Methods
Study design and patients
The PROGAST trial, a study of budesonide as an agent for prevention of acute intestinal GvHD was a randomised, double-blind, placebo-controlled multicentre trial. The study was conducted at 3 centres from March 2003 through May 2007. The medical ethics committee of the TU Dresden and the ethics committee at Charité, Berlin approved the protocol, and all patients provided written informed consent. The trial was registered at
https://clinicaltrials.gov, number NCT00180089.
Eligible male and female patients were at least 12 years of age and in preparation for related or unrelated allogeneic SCT. The stem cell donors –related or unrelated- were selected based on the compatibility for 10 HLA alleles (HLA-A, −B, −C, DRB1 and DQB1) by high-resolution (2 digit for class I, 4 digit for class II) DNA typing. One single allele mismatch was allowed within the same broad serotype or within a cross-reactive group. GvHD prophylaxis regimes followed international standards with cyclosporine A or tacrolimus in combination with methotrexate, optionally combined with anti-thymocyte globulin (ATG) or alemtuzumab.
Patients who received a T-cell-depleted graft, or who had received budesonide within 4 weeks prior to transplantation, as well as patients with local gut infections, apparent infectious disease, portal hypertension, profound liver function impairment, liver cirrhosis or severe psychiatric diseases were excluded.
Study treatment and randomisation
Patients were randomly assigned to receive either oral budesonide (Budenofalk® 3 mg, Dr. Falk Pharma GmbH, Freiburg, Germany) at a daily dose of 9 mg (3 mg TID) or placebo. Budesonide was administered as a capsule. The galenical formulation assured a drug release according to a pH >6.4 which resembles the pH in the terminal ileum. Medication started one day before allogeneic SCT and was continued until day 56. Afterwards the patients went into a follow-up period until 12 months.
Randomisation was performed centrally with the use of a randomisation procedure stratified according to the relationship of the donor (related or unrelated), conditioning regimens ( dosage reduced or intensive), and in-vivo T-cell-depletion (with or without anti-thymocyte globulin (ATG)/alemtuzumab).
Evaluation of efficacy and safety
GvHD evaluation was performed weekly starting from day 5 until day 56 after SCT and followed by visits in week 12, 16, 20, 24 and 56. Clinical signs of intestinal GvHD were classified according to Glucksberg-classification [
24] of acute GvHD: occurrence of diarrhoea, bloody stools, abdominal pain, nausea and vomiting. If one of these symptoms emerged, a colonoscopy with specimens according to a standardized protocol was performed [
25]. GvHD was histologically classified following Lerner's classification [
26]. Monitoring for adverse events using common toxicity criteria (CTC) was performed until 12 months after transplantation.
Primary and secondary end points
The primary efficacy end point was the rate of patients with acute intestinal GvHD > stage 2 until day 100 after transplantation. Patients with histologic GvHD > grade 2 and patients with clinical signs of GvHD > stage 2 together with a positive histologic result for GvHD were classified as failures with respect to the primary end point. Secondary end points included the rate of patients with acute intestinal GvHD > stage 2 during follow-up until 12 months after transplantation, tolerability and safety of budesonide, severity of acute intestinal GvHD, incidence of chronic intestinal GvHD and infectious complications. Survival end points were overall and relapse-free survival, as well as relapse incidence and non-relapse mortality.
Study oversight
The study was jointly designed by haematologists and gastroenterologists of the University Hospital Dresden. A total of three centres participated in this trial (University Hospital Dresden, Charité-Campus Benjamin Franklin in Berlin, German Hospital for Diagnostics, Wiesbaden). Data was collected and analysed by the local Coordination Centre for Clinical Trials (KKS) in Dresden. The academic authors vouch for the veracity and completeness of the data and the data analyses.
Statistical analysis
For the primary end point, the rate of patients with acute intestinal GvHD > stage 2 after transplantation a rate of 30% for the placebo group was assumed. The expected incidence of GI GvHD seems to depend mainly on the frequency of endoscopic investigations. In fact Martin and coworkers [
27] could show that the incidence of early stages of gut GvHD can be as high as 60%, especially in recipients of grafts from unrelated donors. It was calculated that 242 patients would be needed to provide a power of 80% in order to detect a difference in GvHD occurrence of 15% among the two groups (budesonide versus placebo). The software was nQuery Advisor® 7.0.
The overall incidence of acute and chronic GvHD and infectious complications were compared with the use of the chi-square test and accordingly Fisher's exact test. Efficacy analyses were performed according to the intention-to-treat principle. All patients receiving at least one dose of the study drug were included in the safety analysis. Tolerability of budesonide was assessed by means of CTC score. The comparison of overall and relapse-free survival was made with Kaplan-Meier survival analysis [
28] and adjacent log-rank test between the budesonide and the placebo group. The cumulative incidence of stage 3 to 4 GI GvHD until 12 months after transplantation was calculated with death without intestinal GVHD as a competing risk [
29]. Relapse incidence and non-relapse mortality were considered as competing events. Cumulative incidences were compared with the Gray test. Cross tables were analysed by means of Fisher's exact test.
Discussion
GI GvHD remains a huge problem, with few therapeutic options. Acute GvHD is mediated by immunocompetent donor T cells, which migrate to lymphoid tissues soon after allogeneic stem cell transplantation. In the light of the high mortality of severe GI GvHD which often does not respond to steroid therapy, alternative treatments are being actively investigated. Besides the options of in-vivo or in-vitro T-cell-depletion, a prophylactic pharmacologic approach seems to be the most promising. Ideally, prophylactic treatment should not affect transplantation associated mortality and the incidence of relapse. T-cell-depleted grafts effectively reduce the risk of acute GvHD but are associated with a higher relapse rate because of the missing Graft-versus-leukemia effect. An intensified pharmacologic prophylaxis has been associated with an increase in the relapse rate, a higher rate of systemic infections and a late recurrence of GvHD.
A prophylactic approach with budesonide asa locally acting immunosuppressive treatment seems to be attractive because of a lower risk of systemic complications during therapy, as seen in patients with chronic inflammatory bowel disease. Underlying rationale is a strong anti-inflammatory local effect of budesonide on the one hand and a high first pass effect in the liver of more than 90%, which leads to negligible systemic effects on the other hand.
Even though the present study suggests that oral budesonide is not effective for the prevention of acute intestinal GvHD, early intervention in patients with a high-risk of gastrointestinal GvHD still seems to be an attractive strategy.
Furthermore it should be taken into account that the applied galenic formulation of budesonide has its maximum effect in the terminal ileum and right-sided colon. This is based on the pH-modified release of oral budesonide and therefore it is not adequate for prophylaxis of intestinal GvHD in the jejunum or proximal ileum. Some open-label studies showed efficacy in distal ulcerative colitis, but this finding has to be confirmed in controlled trials [
30]. Therefore it remains unclear, if budesonide has a sufficient effect in the prophylaxis of GvHD in the distal colon.
Besides pharmacokinetic analyses suggest that a single dose of 9 mg budesonide may lead to a higher local concentration of budesonide compared to 3 mg three times per day [
31] as performed in this study and therefore, could increase the therapeutic potential.
Overall infectious complications showed a trend to a higher frequency in the budesonide group, but gastrointestinal infections were equal in both groups and reflect better potentially side effects of locally acting budesonide.
As an additional second endpoint there was also no difference in the incidence of liver involvement, a site where the first-pass effect would lead to the assumption of a local efficacy of the study compound.
Competing interests
R. Schmelz has received honoraria for clinical studies and lecture fees from Dr. Falk Pharma GmbH.
M. Bornhäuser has received lecture honoraria from Novartis, Roche and Celgene.
J. Schetelig: has received lecture honoraria from Roche, Genzyme and GSK.
A. Kiani: no financial relationship.
U. Platzbecker has received lecture honoraria from Novartis, Amgen and Celgene.
U. Schwanebeck has received grant/research support for clinical trials from Ardeypharm GmbH, Smith & Nephew, UCB Pharma:Spouse/Partner, Pharmion GmbH, GlaxoSmithKline, Otsuka Frankfurt Research Institute, Support;Bristol-Myers Squibb Co. , Sanofi-Aventis, Support;TEVA, Novartis Pharma GmbH, Apogepha Pharma, GABA, Dr. Falk Pharma GmbH
X. Grählert has received grant/research support for clinical trials from Dr. Falk Pharma GmbH, GABA, Novartis, TEVA, Sanofi-Aventis, Bristol-Myers Squibb, Otsuka, GlaxoSmithKline, Pharmion, UCB Pharma, Smith & Nephew.
L. Uharek: no financial relationship
D. Aust has received lecture fees from Dr. Falk Pharma.
G. Baretton: no financial relationship.
R. Schwerdtfeger: no financial relationship.
J. Hampe: has received lecture honoraria from Dr. Falk Pharma GmbH and grant funding from Metanomics / BASF and Bayer AG.
R. Greinwald is an employee of Dr. Falk Pharma GmbH.
R. Mueller is an employee of Dr. Falk Pharma GmbH.
G. Ehninger: no financial relationship.
S. Miehlke has received honoraria for clinical studies, advisory boards, and lecture fees from Dr. Falk Pharma GmbH.
The trial was in part supported by Dr. Falk Pharma GmbH.