Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC)

a multicentre, double-blind, randomised controlled trial

Craig Mowat, Ian Arnott, Aiden Cahill, Malcolm Smith, Tariq Ahmad, Sreedhar Subramanian, Simon Travis, John Morris, John Hamlin, Anjan Dhar, Chuka Nwokolo, Cathryn Edwards, Tom Creed, Stuart Bloom, Mohamed Yousif, Linzi Thomas, Simon Campbell, Stephen J. Lewis, Shaji Sebastian, Sandip Sen & 23 others Simon Lal, Chris Hawkey, Charles Murray, Fraser Cummings, Jason Goh, James O. Lindsay, Naila Arebi, Lindsay Potts, Aileen J. McKinley, John M. Thomson, John A. Todd, Mhairi Collie, Malcolm G. Dunlop, Ashley Mowat, Daniel R. Gaya, Jack Winter, Graham D. Naismith, Holly Ennis, Catriona Keerie, Steff Lewis, Robin J. Prescott, Nicholas A. Kennedy, Jack Satsangi

    Research output: Contribution to journalArticle

    24 Citations (Scopus)
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    Abstract

    Background: Up to 60% of patients with Crohn's disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease.

    Methods: We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohn's disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohn's disease (Crohn's Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15).

    Findings: Between June 6, 2008, and April 23, 2012, 240 patients with Crohn's disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13%) of patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohn's disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27–1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28–0·99; p=0·046). In a subgroup analysis, three (10%) of 29 smokers in the mercaptopurine group and 12 (46%) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95% CI 0·04–0·46), compared with 13 (13%) of 99 non-smokers in the mercaptopurine group and 14 (16%) of 86 in the placebo group (0·90, 0·42–1·94; pinteraction=0·018). The effect of mercaptopurine did not significantly differ from placebo for any of the other planned subgroup analyses (previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis). The incidence and types of adverse events were similar in the mercaptopurine and placebo groups. One patient on placebo died of ischaemic heart disease. Adverse events caused discontinuation of treatment in 39 (30%) of 128 patients in the mercaptopurine group versus 41 (37%) of 112 in the placebo group.

    Interpretation: Mercaptopurine is effective in preventing postoperative clinical recurrence of Crohn's disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence.

    Original languageEnglish
    Pages (from-to)273-282
    Number of pages10
    JournalLancet Gastroenterology and Hepatology
    Volume1
    Issue number4
    Early online date30 Aug 2016
    DOIs
    Publication statusPublished - Dec 2016

    Fingerprint

    6-Mercaptopurine
    Crohn Disease
    Randomized Controlled Trials
    Placebos
    Recurrence
    thiopurine methyltransferase
    Methotrexate
    Anti-Inflammatory Agents
    Therapeutics
    Smoking
    Intention to Treat Analysis
    Wales
    Scotland
    Smoking Cessation
    Random Allocation
    Postoperative Period
    Tertiary Care Centers
    England
    Caregivers
    Myocardial Ischemia

    Cite this

    Mowat, Craig ; Arnott, Ian ; Cahill, Aiden ; Smith, Malcolm ; Ahmad, Tariq ; Subramanian, Sreedhar ; Travis, Simon ; Morris, John ; Hamlin, John ; Dhar, Anjan ; Nwokolo, Chuka ; Edwards, Cathryn ; Creed, Tom ; Bloom, Stuart ; Yousif, Mohamed ; Thomas, Linzi ; Campbell, Simon ; Lewis, Stephen J. ; Sebastian, Shaji ; Sen, Sandip ; Lal, Simon ; Hawkey, Chris ; Murray, Charles ; Cummings, Fraser ; Goh, Jason ; Lindsay, James O. ; Arebi, Naila ; Potts, Lindsay ; McKinley, Aileen J. ; Thomson, John M. ; Todd, John A. ; Collie, Mhairi ; Dunlop, Malcolm G. ; Mowat, Ashley ; Gaya, Daniel R. ; Winter, Jack ; Naismith, Graham D. ; Ennis, Holly ; Keerie, Catriona ; Lewis, Steff ; Prescott, Robin J. ; Kennedy, Nicholas A. ; Satsangi, Jack. / Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC) : a multicentre, double-blind, randomised controlled trial. In: Lancet Gastroenterology and Hepatology. 2016 ; Vol. 1, No. 4. pp. 273-282.
    @article{525909706f914f7b9e230affc987bbe7,
    title = "Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial",
    abstract = "Background: Up to 60{\%} of patients with Crohn's disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease.Methods: We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohn's disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohn's disease (Crohn's Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15).Findings: Between June 6, 2008, and April 23, 2012, 240 patients with Crohn's disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13{\%}) of patients in the mercaptopurine group versus 26 (23{\%}) patients in the placebo group had a clinical recurrence of Crohn's disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95{\%} CI 0·27–1·06; p=0·07; unadjusted HR 0·53, 95{\%} CI 0·28–0·99; p=0·046). In a subgroup analysis, three (10{\%}) of 29 smokers in the mercaptopurine group and 12 (46{\%}) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95{\%} CI 0·04–0·46), compared with 13 (13{\%}) of 99 non-smokers in the mercaptopurine group and 14 (16{\%}) of 86 in the placebo group (0·90, 0·42–1·94; pinteraction=0·018). The effect of mercaptopurine did not significantly differ from placebo for any of the other planned subgroup analyses (previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis). The incidence and types of adverse events were similar in the mercaptopurine and placebo groups. One patient on placebo died of ischaemic heart disease. Adverse events caused discontinuation of treatment in 39 (30{\%}) of 128 patients in the mercaptopurine group versus 41 (37{\%}) of 112 in the placebo group.Interpretation: Mercaptopurine is effective in preventing postoperative clinical recurrence of Crohn's disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence.",
    author = "Craig Mowat and Ian Arnott and Aiden Cahill and Malcolm Smith and Tariq Ahmad and Sreedhar Subramanian and Simon Travis and John Morris and John Hamlin and Anjan Dhar and Chuka Nwokolo and Cathryn Edwards and Tom Creed and Stuart Bloom and Mohamed Yousif and Linzi Thomas and Simon Campbell and Lewis, {Stephen J.} and Shaji Sebastian and Sandip Sen and Simon Lal and Chris Hawkey and Charles Murray and Fraser Cummings and Jason Goh and Lindsay, {James O.} and Naila Arebi and Lindsay Potts and McKinley, {Aileen J.} and Thomson, {John M.} and Todd, {John A.} and Mhairi Collie and Dunlop, {Malcolm G.} and Ashley Mowat and Gaya, {Daniel R.} and Jack Winter and Naismith, {Graham D.} and Holly Ennis and Catriona Keerie and Steff Lewis and Prescott, {Robin J.} and Kennedy, {Nicholas A.} and Jack Satsangi",
    note = "Funding: Medical Research Council, National Institute of Health Research's Efficacy and Mechanism Evaluation Programme, Scottish Government Chief Scientist Office, and the National Institute of Health Research National Portfolio",
    year = "2016",
    month = "12",
    doi = "10.1016/S2468-1253(16)30078-4",
    language = "English",
    volume = "1",
    pages = "273--282",
    journal = "Lancet Gastroenterology and Hepatology",
    issn = "2468-1253",
    publisher = "Elsevier",
    number = "4",

    }

    Mowat, C, Arnott, I, Cahill, A, Smith, M, Ahmad, T, Subramanian, S, Travis, S, Morris, J, Hamlin, J, Dhar, A, Nwokolo, C, Edwards, C, Creed, T, Bloom, S, Yousif, M, Thomas, L, Campbell, S, Lewis, SJ, Sebastian, S, Sen, S, Lal, S, Hawkey, C, Murray, C, Cummings, F, Goh, J, Lindsay, JO, Arebi, N, Potts, L, McKinley, AJ, Thomson, JM, Todd, JA, Collie, M, Dunlop, MG, Mowat, A, Gaya, DR, Winter, J, Naismith, GD, Ennis, H, Keerie, C, Lewis, S, Prescott, RJ, Kennedy, NA & Satsangi, J 2016, 'Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial', Lancet Gastroenterology and Hepatology, vol. 1, no. 4, pp. 273-282. https://doi.org/10.1016/S2468-1253(16)30078-4

    Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC) : a multicentre, double-blind, randomised controlled trial. / Mowat, Craig; Arnott, Ian; Cahill, Aiden; Smith, Malcolm; Ahmad, Tariq; Subramanian, Sreedhar; Travis, Simon; Morris, John; Hamlin, John; Dhar, Anjan; Nwokolo, Chuka; Edwards, Cathryn; Creed, Tom; Bloom, Stuart; Yousif, Mohamed; Thomas, Linzi; Campbell, Simon; Lewis, Stephen J.; Sebastian, Shaji; Sen, Sandip; Lal, Simon; Hawkey, Chris; Murray, Charles; Cummings, Fraser; Goh, Jason; Lindsay, James O.; Arebi, Naila; Potts, Lindsay; McKinley, Aileen J.; Thomson, John M.; Todd, John A.; Collie, Mhairi; Dunlop, Malcolm G.; Mowat, Ashley; Gaya, Daniel R.; Winter, Jack; Naismith, Graham D.; Ennis, Holly; Keerie, Catriona; Lewis, Steff; Prescott, Robin J.; Kennedy, Nicholas A.; Satsangi, Jack.

    In: Lancet Gastroenterology and Hepatology, Vol. 1, No. 4, 12.2016, p. 273-282.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC)

    T2 - a multicentre, double-blind, randomised controlled trial

    AU - Mowat, Craig

    AU - Arnott, Ian

    AU - Cahill, Aiden

    AU - Smith, Malcolm

    AU - Ahmad, Tariq

    AU - Subramanian, Sreedhar

    AU - Travis, Simon

    AU - Morris, John

    AU - Hamlin, John

    AU - Dhar, Anjan

    AU - Nwokolo, Chuka

    AU - Edwards, Cathryn

    AU - Creed, Tom

    AU - Bloom, Stuart

    AU - Yousif, Mohamed

    AU - Thomas, Linzi

    AU - Campbell, Simon

    AU - Lewis, Stephen J.

    AU - Sebastian, Shaji

    AU - Sen, Sandip

    AU - Lal, Simon

    AU - Hawkey, Chris

    AU - Murray, Charles

    AU - Cummings, Fraser

    AU - Goh, Jason

    AU - Lindsay, James O.

    AU - Arebi, Naila

    AU - Potts, Lindsay

    AU - McKinley, Aileen J.

    AU - Thomson, John M.

    AU - Todd, John A.

    AU - Collie, Mhairi

    AU - Dunlop, Malcolm G.

    AU - Mowat, Ashley

    AU - Gaya, Daniel R.

    AU - Winter, Jack

    AU - Naismith, Graham D.

    AU - Ennis, Holly

    AU - Keerie, Catriona

    AU - Lewis, Steff

    AU - Prescott, Robin J.

    AU - Kennedy, Nicholas A.

    AU - Satsangi, Jack

    N1 - Funding: Medical Research Council, National Institute of Health Research's Efficacy and Mechanism Evaluation Programme, Scottish Government Chief Scientist Office, and the National Institute of Health Research National Portfolio

    PY - 2016/12

    Y1 - 2016/12

    N2 - Background: Up to 60% of patients with Crohn's disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease.Methods: We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohn's disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohn's disease (Crohn's Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15).Findings: Between June 6, 2008, and April 23, 2012, 240 patients with Crohn's disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13%) of patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohn's disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27–1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28–0·99; p=0·046). In a subgroup analysis, three (10%) of 29 smokers in the mercaptopurine group and 12 (46%) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95% CI 0·04–0·46), compared with 13 (13%) of 99 non-smokers in the mercaptopurine group and 14 (16%) of 86 in the placebo group (0·90, 0·42–1·94; pinteraction=0·018). The effect of mercaptopurine did not significantly differ from placebo for any of the other planned subgroup analyses (previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis). The incidence and types of adverse events were similar in the mercaptopurine and placebo groups. One patient on placebo died of ischaemic heart disease. Adverse events caused discontinuation of treatment in 39 (30%) of 128 patients in the mercaptopurine group versus 41 (37%) of 112 in the placebo group.Interpretation: Mercaptopurine is effective in preventing postoperative clinical recurrence of Crohn's disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence.

    AB - Background: Up to 60% of patients with Crohn's disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease.Methods: We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohn's disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohn's disease (Crohn's Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15).Findings: Between June 6, 2008, and April 23, 2012, 240 patients with Crohn's disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13%) of patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohn's disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27–1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28–0·99; p=0·046). In a subgroup analysis, three (10%) of 29 smokers in the mercaptopurine group and 12 (46%) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95% CI 0·04–0·46), compared with 13 (13%) of 99 non-smokers in the mercaptopurine group and 14 (16%) of 86 in the placebo group (0·90, 0·42–1·94; pinteraction=0·018). The effect of mercaptopurine did not significantly differ from placebo for any of the other planned subgroup analyses (previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis). The incidence and types of adverse events were similar in the mercaptopurine and placebo groups. One patient on placebo died of ischaemic heart disease. Adverse events caused discontinuation of treatment in 39 (30%) of 128 patients in the mercaptopurine group versus 41 (37%) of 112 in the placebo group.Interpretation: Mercaptopurine is effective in preventing postoperative clinical recurrence of Crohn's disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence.

    UR - http://www.scopus.com/inward/record.url?scp=84996527564&partnerID=8YFLogxK

    U2 - 10.1016/S2468-1253(16)30078-4

    DO - 10.1016/S2468-1253(16)30078-4

    M3 - Article

    VL - 1

    SP - 273

    EP - 282

    JO - Lancet Gastroenterology and Hepatology

    JF - Lancet Gastroenterology and Hepatology

    SN - 2468-1253

    IS - 4

    ER -