Randomised, double-blind, placebo-controlled trial of oral budesonide for prophylaxis of acute intestinal graft-versus-host disease after allogeneic stem cell transplantation (PROGAST)
© Schmelz et al.; licensee BioMed Central Ltd. 2014
Received: 26 August 2013
Accepted: 31 October 2014
Published: 26 November 2014
Gastrointestinal graft–versus-host disease (GvHD) is a potentially life-threatening complication after allogeneic stem cell transplantation (SCT). Since therapeutic options are still limited, a prophylactic approach seems to be warranted.
In this randomised, double-blind-phase III trial, we evaluated the efficacy of budesonide in the prophylaxis of acute intestinal GvHD after SCT. The trial was registered at https://clinicaltrials.gov, number NCT00180089.
Patients were randomly assigned to receive either 3 mg capsule three times daily oral budesonide or placebo. Budesonide was applied as a capsule with pH-modified release in the terminal ileum. Study medication was administered through day 56, follow-up continued until 12 months after transplantation. If any clinical signs of acute intestinal GvHD appeared, an ileocolonoscopy with biopsy specimens was performed.
The crude incidence of histological or clinical stage 3–4 acute intestinal GvHD until day 100 observed in 91 (n =48 budesonide, n =43 placebo) evaluable patients was 12.5% (95% CI 3-22%) under treatment with budesonide and 14% (95% CI 4-25%) under placebo (p = 0.888). Histologic and clinical stage 3–4 intestinal GvHD after 12 months occurred in 17% (95% CI 6-28%) of patients in the budesonide group and 19% (CI 7-32%) in the placebo group (p = 0.853). Although budesonide was tolerated well, we observed a trend towards a higher rate of infectious complications in the study group (47.9% versus 30.2%, p = 0.085). The cumulative incidences at 12 months of intestinal GvHD stage >2 with death as a competing event (budesonide 20.8% vs. placebo 32.6%, p = 0.250) and the cumulative incidence of relapse (budesonide 20.8% vs. placebo 16.3%, p = 0.547) and non-relapse mortality (budesonide 28% (95% CI 15-41%) vs. placebo 30% (95% CI 15-44%), showed no significant difference within the two groups (p = 0.911). The trial closed after 94 patients were enrolled because of slow accrual. Within the limits of the final sample size, we were unable to show any benefit for the addition of budesonide to standard GvHD prophylaxis.
Budesonide did not decrease the occurrence of intestinal GvHD in this trial. These results imply most likely that prophylactic administration of budenoside with pH-modified release in the terminal ileum is not effective.
KeywordsAcute intestinal Graft-versus-host disease Prophylaxis Allogeneic stem cell transplantation Budesonide
Acute intestinal GvHD is a frequent complication after allogeneic stem cell transplantation (SCT) and remains a major cause of morbidity and mortality. In spite of standard GvHD prophylaxis between 20 to 80% of the patients suffer from clinically relevant acute GvHD -. Whereas acute GvHD with affection of the skin and/or liver rarely becomes life-threatening, acute intestinal GvHD represents one of the most frequent causes of death after allogeneic SCT. Severe cases may suffer from watery stools up to a volume of several litres, bloody stools or ileus. The median survival of correspondent patients with acute GvHD grade 3 and 4 constitute between two and three months only . Therefore a prophylactic approach seems to be warranted.
Budesonide has demonstrated its efficacy in the treatment of various chronic inflammatory bowel diseases -. It is a locally acting steroid derived from 16α-hydroxyprednisolon with strong anti-inflammatory, antiexudative and anti-oedematous characteristics. The local effect of budesonide is comparable to prednisolone ,,. It underlies a high first pass effect in the liver and therefore is associated with fewer side effects compared to corticosteroids with systemic efficacy. The bioavailability accounts for 9 to 12%. Some reports of the effectiveness of budesonide and other locally acting steroids in acute GvHD already exist ,. A study on the potential value of budesonide for the prophylaxis of intestinal GvHD has not been performed.
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  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 . GvHD was histologically classified following Lerner's classification . 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.
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.
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  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  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 . 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.
Demographic and clinical characteristics at baseline
Budesonide (N = 48)
Placebo (N = 43)
Male sex - no. (%)
0.662 Median age (yrs) - Mean (SD)
53.1 + 12.2
52.0 + 12.9
Duration of disease (mths) -Mean (SD)
23.4 + 33.4
15.4 + 15.4
Complete remission pre-SZT - no. (%)
Basic disease - no. (%)
Myelodysplastic syndrome - MDS
Acute myeloid leucemia - AML
Acute lymphoblastic leucemia - ALL
Chronic myeloid leucemia - CML
Chronic lymphocytic leucemia - CLL
Non Hodgkin lymphoma - NHL /M. Hodgkin
Chemotherapeutic conditioning - no. (%)
Total body irradiation -TBI - no. (%)
Dosage reduced induction regimen (%)
In-vivo T-cell depletion (%)
Sibling transplant (%)
CMV-status positive - no. (%)
Primary end point
Incidence of acute intestinal GvHD > grade 2 until day 100 (p = 0.888 n.s.)
Acute intestinal GvHD grade 0-2
Acute intestinal GvHD grade 3-4
Nevertheless if the trial would have continued to enroll and results continued on current trajectory there would be no significant difference (1.5%) within the two groups.
Secondary end points
Adverse events and serious adverse events
Budesonide Budesonide (N = 48)
Placebo (N = 43)
Patients with any adverse event - no. (%)
Any serious adverse event - no. (%)
Infectious complications - no. (%)
Serious adverse event
The incidence of chronic intestinal GvHD showed a higher percentage in the placebo group (budesonide 6.3% (n = 3), placebo 11.6% (n = 5), but failed to reach significance.
The distribution of the severity stages of acute intestinal GvHD, as well as incidence and severity stages of skin, liver and grades of overall GvHD showed no difference between the two groups.
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 . 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  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.
In summary, this study failed to show a significant effect of prophylactic treatment with oral budesonide in preventing gastrointestinal GvHD. This study was closed prematurely because of slow accrual. Within the limitations of the sample size, no significance difference in outcomes were able to be detected in primary and secondary outcomes.
RS coordinated the study, performed statistical analysis and drafted the manuscript. MB conceived of the study, and participated in its design and coordination and helped to draft the manuscript. JS performed the statistical analysis and helped to draft the manuscript. AK helped to draft the manuscript.UP helped to draft the manuscript. US performed the statistical analysis. XG performed the statistical analysis. LU participated in the study design. DA performed histology. GB performed histology. RS participated in the study design. JH helped to draft the manuscript. RG participated in the study design. RM participated in the study design. GE conceived of the study and participated in its design. SM conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.
The study was partly supported by Dr. Falk Pharma GmbH, Freiburg, Germany.
- Deeg HJ, Antin JH: The clinical spectrum of acute graft-versus-host disease. Semin Hematol. 2006, 43 (1): 24-31. 10.1053/j.seminhematol.2005.09.003.View ArticlePubMedGoogle Scholar
- Washington K, Jagasia M: Pathology of graft-versus-host disease in thegastrointestinal tract. Hum Pathol. 2009, 40 (7): 909-917. 10.1016/j.humpath.2009.04.001.View ArticlePubMedGoogle Scholar
- Gratwohl A, Hermans J, Apperley J, Arcese W, Bacigalupo A, Bandini G, di Bartolomeo P, Boogaerts M, Bosi A, Carreras E: Acute graft-versus-host disease: grade and outcome in patients with chronic myelogenous leukemia. Working party chronic leukemia of the european group for blood and marrow transplantation. Blood. 1995, 86 (2): 813-818.PubMedGoogle Scholar
- Nash RA, Pepe MS, Storb R, Longton G, Pettinger M, Anasetti C, Appelbaum FR, Bowden RA, Deeg HJ, Doney K: Acute graft-versus-host disease: analysis of risk factors after allogeneic marrow transplantation and prophylaxis with cyclosporine and methotrexate. Blood. 1992, 80 (7): 1838-1845.PubMedGoogle Scholar
- Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D, Fay JW, Nademanee A, Antin JH, Christiansen NP, van der Jagt R, Herzig RH, Litzow MR, Wolff SN, Longo WL, Petersen FB, Karanes C, Avalos B, Storb R, Buell DN, Maher RM, Fitzsimmons WE, Wingard JR: Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood. 1998, 92 (7): 2303-2314.PubMedGoogle Scholar
- Vogelsang GB, Arai S: Mycophenolate mofetil for the prevention and treatment of graft-versus-host disease following stem cell transplantation: preliminary findings. Bone Marrow Transplant. 2001, 27 (12): 1255-1262. 10.1038/sj.bmt.1703076.View ArticlePubMedGoogle Scholar
- Weisdorf D, Haake R, Blazar B, Miller W, McGlave P, Ramsay N, Kersey J, Filipovich A: Treatment of moderate/severe acute graft-versus-host disease after allogeneic bone marrow transplantation: an analysis of clinical risk features and outcome. Blood. 1990, 75 (4): 1024-1030.PubMedGoogle Scholar
- Nevo S, Enger C, Swan V, Wojno KJ, Fuller AK, Altomonte V, Braine HG, Noga SJ, Vogelsang GB: Acute bleeding after allogeneic bone marrow transplantation: association with graft versus host disease and effect on survival. Transplantation. 1999, 67 (5): 681-689. 10.1097/00007890-199903150-00007.View ArticlePubMedGoogle Scholar
- Ferrara JL, Deeg HJ: Graft-versus-host disease. N Engl J Med. 1991, 324: 667-674. 10.1056/NEJM199103073241005.View ArticlePubMedGoogle Scholar
- Seow CH, Benchimol EI, Steinhart AH, Griffiths AM, Otley AR: Budesonide for Crohn's disease. Expert Opin Drug Metab Toxicol. 2009, 5 (8): 971-979. 10.1517/17425250903124355.View ArticlePubMedGoogle Scholar
- Campieri M, Ferguson A, Doe W, Persson T, Nilsson LG: Oral budesonide is as effective as oral Prednisolone in active Crohn's disease. The global budesonide study group. Gut. 1997, 41 (2): 209-214. 10.1136/gut.41.2.209.View ArticlePubMedPubMed CentralGoogle Scholar
- Ferguson A, Campieri M, Doe W, Persson T, Nygård G: Oral budesonide as maintenance therapy in Crohn's disease-results of a 12-month study. Global budesonide study group. Aliment Pharmacol Ther. 1998, 12 (2): 175-183. 10.1046/j.1365-2036.1998.00285.x.View ArticlePubMedGoogle Scholar
- Greenberg GR, Feagan BG, Martin F, Sutherland LR, Thomson AB, Williams CN, Nilsson LG, Persson T: Oral budesonide as maintenance treatment for Crohn's disease: a placebo-controlled, dose-ranging study. Gastroenterology. 1996, 110 (1): 45-51. 10.1053/gast.1996.v110.pm8536887.View ArticlePubMedGoogle Scholar
- Hellers G, Cortot A, Jewell D, Leijonmarck CE, Löfberg R, Malchow H, Nilsson LG, Pallone F, Pena S, Persson T, Prantera C, Rutgeerts P: Oral budesonide for prevention of postsurgical recurrence in Crohn's disease. Gastroenterology. 1999, 116 (2): 294-300. 10.1016/S0016-5085(99)70125-3.View ArticlePubMedGoogle Scholar
- Löfberg R, Danielsson A, Suhr O, Nilsson A, Schiöler R, Nyberg A, Hultcrantz R, Kollberg B, Gillberg R, Willén R, Persson T, Salde L: Oral budesonide versus Prednisolone in patients with active extensive and left-sided ulcerative colitis. Gastroenterology. 1996, 110 (6): 1713-1718. 10.1053/gast.1996.v110.pm8964395.View ArticlePubMedGoogle Scholar
- Miehlke S, Heymer P, Bethke B, Bästlein E, Meier E, Bartram HP, Wilhelms G, Lehn N, Dorta G, DeLarive J, Tromm A, Bayerdörffer E, Stolte M: Budesonide treatment for collagenous colitis: a randomized, double-blind, placebo-controlled, multicenter trial. Gastroenterology. 2002, 123 (4): 978-984. 10.1053/gast.2002.36042.View ArticlePubMedGoogle Scholar
- Miehlke S, Madisch A, Karimi D, Wonschik S, Kuhlisch E, Beckmann R, Morgner A, Mueller R, Greinwald R, Seitz G, Baretton G, Stolte M: Budesonide is effective in treating lymphocytic colitis: a randomized double-blind placebo-controlled study. Gastroenterology. 2009, 136 (7): 2092-2100. 10.1053/j.gastro.2009.02.078.View ArticlePubMedGoogle Scholar
- McDonald GB: Oral beclomethasone dipropionate: a topically active corticosteroid for the treatment of gastrointestinal graft-versus-host disease following allogeneic hematopoietic cell transplantation. Expert Opin Investig Drugs. 2007, 16 (10): 1709-1724. 10.1517/13543718.104.22.1689.View ArticlePubMedGoogle Scholar
- McKeage K, Goa KL: Budesonide (Entocort EC Capsules): a review of its therapeutic use in the management of active Crohn's disease in adults. Drugs. 2002, 62 (15): 2263-2282. 10.2165/00003495-200262150-00015.View ArticlePubMedGoogle Scholar
- Rutgeerts P, Löfberg R, Malchow H, Lamers C, Olaison G, Jewell D, Danielsson A, Goebell H, Thomsen OO, Lorenz-Meyer H, Hodgson H, Persson T, Seidegard C: A comparison of budesonide with prednisolone for active Crohn's disease. N Engl J Med. 1994, 331 (13): 842-845. 10.1056/NEJM199409293311304.View ArticlePubMedGoogle Scholar
- Brogden RN, McTavish D: Budesonide. An updated review of its pharmacological properties, and therapeutic efficacy in asthma and rhinitis. Drugs. 1992, 44 (3): 375-407. 10.2165/00003495-199244030-00007. Erratum in: Drugs. 1992 Dec;44(6):1012. Drugs. 1993 Jan;45(1):1301View ArticlePubMedGoogle Scholar
- Bertz H, Afting M, Kreisel W, Duffner U, Greinwald R, Finke J: Feasibility and response to budesonide as topical corticosteroid therapy for acute intestinal GVHD. Bone Marrow Transplant. 1999, 24 (11): 1185-1189. 10.1038/sj.bmt.1702055.View ArticlePubMedGoogle Scholar
- McDonald GB, Bouvier M, Hockenbery DM, Stern JM, Gooley T, Farrand A, Murakami C, Levine DS: Oral beclomethasone dipropionate for treatment of intestinal graft-versus-host disease: a randomized, controlled trial. Gastroenterology. 1998, 115 (1): 28-35. 10.1016/S0016-5085(98)70361-0.View ArticlePubMedGoogle Scholar
- Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, Lerner KG, Thomas ED: Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974, 18 (4): 295-304. 10.1097/00007890-197410000-00001.View ArticlePubMedGoogle Scholar
- Cruz-Correa M, Poonawala A, Abraham SC, Wu TT, Zahurak M, Vogelsang G, Kalloo AN, Lee LA: Endoscopic findings predict the histologic diagnosis in gastrointestinal graft-versus-host disease. Endoscopy. 2002, 34 (10): 808-813. 10.1055/s-2002-34257.View ArticlePubMedGoogle Scholar
- Lerner KG, Kao GF, Buckner CD, Clift RA, Thomas ED: Histopathology of graft-vs.-host reaction (GvHR) in human recipients of marrow from HL-A-matched sibling donors. Transplant Proc. 1974, 6: 367-371.PubMedGoogle Scholar
- Martin PJ, McDonald GB, Sanders JE, Anasetti C, Appelbaum FR, Deeg HJ, Nash RA, Petersdorf EW, Hansen JA, Storb R: Increasingly frequent diagnosis of acute gastrointestinal graft-versus-host disease after allogeneic hematopoietic celltransplantation. Biol Blood Marrow Transplant. 2004, 10 (5): 320-327. 10.1016/j.bbmt.2003.12.304.View ArticlePubMedGoogle Scholar
- Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958, 53: 457-462. 10.1080/01621459.1958.10501452.View ArticleGoogle Scholar
- Lin DY: Non-parametric inference for cumulative incidence functions in competing risks studies. Stat Med. 1997, 16: 901-910. 10.1002/(SICI)1097-0258(19970430)16:8<901::AID-SIM543>3.0.CO;2-M.View ArticlePubMedGoogle Scholar
- Gross V: Oral pH-modified release budesonide for treatment of inflammatory bowel disease, collagenous and lymphocytic colitis. Expert Opin Pharmacother. 2008, 9 (7): 1257-1265. 10.1517/14656522.214.171.1247.View ArticlePubMedGoogle Scholar
- Kolkman JJ, Möllmann HW, Möllmann AC, Penã AS, Greinwald R, Tauschel HD, Hochhaus G: Evaluation of oral budesonide in the treatment of active distal ulcerative colitis. Drugs Today (Barc). 2004, 40 (7): 589-601. 10.1358/dot.2004.40.7.850477.View ArticleGoogle Scholar
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