Remission Trials Research Articles

Ethical issues in HIV remission trials.

Purpose of reviewSeveral promising experimental pathways exist for long-term control of HIV in the absence of antiretroviral therapy (HIV ‘remission’) and are now being tested in early clinical studies. These studies can be invasive and pose a host of distinctive risks to participants, as well as to nonparticipants, especially to participants’ fetuses, and sexual partners.Recent findingsEthical analyses of these studies have mainly focused on the risks to study participants. They recommend, and some investigators implement, procedures to mitigate risks for participants or to offset them with direct, indirect, and nonmedical benefits. They also suggest ways to keep participants’ consent highly voluntary and informed. Rarely do ethicists propose keeping the social value of studies high. Of these recommended responses, only the latter, rarer proposals help address the risk to nonparticipants, as would some novel ways to address that risk.SummaryHIV remission studies pose a number of ethical dilemmas. Many current investigative approaches put the participant at significant risk, but well established guidelines exist for mitigating this risk. Ethical issues that are not being fully addressed include risk to nonparticipants and the need to consider the societal value of studies, for example, their prospective impact on the global HIV burden.Video abstract

A-107 Early ART and HIV Remission: Experience from the RV254 and related HIV remission studies

Early antiretroviral therapy (ART) is an important step in the path towards an HIV cure. Acute HIV infection studies have demonstrated the ability to identify and treat very early infection in adults, resulting in significantly smaller HIV reservoirs, preserved immune functions with little viral escape to immune pressure. These results have been illustrated in the ongoing RV254 acute HIV infection study in Thailand that has enrolled close to 500 individuals. It has served as a platform to learn the effects of early ART and recruit participants for HIV remission trials. Despite the favorable qualities, the majority of early treated individuals do not achieve HIV remission. Indeed this has been the experience to date in the RV254 HIV remission trials, which include 3 completed studies and one ongoing, with others in development. The interventions have included latency-reversing agent, broadly neutralizing antibody and therapeutic HIV vaccine. However, there are important lessons to be learned that would inform the design of future HIV remission trials. There continues to be exciting new development of immune-based interventions. It is highly likely that combination therapies that can generate persistent and effective immune responses to control HIV will be required for a durable ART-free sustained remission of HIV.

53 Perceptions of HIV remission (“cure”) trials and trial intentions among potential participants treated in acute HIV infection

53 Perceptions of HIV remission (“cure”) trials and trial intentions among potential participants treated in acute HIV infection

Experience with outcomes research into the real-world effectiveness of novel therapies in Dutch daily practice from the context of conditional reimbursement

Policymakers more often request outcomes research for expensive therapies to help resolve uncertainty of their health benefits and budget impact at reimbursement. Given the limitations of observational data, we assessed its usefulness in evaluating clinical outcomes for bortezomib in advanced multiple myeloma patients. Data were retrospectively collected from patients included in the pivotal Assessment of Proteasome Inhibition for Extending Remissions trial (APEX; n=333) and two groups of daily practice patients treated with bortezomib following progression from upfront therapy (n=201): real-world patients treated as of May 2009 (RW-1; n=72) and June 2012 (RW-2; n=129). Prognosis, treatment, and effectiveness were compared. Outcomes research was useful for policymakers for addressing to whom and how bortezomib was administered in daily practice. It was limited however in generating robust evidence on real-world safety and effectiveness. The quality of real-world evidence on effectiveness was low due to missing data in patient charts, existing treatment variation and the dynamics in care during the novel drug's initial market uptake period. Policymakers requesting real-world evidence on clinical outcomes for reimbursement decisions should be aware of these limitations and advised to carefully consider beforehand the type of evidence that best addresses their needs for the re-assessment phase.

Suppression Of Uninvolved Immunoglobulin Has Significant Clinical Implication Including Predicting Relapse In Multiple Myeloma

IntroductionIn multiple myeloma, immunoparesis, defined as suppression of uninvolved immunoglobulins (UIg), is one of the most common indicators of immune dysfunction. UIgs are known to improve following therapy but its clinical significance remains under studied. Here, we have looked at frequency and significance of suppressed UIG and its recover following therapy as well as its recurrence at relapse. MethodsWe analyzed the data from the APEX trial to assess the frequency of UIg suppression in multiple myeloma and its impact on outcome. The APEX (Assessment of Proteosome Inhibition of Extending Remissions) trial was a randomized, international, Phase 3 trial in relapsed multiple myeloma comparing bortezomib 1.3 mg/m2 and dexamethasone 40 mg, as described in Richardson et al(NEJM 2005 Jun 16;352(24):2487-98). All patients previously received between 1 and 3 prior therapies. Immunoparesis was defined as one or two suppressed, UIgs. ResultsOf the 639 patients with measured immunoglobulins, 561 (88%) had suppression of at least one UIG. IgA was most commonly suppressed at 82% (n=390) of patients, followed by IgG at 76% (n=182), and IgM at 74% (n=468). Patients with suppressed UIg, as compared to patients with normal UIg were more likely have a higher ISS Stage (Stage 3 was 30% vs. 12%), and received more therapies (>2 therapies in 64% vs. 50%). Eight-seven % (n=270) and 88% (n=267) of patients receiving bortezomib or dexamethasone, respectively, had suppressed UIg. In the bortezomib arm, patients with and without suppressed UIgs had similar ORR (44% vs. 38%, p=.568). However, patients with normal baseline uninvolved Ig had longer median TTP (276 vs. 169 days, p=0.023) and trend towards longer median OS (NR vs. 836 days, p=0.0832) compared to suppressed UIg. Fifty-three patients (19%) that received bortezomib had normalization of uninvolved Ig. Compared to those with persistently suppressed UIgs, patients with normalized Ig had longer median TTP (HR=0.40, p=0.0003) and OS (HR 0.47, p=0.006). In the dexamethasone arm, patients without suppressed UIgs had a trend toward higher ORR (44% vs 38%, p=.145). Patients with normal baseline uninvolved Ig had longer median TTP (191 vs. 106 days, p=0.012) and trend towards longer median OS (956 vs. 640 days, p=0.066). Thirty-two patients (11%) receiving dexamethasone had normalization of uninvolved Ig. Compared to those with persistently suppressed UIg, patients with normalized Ig had longer median TTP (HR=0.52, p=0.0123) and OS (HR 0.43, p=0.0184). Interstingly in both arms, recurrence of suppression of UIg preceded clinical disease progression by 64 days (range, 1-227) suggesting suppressed UIg as one of the early indicator or impending relapse. ConclusionIn summary, patients with normal baseline uninvolved Ig have better TTP, and OS; that improvement in UIg correlates with improved TTP and OS and importantly UIg suppression can occur 2 months prior to disease progression, confirming a benefit to monitoring uninvolved immunoglobulins in myeloma. Disclosures:Neuwirth:Millennium: The Takeda Oncology Company: Employment. Esseltine:Millenium: The Takeda Oncology Company: Employment. Anderson:celgene: Consultancy; onyx: Consultancy; gilead: Consultancy; sanofi aventis: Consultancy; oncopep: Equity Ownership; acetylon: Equity Ownership. Richardson:Millennium: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Single-Arm, Open-Label, Multicenter Study Of Deep Molecular Response (MR4.5) With Nilotinib In Adult Patients (pts) With Newly Diagnosed Philadelphia Chromosome–Positive Chronic Myeloid Leukemia In Chronic Phase (CML-CP): ENESTnext Study Update

Single-Arm, Open-Label, Multicenter Study Of Deep Molecular Response (MR4.5) With Nilotinib In Adult Patients (pts) With Newly Diagnosed Philadelphia Chromosome–Positive Chronic Myeloid Leukemia In Chronic Phase (CML-CP): ENESTnext Study Update

Achievement and Maintenance Of Deeper Molecular Response By Switching To Nilotinib In Patients (pts) With Chronic Myeloid Leukemia In Chronic Phase (CML-CP) With Residual Disease On Long-Term Imatinib: ENESTcmr 36-Month Follow-Up

IntroductionThe 12- and 24-mo results of the Evaluating Nilotinib Efficacy and Safety in clinical Trials–complete molecular response (ENESTcmr) trial showed that pts with CML-CP with minimal residual disease after ≥ 2 y on imatinib achieved deeper molecular responses with switch to nilotinib. Results from ENESTcmr with 36-mo follow-up will be presented. MethodsPts with Philadelphia chromosome–positive (Ph+) CML-CP who had achieved complete cytogenetic response (CCyR) but had detectable BCR-ABL after ≥ 2 y on imatinib were included. Pts (N = 207) were randomized 1:1 to continue the same dose of imatinib (400 or 600 mg once daily [QD]; n = 103) or switch to nilotinib 400 mg twice daily (BID; n = 104). Rates of major molecular response (MMR; BCR-ABL ≤ 0.1% according to the International Scale [IS]) and MR4.5 (BCR-ABLIS ≤ 0.0032%) were evaluated by real-time quantitative polymerase chain reaction (RQ-PCR). Confirmed undetectable BCR-ABL was measured by RQ-PCR with a sensitivity of ≥ 4.5 logs, confirmed with a sensitivity of at least 4 logs in the next sample. Predictors of response were evaluated by multivariate logistic regression. Pts receiving imatinib were allowed to cross over to nilotinib if they had not achieved confirmed undetectable BCR-ABL by 24 mo or if they experienced treatment failure or confirmed loss of undetectable BCR-ABL at any time. ResultsBy 24 mo, 77% of pts in the nilotinib arm and 91% in the imatinib arm remained on study treatment. Discontinuation rates were comparable between arms during year 2; 7% and 5% of pts discontinued study treatment in the nilotinib and imatinib arms, respectively, between years 1 and 2. Three pts crossed over to nilotinib before 24 mo; the no. of pts who crossed over at or after 24 mo will be presented. By 24 mo, more pts in the nilotinib arm achieved confirmed undetectable BCR-ABL compared with imatinib (22.1% vs 8.7%; P = .0087; Table). Regardless of molecular response at study start, more pts in the nilotinib arm than the imatinib arm achieved MR4.5 by 24 mo. None of the pts in the imatinib arm who lacked MMR at study start achieved confirmed MR4.5 or confirmed undetectable BCR-ABL by 24 mo (vs 20.8% and 16.7% in the nilotinib arm, respectively). Twice as many pts achieved and maintained MR4.5 in 3 consecutive assessments in the nilotinib vs imatinib arm (n = 12 vs 6). Age, sex, BCR-ABL level at study start, duration of prior imatinib (≤ 36 mo vs > 36 mo), and prior interferon were analyzed as predictors of response in univariate and multivariate analyses. None of these was clearly predictive of achieving MR4.5 or undetectable BCR-ABL in multivariate logistic regression. No cases of progression to accelerated phase/blast phase were observed with 24 mo follow-up. Three pts in the imatinib arm had confirmed loss of CCyR vs 0 in the nilotinib arm. ConclusionsSwitching to nilotinib continues to induce deeper molecular responses in pts with minimal residual disease on long-term imatinib therapy. More pts achieved confirmed undetectable BCR-ABL in the nilotinib arm vs the imatinib arm, with the difference between arms increasing between 12 and 24 mo and notably marked in pts lacking MMR at study start. Maintenance of deeper molecular responses achieved with nilotinib therapy may enable more pts to benefit from treatment-free remission trials. Disclosures:Leber:novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cervantes:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Spector:Novartis: Honoraria, Research Funding. Lipton:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Etienne:Pfizer: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees. Guerci-Bresler:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis : Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN: Honoraria. Forrest:Bristol Myers Squibb: Consultancy. Schwarer:Bristol Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Collins:Novartis: Employment. Szczudlo:Novartis: Employment, Equity Ownership. Hughes:Araid: Consultancy, Honoraria; Bristol Myers Squib: Consultancy, Honoraria, Research Funding; Novarits: Consultancy, Honoraria, Research Funding; CSL: Research Funding.

Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT-Japan): Rationale and study design

The prevalence of end-stage renal disease (ESRD) is uprising in the paralleled with the increase of chronic kidney disease (CKD) patients. Diabetic nephropathy (DN) is the most important underlying disease of CKD and a leading cause of ESRD in Japan. Intensified multifactorial intervention in patients with type 2 diabetes with microalbuminuria slows the progression to nephropathy, and progression of retinopathy and autonomic neuropathy. However, further studies are needed to establish the effect of intensified multifactorial treatment on DN with overt proteinuria. In this trial, doctors and co-medicals collaborate to treat the DN patients to prevent the deterioration of DN by multifactorial intensive therapy. Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT-Japan) is an open, randomized controlled trial to evaluate the efficacy of renal protection of multifactorial intensive therapy in type 2 diabetes patients with overt proteinuria (urinary albumin-to-creatinine ratio ≥300 mg/g creatinine). The study has a targeted enrollment of 600 Japanese patients, and divided into two protocols by renal insufficiency (protocol A: serum creatinine: <1.2 mg/dl in male and <1.0 mg/dl in female, and protocol B: serum creatinine: 1.2–2.5 mg/dl in male and 1.0–2.5 mg/dl in female). The patients were allocated standard treatment or intensive multifactorial treatment. Intensive treatment was a stepwise implementation of behavior modification, pharmacological therapy targeting hyperglycaemia, hypertension, dyslipidaemia, and proteinuria. The primary outcome is the proteinuria in protocol A and the composite endpoint of time to the first occurrence of doubling of serum creatinine, ESRD (the need for chronic dialysis, or renal transplantation) or death in protocol B. The follow-up period is 5 years and the study ends in 2014.

Impact of prior therapies on the relative efficacy of bortezomib compared with dexamethasone in patients with relapsed/refractory multiple myeloma

This subgroup analysis of the phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial examined whether prior exposure to specific therapies affected the relative efficacy of bortezomib versus dexamethasone in relapsed/refractory myeloma. Time to progression and overall survival were superior with bortezomib in all subgroups, with no evidence of interaction between any prior therapies and assignment to study therapy. Patients with prior thalidomide exposure had worse outcomes overall, but neither prior thalidomide nor prior autologous stem cell transplantation affected the relative efficacy of bortezomib versus dexamethasone. These results confirm the superiority of bortezomib over dexamethasone, regardless of prior exposure to specific therapies (clinicaltrials.gov: NCT00048230).

Iatrogenic neuropathies

This review discusses the literature on peripheral neuropathy caused by medication-induced toxicity or immunological mechanism with special attention to recent advancements. The number of reports of immune-mediated neuropathies associated with antitumor necrosis factor alpha (anti-TNFalpha) therapy is increasing. But long-term follow-up suggests that the cessation of anti-TNFalpha therapy is not always necessary. The cases of acute inflammatory demyelinating polyneuropathy induced by polyethylene glycol-interferon alpha-2a and of polyradiculoneuropathy induced by polyethylene glycol-interferon alpha-2b were reported for the first time, and the latter was associated with antiganglioside antibodies. The mechanism of chemotherapy-induced peripheral neuropathy is still in the process of being elucidated with the use of animal models or axonal excitability techniques. In the phase III Assessment of Proteasome Inhibitor for Extending Remissions trial, it proved that dose modification using a specific guideline improved bortezomib-induced peripheral neuropathy management. Peripheral neuropathy can be associated with anti-TNFalpha therapy or interferon alpha therapy, and to the contrary, anti-TNFalpha therapy or interferon alpha therapy may have potential as a treatment option for a spectrum of immune-mediated neuropathy, similar to a double-edged sword. To take advantage of the effect of chemotherapy and to reduce neurotoxicity, a guideline of dose modification is useful.

Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose‐modification guideline

The frequency, characteristics and reversibility of bortezomib-associated peripheral neuropathy were evaluated in the phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial in patients with relapsed myeloma, and the impact of a dose-modification guideline on peripheral neuropathy severity and reversibility was assessed. Patients received bortezomib 1.3 mg/m(2) (days 1, 4, 8, 11, eight 21-d cycles, then days 1, 8, 15, 22, three 35-d cycles); bortezomib was held, dose-reduced or discontinued depending on peripheral neuropathy severity, according to a protocol-specified dose-modification guideline. Overall, 124/331 patients (37%) had treatment-emergent peripheral neuropathy, including 30 (9%) with grade >or=3; incidence and severity were not affected by age, number/type of prior therapies, baseline glycosylated haemoglobin level, or diabetes history. Grade >or=3 incidence appeared lower versus phase II trials (13%) that did not specifically provide dose-modification guidelines. Of patients with grade >or=2 peripheral neuropathy, 58/91 (64%) experienced improvement or resolution to baseline at a median of 110 d, including 49/72 (68%) who had dose modification versus 9/19 (47%) who did not. Efficacy did not appear adversely affected by dose modification for grade >or=2 peripheral neuropathy. Bortezomib-associated peripheral neuropathy is manageable and reversible in most patients with relapsed myeloma. Dose modification using a specific guideline improves peripheral neuropathy management without adversely affecting outcome.

The relationship between quality of response and clinical benefit for patients treated on the bortezomib arm of the international, randomized, phase 3 APEX trial in relapsed multiple myeloma

Quality of response is associated with prolonged overall survival (OS) in newly diagnosed multiple myeloma patients. This cohort study within the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of bortezomib versus dexamethasone in relapsed myeloma assessed the relationship between quality of response to bortezomib (n = 315) and clinical benefit. Treatment-free interval (TFI), time to alternative therapy (TTAT), time to progression (TTP) and OS were assessed in response-evaluable patients in the bortezomib arm in cohorts defined by achievement of complete response (CR; n = 27), very good partial response (VGPR; n = 31), partial response (PR; n = 77), minimal response (MR; n = 21) or non-response (NR, including stable and progressive disease; n = 159). CR was associated with significantly longer median TFI (24.1 vs. 6.9/6.4 months) and TTAT (27.1 vs. 13.6/14 months) versus VGPR/PR. Median TTP was similar in CR, VGPR and PR cohorts; median OS was not reached. Patients achieving MR appeared to have prolonged median TFI (3.8 vs. 2.3 months), TTAT (8.7 vs. 6.2 months), TTP (4.9 vs. 2.8 months) and OS (24.9 vs. 18.7 months) versus NR. In conclusion, bortezomib had substantial activity in relapsed myeloma patients; CR may be a surrogate marker for significant clinical benefit with bortezomib. MR appeared to be valid as a separate response category in this setting.

Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial

AbstractInitial analysis of the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of relapsed multiple myeloma patients showed significantly longer time to progression, higher response rate, and improved survival with single-agent bortezomib versus high-dose dexamethasone. In this updated analysis (median follow-up: 22 months), survival was assessed in both arms, and efficacy updated for the bortezomib arm. Median survival was 29.8 months for bortezomib versus 23.7 months for dexamethasone, a 6-month benefit, despite substantial crossover from dexamethasone to bortezomib. Overall and complete response rates with bortezomib were 43% and 9%, respectively; among responding patients, 56% improved response with longer therapy beyond initial response, leading to continued improvement in overall quality of response. Higher response quality (100% M-protein reduction) was associated with longer response duration; response duration was not associated with time to response. These data confirm the activity of bortezomib and support extended treatment in relapsed multiple myeloma patients tolerating therapy. This study is registered at http://clinicaltrials.gov (Study ID NCT00048230).

This Month in Gastroenterology

This Month in Gastroenterology

Enteral nutritional therapy for induction of remission in Crohn's disease

The role of enteral nutrition in Crohn's disease is controversial. Increasing research on the mechanisms by which nutritional therapy improves the clinical well being of patients with Crohn's disease has led to novel formula design and trials comparing two different forms of enteral nutrition. This meta-analysis aims to provide an update on the existing effectiveness data for both corticosteroids versus enteral nutrition and for one form of enteral nutrition versus another for inducing remission of active Crohn's disease. To evaluate the effectiveness of exclusive enteral nutrition (EN) as primary therapy to induce remission in Crohn's disease and to examine the importance of formula composition on effectiveness. Studies were selected using a computer-assisted search of the on-line bibliographic databases MEDLINE (1966-2006) and EMBASE (1984-2006), as well as the Science Citation Index on Web of Science. Additional citations were sought by manual search of references of articles retrieved from the computerized search, abstracts submitted to major gastroenterologic meetings and published in the journals: American Journal of Gastroenterology, Gut, Gastroenterology, Journal of Pediatric Gastroenterology and Nutrition, and Journal of Parenteral and Enteral Nutrition, and from the reviewers' personal files or contact with leaders in the field. All randomized and quasi-randomized controlled trials involving patients with active Crohn's disease defined by a clinical disease activity index were considered for review. Studies evaluating the administration of one type of enteral nutrition to one group of patients and another type of enteral nutrition or conventional corticosteroids to the other group were selected for review. Data were extracted independently by two authors and any discrepancies were resolved by rereading and discussion. For the dichotomous variable, achievement of remission, individual and pooled trial statistics were calculated as odds ratios (OR) with 95% confidence intervals (CI); both fixed and random effect models were used. The results for each analysis were tested for heterogeneity using the chi square statistic. The studies were separated into two groups: A. one form of enteral nutrition compared with another form of enteral nutrition and B. one form of enteral nutrition compared with corticosteroids. Subgroup analyses were conducted on the basis of clinical or disease criteria and formula composition. Sensitivity analyses were conducted on the basis of the inclusion of abstract publications, methodologic quality and by random or fixed effects models. In part A, of the 15 included eligible trials (one abstract) comparing different formulations of EN for the treatment of active CD, 11 compared one (or more) elemental formula to a non-elemental one, three compared enteral diets of similar protein composition but different fat composition, and one compared non-elemental diets differing only in glutamine enrichment. Meta-analysis of ten trials comprising 334 patients demonstrated no difference in the efficacy of elemental versus non-elemental formulas (OR 1.10; 95% CI 0.69 to 1.75). Subgroup analyses performed to evaluate the different types of elemental and non-elemental diets (elemental, semi-elemental and polymeric) showed no statistically significant differences. Further analysis of seven trials including 209 patients treated with EN formulas of differing fat content (low fat: < 20 g/1000 kCal versus high fat: > 20 g/1000 kCal) demonstrated no statistically significant difference in efficacy (OR 1.13; 95% CI 0.63 to 2.01). Similarly, the effect of very low fat content (< 3 g/1000 kCal) or type of fat (long chain triglycerides) were investigated, but did not demonstrate a difference in efficacy in the treatment of active CD, although a non significant trend was demonstrated favoring very low fat and very low long chain triglyceride content. This result should be interpreted with caution due to statistically significant heterogeneity and small sample size. Sensitivity analyses had no significant effects on the results. The role of specific fatty acids or disease characteristics on response to therapy could not be evaluated. In part B, eight trials (including two abstracts) comparing enteral nutrition to steroid therapy met the inclusion criteria for review. Meta-analysis of six trials that included 192 patients treated with enteral nutrition and 160 treated with steroids yielded a pooled OR of 0.33 favouring steroid therapy (95% CI 0.21 to 0.53). A sensitivity analysis including the abstracts resulted in an increase in the number of participants to 212 in the enteral nutrition group and 179 in the steroid group but the meta-analysis yielded a similar result (OR 0.36; 95% CI 0.23 to 0.56). There were inadequate data from full publications to perform further subgroup analyses by age, disease duration and disease location. Corticosteroid therapy is more effective than enteral nutrition for inducing remission of active Crohn's disease as was found in previous systematic reviews. Protein composition does not influence the effectiveness of EN in the treatment of active CD. A non significant trend favouring very low fat and/or very low long chain triglyceride content exists but larger trials are required to explore the significance of this finding.

Novel Treatment Options for Inflammatory Bowel Disease

The aetiology of inflammatory bowel disease (IBD) is complex and many aspects still remain unclear. However, significant progress has been made in understanding the pathogenesis of chronic inflammation in the intestine, and new insights have been gained recently. A better understanding of the immunopathology of IBD has led to the development of novel biological agents to target crucial molecules and processes in the inflammatory cascade. The development of novel therapies in the management of IBD has moved from empirical to scientific rational translation from bench to bedside. Lymphocyte infiltration into the intestinal tract in Crohn's disease (CD) is mediated by interaction between alpha4 integrin expressed on lymphocytes and its specific ligand mucosal vascular addressin cell adhesion molecule-1, expressed on the endothelial cells of the microvasculature in the inflamed intestinal tract. Development of monoclonal antibodies against alpha4 integrin permitted the targeting of lymphocyte trafficking into the intestine as a novel therapeutic intervention. Natalizumab, a recombinant humanised monoclonal antibody against alpha4 integrin, was effective in CD in a phase II randomised controlled trial. The highest response rate and remission rate were 71% and 44%, respectively, at 6 weeks after two infusions of natalizumab 3mg administered 4 weeks apart. Natalizumab was well tolerated in this trial. The phase III trial results are encouraging, although the primary efficacy endpoint of response at week 10 was not achieved. The maintenance of response and remission trial, ENACT (Evaluation of Natalizumab as Continuous Therapy)-2, has reported impressive efficacy in maintaining response and remission in those who responded in the initial induction of remission (ENACT-1) trial. This was associated with an improvement in quality-of-life parameters. A second humanised monoclonal antibody, MLN-02 (LDP-02), developed against alpha4beta7 has also shown evidence of efficacy in ulcerative colitis and CD. Although the clinical trials showed that inhibition of alpha4 integrin was well tolerated, use of natalizumab in multiple sclerosis and CD has raised serious concerns about the association with progressive multifocal leukoencephalopathy (PML) in a small number of patients, and the drug has been withdrawn from the market pending further safety evaluation. PML is caused by polyoma JC virus infection, is progressive and generally fatal, and is recognised to occur in patients with severe immunosuppression. Initial safety evaluation suggests that PML is very rare, despite its occurrence in one patient with CD receiving open-label natalizumab treatment.

The course of chronic plaque-type psoriasis in placebo groups of randomized controlled studies.

To determine the outcome in placebo-treated patients with plaque-type psoriasis. Online search of MEDLINE and EMBASE until January 2001 and the Cochrane Library (2001, issue 1), supplemented by references, reviews, guidelines, and textbooks. Randomized controlled induction of remission trials of patients with chronic plaque-type psoriasis with systemic treatments with a placebo group not treated with antipsoriatic medication. Identified studies were examined by 2 independent reviewers. Through MEDLINE, 290 studies could be identified. Twenty-seven placebo-controlled studies were included (488 patients). Two independent reviewers extracted data on first author, year of publication, design, comparison, placebo treatment, number of patients, treatment duration, type of psoriasis and baseline severity in the placebo group, mean relative change in outcome measures, and/or percentage of patients with worsening of psoriasis; no change; minimal, moderate, or good improvement; or complete clearance. Owing to substantial heterogeneity and differences in the way outcomes were reported, no summary estimates could be obtained. The outcome of placebo treatment was poor in most studies. Some reported a mean relative change of 11% to 47%. The highest percentages of patients ended up in the worsening, no change, or minimal improvement categories. Also, complete clearance was possible. No explanation for the differences in outcome between placebo groups could be found. Description of placebo groups was often insufficient. The effect of treatment in placebo groups varied across studies in an unpredictable way. To evaluate the variability, improvement of the standardization of study designs, entry criteria, and outcome measures is necessary in psoriasis trials.

Enteral nutritional therapy for inducing remission of Crohn's disease.

The role of enteral nutrition in Crohn's disease is controversial. Increasing research on the mechanisms by which nutritional therapy improves the clinical well being of patients with Crohn's disease has led to novel formula design and trials comparing two different forms of enteral nutrition. This systematic review aims to provide an update on the existing efficacy data for both corticosteroids versus enteral nutrition and for one form of enteral nutrition versus another for inducing remission of active Crohn's disease. To evaluate the efficacy of exclusive enteral nutrition as primary therapy to induce remission in Crohn's disease and to examine the importance of formula composition on efficacy. Studies were selected using a computer-assisted search of the on-line bibliographic databases MEDLINE (1966-2000) and EMBASE (1984-2000), as well as the Science Citation Index on Web of Science. Additional citations were sought by manual search of references of articles retrieved from the computerized search, abstracts submitted to major gastroenterologic meetings and published in the journals: Gut, Gastroenterology, Journal of Pediatric Gastroenterology and Nutrition, and Journal of Parenteral and Enteral Nutrition, and from the reviewers' personal files or contact with leaders in the field. All randomized and quasi-randomized controlled trials involving patients with active Crohn's disease defined by a clinical disease activity index were considered for review. Studies evaluating the administration of one type of enteral nutrition to one group of patients and another type of enteral nutrition or conventional corticosteroids to the other group were selected for review. Data were extracted independently by two reviewers and any discrepancies were resolved by rereading and discussion. For the dichotomous variable, achievement of remission, individual and pooled trial statistics were calculated as odds ratios (OR) with 95% confidence intervals (CI); both fixed and random effect models were used. The results for each analysis were tested for heterogeneity using the chi square statistic. The studies were separated into two groups: A. one form of enteral nutrition compared with another form of enteral nutrition and B. one form of enteral nutrition compared with corticosteroids. Subgroup analyses were conducted on the basis of clinical or disease criteria and formula composition. Sensitivity analyses were conducted on the basis of the inclusion of abstracts of studies not yet fully published, methodologic quality and by random or fixed effects models. In part A, of the 11 trials (one abstract) comparing different formulations of enteral nutrition ten compared one [or more (Middleton (a)1995)] elemental formulas to a non-elemental diet. The eleventh study (Akobeng 2000) compared two non-elemental diets differing only by glutamine enrichment in one group. This study was therefore not included in the primary analysis but was part of the subgroup analyses. Meta-analysis of nine studies which included 170 patients treated with an elemental diet and 128 patients treated with a non-elemental diet for active Crohn's disease demonstrated no significant difference among diet formulations [OR 1.15 (95% CI: 0.64, 2.08)]. Significant heterogeneity was not present [chi-square 9.77 (df=8)]. Subgroup and sensitivity analyses had no significant effect on the results. In part B, six trials (two abstracts) comparing enteral nutrition to steroid therapy met the inclusion criteria for review. Meta-analysis of four trials that included 130 patients treated with enteral nutrition and 123 treated with steroids yielded a pooled OR of 0.30 favouring steroid therapy (95% CI: 0.17, 0.52). Heterogeneity was not demonstrated [chi-square 0.43 (df=3)]. The risk difference calculated from this meta-analysis was 0.26, and the NNT (number of patients needed to treat with steroids rather than enteral nutrition to achieve one remission) was four. The same result was found in a sensitivity analysis that included abstracts. The inclusion of abstracts resulted in an increase in the number of participants to 150 in the enteral nutrition group and 142 in the steroid group but the meta-analysis yielded a similar result [OR 0.34 (95% CI: 0.20, 0.56)]. There were inadequate data from full publications to perform further subgroup analyses by age, disease duration and disease location. Corticosteroid therapy is more effective than enteral nutrition for inducing remission of active Crohn's disease as was found in past meta-analyses. There is no significant difference in the efficacy of elemental and non-elemental diets for induction of remission of Crohn's disease.

Medical therapy for induction and maintenance of remission in pouchitis: a systematic review.

To determine the effectiveness of medical therapy (including metronidazole, bismuth carbomer enemas, oral probiotic bacteria, butyrate suppositories, and glutamine suppositories) for inducing a response or for maintaining remission in pouchitis. Studies were selected using the MEDLINE data base (1966-December 1997), abstracts from major gastrointestinal meetings, and references from published articles and reviews. Four randomized controlled trials of medical therapy in adult patients with pouchitis were identified: two placebo controlled trials in active chronic pouchitis; one maintenance of remission trial comparing two active agents in chronic pouchitis; and one placebo-controlled maintenance of remission trial for chronic pouchitis. A single patient "n-of-1" trial for active chronic pouchitis was excluded. Data were extracted by three independent observers based on the intention to treat principle. Extracted data were converted to 2 x 2 tables (response versus no response and medical therapy versus placebo or medical therapy versus medical therapy) and an odds ratio with 95% confidence intervals (CI) were determined as described by Cochrane and Mantel and Haenszel. In addition, the absolute risk reduction, relative risk reduction, and number needed to treat were determined. The odds ratios of inducing a response using oral metronidazole or bismuth carbomer foam enemas compared with placebo in active chronic pouchitis were 12.34 (95% CI 2.34-64.95) and 1.00 (95% CI 0.29-3.42), respectively. The odds ratio of maintaining remission in chronic pouchitis for oral probiotic bacteria (VSL-3) compared with placebo was 15.33 (95% CI 4.51-52.14). There was no difference in the odds ratio of inducing symptomatic remission and then maintaining symptomatic remission after discontinuing suppressive medical therapy for chronic pouchitis with glutamine suppositories compared with butyrate suppositories, 2.75 (95% CI 0.48-15.94). Metronidazole is an effective therapy for active chronic pouchitis. Bismuth carbomer foam enemas are not effective therapy for active chronic pouchitis. Oral probiotic therapy with VSL-3 is an effective therapy for maintaining remission in patients with chronic pouchitis in remission. There is no difference in maintenance of symptomatic remission in patients with chronic pouchitis treated with glutamine versus butyrate suppositories, and it is unknown whether glutamine and butyrate are equally effective or ineffective. Additional randomized, double-blind, placebo-controlled, dose-ranging clinical trials are needed to determine the efficacy of empiric medical therapies currently being used in patients with pouchitis.

Pharmacotherapy for inducing and maintaining remission in pouchitis.

To determine the effectiveness of medical therapy (including metronidazole, bismuth carbomer enemas, oral probiotic bacteria, butyrate suppositories, and glutamine suppositories) for inducing a response or maintaining remission in pouchitis. Studies were selected using the MEDLINE data base (1966 - December 1997), abstracts from major gastrointestinal meetings and references from published articles and reviews. The Cochrane Controlled Trials Register and the Inflammatory Bowel Disease Review Group Trials Register were also searched. Four randomized controlled trials of medical therapy in adult patients with pouchitis were identified: two placebo controlled trials in active chronic pouchitis; one maintenance of remission trial comparing two active agents in chronic pouchitis; and one placebo-controlled maintenance of remission trial for chronic pouchitis. A single patient "n-of-1" trial for active chronic pouchitis was excluded. Data were extracted by three independent observers based on the intention to treat principle. Each study was given a quality score based on predetermined criteria. Extracted data were converted to 2X2 tables (response versus no response and medical therapy versus placebo or medical therapy versus medical therapy) and then synthesized in to a summary statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel (the "odds ratio" in MetaView). The odds ratios of inducing a response using oral metronidazole or bismuth carbomer foam enemas compared with placebo in active chronic pouchitis were 26.67 (95% CI 2.31-308.01) and 1.00 (95% CI 0.29-3.48), respectively. The numbers needed to treat with these therapies to prevent an additional relapse was 2 for oral metronidazole, and undefined for bismuth carbomer foam enemas (due to equal efficacy between the enema and placebo). The odds ratio of maintaining remission in chronic pouchitis for oral probiotic bacteria (VSL-3) compared with placebo was 205.00 (95% CI 9.89-4247.71), while the number needed to treat to prevent one additional relapse was 2. After discontinuation of suppressive medical therapy for chronic pouchitis, there was no difference in the odds ratio of maintaining symptomatic remission with glutamine suppositories compared to butyrate suppositories, 3. 00 (95% CI 0.46-19.59). The numbers needed to treat with glutamine suppositories to prevent an additional relapse was 4. The results presented in this review must be interpreted with extreme caution given the small numbers of trials and patients evaluated for any one comparison. Metronidazole appears to be an effective therapy for active chronic pouchitis. Bismuth carbomer foam enemas may not be an effective therapy for chronic active pouchitis. Oral probiotic therapy with VSL-3 appears to be an effective therapy for maintaining remission in patients with chronic pouchitis in remission. There is no evidence of a difference in the maintenance of symptomatic remission in patients with chronic pouchitis treated with glutamine versus butyrate suppositories, and it is unknown whether glutamine and butyrate are equally effective or ineffective. Additional randomized, double-blind, placebo-controlled, dose-ranging clinical trials are needed to determine the efficacy of empiric medical therapies currently being used in patients with pouchitis.