\VRIWKHGHDGOLQHRIRUGD\V DFFRUGLQJWRWKHVHULRXVQHVV
$OOVXVSHFWHGXQH[SHFWHGVHULRXVDGYHUVHUHDFWLRQVDUHGHFODUHGHOHFWURQLFDOO\WRWKH (XURSHDQ'DWDEDVH(XGUD9LJLODQFHIRUDGYHUVHUHDFWLRQVRIPHGLFLQDOSURGXFWVHVWDEOLVKHG E\WKH(XURSHDQ0HGLFLQHV$JHQF\ (0$
7KHVSRQVRULQIRUPVDOOWKHLQYHVWLJDWRUVFRQFHUQHGRIDQ\GDWDZKLFKPLJKWKDYHDQ XQIDYRXUDEOHLPSDFWRQWKHVDIHW\RIVXEMHFWVSDUWLFLSDWLQJLQWKHUHVHDUFK
Clinical trials with blinded products
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϯϴͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 $VDJHQHUDOUXOHWKHVSRQVRUGHFODUHVXQH[SHFWHGVHULRXVDGYHUVHUHDFWLRQVWRWKHQDWLRQDO FRPSHWHQWDXWKRULW\DQGWKHFRQFHUQHGHWKLFFRPPLWWHHDIWHUXQEOLQGLQJWKHWUHDWPHQW DOORFDWLRQRIWKHVXEMHFW Assessment and declaration of the other safety issue
7KLVFRQFHUQVDOOQHZVDIHW\LVVXHWKDWPLJKWVLJQLILFDQWO\PRGLI\WKHHYDOXDWLRQRIWKH EHQHILWVULVNVUDWLRRIDQLQYHVWLJDWLRQDOPHGLFLQDOSURGXFWRUWKHUHVHDUFKRUWKDWPLJKWOHDG WRHQYLVDJLQJPRGLILFDWLRQVFRQFHUQLQJWKHLQYHVWLJDWLRQDOPHGLFLQDOSURGXFWDGPLQLVWUDWLRQ RULQWKHRYHUDOOFRQGXFWRIWKHWULDO
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϯϵͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 ͳʹ $ PHHWLQJ WR LPSOHPHQW WKH SURWRFRO ZLOO EH RUJDQL]HG E\ WKH FRRUGLQDWRU 3U %HUJHURQ 7KHSDWLHQWVZLOOEHLQFOXGHGE\WKHLQYHVWLJDWRUDWHDFKFHQWUH
$FOLQLFDOUHVHDUFKDVVRFLDWHZLOOFRQGXFWDGD\WRGD\PRQLWRULQJ7KLVW\SLFDOO\ZRXOG LQFOXGHWKHIROORZLQJFKHFNV
WKDWGDWDFROOHFWHGDUHFRQVLVWHQWZLWKDGKHUHQFHWRWKHWULDOSURWRFRO
WKDWH&5)VDUHRQO\EHLQJFRPSOHWHGE\DXWKRUL]HGSHUVRQV
WKDWQRNH\GDWDDUHPLVVLQJ
WKDWGDWDDSSHDUWREHYDOLG IRUH[DPSOHUDQJHDQGFRQVLVWHQF\FKHFNV
UHYLHZRIUHFUXLWPHQWUDWHVZLWKGUDZDOVDQGORVVHVWRIROORZXSRYHUDOODQGE\FOLQLFDO VLWH
(DFKFHQWUHKDVDFFHVV WRDSK\VLRORJ\GHSDUWPHQWWKDWLVDEOHWRSHUIRUPWKHSXOPRQDU\ IXQFWLRQ WHVWV 7KH PRGDOLWLHV RI LPSOHPHQWDWLRQ ZLOO EH KDUPRQL]HG EDVHG RQ (XURSHDQ UHFRPPHQGDWLRQVLIQHFHVVDU\
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
$ PHHWLQJ ZLOO EH VFKHGXOHG HYHU\ LQFOXVLRQV 7KH GDWHV ZLOO EH GHILQHG LQ DGYDQFH DFFRUGLQJWRWKHUK\WKPRIWKHLQFOXVLRQVLQWKHFHQWHUV7KHFOLQLFDOUHVHDUFKDVVRFLDWHDQG WKH VWXG\ VWDWLVWLFLDQ ZLOO EH UHVSRQVLEOH IRU WUDQVPLWWLQJWKH GDWD QHHGHG E\WKH '60% WR HQVXUHLWVPLVVLRQ7KH'60%ZLOOFRQVLVWRIRQHPHWKRGRORJLVW 3U)DEULFH&DUUDW+{SLWDO 6DLQW$QWRLQHFDUUDW#XMXVVLHXIU RQHFKHVWSK\VLFLDQ 3U*DEULHO7KDEXW5HVSLUDWRU\ GLVHDVHV GHSDUWPHQW %LFKDW +RVSLWDO 3DULV *DEULHOWKDEXW#EFKDSKSIU DQG RQH KHPDWRORJLVW 3U 7KLHUU\ 'H 5HYHO +HPDWRORJ\ GHSDUWPHQW +{SLWDO 3HUF\ &ODPDUW WKGHUHYHO#JPDLOFRP LQYROYHGLQDOORJHQHLF+6&7ERWKLQGHSHQGHQWIURPWKHWULDODQGZLWK H[SHUWLVHLQFXUUHQWFOLQLFDOWULDOVFRQGXFWDQGPHWKRGRORJ\
$ 7ULDO 6WHHULQJ &RPPLWWHH H[HFXWLYH ERDUG FRPSRVHG RI WKH FRRUGLQDWRU 'U %HUJHURQ DQGRIDQLQGHSHQGHQWFKDLUSHUVRQZKRLVDQLQWHUQDWLRQDOH[SHUWRIWKHILHOGV 'U&KLHQ
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϰϬͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 ZLOO SURYLGH RYHUDOO VXSHUYLVLRQ RI WKH WULDO DQG HQVXUH WKDW LWLVEHLQJFRQGXFWHGLQ DFFRUGDQFH ZLWK WKH SULQFLSOHV RI *RRG &OLQLFDO 3UDFWLFH DQG WKH UHOHYDQW UHJXODWLRQV 7KH 7ULDO 6WHHULQJ &RPPLWWHH ZLOO DJUHH WKH WULDO SURWRFRO DQG DQ\ SURWRFRO DPHQGPHQWV DQG SURYLGHDGYLFHWRWKHLQYHVWLJDWRUVRQDOODVSHFWVRIWKHWULDO,WZLOOYDOLGDWH±EOLQGO\RIWKH UDQGRPL]DWLRQ DUP WKH GLDJQRVHV RI QRQLQIHFWLRXV SXOPRQDU\ FRPSOLFDWLRQV LQWHUVWLWLDO SQHXPRQLD RU 6%2 WKURXJKRXW WKHSURWRFRODVZHOODVWKHEUHDNLQJ EOLQGLQJ )LQDOO\ GHFLVLRQDERXWVXEVWDQWLDODPHQGPHQWVWRWKHSURWRFROZLOOEHWKHUHVSRQVLELOLW\RIWKH7ULDO 6WHHULQJ&RPPLWWHH
'U&KLHQZRUNVDW)UHG+XWFKLQVRQ&HQWHULQ6HDWWOHDQGLVWKHZRUOGOHDGHULQWKHILHOGRI QRQLQIHFWLRXVSXOPRQDU\FRPSOLFDWLRQVRFFXUULQJDIWHUDOORJHQHLF+6&77KHFXUUHQWSURWRFRO LVEDVHGRQWKHUHVXOWVRIKLVZRUNV'U&KLHQJDYHKLVFRQVHQWWRVHUYHRQWKHVWHHULQJ FRPPLWWHH 7KH FRPPLWWHH ZLOO ZRUN YLD LQWHUQHW DQG ZLOO DOVR PHHWWZLFHD\HDUDWWKH $PHULFDQ7KRUDFLF6RFLHW\DQGWKH(XURSHDQ5HVSLUDWRU\6RFLHW\PHHWLQJV
ͳ͵
• Right to access source data and documents
Data access In accordance with Good Clinical Practices:
- the sponsor is responsible for obtaining agreement from all the parties involved in the research in order to ensure direct access to all locations where the research is carried out as well as to source data, source documents and reports so that the sponsor can conduct quality control and audits,
- the investigators shall make available to the persons responsible for the monitoring, quality control and audit of the biomedical research, the documents and individual data that are strictly necessary for this control, in conformance with the applicable legal and regulatory requirements (articles L.1121-3 and R.5121-13 of the Public Health Code).
Source documents
Source documents, defined as any original document or object through which the existence or accuracy of a data or fact recorded during the research can be proven, shall be kept by the investigator or the hospital, if it concerns a hospital medical record, for 15 years
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϰϭͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021
Data confidentiality
The persons responsible for the quality control of a biomedical research (article L.1121-3 of the Public Health Code) shall take all the necessary precautions to ensure the confidentiality of the information related to the experimental medicines, the research and the trial subjects, notably in relation to their identity as well as the results obtained.
Like the investigators themselves, these persons are bound by professional secrecy (according to the conditions defined in articles 226-13 and 226-14 of the Criminal Code).
During the biomedical research or at its conclusion, the data collected concerning the trial subjects and transmitted to the sponsor by the investigators (or any other specialised intervening party) shall be depersonalised.
Under no circumstances should the names or addresses or any information allowing identification of the persons be visible.
KŶůLJƚŚĞŝŶŝƚŝĂůƐŽĨƚŚĞĨŝƌƐƚŶĂŵĞĂŶĚƐƵƌŶĂŵĞƐŚĂůůďĞƌĞĐŽƌĚĞĚ͕ĂĐĐŽŵƉĂŶŝĞĚďLJĂĐŽĚĞĚƌĞƐĞĂƌĐŚ ŶƵŵďĞƌŝŶĚŝĐĂƚŝŶŐƉĂƚŝĞŶƚƐΖŽƌĚĞƌŽĨŝŶĐůƵƐŝŽŶ͘
The sponsor shall ensure that each trial subject gives written consent for access to his/her personal data concerning which is strictly necessary for quality control of the research
ͳͶ
• Data processing (CNIL [French National Commission on Information Technology and Data Privacy])
Processing of personal data from this research falls within the scope of the application of the provisions of articles 53 to 61 of the law of January 6, 1978 concerning information technology, files and data privacy, amended by law n° 0204-801 of August 6, 2004.
As sponsor, AP-HP has obtained the authorisation from the CNIL for processing the data from this research. The research sponsor, signed an agreement of conformance to this "Reference Methodology", MR001.
• Archiving
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϰϮͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 The specific documents of a biomedical research on a medicinal product for use in humans shall be archived by the investigator and the sponsor for a period of 15 after the conclusion of the research.
This indexed archiving includes notably:
- A sealed envelope containing the original copies of all the information forms and signed consent forms of all persons from the centre who participated in the research, for the investigator; - A copy of all the information forms and signed consent forms of all the persons from the centre who participated in the research, for the sponsor;
- The "research" binders for the investigator and the sponsor with:
• the successive versions of the protocol (identified by the n° and date of the version) and their appendices • the ANSM (French National Medicinal and Healthcare Products Safety Bureau) authorisations and the CPP (French Institutional Review Board) opinions • the letters, • the inclusion list or register, • the research-specific appendices • the final research report. - The data recording documents
͘
• Data ownership WͲ,WŝƐƚŚĞŽǁŶĞƌŽĨƚŚĞĚĂƚĂǁŚŝĐŚĐĂŶŶŽƚďĞƵƐĞĚďLJŽƌƚƌĂŶƐŵŝƚƚĞĚ ƚŽ ĂŶLJ ƚŚŝƌĚ ƉĂƌƚLJ ǁŝƚŚŽƵƚƉƌŝŽƌĂŐƌĞĞŵĞŶƚ͘
ͳͷ Each biomedical research project sponsored by AP-HP is classified from A to D according to the provisional risk to which the trial subjects are exposed, where A is the lowest risk and D the highest risk.
• General organisation The sponsor must ensure the safety and respect of subjects who have agreed to participate in the research. The sponsor should implement a quality assurance system through which the research procedure in the research centres can be best monitored.
For this purpose, the sponsor commissions Clinical Research Associates (CRA) whose main mission is to carry out regular control visits at the research location after conducting opening visits.
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϰϯͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 The goals of research monitoring, as they are defined in Good Clinical Practices, (BPC § 5.18.1) are to verify whether:
• the rights, safety and protection of trial subjects are ensured,
• the reported data are accurate, complete and consistent with the source documents,
• the research is conducted in conformance with the applicable protocol, the GCP, and the current legal and regulatory requirements.
• Strategy for opening centers The strategy for site initiation visit established for this research is determined by an adapted monitoring plan.
• Quality control
A Clinical Research Associate (CRA) commissioned by the sponsor shall ensure proper conducting of the research, written data recording, data documentation, registration and reporting in compliance with Standard Operating Procedures implemented within the DRCD and in conformance with Good Clinical Practices as well as the applicable legal and regulatory requirements.
The investigator and the members of his/her team agree to be available during Quality Control visits conducted at regular intervals by the Clinical Research Associate. During these visits, the following elements shall be reviewed:
- written consents; - compliance with the research protocol and the procedures defined therein; - the quality of the data entered in the case report form: accuracy, missing data, consistency of data with the source documents (medical records, appointment book, original laboratory results, etc.); - management of the treatments used.
• Case report form
Electronic CRF:
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϰϰͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 All the information required by the protocol should be entered in the case report forms. Data should be entered as they are obtained and recorded in these forms in a clear manner. Each missing data should be coded.
This electronic case report form shall be implemented in each centre through an on-line data collection medium. A help document for the use of this tool shall be provided for investigators.
By filling out the case report form via the Internet the investigator enables rapid remote viewing of the data by the CRA. The investigator is responsible for the accuracy, quality and pertinence of all data that is entered. In addition, as they are being entered, these data are immediately verified by consistency checks. For this reason, the investigator should validate any value modification in the CRF. These modifications are the subject of an audit trail. An explanation can be included as a comment, if necessary. At the end of the study a printed hard copy authenticated (dated and signed) by the investigator shall be required. An authenticated copy of the document should be archived by the investigator for the sponsor.
• Management of breaches
Any event that occurs as a result of a breach of the protocol, standardised operating procedures, good clinical practices or applicable legal and regulatory requirements by the investigator or any other person involved in conducting the research, must be reported to the sponsor. These reports shall first be reviewed and processed by the DRCD medical coordinator in order to provide the required corrective or preventive actions. They shall then be sent to the DRCD risk management Quality centre for verification and analysis. These verifications might be the subject of a request for information, compliance checks or audits through the investigator in charge of the research location concerned.
• Audit/inspections The investigators agree to cooperate with quality assurance audits carried out by the sponsor as well as inspections by the competent authorities. All data, documents and reports can be subjected to regulatory audits and inspections without obstruction by medical confidentiality.
An audit can be carried out at any moment by persons commissioned by the sponsor and without the involvement of the research managers. Its purpose is to ensure the quality of the research, the validity of its results, and compliance with the applicable laws and regulations.
The persons running and monitoring the research agree to comply with the requirements of the sponsor and the competent authority in relation to research audits or inspections.
The audit might apply to any stage of the research, from the development of the protocol to publication of the results and classification of the data used or produced in the framework of the research.
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϰϱͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021
ͳ
• Methods of informing and obtaining consent from trial subjects
In conformance with article L1122-1-1 of the Public Health Code, biomedical research cannot be conducted on a person without his/her free and informed consent, obtained after he/she has been provided with the information mentioned in article L. 1122-1 of the same Code
Informing trial subjects
In application of the provisions of article L 1122-1 of the Public Health Code, a trial subject receives first oral and written information on the biomedical research that enables him/her to give free and informed consent. He/she is informed in a complete and honest manner and in comprehensible terms, of the objectives, risks and constraints of the research, the required monitoring and safety measures, the processing of his/her personal data required for the research, his/her registration in a national trial subject database, his/her right to refuse to participate in the research or the possibility to withdraw his/her consent at any moment, etc. All this information should appear in a written document.
Obtaining the subject's consent
The subject is allowed a reflection period between the time when he/she is informed and the time when he/she signs the consent form.
Free, informed written consent of the subject is obtained by the investigator or by a physician on his behalf before the inclusion of the subject in the research.
The information form and a copy of the consent form, dated and signed by the trial subject, as well as the investigator or the representing physician are given to the subject prior to his/her participation in the research. The investigator keeps the original.
Notification in the medical record
In addition, in the subject's medical record, the investigator shall specify the subject's participation in the research, the methods of obtaining his/her consent as well as the methods of providing information in view of obtaining it. The investigator keeps the subject's original dated and signed consent form.
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϰϲͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 At the end of the study, a copy of the information form and the consent form shall be placed in a sealed tamper-proof envelope with all of the consent forms. This shall be archived by the sponsor.
Review of the information form and the consent form
The information form and the consent form shall be reviewed notably in case of substantial modification of the research or the occurrence of adverse reactions, under circumstances and conditions provided for by the law (articles L .1123-9 and L. 1123-10 of the Public Health Code).
Informing and obtaining consent from persons with parental authority in the framework of a research protocol concerning minors
In conformance with article L1122-2 of the Public Health Code, when a biomedical research is conducted on a non-emancipated minor, authorisation is given by those responsible for exercising parental authority.
The persons with parental authority are completely and honestly informed, in comprehensible terms, of the objectives and constraints of the research, the possible risks, the required monitoring and safety measures, their right to refuse to allow their child to participate in the research and the possibility of withdrawing at any time.
All this information appears in the information form and the consent form given to the person with parental authority.
Free, informed written consent by persons with parental authority is obtained by the investigator or a physician on his behalf before final inclusion of the minor in the trial.
. Informing trial subjects who are minors
Minors receive information according to article L. 1122-1 of the Public Health Code, adapted to their ability to understand, from the investigator as well as from the persons responsible for exercising parental authority.
Their personal agreement to participate in the biomedical research is sought. In any event, their refusal or revocation of their agreement cannot be disregarded.
A copy of the information form and the consent form, dated and signed, is given to the persons with parental authority as well as to the investigator or the representing physician. The investigator keeps the originals.
At the end of the study, a copy shall be placed in a sealed tamper-proof envelope with all the consent forms and this shall be archived by the sponsor.
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϰϳͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 Special case: the minor becomes an adult while participating in the research
Minors who become adults while participating in the research shall receive new appropriate information when the time comes. Confirmation of his/her consent shall be required after this information is provided.
Notification in the minor's medical record
In the medical record of the minor participating in the research, the investigator specifies the minor's participation in the research, the methods of informing and obtaining consent from the persons with parental authority as well as the methods of providing the minor with the information.
Review of the information form and the consent form
The information form and the consent form shall be reviewed, notably in case of substantial modification of the research or the occurrence of adverse reactions, under circumstances and conditions provided for by the law. (Articles L .1123-9 and L. 1123-10 of the Public Health Code)
• Legal requirements
The sponsor's role The public assistance Paris hospitals (AP-HP) is the sponsor of this research, and by appointment of the French Clinical Research and Development Department (DRCD), ensures its missions in conformance with article L.1121-1 of the Public Health Code. The Public Assistance - Paris Hospitals reserves the right to stop the research at any time for medical or administrative reasons. If this should occur, the investigator shall be notified.
Request for the opinion of the French Institutional Review Board (CPP) As the sponsor, prior to the implementation of biomedical research on a medicinal product for use in humans, the AP-HP must obtains a favourable opinion from the appropriate CPP in the framework of its competences and in accordance with the applicable legal and regulatory requirements.
Request for authorisation from the ANSM As the sponsor, prior to the implementation of biomedical research on a medicinal product for use in humans, the AP-HP obtains authorisation from the ANSM in the framework of its competences and in conformance with the applicable legal and regulatory requirements.
Commitment to conformance with the "Reference methodology", MR 001
AP-HP (Public Assistance - Paris Hospitals), the research sponsor, signed an agreement of conformance to this "Reference Methodology".
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϰϴͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 Research modifications Any significant modification to the protocol by the coordinating investigator should be sent to the sponsor for approval. After this agreement, the sponsor should obtain a favourable opinion from the CPP and authorisation from the ANSM in the framework of their respective competences prior to its implementation. A new consent from trial subjects shall be obtained if necessary
The final research report The final biomedical research report mentioned in article R1123-60 of the Public Health Code is established and signed by the sponsor and the investigator. A final report summary, written according to the competent authority's reference plan, should be sent to the competent authority as well as the CPP within a deadline of one year after the end of the research, corresponding to the end of participation of the last trial subject or another definition specified in the protocol.
Insurance The Sponsor subscribes to an insurance that guarantees their civil liability as well as that of any physician involved in conducting the research, for the entire duration of the research. They also ensure the entire compensation for harmful consequences of the research to the trial subjects and their beneficiaries, unless proof is provided by the sponsor that the responsibility for harm cannot be attributed to them or to any intervening party, without the possibility of opposing the action of a third party or the withdrawal of the trial subject who had initially consented to participating in the research.
The Public Assistance - Paris Hospitals (AP-HP) has taken out insurance with HDI-GERLING through BIOMEDIC-INSURE for the entire duration of the research, that guarantees their civil liability as well as that of any intervening party (physician or personnel involved in conducting the research), in conformance with article L.1121-10 of the Public Health Code.
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϰϵͬϲϯ
Downloaded From: https://jamanetwork.com/ on 09/29/2021 ͳ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
Downloaded From: https://jamanetwork.com/ on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
>>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϱϭͬϲϯ
Downloaded From: https://jamanetwork.com/ on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d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϱϮͬϲϯ Downloaded From: https://jamanetwork.com/ on 09/29/2021 ͳͺ ǣ ͳͺǤͳ AZITHROMYCINE >>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϱϯͬϲϯ Downloaded From: https://jamanetwork.com/ on 09/29/2021 >>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϱϰͬϲϯ Downloaded From: https://jamanetwork.com/ on 09/29/2021 >>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϱϱͬϲϯ Downloaded From: https://jamanetwork.com/ on 09/29/2021 >>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϱϲͬϲϯ Downloaded From: https://jamanetwork.com/ on 09/29/2021 >>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϱϳͬϲϯ Downloaded From: https://jamanetwork.com/ on 09/29/2021 >>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϱϴͬϲϯ Downloaded From: https://jamanetwork.com/ on 09/29/2021 >>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϱϵͬϲϯ Downloaded From: https://jamanetwork.com/ on 09/29/2021 >>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϲϬͬϲϯ Downloaded From: https://jamanetwork.com/ on 09/29/2021 >>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϲϭͬϲϯ Downloaded From: https://jamanetwork.com/ on 09/29/2021 ͳͺǤʹ ȋ Ȍ 4WVHF 55VHF 547F)VHF 47F) 4755 ͳͺǤ͵ >>K/d,ZKWϭϮϬϭϭϬͺsϭ͘ϮĚƵϮϴͬϬϴͬϮϬϭϯ ϲϮͬϲϯ Downloaded From: https://jamanetwork.com/ on 09/29/2021 Evaluation de l’efficacité de l’azithromycine dans la prévention du syndrome de bronchiolite oblitérante au décours de l’allogreffe de cellules souches hématopoïétiques Evaluation of the efficacy of azithromycin to prevent bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation ALLOZITHRO P120110/ EudraCT 2013-000499-14 Statistical Analysis Plan (SAP) Version 5 Author: Professeur Sylvie CHEVRET URC du GH Saint Louis Lariboisière Site Saint Louis 1, avenue Claude Vellefaux - 75010 Paris Tel. : +33 (0) 1 42 49 97 42 Fax : +33 (0) 1 42 49 97 45 E-mail : [email protected] Date: October, 2016 Page 1 of 7 Downloaded From: https://jamanetwork.com/ on 09/29/2021 Protocol ALLOZITHRO Statistical Analysis Plan 1. INTRODUCTION The occurrence of bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (HSCT) is considered to be a chronic pulmonary graft versus host disease (GVHD) that is associated with significant mortality and morbidity. The reported incidence of BOS varies from 6 to 26% of allogeneic HSC recipients and is usually diagnosed within 2 years after transplantation. The diagnosis of BOS relies on the occurrence of a new airflow obstruction identified during pulmonary function testing, and the definition differs between studies. Currently, no curative immunosuppressive treatment is available, and recent data suggest that the use of these treatments, especially corticosteroids, should be limited because of their toxicity. The impairment of lung function parameters is likely caused by fibrous small airway lesions. Few data on the pathogenesis of BOS after allogeneic HSCT are available. Several hypotheses are based on the occurrence of BOS during chronic graft rejection after lung transplantation, which shares many clinical and histopathological similarities with BOS after allogeneic HSCT. One hypothesis is that the first step leading to BOS is lung epithelium injury. BOS is then identified as an allogeneic immune reaction with only one clearly identified risk factor, extra-thoracic chronic GVHD. Due to their anti-inflammatory and immunomodulatory properties, recent data suggest that low-dose macrolides may be effective at preventing BOS after lung transplants. This well-tolerated treatment may be useful for preventing BOS after allogeneic HSCT. The objectives of this randomized clinical trial, is to evaluate the efficacy of azithromycin in preventing BOS syndrome after allogeneic HSCT in patients with malignant hematological diseases. 2. DATA SOURCE The eCRF data were extracted then, structured by data managers. See Appendix reporting the Data Handling Manual of the study. The trial is registered with the NCT number NCT01959100. 3. ANALYSIS OBJECTIVES The objectives of the analysis are to provide estimates of treatment effect, using all defined end points, based on comparison of those end points according to the randomized treatment arm. Point estimates with 95% confidence intervals are to be provided. The study's primary aim tests a hypothesis, that azithromycin may delay the occurrence of BOS. The statistical power has been computed to choose a sample size adequate for detecting the predicted effects if present. Page 2 of 7 Downloaded From: https://jamanetwork.com/ on 09/29/2021 Protocol ALLOZITHRO Statistical Analysis Plan 4. STUDY DESIGN The Allozithro Study is a multi-center double-blind randomized controlled trial of prevention of BOS by azithromycin in patients undergoing allogeneic stem cell transplantation. Multi-center ethical approval was granted by the Ethics Committee on 15 July 2013, and by the French Agence Nationale de Sécurité des Médicaments (ANSM) on 04 September 2013. Randomization Randomization is conducted via a web-based interface. The study web site was accessible 24 hours a day, seven days a week. This academic web site (cleanWeb®) has been used to host numerous secure research projects. Patients are randomized in a ratio of 1:1 to two groups: (1) placebo; (2) azithromycin. The randomisation sequence was generated using R code with blocks of unreported fixed size and random seeds to ensure allocation concealment could not be violated by guessing the allocation sequence at the end of each block. Randomisation was stratified within study site by Age (≤, > 50 years old) and FEV1/FVC (≤, > 85%). Data collection and follow-up Every randomized patient was followed up until 2 years post-randomisation. If patients were followed after 2 years, follow-up was censored and outcomes were recorded as per status at month 24. 5. ANALYSIS SETS/ POPULATIONS/SUBGROUPS Statistical analysis will be performed based on an intent-to-treat principle; once patients are randomized, all will be analyzed. This policy, known as the intent-to-treat (ITT) analysis principle, is a cornerstone of good clinical trial practice. All participants randomized and entered into the trial should be included in the analysis of the group to which they were assigned including loss of follow-up, regardless of whether they completed the trial or switched to receive different treatment. Protocol deviations and exclusions (and reasons for any such exclusion) will be reported for each arm of the trial. (on March, 2015) - To handle potential study dropouts due to consent withdrawals the sample size was reevaluated given analysis could not include those patients, due to the French regulation at the time. (on July, 2015) Thus, a modified intention-to-treat sample will be used for both efficacy and toxicity assessments. (on October, 2016) Post-hoc secondary analyses were performed to get further insight in the relationship between treatment arm and incidence of relapse. Page 3 of 7 Downloaded From: https://jamanetwork.com/ on 09/29/2021 Protocol ALLOZITHRO Statistical Analysis Plan 6. ENDPOINTS AND COVARIATES Efficacy endpoints will be computed as defined in the protocol. All time to failure outcomes will be measured from the date of randomization. (on May, 2014) Overall survival at 2 years was added as a secondary outcome. (on July, 2014) Cumulative dosage of steroids as a secondary outcome was deleted. (on July, 2015) The main endpoint of the trial (airflow obstruction, (AFO)-free survival) has been switched to survival free of airflow decline (AFD). Adjustments for potential imbalances in prognostic variables will be performed, using covariates selected by univariable analyses at the 5% level. 7. HANDLING OF MISSING VALUES AND OTHER DATA CONVENTIONS Every effort will be made to obtain missing data, even after the follow-up time has passed. The main analyses will be based on available data only. Analyses based on imputed data will be reported as part of the sensitivity analyses. Missing data will be imputed. Simple or multiple imputation techniques will be used according to the amount and underlying potential mechanisms of missingness. 8. STATISTICAL METHODOLOGY 8.1 GENERAL PRINCIPLES • Analyses will be conducted according to the modified intention-to-treat principle (ITT) [Fergusson 2002] if not otherwise stated. More specifically, patients who withdrew consent for use of their data will not be included in any analysis. Only the facts that they were enrolled into the trial and withdrew consent, and the original study group to which they were allocated, will be reported. • All tests will be two-sided. Unless otherwise specified, estimates of treatment effects will be presented with 95% confidence intervals. A two-tailed P value of ≤0.05 will be considered statistically significant for the primary and secondary outcome measures. • The primary analyses of primary and secondary outcomes will be those of the modified ITT population unadjusted analyses. An analysis adjusting for both stratification and pre- defined variables will be carried out as sensitivity analyses. Other analyses may also be performed using, for example, subset population. If the results of these analyses are not consistent with the primary analyses this will be discussed. Nevertheless, the conclusions of the study will still be those based on the primary analyses. • The tests for interaction between the intervention and each design variable used to identify subgroups are exploratory • Risks will be reported as hazard ratios or risk ratios with 95% confidence interval (CI). • If there is data missingness for a specified primary or secondary outcome of less than 5% Page 4 of 7 Downloaded From: https://jamanetwork.com/ on 09/29/2021 Protocol ALLOZITHRO Statistical Analysis Plan a complete case analysis without imputing missing values will be performed. If there is a missingness of more than 5% multiple imputation will be performed. 8.2 INTERIM ANALYSES An independent Safety and Data Monitoring Committee (SDMC), comprising experts in clinical trials, biostatistics, respiratory diseases and bone-marrow transplantation was established. The committee reviewed information on all serious adverse events and conducted a blinded interim analysis of these data. These analyses will be considered in the closed session of the committee. The committee will advise the chair of the trial steering committee if, in their view, the randomized comparisons in the trial have provided ‘proof beyond reasonable doubt’ that for all or for some types of, patients one particular treatment is definitely contraindicated in terms of a net difference I serious adverse events. None interim analysis of efficacy will be performed. The analysis will be terminal, based on the previously calculated required sample size. (on December 2016) The trial was stopped due to safety concerns. 8.3 STATISTICAL PROCEDURES The statistical report will be based on the Consolidated Standards of Reporting Trials (CONSORT). First, the flow of study participants will displayed in a Consolidated Standards of Reporting Trials (CONSORT) diagram. The number of patients who fulfilled study inclusion criteria, and the number included in the primary and secondary analyses as well as all reasons for exclusions in primary and secondary analyses will be reported. Baseline data The baseline (i.e., at randomization) characteristics of the randomized groups will be compared roughly, based on point estimates without significance testing. Discrete variables will be summarized by frequencies and percentages. Percentages will be calculated according to the number of patients where data are available. Where values are missing, the actual denominator will be stated. Continuous variables will be summarized using standard measures of central tendency and dispersion, using either mean ± SD for data with normal distribution or median and interquartile range for non-normally distributed data. Efficacy outcome measures The right-censored endpoints (AFO-free survival and overall survival) will be estimated by the nonparametric Kaplan-Meier method and compared between randomized groups by the log-rank test after checking for the proportionality of hazard functions. Competing risks endpoints (the occurrence of late-onset, pulmonary, non-infectious complications or acute and chronic extra-thoracic GVHD) will be analysed using competing risks methods. Specifically, the cumulative incidences of late-onset, pulmonary, non-infectious complications and acute and chronic extra-thoracic GVHD Page 5 of 7 Downloaded From: https://jamanetwork.com/ on 09/29/2021 Protocol ALLOZITHRO Statistical Analysis Plan will be estimated considering deaths prior to the event of interest as competing risk outcomes and compared using the Gray test. (in July, 2015) Given the primary outcome measure is a composite end point, the estimation of the cumulative incidence of both components (namely, cumulative incidence of AFD, and that of death free of AFD) will be computed using competing-risk methods, with comparison across randomized arms based on Gray’s test and cause- specific hazard models. Variations in pulmonary function testing parameters (FVC, RV, FEF25-75%) will be summarized using compared between randomized groups by generalized linear models. The heterogeneity of the population given by the inclusion of additional subjects undergoing second allogeneic hematopoietic stem cell transplantation will potentially increase and may lead to more imprecision in estimating of treatment effect evaluated in the trial. If these patients are insufficient number we will test the potential heterogeneity of treatment effect with this parameter. Serious Adverse Events The proportion of patients who experience at least one serious adverse event will be analyzed as a categorical variable (with patients classified as either having experienced at least one serious adverse event, or not) using a χ-squared or Fisher’s exact test (as appropriate). If appropriate, a more complex model of serious adverse event occurrences will be constructed utilizing adverse events as count variables. Possible models for this analysis include Poisson regression and negative binomial regression. An analysis of subgroups of serious adverse events will be performed separately, but in an identical manner to the overall adverse events analyses. 8.4 PROGRAMMATION All analyses will be performed using the SAS (SAS Inc., Cary, NC) and R (http://www.R-project.org/) software packages. 8.5 MEASURES TO ADJUST FOR MULTIPLICITY, CONFOUNDERS, HETEROGENEITY, ETC. For each outcome variable, the unadjusted analysis will be designated the primary analysis; the covariate-adjusted analysis will be designated the secondary analysis. Prognostic variables shown to be strongly associated with outcome, even if not shown to be imbalanced between treatment groups, will be screened for inclusion in the covariate adjusted model as they may remove bias from the estimate of treatment effect [Pocock 2002; Senn 1989]. Univariate Cox regression analysis will be conducted to evaluate the relationship between each prognostic variable and allocated treatment group. Then, the treatment comparisons will be adjusted for such prognostic covariates using a multivariable Cox model. The models will be evaluated based on the testing assumptions of the proportionality of hazard functions and log-linear relationships between the predictors and hazard. (on December 2016) Post-hoc secondary analyses have been performed to get further insights in the effect of azithromycin in the incidence of relapse. Page 6 of 7 Downloaded From: https://jamanetwork.com/ on 09/29/2021 Protocol ALLOZITHRO Statistical Analysis Plan 9. REFERENCES Cox DR. Regression models and life-tables (with discussion). J R Stat Soc Ser B 1972;34:187–220. Fergusson D, Aaron SD, Guyatt G, Hérbert P: Post-randomisation exclusions: the intention- to-treat principle and excluding patients from analysis. BMJ. 2002, 325: 652-654. 10.1136/bmj.325.7365.652. Gail M SR. Testing for qualitative interactions between treatment effects and patient subsets. Biometrics 1985;41:361-72. Gray RJ. A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988;16:1141–54. Pocock SJ, Assmann SE, Enos LE, Kastan LE. Subgroup analysis, covariate adjustment and baseline comparisons in clinical trial reporting: Current practice and problems. Statistics in Medicine 2002;21:2197-2930. Senn SJ. Covariate imbalance in randomized clinical trials. Statistics in Medicine 1989;8:467-475. 10. APPENDIX Competing interests The author declare that they have no competing interests Page 7 of 7 Downloaded From: https://jamanetwork.com/ on 09/29/2021 1 AALLLLOOZZIIITTHHRROO TTRRIIIAALL AAMMEENNDDMMEENNTT 111 2 AAPPPPRROOVVEEDD EETTHHIIICCSS CCOOMMMMIIITTTTEEEE 111000///33311///222000111333 ;;; AAPPPPRROOVVEEDD RREEGGUULLAATTOORRYY AAGGEENNCCYY 000111///22277///22000111444 3 4 All changes to the original protocol text are listed in the table below. They are mentioned explicitly in the right-hand column, with yellow highlighting of the additions. 5 The changes focus on the reporting of adverse events and randomization. 6 7 1) Modifications in the protocol: Page Original text version 1.0 01/03/2013 Page Revised text version 1.1 14/06/2013 Justification in in V1.0 V1.1 30 28 Ongoing analyzes of a 8.1.2Randomization list (pages 28) previous prospective study The randomization list stratified by center, FEV1/FVC ratio ((≤ conducted to determine the ou > 85%) and age ((≤ ou > à 50 yrs old) will be established by risk factors for a non- the Clinical and Biostatistics research unit of Saint-Louis infectious pulmonary Hospital before the beginning of the study according to a complication following method based on permutation block whose size will be kept allogeneic haematopoietic confidential. Randomization of patients will be centralized and stem cell transplantation carried out using a computerized system. Distribution in the showed that the age and The two groups (azothomycine versus placebo) is made in a 1/1 pre-graft FEV1 / FVC value ratio. Inclusion criteria will be checked before randomization. were associated with the occurrence of bronchiolitis obliterans (Results not yet published). In order to balance the 2 groups of patients studied, we wish to stratify the randomization in addition to the investigating center but also on the age (≤ or> at 50 years) and the pre-HSCT FEV1 / CVF (≤ or> 85%). . 37 Definitions 35 11.1 Definitions Mme Fadila AMERALI : • Adverse event • Adverse event …………………….. An adverse event is…….. and blood any untoward medical occurrence…………. stay in a dyscrasias. healthcare facility. Downloaded From: https://jamanetwork.com/ on 09/29/2021 38 The investigator's role 36 11.2 The investigator's role • Immediate reporting of adverse events 11.2.1 Immediate reporting of adverse events to the sponsor Mme Fadila AMERALI : to the sponsor - …… that the protocol (cf. 11.2.2) or investigator’s…. …………………….. - …… that the protocol or investigator’s brochure…… 38 36 - Results in death, Mme Fadila AMERALI : - is life-threatening, …………………….. - requires inpatient hospitalization or prolongation of existing hospitalization, - Results in persistent or significant disability/incapacity, The investigator shall report all serious adverse events associated with azythromycin immediately to the sponsor (cf. RCP Appendix 1) 39 • Adverse events that do not require 37 11.2.2 Adverse events that do not require immediate reporting Mme Fadila AMERALI : immediate reporting to the sponsor to the sponsor …………………….. Adverse events that do not require Adverse events that do not require immediate reporting: immediate reporting are recorded on the Everything that is related to the known complications that can case report "adverse events" form. occur after allogeneic hematopoietic stem cell transplantation: Graft versus host disease Relapse of the haematological disease Intercurrent infection Adverse side effects of treatments other than azithromycin Scheduled hospitalization Do not report the non-serious adverse events associated with azythromycin (cf. RCP Appendix 1) 43 There are two steps in the applicable 41 There are two steps in the applicable procedure: a procedure: a request for opinion from the request for opinion from the CCTIRS (French Advisory Mme Fadila AMERALI : CCTIRS (French Advisory Board on the Board on the Processing of Health Research Data) …………………….. Processing of Health Research Data) followed by a request for authorisation from the CNIL. followed by a request for authorisation from the CNIL. As sponsor, AP-HP has obtained the opinion of the As sponsor, AP-HP has obtained the opinion of the CCTIRS and authorisation CCTIRS and authorisation from the CNIL for processing from the CNIL for processing the data the data from this research. The research sponsor, signed from this research. an agreement of conformance to this "Reference Methodology", MR001. Downloaded From: https://jamanetwork.com/ on 09/29/2021 47, Notification in the medical record 45, Notification in the medical record Mme Fadila AMERALI : 48 In addition, in the subject's medical 46 In addition, in the subject's medical record, the investigator …………………….. record, the investigator shall specify the shall specify the subject's participation in the research, the subject's participation in the research, the methods of obtaining his/her consent [or the consent of any methods of obtaining his/her consent [or other person in cases provided for in articles L. 1122-1-1 to L. the consent of any other person in cases 1122-2 of the Public Health Code] as well as the………. provided for in articles L. 1122-1-1 to L. 1122-2 of the Public Health Code] as well as the……. 8 9 10 11 12 13 2) Modification of information notices for patients ( in French): these modifications (highlighted in yellow in the version 1-1 of 06/06/2013) concern 14 modifications and comments from the CPP (ethical committee): 15 - Paragraph 1 (research goal): "Studies have shown that taking Azithromycin is effective in preventing bronchiolitis obliterans syndrome and improves survival 16 after pulmonary transplantation ..." Was this really proven by Published studies, or are they just preliminary observations? "Studies have shown that taking 17 Azithromycin is effective in preventing bronchiolitis obliterans syndrome and improves survival after pulmonary transplantation" 18 19 A randomized, double-blind, placebo-controlled study showed a decrease in the incidence of bronchiolitis obliterans syndrome in pulmonary transplant 20 patients and improved survival without bronchiolitis obliterans. This study did not show any improvement in overall survival (Vos, Eur Respir J, 2011, Protocol 21 page 19, PDF attached). I propose to amend the sentence as follows to be more specific: 22 23 "One study showed that taking Azithromycin is effective in preventing bronchiolitis obliterans syndrome after pulmonary transplantation." Page Original text NIFC autorité parentale V 1 du Page Revised text NIFC autorité parentale version 1.1 du Justification in V1 08.03.2013 in 14/06/2013 V1.1 1 - 1) le but de cette recherche 1 - 1) Quel est le but de cette recherche - Formatting the title 1 - …votre enfant peut développer au décours de 1 - …votre enfant peut développer au décours à la suite de votre allogreffe de CSH… votre son allogreffe de CSH…. Request from the Ethics - ……bronchiolite oblitérante développé au décours - … bronchiolite oblitérante développé au décours à la suite Committee d’une allogreffe… d’une allogreffe…. -….la prévention du syndrome de bronchiolite - ….la prévention du syndrome de bronchiolite oblitérante oblitérante au décours d’une allogreffe…. au décours à la suite d’une allogreffe…… 2 3) le calendrier de la recherche 2 3) Quel est le calendrier de la recherche -- Formatting the title - - ….et il devra remplir un questionnaire…. - …..et il sera demandé de remplir un questionnaire Request from the Ethics Committee Downloaded From: https://jamanetwork.com/ on 09/29/2021 2 2 Durant la période de participation de votre enfant un Request from the Ethics nouveau consentement sera demandé de l’enfant lorsque Committee celui-ci atteint l’âge adulte au cours de l’étude. 3 4) les bénéfices et les contraintes liés à sa 3 4) Quels sont les bénéfices et les contraintes liés à sa -- Formatting the title participation participation Request from the Ethics - Compte tenu ……… développement - Compte tenu ……… développement du syndrome…… Committee syndrome…… - De plus, en participant à cette recherche, votre enfant - De plus, en participant à cette recherche, votre bénéficiera d’un suivi médical étroit et spécifique pour enfant bénéficiera d’un suivi médical étroit et lequel aucun frais supplémentaire ne vous sera demandé. spécifique pour lequel aucun frais supplémentaire - …il contribuera à une meilleure connaissance des ne vous sera demandé. complications pulmonaires au décours à la suite d’allogreffe -…il contribuera à une meilleure connaissance des de CSH… complications pulmonaires au décours d’allogreffe de CSH… Downloaded From: https://jamanetwork.com/ on 09/29/2021 3 3 5) Quels sont les traitements autorisés et non autorisés ? Votre enfant ne sera pas autorisé(e) à recevoir certains traitements tant qu’il recevra le traitement de l’étude sauf si votre enfant, vous ou votre médecin décidiez d’arrêter l’étude. Il est très important que vous informiez le médecin de l’étude de l’utilisation par votre enfant de tout médicament tant qu’il participe à la recherche. En effet, certains médicaments (liste ci-dessous) peuvent modifier la façon dont le corps de votre enfant métabolise d’autres médicaments et ceci peut augmenter les effets indésirables. Si votre enfant doit prendre un nouveau traitement pendant l’étude, informez-en votre médecin dès que possible. Liste des traitements non autorisés et déconseillés : Traitements non autorisés : Cisapride, ergotamine, dyhydroergotamine Traitements déconseillés : bromocriptine, cabergoline, lisuride, pergolide, colchicine Associations nécessitant une surveillance par votre médecin hématologues : Adaptation des doses selon les dosages sanguins indiqués selon les bonnes règles de prescription (hors toute recherche) pour la ciclosporine et les anti-vitamines K (anticoagulants). Surveillance clinique et électrocardiogramme (prévus de façon systématique dans le cadre de la recherche): Antiarythmiques de classe Ia [quinidine, hydroquinidine, disopyramide], antiarythmiques de classe III [amiodarone, sotalol, dofétilide, ibutilide], certains neuroleptiques [amisulpride, chlorpromazine, cyamémazine, dropéridol, fluphénazine, halopéridol, lévomépromazine, pimozide, pipampérone, pipotiazine, sultopride, sulpiride, tiapride]), autres (bépridil, cisapride, diphémanil, érythromycine IV, halofantrine, luméfantrine, méthadone, moxifloxacine, mizolastine, pentamidine, sertindole, spiramycine IV, vincamine IV). Downloaded From: https://jamanetwork.com/ on 09/29/2021 4 6) Quels sont les risques prévisibles de la 4 6) Quels sont les risques prévisibles de la Request from the Ethics recherche? recherche? Committee - ….Les effets secondaires les plus ………troubles - ….Les effets secondaires les plus ….troubles du rythme du rythme cardiaque. cardiaque (prolongation de l’intervalle QT, arythmie). - Risque prévisibles, dangers, effets indésirables (rarement, rares cas, c’est combien de cas en %) 4 4 7) Quelles sont les éventuelles alternatives médicales? En cas de refus de participation à cette étude et dans la mesure où il n’existe pas de traitement préventif du syndrome de bronchiolite oblitérante que vous enfant pourrait développer, il n’y a pas d’alternative médicale. Si votre enfant dévellope un syndrome de bronchiolite oblitérante au cours de son suivi post greffe, le choix du traitement reviendra à votre médecin hématologue ou pneumologue. 8) Quelles sont les modalités de prise en charge médicale à la fin de la participation de votre enfant ? Votre médecin pourra décider à tout moment de l’arrêt de la participation de votre enfant ; il vous en expliquera les raisons. Son suivi après la fin de l’étude sera celui de l’allogreffe de CSH. Si votre enfant n’a pas développé d’altération de la fonction respiratoire, il n’y aura pas d’introduction d’un quelconque traitement à visée respiratoire. Dans le cas contraire, votre médecin lui proposera le traitement et le suivi qui lui semblera optimal. A la fin de l’étude votre enfant retrouvera le suivi habituel et adapté au stade de sa maladie Downloaded From: https://jamanetwork.com/ on 09/29/2021 4 Traitement informatique des données 4 9) Si vous participez, que vont devenir les - Formatting personnelles : données recueillies pour la recherche ? - Cette étude sera réalisée conformément aux dispositions Formatted: Font: (Default) Arial, 10 pt, Cette étude sera réalisée conformément aux de la loi n°78-17 du 6 janvier 1978 relative à l’informatique, Highlight dispositions de la loi n°78-17 du 6 janvier 1978 aux fichiers et aux libertés modifiée par la loi n°2004-801 du relative à l’informatique, aux fichiers et aux libertés 6 août 2004 relative à la protection des personnes modifiée par la loi n°2004-801 du 6 août 2004 physiques à l’égard des traitements de données à caractère relative à la protection des personnes physiques à personnel, de la Commission Nationale de l’Informatique et l’égard des traitements de données à caractère des Libertés (CNIL). personnel, de la Commission Nationale de A cette fin,lLes données médicales concernant votre enfant l’Informatique et des Libertés (CNIL). et les données relatives à ses habitudes de vie, seront Les données médicales concernant votre enfant et transmises au Promoteur de la recherche Ces données les données nécessaires à l’étude seront identifiées seront identifiées par un numéro de code et vos initiales. par un numéro de code et ses initiales et seront Ces données pourront également, dans des conditions recueillies et transmises au Promoteur de la assurant leur confidentialité, être transmises aux autorités recherche ou aux personnes ou sociétés agissant de santé françaises. Formatted: Font: (Default) Arial, 10 pt, Not pour son compte, en France. nécessaires à l’étude seront identifiées par un numéro de Italic, Font color: Auto Un traitement de ses données personnelles va être code et ses initiales et seront recueillies et transmises au mis en œuvre pour permettre l’analyse des Promoteur de la recherche ou aux personnes ou sociétés résultats, dans des conditions assurant leur agissant pour son compte, en France. confidentialité. Un traitement de ses données personnelles va être mis en Vous disposez d’un droit d’accès et de œuvre pour permettre l’analyse des résultats, dans des rectification. conditions assurant leur confidentialité. Vous disposez également d’un droit d’opposition Vous disposez d’un droit d’accès et de rectification. à la transmission de ses données personnelles Vous disposez également d’un droit d’opposition à la utilisées dans le cadre de cette étude. Ces droits transmission de ses données personnelles utilisées dans le s’exercent auprès du médecin Investigateur qui le cadre de cette étude. Ces droits s’exercent auprès du suit dans le cadre de l’étude et qui connaît son médecin Investigateur qui le suit dans le cadre de l’étude et identité. qui connaît son identité. 4 Aspects éthiques et réglementaires 4 10) Comment cette recherche est-elle encadrée ? Formating 5 Quels sont vos droits ? 5 11) Quels sont vos droits ? Formating - …Vous pouvez vous retirer à tout moment………. - ……Vous pouvez retirer la participation de votre enfant à - Request from the - Conformément aux dispositions de la CNIL (loi tout moment Ethics Committee relative à l’informatique, aux fichiers et aux libertés), - Conformément aux dispositions de la CNIL (loi relative à l’informatique, aux fichiers et aux libertés loi n°78-17 du 6 janvier 1978 relative à l’informatique, aux fichiers et aux libertés modifiée par la loi n°2004-801 du 6 août 2004 relative à la protection des personnes physiques à l’égard des traitements de données à caractère personnel), Downloaded From: https://jamanetwork.com/ on 09/29/2021 6 -Nous avons pris connaissance de la note 6 -Nous avons pris connaissance de la note d’information Specification of the d’information version 1.1 du 14.06.2013 nous version 1.1 du 14.06.2013 comportant 5 pages nous……. number of pages -Nous avons compris que …………moindre - Nous avons compris que …………moindre responsabilité - Request from the responsabilité et préjudice….. ni préjudice….. Ethics Committee 24 Page Texte initial NIFC Adulte V 1 du Page Texte modifié NIFC Adulte version 1.1 du 14/06/2013 Justification dans 08.03.2013 dans V1 V1.1 1 - …votre enfant peut développer au 1 - …votre enfant peut développer au décours à la suite de votre son Request from the Ethics décours de votre allogreffe de CSH… allogreffe de CSH…. Committee - ……bronchiolite oblitérante développé au - … bronchiolite oblitérante développé au décours à la suite d’une décours d’une allogreffe… allogreffe…. -….la prévention du syndrome de - ….la prévention du syndrome de bronchiolite oblitérante au bronchiolite oblitérante au décours d’une décours à la suite d’une allogreffe…… allogreffe…. 2 2 Request from the Ethics - ….et il devra remplir un questionnaire…. - …..et il sera demandé de remplir un questionnaire Committee 3 4) Quels sont les bénéfices et les 3 4) Quels sont les bénéfices et les contraintes liés à sa Request from the Ethics contraintes liés à sa participation participation Committee CPP - Compte tenu …….développement -Compte tenu …… le développement du syndrome…. syndrome.. - De plus, en participant à cette recherche, votre enfant bénéficiera - De plus, en participant à cette recherche, d’un suivi médical étroit et spécifique pour lequel aucun frais votre enfant bénéficiera d’un suivi médical supplémentaire ne vous sera demandé. étroit et spécifique pour lequel aucun frais - vous contribuerez à une meilleure connaissance des supplémentaire ne vous sera demandé. complications pulmonaires à la suite au décours d’allogreffe de - vous contribuerez à une meilleure CSH connaissance des complications pulmonaires d’allogreffe de CSH 3 5) Quels sont les traitements autorisés 3 5) Quels sont les traitements autorisés et non autorisés ? Request from the Ethics et non autorisés ? Committee …… le traitement de l’étude ou que vous …..le traitement de l’étude sauf si vous ou…….. ou… 4 6)Quels sont les risques prévisibles de 4 6)Quels sont les risques prévisibles de la recherche? Request from the Ethics la recherche? ….Les effets secondaires les plus ….troubles du rythme cardiaque Committee ….Les effets secondaires les plus (prolongation de l’intervalle QT, arythmie). ………troubles du rythme cardiaque. - Risque prévisibles, dangers, effets indésirables (rarement, rares cas, c’est combien de cas en %) 4 10) Si vous participez, que vont 4 09) Si vous participez, que vont devenir les données Formating devenir les données recueillies pour recueillies pour la recherche ? la recherche ? Downloaded From: https://jamanetwork.com/ on 09/29/2021 4 11)Comment cette recherche est-elle 4 10) Comment cette recherche est-elle encadrée ? Formating encadrée ? 5 12) Quels sont vos droits ? 5 11) Quels sont vos droits ? - Formating - Request from the - Conformément aux dispositions de la - Conformément aux dispositions de la CNIL (loi relative à Ethics Committee CNIL (loi relative à l’informatique, aux l’informatique, aux fichiers et aux libertés loi n°78-17 du 6 janvier fichiers et aux libertés), 1978 relative à l’informatique, aux fichiers et aux libertés modifiée par la loi n°2004-801 du 6 août 2004 relative à la protection des personnes physiques à l’égard des traitements de données à caractère personnel), 6 - J’ai compris que ma…………moindre 6 - J’ai compris que ma…………moindre responsabilité ni - Request from the responsabilité et préjudice….. préjudice….. Ethics Committee 25 System organ classes- Side effects Fréquency Infections et Infestations -Uncommon candidiasis, oral candidiasis, vaginitis - Indetermined pseudomembranous colitis Blood and lymphatic system - Uncommon leucopenia, neutropenia - Indetermined thrombocytopenia, hemolytic anemia Immune system - Uncommon angioedema, hypersensitivity - Indetermined anaphylactic reactions Metabolism and nutrition - Common anorexia Psychiatric disorders - Uncommon nervousness - Rare agitation - Indetermined aggression, anxiety Nervous system disorders - Common dizziness, headache, paresthesia, dysgeusia - Uncommon hypoaesthesia, somnolence, insomnia Downloaded From: https://jamanetwork.com/ on 09/29/2021 - Indetermined syncope, seizures, psychomotor hyperactivity, anosmia, taste loss, parosmia, myasthenia gravis Eye disorders - Common visual disturbances Ear - Common deafness - Uncommon hearing disorders - Rare dizziness Cardiac - Uncommon palpitations - Indetermined torsades de pointes, arrhythmia with ventricular tachycardia Vascular - Indetermined hypotension Gastrointestinal disorders - Very common diarrhea, abdominal pain, nausea, flatulence - Common vomiting, dyspepsia - Uncommon gastritis, constipation - Indetermined pancreatitis, tongue discoloration Hepatobiliary dosorders - Uncommon hepatitis - Rare disorders of liver function - Indetermined hepatic impairment, fulminant hepatitis, hepatic necrosis, cholestatic jaundice Skin and subcutaneous tissue disorders - Common rash, pruritus - Uncommon stevens-Johnson syndrome, photosensitivity, urticaria - Indetermined toxic epidermal necrolysis, erythema multiforme Musculoskeletal and systemic - Common arthralgia Renal and urinary tract - Indetermined acute renal failure, interstitial nephritis General symptoms Downloaded From: https://jamanetwork.com/ on 09/29/2021 - Common fatigue - Uncommon chest pain, edema, malaise, asthenia Investigations - Common decrease in lymphocyte count, increased eosinophil count, decrease in bicarbonate concentration in the blood - Uncommon increased aspartate aminotransferase, increased alanine aminotransferase, increased bilirubin, increased blood urea, creatinine increase, abnormal concentration of potassium in the blood - Indetermined prolongation of the QT interval on the electrocardiogram 26 27 Downloaded From: https://jamanetwork.com/ on 09/29/2021 28 AALLLLOOZZIIITTHHRROO TTRRIIIAALL AAMMEENNDDMMEENNTT 222 29 APPROVED ETHICS COMMITTEE 04/24/2014 ; APPROVED REGULATORY AGENCY 05/30/2014 30 31 All changes to the original protocol text are listed in the table below. They are mentioned explicitly in the right-hand column, with yellow highlighting of the additions. 32 The changes focus on the reporting of adverse events and randomization. 33 34 2) Modifications dans le protocole: Page Original text version 1.2 28/08/2013 Page Revised text version 2.0 11/03/2014 Justification in in V1.2 V2.0 Modification of the participating centers in Modification of the participating centers in the text cf. Annex 1 4 the text cf. Annex 1 4 Secondary endpoints Make a clarification at this point of the protocol on this • Overall survival at two years Secondary endpoints secondary endpoint (the timing of evaluation of overall 8 • Overall survival 8 survival was obvious for us, 2 years being the primary endpoint, but not clearly stated in the protocol;) 2 Synopsis 2 Synopsis Secondary endpoints Secondary endpoints Same 9 9 Overall survival Overall survival at two years 6.2 Secondary endpoints Same 25 6.2 Secondary endpoints 25 • Overall survival at two years • Overall survival Downloaded From: https://jamanetwork.com/ on 09/29/2021 An obliterans bronchiolitis (i.e obstructive lung disease) may occur after an allogeneic HSCT whether or not it is the first one. Some rare patients undergo a second allogeneic HSCT. No reason to exclude 7.1 Inclusion criteria 7.1 Inclusion criteria these patients, especially 26 • Receive an allogeneic HSCT for 26 • Receive an allogeneic HSCT (even if it is the 2nd) because the endpoints take a hematologic malignancy for a hematologic malignancy into account the variations between the pre-transplant PFT (performed just before the second transplant) and the sequential PFT performed after the second transplant. Downloaded From: https://jamanetwork.com/ on 09/29/2021 7.3 Sample size computation 7.3 Sample size computation The calculated sample size to test our hypothesis is 460 patients. 12 French The calculated sample size to test our hypothesis is 460 Increase the number of centers is the best guarantee centres will participate in the study. patients. 21 French centres will participate in the study. to include the number of patients expected in the scheduled time. The study - The latest data from the Agency for - The latest data from the Agency for Biomedicine finally began on 02/12/2014 Biomedicine regarding allogeneic HSCT regarding allogeneic HSCT in France when all centers were not in France (http://www.agence- (http://www.agence- open. It takes one month of biomedecine.fr/annexes/bilan2010/don biomedecine.fr/annexes/bilan2010/donnees/cellules/01- screening before inclusion of nees/cellules/01-greffe/synthese.htm), patients that we could not 26/2 26/2 greffe/synthese.htm), which reports the number of 7 which reports the number of 7 transplantations in each centre as follows: 764 transplant have been anticipated due to the postponement of the transplantations in each centre as recipients were reported in 2010 in the 21 participating follows: 764 transplant recipients were opening of the trial several centres (Saint Louis, Bordeaux, Lyon, Marseille, Nantes, times. Approximately 50% of reported in 2010 in the 11 participating Toulouse, Grenoble, Saint Antoine , Clermont Ferrand, the scheduled inclusions centres (Saint Louis, Bordeaux, Lyon, Montpellier , Lille, Besançon, Caen, Rennes, Strasbourg, were performed in this 1st Marseille, Nantes, Toulouse, Grenoble, IGR, Rouen, Poitiers, Clamart, and Angers) with an month. Given the short Saint Antoine , Clermont Ferrand, increase of 8.6% in 2010 and overall survival of 66% period of planned inclusion, Montpellier , And Lille) with an increase after 1 year and 54% after 2 years. we feel it is important to open of 8.6% in 2010 and overall survival of new centers now. 66% after 1 year and 54% after 2 years. Downloaded From: https://jamanetwork.com/ on 09/29/2021 No substantial modification; only 9.1 Timing and content of visits 9.1 Timing and content of visits clarifications. … The pulmonary function tests are included … The pulmonary function tests are included in the in the normal follow-up for recipients of normal follow-up for recipients of allogeneic HSCT Instead of giving a fixed allogeneic HSCT but at a frequency that but at a frequency that varies among different time for the control of PFT varies among different centres. For the centres. For the protocol, plethysmography will be we allow a period of time of 2 weeks, which is protocol, plethysmography will be conducted conducted during the scheduled visits. If patients closer to current practice. during the scheduled visits. If patients have have developed an infectious respiratory disease or We specify that the developed an infectious respiratory disease or any symptom leading to difficulties in performing the control PFT values after infection will be those any symptom leading to difficulties in PFT at the scheduled time, the PFT will be used for the assessment performing the PFT at the scheduled time, performed one month later 4 or 6 weeks later and of the primary endpoint. the PFT will be performed one month later. the results of this PFT will be considered in the systematic calculation of the decline in In order to react faster The eCRF will be fulfilled by the clinical FEV1. and reduce the research assistant after each visit in each occurrence of new center, including the results of the pulmonary The eCRF will be fulfilled by the clinical research intercurrent episodes, we shortened the time function tests. The calculation of the decline assistant in the 4 2 weeks following each visit information of respiratory in FEV1 will be done systematically in the 4 in each center, including the results of the function in the eCRF, 30 weeks following the visit by the 30 pulmonary function tests. The calculation of the allowing faster calculation of decline in FEV. Each methodologist, validated by the coordinator. decline in FEV1 will be done systematically by the center was notified and In the event of AFO (primary endpoint), the methodologist, validated by the coordinator. In the agreed. investigator will be notified by the event of AFO (primary endpoint), the investigator coordinator, both blindly of the randomization will be notified by the coordinator an e-mail To be more reactive, and arm. Control of pulmonary function testing alert, both blindly of the randomization arm. The in regard to the number of will be performed 4 weeks later to remove need to rule out an infection will be patients, the FEV decline the role of an intercurrent event, such as an automatically notified. Control of pulmonary will be automatically calculated in the eCRF infectious one. AFO will be validated only if function testing will be performed 4 to 6 weeks later and if an action must be AFO is persistent… to remove the role of an intercurrent event, such as done according to the an infectious one. AFO will be validated only if AFO protocol, a email alert will be automatically sent to is persistent… the investigator and the coordinator to specify the action. Downloaded From: https://jamanetwork.com/ on 09/29/2021 9.1 Timing and content of visits 9.1 Timing and content of visits No modification of the … In case of increase in liver enzymes … In case of increase in liver enzymes (ASAT,ALAT) protocol. Clarification of the (ASAT,ALAT) during the follow up more during the follow up more than 5 times normal range text of the protocol. than 5 times normal range (5N) and/or (5N) and/or bilirubin more than 3 times normal bilirubin more than 3 times normal range range (3N), treatment will be stopped. The (3N), treatment will be stopped. The treatment will be reintroduced if ASAT/ALAT < 4N 31 treatment will be reintroduced if 31 and bilirubin ≤ 2N. In the case of an intercurrent ASAT/ALAT < 4N and bilirubin ≤ 2N. The event requiring the administration of a curative patient will remain in the study if macrolide, prophylactic treatment with azithromycin discontinuation ≤ 1 month. will be suspended and reintroduced at the end of curative treatment. If the discontinuation of In the case of an intercurrent event treatment by azithromycin is > 1 consecutive month requiring the administration of a curative the patient will stop the experimental treatment and macrolide, prophylactic treatment with will have a follow-up two years after inclusion. azithromycin will be suspended and reintroduced at the end of curative treatment. The patient will remain in the study. Summary table of the examinations to be Summary table of the examinations to be performed Clarification. performed at each visit at each visit 31 31 Obstructive lung diseases are Cf. Annexe 2. currently evaluated using the post bronchodilator FEV1. Downloaded From: https://jamanetwork.com/ on 09/29/2021 9.3 Causes of permanent cessation of the 9.3 Causes of permanent cessation Summary of the causes of protocol patient participation Permanent permanent cessation of the of the protocol patient cessations of the protocol patient patient participation at this participation point. No change except for participation are: death, loss of follow-up, and the second stem cell a second stem cell transplantation for a transplant for a patient who patient already included for the first stem cell would already be included in the protocol for the first transplantation. transplantation. Indeed, it would not be easy to schedule PFT and interpret them in regard to the 1st or second transplantation. This 32 32 point only affects a very small number of patients. Considering that the aim of the 9.4 Causes of premature cessation 9.4 Causes of premature cessation of treatment is to avoid the occurrence of BOS diagnosed of experimental treatment experimental treatment using PFT criteria, in case of Occurrence of a BOS systematically calculated BOS diagnosis, patients will by eCRF after a scheduled visit will stop the stop the experimental treatment. However they will experimental treatment.Anyway, causes of remain in the study in regard to premature cessation of experimental the endpoint that evaluates treatment are not considered as a cessation of AFO-free survival at 2 years. patient participation to the study. 32/33 32/33 All patients who stopped prematurely the experimental treatment will have a follow-up two years after inclusion. Downloaded From: https://jamanetwork.com/ on 09/29/2021 34 34 Clarification 10.1 Main principles 10.1 Main principles An analysis will be performed based on an An analysis will be performed based on an intent-to- intent-to-treat principle; once patients are treat principle; once patients are randomized, all will randomized, all will be analysed. This be analysed. This policy, known as the intent-to- policy, known as the intent-to-treat (ITT) treat (ITT) analysis principle, is a cornerstone of analysis principle, is a cornerstone of good good clinical trial practice. All participants clinical trial practice. All participants randomized and entered into the trial should be randomized and entered into the trial included in the analysis of the group to which they should be included in the analysis of the were assigned including loss of follow-up, group to which they were assigned, regardless of whether they completed the trial or regardless of whether they completed the switched to receive different treatment. trial or switched to receive different treatment. 36 37 Annexe 1 : Downloaded From: https://jamanetwork.com/ on 09/29/2021 Nom Téléphone Discipline Etablissement de santé Prénom E-mail Investigateur Coordonnateur 01.42.49.41.66 Team 1 Pneumologie Hôpital Saint Louis, APHP Pr BERGERON-LAFAURIE [email protected] 01.42.49.96.45 Team 2 Pr SOCIE Hématologie Hôpital Saint Louis, APHP [email protected] 05.57.65.65.11 Team 3 Pr MILPIED Hématologie Hôpital Haut Lévêque, Bordeaux [email protected] 04.78.86.22.33 Team 4 Pr MICHALLET Hématologie CHU Lyon-Sud, Lyon [email protected] 04.91.22.37.54 Team 5 Dr Patrice CHEVALLIER Hématologie CHU Nantes [email protected] Dr GRANATA Angela 04.91.22.37.54 Team 6 Hématologie Institut Paoli Calmette, Marseille (Service du Pr BLAISE) [email protected] Dr HERMET 04.73.75.00.66 Team 7 Hématologie CHU Estaing, Clermont-Ferrand (Service du Pr BAY) [email protected] 01.49.28.26.20 Team 8 Dr RUBIO Hématologie Hôpital Saint Antoine, APHP, Paris [email protected] 04 76 76 57 55 Team 9 Dr THIEBAUT Hématologie CHU Grenoble [email protected] 05 61 77 76 05 Team 10 Dr HUYNH Hématologie CHU Toulouse [email protected] Team 11 Dr VINCENTLaure Hématologie CHU Montpellier [email protected] 03 20 44 55 51 Team 12 Dr Coiteux Hématologie CHU de Lille [email protected] Hématologie Team 13 Dr. Anne SIRVENT Hôpital Arnaud de Villeneuve, Montpellier [email protected] pédiatrique Team 14 Pr. Eric DECONINCK Hématologie Hôpital Jean Minjoz, Besançon 03 81 66 84 04 [email protected] Team 15 Dr. REMAN Hématologie CHU de Caen [email protected] Team 16 Dr. Marc BERNARD Hématologie CHU Rennes [email protected] Team 17 Dr Bruno LIOURE Hématologie Hôpital de Hautepierre de Strasbourg 08 88 12 76 76 [email protected] Team 18 Dr. Jean Henri BOURHIS Hématologie IGR de Villejuif Team 19 Dr. Nathalie CONTENTIN Hématologie CHU de Rouen Downloaded From: https://jamanetwork.com/ on 09/29/2021 Team 20 Dr. Natacha MAILLARD Hématologie CHU de Poitiers [email protected] Team 21 Dr. Jean-Valère MALFUSON Hématologie Hôpital militaire Percy Clamard [email protected] Team 22 Dr. Sylvie FRANCOIS Hématologie CHU d’ANGERS [email protected] 38 39 Annexe 2 : 40 Summary table of the examinations to be performed at each visit D0 M3 M6 M9 M12 M15 M18 M21 M24 Informed consent X Clinical exam X X X X X Plethysmography; pre and post X X X X X bronchodilator spirometry Electrocardiogram X X X X X Blood count, urea, creatinine, liver X X X X X enzymes, bilirubin, bicarbonates, potassium concentrations and Magnesium concentrations (Blood volume: 15 mL) Lung CT scan X St George’s Hospital questionnaire X X X Treatment prescription and delivery X X X X X X X X 41 42 Downloaded From: https://jamanetwork.com/ on 09/29/2021 43 AALLLLOOZZIIITTHHRROO TTRRIIIAALL AAMMEENNDDMMEENNTT 333 44 AAPPPPRROOVVEEDD EETTHHIIICCSS CCOOMMMMIIITTTTEEEE 000777///22244///222000111444 ;;; 45 46 All changes to the original protocol text are listed in the table below. They are mentioned explicitly in the right-hand column, with yellow highlighting of the additions. 47 48 3) Modifications dans le protocole: Page Original text version 2.0 11/03/2014 Page Revised text version 3.0 13/06/2014 Justification in in V2.0 V3.0 Change of address of center n ° 10 Change of address of center n ° 10 Toulouse 4 Toulouse 4 Exclusion criteria Exclusion criteria • Allergy or Intolerance to • Allergy or Intolerance to azithromycin, macrolides azithromycin, macrolides or ketolide or or ketolide or excipient excipient • Patient allergic to Penicillin and who will • Prolonged corrected QT (QTc) receive prophylaxis by Macrolides (Erythromycin, interval (>450 msec) Clarithromycin, roxithromycin, Troleandomycin and azithromycin and/or Ketolide (Telithromycin). Taking medications that prolong the QTc interval (Cisapride, • Prolonged corrected QT (QTc) interval (>450 ergotamine, dyhydroergotamine) msec) In order to avoid obvious bias Taking ergotamine and Taking medications that prolong the QTc interval in the statistical analysis, patient that will have 7 dyhydroergotamine due to the risk of 7 (Cisapride, ergotamine, dyhydroergotamine) ergotism prophylaxis with Macrolides Taking ergotamine and dyhydroergotamine due to and/or Ketolide cannot be Family history of a prolonged the risk of ergotism included in the study QTc interval. Family history of a prolonged QTc interval. History of congestive heart History of congestive heart failure failure Taking colchicine Taking colchicine Severe liver insufficiency Severe liver insufficiency • History of infection due to atypical mycobacteria • History of infection due to atypical mycobacteria Secondary endpoints The cumulative dose of 8 Secondary endpoints 8 steroids treatment for the duration of the study will be Downloaded From: https://jamanetwork.com/ on 09/29/2021 • Overall survival at two years • Overall survival at two years impossible to collect with accurate value. The data will • Occurrence of late-onset • Occurrence of late-onset pulmonary non- not be reliable. pulmonary non-infectious complications infectious complications • Variation of pulmonary function • Variation of pulmonary function testing testing parameters (FVC, RV, FEF25- parameters (FVC, RV, FEF25-75%) 75%) • Occurrence of acute and chronic extra-thoracic • Occurrence of acute and chronic GVHD extra-thoracic GVHD • Quality of life • Quality of life • Tolerance of azithromycin • Tolerance of azithromycin • Cumulative dose of steroids treatment for the • Cumulative dose of steroids duration of the study treatment for the duration of the study 3 Synopsis 3 Synopsis Secondary endpoints Secondary endpoints Same 9 9 Cumulative dose of steroids treatment Cumulative dose of steroids treatment for the duration of for the duration of the study the study Downloaded From: https://jamanetwork.com/ on 09/29/2021 Exclusion criteria Exclusion criteria • Allergy or intolerance to • Allergy or intolerance to azithromycin, macrolides, azithromycin, macrolides, ketolide or ketolide or excipient excipient • Patient allergic to Penicillin and who will receive • Prolonged corrected QT (QTc) prophylaxis by Macrolides (Erythromycin, interval (>450 msec) Clarithromycin, roxithromycin, Troleandomycin and Taking medications that prolong azithromycin and/or Ketolide (Telithromycin ). the QTc interval • Prolonged corrected QT (QTc) interval (>450 msec) Family history of a prolonged QTc Taking medications that prolong the QTc interval Same 10 10 interval Family history of a prolonged QTc interval History of congestive heart failure History of congestive heart failure Taking colchicine Taking colchicine Taking ergotamine and Taking ergotamine and dyhydroergotamine due to the dyhydroergotamine due to the risk risk of ergotism of ergotism Severe liver insufficiency Severe liver insufficiency • History of infection due to atypical • History of infection due to atypical mycobacteria mycobacteria 6.2 Secondary endpoints 6.2 Secondary endpoints 25 24 • Cumulative dose of steroids treatment for the Same • Cumulative dose of steroids duration of the study treatment for the duration of the study Downloaded From: https://jamanetwork.com/ on 09/29/2021 7.2 Exclusion criteria 7.2 Exclusion criteria Allergy or intolerance to Allergy or intolerance to azithromycin, macrolides azithromycin, macrolides or or ketolides or excipient ketolides or excipient Patient allergic to Penicillin and who will Prolonged corrected QT (QTc) receive prophylaxis by Macrolides (Erythromycin, interval (>450 msec) Clarithromycin, roxithromycin, Troleandomycin Taking medications that prolong and azithromycin and/or Ketolide In order to avoid obvious bias the QTc interval (Cisapride, (Thelithromycin). in the statistical analysis, ergotamine, dyhydroergotamine) Prolonged corrected QT (QTc) interval (>450 patient that will have 26 Family history of a prolonged QTc 25 msec) prophylaxis with Macroldes interval. Taking medications that prolong the QTc interval and/or Ketolide cannot be History of congestive heart failure (Cisapride, ergotamine, dyhydroergotamine) included in the study. Taking colchicine Family history of a prolonged QTc interval. Taking ergotamine and History of congestive heart failure dyhydroergotamine due to the Taking colchicine risk of ergotism Taking ergotamine and dyhydroergotamine due to Severe liver insufficiency the risk of ergotism History of nontuberculous Severe liver insufficiency mycobacterial infection History of nontuberculous mycobacterial infection Downloaded From: https://jamanetwork.com/ on 09/29/2021 8 Treatment 8 Treatment Regarding the difficulties of organization between the different services, the Each patient will receive either 250 mg Each patient will receive either 250 mg of azithromycin possibility to delay the first of azithromycin or a placebo orally 3 administration of the or a placebo orally 3 times a week for two years. The times a week for two years. The first experimental treatment first day of treatment will be the first day of conditioning 28 day of treatment will be the first day of 27 (previously J1 of the The treatment must start during the conditioning conditioning period), is given conditioning. Patients will be told to period. Patients will be told to take their treatment to the investigators. But the take their treatment during a meal. The during a meal. The treatment batches will be packaged treatment must start as soon treatment batches will be packaged in in an identical manner to ensure double-blind conditions as possible within the an identical manner to ensure double- conditioning period. throughout the trial. blind conditions throughout the trial. Downloaded From: https://jamanetwork.com/ on 09/29/2021 The cumulative dose of steroids treatment for the 9.1 Timing and content of visits 9.1 Timing and content of visits duration of the study will … … The immunosuppressive therapy will be managed be impossible to collect with accurate value. The with normal medication doses, and doses will be data will not be reliable. The immunosuppressive therapy will be adjusted based on drug interactions. In studies managed with normal medication doses, and performed in lung transplant recipients receiving doses will be adjusted based on drug immunosuppressive therapy (particularly calcineurin interactions. In studies performed in lung inhibitors or mTOR inhibitors), difficulties in dose transplant recipients receiving adjustment have not been reported at the onset of immunosuppressive therapy (particularly azithromycin administration, which is consistent calcineurin inhibitors or mTOR inhibitors), with our experience. Many patients in our centre difficulties in dose adjustment have not been currently receive azithromycin to treat SBO without reported at the onset of azithromycin difficulties. Cumulative doses of immunosuppressive administration, which is consistent with our treatment administered to each patient between experience. Many patients in our centre two visits will be evaluated. currently receive azithromycin to treat SBO without difficulties. Cumulative doses of immunosuppressive treatment administered 30 to each patient between two visits will be 29 evaluated. Downloaded From: https://jamanetwork.com/ on 09/29/2021 35 34 Point added following the 10.2 Statistical tests 10.2 Statistical tests remark of the regulatory agency when issuing authorization for amendment 2 ….... ….... Variations in pulmonary function testing Variations in pulmonary function testing parameters parameters (FVC, RV, FEF25-75%) will be (FVC, RV, FEF25-75%) will be compared between compared between randomized groups by randomized groups by generalized linear models. generalized linear models. The heterogeneity of the population given by the All tests will be two-sided, with p-values of inclusion of additional subjects undergoing a second 0.05 or less denoting statistical significance. allogeneic hematopoietic stem cell transplantation All analyses will be performed using the SAS will potentially increase and may lead to more (SAS Inc., Cary, NC) and R (http://www.R- imprecision in estimating of treatment effect project.org/) software packages. evaluated in the trial. If these patients are insufficient number we will test the potential heterogeneity of treatment effect with this parameter. All tests will be two-sided, with p-values of 0.05 or less denoting statistical significance. All analyses will be performed using the SAS (SAS Inc., Cary, NC) and R (http://www.R-project.org/) software packages. Downloaded From: https://jamanetwork.com/ on 09/29/2021 11.2.1 Immediate reporting of adverse 11.2.1 Immediate reporting of adverse events to the events to the sponsor sponsor The investigator shall report all serious The investigator shall report all serious adverse events adverse events immediately to the immediately to the sponsor except for those that the sponsor except for those that the protocol protocol (cf. 11.2.2) or investigator’s brochure identifies (cf. 11.2.2) or investigator’s brochure as not requiring immediate reporting 37/38 identifies as not requiring immediate 36/37 reporting - Results in death, - Results in death, - is life-threatening, - is life-threatening, - requires inpatient hospitalization or prolongation of existing hospitalization, - requires inpatient hospitalization or prolongation of existing hospitalization, - Results in persistent or significant disability/incapacity, - Results in persistent or significant - requires inpatient hospitalization in recovery disability/incapacity, service … - All acute heart pathology All adverse events are monitored until … they are completely resolved (stabilisation All adverse events are monitored until they are at a level considered to be acceptable by completely resolved (stabilisation at a level considered the investigator or return to the prior to be acceptable by the investigator or return to the status) even if the patient is removed prior status) even if the patient is removed from the from the trial. trial. Also, the following adverse event have to be reported in the eCRF : - QTc > 450 msec - anaphylactic reaction - heart rhythm disorder - deafness - auditory trouble - digestive disorder such as nausea, vomitus, diarrhea and not imputable to GvH or conditioning Downloaded From: https://jamanetwork.com/ on 09/29/2021 62 61/62 18.3 SAE report form 18.3 SAE report form SAE Form Version 1 du 12/12/2013 50 51 52 4) Modifications in Patients information forms (French): 53 Page Original text version 2.1 11/09/2013 Page Revised text version 3.0 16/06/2014 Justification in in V2.1 V3.0 1) Quel est le but de cette recherche? 1 1) Quel est le but de cette recherche? 1 …………….. …………….. Pour évaluer cette hypothèse, ……………, situés en France Pour évaluer cette hypothèse, ……………, métropolitaine situés en France métropolitaine (Paris, Lyon, Marseille, Toulouse, Grenoble, Nantes et Clermont-Ferrand, Montpellier et Lille ). 2 3) Quel est le calendrier de la 2 3) Quel est le calendrier de la recherche ? recherche ? En cas d’aggravation de votre fonction respiratoire, le En cas d’aggravation de votre fonction traitement de l’étude sera arrêté et vous bénéficierez du respiratoire, le traitement de l’étude sera traitement que le médecin jugera le plus adapté. Un recueil de arrêté et vous bénéficierez du traitement que le médecin jugera le plus adapté. données concernant l’apparition éventuelle d’un syndrome de bronchiolite oblitérante sera effectuée dans le cadre de la recherche à 24 mois après le début du traitement de la recherche. 54 55 56 Downloaded From: https://jamanetwork.com/ on 09/29/2021 57 AALLLLOOZZIIITTHHRROO TTRRIIIAALL AAMMEENNDDMMEENNTT 44 58 APPROVED ETHICS COMMITTEE 03/05/2015 ; APPROVED REGULATORY AGENCY 04/17/2015 59 60 Pages Original text [1] Revised text [2] Justification Protocol V.3.0_13.06.2014 Protocol V.4.0_ 18.11.2014 P4/62 Sites involved in recruiting patients: Sites involved in recruiting patients: Participation of two new centers Team 22 : Dr. Jean-Henri BOURHIS, service Hématologie to increase the Institut Gustave Roussy number of E mail : Jean- inclusions in the [email protected] trial. Team 23 : Dr LEGRAND-IZADEFAR service Hématologie, CHU de Nice E mail : [email protected] P5/62 Plan Plan Replacement of 10 STATISTICS 10 STATISTICS patients with premature 10.3 Specify if subjects who leave the research withdrawal of prematurely will be replaced and in what consent. proportion P7 et 1 Abstract 1 Abstract Prolongation of 8/63 the duration of Study period Study period the inclusions in order to make up The recruitment period will be of 1 year. The duration of The recruitment period will be of 2 years. The duration of for the delay of participation for a patient will be 2 years. The duration of participation for a patient will be 2 years. The duration of the inclusions the study is thus 3 years. the study is thus 4 years. whose end was originally planned … … on 12/02/2015. Currently 65% of Exclusion criteria expected • Allergy or Intolerance to azithromycin, macrolides Exclusion criteria • Allergy or Intolerance to azithromycin, macrolides inclusions. or ketolide or excipient The study will or ketolide or excipient • Patient allergic to Penicillin and who will receive stop when the • Patient allergic to Penicillin and who will receive prophylaxis by Macrolides (Erythromycin, Clarithromycin, expected number prophylaxis by Macrolides (Erythromycin, Clarithromycin, roxithromycin, Troleandomycin and azithromycin and/or of patients will be Ketolide (Telithromycin). roxithromycin, Troleandomycin and azithromycin and/or completed • Prolonged corrected QT (QTc) interval (>450 Ketolide (Telithromycin). msec) • Prolonged corrected QT (QTc) interval (>450 Downloaded From: https://jamanetwork.com/ on 09/29/2021 Taking medications that prolong the QTc interval msec) (value from ECG within a month before For reasons of (Cisapride, ergotamine, dyhydroergotamine) inclusion) internal Taking ergotamine and dyhydroergotamine due Taking medications that prolong the QTc interval organization of to the risk of ergotism (Cisapride, ergotamine, dyhydroergotamine) the centers Family history of a prolonged QTc interval. Taking ergotamine and dyhydroergotamine due participating in History of congestive heart failure to the risk of ergotism the trial, the ECG Taking colchicine Family history of a prolonged QTc interval. which will Severe liver insufficiency History of congestive heart failure indicate the value of the QTc used • History of infection due to atypical mycobacteria Taking colchicine to validate the Severe liver insufficiency criteria for non- • History of infection due to atypical mycobacteria inclusion of patients in the trial may be the examination carried out during the pre- HSCT workunp that it is not more than one month before the time of the patient's inclusion. P 9 et Prolongation of 10 /63 the duration of 2 Synopsis 2 Synopsis the inclusions in order to make up Experimental plan Experimental plan for the delay of the inclusions Phase 3 multicenter randomized, double-blind, clinical Phase 3 multicenter randomized, double-blind, clinical whose end was trial, with 2 parallel arms: trial, with 2 parallel arms: originally planned on 12/02/2015. • oral azithromycin 250 mg x 3/week durant 2 ans • oral azithromycin 250 mg x 3/week for two years Currently 65% of expected • placebo 250 mg x 3/ week durant 2 ans • placebo 250 mg x 3/ week for two years inclusions. The study will stop when the Study duration expected number of patients will be Study duration Inclusion: 2 years completed Inclusion: 1 year Length of follow-up of each patient: 2 years Overall study duration: 4 years Downloaded From: https://jamanetwork.com/ on 09/29/2021 Length of follow-up of each patient: 2 years For reasons of … internal Overall study duration: 3 years organization of Exclusion criteria the centers … participating in the trial, the ECG Allergy or intolerance to azithromycin, which will Exclusion criteria macrolides, ketolide or excipient • Patient allergic to Penicillin and who will receive indicate the value of the QTc used prophylaxis by Macrolides (Erythromycin, Allergy or intolerance to azithromycin, to validate the Clarithromycin, roxithromycin, Troleandomycin and macrolides, ketolide or excipient criteria for non- azithromycin and/or Ketolide (Telithromycin). • Patient allergic to Penicillin and who will receive inclusion of prophylaxis by Macrolides (Erythromycin, • Prolonged corrected QT (QTc) interval (>450 patients in the Clarithromycin, roxithromycin, Troleandomycin and msec) (value from ECG within a month before trial may be the azithromycin and/or Ketolide (Telithromycin). inclusion) examination • Prolonged corrected QT (QTc) interval (>450 Taking medications that prolong the QTc interval carried out during msec) Family history of a prolonged QTc interval the pre- HSCT Taking medications that prolong the QTc interval History of congestive heart failure workup that it is Family history of a prolonged QTc interval Taking colchicine not more than History of congestive heart failure Taking ergotamine and dyhydroergotamine due one month before Taking colchicine to the risk of ergotism the time of the Taking ergotamine and dyhydroergotamine due Severe liver insufficiency patient's to the risk of ergotism • History of infection due to atypical mycobacteria inclusion. Severe liver insufficiency • History of infection due to atypical mycobacteria P11/6 3 3.1.1 Complications of allogeneic HSCT 3.1.1 Complications of allogeneic HSCT The incidence of GVHD depends on various factors The incidence of GVHD depends on various factors ; and most commonly occurs during unrelated itmost commonly occurs during unrelated transplantations and peripheral stem cell transplantations and peripheral stem cell transplantations. transplantations. P 25/63 6 Study endpoints 6 Study endpoints 6.1 Primary end point 6.1 Primary end point Airflow obstruction-free survival at 2 years after Airflow obstruction-free survival at 2 years after allogeneic HSCT. allogeneic HSCT. Downloaded From: https://jamanetwork.com/ on 09/29/2021 The airflow obstruction (AFO) is defined on the The airflow obstruction (AFO) is defined on the Precision in the criteria proposed by Chien JW et al which include an criteria proposed by Chien JW et al which include an calculations of annualized decline of FEV1 of at least 5%, and the annualized decline of FEV1 of at least 5%, and the the annualized decline in FEV1 lowest documented post-transplant FEV1/FVC ratio lowest documented post-transplant FEV1/VC ratio of 12 12 between each of < 0.8. The PFT obtained immediately before < 0.8. The PFT obtained immediately before HSCT visit (primary HSCT will be considered the baseline lung function. will be considered the baseline lung function. In objective) and PFTs obtained within the first 6 months after HSCT order to determine the annualized decline of precision in the are not considered because changes in pulmonary FEV1 between 2 visits the considered values definition of function during the first 6 months after transplant of FEV1 will be those after bronchodilator test bronchiolitis obliterans may be reversible and reflect temporary functional (post B2). PFTs obtained within the first 6 months 57 (secondary changes related to peritransplant events. All PFTs after HSCT are not considered because changes in objective) during obtained after the initial 6 months will be used to pulmonary function during the first 6 months after the trial whether calculate an annualized rate of decline for the transplant may be reversible and reflect temporary or not the patient predicted FEV1. functional changes related to peritransplant had a ventilatory events.57 All PFTs obtained after the initial 6 months Obstructive will be used to calculate an annualized rate of disorder prior to HSCT. decline for the predicted FEV1. 6.2 Secondary endpoints 6.2 Secondary endpoints • Overall survival at two years • Overall survival at two years • The occurrence of the following late-onset • The occurrence of the following late-onset pulmonary non-infectious complications: pulmonary non-infectious complications: SBO, which BOS, which is defined as (i) the absence is defined as the absence of infection with an FEV1 of infection (ii) either with an FEV1 of <75% of <75% of predicted or a decline of > 10% and of predicted or a decline of > 10% of FEV1 FEV1/SVC < 0.7 or RV or RV/TLC > 120%,30 and from baseline (pre-graft), and (iii) FEV1/VC interstitial lung disease, which is defined as the < 0.7 and/or (RV or RV/TLC) > 120% of onset of new interstitial lung abnormalities observed predicted,30 with a lung CT scan and the absence of infection. If the plethysmogram baseline was • Variation of pulmonary function testing abnormal and a FEV1<75% of predicted, parameters (FVC, RV, FEF25-75%) then the BOS during the study will be • Occurrence of acute and chronic extra- defined as follows: thoracic GVHD the absence of infection • Quality of life an FEV1 of <75% of predicted • Azithromycin tolerance AND a > 10% decline in FEV1 as compared to baseline, AND Downloaded From: https://jamanetwork.com/ on 09/29/2021 a FEV1/VC ratio < 0.7 In case of a and/or (RV or RV/TLC) > 120% ventilatory And the validation of the Trial disorder on the pre-HSCT PFT, Steering Committee (Pr. A. the diagnosis of BERGERON and J. CHIEN) Bornchiolitis Interstitial lung disease, which is defined as obliterans the onset of new interstitial lung abnormalities syndrome will be observed with a lung CT scan and the absence of validated by the infection. steering committee of the • Variation of pulmonary function testing trial (Pr. A. parameters (FVC, RV, FEF25-75%) Bergeron and J. • Occurrence of acute and chronic extra- Chien) case by thoracic GVHD case. • Quality of life • Azithromycin tolerance P25/6 For reasons of 3 Exclusion criteria Exclusion criteria internal Allergy or intolerance to azithromycin, Allergy or intolerance to azithromycin, organization of the centers macrolides or ketolides or excipient macrolides or ketolides or excipient participating in Patient allergic to Penicillin and who will Patient allergic to Penicillin and who will the trial, the ECG receive prophylaxis by Macrolides (Erythromycin, receive prophylaxis by Macrolides (Erythromycin, which will Clarithromycin, roxithromycin, Troleandomycin and Clarithromycin, roxithromycin, Troleandomycin and indicate the value azithromycin and/or Ketolide (Telithromycin). azithromycin and/or Ketolide (Telithromycin). of the QTc used Prolonged corrected QT (QTc) interval (>450 Prolonged corrected QT (QTc) interval (>450 to validate the msec) msec) (value from ECG within a month criteria for non- inclusion of Taking medications that prolong the QTc before inclusion) patients in the interval (Cisapride, ergotamine, Taking medications that prolong the QTc trial may be the dyhydroergotamine) interval (Cisapride, ergotamine, examination Family history of a prolonged QTc interval. dyhydroergotamine) carried out during History of congestive heart failure Family history of a prolonged QTc interval. the pre- HSCT Taking colchicine History of congestive heart failure workup that it is not more than Taking ergotamine and dyhydroergotamine Taking colchicine one month before due to the risk of ergotism Taking ergotamine and dyhydroergotamine the time of the Severe liver insufficiency due to the risk of ergotism patient's Severe liver insufficiency inclusion History of nontuberculous mycobacterial infection History of nontuberculous mycobacterial infection P 7.3 Sample size computation 7.3 Sample size computation Downloaded From: https://jamanetwork.com/ on 09/29/2021 27/63 … … Participation of 2 new centers to - The latest data from the Agency for Biomedicine - The latest data from the Agency for Biomedicine increase the regarding allogeneic HSCT in France regarding allogeneic HSCT in France number of (http://www.agence- (http://www.agence- inclusions in the biomedecine.fr/annexes/bilan2010/donnees/cellules biomedecine.fr/annexes/bilan2010/donnees/cellules trial. /01-greffe/synthese.htm), which reports the number /01-greffe/synthese.htm), which reports the number of transplantations in each centre as follows: 764 of transplantations in each centre as follows: 764 transplant recipients were reported in 2010 in the transplant recipients were reported in 2010 in the 22 participating centres (Saint Louis, Bordeaux, 23 participating centres (Saint Louis, Bordeaux, Lyon, Marseille, Nantes, Toulouse, Grenoble, Saint Lyon, Marseille, Nantes, Toulouse, Grenoble, Saint Antoine , Clermont Ferrand, Montpellier , Lille, Antoine , Clermont Ferrand, Montpellier , Lille, Besençon, Caen, Rennes, Strasbourg, Rouen, Besancon, Caen, Rennes, Strasbourg, Rouen, Poitiers, Clamart and Angers) with an increase of Poitiers, Clamart, Angers, Nice and Institut Gustave 8.6% in 2010 and overall survival of 66% after 1 Roussy) with an increase of 8.6% in 2010 and year and 54% after 2 years. overall survival of 66% after 1 year and 54% after 2 years. P Prolongation of 28/63 8.1.3 Duration of patients participation and 8.1.3 Duration of patients participation and the duration of description of the timing and duration of all description of the timing and duration of all the inclusions in of the test periods of the test periods order to make up The recruitment period will last for 1 year. The recruitment period will last for 2 1 years. for the delay of the inclusions The duration of participation for a patient The duration of participation for a patient whose end was will be 2 years. The duration of the study will will be 2 years. The duration of the study will originally planned be 3 years. be 4 3 years. on 12/02/2015. Currently 65% of expected inclusions. P For ethical 31/63 9.4 Causes of premature cessation of 9.4 Causes of premature cessation of reasons, patients experimental treatment experimental treatment diagnosed with hematologic relapse or Occurrence of a BOS systematically calculated Occurrence of a BOS systematically calculated transplant by eCRF after a scheduled visit will stop the by eCRF after a scheduled visit will stop the rejection should experimental treatment. experimental treatment. terminate the trial The occurrence of drug toxicity may interrupt The occurrence of drug toxicity may interrupt treatment prematurely and treatment if the following occur: treatment if the following occur: definitively on the - Unmanageable drug interactions according - Unmanageable drug interactions according date of the event. to the investigator to the investigator Downloaded From: https://jamanetwork.com/ on 09/29/2021 - Decision of the investigator in the case of, - Decision of the investigator in the case of, They will not be for example, a serious adverse event. for example, a serious adverse event. monitored in the - Occurrence of a prolonged QTc interval - Occurrence of a prolonged QTc interval trial (PFT every 6 months) because (>450 msec) during the follow-up (>450 msec) during the follow-up PFT are - Relapse of the haematological disease - Relapse of the haematological disease considered too or graft rejection or graft rejection tiring for patients. Transient interruption of treatment for a period not Transient interruption of treatment for a period not These patients exceeding one month is tolerated and does not exceeding one month is tolerated and does not will simply justify exclusion from the study. justify exclusion from the study. receive the latest news from M24 Also, patients with relapses or transplant rejection will be likely to receive new treatment lines that could impair their respiratory function during PFT and thus introduce bias in the analysis of the data. Moreover, these patients have a poor prognosis; They have been taken into account in the computation of the population (main objective: survival without airflow decline). Some of these patients receive a second transplant which was already a criterion of exit of study. P34/6 indeed, given the 3 10.3 Replacements of the subjects cause of early Downloaded From: https://jamanetwork.com/ on 09/29/2021 withdrawal is All patients who will withdraw prematurely their likely consent will be replaced. independent of the trial arm, and given those patients cannot be included in the intent-to-treat analysis due to ethical and regulatory concerns, it is required to replace these patients to control the type II error rate P Clarification 37/63 11.2 The investigator's role 11.2 The investigator's role provided by the 11.2.1 Immediate reporting of adverse events to 11.2.1 Immediate reporting of adverse events to pharmacovigilanc e unit concerning the sponsor the sponsor the AE and SAE to be notified and The investigator shall report all serious adverse The investigator shall report all serious adverse / or mentioned in events immediately to the sponsor except for those events immediately to the sponsor except for those the that the protocol (cf. 11.2.2) or investigator’s that the protocol (cf. 11.2.2) or investigator’s ALLOZITHRO brochure identifies as not requiring immediate brochure identifies as not requiring immediate CRF throughout the study period. reporting reporting - Results in death, - Results in death, - is life-threatening, - is life-threatening, - requires inpatient hospitalization or prolongation of - requires inpatient hospitalization or prolongation of existing hospitalization, existing hospitalization, - Results in persistent or significant - Results in persistent or significant disability/incapacity, disability/incapacity, The investigator shall report all serious adverse - Congenital abnormality or birth defect events associated with azythromycin immediately to - Or any other adverse event considered the sponsor (cf. RCP Appendix 1) “medically significant” All acute heart pathology The investigator shall report all serious adverse events associated with azithromycin immediately to the sponsor (cf. RCP Appendix 1) Downloaded From: https://jamanetwork.com/ on 09/29/2021 P 11.2.2 Adverse events that do not require 11.2.2 Serious adverse events that do not Clarification 38/63 immediate reporting to the sponsor require immediate reporting to the sponsor provided by the pharmacovigilanc e unit concerning Adverse events that do not require immediate Serious Adverse Events (SAE) that do not require the AE and SAE reporting: immediate reporting but must be reported in the to be notified and Everything that is related to the known CRF : / or mentioned in complications that can occur after allogeneic Hospitalizations related to the known the hematopoietic stem cell transplantation: complications that can occur after allogeneic ALLOZITHRO Graft versus host disease hematopoietic stem cell transplantation CRF throughout Relapse of the haematological disease (except hospitalization in reanimation) : the study period.. Intercurrent infection - Graft versus host disease Adverse side effects of treatments other than - Intercurrent infection azithromycin Scheduled hospitalization Serious Adverse events and Do not report the non-serious adverse events hospitalization related to relapse of the associated with azythromycin (cf. RCP Appendix 1) haematological disease Serious Adverse side effect events reactions and hospitalization of related to treatments other than azithromycin, used for the standard care of the patient Scheduled hospitalization The non-serious adverse events associated with azythromycin (cf. RCP Appendix 1) not require immediate reporting but are to be reported in the eCRF. In utero exposure The sponsor must be notified immediately about any pregnancy during which the foetus (from the pre-embryonic stage up to birth) could have been exposed at a given time to an experimental medication, even if the pregnancy is not associated with an adverse event. Notification is required if the exposure involves: - the mother, - the father if the experimental medication is genotoxic. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Exposure while breastfeeding Exposure while breastfeeding occurs if an infant or child could have been exposed to a medication via the breast milk of a mother being treated with an experimental medication. Even if such exposure is not associated with an adverse event, the investigator must always notify the sponsor about exposure while breastfeeding as soon as the investigator becomes aware. Period for notifying the sponsor The investigator must report all SAE that occur in research subjects: - after the date on which treatment with the investigational drug (azithromycin or placebo) began - throughout the duration of the treatment - for up to 4 weeks after the participant stops treatment using the experimental medication 61 62 Modifications in the Patients’ forms: 63 64 2) Information Teenagers : 65 - Page 2 : Changement de la durée de la recherche. 66 Quel est le calendrier de la recherche ? La recherche durera 4 années et votre participation sera au maximum de 24 mois. 67 3) Note d’information consentement autorité parentale et note d’information consentement adulte : 68 - Page 2 : Changement de la durée de la recherche. 69 Quel est le calendrier de la recherche ? La recherche durera 4 années et votre participation sera au maximum de 24 mois. 70 - Page 6 : Changement du numéro de version. Downloaded From: https://jamanetwork.com/ on 09/29/2021 71 Nous avons pris connaissance de la note d’information version 4 du 03.12.2014 comportant 5 pages nous expliquant l’objectif 72 de cette recherche, la façon dont elle va être réalisée et ce que la participation de mon enfant va impliquer, 73 74 Downloaded From: https://jamanetwork.com/ on 09/29/2021 75 ALLOZITHRO TRIAL AMENDMENT 5 76 APPROVED ETHICS COMMITTEE 07/23/2015 ; APPROVED REGULATORY AGENCY 07/22/2015 77 78 Original text Revised text Justification Contact List Contact List Page Trial Sponsor Trial Sponsor P.3 Monsieur Christophe Misse, directeur Mme FAVREL FEUILLADE FlorenceMonsieur Christophe Misse, directeurdirectrice Sites involved in recruiting Sites involved in recruiting Change of PI in the center of Nice. Dr. patients: patients: Risso becomes PI and replaces Dr. P.4 Dr Hématologie CHU legrand.ff@chu- Dr Hématologie CHU risso.k@chu- Legrand-Izadefar in this function. Team LEGRAND- de nice.fr Team Karine de nice.fr 23 IZADEFAR Nice 23 RISSO Nice 1 Abstract 1 Abstract Main endpoint Main endpoint Airflow obstruction (AFO)-free survival at 2 year Airflow obstruction decline (AFDO)-free after allogeneic HSCT. survival at 2 year after allogeneic HSCT. Secondary endpoints Secondary endpoints • Overall survival at two years • Overall survival at two years We specified the timing of the ventilatory P.8 • Occurrence of late-onset pulmonary non- • Occurrence of late-onset pulmonary functional parameters we will analyze infectious complications non-infectious complications • Variation of pulmonary function testing • Variation of pulmonary function parameters (FVC, RV, FEF25-75%) testing parameters within the 2 years (Mean FEV1 decline, FVC, TLC, RV, FEF25- • Occurrence of acute and chronic extra- 75%) thoracic GVHD • Occurrence of acute and chronic Downloaded From: https://jamanetwork.com/ on 09/29/2021 • Quality of life extra-thoracic GVHD • Tolerance of azithromycin • Quality of life • Tolerance of azithromycin Sample size computation Sample size computation Based on a 2 year estimated AFO-free survival Based on a 2 year estimated AFOD-free of 45% in the control arm, ……. survival of 45% in the control arm,….. Recent data published by our team and 2 Synopsis 2 Synopsis others have shown that the respiratory functional profile of a bronchiolitis obliterans is not systematically associated with a decrease in the FEV1 Main endpoints Main endpoints / FVC ratio. Indeed, a concomitant AFO-free survival at 2 years after allogeneic HSCT. AFOAFD-free -free survival at 2 years after decrease in FEV1 and FVC (with a The airflow obstruction (AFO) is defined on the allogeneic HSCT. normal FEV 1/ FVC ratio) is observed in criteria from Chien JW et al (Am J Respir Crit Care The airflow obstruction decline (AFOAFD) is 30 -50% of cases (Bergeron, Bone Med. 2003; 168:208-14), by an annualized decline defined on the criteria from Chien JW et al (Am Marrow Transplant, 2013; Ulhving, Biol of FEV1 of at least 5%, and the lowest J Respir Crit Care Med. 2003; 168:208-14), by Blood Marrow Transplant, 2015). In documented post-transplant FEV1/FVC ratio < 0.8. an annualized decline of percent predicted FEV1 addition, the new NIH consensus on diagnostic criteria of chronic graft versus of more than 5% host disease keeps the change in FEV1 FEV1 of at least 5%, and the lowest Formatted: Font: Highlight as the most specific value of the documented post-transplant FEV1/FVC ratio < pulmonary function testing to assess the P.9 0.8. severity of bronchiolitis obliterans syndrome (Jagasia, Biol Blood Marrow Transplant, 2015). Therefore, the word « airflow decline (AFD)» is more accurate than « airflow obstruction (AFO) » Secondary endpoints Secondary endpoints Furthermore, we have specified and Overall survival at two years standardized the definition of AFD from Overall survival at two years Occurrence of late-onset pulmonary non- Chien et al, Am J Respir Crit Care Med, Occurrence of late-onset pulmonary non- infectious complications (both SBO and 2003) throughout the manuscript. infectious complications (both SBO and interstitial lung disease) interstitial lung disease) Variation of pulmonary function testing Variation of pulmonary function testing parameters within the 2 years (Mean parameters (FVC, RV, FEF25-75%) FEV1 decline, FVC, TLC, RV, FEF25-75%) Occurrence of acute and chronic GVHD Downloaded From: https://jamanetwork.com/ on 09/29/2021 Quality of life Occurrence of acute and chronic GVHD Tolerance of azithromycin Quality of life Tolerance of azithromycin 3.1.1.2 Bronchiolitis obliterans 3.1.1.2 Bronchiolitis obliterans a) Diagnostic criteria of BO a) Diagnostic criteria of BO …………. Thus, the diagnosis of post-allogeneic HSCT BO Thus, the diagnosis of post-allogeneic HSCT BO is most frequently based on is most frequently based on the detection of the detection of airflow obstruction airflow obstruction (AFO)……. (AFOAFD)………. ……….. ………… However, it is likely that this definition still does not apply to earliest forms of BO. A few years ago, Chien et al conducted a study using a However, it is likely that this definition still does not apply to earliest forms of BO. P.14 et different definition of airflow obstruction in the A few years ago, Chien et al conducted 15 setting of allogeneic HSCT showing that a study using a different definition of standard definitions probably underestimate the airflow obstruction in the setting of 12 incidence of AFO. Using the rate of per cent allogeneic HSCT showing that standard predicted FEV1 decline after transplant, they definitions probably underestimate the defined AFO as a more than 5% per year incidence of of AFOAFD.12 Using the decline in per cent predicted FEV1 with the rate of per cent predicted FEV1 lowest post-transplant FEV1/FVC ratio less than (pFEV1) decline after transplant, they defined AFO AFD as a more than 5% 0.8. Of note, the mean rate of predicted FEV1 per year decline in per cent predicted decline in a normal population is less than 1% FEV1 with the lowest post-transplant per year, well over two SDs lower than this 5% FEV1/FVC ratio less than 0.8. Of note, criterion. With this definition, they found a 26% the mean rate of predicted FEV1 incidence with a significant association with decline in a normal population is less older age at transplantation, lower pre- than 1% per year, well over two SDs transplant FEV1/FVC ratio, and history of both lower than this 5% criterion. With this definition, they found a 26% incidence acute and chronic GVHD and respiratory viral with a significant association with older Downloaded From: https://jamanetwork.com/ on 09/29/2021 infections within the first 100 days after age at transplantation, lower pre- transplant. Moreover, they found that AFO was transplant FEV1/FVC ratio, and history associated with significant attributable of both acute and chronic GVHD and respiratory viral infections within the mortality.12 Thus, this rate of percent predicted first 100 days after transplant. FEV1 decline definition may more accurately Moreover, they found that AFO AFD identify patients who experienced a significant was associated with significant decline in their airflow after HSCT and reflect attributable mortality.12Thus, this rate the true incidence of HSCT-related AFO. In fact, of percent predicted FEV1 decline this measure makes it possible to recognize definition may more accurately identify early patients with declining airflow, including patients who experienced a significant decline in their airflow after HSCT and some who do not meet criteria for AFO by other reflect the true incidence of HSCT- standards. As BOS definition is probably only related AFOAFD. In fact, this measure one extreme form of AFO, we find accurate to makes it possible to recognize early use this definition of AFO and its prevalence of patients with declining airflow, 26% in our study. This will make the study including some who do not meet more feasible with fewer patients than if we criteria for AFO AFD by other used the NIH definition of BOS. standards. As BOS definition is probably only one extreme form of AFOAFD, we find accurate to use this definition of AFO AFD and its prevalence of 26% in our study. This will make the study more feasible with fewer patients than if we used the NIH definition of BOS. ……… a) Outcome ……… However, Chien et al. have shown that the patients’ outcome was altered as soon as an b) Outcome annual decline in FEV1 of over 5%.12 However, Chien et al. have shown that the patients’ outcome was altered as soon as an annual decline in percent predicted FEV1 of over 5%.12 Downloaded From: https://jamanetwork.com/ on 09/29/2021 6 Study endpoints 6 Study endpoints Primary end point Primary end point Airflow obstruction-free survival at 2 years after Airflow obstruction decline-free survival at allogeneic HSCT. 2 years after allogeneic HSCT. The airflow obstruction (AFO) is defined on the The airflow obstruction decline criteria proposed by Chien JW et al which (AFOAFD) is defined on the criteria Given that the bronchodilator test is not include an annualized decline of FEV1 of at least proposed by Chien JW et al which recommended and therefore not 5%, and the lowest documented post-transplant include an annualized decline of systematically conducted during the FEV1/VC ratio of < 0.8.12 The PFT obtained percent predicted FEV1 of more than realization of pulmonary function testing immediately before HSCT will be considered the 5%at least 5%, and the lowest in patients with normal FEV1 (ie ≥ 80% baseline lung function. In order to determine documented post-transplant FEV1/VC of predicted), we will compare the pre the annualized decline of pFEV1 between 2 ratio of < 0.8.12 The PFT obtained bronchodilator values. P.24 visits the considered values of FEV1 will be immediately before HSCT will be those after bronchodilator test (post B2). PFTs considered the baseline lung function. obtained within the first 6 months after HSCT In order to determine the annualized are not considered because changes in decline of pFEV1 between 2 visits the pulmonary function during the first 6 months considered values of FEV1 will be after transplant may be reversible and reflect those after before bronchodilator test temporary functional changes related to peri- (post pre B2). PFTs obtained within the transplant events.57 All PFTs obtained after the first 6 months after HSCT are not initial 6 months will be used to calculate an considered because changes in annualized rate of decline for the predicted pulmonary function during the first 6 FEV1. months after transplant may be reversible and reflect temporary functional changes related to peri- transplant events.57 All PFTs obtained after the initial 6 months will be used to calculate an annualized rate of decline for the predicted FEV1. New NIH diagnostic criteria for 6.2 Secondary endpoints 6.2 Secondary endpoints bronchiolitis obliterans were published: P.24 et • Overall survival at two years • Overall survival at two years Jagasia, Biol Blood Marrow Transplant, 25 • The occurrence of the following late- • The occurrence of the following 2015. These standards are intended to onset pulmonary non-infectious late-onset pulmonary non-infectious harmonize the diagnostic criteria of Downloaded From: https://jamanetwork.com/ on 09/29/2021 complications: complications: bronchiolitis obliterans in clinical studies. BOS, which is defined as (i) the BOS, which is defined as (i) the It seems essential to include these absence of infection (ii) either with an absence of infection (ii) either an criteria in ALLOZITHRO FEV1 of <75% of predicted or a decline FEV1 of <75% of predicted or with of > 10% of FEV1 from baseline (pre- a decline of >≥ 10% of FEV1 from graft), and (iii) FEV1/VC < 0.7 and/or baseline (pre-graft), and FEV1 (RV or RV/TLC) > 120% of predicted,30 should not correct to >75% of If the plethysmogram baseline was predicted with bronchodilator, and abnormal and a FEV1<75% of predicted, the absolute decline for the then the BOS during the study will be corrected values should still remain defined as follows: at ≥10% and (iii) FEV1/VC < 0.7 the absence of infection and /or the fifth percentile of an FEV1 of <75% of predicted predicted and/or one of the 2 supporting features of BOS: AND A. Evidence of air trapping by a > 10% decline in FEV1 as expiratory CT or small airway compared to baseline, thickening or bronchiectasis by high AND resolution chest CT, or a FEV1/VC ratio < 0.7 B. Evidence of air trapping by and/or (RV or RV/TLC) > 120% PFTs: residual volume >120% of And the validation of the Trial predicted or residual volume/total Steering Committee (Pr. A. lung capacity elevated outside the BERGERON and J. CHIEN) 90% confidence interval. (Jagasia, Interstitial lung disease, which is defined as the Biol Blood Marrow Transplant, onset of new interstitial lung abnormalities 2015). observed with a lung CT scan and the absence (RV or RV/TLC) > 120% of of infection. predicted,30 • Variation of pulmonary function testing If the plethysmogram baseline parameters (FVC, RV, FEF25-75%) was abnormal and a FEV1<75% of • Occurrence of acute and chronic extra- predicted, then the BOS during the thoracic GVHD study will be defined as follows: • Quality of life the absence of infection • Azithromycin tolerance an FEV1 of <75% of predicted AND a > 10% decline in FEV1 as compared to baseline, AND Downloaded From: https://jamanetwork.com/ on 09/29/2021 a FEV1/VC ratio < 0.7 and/or (RV or RV/TLC) > 120% And the validation of the Trial Steering Committee (Pr. A. BERGERON and J. CHIEN) Interstitial lung disease, which is defined as the onset of new interstitial lung abnormalities observed with a lung CT scan and the absence of infection. • Variation of pulmonary function testing parameters within the 2 years (Mean FEV1 decline, FVC, TLC, RV, FEF25-75%) • Occurrence of acute and chronic extra-thoracic GVHD • Quality of life • Azithromycin tolerance 7.3 Sample size computation 7.3 Sample size computation Based on a 2-year estimated AFO-free survival Based on a 2-year estimated AFOAFD-free of 45% in the control arm, it has been survival of 45% in the control arm, it has computed that a total of 218 events and been computed that a total of 218 460 patients (230 in each arm) are events and 460 patients (230 in each required in each arm to demonstrate a 15% arm) are required in each arm to P.26 benefit in the experimental arm, with an overall demonstrate a 15% benefit in the type I error of 0.05 and a statistical power of experimental arm, with an overall type I 0.9 based on a two-sided log-rank test. This error of 0.05 and a statistical power of 0.9 estimation takes into account both the 26% based on a two-sided log-rank test. This incidence of AFO post allogeneic HSCT and the estimation takes into account both the 26% survival after transplantation (66% after one incidence of AFO AFD post allogeneic HSCT and the survival after transplantation (66% Downloaded From: https://jamanetwork.com/ on 09/29/2021 year and 54% after 2 years). after one year and 54% after 2 years). …….. …….. The prevalence of AFO in allogeneic HSCT The prevalence of AFO AFD in allogeneic recipients according to the study by Chien JW,12 HSCT recipients according to the study by which is the source of our definition of AFO, was Chien JW,12 which is the source of our 26% in the population of patients alive at day definition of AFOAFD, was 26% in the 100 after allogeneic HSCT. population of patients alive at day 100 after allogeneic HSCT. - We predicted that AFO-free survival would be 45% in the placebo group and 60% in the - We predicted that AFOAFD-free survival group of patients treated with azithromycin. would be 45% in the placebo group and This estimation takes into account both the 60% in the group of patients treated with 26% incidence of AFO and the survival after azithromycin. This estimation takes into transplantation (66% after 1 year, 54% after 2 account both the 26% incidence of AFO years). AFD and the survival after transplantation (66% after 1 year, 54% after 2 years). 9 Evaluation 9 Evaluation Correction of an error In addition to clinical visits, which are routinely In addition to clinical visits, which are performed in these patients, The respiratory routinely performed in these patients, The P. 28, Saint George’s hospital quality of life respiratory Saint George’s hospital quality 29, 30 questionnaire will be submitted by each patient of life questionnaire will be submitted by before transplantation at M12 and M24. If each patient before transplantation at M12 patients have developed an infectious and M24. If patients have developed an respiratory disease or any symptom leading to infectious respiratory disease or any difficulties in performing the PFT at the symptom leading to difficulties in scheduled time, the PFT will be performed one performing the PFT at the scheduled time, month later. Erythromycin tolerance will be the PFT will be performed one month later. Downloaded From: https://jamanetwork.com/ on 09/29/2021 assessed at each visit. Erythromycin Azithromycin tolerance will be assessed at each visit. 9.1 Timing and content of visits 9.1 Timing and content of visits ……… In the event of AFO (primary endpoint), the ……… investigator will be notified by an e-mail alert, In the event of AFD (primary endpoint), the both blindly of the randomization arm. The need investigator will be notified by an e-mail to rule out an infection will be automatically alert, both blindly of the randomization notified. Control of pulmonary function testing arm. The need to rule out an infection will will be performed 4 to 6 weeks later to remove be automatically notified. Control of the role of an intercurrent event, such as an pulmonary function testing will be infectious one. AFO will be validated only if AFO performed 4 to 6 weeks later to remove the is persistent. role of an intercurrent event, such as an infectious one. AFO AFD will be validated ……….. only if AFO AFD is persistent. If the discontinuation of treatment by If the discontinuation of treatment by azithromycin is > 1 consecutive month the azithromycin is > 1 consecutive Clarification on follow-up des patients patient will stop the experimental month the patient will stop the cas d’arrêt prématuré de traitement treatment and will have a follow-up two experimental treatment and will have years after inclusion. a follow-up of sequential pulmonary …………….. function testing (PFT) during the scheduled visits up to two years after inclusion except in cases of relapse of the haematological disease requiring intensive chemotherapy or supportive care (or any ethical reason according 9.4 Causes of premature cessation of to investigator) or graft rejection. experimental treatment …………. 9.4 Causes of premature All patients who stopped prematurely the cessation of experimental Downloaded From: https://jamanetwork.com/ on 09/29/2021 experimental treatment will have a treatment follow-up two years after inclusion. …………. All patients who stopped prematurely the experimental treatment will have a follow-up of sequential pulmonary function testing (PFT) during the scheduled visits up to two years after inclusion except in cases of relapse of the haematological disease requiring intensive chemotherapy or supportive care (or any ethical reason according to investigator) or graft rejection. 10 Statistics 10 Statistics 1.1 Main principles 1.1 Main principles An The primary analysis will be performed An analysis will be performed based on an based on an intent-to-treat principle; once intent-to-treat principle; once patients are patients are randomized, all will be randomized, all will be analysed. This policy, analysed. This policy, known as the intent- To provide a lower level of evidence but known as the intent-to-treat (ITT) analysis to-treat (ITT) analysis principle, is a principle, is a cornerstone of good clinical trial to better reflect the effects of treatment cornerstone of good clinical trial practice. when taken in an optimal manner, we P.33 practice. All participants randomized and All participants randomized and entered chose to add a secondary and entered into the trial should be included in the into the trial should be included in the exploratory “Per protocol” (PP) analysis. analysis of the group to which they were analysis of the group to which they were This PP analysis will exclude patients assigned including loss of follow-up, regardless assigned including loss of follow-up, who deviated from the protocol. of whether they completed the trial or switched regardless of whether they completed the to receive different treatment. trial or switched to receive different treatment. The study's primary aim tests a hypothesis and corresponds with an analytical plan (see above). To provide a lower level of evidence but to The statistical power has been computed to better reflect the effects of treatment when choose a sample size adequate for detecting the predicted effects if present (see below, section taken in an optimal manner, a secondary Downloaded From: https://jamanetwork.com/ on 09/29/2021 3.3.3.9). and exploratory “Per protocol” (PP) analysis None interim analysis will be performed. The will be performed. This PP analysis will analysis will be terminal, based on the exclude patients who deviated from the previously calculated required sample size. protocol, listed below: The statistical report will be based on the Consolidated Standards of Reporting Trials Patients with macrolides as post HSCT (CONSORT). antibacterial prophylaxis due to penicillin allergy, HSCT actually not performed, Patients who took the experimental treatment for less than 3 consecutive months The study's primary aim tests a hypothesis and corresponds with an analytical plan (see above). The statistical power has been computed to choose a sample size adequate for detecting the predicted effects if present (see below, section 3.3.3.9). None interim analysis will be performed. The analysis will be terminal, based on the previously calculated required sample size. The statistical report will be based on the Consolidated Standards of Reporting Trials (CONSORT). 10.2 Statistical tests 10.2 Statistical tests …The outcome, change in pFEV1, will be annualized and expressed in milliliters per year. …The outcome, change in pFEV1, will be We specified the timing of the P.34 Failure will thus be defined as an estimated annualized and expressed in millilitres per ventilatory functional parameters we will analyze annualized decline of FEV1 of at least 5%, and year. Failure will thus be defined as an estimated annualized decline of FEV1 of at the lowest observed post-transplant FEV1/FVC least 5% and the lowest observed post- ratio < 0.8. transplant FEV1/FVC ratio < 0.8. Downloaded From: https://jamanetwork.com/ on 09/29/2021 The right-censored endpoints (AFO-free survival The right-censored endpoints (AFOAFD- and overall survival) will be estimated by the free survival and overall survival) will be nonparametric Kaplan-Meier method and estimated by the nonparametric Kaplan- Meier method and compared between compared between randomized groups by the randomized groups by the log-rank test log-rank test after checking for the after checking for the proportionality of proportionality of hazard functions. The hazard functions. The treatment treatment comparisons will be adjusted for comparisons will be adjusted for imbalances or prognostic covariates using a imbalances or prognostic covariates using multivariable Cox model. The models will be a multivariable Cox model. The models will evaluated based on the testing assumptions of be evaluated based on the testing assumptions of the proportionality of the proportionality of hazard functions and log- hazard functions and log-linear linear relationships between the predictors and relationships between the predictors and hazard. hazard. Competing risks endpoints (the occurrence of Competing risks endpoints (the occurrence late-onset, pulmonary, non-infectious of late-onset, pulmonary, non-infectious complications or acute and chronic extra- complications or acute and chronic extra- thoracic GVHD) will be analysed using thoracic GVHD) will be analysed using competing risks methods. Specifically, the competing risks methods. Specifically, the cumulative incidences of late-onset, cumulative incidences of late-onset, pulmonary, pulmonary, non-infectious complications non-infectious complications and acute and and acute and chronic extra-thoracic GVHD chronic extra-thoracic GVHD will be estimated will be estimated considering deaths prior considering deaths prior to the event of interest to the event of interest as competing risk as competing risk outcomes and compared outcomes and compared using the Gray test. The adjustments for potential using the Gray test. The adjustments for confounders will be based on the Fine and potential confounders will be based on the Fine Gray model. and Gray model. Variations in pulmonary function testing Variations in pulmonary function testing parameters within the 2 years (Mean parameters ( FVC, RV, FEF25-75%) will be FEV1 decline, FVC, TLC, RV, FEF25- compared between randomized groups by 75%) will be compared between generalized linear models. randomized groups by generalized linear models. Downloaded From: https://jamanetwork.com/ on 09/29/2021 10.3 Replacements of the subjects 10.3 Replacements of the subjects The number of patient who will withdraw All patients who will withdraw prematurely their All patients who will withdraw prematurely P.34 prematurely their consent is estimated consent will be replaced. their consent will be replaced (n=20). to 20. 79 80 81 82 83 2) Modifications of patients’ forms (in French) 84 Justification de la modification Texte initial Texte modifié ou ajouté substantielle Note d’information consentement Précision apportée concernant le suivi Note d’information consentement autorité autorité parentale des patients en cas d’arrêt prématuré de parentale traitement 3) Quel est le calendrier de la 3) Quel est le calendrier de la recherche recherche En cas d’aggravation de sa fonction respiratoire, le En cas d’aggravation de sa fonction respiratoire, le traitement de l’étude sera arrêté et il bénéficiera du Page et traitement de l’étude sera arrêté et il bénéficiera du traitement que le médecin jugera le plus adapté. section traitement que le médecin jugera le plus adapté. En cas d’arrêt prématuré du traitement au cours concernée Un recueil de données concernant l’apparition de l’essai et si l’état de la maladie hématologique éventuelle d’un syndrome de bronchiolite oblitérante le permet, votre enfant bénéficiera de la P.2 sera effectuée dans le cadre de la recherche à 24 mois surveillance de sa fonction respiratoire (Epreuves après le début du traitement de la recherche. fonctionnelles respiratoires) comme le prévoit le calendrier des visites protocolaires. Un recueil de données concernant l’apparition éventuelle d’un syndrome de bronchiolite oblitérante sera effectuée dans le cadre de la recherche à 24 mois après le début du traitement de la recherche. Note d’information Adolescents et note Note d’information Adolescents et note Précision apportée concernant le suivi des d’information consentement adulte d’information consentement adulte patients en cas d’arrêt prématuré de traitement P.2 3) Quel est le calendrier de la 3) Quel est le calendrier de la recherche recherche Downloaded From: https://jamanetwork.com/ on 09/29/2021 En cas d’aggravation de votre fonction respiratoire, le En cas d’aggravation de votre fonction respiratoire, traitement de l’étude sera arrêté et vous bénéficierez du le traitement de l’étude sera arrêté et vous traitement que le médecin jugera le plus adapté. Un bénéficierez du traitement que le médecin jugera recueil de données concernant l’apparition éventuelle le plus adapté. d’un syndrome de bronchiolite oblitérante sera effectuée En cas d’arrêt prématuré du traitement au cours dans le cadre de la recherche à 24 mois après le début de l’essai et si l’état de votre maladie du traitement de la recherche. hématologique le permet, vous bénéficierez de la surveillance de votre fonction respiratoire (Epreuves fonctionnelles respiratoires) comme le prévoit le calendrier des visites protocolaires. Un recueil de données concernant l’apparition éventuelle d’un syndrome de bronchiolite oblitérante sera effectuée dans le cadre de la recherche à 24 mois après le début du traitement de la recherche. 85 86 87 88 89 Downloaded From: https://jamanetwork.com/ on 09/29/2021 90 ALLOZITHRO TRIAL AMENDMENT 6 91 APPROVED ETHICS COMMITTEE 11/03/2016 ; APPROVED REGULATORY AGENCY 10/21/2016 92 Original text Revised text Justification Sites involved in recruiting Sites involved in recruiting Change of PI in the center of Caen. Dr. patients: patients: Chantepie becomes PI and replaces Dr. P.4 Dr Hématologie CHU Reman- Dr Hématologie CHU chantepie- Reman in this position. Team REMAN de Nice o@chu- Team CHANTEPIE de s@chu- 15 caen.fr 15 Nice caen.fr Abstract Abstract Secondary endpoints Secondary endpoints DSMB required • Overall survival at two years • Overall survival at two years • Occurrence of late-onset pulmonary non- • Occurrence of late-onset pulmonary non- infectious complications infectious complications • Variation of pulmonary function testing • Variation of pulmonary function testing parameters within the 2 years (Mean FEV1 parameters within the 2 years (Mean FEV1 P. 8 decline, FVC, TLC, RV, FEF25-75%) decline, FVC, TLC, RV, FEF25-75%) • Occurrence of acute and chronic extra-thoracic • Occurrence of acute and chronic extra-thoracic GVHD GVHD • Quality of life • Cumulative incidence of haematological relapse • Tolerance of azithromycin at two years • Quality of life • Tolerance of azithromycin 2. Synopsis 2. Synopsis …………… …………… DSMB required Endpoint Endpoint ……….. ……….. Secondary : Secondary : Overall survival at two years Overall survival at two years Occurrence of late-onset pulmonary non- Occurrence of late-onset pulmonary non- infectious complications (both SBO and infectious complications (both SBO and interstitial lung disease) interstitial lung disease) P.9 Variation of pulmonary function testing Variation of pulmonary function testing parameters within the 2 years (Mean parameters within the 2 years (Mean FEV1 decline, FVC, TLC, RV, FEF25-75%) FEV1 decline, FVC, TLC, RV, FEF25-75%) Occurrence of acute and chronic GVHD Occurrence of acute and chronic GVHD Quality of life Quality of life Tolerance of azithromycin Tolerance of azithromycin Cumulative incidence of haematological relapse at two years Downloaded From: https://jamanetwork.com/ on 09/29/2021 6.2 Secondary endpoints 6.2 Secondary endpoints DSMB required Overall survival at two years Overall survival at two years • The occurrence of the following late- • The occurrence of the following late- onset pulmonary non-infectious onset pulmonary non-infectious complications: complications: BOS, which is defined as (i) the absence of BOS, which is defined as (i) the absence of infection (ii) either with an FEV1 of <75% of infection (ii) either with an FEV1 of predicted with a decline of ≥ 10% of FEV1 <75% of predicted with a decline of from baseline (pre-graft), and FEV1 should ≥ 10% of FEV1 from baseline (pre- not correct to >75% of predicted with graft), and FEV1 should not correct to bronchodilator, and the absolute decline for >75% of predicted with the corrected values should still remain at bronchodilator, and the absolute ≥10% and (iii) FEV1/VC < 0.7 or the fifth decline for the corrected values percentile of predicted and one of the 2 should still remain at ≥10% and (iii) supporting features of BOS: FEV1/VC < 0.7 or the fifth percentile A. Evidence of air trapping by expiratory CT of predicted and one of the 2 or small airway thickening or bronchiectasis supporting features of BOS: P. 25 by high resolution chest CT, or A. Evidence of air trapping by expiratory CT B. Evidence of air trapping by PFTs: residual or small airway thickening or volume >120% of predicted or residual bronchiectasis by high resolution volume/total lung capacity elevated outside chest CT, or the 90% confidence interval. (Jagasia, Biol B. Evidence of air trapping by PFTs: residual Blood Marrow Transplant, 2015). volume >120% of predicted or residual volume/total lung capacity elevated outside the 90% confidence And the validation of the Trial interval. (Jagasia, Biol Blood Marrow Steering Committee (Pr. A. Transplant, 2015). BERGERON and J. CHIEN) Interstitial lung disease, which is defined as the onset of new interstitial lung And the validation of the Trial abnormalities observed with a lung CT scan Steering Committee (Pr. A. and the absence of infection. BERGERON and J. CHIEN) Interstitial lung disease, which is defined as • Variation of pulmonary function the onset of new interstitial lung testing parameters within the 2 years (Mean abnormalities observed with a lung CT FEV1 decline, FVC, TLC, RV, FEF25-75%) scan and the absence of infection. • Occurrence of acute and chronic Downloaded From: https://jamanetwork.com/ on 09/29/2021 extra-thoracic GVHD • Variation of pulmonary function • Quality of life testing parameters within the 2 years • Azithromycin tolerance (Mean FEV1 decline, FVC, TLC, RV, FEF25-75%) • Occurrence of acute and chronic extra-thoracic GVHD • Occurrence of haematological relapse within the 2 years • Quality of life • Azithromycin tolerance Clarification of statistical analysis of 10.2 Statistical tests 10.2 Statistical tests secondary criteria. The baseline (i.e., at randomization) The baseline (i.e., at randomization) characteristics of the randomized groups will characteristics of the randomized groups will be compared roughly, based on estimations, be compared roughly, based on estimations, with 95% confidence intervals and without with 95% confidence intervals and without any statistical tests of significance. any statistical tests of significance. Randomization is the best means for creating Randomization is the best means for creating balanced groups. balanced groups. Changes in FEV1 will be first estimated, Changes in FEV1 will be first estimated, based on differences in base line based on differences in base line measurements between each study measurements between each study assessment over the entire follow-up. To assessment over the entire follow-up. To P.34 account for repeated measures in estimating account for repeated measures in estimating the changes in FEV1, mixed model will be the changes in FEV1, mixed model will be used. Such an analysis allows for efficient used. Such an analysis allows for efficient use of all data, because the mean slopes are use of all data, because the mean slopes are not distorted by subjects with incomplete not distorted by subjects with incomplete data. This model effectively weights the data. This model effectively weights the contributions of individuals with shorter contributions of individuals with shorter follow-up or missed observations, ensuring follow-up or missed observations, ensuring that the estimates of mean and variance of that the estimates of mean and variance of the slope are not biased. The outcome, the slope are not biased. The outcome, change in pFEV1, will be annualized and change in pFEV1, will be annualized and expressed in millilitres per year. Failure will expressed in millilitres per year. Failure will thus be defined as an estimated annualized thus be defined as an estimated annualized decline of FEV1 of at least 5%. decline of FEV1 of at least 5%. Downloaded From: https://jamanetwork.com/ on 09/29/2021 The right-censored endpoints (AFD-free The right-censored endpoints (AFD-free survival and overall survival) will be survival and overall survival) will be estimated by the nonparametric Kaplan- estimated by the nonparametric Kaplan- Meier method and compared between Meier method and compared between randomized groups by the log-rank test after randomized groups by the log-rank test after checking for the proportionality of hazard checking for the proportionality of hazard functions. The treatment comparisons will be functions. The treatment comparisons will be adjusted for imbalances or prognostic adjusted for imbalances or prognostic covariates using a multivariable Cox model. covariates using a multivariable Cox model. The models will be evaluated based on the The models will be evaluated based on the testing assumptions of the proportionality of testing assumptions of the proportionality of hazard functions and log-linear relationships hazard functions and log-linear relationships between the predictors and hazard. between the predictors and hazard. Competing risks endpoints (the occurrence of Given the primary outcome measure is a late-onset, pulmonary, non-infectious composite endpoint, the estimation of the complications or acute and chronic extra- cumulative incidence of both components thoracic GVHD) will be analysed using (namely, cumulative incidence of AFD, and competing risks methods. Specifically, the that of death free of AFD) will be computed cumulative incidences of late-onset, using competing-risk methods, with pulmonary, non-infectious complications and comparison across randomized arms based acute and chronic extra-thoracic GVHD will on Gray’s test and cause-specific hazard be estimated considering deaths prior to the models. event of interest as competing risk outcomes Competing risks endpoints (the occurrence of and compared using the Gray test. The late-onset, pulmonary, non-infectious adjustments for potential confounders will be complications or acute and chronic extra- based on the Fine and Gray model. thoracic GVHD, relapse) will be analysed Variations in pulmonary function testing using competing risks methods. Specifically, parameters within the 2 years (Mean FEV1 the cumulative incidences of late-onset, decline, FVC, TLC, RV, FEF25-75%) will be pulmonary, non-infectious complications and compared between randomized groups by acute and chronic extra-thoracic GVHD will generalized linear models. be estimated considering deaths prior to the The heterogeneity of the population given by event of interest as competing risk outcomes the inclusion of additional subjects and compared using the Gray test. The undergoing a second allogeneic adjustments for potential confounders will be hematopoietic stem cell transplantation will based on the Fine and Gray model. potentially increase and may lead to more Variations in pulmonary function testing imprecision in estimating of treatment effect parameters within the 2 years (Mean FEV1 evaluated in the trial. If these patients are decline, FVC, TLC, RV, FEF25-75%) will be insufficient number we will test the potential compared between randomized groups by Downloaded From: https://jamanetwork.com/ on 09/29/2021 heterogeneity of treatment effect with this generalized linear models. parameter. The heterogeneity of the population given by All tests will be two-sided, with p-values of the inclusion of additional subjects 0.05 or less denoting statistical significance. undergoing second allogeneic hematopoietic All analyses will be performed using the SAS stem cell transplantation will potentially (SAS Inc., Cary, NC) and R (http://www.R- increase and may lead to more imprecision in project.org/) software packages. estimating of treatment effect evaluated in the trial. If these patients are insufficient number we will test the potential heterogeneity of treatment effect with this parameter. All tests will be two-sided, with p-values of 0.05 or less denoting statistical significance. All analyses will be performed using the SAS (SAS Inc., Cary, NC) and R (http://www.R- project.org/) software packages. 93 94 Downloaded From: https://jamanetwork.com/ on 09/29/2021 95 96 ALLOZITHRO TRIAL AMENDMENT 7 97 APPROVED ETHICS COMMITTEE 02/24/2017 ; APPROVED REGULATORY AGENCY 02/17/2017 98 Justification de la modification Texte initial Texte modifié ou ajouté substantielle Abstract Abstract Secondary endpoints Secondary endpoints - Extension of patient follow-up following P. 8 • Overall survival at two years • Overall survival at two years and 5 years the regulatory agency request Statistics Statistics Analysis will be made on an intent-to-treat principle. Analysis will be made on an intent-to-treat principle. Final analysis will be performed after recruitment of Final analysis will be performed after recruitment of all all the scheduled patients and/or observation of the P.8 the scheduled patients and/or observation of the required 218 events, based on time-to-failure required 218 events, based on time-to-failure methods, methods, at the nominal value of 0.0415. All at the nominal value of 0.0415. analyses will be also performed on the 5-year data. 2. Synopsis 2. Synopsis …………… …………… Endpoint Endpoint ……….. ……….. P.9 Secondary : Secondary : Overall survival at two years Overall survival at two years and 5 years 6.2 Secondary endpoints 6.2 Secondary endpoints Overall survival at two years Overall survival at two years and 5 years P. 24 et • The occurrence of the following late-onset pulmonary non-infectious complications: • Occurrence of haematological relapse within 25 the 2 years and 5 years Occurrence of haematological relapse within the 2 years 8. Treatment 8 . Treatment ………. ………. P.27 8.1.3 Update of the trial The trial was interrupted prematurely on December 26, 2016 by joint decision of the DSMB, the investigator coordinator and the sponsor due to a Downloaded From: https://jamanetwork.com/ on 09/29/2021 significant imbalance in both the risk of hematological relapse and mortality between the two experimental arms being to the azithromycin group disadvantage (relapse: control 47/235, 20%; azithromycin 75/241, 31%, p=0.003). All the patients have stopped the treatment on January 12, 2017. We are currently investigating the causes of this SUSAR. 9. Evaluation 9. Evaluation ………… ………… 9.1 Timing and content of visits 9.1 Timing and content of visits ………………. ………………. Update of the trial Because we have no idea of the duration of the increased risk of relapse, we have discussed with the national drug administration (ANSM) and we decided to extend the follow-up for a total of 5 years for all patients alive except those who relapsed. Investigators will have to notify each relapse and death to the sponsor at the time they are diagnosed as well as they will have to record these events in the P.30 CRF. Each site will also be specifically contacted and questioned about these data. Due to a potential interaction between relapse and GVHD, occurrence of GVHD during the 5 years follow-up will also be recorded in the CRF. Thus, hematological relapse, death and occurrence of GVHD will also be recorded at M36, M48 and M60. PFT will be performed at the end of follow-up (5 years). All patients will be informed (see attachment); The signature of a consent to the prolongation of the follow-up within the study will be requested to them (cf. attachment). Patients who wish to do so can ask the investigator from their center where they were randomized. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Summary table of the examinations to be Mise à jour du Summary table of the Addition of annual visits at M36, M48 and performed at each visit examinations to be performed at each visit: M60 including a medical examination, Specific investigations to diagnose a relapse according to the investigator and Ajout de visites annuelles à M36, M48 et M60 an PFT (only at M60) P. 30 Comprenant un examen médical, Des investigations précises pour diagnostiquer une rechute selon l'investigateur et un EFR (seulement à M60) 9.5 Update of the study Following a decision from the PI, the DSMB and the sponsor, all the investigators were told to ask their patients to discontinue treatment on December 26, 2016 due to a relapse imbalance in the two experimental arms in disfavour of the azithromycin P.32 arm. All patients had stopped the treatment on January 12, 2017. The follow-up of the patients is still going on and extended. 10.2 Statistical tests 10.2 Statistical tests ……………. ……………. Variations in pulmonary function testing parameters Variations in pulmonary function testing parameters within the 2 years (Mean FEV1 decline, FVC, TLC, within the 2 years (Mean FEV1 decline, FVC, TLC, RV, RV, FEF25-75%) will be compared between FEF25-75%) will be compared between randomized randomized groups by generalized linear models. groups by generalized linear models. The heterogeneity of the population given by the All analyses will be also performed both at the end of inclusion of additional subjects undergoing second P.34 allogeneic hematopoietic stem cell transplantation will the trial and on the 5-year data. potentially increase and may lead to more imprecision in estimating of treatment effect evaluated in the trial. If The heterogeneity of the population given by the these patients are insufficient number we will test the inclusion of additional subjects undergoing second potential heterogeneity of treatment effect with this allogeneic hematopoietic stem cell transplantation parameter. will potentially increase and may lead to more All tests will be two-sided, with p-values of 0.05 or less imprecision in estimating of treatment effect denoting statistical significance. All analyses will be evaluated in the trial. If these patients are insufficient performed using the SAS (SAS Inc., Cary, NC) and R number we will test the potential heterogeneity of (http://www.R-project.org/) software packages. treatment effect with this parameter. All tests will be two-sided, with p-values of 0.05 or Downloaded From: https://jamanetwork.com/ on 09/29/2021 less denoting statistical significance. All analyses will be performed using the SAS (SAS Inc., Cary, NC) and R (http://www.R-project.org/) software packages. 11.2 The investigator's role 11.2 The investigator's role 11.2.1 Immediate reporting of adverse events 11.2.1 Immediate reporting of adverse to the sponsor events to the sponsor The investigator shall report all serious adverse events The investigator shall report all serious adverse immediately to the sponsor except for those that the events immediately to the sponsor except for those protocol (cf. 11.2.2) or investigator’s brochure identifies that the protocol (cf. 11.2.2) or investigator’s as not requiring immediate reporting brochure identifies as not requiring immediate - Results in death, reporting - is life-threatening, - Results in death, - requires inpatient hospitalization or prolongation of - is life-threatening, existing hospitalization, - requires inpatient hospitalization or prolongation of - Results in persistent or significant disability/incapacity, existing hospitalization, - Congenital abnormality or birth defect - Results in persistent or significant - Or any other adverse event considered “medically disability/incapacity, significant” - Congenital abnormality or birth defect - all acute heart pathology - Or any other adverse event considered “medically P.36 et significant” 37 …………………… - all acute heart pathology - Hematological relapse ………………… 11.2.2 Serious adverse events that do not require immediate reporting to the sponsor 11.2.2 Serious adverse events that do not require immediate reporting to the sponsor Serious Adverse Events (SAE) that do not require immediate reporting but must be reported in the CRF : Hospitalizations related to the known complications that Serious Adverse Events (SAE) that do not require can occur after allogeneic hematopoietic stem cell immediate reporting but must be reported in the CRF transplantation (except hospitalization in reanimation) : : - Graft versus host disease Hospitalizations related to the known complications - Intercurrent infection that can occur after allogeneic hematopoietic stem Relapse of the haematological disease cell transplantation (except hospitalization in reanimation) : Relapses are closely monitored by the sponsor. - Graft versus host disease An extraction of relapses registered in the CRF will be - Intercurrent infection realized every 3 months. A summary tabulation will be Relapse of the haematological disease forwarded to DSMB. In case of significant unbalance between the 2 arms requiring safety actions by the Relapses are closely monitored by the sponsor. sponsor, ANSM will be informed immediately by the An extraction of relapses registered in the CRF will Downloaded From: https://jamanetwork.com/ on 09/29/2021 sponsor. be realized every 3 months. A summary tabulation Serious Adverse events and hospitalization related to will be forwarded to DSMB. In case of significant treatments other than azithromycin, used for the unbalance between the 2 arms requiring safety standard care of the patient actions by the sponsor, ANSM will be informed Scheduled hospitalization immediately by the sponsor. Serious Adverse events and hospitalization related to treatments other than azithromycin, used for the standard care of the patient Scheduled hospitalization After the two first years of follow-up, an annual visit is scheduled for patients alive except those who relapsed and relapses, death and GVHD are registered in the CRF until 5 years-follow-up. 99 Downloaded From: https://jamanetwork.com/ on 09/29/2021