Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves' orbitopathy (MINGO): a randomised, observer-masked, multicentre trial

European Group on Graves' Orbitopathy (EUGOGO)

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Background: European guidelines recommend intravenous methylprednisolone as first-line treatment for active and severe Graves' orbitopathy; however, it is common for patients to have no response or have relapse after discontinuation of treatment. We aimed to compare the efficacy and safety of add-on mycophenolate to methylprednisolone in comparison with methylprednisolone alone in patients with moderate-to-severe Graves' orbitopathy. Methods: MINGO was an observer-masked, multicentre, block-randomised, centre-stratified trial done in two centres in Germany and two in Italy. Patients with active moderate-to-severe Graves' orbitopathy were randomly assigned to receive intravenous methylprednisolone (500 mg once per week for 6 weeks followed by 250 mg per week for 6 weeks) either alone or with mycophenolate (one 360 mg tablet twice per day for 24 weeks). The prespecified primary endpoints were rate of response (reduction of at least two parameters of a composite ophthalmic index [eyelid swelling, clinical activity score, proptosis, lid width, diplopia, and eye muscle motility] without deterioration in any other parameter) at 12 weeks and rate of relapse (a worsening of symptoms that occurred after a response) at 24 and 36 weeks. Rates of response at week 24 and sustained response at week 36 were added as post-hoc outcomes. Prespecified primary outcomes and post-hoc outcomes were assessed in the modified intention-to-treat population (defined as all patients assigned to treatment who received at least one infusion of methylprednisolone, when outcome data were available), and safety was assessed in all patients who received at least one dose of study drug. This trial is registered with the EU Clinical Trials Register, EUDRACT number 2008-002123-93. Findings: 164 patients were enrolled and randomised between Nov 29, 2009, and July 31, 2015. 81 were randomly assigned to receive methylprednisolone alone and 83 to receive methylprednisolone with mycophenolate. In the intention-to-treat population at 12 weeks, responses were observed in 36 (49%) of 73 patients in the monotherapy group and 48 (63%) of 76 patients in the combination group, giving an odds ratio (OR) of 1·76 (95% CI 0·92–3·39, p=0·089). At week 24, 38 (53%) of 72 patients remaining in the monotherapy group and 53 (71%) of 75 patients remaining in the combination therapy group had responded to treatment (2·16, 1·09–4·25, p=0·026). At week 24, relapse occurred in four (11%) of 38 patients in the monotherapy group and four (8%) of 53 patients in the combination group (OR 0·71, 0·17–3·03, p=0·72). At week 36, relapse occurred in an additional three (8%) patients in the monotherapy group and two (4%) patients in the combination group (0·65, 0·12–3·44, p=0·61). At week 36, 31 (46%) of 68 patients in the monotherapy group and 49 (67%) of 73 patients in the combination group had a sustained response (OR 2·44, 1·23–4·82, p=0·011). 23 patients had 24 serious adverse events, with 11 events in ten patients in the combination group and 13 events in 13 patients in the monotherapy group. Mild and moderate (grade 1–2) drug-related adverse events occurred in 16 (20%) of 81 patients receiving monotherapy and 21 (25%) of 83 patients receiving combination therapy (p=0·48). Interpretation: Although no significant difference was seen in the rate of response at 12 weeks or rate of relapse at 24 and 36 weeks, post-hoc analysis suggested that addition of mycophenolate to treatment with methylprednisolone improved rate of response to therapy by 24 weeks in patients with active and moderate-to-severe Graves' orbitopathy. Funding: Novartis, Germany.

Original languageEnglish
Pages (from-to)287-298
Number of pages12
JournalThe Lancet Diabetes and Endocrinology
Volume6
Issue number4
DOIs
Publication statusPublished - Apr 1 2018

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Methylprednisolone
Multicenter Studies
Recurrence
Odds Ratio
Therapeutics
Germany
Safety

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves' orbitopathy (MINGO) : a randomised, observer-masked, multicentre trial. / European Group on Graves' Orbitopathy (EUGOGO).

In: The Lancet Diabetes and Endocrinology, Vol. 6, No. 4, 01.04.2018, p. 287-298.

Research output: Contribution to journalArticle

@article{9b7ea569963f47c4825db27dc2ab283a,
title = "Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves' orbitopathy (MINGO): a randomised, observer-masked, multicentre trial",
abstract = "Background: European guidelines recommend intravenous methylprednisolone as first-line treatment for active and severe Graves' orbitopathy; however, it is common for patients to have no response or have relapse after discontinuation of treatment. We aimed to compare the efficacy and safety of add-on mycophenolate to methylprednisolone in comparison with methylprednisolone alone in patients with moderate-to-severe Graves' orbitopathy. Methods: MINGO was an observer-masked, multicentre, block-randomised, centre-stratified trial done in two centres in Germany and two in Italy. Patients with active moderate-to-severe Graves' orbitopathy were randomly assigned to receive intravenous methylprednisolone (500 mg once per week for 6 weeks followed by 250 mg per week for 6 weeks) either alone or with mycophenolate (one 360 mg tablet twice per day for 24 weeks). The prespecified primary endpoints were rate of response (reduction of at least two parameters of a composite ophthalmic index [eyelid swelling, clinical activity score, proptosis, lid width, diplopia, and eye muscle motility] without deterioration in any other parameter) at 12 weeks and rate of relapse (a worsening of symptoms that occurred after a response) at 24 and 36 weeks. Rates of response at week 24 and sustained response at week 36 were added as post-hoc outcomes. Prespecified primary outcomes and post-hoc outcomes were assessed in the modified intention-to-treat population (defined as all patients assigned to treatment who received at least one infusion of methylprednisolone, when outcome data were available), and safety was assessed in all patients who received at least one dose of study drug. This trial is registered with the EU Clinical Trials Register, EUDRACT number 2008-002123-93. Findings: 164 patients were enrolled and randomised between Nov 29, 2009, and July 31, 2015. 81 were randomly assigned to receive methylprednisolone alone and 83 to receive methylprednisolone with mycophenolate. In the intention-to-treat population at 12 weeks, responses were observed in 36 (49{\%}) of 73 patients in the monotherapy group and 48 (63{\%}) of 76 patients in the combination group, giving an odds ratio (OR) of 1·76 (95{\%} CI 0·92–3·39, p=0·089). At week 24, 38 (53{\%}) of 72 patients remaining in the monotherapy group and 53 (71{\%}) of 75 patients remaining in the combination therapy group had responded to treatment (2·16, 1·09–4·25, p=0·026). At week 24, relapse occurred in four (11{\%}) of 38 patients in the monotherapy group and four (8{\%}) of 53 patients in the combination group (OR 0·71, 0·17–3·03, p=0·72). At week 36, relapse occurred in an additional three (8{\%}) patients in the monotherapy group and two (4{\%}) patients in the combination group (0·65, 0·12–3·44, p=0·61). At week 36, 31 (46{\%}) of 68 patients in the monotherapy group and 49 (67{\%}) of 73 patients in the combination group had a sustained response (OR 2·44, 1·23–4·82, p=0·011). 23 patients had 24 serious adverse events, with 11 events in ten patients in the combination group and 13 events in 13 patients in the monotherapy group. Mild and moderate (grade 1–2) drug-related adverse events occurred in 16 (20{\%}) of 81 patients receiving monotherapy and 21 (25{\%}) of 83 patients receiving combination therapy (p=0·48). Interpretation: Although no significant difference was seen in the rate of response at 12 weeks or rate of relapse at 24 and 36 weeks, post-hoc analysis suggested that addition of mycophenolate to treatment with methylprednisolone improved rate of response to therapy by 24 weeks in patients with active and moderate-to-severe Graves' orbitopathy. Funding: Novartis, Germany.",
author = "{European Group on Graves' Orbitopathy (EUGOGO)} and Kahaly, {George J.} and Michaela Riedl and Jochem K{\"o}nig and Susanne Pitz and Katharina Ponto and Tanja Diana and Elena Kampmann and Elisa Kolbe and Anja Eckstein and Moeller, {Lars C.} and Dagmar F{\"u}hrer and Mario Salvi and Nicola Curro and Irene Campi and Danila Covelli and Marenza Leo and Michele Marin{\`o} and Francesca Menconi and Claudio Marcocci and Luigi Bartalena and Petros Perros and Wiersinga, {Wilmar M.} and G{\"o}ksun Ayvaz and Lelio Baldeschi and Kostas Boborides and Antonella Boschi and Brix, {Thomas H.} and Lucy Clarke and Colin Dayan and Chantal Daumerie and Dickinson, {A. Jane} and Nicole Fichter and Laszlo Heged{\"u}s and Onur Konuk and Krassas, {Gerassimos E.} and Carol Lane and John Lazarus and Morris, {Dan S.} and Maarten Mourits and Marco Nardi and Chris Neoh and Jacques Orgiazzi and Pearce, {Simon H.S.} and {von Arx}, Georg and Milos Zarkovic",
year = "2018",
month = "4",
day = "1",
doi = "10.1016/S2213-8587(18)30020-2",
language = "English",
volume = "6",
pages = "287--298",
journal = "The Lancet Diabetes and Endocrinology",
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TY - JOUR

T1 - Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves' orbitopathy (MINGO)

T2 - a randomised, observer-masked, multicentre trial

AU - European Group on Graves' Orbitopathy (EUGOGO)

AU - Kahaly, George J.

AU - Riedl, Michaela

AU - König, Jochem

AU - Pitz, Susanne

AU - Ponto, Katharina

AU - Diana, Tanja

AU - Kampmann, Elena

AU - Kolbe, Elisa

AU - Eckstein, Anja

AU - Moeller, Lars C.

AU - Führer, Dagmar

AU - Salvi, Mario

AU - Curro, Nicola

AU - Campi, Irene

AU - Covelli, Danila

AU - Leo, Marenza

AU - Marinò, Michele

AU - Menconi, Francesca

AU - Marcocci, Claudio

AU - Bartalena, Luigi

AU - Perros, Petros

AU - Wiersinga, Wilmar M.

AU - Ayvaz, Göksun

AU - Baldeschi, Lelio

AU - Boborides, Kostas

AU - Boschi, Antonella

AU - Brix, Thomas H.

AU - Clarke, Lucy

AU - Dayan, Colin

AU - Daumerie, Chantal

AU - Dickinson, A. Jane

AU - Fichter, Nicole

AU - Hegedüs, Laszlo

AU - Konuk, Onur

AU - Krassas, Gerassimos E.

AU - Lane, Carol

AU - Lazarus, John

AU - Morris, Dan S.

AU - Mourits, Maarten

AU - Nardi, Marco

AU - Neoh, Chris

AU - Orgiazzi, Jacques

AU - Pearce, Simon H.S.

AU - von Arx, Georg

AU - Zarkovic, Milos

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Background: European guidelines recommend intravenous methylprednisolone as first-line treatment for active and severe Graves' orbitopathy; however, it is common for patients to have no response or have relapse after discontinuation of treatment. We aimed to compare the efficacy and safety of add-on mycophenolate to methylprednisolone in comparison with methylprednisolone alone in patients with moderate-to-severe Graves' orbitopathy. Methods: MINGO was an observer-masked, multicentre, block-randomised, centre-stratified trial done in two centres in Germany and two in Italy. Patients with active moderate-to-severe Graves' orbitopathy were randomly assigned to receive intravenous methylprednisolone (500 mg once per week for 6 weeks followed by 250 mg per week for 6 weeks) either alone or with mycophenolate (one 360 mg tablet twice per day for 24 weeks). The prespecified primary endpoints were rate of response (reduction of at least two parameters of a composite ophthalmic index [eyelid swelling, clinical activity score, proptosis, lid width, diplopia, and eye muscle motility] without deterioration in any other parameter) at 12 weeks and rate of relapse (a worsening of symptoms that occurred after a response) at 24 and 36 weeks. Rates of response at week 24 and sustained response at week 36 were added as post-hoc outcomes. Prespecified primary outcomes and post-hoc outcomes were assessed in the modified intention-to-treat population (defined as all patients assigned to treatment who received at least one infusion of methylprednisolone, when outcome data were available), and safety was assessed in all patients who received at least one dose of study drug. This trial is registered with the EU Clinical Trials Register, EUDRACT number 2008-002123-93. Findings: 164 patients were enrolled and randomised between Nov 29, 2009, and July 31, 2015. 81 were randomly assigned to receive methylprednisolone alone and 83 to receive methylprednisolone with mycophenolate. In the intention-to-treat population at 12 weeks, responses were observed in 36 (49%) of 73 patients in the monotherapy group and 48 (63%) of 76 patients in the combination group, giving an odds ratio (OR) of 1·76 (95% CI 0·92–3·39, p=0·089). At week 24, 38 (53%) of 72 patients remaining in the monotherapy group and 53 (71%) of 75 patients remaining in the combination therapy group had responded to treatment (2·16, 1·09–4·25, p=0·026). At week 24, relapse occurred in four (11%) of 38 patients in the monotherapy group and four (8%) of 53 patients in the combination group (OR 0·71, 0·17–3·03, p=0·72). At week 36, relapse occurred in an additional three (8%) patients in the monotherapy group and two (4%) patients in the combination group (0·65, 0·12–3·44, p=0·61). At week 36, 31 (46%) of 68 patients in the monotherapy group and 49 (67%) of 73 patients in the combination group had a sustained response (OR 2·44, 1·23–4·82, p=0·011). 23 patients had 24 serious adverse events, with 11 events in ten patients in the combination group and 13 events in 13 patients in the monotherapy group. Mild and moderate (grade 1–2) drug-related adverse events occurred in 16 (20%) of 81 patients receiving monotherapy and 21 (25%) of 83 patients receiving combination therapy (p=0·48). Interpretation: Although no significant difference was seen in the rate of response at 12 weeks or rate of relapse at 24 and 36 weeks, post-hoc analysis suggested that addition of mycophenolate to treatment with methylprednisolone improved rate of response to therapy by 24 weeks in patients with active and moderate-to-severe Graves' orbitopathy. Funding: Novartis, Germany.

AB - Background: European guidelines recommend intravenous methylprednisolone as first-line treatment for active and severe Graves' orbitopathy; however, it is common for patients to have no response or have relapse after discontinuation of treatment. We aimed to compare the efficacy and safety of add-on mycophenolate to methylprednisolone in comparison with methylprednisolone alone in patients with moderate-to-severe Graves' orbitopathy. Methods: MINGO was an observer-masked, multicentre, block-randomised, centre-stratified trial done in two centres in Germany and two in Italy. Patients with active moderate-to-severe Graves' orbitopathy were randomly assigned to receive intravenous methylprednisolone (500 mg once per week for 6 weeks followed by 250 mg per week for 6 weeks) either alone or with mycophenolate (one 360 mg tablet twice per day for 24 weeks). The prespecified primary endpoints were rate of response (reduction of at least two parameters of a composite ophthalmic index [eyelid swelling, clinical activity score, proptosis, lid width, diplopia, and eye muscle motility] without deterioration in any other parameter) at 12 weeks and rate of relapse (a worsening of symptoms that occurred after a response) at 24 and 36 weeks. Rates of response at week 24 and sustained response at week 36 were added as post-hoc outcomes. Prespecified primary outcomes and post-hoc outcomes were assessed in the modified intention-to-treat population (defined as all patients assigned to treatment who received at least one infusion of methylprednisolone, when outcome data were available), and safety was assessed in all patients who received at least one dose of study drug. This trial is registered with the EU Clinical Trials Register, EUDRACT number 2008-002123-93. Findings: 164 patients were enrolled and randomised between Nov 29, 2009, and July 31, 2015. 81 were randomly assigned to receive methylprednisolone alone and 83 to receive methylprednisolone with mycophenolate. In the intention-to-treat population at 12 weeks, responses were observed in 36 (49%) of 73 patients in the monotherapy group and 48 (63%) of 76 patients in the combination group, giving an odds ratio (OR) of 1·76 (95% CI 0·92–3·39, p=0·089). At week 24, 38 (53%) of 72 patients remaining in the monotherapy group and 53 (71%) of 75 patients remaining in the combination therapy group had responded to treatment (2·16, 1·09–4·25, p=0·026). At week 24, relapse occurred in four (11%) of 38 patients in the monotherapy group and four (8%) of 53 patients in the combination group (OR 0·71, 0·17–3·03, p=0·72). At week 36, relapse occurred in an additional three (8%) patients in the monotherapy group and two (4%) patients in the combination group (0·65, 0·12–3·44, p=0·61). At week 36, 31 (46%) of 68 patients in the monotherapy group and 49 (67%) of 73 patients in the combination group had a sustained response (OR 2·44, 1·23–4·82, p=0·011). 23 patients had 24 serious adverse events, with 11 events in ten patients in the combination group and 13 events in 13 patients in the monotherapy group. Mild and moderate (grade 1–2) drug-related adverse events occurred in 16 (20%) of 81 patients receiving monotherapy and 21 (25%) of 83 patients receiving combination therapy (p=0·48). Interpretation: Although no significant difference was seen in the rate of response at 12 weeks or rate of relapse at 24 and 36 weeks, post-hoc analysis suggested that addition of mycophenolate to treatment with methylprednisolone improved rate of response to therapy by 24 weeks in patients with active and moderate-to-severe Graves' orbitopathy. Funding: Novartis, Germany.

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JF - The Lancet Diabetes and Endocrinology

SN - 2213-8587

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