Randomised non-inferiority trial: 1600 mg versus 400 mg tablets of mesalazine for the treatment of mild-to-moderate ulcerative colitis.

BACKGROUND: High concentration mesalazine formulations are more convenient than conventional low concentration formulations for the treatment of ulcerative colitis (UC). AIM: To compare the efficacy and safety of 1600 mg and 400 mg tablet mesalazine formulations. METHODS: Patients with mild-to-moderate active UC (Mayo Clinic Score >5; N=817) were randomised to 3.2 g of oral mesalazine, administered as two 1600 mg tablets once, or four 400 mg tablets twice daily. We hypothesised that treatment with the 1600 mg tablet was non-inferior (within a 10% margin) to the 400 mg tablet for induction of clinical and endoscopic remission at week 8. Open-label treatment with the 1600 mg tablet continued for 26-30 weeks based on induction response. Predictors of treatment response were also explored. RESULTS: At week 8, remission occurred in 22.4% and 24.6% of patients receiving the 1600 mg and 400 mg tablets, respectively (absolute difference -2.2%, 95% CI: -8.1% to 3.8%, non-inferiority P=.005). Endoscopic and histopathologic disease activity, leucocyte concentration and age were significantly associated with clinical remission (P=.022, .042, .014 and .023, respectively). At week 38, 43.9% (296/675) of patients who continued treatment with the 1600 mg formulation were in remission, including 70.3% (142/202) of patients who received a reduced dose of mesalazine (1.6 g/d). The overall incidence of serious adverse events was low. CONCLUSIONS: Induction therapy with 3.2 mg mesalazine using two 1600 mg tablets once-daily was statistically and clinically non-inferior to a twice-daily regimen using four 400 mg tablets (NCT01903252).

The development of a magnetic resonance imaging index for fistulising Crohn's disease.

BACKGROUND: Magnetic resonance imaging (MRI) is the gold standard for assessment of perianal fistulising Crohn's disease (CD). The Van Assche index is the most commonly used MRI fistula index. AIMS: To assess the reliability of the Van Assche index, and to modify the instrument to improve reliability and create a novel index for fistulising CD. METHODS: A consensus process developed scoring conventions for existing Van Assche index component items and new items. Four experienced radiologists evaluated 50 MRI images in random order on three occasions. Reliability was assessed by estimates of intraclass correlation coefficients (ICCs). Common sources of disagreement were identified and recommendations made to minimise disagreement. A mixed effects model used a 100 mm visual anologue scale (VAS) for global severity as outcome and component items as predictors to create a modified Van Assche index. RESULTS: Intraclass correlation coefficients (95% confidence intervals) for intra-rater reliability of the original and modified Van Assche indices and the VAS were 0.86 (0.81-0.90), 0.90 (0.86-0.93) and 0.86 (0.82-0.89). Corresponding ICCs for inter-rater reliability were 0.66 (0.52-0.76), 0.67 (0.55-0.75) and 0.58 (0.47-0.66). Sources of disagreement included number, location, and extension of fistula tracts, and rectal wall involvement. A modified Van Assche index (range 0-24) was created that included seven component items. CONCLUSIONS: Although "almost perfect" intra-rater reliability was observed for the assessment of MRI images for fistulising CD using the Van Assche index, inter-rater reliability was considerably lower. Our modification of this index should result in a more optimal instrument.

Development of interim patient-reported outcome measures for the assessment of ulcerative colitis disease activity in clinical trials.

BACKGROUND: Patient-reported outcomes (PROs) have an increasingly important role in the evaluation of new therapies for inflammatory bowel disease. The US Food and Drug Administration has issued formal guidance to describe the role of PRO instruments in evaluation of claims for product labelling. However, no validated PRO exists for ulcerative colitis. AIM: To investigate whether the PROs from the Mayo Clinic Score (MCS) for UC can be modified, to develop an interim PRO for use in clinical trials, alone or in combination with endoscopy. METHODS: Data from an induction trial of a mesalazine (mesalamine) formulation were used to compare effect sizes between mesalazine and placebo for PRO items (stool frequency and rectal bleeding) alone and in combination with endoscopy. The operating properties of the PRO were validated using data from a phase 2 trial of MLN02, a humanised antibody to the α4ß7 integrin in patients with UC. RESULTS: A two-item PRO (PRO2) consisting of rectal bleeding = 0 and stool frequency ≤1 or ≤2, combined with an endoscopy subscore ≤1 yielded statistically significant differences between active drug and placebo. This combination yielded the most similar effect sizes and placebo rates for remission, compared to the primary trials. Use of PRO items alone yielded high placebo remission rates in both data sets, although rates were lower when the items were combined and remission defined as PRO2 = 0. CONCLUSION: Patient-reported outcomes items derived from the Mayo Clinic Score combined with endoscopy as a co-primary endpoint may be an appropriate interim outcome measure for ulcerative colitis trials.

A retrospective analysis: the development of patient reported outcome measures for the assessment of Crohn's disease activity.

BACKGROUND: The Crohn's Disease Activity Index (CDAI) is a measure of disease activity based on symptoms, signs and a laboratory test. The US Food and Drug Administration has indicated that patient reported outcomes (PROs) should be the primary outcome in randomised controlled trials for Crohn's disease (CD). AIM: As no validated PRO exists for CD, to investigate whether CDAI diary card items could be modified for this purpose. METHODS: Data from a trial of rifaximin-extended intestinal release were used to identify cut-points for stool frequency, pain and general well-being using receiver operating characteristic curves with CDAI <150 as criterion. The operating properties of 2- and 3-item PRO were evaluated using data from a trial of methotrexate in CD. Regression analysis determined PRO2 and PRO3 scores that correspond to CDAI-defined thresholds of 150, 220 and 450 and changes of 50, 70 and 100 points. RESULTS: Optimum cut-points for CDAI remission were mean daily stool frequency ≤1.5, abdominal pain ≤1, and general well-being score of ≤1 (areas under the ROC curve 0.79, 0.91 and 0.89, respectively). The effect estimates were similar using 2- and 3-item PROs or CDAI. PRO2 and PRO3 values corresponding to CDAI scores of 150, 220 and 450 points were 8, 14, 34 and 13, 22, 53. The corresponding values for CDAI changes of 50, 70 and 100, were 2, 5, 8 and 5, 9, 14. Responsiveness to change was similar for both PROs. CONCLUSION: Patient reported outcomes derived from CDAI diary items may be appropriate for use in clinical trials for CD.

A referendum on clinical trial research in multiple sclerosis: the opinion of the participants at the Jekyll Island workshop.

Sixty-two experienced multiple sclerosis (MS) investigators attending a research workshop were asked their opinions about clinical trial design, outcome measures, and treatment. Respondents favored repeated clinical observations of neurologic function (eg, Expanded Disability Status Scale or Ambulation Index) over the opinion of a blinded physician and changes on magnetic resonance imaging. There was agreement that stable MS should not be treated with immunosuppressives. Corticosteroids were rated the most effective treatment for recent disease activity. Total lymphoid irradiation and immunosuppressives were judged more potent for the long-term management of progressive disease. No treatment, however, received the support of more than 11% of the respondents for being of "considerable efficacy" in the long-term management of MS. Most favored a placebo-controlled design in future trials. In order to judge the acceptability of current trial design, participants were asked to act as patient surrogates and to indicate whether they would agree to participate in 4 randomized trials for which they would be eligible. The majority consented to participate in the 3 major trials currently under way, and most refused to enroll in the 1 trial that had never been initiated.

The impact of blinding on the results of a randomized, placebo-controlled multiple sclerosis clinical trial.

In the randomized, placebo-controlled, physician-blinded Canadian cooperative trial of cyclophosphamide and plasma exchange, neither active treatment regimens (group I: i.v. cyclophosphamide and prednisone; group II: weekly plasma exchange, oral cyclophosphamide, and prednisone) were superior to placebo (group III: sham plasma exchange and placebo medications) using the blinded, evaluating neurologists' assessments of disease course (primary analysis). All patients were examined by both a blinded and an unblinded neurologist at each assessment in this trial. We compared the blinded and unblinded neurologists' judgment of treatment response and analyzed the clinical behavior of patients who correctly guessed their treatment. The unblinded (but not the blinded) neurologists' scores demonstrated an apparent treatment benefit at 6, 12, and 24 months for the group II patients (not group I or placebo; p < 0.05, two-tailed). There were no significant differences in the time to treatment failure or in the proportions of patients improved, stable, or worse between the group II and group III patients who correctly guessed their treatment assignments and those who did not. Physician blinding prevented an erroneous conclusion about treatment efficacy (false positive, type 1 error).

Interrater variability with the Expanded Disability Status Scale (EDSS) and Functional Systems (FS) in a multiple sclerosis clinical trial. The Canadian Cooperation MS Study Group.

We describe the interrater variability in the Expanded Disability Status Scale (EDSS) and Functional Systems (FS) in a multiple sclerosis clinical trial. Two physicians blinded to their previous assessments and to each other's scores consecutively examined 168 patients (545 paired examinations). Perfect agreement on the assignment of the disability scores ranged from 48% (cerebellar functional group) to 69% (EDSS and pyramidal functional group). Only 31% to 62% of this agreement occurred independently of that expected by chance (kappa). With the exception of the cerebellar and sensory functional groups, agreement within 1 step occurred in at least 92% of cases. These findings suggest that differences of a single step on these scales may not reflect an important functional change. We recommend that at least a 2-step change (1.0 point on the EDSS and 2 points on the FS) is needed to be confident of an important change in the degree of disability or response to treatment in this disease.

An open-trial evaluation of mitoxantrone in the treatment of progressive MS.

We treated 13 patients with progressive MS with mitoxantrone. All patients received a standard IV dose of mitoxantrone (8 mg/m2) every 3 weeks for a total of seven infusions, with dosage adjustments depending on the hematologic profile at the nadir. The treatment was well tolerated, with the most common side effect being mild nausea. Four of seven women developed transient secondary amenorrhea. The postenrollment clinical behavior of these patients was generally more favorable than during the 18 months prior to enrollment (only three of 13 patients developed an increase in the Expanded Disability Status Scale of more than 0.5 points), suggesting a possible treatment effect, but comparison with two historical control groups (both the active and placebo groups from the Canadian Cooperative Trial of Cyclophosphamide and Plasma Exchange) does not suggest that mitoxantrone was efficacious. Eight of 12 patients had evidence of MRI activity on 13 of 29 follow-up visits. This small, open-labeled pilot study did not provide strong support for proceeding with a randomized, controlled trial of this dosage regimen of mitoxantrone in patients with progressive MS.

Evaluation of portable bladder ultrasound: accuracy and effect on nursing practice in an acute care neuroscience unit.

The purpose of this evaluation was to determine the accuracy of a portable ultrasound instrument in assessing bladder volume in an acute care neuroscience population and the effect of ultrasound assessment on nursing practice in an acute care neuroscience unit. In a 6-week prospective evaluation, 105 paired ultrasound measurements were performed by 45 nurses on 30 patients suspected to be retaining urine. Sixty-seven catheterizations were performed, and volumes were compared with corresponding ultrasound readings. The first ultrasound volume readings slightly underestimated the catheterized volumes, but the volumes from the first ultrasound readings and the catheterized volumes were highly correlated. Volume readings from a second ultrasound, the average of the first and second ultrasound readings, and the higher of the two ultrasound readings did not add to the ability of the ultrasound instrument to predict catheterized volumes. Patient age and gender did not change the relationship between ultrasound and catheterized volumes. The ultrasound assessment changed nursing practice in 51% of the instances; the most common change (32%) was that nurses did not catheterize the patient. The ultrasound assessment did not change nursing practice in 49% of the instances; the most common reason (41%) was that the ultrasound confirmed the need to catheterize the patient. The instrument was therefore judged to be an accurate and reliable tool that changed nursing practice in an acute care neuroscience unit.

Long-term use of antecubital veins for plasma exchange. The Canadian Cooperative Multiple Sclerosis Study Group.

True or sham plasma exchange was done weekly for 20 weeks in patients in two of the randomization groups in a prospective, blind clinical trial of experimental treatments for multiple sclerosis. Because patients could be randomized to receive sham plasma exchange and placebo medications, it was decided when the trial was designed that the use of fistulae, arteriovenous shunts, venous cutdowns, or other aggressive forms of venous access would not be permitted for any patient. Accordingly, patients judged to have inadequate superficial antecubital veins were ineligible for the trial. To date, only 13 (4.4%) of 294 patients considered for entry into the trial have been rejected on these grounds. In only 4 of the 93 patients undergoing exchange was it necessary to discontinue plasma exchange because of inadequate venous access. In 79.3 percent of the 1207 exchanges done in these patients, there were no problems of any kind with venous access. In 5.4 percent of these 1207 exchanges, it was necessary to terminate the procedure prematurely because of difficulties with patients' veins. Thus, the great majority of patients free of serious systemic illness (other than chronic progressive multiple sclerosis) can undergo weekly plasma exchange for up to 20 weeks using superficial antecubital veins without the need to resort to more invasive methods of venous access.

NMR studies in experimental allergic encephalomyelitis: factors which contribute to T1 and T2 values.

To determine the factors which may alter NMR relaxation times in multiple sclerosis (MS) lesions we measured the proton T1 and T2, specific gravity (SG), and histology in the central nervous system (CNS; 13-19 levels per animal) in the myelin basic protein (MBP) and CNS-induced acute and relapsing EAE models in 44 juvenile Hartley guinea pigs. In the MBP model, T1 is unchanged but T2 is prolonged before symptoms and pathological changes occur. T2 remains prolonged during the acute phase of MBP-induced EAE. In the acute CNS model, T1 and T2 were not different from control despite advanced pathological changes of inflammation and demyelination and changes in specific gravity, indicating a marked change in tissue water content. No single variable, pathological or SG, could predict T1 or T2 values in the CNS-induced model. In active disease in the MBP model, when edema occurs in the presence or absence of parenchymal infiltration, T2 values are increased. However, as the factors which influence tissue NMR characteristics are complex in these MS models, it is likely difficult to infer specific pathological events from MRI findings in patients with MS.

Postnatal NMR changes in guinea pig central nervous system: potential relevance to experimental allergic encephalomyelitis.

The age of sensitization determines the clinical course of experimental allergic encephalomyelitis (EAE) in the guinea pig. Adult animals immunized with central nervous system (CNS) tissue develop acute, fulminant EAE, whereas a relapsing-remitting illness resembling multiple sclerosis occurs if sensitization occurs in the first 2 weeks of life. This study characterized the changes in the proton nuclear magnetic resonance (NMR) relaxometry and imaging of the CNS during the immediate postnatal period. T1 and T2 relaxation times in cerebral hemispheres and spinal cords of strain 13 guinea pigs were consistently prolonged at birth, progressively shortened in the first few weeks of life, and achieved adult levels by age 6 to 11 weeks. There were no age-dependent differences in T1 and T2 relaxation times and tissue specific gravity in either strain 13 or Hartley guinea pigs following immunization with complete Freund's adjuvant, an agent previously reported to disrupt the blood-brain barrier to IgG and albumin in strain 13 guinea pigs. The CNS of neonatal guinea pigs appeared well myelinated by light microscopy and there was no apparent difference in the extent of myelination between newborn and adult animals. Although it was possible to distinguish gray from white matter in the cervical spinal cord of newborn guinea pigs by magnetic resonance imaging (MRI) techniques, gray/white contrast was less satisfactory in the cerebral hemispheres until approximately 6 weeks of life when it was possible to differentiate gray matter, white matter, and cerebrospinal fluid. This study indicates that NMR relaxation times change during early postnatal life, at a time corresponding to the unexplained differences in susceptibility to an immune challenge. These developmental changes appear to be independent of the degree of CNS myelination.

A controlled trial of a critical pathway for treatment of community-acquired pneumonia. CAPITAL Study Investigators. Community-Acquired Pneumonia Intervention Trial Assessing Levofloxacin.

CONTEXT: Large variations exist among hospitals in the use of treatment resources for community-acquired pneumonia (CAP). Lack of a common approach to the diagnosis and treatment of CAP has been cited as an explanation for these variations. OBJECTIVE: To determine if use of a critical pathway improves the efficiency of treatment for CAP without compromising the well-being of patients. DESIGN: Multicenter controlled clinical trial with cluster randomization and up to 6 weeks of follow-up. SETTING: Nineteen teaching and community hospitals in Canada. PATIENTS: A total of 1743 patients with CAP presenting to the emergency department at 1 of the participating institutions between January 1 and July 31, 1998. INTERVENTION: Hospitals were assigned to continue conventional management (n = 10) or implement the critical pathway (n = 9), which consisted of a clinical prediction rule to guide the admission decision, levofloxacin therapy, and practice guidelines. MAIN OUTCOME MEASURES: Effectiveness of the critical pathway, as measured by health-related quality of life on the Short-Form 36 Physical Component Summary (SF-36 PCS) scale at 6 weeks; and resource utilization, as measured by the number of bed days per patient managed (BDPM). RESULTS: Quality of life and the occurrence of complications, readmission, and mortality were not different for the 2 strategies; the 1-sided 95% confidence limit of the between-group difference in the SF-36 PCS change score was 2.4 points, which was within a predefined 3-point boundary for equivalence. Pathway use was associated with a 1.7-day reduction in BDPM (4.4 vs 6.1 days; P = .04) and an 18% decrease in the admission of low-risk patients (31% vs 49%; P = .01). Although inpatients at critical pathway hospitals had more severe disease, they required 1.7 fewer days of intravenous therapy (4.6 vs 6.3 days; P = .01) and were more likely to receive treatment with a single class of antibiotic (64% vs 27%; P<.001). CONCLUSION: In this study, implementation of a critical pathway reduced the use of institutional resources without causing adverse effects on the well-being of patients.

Treatment and outcomes of community-acquired pneumonia at Canadian hospitals.

BACKGROUND: Community-acquired pneumonia is a common disease with a large economic burden. We assessed clinical practices and outcomes among patients with community-acquired pneumonia admitted to Canadian hospitals. METHODS: A total of 20 hospitals (11 teaching and 9 community) participated. Data from the charts of adults admitted during November 1996, January 1997 and March 1997 were reviewed to determine length of stay (LOS), admission to an intensive care unit and 30-day in-hospital mortality. Multivariate analyses examined sources of variability in LOS. The type and duration of antibiotic therapy and the proportion of patients who were treated according to clinical practice guidelines were determined. RESULTS: A total of 858 eligible patients were identified; their mean age was 69.4 (standard deviation 17.7) years. The overall median LOS was 7.0 days (interquartile range [IQR] 4.0-11.0 days); the median LOS ranged from 5.0 to 9.0 days across hospitals (IQR 6.0-7.8 days). Only 22% of the variability in LOS could be explained by known factors (disease severity 12%; presence of chronic obstructive lung disease or bacterial cause for the pneumonia 2%; hospital site 7%). The overall 30-day mortality was 14.1% (95% confidence interval [CI] 11.8%-16.6%); 13.6% of the patients were admitted to an intensive care unit (95% CI 11.4%-16.1%). The median duration of intravenous antibiotic therapy was 5 days (range 3.0-6.5 days across hospitals). Although 79.8% of patients received treatment according to clinical practice guidelines, the rate of compliance with the guidelines ranged from 47.9% to 100% across hospitals. INTERPRETATION: Considerable heterogeneity exists in the management of community-acquired pneumonia at Canadian hospitals, the causes of which are poorly understood.

Plasma-exchange therapy in chronic inflammatory demyelinating polyneuropathy. A double-blind, sham-controlled, cross-over study.

Eighteen patients with definite, untreated chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) of chronic progressive (nine patients) or relapsing course (nine patients) were randomized prospectively to receive 10 plasma-exchange (PE) or sham plasma-exchange (SPE) treatments over 4 weeks in a double-blind trial. After a wash-out period of 5 weeks or when they returned to baseline scores, patients were crossed over to the alternate treatments. Neurological function was assessed serially using a quantitative neurological disability score (NDS), a functional clinical grade (CG) and grip strength (GS) measurements. Electrophysiological studies were done at the beginning and end of each treatment. A primary 'intention to treat' analysis showed significant improvement with PE in all clinical outcome measures: NDS by 38 points, P < 0.001; CG by 1.6 points, P < 0.001; GS by +13 kg, P < 0.003 and in selected electrophysiological measurements, sigma proximal CMAP, P < 0.01; sigma motor conduction velocities, P < 0.006; sigma distal motor latencies, P < 0.01. Fifteen patients completed the trial and of those, 12 patients (80%) improved substantially with PE; i.e. five out of seven patients with chronic progressive course and seven out of eight patients with relapsing CIDP improved. There were three drop-outs; one patient lost venous access; one patient suffered a stroke and one patient left the trial to receive open treatment elsewhere. The improvement in motor functions correlated with the electrophysiological data, i.e. with improved motor conduction velocities and reversal of conduction block. Eight of 12 PE responders (66%) relapsed within 7-14 days after stopping PE. All improved with subsequent open label PE; all but two patients required long-term immunosuppressive drug therapy for stabilization. The PE non-responders improved with prednisone. We conclude that PE is a very effective adjuvant therapy for CIDP of both chronic progressive and relapsing course; concurrent immunosuppressive drug treatment is required. Exchange treatments should be given two to three times per week until improvement is established; the treatment frequency should then be tapered over several months.

The prevalence of primary Sjögren's syndrome in a multiple sclerosis population.

A central nervous system illness closely resembling multiple sclerosis has been described in patients with primary Sjögren's syndrome. From these reports, the estimated prevalence of this syndrome could be similar to that of multiple sclerosis in a high-frequency area. We evaluated 192 consecutive patients in our multiple sclerosis clinic to determine if such cases had gone unrecognized. We did not find any patients with clinical or serological evidence of primary Sjögren's syndrome. We conclude that it is rare for neurological manifestations of Sjögren's syndrome to mimic multiple sclerosis in our population.