Abstract Background and Aims Steroid-dependency occurs in up to 30% of patients with ulcerative colitis [UC]. In this setting, few drugs have demonstrated efficacy in inducing steroid-free remission. The aim of this study was to evaluate the efficacy and safety of adding granulocyte/monocyte apheresis [GMA] to oral prednisone in patients with steroid-dependent UC. Methods This was a randomized, multicentre, open trial comparing 7 weekly sessions of GMA plus oral prednisone [40 mg/day and tapering] with prednisone alone, in patients with active, steroid-dependent UC [Mayo score 4–10 and inability to withdraw corticosteroids in 3 months or relapse within the first 3 months after discontinuation]. Patients were stratified by concomitant use of thiopurines at inclusion. A 9-week tapering schedule of prednisone was pre-established in both study groups. The primary endpoint was steroid-free remission [defined as a total Mayo score ≤2, with no subscore >1] at Week 24, with no re-introduction of corticosteroids. Results In all 123 patients were included [63 GMA group, 62 prednisone alone]. In the intention-to-treat analysis, steroid-free remission at Week 24 was achieved in 13% (95% confidence interval [CI] 6–24) in the GMA group and 7% [95% CI 2–16] in the control group [p = 0.11]. In the GMA group, time to relapse was significantly longer (hazard ratio [HR] 1.7 [1.16–2.48], P = 0.005) and steroid-related adverse events were significantly lower [6% vs 20%, P < 0.05]. Conclusions In a randomized trial, the addition of 7 weekly sessions of GMA to a conventional course of oral prednisone did not increase the proportion of steroid-free remissions in patients with active steroid-dependent UC, though it delayed clinical relapse. Ulcerative colitis, apheresis, steroid dependence 1. Introduction Inflammatory bowel diseases affect 2.5–3 million people in Europe.1 Ulcerative colitis [UC], its commonest phenotypic form, is a relapsing-remitting, chronic, inflammatory condition of the rectum and colon. Treatment in UC is mainly driven by disease severity and follows a step-up approach. Fifty percent of UC patients require at least one course of systemic corticosteroids in their lifetime for the treatment of moderate or severe flares.2 Although most of these patients improve clinically with corticosteroids, up to 40% relapse while tapering corticosteroid dose or soon after discontinuing the drug,3,4 a phenomenon known as steroid dependency. Moreover, corticosteroids are associated with a high rate of related adverse effects5 that become more frequent and severe in cases of prolonged or recurrent use. For these reasons, in recent years, treatment goals in UC have changed from clinical remission to steroid-free clinical remission.6 In steroid-dependent UC, immunosuppressants and biologic agents are usually indicated, though only thiopurines have demonstrated their efficacy in randomized controlled trials.7,8 These drugs are hampered by the risk of infections and neoplasms. In addition, more than 50% of the treated patients are intolerant, do not respond completely, or lose their initial response to these drugs. As proctocolectomy remains the only alternative, the need for safer and efficient therapies is evident. One of the crucial pathways in the inflammatory cascade in UC is the migration of leukocytes from the systemic circulation to the colon. Several monoclonal antibodies targeting adhesion molecules to avoid lymphocyte migration have proven their efficacy in UC,9,10 and this has become a field of interest in the treatment of inflammatory bowel diseases. Granulocyte and monocyte adsorptive apheresis [GMA] is a therapeutic procedure by which activated neutrophils, monocytes, and platelets are selectively removed from the bloodstream, thereby avoiding their migration to the inflamed tissues. GMA has been shown to modulate levels of pro-inflammatory cytokines such as tumour necrosis factor alpha [TNF-α] and reduce the cell-surface levels of the adhesion molecule L-selectin.11,12 The clinical efficacy of GMA in steroid-dependent UC has been observed in small observational studies.13–17 Moreover, this non-pharmacological therapeutic device has proven to be extremely safe in clinical practice registries.13 However, a systematic review on the efficacy of GMA in UC concluded that though it appears to be of some benefit, high-quality randomized controlled trials [RCTs] comparing GMA with conventional medical therapy and sham procedures in Western populations with endoscopically confirmed disease activity were required.18 The ATICCA study aimed to evaluate the efficacy and safety of adding GMA to a conventional course of oral prednisone in patients meeting the criteria of steroid-dependent UC, by means of a prospective, randomized, controlled trial. 2. Methods 2.1. Study design The ATICCA [Adacolumn Therapy In Corticosteroid-dependent Colitis] study was a controlled, randomized, open study that assessed the efficacy and safety of the addition of seven sessions of GMA to a conventional 9-week course of prednisone in patients with UC meeting corticosteroid-dependence criteria. The study was designed and implemented by GETECCU [Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa], and conducted at 39 medical centres in five European countries [Austria, Germany, Italy, Portugal, and Spain] from 2008 to 2013. Written informed consent was obtained from all the participants. The study was approved by the Institutional Review Board of the Hospital Universitari Germans Trias i Pujol [Badalona, Spain] and by the Spanish Health Authority [Agencia Española del Medicamento] in November 2007, and was registered under ClinicalTrials.gov ID: NCT00702611 and EU Clinical Trials Registry EudracCT number 2007-003815-30. Funding was provided by an unrestricted research grant from Otsuka Pharmaceuticals. 2.2. Patients Eligible patients were adults younger than 75 years of age who fulfilled all the following criteria: active disease as defined by a total Mayo score ≥4 and ≤12 with at least 1 point scored in flexible sigmoidoscopy; steroid dependency as defined by the inability to withdraw corticosteroids within 3 months of starting treatment without recurrent active disease, or the appearance of relapse within 3 months after withdrawal of corticosteroids; colonic involvement with ulcerative colitis beyond 15 cm of the anal verge; stable doses of aminosalicylates for the past 4 weeks, prednisolone or an equivalent dose ≤20 mg/day for the past 2 weeks, and azathioprine or mercaptopurine at stable doses for the past 12 weeks. Patients of childbearing potential were required to use an adequate method of contraception throughout the study. Patients were ineligible if: they were febrile [>38°C]; had evidence of toxic megacolon, when surgery was anticipated in the following 24 weeks; had inadequate peripheral venous access; had a history of allergic reaction to heparin or heparin-induced thrombocytopenia, haemoglobin level <8.5 g/dL, a white blood cell count of <3500/μL or a granulocyte count <2000/μL. Other exclusion criteria included: proctocolectomy, total colectomy, ileostomy, stoma or ileal pouch-anal anastomosis; known infection with enteric pathogens, pathogenic ova or parasites, C.difficile toxin, cytomegalovirus, hepatitis B or C, or human immunodeficiency virus; ischaemic heart disease within the past 6 months, a history of coronary artery bypass grafting surgery or angioplasty within the past 6 months, prosthetic heart valve, pacemaker, or other permanent implant; severe cardiovascular or peripheral vascular disease, severe renal disease, cirrhosis, coagulation disorder [including one or more episodes of pulmonary embolism or deep vein thrombosis]; malignancy within the past 2 years other than surgically cured skin carcinoma or cervical dysplasia; dysplasia or carcinoma of the colon or lack of a complete colonoscopy in the past 12 months in patients with longstanding UC; alcohol abuse; pregnancy, breastfeeding or [women] plans to become pregnant during the course of the clinical investigation; use of cyclosporine or tacrolimus within the past 8 weeks, or use of infliximab or adalimumab within the past 8 weeks. 2.3. Therapeutic study groups Randomization codes were centrally generated using a computer procedure, with a 1:1 sequence with a block size of 2, balanced by centre. Patients were stratified regarding their current use of thiopurines. Patients assigned to the GMA group were treated with seven apheresis treatments [AdacolumnTM, JIMRO Ltd, Japan] over 7 consecutive weeks [one per week] together with a starting dose of 40 mg of oral prednisone per day at Week 0 for 2 weeks, which was then tapered by 5 mg weekly over 9 weeks [Figure 1]. The AdacolumnTM apheresis unit comprises a granulocyte and monocyte/macrophage apheresis device, circuit lines, and an AdamonitorTM. The apheresis column is manufactured under stringent sterilization and quality testing conditions. Each column contains 35000 beads of cellulose diacetate [2-mm diameter] soaked in isotonic saline within a 335-mL polycarbonate housing. The AdamonitorTM has a built-in safety feature which, in the event of an abnormality in blood flow [such as appearance of an air bubble in the flow lines arising during the apheresis], can automatically switch off the apheresis, stop the blood return to the patient and warn the operator/nurse by an alarm sound. Patients required the insertion of two venous lines, preferably into antecubital veins. The duration of each GMA session was approximately 60 min at a flow rate of 30 mL/min, thus processing approximately 1800 ml of blood. Before the GMA session, flow rate and apheresis times could be set on the AdamonitorTM. Patients allocated to the prednisone-only group only received the above-mentioned prednisone scheduled regimen. Prednisone pills were supplied by the sponsor in both study groups, with the same package. Compliance with steroid treatment was based on drug accountability at each visit. GMA procedure parameters were recorded in the case report form [CRF]. Figure 1. View largeDownload slide Study design. Figure 1. View largeDownload slide Study design. Patients who were on aminosalicylates or thiopurines at baseline were maintained on these drugs at the same dosage throughout the study period. Steroids were tapered according to a pre-defined schedule; the need for additional steroids, as well as other rescue therapies such as cyclosporin, anti-TNF agents, or surgery, was considered to be treatment failure. 2.4. Baseline and follow-up assessments Patients were evaluated at baseline and weekly for the first 7 weeks, and then at Weeks 12, 18, and 24. At each visit, the partial Mayo score [i.e. the Mayo score without the endoscopic subscore] was assessed and adverse effects were recorded. Steroid doses and concomitant medication were also recorded and adapted according to the pre-established tapering schedule. Blood samples for biochemical and haematological testing were obtained at each visit. Flexible sigmoidoscopies were performed in each centre by a local investigator at the screening visit [unless there was one available within the previous 15 days], and at Weeks 12 and 24. The endoscopist was not necessarily blinded to treatment allocation, and no central endoscopy reading was used. 2.5. Outcomes The outcome following treatment was classified as remission, response, or treatment failure by means of the complete Mayo score and steroid requirements. Clinical remission was defined as a total Mayo score ≤2 with no individual subscore >1 point and no steroid use. Clinical response was defined as a Mayo score decrease of 3 points or at least 30% compared with baseline, with a decrease in the subscore for rectal bleeding of at least 1 point or an absolute subscore for rectal bleeding of 0 or 1. All other outcomes were defined as treatment failures. Patients needing an increase in steroid dosage or a new course of steroids, as well as prohibited concomitant medication during the 24-week study period to control clinical symptoms of UC, were considered to be treatment failures. The primary endpoint was steroid-free clinical remission defined at Week 24. Secondary endpoints were steroid-free clinical remission at Week 12, clinical response at Weeks 12 and 24, changes in acute phase reactants, time to relapse [weeks], and clinical remission and response at Weeks 12 and 24 according to the concomitant use of thiopurines. 2.6. Statistical analysis Demographics and baseline characteristics were summarized using descriptive statistics. Continuous variables were compared using the analysis of variance and dichotomous variables by the chi square test. The results are expressed by odds ratios [adjusted and unadjusted] and the corresponding 95% confidence intervals. To analyse the time to relapse [weeks], a Kaplan-Meier model stratified by treatment group was applied. Comparisons of survival functions for the two treatments were carried out using the log-rank test. For study purposes, the following populations were defined: [i] intention-to-treat population [ITT], which included all the randomized patients; and [ii] per protocol population [PP], which included all randomized patients satisfying inclusion/exclusion criteria and without major protocol deviations. Patients in this population also had to satisfy the following criteria: having received treatment up to Week 5 [in both treatment arms] and no use of forbidden medication [additional steroids, cyclosporin, anti-TNF agents, surgery, or unstable doses of aminosalicylates or thiopurines during the study]. The efficacy analyses shown in the manuscript refer to the intention-to-treat population. Missing response values were dealt with by using the non-responder imputation method [NRI], leading the patient to be considered a treatment failure. The analyses of secondary endpoints were to proceed regardless of the outcomes for the primary endpoints. These secondary endpoints were not adjusted for multiplicity. Statements of significance for these secondary endpoints are based on nominal p-values and should be interpreted with caution. The expected proportion of remission in the control group was 15%. For a 30% remission rate in the experimental group, a study with a sample size of 197 subjects [split equally between the two groups] achieved 80% power to detect a significant difference at 0.05 level using the one-sided chi square test. In order to allow for 20% of losses, the total sample size was 246 subjects [post-authorization safety studies, European Medicines Agency 2002]. The study planned two interim analyses when 50% and 75% of the patients completed the follow-up, and a final analysis at the end of the study. Following the rule proposed by Peto et al., the trial would stop if a p-value < 0.001 was found in any of the interim analyses. Due to slow recruitment and concern that the trial would not be successfully completed, and since 50% of the planned sample had already finished the study, a protocol amendment was approved for stopping the trial only for futility if the upper 95% confidence interval [CI] limit of the corticosteroid-free remission rate in the experimental group was lower than the initially expected GMA remission rate [30%] or if the upper 95% CI limit of the difference in sustained corticosteroid-free remission rate was lower than the expected difference [0.15]. The first criterion was met, and the trial was stopped after the inclusion of 62 patients in the GMA group and 61 patients in the control group. 3. Results 3.1. Baseline characteristics and patient disposition A total of 133 patients were assessed for eligibility and 125 were randomized. Two patients were excluded from the analysis because of protocol deviations [one had no disease activity at inclusion and one was steroid-refractory instead of steroid-dependent], leading to 123 patients being included in the final analysis [62% of the required sample size]; 62 patients were assigned to the GMA arm and 61 to the prednisone-alone arm. Baseline characteristics of the patients are summarized in Table 1. No differences in demographic or clinical characteristics were found between the two study groups. Of note, most patients were non-smokers, 41% had experienced less than 5 years of duration of UC, 61% were thiopurine-experienced [though only 27% of the whole cohort was on thiopurine therapy during the study period], and 15% had ever been exposed to anti-TNF agents. A total of 42 patients completed the scheduled treatment regimen, 27 [43%] in the GMA arm and 15 [25%] in the prednisone-alone arm [p = 0.027]. Moreover, 41 of 62 [66%] patients and 48 of 61 [78%] patients discontinued the study in the GMA and the prednisone-alone groups, respectively [p = 0.12]. The reasons for study discontinuation were worsening in health status [n = 51], protocol violation [n = 17], withdrawal of consent [n = 8], adverse events [n = 3], missing [n = 3] and other [n = 7] [Figure 2]. Table 1. Baseline characteristics of patients according to the study group. Apheresis plus prednisone [n = 62] Prednisone alone [n = 61] Age [years] 44 ± 11.5 43 ± 12.7 Male gender 61% 65% Active smokers 16% 7% Body mass index 24.6 ± 3.6 24.7 ± 3.4 Extensive colitis 45% 46% Disease duration [years] 6.4 ± 5.2 7.9 ± 7.6 Total Mayo score 7.3 ± 1.7 7.2 ± 1.6 On steroids at screening 55% 56% Concomitant thiopurines 27% 26% Never exposed to thiopurines 37% 41% Ever exposed to anti-TNF 15% 25% Apheresis plus prednisone [n = 62] Prednisone alone [n = 61] Age [years] 44 ± 11.5 43 ± 12.7 Male gender 61% 65% Active smokers 16% 7% Body mass index 24.6 ± 3.6 24.7 ± 3.4 Extensive colitis 45% 46% Disease duration [years] 6.4 ± 5.2 7.9 ± 7.6 Total Mayo score 7.3 ± 1.7 7.2 ± 1.6 On steroids at screening 55% 56% Concomitant thiopurines 27% 26% Never exposed to thiopurines 37% 41% Ever exposed to anti-TNF 15% 25% TNF, tumour necrosis factor. View Large Table 1. Baseline characteristics of patients according to the study group. Apheresis plus prednisone [n = 62] Prednisone alone [n = 61] Age [years] 44 ± 11.5 43 ± 12.7 Male gender 61% 65% Active smokers 16% 7% Body mass index 24.6 ± 3.6 24.7 ± 3.4 Extensive colitis 45% 46% Disease duration [years] 6.4 ± 5.2 7.9 ± 7.6 Total Mayo score 7.3 ± 1.7 7.2 ± 1.6 On steroids at screening 55% 56% Concomitant thiopurines 27% 26% Never exposed to thiopurines 37% 41% Ever exposed to anti-TNF 15% 25% Apheresis plus prednisone [n = 62] Prednisone alone [n = 61] Age [years] 44 ± 11.5 43 ± 12.7 Male gender 61% 65% Active smokers 16% 7% Body mass index 24.6 ± 3.6 24.7 ± 3.4 Extensive colitis 45% 46% Disease duration [years] 6.4 ± 5.2 7.9 ± 7.6 Total Mayo score 7.3 ± 1.7 7.2 ± 1.6 On steroids at screening 55% 56% Concomitant thiopurines 27% 26% Never exposed to thiopurines 37% 41% Ever exposed to anti-TNF 15% 25% TNF, tumour necrosis factor. View Large Figure 2. View largeDownload slide Flow diagram of the study. Figure 2. View largeDownload slide Flow diagram of the study. 3.2. Primary and secondary outcomes Regarding the primary endpoint, the proportion of patients in steroid-free clinical and endoscopic remission at Week 24 was 13% [95% CI 6%–24%] in the GMA group and 7% [95% CI 2%–16%] in the prednisone alone group [p = 0.12] [Figure 3]. Similarly, no differences were found in the remission rates at Week 12 (19% [95% CI 10%–31%) vs 18% [95% CI 9%–30%], respectively; p = 0.42), and the response rates at Week 24 (16% [95% CI 8%–28%] vs 10% [95% CI 4%–20%], respectively; p = 0.15) and Week 12 (39% [95% CI 27%–52%] vs 31% [95% CI 20%–44%], respectively; p = 0.19). Conversely, patients in the GMA group had a significantly longer time to relapse as compared with those treated with prednisone alone (13 weeks [95% CI 12.2–15.4] vs 11 weeks [95% CI 7.6–12.3], respectively; p = 0.005) [Figure 4]. Figure 3. View largeDownload slide Steroid-free clinical and endoscopic remission at Weeks 12 and 24. Figure 3. View largeDownload slide Steroid-free clinical and endoscopic remission at Weeks 12 and 24. Figure 4. View largeDownload slide Relapse-free survival. Figure 4. View largeDownload slide Relapse-free survival. At Week 12, 23 patients were in remission [12 in the GMA arm and 11 in the prednisone-alone arm]; seven out of 23 [30%] scored 0 in the endoscopic Mayo subscore, whereas the remaining 16 [70%] scored 1. Regarding rectal bleeding, 20 out of 23 [87%] scored 0. No differences were observed between the two treatment groups. At Week 24, 12 patients [eight in the GMA arm and four in the prednisone-alone arm] reached remission. Nine of them were already in remission at Week 12 and three showed clinical response at Week 12. Two of the patients who were in remission at Week 12 [both from the GMA arm] lacked a final endoscopic examination and they were considered treatment failures as per NRI. Of note, all the patients who were in remission at Week 24 scored 0 for rectal bleeding, and eight [66%] scored 0 in the endoscopic evaluation. A number of the secondary endpoints aimed to assess the impact of other drugs on the efficacy of GMA. The study protocol had two different criteria to define steroid-dependency: [i] inability to withdraw steroids because of relapse; or [ii] clinical relapse within 3 months after stopping steroids; 72 patients [59%] met the first criterion, suggesting a ‘harder’ dependency on corticosteroids. In this subset of patients [but not in those meeting the second criterion], patients who were treated with GMA showed a significantly higher rate of response at 12 weeks (45% [95% CI 29%–22%] vs 24% [95% CI 11%–41%]; -Pp = 0.025-) and a clear but non-significant trend towards a better response rate at 24 weeks (21% [95% CI 10%–37%] vs 9% [95% CI 2%–24%]; -p = 0.068-), in the GMA and the prednisone-alone arms, respectively. A total of 33 patients were on concomitant thiopurines during the study period [17 in the GMA group and 16 in the prednisone-alone group], whereas the remaining 90 patients were not receiving any immunosuppressant or biologic agent. No differences in clinical remission or response rates were observed between the study groups when analyses were performed only in patients receiving thiopurines or in those not receiving them during the study period, except for a higher response rate at Week 12 in patients on thiopurines treated with GMA as compared with those treated only with prednisone (59% [95% CI 33%–82%] vs 25% [95% CI 7%–52%], respectively; p = 0.018). Regarding previous exposure to thiopurines, no differences in remission and response rates were observed between study groups when looking at patients ever exposed to thiopurines [n = 75, 39 in the GMA group and 36 in the prednisone-alone group]. However, in thiopurine-naïve patients [n = 48, 23 in the GMA group and 25 in the prednisone-alone group), GMA achieved a significantly higher rate of remission at 24 weeks (13% [95% CI 3%–34%] vs 0%; p = 0.003] [Figure 5]. Figure 5. View largeDownload slide Steroid-free clinical and endoscopic remission rates at Week 24 regarding previous exposure or concomitant use of thiopurines. Figure 5. View largeDownload slide Steroid-free clinical and endoscopic remission rates at Week 24 regarding previous exposure or concomitant use of thiopurines. 3.3. Safety The global incidence of adverse events was low. Table 2 summarizes the reported adverse events in both study groups. Regarding steroid-related side effects, there was a significantly higher rate among patients treated with prednisone alone as compared with those patients receiving GMA [6% vs 20%; p < 0.05]. There were nine serious adverse events in eight patients: three cases were related to UC worsening, three infectious episodes [one varicella infection and one pulmonary tuberculosis in patients treated with prednisone alone, and one human immunodeficiency virus infection in a patient from the GMA group], one pregnancy with spontaneous abortion in a patient treated with GMA, and one patient treated with GMA who developed two serious adverse events that led to death [intracranial haemorrhage and pulmonary embolism]. Only five out of the 62 patients treated with GMA reported adverse events related to the apheresis device, most of which were mild in severity [Table 3]. Table 2. List of adverse events reported in both study groups. Adverse event Apheresis + prednisone Prednisone alone Total Ear pain 1 0 1 Vomiting 1 0 1 Dyspepsia 1 0 1 Constipation 0 1 1 Abdominal pain 2 0 2 Pyrexia 1 0 1 Feeling cold 1 0 1 Varicella 0 1 1 Tuberculosis 0 1 1 HIV infection 1 0 1 Tracheitis 1 0 1 Nasopharyngitis 1 0 1 Bronchitis 1 0 1 Hyperglycaemia 0 1 1 Muscular weakness 1 0 1 Arthralgia 1 1 2 Headache 2 1 3 Dizziness 1 1 2 Insomnia 1 1 2 Cough 1 0 1 Hypertension 0 3 3 Haematoma 1 0 1 Circulatory collapse 1 0 1 Intracranial haemorrhage 1 0 1 Pulmonary embolism 1 0 1 Superficial thrombophlebitis 0 1 1 Spontaneous abortion 1 0 1 Total 23 12 35 Adverse event Apheresis + prednisone Prednisone alone Total Ear pain 1 0 1 Vomiting 1 0 1 Dyspepsia 1 0 1 Constipation 0 1 1 Abdominal pain 2 0 2 Pyrexia 1 0 1 Feeling cold 1 0 1 Varicella 0 1 1 Tuberculosis 0 1 1 HIV infection 1 0 1 Tracheitis 1 0 1 Nasopharyngitis 1 0 1 Bronchitis 1 0 1 Hyperglycaemia 0 1 1 Muscular weakness 1 0 1 Arthralgia 1 1 2 Headache 2 1 3 Dizziness 1 1 2 Insomnia 1 1 2 Cough 1 0 1 Hypertension 0 3 3 Haematoma 1 0 1 Circulatory collapse 1 0 1 Intracranial haemorrhage 1 0 1 Pulmonary embolism 1 0 1 Superficial thrombophlebitis 0 1 1 Spontaneous abortion 1 0 1 Total 23 12 35 View Large Table 2. List of adverse events reported in both study groups. Adverse event Apheresis + prednisone Prednisone alone Total Ear pain 1 0 1 Vomiting 1 0 1 Dyspepsia 1 0 1 Constipation 0 1 1 Abdominal pain 2 0 2 Pyrexia 1 0 1 Feeling cold 1 0 1 Varicella 0 1 1 Tuberculosis 0 1 1 HIV infection 1 0 1 Tracheitis 1 0 1 Nasopharyngitis 1 0 1 Bronchitis 1 0 1 Hyperglycaemia 0 1 1 Muscular weakness 1 0 1 Arthralgia 1 1 2 Headache 2 1 3 Dizziness 1 1 2 Insomnia 1 1 2 Cough 1 0 1 Hypertension 0 3 3 Haematoma 1 0 1 Circulatory collapse 1 0 1 Intracranial haemorrhage 1 0 1 Pulmonary embolism 1 0 1 Superficial thrombophlebitis 0 1 1 Spontaneous abortion 1 0 1 Total 23 12 35 Adverse event Apheresis + prednisone Prednisone alone Total Ear pain 1 0 1 Vomiting 1 0 1 Dyspepsia 1 0 1 Constipation 0 1 1 Abdominal pain 2 0 2 Pyrexia 1 0 1 Feeling cold 1 0 1 Varicella 0 1 1 Tuberculosis 0 1 1 HIV infection 1 0 1 Tracheitis 1 0 1 Nasopharyngitis 1 0 1 Bronchitis 1 0 1 Hyperglycaemia 0 1 1 Muscular weakness 1 0 1 Arthralgia 1 1 2 Headache 2 1 3 Dizziness 1 1 2 Insomnia 1 1 2 Cough 1 0 1 Hypertension 0 3 3 Haematoma 1 0 1 Circulatory collapse 1 0 1 Intracranial haemorrhage 1 0 1 Pulmonary embolism 1 0 1 Superficial thrombophlebitis 0 1 1 Spontaneous abortion 1 0 1 Total 23 12 35 View Large Table 3. Apheresis-related adverse effects. Adverse event Number of episodes Number of patients Severity Haematoma 2 1 Mild Dizziness 3 1 Mild Circulatory collapse 3 1 Moderate Feeling cold 4 1 Mild Medical device complication 1 1 Mild Adverse event Number of episodes Number of patients Severity Haematoma 2 1 Mild Dizziness 3 1 Mild Circulatory collapse 3 1 Moderate Feeling cold 4 1 Mild Medical device complication 1 1 Mild View Large Table 3. Apheresis-related adverse effects. Adverse event Number of episodes Number of patients Severity Haematoma 2 1 Mild Dizziness 3 1 Mild Circulatory collapse 3 1 Moderate Feeling cold 4 1 Mild Medical device complication 1 1 Mild Adverse event Number of episodes Number of patients Severity Haematoma 2 1 Mild Dizziness 3 1 Mild Circulatory collapse 3 1 Moderate Feeling cold 4 1 Mild Medical device complication 1 1 Mild View Large 4. Discussion To date, azathioprine is the only drug that has demonstrated efficacy in inducing steroid-free remission in patients with steroid-dependent UC in randomized controlled studies.7 More recently, the METEOR study was not able to demonstrate the usefulness of methotrexate in inducing steroid-free remission in a population very similar to that of the present study.19 Anti-TNF agents, though widely used, have never been appropriately tested in this clinical scenario by means of RCTs. In the ART trial, a single-arm, open-label multicentre European trial in which 86 patients with multi-refractory UC were treated with GMA, clinical remission was achieved in 39% of them.16 The present study is the first randomized, controlled trial to assess the efficacy of GMA in active, steroid-dependent UC. Of note, all the patients were treated with the same dose of oral prednisone and followed a pre-established tapering schedule. We found that the addition of seven sessions of GMA was not superior to a conventional course of oral prednisone to induce long-term clinical and endoscopic, steroid-free remission. However, there are signs that might suggest some therapeutic effect of GMA in these patients. Interestingly, patients treated with GMA showed a significantly longer time to relapse. Moreover, among those patients who achieved early remission at 12 weeks, remission was maintained in a higher proportion at Week 24 in the GMA group [68% vs 38%]. Finally, the addition of GMA showed results superior to those of the conventional prednisone regimen, in those patients who had never been exposed to thiopurines. Many factors may have played a role in our negative results. First, the present trial used a stringent definition of the primary endpoint: clinical plus endoscopic, steroid-free remission at 6 months, and disease had to be active [clinically and endoscopically] at the time of inclusion. The METEOR study, which dealt with a very similar population, allowed for inactive cases at inclusion and changed the primary endpoint from 24 to 16 weeks while the study was ongoing.19 Similarly, in the ART trial, the primary endpoint was clinical [but not endoscopic] remission at Week 12.16 Furthermore, we carried out a non-response imputation in cases of missing response values. Only two patients in the study had missing response values, both from the GMA arm; both were in steroid-free clinical remission at Week 24 but lacked the final endoscopic examination [one patient refused and the other one was pregnant at that time] and they were considered to be treatment failures. With a more conservative analysis by means of a last observation carried forward for missing values [LOCF], these two patients would have been considered to be treatment successes [both of them scored 0 for rectal bleeding and endoscopic evaluation at Week 12] and GMA would have resulted as significantly superior to prednisone alone [16% vs 6%, p = 0.045]. Second, the GMA regimen used may have been suboptimal. Yoshimura and colleagues performed a study in which patients with moderate to severe active UC were randomly assigned to a ‘routine’ GMA schedule [30 mL/min x 60 min] or to GMA adjusted to patients’ body weight. GMA adjustment by body weight resulted in a higher processed blood volume per session and in a significantly higher remission rate.20 On the other hand, when looking at the relapse-free survival curve [Figure 4], it becomes apparent that most of relapses in the GMA group occurred after Week 8 [just after the last GMA session] as opposed to what occurred in the control group in which there was a steady rate of relapse throughout the study period. This suggests that a longer GMA programme might benefit the long-term remission rate. The present study was prematurely terminated for futility. An interim analysis performed after recruiting half of the planned population showed that the upper 95% CI limit of the remission rate in the GMA group [24%] was lower than initially expected in this group [30%]. This makes the interpretation of our negative results difficult, since confidence bounds became much wider than they would have been if the study had continued, and the estimated treatment difference is therefore biased downward. A second limitation of the study is that the endoscopic evaluation was not centrally read. However, it is noteworthy that all the patients who were considered to be in remission scored 0 at rectal bleeding in the Mayo activity index. As this has been reported to correlate highly with mucosal healing in UC,21 it could considered to be a proxy of the quality of the endoscopic assessment. Finally, GMA demonstrated once again an optimal safety profile even when added to a conventional course of prednisone [which is known to be associated with a high rate of adverse effects], and we even observed a lower number of steroid-related adverse effects in the GMA group. Although we do not have an explanation for this, it warrants attention in further studies. In an era of conventional and selective immunosuppressive therapies, such a safe therapeutic approach would become appealing, particularly in frail patients such as the elderly and those with comorbidities or a recent diagnosis of cancer, if its efficacy could be demonstrated. In conclusion, our study failed to demonstrate that GMA is beneficial for the induction of steroid-free remission in patients with steroid-dependent UC. However, GMA increased time to relapse and was associated with a higher remission rate in patients who were naïve to thiopurines; these findings and the excellent safety profile of this non-pharmaceutical therapy warrant additional studies with more intensive or longer-lasting apheresis schedules. Funding This work was supported by an unrestricted research grant from Otsuka Pharmaceuticals. Conflict of Interest ED has received consulting or speaking fees from Abbvie, Janssen, MSD, Pfizer, Takeda, Kern Pharma, Otsuka Pharmaceuticals, Shield Therapeutics, and Shire. JP has received consulting or speaking fees from Abbvie, Amgen, Boehringuer-Ingelheim, Celgene, Ferring, Genentech, Janssen, MSD, Oppilan, Pfizer, Roche, Second Genome, Shire, Takeda, Theravance, and TiGenix. JH received consulting or speaking fees from MSD, Abbvie, Ferring, Faes Farma, Shire Pharmaceuticals, Chiesi, Otsuka Pharmaceutical, Pfizer—Hospira, Kern Pharma, UCB Pharma, Vifor Pharma, Janssen, Takeda, and Dr Falk Pharma. VA received consulting or speaking fees from Abbvie, Ferring, Pfizer—Hospira, Janssen, Takeda, Mundiplan, Alpha Wasserman, and Giuliani. FM received consulting or speaking fees from Ferring, OmPharma, MSD, Abbvie, Lab Vitoria, Vifor, Dr Falk, Takeda, and Hansen. VGS received consulting or speaking fees from MSD, Abbvie, Hospira, Kern Pharma, Takeda, Pfizer, Ferring, Faes Farma, Shire Pharmaceuticals, Dr Falk Pharma, Gebro Pharma, and Otsuka Pharmaceutical. AD received consulting or speaking fees from Abbvie, MSD, Ferring, Roche/Genentech, Vifor Pharma, Dr Falk Pharma, Takeda, Pharmacosmos, Mundipharma, Janssen, Allergosan, Hospira, Robarts, Pfizer, Sandoz/Hexal, Celgene, and Boehringuer-Ingelheim. JC has received consulting or speaking fees from Otsuka, MSD, Takeda, Pfizer, and Kern Pharma. JG has received consulting or speaking fees or research funding from MSD, AbbVie, Kern Pharma, Pfizer, General Electric Healthcare, and Ferring. DG received consulting or speaking fees from MSD, Abbvie, Janssen, Chiesi, Takeda, and Otsuka Pharmaceutical. All the remaining authors declare no conflict of interest. Author Contributions ED designed the research study, performed the research, analysed the data, and wrote the paper. JP, JH, VA, FM, and DG designed the research study, performed the research, analysed the data, and drafted the paper. GCS, FB, FF, BG-C, VG-S, AD, JMH, JLC, JG, MV, and FP performed the research, and critically revised the draft of the article. All authors approved the final version of the article, including the authorship list. Acknowledgement The authors thank the staff from Otsuka Pharmaceuticals in Spain, particularly Dr Raúl Lafuente for investing so much of his time and effort in this study. Appendix. List of investigators and centres of the ATICCA study group Luis Abreu, Hospital Puerta de Hierro, Madrid [Spain]; Xavier Aldeguer, Hospital Josep Trueta, Girona [Spain]; Montserrat Andreu, Hospital Parc de Mar, Barcelona [Spain]; Vito Anesse, AOU Careggi, Florence [Italy]; Juan Ignacio Arenas, Hospital de Donosti, Guipúzcoa [Spain]; Daniel C. Baumgart, Charité-Campus Virchow Klinikum, Berlin [Germany]; Manuel Barreiro-de-Acosta, Hospital Santiago de Compostela, Santiago [Spain]; Stephan Böhm, Kath Kliniken Ruhrhalbinsel, Essen [Germany]; Fabrizzio Bossa, Casa della Soferenza, San Giovanni Rotondo [Italy]; José Luis Cabriada, Hospital de Galdakao, Vizcaya [Spain]; Félix Calvo, Hospital de Albacete, Albacete [Spain]; Fernando Carballo, Hospital Virgen de la Arrixaca, Murcia [Spain]; Xavier Cortés, Hospital de Sagunto, Valencia [Spain]; Silvio Danese, Humanitas Clinical and Research Center, Rozzano [Italy]; Axel Dignass, Agaplesion Markus-Krankenhaus, Frankfurt/Main [Germany]; Eugeni Domènech, Hospital Universitari Germans Trias i Pujol, Badalona [Spain]; Maria Esteve, Hospital Mutua de Terrassa, Terrassa [Spain]; Francisco Fernández, Hospital Costa del Sol, Málaga [Spain]; Esther Garcia-Planella, Hospital de la Santa Creu i Sant Pau, Barcelona [Spain]; Bastianello Germanà, San Martino Hospital, Belluno [Italy]; Daniel Ginard, Hospital Son Dureta, Palma de Mallorca [Spain]; Benito González, Hospital Juan Canalejo, A Coruña [Spain]; Federico Gómez-Camacho, Hospital Reina Sofía, Córdoba [Spain]; Jordi Guardiola, Hospital de Bellvitge, L’Hospitalet del Llobregat [Spain]; Ana Gutiérrez, Hospital General de Alicante, Alicante [Spain]; José Manuel Herrera, Hospital Virgen del Rocío, Sevilla [Spain]; Vicent Hernández, Hospital do Meixoeiro, Vigo [Spain]; Joaquín Hinojosa, Hospital de Manises, Valencia [Spain]; Paula Lago, Geral de Santo António Hospital, Porto [Portugal]; Fernando Magro, São João Hospital, Porto [Portugal]; Míriam Mañosa, Hospital Universitari Germans Trias i Pujol, Badalona [Spain]; José Miguel Marrero, Hospital Insular de Las Palmas, Gran Canaria [Spain]; Paula Ministro, Centro Hospitalar Tondela-Viseu, Viseu [Portugal]; Fernando Muñoz, Hospital de León, León [Spain]; Francesco Pallone, Tor Vergata Hospital, Rome [Italy]; Julián Panés, Hospital Clínic, Barcelona [Spain]; José Lázaro Pérez-Calle, Hospital Fundación Alcorcón, Madrid [Spain]; Francisco Portela, Universidade de Coimbra, Coimbra [Portugal]; Walter Reinisch, Universitätsklinik Innere Medizin III, Vienna [Austria]; Giacomo Carlo Sturniolo, Padova Hospital, Padova [Italy]; Carlos Taxonera, Hospital Clínico San Carlos, Madrid [Spain]; Narcís Vázquez, Hospital de Elche, Elche [Spain]; Maurizio Vecchi, Policlinico San Donato, Milan [Italy]. 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Published by Oxford University Press. All rights reserved. For permissions, please email: firstname.lastname@example.org This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
Journal of Crohn's and Colitis – Oxford University Press
Published: Feb 27, 2018
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