An open-label prospective randomized multicenter study of intensive versus weekly granulocyte and monocyte apheresis in active crohn’s disease

This was an open-label, prospective, randomized, multicenter study aimed at evaluating the clinical efficacy, safety, and the appropriate treatment schedule for GMA in patients with mild-to-moderately active CD. The study was conducted at 31 medical institutions from June 2010 to July 2014. Among the 31 study centers, 22 were academic, university institutes, 7 were municipal hospital centers, and 2 were private community clinics. All involved centers had adequate experience to undertake GMA therapy for patients with inflammatory bowel disease (IBD) (Additional file 1).

Male or non-pregnant female with a definitive diagnosis of CD (12–75 years of age) were eligible if they had their first CD episode or had relapsed with mild-to- moderately active CD. The severity of CD was determined by the Crohn’s disease activity index (CDAI) according to Becktel et al. [25]. Patients who had a CDAI score of 200 to 450 were classified as having mild-to-moderately active CD and were eligible. Disease location was to be in the colon or in the ileum and the colon (ileocolic). Patients with granulocytopaenia (neutrophil count <2000 per μl), serious heart or kidney malfunction, coagulation disorder, or had infection were to be excluded. Further, patients who had started a corticosteroid within one week, adalimumab within 2 weeks or infliximab within 6 weeks were excluded. Oral maintenance aminosalicylate was allowed if it had been given at a stable dose for at least 2 weeks before entry. This was at least 8 weeks for azathioprine/6-mercaptopurine. Concomitant medications for diseases other than CD, which did not violate the protocol inclusion criteria were allowed.

After screening and enrollment for this study, patients were randomly assigned to receive weekly GMA or receive intensive GMA, at two sessions per week in a 1:1 ratio. Randomization was done by a central computer-generated randomization scheme that assigned the eligible patient to a study centre.

GMA treatment was done as previously described [16]. Briefly, the Adacolumns® and blood circuit lines were primed with sterile saline to remove air bubbles from the column void volume and flow lines. A second priming of the system was done with heparinized saline. Blood access was through the antecubital vein in one arm and from the column outflow, blood returned to the patient via the antecubital vein in the contralateral arm. The duration of one GMA session was 60 min at a flow rate of 30 ml/min. Treatment was carried out partly in an outpatient setting and partly in an inpatient setting. Patients in the weekly GMA arm received one GMA session per week and those in the intensive GMA arm received two treatments sessions per week. The maximum number of GMA sessions allowed was 10. However, when a patient achieved remission (CDAI <150), GMA could be discontinued. The treatment and observation time was 77 days in the weekly GMA and 42 days in the intensive GMA.

With respect to the CD activity level, each patient was evaluated by determining the CDAI score at screening, baseline, and before each GMA session. The study primary end point was the rate of clinical remission defined as CDAI <150. The secondary end point was the time to remission, a key measurement for comparison of intensive GMA with weekly GMA. Evaluation of time to remission was according to a life-table analysis by using the Kaplan-Meier estimator graphs.

In Japan, GMA with the Adacolumn® is an officially approved treatment option for patients with IBD. However, before initiating the GMA therapy, our study protocol and patients’ informed consent forms were reviewed and approved by the Institutional Review Board at each study centre. Patients agreed to participate in this study after being informed of the study purpose, actions of GMA and the nature of the procedures involved. In case of an under-age patient, consent from one of the patient’s parents was sought. Written informed consent was obtained from all patients. The study was conducted with strict adherence to the Helsinki Declaration.

A total of 104 patients who were registered after screening were randomized to the weekly GMA arm (n = 49) or to the intensive GMA arm (n = 55). Five patients in the weekly GMA could not be included in the efficacy analysis, two had not reached CDAI score ≥200 at screening, one patient was not available for GMA therapy and the remaining two patients were found to have received GMA prior to assignment. Additionally, one patient who was assigned to the intensive GMA arm had received weekly GMA, this patient was included in the weekly GMA arm during the analysis of the treatment outcome (Fig. 1). Therefore, a total of 99 cases (45 in the weekly GMA and 54 in the intensive GMA) were available for efficacy evaluations as per protocol. There was no significant difference between the two groups with respect to patients’ baseline demographic variables including gender, age, CD duration, inpatient, outpatient, CDAI score and disease location (Table 1). Concomitant conventional pharmacological agents used by these patients included sulphasalazine, 5-aminosalicylic acid, prednisolone, azathioprine, and 6-mercaptopurine. There was no significant difference between the two groups with respect to concomitant medications.

As stated above, 45 of 49 patients randomized to the weekly GMA arm and 54 of 55 patients randomized to the intensive GMA arm were available for efficacy assessment as per protocol. During the 77 days of the study period in the weekly GMA arm, 16 of 45 patients (35.6 %) achieved clinical remission. Likewise, during the 42 days of the study period in the intensive GMA arm, 19 of 54 patients (35.2 %) achieved clinical remission, not significantly different from the weekly GMA arm.

In Fig. 2, the Kaplan-Meier estimator graphs show the cumulative remission rate in the weekly and the intensive GMA arms. The mean time to remission among the 16 patients in the weekly GMA who achieved clinical remission was 35.4 ± 5.3 days, while the mean time to remission in the 19 patients of the intensive GMA arm who achieved remission was 21.7 ± 2.7 days (P = 0.0373). Therefore, in CD patients, intensive GMA was associated with significantly more rapid remission as compared with the routinely applied weekly GMA.

In spite of randomized assignment of enrolled patients, baseline leucocyte count (normal range: 4000–9000/μL), erythrocyte sedimentation rate (ESR) (normal range: < 10 mm/hr (male); < 15 mm/hr (female)) and C-reactive protein (CRP) (normal range: < 0.3 mg/dL) concentration were found to be significantly higher in the intensive GMA group compared with the weekly GMA group, 8005/μL vs 7100/μL (P = 0.0273), 54.5 mm/hr vs 24.5 mm/hr (P = 0.0146) and 1.90 mg/dL vs 0.90 mg/dL (P = 0.0478), respectively. However, only in the intensive GMA group, leucocyte count (P = 0.0461) and ESR (P = 0.0059) were significantly reduced. Likewise, CRP level had decreased from 1.90 mg/dL to 0.80 mg/dL (P = 0.0941). In the weekly GMA, CRP level was significantly (P = 0.0277) decreased from 0.90 mg/dL at baseline to 0.35 mg/dL (P = 0.0277), but, leucocyte count and ESR level were not significantly affected (Table 2).

No device-related serious adverse event or unexpected adverse event was observed in either group. Adverse events were consistent with those generally observed during extracorporeal procedures including transient headache, dizziness, flushing, and pyrexia (Table 3). A total of 22 patients experienced none serious adverse events in the weekly GMA (n = 11) and the intensive GMA (n = 11) arms. In 5 of 11 patients in the weekly GMA and 6 of 11 patients in the intensive GMA, the adverse events were considered to be likely treatment related. No episode of opportunistic infection was observed in either group, suggesting that therapeutic depletion of large numbers of leucocytes by GMA might not lead to a weakened immune function. Further, both intensive and weekly GMA treatments were well tolerated by patients and there were no technical problems.