Randomised clinical trial: identification of responders to short-term treatment with esomeprazole for dyspepsia in primary care - a randomised, placebo-controlled study

Aliment Pharmacol Ther 2011; 33: 41–49

Summary

Background Response to proton pump inhibitor (PPI) treatment in dyspepsia is unpredictable. Aim To identify symptoms associated with response to esomeprazole in order to target patients for empirical treatment. Methods Eight hundred and five uninvestigated, primary care patients with upper GI symptoms that were considered to be acid‐related were randomised to 2 weeks’ treatment with esomeprazole 40 mg or placebo. The study population was divided into a model sample (N = 484) and a validation sample (N = 321). We developed a therapeutic index to predict PPI response from the model sample and tested this in the validation sample. Results Response to PPI was found in 68% of patients (44% in placebo arm). Bothersome heartburn and early satiety were associated with increased likelihood of PPI response, whereas dull abdominal pain, pain relieved by bowel movements and nausea in women were associated with a decreased likelihood of PPI response. Patients in the validation sample could be classified as having a ‘very high’ (n = 55), ‘high’ (n = 123), ‘medium’ (n = 78) or ‘low’ (n = 65) probability of PPI response. The therapeutic gains over placebo were 55%, 31%, 20% and 22%, respectively. Conclusions In patients with uninvestigated dyspepsia, PPI responders can be reliably identified by a simple pocket chart using symptoms and patient characteristics (ClinicalTrials.gov NCT00318968).     

Symptom overlap in patients with upper gastrointestinal complaints in the Canadian confirmatory acid suppression test (CAST) study: further psychometric validation of the reflux disease questionnaire

BACKGROUND: The reflux disease questionnaire (RDQ) is a short, patient-completed instrument. AIMS: To investigate the psychometric characteristics of the RDQ in patients with heartburn-predominant (HB) and non-heartburn predominant (NHB) dyspepsia. METHODS: HB (n = 388) and NHB (n = 733) patients were randomized to esomeprazole 40 mg daily or twice daily for 1 week, followed by 3 weeks of esomeprazole 40 mg daily. RESULTS: High factor loadings (0.78-0.86) supported the 'regurgitation' dimension of the RDQ. Overlapping factor loadings in the 'heartburn' and 'dyspepsia' dimensions suggested symptom overlap. All dimensions demonstrated high internal consistency (Cronbach's alpha: 0.79-0.90). Intra-class correlation coefficients over 4 weeks were good (0.66-0.85). The RDQ showed good responsiveness over 4 weeks of treatment, with high effect sizes (> or =0.80). Moderate or large symptom improvements were reported by 90% and 77% of HB and NHB patients, respectively, following treatment. Patients who responded to acid suppression also experienced symptom benefits in all RDQ dimensions. CONCLUSIONS: The RDQ is reliable, valid and responsive to change in HB and NHB patients. The symptom overlap is important but need not play a major role in determining treatment strategy as both patient groups benefited from proton pump inhibitor treatment.     

Clinical trial: the effects of certolizumab pegol therapy on work productivity in patients with moderate‐to‐severe Crohn’s disease in the PRECiSE 2 study

Aliment Pharmacol Ther 31 , 1276–1285

Summary

Background The effect of certolizumab pegol on employment status and work productivity has not been previously assessed. Aim To assess the impact of treatment with certolizumab pegol, the only PEGylated, Fab′ TNF antagonist, on work productivity in patients with active Crohn’s disease (CD) from the PRECiSE 2 study. Methods Patients (n = 668) with active disease [CD activity index (CDAI) score of 220–450] were treated with open‐label subcutaneous certolizumab pegol 400 mg (week 0, 2, 4). Responders (n = 425) (≥100‐point decrease in CDAI from baseline) were randomized to receive certolizumab pegol 400 mg or placebo every 4 weeks until week 24, with final evaluation at week 26. Patients completed the Work Productivity and Activity Impairment for CD questionnaire (WPAI:CD) and the Inflammatory Bowel Disease Questionnaire (IBDQ) at weeks 0, 6, 16 and 26 and at the withdrawal visit. Results Work productivity improved following induction with certolizumab pegol. Between week 6 and 26, certolizumab pegol‐treated patients experienced significant improvement in work productivity compared with placebo recipients (11% and 10% overall improvement in work and activity impairment, respectively). During the maintenance phase, impairments in productivity and activities due to CD were significantly less in the certolizumab pegol group than in the placebo group. Conclusion Induction and maintenance therapy with certolizumab pegol significantly improved the work productivity of patients with active CD compared with those in the placebo group.     

Randomized‐controlled trial of esomeprazole in functional dyspepsia patients with epigastric pain or burning: does a 1‐week trial of acid suppression predict symptom response?

BACKGROUND: Early identification of true responders to acid suppression in functional dyspepsia patients with symptoms of epigastric pain or burning may enable clinicians to optimally tailor treatment. AIM: To evaluate whether a 1-w acid suppression trial is useful for identifying true responders in this population. METHODS: Patients (18-70 years) were randomized to either esomeprazole 40 mg q.d.s., b.d. or placebo for 1w, and then esomeprazole 40 mg q.d.s. or placebo for 7w. Epigastric pain and/or burning were recorded on a 4-point scale (0 = none, 3 = severe). Trial-week response was defined as symptom score sum < or = 1 on last 3d of therapy; response at 8w was symptom score sum < or = 1 over preceding 7d. RESULTS: 1-w response rates were 33% (199 of 597), 29% (188 of 629) and 23% (71 of 315) with esomeprazole q.d.s., esomeprazole b.d. and placebo, respectively (P = 0.002 for esomeprazole groups vs. placebo). At 8w, trial week sensitivity and specificity were 46% and 80%, respectively, for esomeprazole (40 or 80 mg), and 33% and 87%, respectively, for placebo. The positive and negative predictive values for esomeprazole were 60% and 69%. CONCLUSION: Response to a 1-w acid suppression trial is of limited use for predicting symptom response at 8w in patients with unexplained epigastric pain or burning.     

One-week acid suppression trial in uninvestigated dyspepsia patients with epigastric pain or burning to predict response to 8 weeks' treatment with esomeprazole: a randomized, placebo-controlled study

BACKGROUND: While empiric acid-suppressive therapy for uninvestigated dyspepsia patients with symptoms of epigastric pain or burning is standard practice, it is unknown whether an early response to therapy predicts outcome. AIM: To evaluate whether a 1-w acid suppression trial is effective for predicting 8-w response in such patients. METHODS: Helicobacter pylori-negative patients (aged 18-50 years) in primary care with uninvestigated epigastric pain or burning were randomized to esomeprazole 40 mg q.d.s. or b.d. for 1w, followed by esomeprazole 40 mg q.d.s. or placebo for 7w. Each day, patients rated the severity of their symptoms. RESULTS: Based on the last 3d, 1-w response rates were 39% (231 of 588) and 43% (258 of 596) with esomeprazole 40 mg q.d.s. and b.d., respectively. Based on the last 7d, response rates at 4w were 38% (283 of 738) and 25% (93 of 380) for esomeprazole and placebo, respectively, and 47% (339 of 716) and 34% (124 of 368), respectively, at 8w (both P < 0.001 vs. placebo). The sensitivity and specificity of esomeprazole treatment were 58% and 70%, respectively, at 8w. CONCLUSION: A 1-w acid suppression trial is of limited clinical value for predicting 8-w response in patients with symptoms of epigastric pain or burning. Esomeprazole provides greater symptom control than placebo at 4w and 8w.     

The Work Productivity and Activity Impairment Questionnaire for Patients with Gastroesophageal Reflux Disease (WPAI-GERD): responsiveness to change and English language validation

BACKGROUND: A validated productivity questionnaire, the Work Productivity and Activity Impairment questionnaire for Gastroesophageal Reflux Disease (WPAI-GERD), exists for Swedish patients with GERD. OBJECTIVE: To assess responsiveness to change of the WPAI-GERD and construct validity of the English language version. METHODS: We used the WPAI-GERD in a before-after treatment clinical study of Canadian GERD patients with moderate or severe symptoms treated with esomeprazole 40 mg once daily for 4 weeks. We measured productivity variables including GERD-specific absence from work, reduced productivity while at work and reduced productivity while carrying out regular daily activities other than work during the preceding week. RESULTS: The analysis included 217 patients, of whom 71% (n = 153) were employed. Before treatment, employed patients reported an average 0.9 hours of absence from work due to GERD and 14.0% reduced work productivity (5.8 hours equivalent) in the previous week, as well as 21.0% reduced productivity in daily activities (all patients). After treatment, the corresponding figures decreased to 0.3 hours, 3.0% (1.1 hours equivalent) and 4.9%, respectively. Thus, the improvement (difference from start of treatment) in productivity was 0.6 hours (p = 0.011) for absence from work and 11.0% units (p < 0.001) for reduced work productivity (4.7 hours equivalent, p < 0.001). This translated into an avoided loss of work productivity of 5.3 hours in total on a weekly basis per employed patient. In addition, a 16.1% unit (p < 0.001) improvement for reduced productivity in activities was observed. Cross-sectional correlation coefficients of WPAI variables with symptoms (range 0.04-0.63) and health-related quality of life (HR-QOL; range 0.02-0.65) supported cross-sectional construct validity. Corresponding change score correlations between WPAI variables and HR-QOL (range 0.05-0.56) supported longitudinal construct validity of the WPAI-GERD while low change score correlations between productivity variables and relevant symptoms (range 0.06-0.34) did not. CONCLUSION: The English version of the WPAI-GERD showed good cross-sectional construct validity, and results indicated that the WPAI-GERD is responsive to change. Although the results also indicated that longitudinal construct validity may be poor, the overall findings suggest that further study of the instrument remains warranted.     

Clinical trial: esomeprazole for moderate‐to‐severe nighttime heartburn and gastro‐oesophageal reflux disease‐related sleep disturbances

Aliment Pharmacol Ther 2010; 32: 182–190

Summary

Background Nighttime heartburn, common among patients with gastro‐oesophageal reflux disease (GERD), is associated with substantial clinical effects. GERD‐related sleep disturbances are underappreciated and undertreated. Aim To evaluate the efficacy of esomeprazole on GERD‐related nighttime heartburn and associated sleep disturbances. Methods In this multicentre, randomized, double‐blind, placebo‐controlled study, patients with moderate‐to‐severe nighttime heartburn and GERD‐related sleep disturbances (endoscopies not required) received esomeprazole 20 mg or placebo each morning for 4 weeks. Heartburn symptoms and GERD‐related sleep disturbances were evaluated using the validated Pittsburgh Sleep Quality Index and validated Work Productivity and Activity Impairment Questionnaire. Results The analysis included 262 patients (esomeprazole, n = 137; placebo, n = 125). Significantly more patients receiving esomeprazole achieved nighttime heartburn relief (primary end point) than those receiving placebo (34.3% vs. 10.4%; P < 0.0001). Secondary end points such as relief of GERD‐related sleep disturbances (P = 0.006), days without GERD‐related sleep disturbances (P = 0.0003) and complete resolution of sleep disturbances (P < 0.0001) favoured esomeprazole over placebo. Sleep quality, work productivity and regular daily activities also improved significantly with esomeprazole vs. placebo. Conclusions Esomeprazole 20 mg is effective for patients with moderate‐to‐severe nighttime heartburn and GERD‐related sleep disturbances, improving heartburn symptoms, sleep quality, work productivity and functionality.

     

Randomised clinical trial: a novel rabeprazole extended release 50 mg formulation vs. esomeprazole 40 mg in healing of moderate-to-severe erosive oesophagitis - the results of two double-blind studies

Aliment Pharmacol Ther 2011; 33: 203–212

Summary

Background Current PPIs may not achieve desired outcomes in some GERD patients due to limited duration of acid inhibition. Aim To evaluate a novel rabeprazole extended release (ER), which provides longer duration of drug exposure and acid suppression, in healing and symptomatic resolution of moderate‐severe erosive oesophagitis. Methods Patients with LA grade C or D oesophagitis were randomised to rabeprazole‐ER 50 mg or esomeprazole 40 mg once daily in two identical 8‐week double‐blind trials (N = 2130). Two primary endpoints were tested sequentially: (1) healing by 8 weeks [hypothesis: rabeprazole‐ER non‐inferior to esomeprazole (non‐inferiority margin = 8%)], (2) healing by 4 weeks [hypothesis: rabeprazole‐ER superior to esomeprazole (P < 0.05)]. The secondary endpoint was sustained heartburn resolution at 4 weeks. Results Rabeprazole‐ER was non‐inferior to esomeprazole in week‐8 healing (80.0% vs. 75.0%; 77.5% vs. 78.4%). Week‐4 healing (54.8% vs. 50.3%; 50.9% vs. 50.7%) and sustained heartburn resolution (48.3% vs. 48.2%; 53.2% vs. 52.5%) were not significantly different. Post hoc combined results for grade D revealed rabeprazole‐ER vs. esomeprazole differences in week‐8 healing = 10.4% (95% CI: ?1.4%, 22.2%) and week‐4 healing = 12.0% (P = 0.048). Conclusions Rabeprazole‐ER is as effective as esomeprazole in healing moderate‐severe oesophagitis and achieves similar rates of heartburn resolution. Subgroup analysis suggests the possibility of benefit in severe oesophagitis, but this requires further evaluation (ClinicalTrials.gov: NCT00658528 and NCT00658775).

     

Relationship between symptom load of gastro-oesophageal reflux disease and health-related quality of life, work productivity, resource utilization and concomitant diseases: survey of a US cohort

Background Analysis of the burden of gastro‐oesophageal reflux disease (GERD) in relation to the severity and frequency of symptoms is essential to identify individuals and groups in whom targeted management is justified. Aim To describe the relationship between symptoms of GERD and self‐reported health‐related quality of life (HRQL), work productivity, healthcare utilization and concomitant diseases. Methods US respondents to the Internet‐based 2004 National Health and Wellness Survey who had self‐reported GERD (n = 10 028, mean age: 52 years, 58% female) were age‐ and gender‐matched to a control group without GERD (n = 10 028). Respondents with GERD were classified according to symptom severity and frequency. HRQL and productivity were assessed using the Short‐Form 8 survey (SF‐8) and Work Productivity and Activity Impairment questionnaire, respectively. Results Symptom frequency increased with increasing symptom severity. Compared with controls, respondents with GERD had more concomitant diseases [mean difference (MD): 1.6], lower SF‐8 physical and mental health scores (MD: 4.1 units and 3.1 units, respectively), increased absenteeism (MD: 0.9 h/week), reduced percent productivity at work (MD: 7.5%) and increased healthcare utilization. All tested variables deteriorated with increasing symptom severity and/or frequency. Conclusions Increasing severity and frequency of GERD symptoms is associated with more concomitant diseases, lower HRQL, lower work productivity and increased healthcare utilization, suggesting that patients with moderate or severe GERD should receive targeted management with the most effective treatment strategies.     

Empirical treatment for the management of patients presenting with uninvestigated reflux symptoms: a prospective study in an Asian primary care population

BACKGROUND: Data on Asian patients who present with reflux symptoms to their primary care physicians are limited. AIM: To determine whether empirical therapy without endoscopy is appropriate for patients who present to their primary care physicians with uninvestigated reflux symptoms without alarm symptoms. METHOD: Forty-seven patients presenting with uninvestigated, dominant reflux symptoms but without alarm features to their primary care physicians underwent endoscopy within 2 weeks of referral. Their endoscopic findings were compared with those of 162 primary care patients presenting with uninvestigated dominant dyspepsia. All patients, except those with ulcers, were treated with esomeprazole 20 mg b.d. for 2 weeks. Their treatment response was assessed at 2 weeks using a symptom score. RESULTS: Among patients with dominant reflux symptoms, 14 (30%) had erosive oesophagitis. No other clinically significant endoscopic findings were detected among them. In contrast, erosive oesophagitis and peptic ulcer were found in 13 (8%, P < 0.001 vs. reflux group), and 12 (7%, P = 0.06 vs. reflux group), respectively, of patients with dominant dyspepsia. Thirty-seven of forty-five (82%) of those with dominant reflux symptoms and 109 of 139 (78%; P = N.S. vs. reflux group) of those with dominant dyspepsia reported > or = 50% resolution of symptoms after esomeprazole treatment. CONCLUSIONS: Empirical proton pump inhibitor without endoscopy is reasonable for uninvestigated patients who present to primary care physicians with dominant reflux symptoms.     

Health-related quality of life in patients with gastro-oesophageal reflux disease under routine care: 5-year follow-up results of the ProGERD study

Background  Gastro-oesophageal reflux disease (GERD) is a common disorder associated with substantial reductions in health-related quality of life (HRQL).
Aim  To describe patterns of change in HRQL during 5 years of follow-up in a large population of GERD patients.
Methods  In 2000, a total of 6215 GERD patients were enrolled in the Progression of GERD (ProGERD) study. During follow-up, patients received any medication considered necessary. HRQL was assessed yearly with the Short-Form 36 and the Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaires. Associations between patient characteristics and changes in HRQL were analysed using multiple logistic regression models.
Results  After 5 years, data on HRQL were available for 4597 (74%) patients. Both generic and disease-specific HRQL improved after baseline and remained well above baseline levels in the following years. A clinically relevant decrease in QOLRAD scores was reported by 3–5% of patients. According to our multivariate analysis, a decrease in HRQL was associated with a higher reflux symptom load and the presence of night-time heartburn.
Conclusions  Only a small minority of the ProGERD population reported a clinically relevant decrease in HRQL, which was associated most strongly with nocturnal heartburn.     

Randomised clinical trial: high-dose acid suppression for chronic cough - a double-blind, placebo-controlled study

Aliment Pharmacol Ther 2011; 33: 225–234

Summary

Background Cough may be a manifestation of gastro‐oesophageal reflux disease (GERD). The utility of acid suppression in GERD‐related cough is uncertain. Aim To assess the impact of high‐dose acid suppression with proton pump inhibitors (PPI) on chronic cough in subjects with rare or no heartburn. Methods Subjects were nonsmokers without history of asthma, with chronic cough for >8 weeks. All subjects underwent a baseline 24‐h pH/impedance study, methacholine challenge test and laryngoscopy. Subjects were randomised to either 40 mg of esomeprazole twice daily or placebo for 12 weeks. The primary outcome measure was the Cough‐Specific Quality of Life Questionnaire (CQLQ). Secondary outcomes were response on Fisman Cough Severity/Frequency scores and change in laryngeal findings. Results Forty subjects were randomised (22 PPI, 18 placebo) and completed the study. There was no difference between PPI and placebo in CQLQ (mean improvement 9.8 vs. 5.9 respectively, P = 0.3), or Fisman Cough Severity/Frequency scores. Proportion of patients who improved by >1 s.d. on the CQLQ was 27.8% (five of 18) and 31.8% (seven of 22) in the placebo and PPI groups respectively. Conclusion In subjects with chronic cough and rare or no heartburn, high‐dose proton pump inhibitor does not improve cough‐related quality of life or symptoms.     

Quality of life in acute and maintenance treatment of non-erosive and mild erosive gastro-oesophageal reflux disease

BACKGROUND: Quality of life has been assessed in a large, multicentre randomized, open label study. AIM: To evaluate the economic and clinical consequences of two different maintenance treatment modalities, administered to 6017 gastro-oesophageal reflux disease patients at 451 gastroenterological centres in Italy. METHODS: Adult gastro-oesophageal reflux disease patients received, at enrolment, an acute treatment of esomeprazole 40 mg/day for 4 weeks and, if successfully treated, were randomized into two maintenance treatment strategies: esomeprazole 20 mg/day or esomeprazole on demand for 6 months. A baseline endoscopy allowed the exclusion of grade II-IV oesophagitis according to Savary-Miller's classification. Burden of gastro-oesophageal reflux disease was measured at baseline by the generic questionnaire Short-Form 36 and by a disease specific instrument, quality of life in reflux and dyspepsia (QOLRAD), also administered at start and conclusion of maintenance period. Investigators were required to collect patient judgement about the degree of satisfaction with treatment effect on heartburn, with a 7-point scale. RESULTS: A comparison between Short-Form 36 scores and the normative source of the Italian general population suggested that symptomatic gastro-oesophageal reflux disease patients experience a worse quality of life than the general population. At the end of the 4-week treatment with esomeprazole 40 mg all (QOLRAD) dimensions showed a statistically significant (P < 0.0001) and clinically meaningful improvement. Satisfaction level towards treatment was reported high in the total enrolled population after acute treatment with esomeprazole 40 mg/day (96.2% satisfied and 64.4% very satisfied). A statistically significant difference in (QOLRAD) scores was registered at the end of maintenance phase in favour of the continuous regimen, nevertheless the size of this difference was very small in all dimensions; similarly, the proportion of patients very satisfied was slightly higher in the continuous treatment arm (64.5%) than in the on-demand arm (59.7%). CONCLUSIONS: Gastro-oesophageal reflux disease can significantly impair health-related quality of life and esomeprazole therapy allows immediate relief in the acute phase of the disease. Quality of life improvement was maintained during the 6-month follow-up with a slight difference in term of quality of life in reflux and dyspepsia scores and patients' satisfaction in favour of the continuous treatment strategy.     

The CHOICE trial: adalimumab demonstrates safety, fistula healing, improved quality of life and increased work productivity in patients with Crohn's disease who failed prior infliximab therapy

Aliment Pharmacol Ther 2010; 32: 1228–1239

Summary

Background Adalimumab induces and maintains remission in adults with Crohn’s disease. Aim To evaluate safety, fistula healing, quality of life and work productivity in adalimumab‐treated patients who failed infliximab, including primary nonresponders. Methods After a ≥8‐week infliximab washout, patients with moderate‐to‐severe Crohn’s disease received open‐label adalimumab as induction (160/80 mg at weeks 0/2) and maintenance (40 mg every other week) therapies. At/after 8 weeks, patients with flare/nonresponse could receive weekly therapy. Minimum study duration was 8 weeks, continuing until the commercial availability of adalimumab for Crohn’s disease. Results Of 673 patients enrolled, 17% were infliximab primary nonresponders and 83% were initial responders. Three percent of patients had serious infections (mainly abscesses). Complete fistula healing was achieved by 34/88 (39%) patients with baseline fistulas. Improvements in quality of life and work productivity were sustained from week 4 to week 24 for all patients, as well as the subgroup of primary nonresponders. Conclusions Blinded clinical trials have shown adalimumab to be both an effective first‐line therapy for anti‐TNF‐naïve patients and an important treatment option for infliximab‐refractory or ‐intolerant patients. This trial presents open‐label experience to support further the safety and effectiveness of adalimumab in patients who failed infliximab therapy, including primary nonresponders (NCT00338650).     

Randomized controlled trial of effectiveness of lafutidine versus pantoprazole in uninvestigated dyspepsia

Objectives:

Lafutidine is a new H₂-blocker in India claimed to be more potent and effective than existing H₂-blockers. Proton pump inhibitors (PPIs), by virtue of their mechanism of action, have greater efficacy than H₂-blockers in gastric acid suppression. However, clinical trials comparing H₂-blockers directly with PPIs are limited. We carried out a head-to-head comparison of the effectiveness of lafutidine versus the PPI pantoprazole in uninvestigated dyspepsia [CTRI/2013/12/004261].

Materials and Methods:

A prospective, open label, randomized, controlled trial was conducted in a tertiary care hospital. Ambulatory adult patients with dyspepsia, not yet subjected to endoscopy, were recruited if they had at least moderately severe symptoms, defined as a score of ≥ 4 on a 7-point Global Overall Symptom (GOS) Scale. Those with alarm features or significant comorbidity were excluded. Subjects received either once daily lafutidine 10 mg or pantoprazole 40 mg, orally, for 8 weeks. Reflux, dysmotility and pain scores were assessed by Modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (mFSSGERD), and quality of life (QoL) by SF-8 scale. The latter had physical and mental components summarized by physical component summary score (PCS) and a mental component summary score (MCS).

Results:

Of 122 patients enrolled, data of 57 on lafutidine and 60 on pantoprazole were analyzed. At 4 weeks, proportion of subjects responding (GOS score ≤ 2) in the two arms (lafutidine 45.61% vs. pantoprazole 48.33%, P = 0.854) or showing symptom resolution (GOS score ≤ 1) (lafutidine 12.28% vs. pantoprazole 5.00%; P = 0.197) were comparable. Similarly at 8 weeks, both responder (lafutidine 52.63% vs. pantoprazole 56.67%; P = 0.712) and symptom resolution proportions (lafutidine 33.33% vs. pantoprazole 30%; P = 0.843) were comparable. Total score on mFSSGERD scale, as well as all its three component scores, and PCS and MCS scores on QoL SF-8 scale showed improvement but no statistically significant difference between the two arms. Tolerability of both drugs was excellent.

Conclusions:

Lafutidine is well-tolerated and there is no clinically worthwhile difference between the two drugs in the empirical treatment of uninvestigated dyspepsia.KEY WORDS: Dyspepsia, lafutidine, pantoprazole, randomized controlled trial     

Randomised clinical trial: certolizumab pegol for fistulas in Crohn's disease - subgroup results from a placebo-controlled study

Aliment Pharmacol Ther 2011; 33: 185–193

Summary

Background Treatment options for fistulizing Crohn’s disease (CD) are limited. Aim To examine whether fistula closure is maintained at week 26 following treatment with certolizumab pegol. Methods Patients with draining fistulas at baseline from PRECiSE 2 (n = 108) received open‐label induction with certolizumab pegol 400 mg at weeks 0 (baseline), 2 and 4. Response was defined as ≥100‐point decrease from baseline in the Crohn’s Disease Activity Index. Nonresponders (50/108) were excluded. At week 6, responders with draining fistulas (N = 58) were randomised to certolizumab pegol 400 mg (n = 28) or placebo (n = 30) every 4 weeks across weeks 8–24. Fistula closure was evaluated throughout the study, with a final assessment at week 26. Results The majority of patients (55/58) had perianal fistula. At week 26, 36% of patients in the certolizumab pegol group had 100% fistula closure compared with 17% of patients receiving placebo (P = 0.038). Protocol‐defined fistula closure (≥50% closure at two consecutive post‐baseline visits ≥3 weeks apart) was not statistically significant (P = 0.069) with 54% and 43% of patients treated with certolizumab pegol and placebo achieving this end point, respectively. Conclusion Continuous treatment with certolizumab pegol improves the likelihood of sustained perianal fistula closure compared with placebo.     

Predictors of the placebo response in functional dyspepsia

BACKGROUND: Trials in functional dyspepsia report placebo response rates of 30% to 40%. AIM: We aimed to identify predictors of the placebo response. METHODS: Patients from primary, secondary and tertiary practices with functional dyspepsia defined by Rome II criteria were enrolled into one of four clinical trials; 220 patients were randomized to receive placebo. Scintigraphic assessment of gastric emptying at baseline was repeated at the end of the treatment in those with delayed emptying. After a 2 week run-in period, patients were followed for 8 weeks on placebo. Response was assessed on a weekly basis and a responder was defined as satisfactory relief of meal-related symptoms on at least 50% of weeks. RESULTS: The mean age was 44 years (range 18-82) and 74% were female; 76 (35%) were placebo responders. The predominant symptom was an unstable measure over the trial. Independent predictors of a lower placebo response were lower body mass index and a more consistent predominant symptom pattern (both P < 0.05). No association was seen with age, gender, centre type, baseline symptom score, baseline or change in gastric emptying, or baseline quality of life. CONCLUSION: In functional dyspepsia, a consistent predominant symptom pattern and lower body mass index may be associated with a lower placebo response rate.     

Validation of the gastrointestinal symptom score for the assessment of symptoms in patients with functional dyspepsia

Aim: To validate the gastrointestinal symptom score as an outcome measure for functional dyspepsia. Methods: In focus groups, 10 dyspepsia‐specific items including nausea, sickness, vomiting, bloating, abdominal cramps, early satiety, acidic eructation/heartburn, loss of appetite, retrosternal discomfort, epigastric pain/upper abdominal pain were identified. Ninety‐five patients with functional dyspepsia and 56 healthy controls were recruited and responsiveness evaluated by analysing gastrointestinal symptom score data from 357 patients from previous placebo‐controlled trials. Gastrointestinal symptom score response data were correlated with the patient's global assessments of efficacy. Convergent validity was assessed by correlating the gastrointestinal symptom score with the results obtained by the Nepean Dyspepsia Index. Results: Sensitivity: In patients and healthy controls gastrointestinal symptom score yielded consistently different scores (all P < 0.0001). Test–retest reliability: Gastrointestinal symptom score determined at the two time points were significantly correlated (r‐values ranging from 0.842 to 0.901). Convergence validity: Gastrointestinal symptom score of both rating groups were significantly correlated with the symptom‐specific component of the Nepean Dyspepsia Index (r‐vales ranging from 0.666 to 0.764, P < 0.01). Responsiveness: Responses of gastrointestinal symptom score during treatment were different for patients with a global self assessment as responders compared with non‐responders (all P < 0.0055). Conclusion: The gastrointestinal symptom score is a valid and reliable instrument to assess symptom intensities in patients with functional dyspepsia.     

Randomised clinical trial: improvement in health outcomes with certolizumab pegol in patients with active Crohn's disease with prior loss of response to infliximab

Aliment Pharmacol Ther 2011; 33: 541–550

Summary

Background Crohn’s disease (CD) is associated with impaired health‐related quality of life (HRQoL). Certolizumab pegol, administered either every 2 weeks (q2w) or q4w, maintains efficacy in patients previously failing on the anti‐TNF agent infliximab (WELCOME study). Aim To investigate the impact of certolizumab pegol administered q2w and q4w on work productivity and HRQoL in the WELCOME study. Methods Patients with loss of response to infliximab received open‐label certolizumab pegol induction and were randomised to receive double‐blind maintenance treatment with certolizumab pegol 400 mg either q4w or q2w through week 24, with a final evaluation at week 26. Work productivity and HRQoL were assessed using the Work Productivity and Activity Impairment:CD questionnaire and Inflammatory Bowel Disease Questionnaire respectively. Results Baseline HRQoL burden was representative of moderately to severely active CD. HRQoL, daily activity and work productivity improved in both treatment groups as early as week 6 and were maintained through week 26. Treatment benefits to HRQoL, daily activity and work productivity were similar between the certolizumab pegol q2w vs. q4w groups. Conclusions Certolizumab pegol therapy results in meaningful improvements in work productivity, daily activities and HRQoL in patients with active CD who previously responded to but either lost response or could not tolerate infliximab (ClinicalTrials.gov number: NCT00308581).     

An open-label, parallel, multiple-dose study comparing the pharmacokinetics and gastric acid suppression of rabeprazole extended-release with esomeprazole 40 mg and rabeprazole delayed-release 20 mg in healthy volunteers

Aliment Pharmacol Ther 2011; 33: 845–854

Summary

Background Novel rabeprazole extended‐release (ER) formulations were developed to provide prolonged gastric acid suppression and potentially improved clinical outcomes in GERD patients. Aim To evaluate the pharmacodynamics and pharmacokinetics of six rabeprazole‐ER formulations vs. esomeprazole 40 mg and rabeprazole delayed‐release (DR) 20 mg. Methods Helicobacter pylori‐negative healthy subjects were randomised to receive one of eight treatments once daily for 5 days. Twenty‐four‐hour intragastric pH was monitored on days ?1, 1 and 5. Rabeprazole plasma concentrations were measured on day 5. Results A total of 248 subjects (N = 31/group) were enrolled in the study. On day 5, rabeprazole‐ER groups provided mean durations of 18.5–20.2 h (77.0–84.1% of 24‐h) with intragastric pH >4.0 vs. esomeprazole 40 mg (15.9 h/66.1% of 24‐h) and rabeprazole‐DR 20 mg (15.2 h/63.2% of 24‐h). A similar increase was observed on day 1. While percentage of daytime (8 am –10 pm ) with intragastric pH >4.0 on day 5 was overall similar across the groups, percentage of night‐time (10 pm ‐8 am ) with intragastric pH >4.0 was higher with the rabeprazole‐ER groups (57.0–72.4%) vs. esomeprazole 40 mg (32.8%) and rabeprazole‐DR 20 mg (34.0%). Conclusion Rabeprazole‐ER once daily for 5 days demonstrated a significantly longer duration of gastric acid suppression in 24 h vs. esomeprazole 40 mg and rabeprazole‐DR 20 mg. The increase in acid suppression was predominantly due to prolonged acid suppression during the night‐time; this was supported by the extended‐release phamacokinetic characteristics.