Megan Bowers

Prednisolone or Pentoxifylline for Alcoholic Hepatitis

BACKGROUND Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver impairment that occurs in patients with a history of heavy and prolonged alcohol use. The short-term mortality among patients with severe disease exceeds 30%. Prednisolone and pentoxifylline are both recommended for the treatment of severe alcoholic hepatitis, but uncertainty about their benefit persists. METHODS We conducted a multicenter, double-blind, randomized trial with a 2-by-2 factorial design to evaluate the effect of treatment with prednisolone or pentoxifylline. The primary end point was mortality at 28 days. Secondary end points included death or liver transplantation at 90 days and at 1 year. Patients with a clinical diagnosis of alcoholic hepatitis and severe disease were randomly assigned to one of four groups: a group that received a pentoxifylline-matched placebo and a prednisolone-matched placebo, a group that received prednisolone and a pentoxifylline-matched placebo, a group that received pentoxifylline and a prednisolone-matched placebo, or a group that received both prednisolone and pentoxifylline. RESULTS A total of 1103 patients underwent randomization, and data from 1053 were available for the primary end-point analysis. Mortality at 28 days was 17% (45 of 269 patients) in the placebo-placebo group, 14% (38 of 266 patients) in the prednisolone-placebo group, 19% (50 of 258 patients) in the pentoxifylline-placebo group, and 13% (35 of 260 patients) in the prednisolone-pentoxifylline group. The odds ratio for 28-day mortality with pentoxifylline was 1.07 (95% confidence interval [CI], 0.77 to 1.49; P=0.69), and that with prednisolone was 0.72 (95% CI, 0.52 to 1.01; P=0.06). At 90 days and at 1 year, there were no significant between-group differences. Serious infections occurred in 13% of the patients treated with prednisolone versus 7% of those who did not receive prednisolone (P=0.002). CONCLUSIONS Pentoxifylline did not improve survival in patients with alcoholic hepatitis. Prednisolone was associated with a reduction in 28-day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year. (Funded by the National Institute for Health Research Health Technology Assessment program; STOPAH EudraCT number, 2009-013897-42 , and Current Controlled Trials number, ISRCTN88782125 ).

Steroids or pentoxifylline for alcoholic hepatitis (STOPAH): study protocol for a randomised controlled trial

AbstractBackgroundAlcoholic hepatitis is the most florid presentation of alcohol-related liver disease. In its severe form, defined by a Maddrey’s discriminant function (DF) ≥32, the 28-day mortality rate is approximately 35%. A number of potential treatments have been subjected to clinical trials, of which two, corticosteroids and pentoxifylline, may have therapeutic benefit. The role of corticosteroids is controversial as trial results have been inconsistent, whereas the role of pentoxifylline requires confirmation as only one previous placebo-controlled trial has been published.Methods/designSTOPAH is a multicentre, double-blind, factorial (2 × 2) trial in which patients are randomised to one of four groups: 1.Group A: placebo / placebo2.Group B: placebo / prednisolone3.Group C: pentoxifylline / placebo4.Group D: pentoxifylline / prednisolone The trial aims to randomise 1,200 patients with severe alcoholic hepatitis, in order to provide sufficient power to determine whether either of the two interventions is effective. The primary endpoint of the study is mortality at 28 days, with secondary endpoints being mortality at 90 days and 1 year.DiscussionSTOPAH aims to be a definitive study to resolve controversy around the existing treatments for alcoholic hepatitis. Eligibility criteria are based on clinical parameters rather than liver biopsy, which are aligned with standard clinical practice in most hospitals. The use of a factorial design will allow two treatments to be evaluated in parallel, with efficient use of patient numbers to achieve high statistical power.Trial registrationEudraCT reference number: 2009-013897-42ISRCTN reference number: ISRCTN88782125

The clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH): a 2 × 2 factorial randomised controlled trial.

BACKGROUND Alcoholic hepatitis (AH) is a distinct presentation of alcoholic liver disease arising in patients who have been drinking to excess for prolonged periods, which is characterised by jaundice and liver failure. Severe disease is associated with high short-term mortality. Prednisolone and pentoxifylline (PTX) are recommended in guidelines for treatment of severe AH, but trials supporting their use have given heterogeneous results and controversy persists about their benefit. OBJECTIVES The aim of the clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis trial was to resolve the clinical dilemma on the use of prednisolone or PTX. DESIGN The trial was a randomised, double-blind, 2 × 2 factorial, multicentre design. SETTING Sixty-five gastroenterology and hepatology inpatient units across the UK. PARTICIPANTS Patients with a clinical diagnosis of AH who had a Maddreys discriminant function value of ≥ 32 were randomised into four arms: A, placebo/placebo; B, placebo/prednisolone; C, PTX/placebo; and D, PTX/prednisolone. Of the 5234 patients screened for the trial, 1103 were randomised and after withdrawals, 1053 were available for primary end-point analysis. INTERVENTIONS Those allocated to prednisolone were given 40 mg daily for 28 days and those allocated to PTX were given 400 mg three times per day for 28 days. OUTCOMES The primary outcome measure was mortality at 28 days. Secondary outcome measures included mortality or liver transplant at 90 days and at 1 year. Rates of recidivism among survivors and the impact of recidivism on mortality were assessed. RESULTS At 28 days, in arm A, 45 of 269 (16.7%) patients died; in arm B, 38 of 266 (14.3%) died; in arm C, 50 of 258 (19.4%) died; and in arm D, 35 of 260 (13.5%) died. For PTX, the odds ratio for 28-day mortality was 1.07 [95% confidence interval (CI) 0.77 to 1.40; p = 0.686)] and for prednisolone the odds ratio was 0.72 (95% CI 0.52 to 1.01; p = 0.056). In the logistic regression analysis, accounting for indices of disease severity and prognosis, the odds ratio for 28-day mortality in the prednisolone-treated group was 0.61 (95% CI 0.41 to 0.91; p = 0.015). At 90 days and 1 year there were no significant differences in mortality rates between the treatment groups. Serious infections occurred in 13% of patients treated with prednisolone compared with 7% of controls (p = 0.002). At the 90-day follow-up, 45% of patients reported being completely abstinent, 9% reported drinking within safety limits and 33% had an unknown level of alcohol consumption. At 1 year, 37% of patients reported being completely abstinent, 10% reported drinking within safety limits and 39% had an unknown level of alcohol consumption. Only 22% of patients had attended alcohol rehabilitation treatment at 90 days and 1 year. CONCLUSIONS We conclude that prednisolone reduces the risk of mortality at 28 days, but this benefit is not sustained beyond 28 days. PTX had no impact on survival. Future research should focus on interventions to promote abstinence and on treatments that suppress the hepatic inflammation without increasing susceptibility to infection. TRIAL REGISTRATION This trial is registered as EudraCT 2009-013897-42 and Current Controlled Trials ISRCTN88782125. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 102. See the NIHR Journals Library website for further project information. The NIHR Clinical Research Network provided research nurse support and the Imperial College Biomedical Research Centre also provided funding.

ProCAID: A phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone (DP) chemotherapy for metastatic castration resistant prostate cancer (mCRPC).

228 Background: DP extends survival in mCRPC. However emergent clinical resistance is effectively inevitable. Serine/threonine protein kinase AKT (protein kinase B) pathway activation is highly prevalent in mCRPC contributing to disease progression and DP therapeutic resistance. AZD5363 is a potent oral pan-AKT inhibitor. Pre-clinical data suggest activity in mCRPC and synergy with docetaxel. This phase I trial was to develop a DP/AZD5363 combination in mCRPC. Methods: Eligibility included chemotherapy naive histologically/cytologically proven measurable/evaluable mCRPC, PSA or radiographic disease progression, ECOG performance status 0 or 1, serum testosterone <1.7 nmol/L. Treatment comprised DP up to 10 cycles (75 mg/m2, IV, day 1; prednisolone 5 mg BID, PO, day 1–21) and AZD5363 to disease progression. Planned AZD5363 dose levels were 320 mg (DL1), 400 mg (DL2) and 480 mg (DL3), BID, PO, 4 days on/3 days off, from cycle 1, day 2. We utilised a conventional 3+3 dose escalation to determine a recommended...

Patterns of progression, treatment of progressive disease and post-progression survival in the New EPOC study.

Background:The addition of cetuximab (CTX) to perioperative chemotherapy (CT) for operable colorectal liver metastases resulted in a shorter progression-free survival. Details of disease progression are described to further inform the primary study outcome.Methods:A total of 257 KRAS wild-type patients were randomised to CT alone or CT with CTX. Data regarding sites and treatment of progressive disease were obtained for the 109 (CT n=48, CT and CTX n=61) patients with progressive disease at the cut-off date for analysis of November 2012.Results:The liver was the most frequent site of progression (CT 67% (32/48); CT and CTX 66% (40/61)). A higher proportion of patients in the CT and group had multiple sites of progressive disease (CT 8%, 4/48; CT and CTX 23%, 14/61 P=0.04). Further treatment for progressive disease is known for 84 patients of whom 69 received further CT, most frequently irinotecan based. Twenty-two patients, 11 in each arm, received CTX as a further line agent.Conclusions:Both the distribution of progressive disease and further treatment are as expected for such a cohort. The pattern of disease progression seen is consistent with failure of systemic micrometastatic disease control rather than failure of local disease control following liver surgery.

Salvage Chemotherapy With Gemcitabine, Paclitaxel, Ifosfamide, and Cisplatin for Relapsed Germ Cell Cancer

Background: Metastatic germ cell tumors remain potentially curable when treated with salvage chemotherapy at first relapse. In the present phase I/II study, we sought to improve on the response rate and duration of the TIP (paclitaxel, ifosfamide, cisplatin) regimen by adding gemcitabine (Gem‐TIP). Materials and Methods: Twenty patients were recruited after failure of first‐line cisplatin‐containing chemotherapy. The primary objectives were to determine the maximum tolerated dose of gemcitabine when combined with TIP and to establish the dose intensity of the TIP drugs in this combination. The secondary objectives were the response rates, failure‐free survival, and overall survival. Results: The maximum tolerated dose of gemcitabine was 1200 mg/m2. The mean relative dose intensity was 95% (95% confidence interval [CI], 90.2%‐99.2%) for gemcitabine, 96% (95% CI, 92.9%‐98.7%) for paclitaxel, 92% (95% CI, 84.5%‐98.8%) for ifosfamide, and 94% (95% CI, 89.3%‐99.0%) for cisplatin. The overall complete response rate was 50%; another 30% of the patients achieved a partial response. The 1‐year failure‐free survival and overall survival rates were 68% (95% CI, 43%‐84%) and 89.5% (95% CI, 64%‐97%), respectively. Conclusion: Gemcitabine can be added to TIP chemotherapy at the full dose, with manageable toxicity and no detrimental effect on the dose intensity of the TIP drugs. The response rate and duration were improved compared with those reported from the Medical Research Council TIP trial; further evaluation is warranted.

Design, method and application of stopping rules in a phase III 2x2 factorial randomised controlled trial.

Background The STOPAH trial was a double-blind, 2x2 factorial, phase III randomised clinical trial assessing the treatment of prednisolone and pentoxifylline in patients with severe alcoholic hepatitis; a study that aimed to evaluate 28-day mortality [1]. At the time of trial development, the benefits/harms of pentoxifylline in this patient population were unknown. Prednisolone had a significant though uncertain evidence base. No treatment interaction was assumed yet there was uncertainty about its effect. Therefore, pre-specified stopping rules to assist decision making in stopping treatment arms were required.

542PANALYSIS OF PROGRESSION FREE SURVIVAL IN THE NEW EPOC STUDY IN AN ALL RAS WILD-TYPE POPULATION

ABSTRACT Aim: The New EPOC study randomised KRAS exon 2 wild-type (WT) patients with resectable or suboptimally resectable colorectal liver metastases (CRLM) to receive chemotherapy with or without cetuximab before and after liver resection. KRAS status was determined using pyrosequencing in codons 12, 13 and 61. The trial demonstrated a detriment in progression free survival (PFS) from 20·5 to 14·1 months with the addition of cetuximab to chemotherapy (HR 1·48 95%CI 1·04-2·12 p = 0·03). Subsequently, benefit from epidermal growth factor inhibition in advanced disease was shown to be improved by further defining the population as all RAS WT (Douillard NEJM 2013). Methods: Samples of tumour from the primary colorectal and liver resections were obtained. Patients were further analysed using MiSeq for KRAS (codon 12, 13, 61, 117 and 146), BRAF (V600E), NRAS (12, 13, 61, 117 and 146), PIK3CA (547 and 1047) and EGFR S492R. Survival analyses were completed using the Kaplan-Meier method and the log-rank test. Results: To date 140 samples of primary tumour and 103 samples of CRLM have been analysed. Paired samples of primary tumour and CRLM were analysed for 61 patients. Further mutations were found in samples from 12 patients in the initial “KRAS WT” group, 8 KRAS (4 in codons previously analysed by pyrosequencing) and 4 NRAS. 3 mutations identified in CRLM were not in the matching primary. Analysis of the all RAS WT primary tumour population (chemo alone arm n = 53, chemo plus cetuximab arm n = 72) demonstrated a detriment in median PFS of 20 months to 15 months respectively (HR 1·4 95%CI 0·82-2·4 p = 0·22). 7 tumours were found to be BRAF mutated in all patients sequenced. Conclusions: In this study the addition of cetuximab to chemotherapy and surgery for operable CRLM in KRAS wild-type patients resulted in an inferior PFS. More stringent selection of an all RAS WT cohort did not alter the detriment observed. BRAF mutation is uncommon and likely reflects the selection of a relatively good prognosis cohort. Differences in mutational status between primary and metastasis were infrequent and could reflect either a treatment effect or clonal outgrowth. Initial pyrosequencing failed to detect Disclosure: J.A. Bridgewater: reports personal fees from Merck advisory board, Bayer advisory board, Sanofi-aventis advisory board, and Roche advisory board; R. Thiebaut: Employee of IntegraGen SA, Evry, France; F. Liebaert: Employee of IntegraGen SA, Evry, France; S. Falk: reports an Advisory board for Merck pharmaceuticals; J.W. Valle: reports personal fees and non-financial support from Merck J. Hornbuckle: reports non-financial support from Merck UK; T. Iveson: reports personal fees from Advisory Board for Merck Serono; T. Hickish: reports personal fees from Roche, Amgen, Sanofi Aventis, Novartis, Merck Serono advisory boards; D. Cunningham: reports grants from Roche, Amgen, Celgene, Sanofi, Merck Serono, Novartis, Astra Zeneca; T.S. Maughan: reports income from advisory board for Merck;J.N. Primrose: reports personal fees from Merck advisory board, Bayer advisory board, Sanofi-aventis advisory board, and Roche advisory board. All other authors have declared no conflicts of interest.