A Randomized, Double-Blind, Sham-Controlled Study of Granulocyte/Monocyte Apheresis for Active Ulcerative Colitis

doi:10.1053/j.gastro.2008.04.023

Gastroenterology

Volume 135, Issue 2, August 2008, Pages 400-409

https://doi.org/10.1053/j.gastro.2008.04.023 Get rights and content

Background & Aims: Activated granulocytes and monocytes/macrophages are implicated in the pathogenesis of ulcerative colitis. Open-label studies and clinical experience in Japan and Europe have suggested that granulocyte/monocyte apheresis is safe and effective in treating ulcerative colitis. Methods: We evaluated the efficacy of granulocyte/monocyte apheresis in a randomized, double-blind, sham-controlled trial in patients with active moderate-to-severe ulcerative colitis (Mayo score 6–11) in community-based and tertiary care centers. As intervention, we used granulocyte/monocyte apheresis with the Adacolumn Apheresis System (JIMRO, Ltd, Takasaki, Japan) or sham apheresis in a 2:1 ratio for 9 weeks of treatment in a North American pivotal study (N = 168) and in a smaller, companion study of identical design conducted in Europe and Japan (N = 47). Results: In the pivotal study, clinical remission rates (Mayo score 0–2, with scores of 0 on rectal bleeding and 0 or 1 on endoscopic examination) were 17% and 11% for the granulocyte/monocyte apheresis (n = 112)- and sham-treatment groups, respectively (n = 56; P = .361). Clinical response (Mayo score reduction of ≥3 points from baseline) was observed in 44% and 39% of patients, respectively (P = .620). Similar changes were observed for the apheresis- and sham-treatment groups for endoscopic remission and response, and changes in Mayo and quality-of-life scores. The companion study and pooled data from both studies also yielded similar results. Conclusions: In this study, granulocyte/monocyte apheresis was well tolerated but did not demonstrate efficacy for induction of clinical remission or response in patients with moderate-to-severe ulcerative colitis.

Section snippets

Objective

The primary objective of this trial (Clinical Trials.gov identifier NCT00102193, and NCT00219414 for the companion study [http://www.clinicaltrials.gov]) was to demonstrate the safety and efficacy of the Adacolumn Apheresis System in inducing remission in patients with moderate-to-severe active UC who had an inadequate response to, or who were intolerant of, conventional therapy.

Study Design

This was a randomized, prospective, double-blind, sham-controlled trial, conducted at 36 centers in the United States

Results

Between July 2004 and July 2006, 248 participants were screened for study participation. A total of 179 participants successfully completed all other screening measures before undergoing venous access challenge. Eleven participants failed this challenge, and 168 (67.7%) were eligible for randomization and participation in the main pivotal study. Of these, 112 were randomized to apheresis, and 56 were randomized to sham treatment. In the companion study, 58 patients were screened at 13 study

Discussion

Leukocyte apheresis is an attractive therapeutic concept. Currently available medical therapies for UC typically suppress the inflammatory or immune response, with associated toxicities. By contrast, leukocyte apheresis does not introduce bioactive agents into the circulation but rather seeks to remove activated leukocyte populations that may be relevant to pathogenesis. The pivotal trial and the smaller companion study we report are, to our knowledge, the first large-scale studies to employ a

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Cited by (186)

GADECCU 2022 Guideline for the treatment of Ulcerative Colitis. Adaptation and updating of the GETECCU 2020 Guideline
2023, Gastroenterologia y Hepatologia
La colitis ulcerosa (CU) es una enfermedad inflamatoria crónica que compromete el colon, afectando la calidad de vida de individuos de cualquier edad. Existe un amplio espectro de situaciones clínicas. Los avances realizados en fisiopatogenia de la CU han permitido desarrollar nuevos agentes terapéuticos más efectivos y seguros.
Actualizar y ampliar la evaluación de la eficacia y seguridad de los tratamientos relevantes para la inducción de la remisión y el mantenimiento luego de un brote leve, moderado o grave de CU.
Gastroenterólogos, coloproctólogos, médicos clínicos, médicos de familia y otros profesionales de la salud, interesados en el tratamiento de la CU.
Las autoridades de GADECCU obtuvieron la autorización de GETECCU para la adaptación y actualización de la «Guía GETECCU 2020 para el tratamiento de la CU. Elaborada con metodología GRADE». Se conformó un equipo que incluyó a autores, panel de expertos, enfermera y un paciente, expertos en metodología y revisores externos. Se utilizó metodología GRADE con la nueva información.
Se elaboró un documento de 118 páginas con las 44 recomendaciones GADECCU 2022, para distintas situaciones clínicas y opciones terapéuticas, según niveles de evidencia. Se agregó un apartado con las nuevas moléculas próximas a estar disponibles.
Esta guía ha sido realizada con el fin de facilitar la toma de decisiones relativas al tratamiento de la CU, adaptando y actualizando la guía elaborada por GETECCU en el año 2020.
Ulcerative colitis (UC) is a chronic inflammatory disease that compromises the colon, affecting the quality of life of individuals of any age. In practice, there is a wide spectrum of clinical situations. The advances made in the physio pathogenesis of UC have allowed the development of new, more effective and safer therapeutic agents.
To update and expand the evaluation of the efficacy and safety of relevant treatments for remission induction and maintenance after a mild, moderate or severe flare of UC.
Gastroenterologists, coloproctologists, general practitioners, family physicians and others health professionals, interested in the treatment of UC.
GADECCU authorities obtained authorization from GETECCU to adapt and update the GETECCU 2020 Guide for the treatment of UC. Prepared with GRADE methodology. A team was formed that included authors, a panel of experts, a nurse and a patient, methodological experts, and external reviewers. GRADE methodology was used with the new information.
A 118-page document was prepared with the 44 GADECCU 2022 recommendations, for different clinical situations and therapeutic options, according to levels of evidence. A section was added with the new molecules that are about to be available.
This guideline has been made in order to facilitate decision-making regarding the treatment of UC, adapting and updating the guide prepared by GETECCU in the year 2020.
GETECCU 2020 guidelines for the treatment of ulcerative colitis. Developed using the GRADE approach
2020, Gastroenterologia y Hepatologia
Desde la publicación de la primera edición de la Guía en 2013, se ha generado mucha información en torno al tratamiento de la colitis ulcerosa, y se han introducido nuevos fármacos y protocolos de actuación. La práctica clínica ha variado substancialmente, lo que justifica nuevas aproximaciones y una revisión exhaustiva, así como la actualización de la evidencia.
Se utiliza nuevamente metodología GRADE, apoyados en una herramienta electrónica (https://gradepro.org). Los escenarios clínicos son los mismos que en la versión previa (inducción y mantenimiento en brote grave y en brote leve-moderado), así como las variables y su evaluación. En la guía actualizada, en relación a la versión previa, se eliminan tres preguntas, se añaden 14 y se mantienen 30, con un total de 44 preguntas clínicas. Tras una exhaustiva revisión de la evidencia, se actualizan las recomendaciones.
De las 44 preguntas analizadas, en dos de ellas no se ha podido establecer ninguna recomendación por muy baja calidad de la evidencia, mientras que en las 42 restantes, basados en diferentes grados de calidad de evidencia, se ha formulado una recomendación de acuerdo con el sistema GRADE. En 25 de estas preguntas la recomendación final es fuerte a favor; en seis, fuerte en contra; mientras que en siete es débil a favor, y en cuatro débil en contra. Siguiendo los escenarios y las recomendaciones, se proponen seis algoritmos como guía sencilla en la toma de decisiones prácticas.
Esta actualización de la guía previa publicada en 2013 intenta dar respuesta basada en la metodología GRADE a las diferentes preguntas que nos hacemos diariamente a la hora de decidir el tratamiento más adecuado de nuestros pacientes con colitis ulcerosa en los diferentes escenarios clínicos.
Since the first edition of the Guidelines was published in 2013, much information has been generated around the treatment of ulcerative colitis, and new drugs and action protocols have been introduced. Clinical practice has changed substantially, warranting new approaches and a comprehensive review and update of the evidence.
Once again, we used the GRADE approach, supported by an electronic tool (https://gradepro.org). The clinical scenarios are the same as in the previous version (induction and maintenance in severe and mild-moderate flare-ups), as are the variables and their evaluation. However, in the updated guidelines, three questions have been deleted, 14 added and 30 maintained, making a total of 44 clinical questions. After an exhaustive review of the evidence, the recommendations are now updated.
Of the 44 questions analysed, no recommendation could be established in two due to the very low quality of the evidence, while in the other 42, based on different degrees of quality of evidence, recommendations were made according to the GRADE system. In 25 of these questions the final recommendation is strongly in favour, in six strongly against, in seven weakly in favour and in four weakly against. According to the scenarios and recommendations, six algorithms are proposed as a simple guide for practical decision-making.
The aim of this update of the 2013 guidelines is to provide answers, based on the GRADE approach, to the different questions we ask ourselves daily when deciding the most appropriate treatment for our patients with ulcerative colitis in the different clinical scenarios.
Adsorptive cytapheresis in ulcerative colitis: A non-pharmacological therapeutic approach revisited
2023, Journal of Clinical Apheresis
Macrophages in intestinal homeostasis and inflammatory bowel disease
2023, Nature Reviews Gastroenterology and Hepatology
Concomitant pharmacologic medications influence the clinical outcomes of granulocyte and monocyte adsorptive apheresis in patients with ulcerative colitis: A multicenter retrospective cohort study
2023, Journal of Clinical Apheresis
Adsorptive cytapheresis for ulcerative colitis with focus on removing platelets and platelet-aggregates
2023, Therapeutic Apheresis and Dialysis

View all citing articles on Scopus

: Supported by Otsuka America Pharmaceutical Inc.

: Conflicts of interest: The authors disclose the following relationships: Bruce E. Sands: grant or research support from Cerimon, Bristol-Myers Squibb, Centocor, Abbott Immunology, Prometheus Laboratories, Shire Pharmaceuticals, Protein Design Laboratories Biopharma, Otsuka America Pharmaceutical Inc, Procter & Gamble Pharmaceuticals; consultant for Axcan, Cerimon, Bristol-Myers Squibb, Centocor, Abbott Immunology, Prometheus Laboratories, Shire Pharmaceuticals, Protein Design Laboratories Biopharma, Otsuka America Pharmaceutical Inc, Procter & Gamble Pharmaceuticals; member of scientific advisory boards of Cerimon, Bristol-Squibb, Centocor, Abbott Immunology, Prometheus Laboratories, Shire Pharmaceuticals, Protein Design Laboratories Biopharma, Otsuka America Pharmaceutical Inc, Procter & Gamble Pharmaceuticals. William J. Sandborn: grant or research support from JIMRO/Otsuka Pharmaceuticals America Inc; consultant for JIMRO/Otsuka America Pharmaceuticals Inc. Brian Feagan: grant or research support from Schering-Plough, Otsuka, Milllennium, Tillotts, Abbott, Protein Design Labs, Boehringer Engelheim, Novartis, Centocor, Berlex, Synta, Schering Canada, Elan/Biogen, UCB Pharma, BMS, Proctor & Gamble, Napo Pharma; consultant for Synta, Millennium, Schering Canada, Celltech, Centocor, Elan/Biogen, Janssen-Ortho, Protein Design Labs, ISIS, Teva Pharmaceuticals, Santarus, Schering Plough, Bristol-Myers Squibb, Celgene, Combinatorx, UCB Pharma, Napo Pharma, Abbott, Proctor & Gamble, Osiris, Berlex, AstraZeneca, GeneLogic Inc, Cerimon Pharm, Tioga Pharm, Serono, Genentech; member of the Speakers Bureau of AstraZeneca; member of the scientific advisory boards of Protein Design Labs, AstraZeneca, Elan/Biogen, Celltech, Synta, Schering Canada, Celgene. Robert Löfberg: grant or research support from Abbott Labs, Asahi, AstraZeneca, Celltech, Centocor, Elan, Ferring, InDex Pharmaceuticals, Meda, Otsuka Frankfurt Research Institute, Otsuka Pharmaceuticals Scandinavia, Pharmacia, Pfizer, Schering Plough, UCB; member of scientific advisory boards of Abbott Labs, Asahi, AstraZeneca, Celltech, Centocor, Connexion, Cosmo, Elan, InDex Pharmaceuticals, Meda, Novartis, Otsuka Frankfurt Research Institute, Pharmacia, Pfizer, Schering Plough, Schering AG, Serono, Therakos, UCB. Toshifumi Hibi: grant or research support from Abbott Japan, Ajinomoto Pharma, Asahi Kasei Kuraray Medical, AstraZeneca Pharmaceuticals, Janssen Pharmaceutical K. K., JIMRO, Nisshin Kyorin Pharmaceutical Company, Otsuka Pharma, Tanabe Mitsubishi Seiyaku, UCB Japan, UMN Pharma, Zeria Pharmaceutical. Lisa-Marie Gustafson and Tao Wang are employees of Otsuka America Pharmaceutical Inc.

: Editorial assistance was provided by Judy Andraski, PhD, and Adelphi Inc, as funded by Otsuka America Pharmaceutical Inc, and by Tina Wright, an employee of Otsuka America Pharmaceutical Inc.

: The investigators disclosed potential conflicts to study participants.

: The statistical analysis of the entire data sets pertaining to efficacy and safety has been independently confirmed by Cindy Wong of Robarts Research Institute. Cindy Wong and Margaret Vandervoort are employees of Robarts Research Institute.

: Dr Sands had full access to all of the data and takes full responsibility for the veracity of the data and analysis.

: Role of the sponsor: The studies were designed by the sponsors, Otsuka America Pharmaceuticals, Inc, and Otsuka Frankfurt Research Institute, GmbH, respectively, in collaboration with the investigators. Trial execution was supervised by the sponsors in collaboration with the investigators and the contract research organizations (Robarts Clinical Trials for the pivotal study and PAREXEL International for the companion study). Data analysis for both studies was performed by Robarts Clinical Trials in collaboration with the sponsors and investigators.

View full text

Clinical—Alimentary TractA Randomized, Double-Blind, Sham-Controlled Study of Granulocyte/Monocyte Apheresis for Active Ulcerative Colitis

Section snippets

Objective

Study Design

Results

Discussion

Clin Gastroenterol Hepatol

Dig Liver Dis

Inflammatory bowel disease

N Engl J Med

Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitisA randomized study

N Engl J Med

A double-blind comparison of oral versus rectal mesalamine versus combination therapy in the treatment of distal ulcerative colitis

Am J Gastroenterol

Comparative tolerability of treatments for inflammatory bowel disease

Drug Saf

Infliximab for induction and maintenance therapy for ulcerative colitis

N Engl J Med

Role of neutrophil-derived oxidants in the pathogenesis of intestinal inflammation

Klin Wochenschr

Mechanisms of neutrophil-mediated tissue injury

Tissue cytokine and chemokine expression in inflammatory bowel disease

Inflamm Res

Leukopheresis for treatment of psoriasis: is therapeutical benefit related to reduced activities of neutral proteinases of polymorphonuclear leukocytes?

Arch Dermatol Res

Immunomodulatory effects of granulocyte and monocyte adsorption apheresis as a treatment for patients with ulcerative colitis

Dig Dis Sci

Granulocytapheresis in the treatment of patients with rheumatoid arthritis

Artif Organs

Granulocyte apheresis in inflammatory bowel disease: possible mechanisms of effect

Ther Apher

Pilot feasibility studies of leukocytapheresis with the Adacolumn Apheresis System in patients with active ulcerative colitis or Crohn's disease

J Clin Gastroenterol

Intensive therapy of granulocyte and monocyte adsorption apheresis induces rapid remission in patients with ulcerative colitis

Clinical—Alimentary Tract
A Randomized, Double-Blind, Sham-Controlled Study of Granulocyte/Monocyte Apheresis for Active Ulcerative Colitis