Once daily versus three times daily mesalazine granules in active ulcerative colitis: a double-blind, double-dummy, randomised, non-inferiority trial

W Kruis, G Kiudelis, I Rácz, I A Gorelov, J Pokrotnieks, M Horynski, M Batovsky, J Kykal, S Boehm, R Greinwald, R Mueller, International Salofalk OD Study Group, Mate Kozic, Ivo Klarin, Zvonimir Matas, Domagoj Kasun, Jadranko Turcinov, Roko Marcelic, Bohumil Fixa, Tomas Vanasek, Libor Gabalec, Vladimir Simon, Pavel Kohout, Jan Kykal, Tomas Vich, Karin Kull, Riina Salupere, Hele Remmel, Peeter Koiva, Katrin Labotkin, Wojtek Baniewicz, Susanne Bonnet, Bernd Vohmann, Wolfgang Kruis, Stephan Böhm, Thomas Zeisler, Jürgen Zeus, János Banai, Tamás Szamosi, Zsófia Czeglédi, Pál Demeter, Róbert Sike, József Penyige, Levente Bálint, Krisztina Sárdi, Ferenc Huoránszki, Zoltan Döbrönte, Lilla Lakner, Zsolt Jakab, László Lakatos, Gábor Mester, Csolnoky Ferenc, István Rácz, Andrea Szabó, Gyula Pécsi, Mihály Csöndes, Hussam Saleh, Tibor Kárász, Zsolt Tulassay, László Herszényi, Anna Mária Németh, Pál Miheller, László Ujszászy, Andor Grenda, Borbala Velösy, Zsolt Virányi, Zsolt Dubravcsik, Simon Bar-Meir, Moshe Nadler, Iris Dotan, Guy Rosner, Roman Grenshpon, Rami Eliakim, Irit Chermesh, Mark Faszczyk, Arkady Berezovsky, Genadi Katz, Dan Keret, Victoria Mindrul, Alexandra Lavy, Dean Keren, Ehud Melzer, Yuval Binder, Yaron Niv, Gerald Martin Fraser, Ebrahim Zebeede, Eyal Gal, Jelena Derova, Aleksejs Derovs, Juris Pokrotnieks, Aldis Pukitis, Mairita Ergle, Gitana Acute, Violeta Vainoriute, Vytautas Metrikis, Algimantas Cepulis, Kestutis Adamonis, Arlandas Modzeliauskas, Audrone Buineviciute, Narimantas Samalavicius, Gintautas Radziunas, Gediminas Kiudelis, Limas Kupcinskas, Laimas Jonaitis, Giedrius Simulionis, Saulius Petrauskas, Valdas Kuolas, Raimonda Vanagaitiene, Antanas Jablonskis, Ausra Navikiene, Marek Horynski, Dariusz Kleczkowski, Adam Kopon, Ewa Kopon, Krzysztof Marlicz, Halina Jaroszewicz-Heigelmann, Izabela Binkowska, Michal Wasilewicz, Aleksander Sieron, Wojciech Latos, Witold Zieleznik, Karolina Sieron-Stoltny, Leszek Szczepanski, Robert Zwolak, Dariusz Chudzik, Mariusz Piotrowski, Marcin Mazurek, Antoni Wysokinski, Romuald Grodzienski, Wojciech Kosikowski, Jaroslaw Drabko, Agnieszka Forys, Igor G Bakulin, Vladislav G Novozhenov, Marina A Ivanova, Vladimir M Ruseikin, Kerimulah D Malabaev, Elena A Belousova, Tamara S Mishurovskaya, Inna V Nikulina, Aleksander I Gorelov, Elena A Sishkova, Dmitry V Raspereza, Tatiana V Tinyakova, Vladimir B Grinevich, Irina V Gubonina, Anatoly M Pershko, Tatyana L Mikhailova, Oleg V Golovenko, Ludmila A Mayat, Pavel A Makarchuk, Natalya S Malakhova, Emilia P Yakovenko, Andrey V Yakovenko, Natalya A Agafonova, Antonina S Pryanishnikova, Aleksandr N Ivanov, Konstantin P Zhidkov, Oleg N Bulavin, Fuza D Albegova, Maria V Vasilukova, Boris Barický, Marian Bátovský, Bozena Pekárková, Boris Pekarek, Milan Stefanovic, Zdravko Tosovic, Ljiljana Ljepovic, Andrey Dorofeyev, Kira Lynevskaya, Olga Rassokhina, Yurii Silvestrovich Lozynsky, Maria Lozynska, Stanislav Golovchansky, Mikhail Petrovich Zakharash, Yurii Zakharash, Tetyana Kravchenko, W Kruis, G Kiudelis, I Rácz, I A Gorelov, J Pokrotnieks, M Horynski, M Batovsky, J Kykal, S Boehm, R Greinwald, R Mueller, International Salofalk OD Study Group, Mate Kozic, Ivo Klarin, Zvonimir Matas, Domagoj Kasun, Jadranko Turcinov, Roko Marcelic, Bohumil Fixa, Tomas Vanasek, Libor Gabalec, Vladimir Simon, Pavel Kohout, Jan Kykal, Tomas Vich, Karin Kull, Riina Salupere, Hele Remmel, Peeter Koiva, Katrin Labotkin, Wojtek Baniewicz, Susanne Bonnet, Bernd Vohmann, Wolfgang Kruis, Stephan Böhm, Thomas Zeisler, Jürgen Zeus, János Banai, Tamás Szamosi, Zsófia Czeglédi, Pál Demeter, Róbert Sike, József Penyige, Levente Bálint, Krisztina Sárdi, Ferenc Huoránszki, Zoltan Döbrönte, Lilla Lakner, Zsolt Jakab, László Lakatos, Gábor Mester, Csolnoky Ferenc, István Rácz, Andrea Szabó, Gyula Pécsi, Mihály Csöndes, Hussam Saleh, Tibor Kárász, Zsolt Tulassay, László Herszényi, Anna Mária Németh, Pál Miheller, László Ujszászy, Andor Grenda, Borbala Velösy, Zsolt Virányi, Zsolt Dubravcsik, Simon Bar-Meir, Moshe Nadler, Iris Dotan, Guy Rosner, Roman Grenshpon, Rami Eliakim, Irit Chermesh, Mark Faszczyk, Arkady Berezovsky, Genadi Katz, Dan Keret, Victoria Mindrul, Alexandra Lavy, Dean Keren, Ehud Melzer, Yuval Binder, Yaron Niv, Gerald Martin Fraser, Ebrahim Zebeede, Eyal Gal, Jelena Derova, Aleksejs Derovs, Juris Pokrotnieks, Aldis Pukitis, Mairita Ergle, Gitana Acute, Violeta Vainoriute, Vytautas Metrikis, Algimantas Cepulis, Kestutis Adamonis, Arlandas Modzeliauskas, Audrone Buineviciute, Narimantas Samalavicius, Gintautas Radziunas, Gediminas Kiudelis, Limas Kupcinskas, Laimas Jonaitis, Giedrius Simulionis, Saulius Petrauskas, Valdas Kuolas, Raimonda Vanagaitiene, Antanas Jablonskis, Ausra Navikiene, Marek Horynski, Dariusz Kleczkowski, Adam Kopon, Ewa Kopon, Krzysztof Marlicz, Halina Jaroszewicz-Heigelmann, Izabela Binkowska, Michal Wasilewicz, Aleksander Sieron, Wojciech Latos, Witold Zieleznik, Karolina Sieron-Stoltny, Leszek Szczepanski, Robert Zwolak, Dariusz Chudzik, Mariusz Piotrowski, Marcin Mazurek, Antoni Wysokinski, Romuald Grodzienski, Wojciech Kosikowski, Jaroslaw Drabko, Agnieszka Forys, Igor G Bakulin, Vladislav G Novozhenov, Marina A Ivanova, Vladimir M Ruseikin, Kerimulah D Malabaev, Elena A Belousova, Tamara S Mishurovskaya, Inna V Nikulina, Aleksander I Gorelov, Elena A Sishkova, Dmitry V Raspereza, Tatiana V Tinyakova, Vladimir B Grinevich, Irina V Gubonina, Anatoly M Pershko, Tatyana L Mikhailova, Oleg V Golovenko, Ludmila A Mayat, Pavel A Makarchuk, Natalya S Malakhova, Emilia P Yakovenko, Andrey V Yakovenko, Natalya A Agafonova, Antonina S Pryanishnikova, Aleksandr N Ivanov, Konstantin P Zhidkov, Oleg N Bulavin, Fuza D Albegova, Maria V Vasilukova, Boris Barický, Marian Bátovský, Bozena Pekárková, Boris Pekarek, Milan Stefanovic, Zdravko Tosovic, Ljiljana Ljepovic, Andrey Dorofeyev, Kira Lynevskaya, Olga Rassokhina, Yurii Silvestrovich Lozynsky, Maria Lozynska, Stanislav Golovchansky, Mikhail Petrovich Zakharash, Yurii Zakharash, Tetyana Kravchenko

Abstract

Objectives: To determine the therapeutic equivalence and safety of once daily (OD) versus three times daily (TID) dosing of a total daily dose of 3 g Salofalk (mesalazine) granules in patients with active ulcerative colitis.

Design: A randomised, double-blind, double-dummy, parallel group, multicentre, international, phase III non-inferiority study.

Setting: 54 centres in 13 countries.

Patients: 380 patients with confirmed diagnosis of established or first attack of ulcerative colitis (clinical activity index (CAI)>4 and endoscopic index > or =4 at baseline) were randomised and treated.

Interventions: 8-week treatment with either 3 g OD or 1 g TID mesalazine granules.

Main outcome measures: Clinical remission (CAI< or =4) at study end.

Results: 380 patients were evaluable for efficacy and safety by intention-to-treat (ITT); 345 for per protocol (PP) analysis. In the ITT population, 79.1% in the OD group (n = 191) and 75.7% in the TID group (n = 189) achieved clinical remission (p<0.0001 for non-inferiority). Significantly more patients with proctosigmoiditis achieved clinical remission in the OD group (86%; n = 97) versus the TID group (73%; n = 100; p = 0.0298). About 70% of patients in both treatment groups achieved endoscopic remission, and 35% in the OD group and 41% in the TID group achieved histological remission. About 80% of all patients preferred OD dosing. Similar numbers of adverse events occurred in 55 patients (28.8%) in the OD group and in 61 patients (32.3%) in the TID group, indicating that the two dosing regimens were equally safe and well tolerated.

Conclusions: OD 3 g mesalazine granules are as effective and safe as a TID 1 g schedule. With respect to the best possible adherence of patients to the treatment, OD dosing of mesalazine should be the preferred application mode in active ulcerative colitis.

Trial registration: ClinicalTrials.gov NCT00449722.

Conflict of interest statement

Competing interests: WK has served as a speaker and consultant for Dr Falk Pharma, Freiburg, Germany. RG and RM are employees of Dr Falk Pharma, Freiburg, Germany. All other authors have declared that they have no competing interests.

Figures

Figure 1. Patient disposition. One patient was…
Figure 1. Patient disposition. One patient was excluded from the intention-to-treat population because he did not receive study medication. Patients were excluded from the per-protocol population because of protocol deviations. AEs, adverse events; ITT, intention-to-treat; OD, once daily; PP, per protocol; SAE, serious adverse event; TID, three times daily.
Figure 2. Clinical remission rates (CAI⩽4) at…
Figure 2. Clinical remission rates (CAI⩽4) at week 8 (LOCF). χ2 test (one-sided) for proving non-inferiority of OD vs TID treatment, with a pre-defined non-inferiority margin of −15% for the difference of the remission rates between treatments. CAI, clinical activity index; CI, confidence interval; ITT, intention-to-treat; LOCF, last observation carried forward; OD, once daily; PP, per protocol; TID, three times daily.
Figure 3. Course of the mean clinical…
Figure 3. Course of the mean clinical activity index during the study (ITT). CAI, clinical activity index; ITT, intention-to-treat; LOCF, last observation carried forward; OD, once daily; SD, standard deviation; TID, three times daily.

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