Randomized phase 1b trial of MOR103, a human antibody to GM-CSF, in multiple sclerosis.

OBJECTIVES: To determine the safety, pharmacokinetics (PK), and immunogenicity of the recombinant human monoclonal antibody MOR103 to granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with multiple sclerosis (MS) with clinical or MRI activity. METHODS: In this 20-week, randomized, double-blind, placebo-controlled phase 1b dose-escalation trial (registration number NCT01517282), adults with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) received an IV infusion of placebo (n = 6) or MOR103 0.5 (n = 8), 1.0 (n = 8), or 2.0 (n = 9) mg/kg every 2 weeks for 10 weeks. Patients had to have ≤10 gadolinium (Gd)-enhancing brain lesions on T1-weighted MRI at baseline. The primary objective was safety. RESULTS: Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity. The most frequent was nasopharyngitis. Between-group differences in TEAE numbers were small. There were no TEAE-related trial discontinuations, infusion-related reactions, or deaths. Nine patients experienced MS exacerbations: 3, 5, 1, and 0 patient(s) in the placebo, 0.5, 1.0, and 2.0 mg/kg groups, respectively. A few T1 Gd-enhancing lesions and/or new or enlarging T2 lesions indicative of inflammation were observed in all treatment groups. No clinically significant changes were observed in other clinical assessments or laboratory safety assessments. No anti-MOR103 antibodies were detected. PK evaluations indicated dose linearity with low/no drug accumulation over time. CONCLUSIONS: MOR103 was generally well-tolerated in patients with RRMS or SPMS. No evidence of immunogenicity was found. CLASSIFICATION OF EVIDENCE: This phase 1b study provides Class I evidence that MOR103 has acceptable tolerability in patients with MS.

Risperidone compared with olanzapine in a naturalistic clinical study: a cost analysis.

BACKGROUND: Risperidone and olanzapine are thought to have broadly similar clinical effects. This study was designed as a cost analysis study comparing costs and basic clinical outcomes of treatment with risperidone or olanzapine in a naturalistic setting. METHOD: The U.K. Risperidone Olanzapine Drug Outcomes Studies in Schizophrenia (RODOS-UK) program consisted of a retrospective review of medical notes and prescription charts for 501 patients with schizophrenia or schizoaffective disorder who had been admitted to the hospital for the treatment of psychosis. The main outcome measure was cost of inpatient drug treatment. Clinical outcomes (clinician-assessed and -documented effectiveness, time to discharge) were also evaluated. Data were collected and verified between June and September 2000. RESULTS: Clinical outcomes were similar for risperidone and olanzapine. Clinician-assessed effectiveness was similar for both treatments (78% risperidone, 74% olanzapine; p =.39), but mean time to documented onset of effectiveness was significantly shorter for those treated with risperidone versus olanzapine (17.6 vs. 22.4 days; p =.01). Risperidone-treated patients stayed a mean of 9 fewer days in the hospital compared with olanzapine-treated patients (49 vs. 58 days; p =.007). The possibility that these observed differences were a result of different baseline characteristics could not be entirely discounted. Mean +/- SD doses of risperidone and olanzapine were 5.5 +/- 2.4 mg/day and 14.1 +/- 4.7 mg/day, respectively. The mean daily cost of all inpatient drugs was significantly higher for olanzapine than for risperidone (pound 5.63 vs. pound 3.92; p <.0001). Mean total costs of all inpatient drugs were significantly higher for olanzapine than for risperidone (pound 164 vs. pound 96; p <.0001), which partly reflected the longer mean treatment duration for olanzapine compared with risperidone (44 vs. 37 days). Concomitant antipsychotic use was similar for both groups (66% risperidone, 67% olanzapine). The number of patients documented as experiencing adverse events was not different between groups (22% risperidone, 19% olanzapine; p =.32). CONCLUSION: Risperidone and olanzapine produced broadly comparable clinical outcome in this cohort of hospitalized patients, but the use of risperidone was associated with significantly lower drug treatment costs.

Patients have treatment preferences: a multicentre, double-blind, crossover study comparing rabeprazole and omeprazole.

It is increasingly common practice to change patients from one medication in a drug class to another, often as part of a general formulary change. The underlying assumption and accepted wisdom is that all compounds within a class are identical. To our knowledge, there has been no published investigation into the patients' views on such changes or on the individual medications. These views may be affected by positive side-effects, not normally sought in clinical trials, as well as negative side-effects, which are always reported. The objectives of this study were to determine whether patients whose primary symptoms were already controlled by a proton pump inhibitor (PPI) could distinguish between rabeprazole and omeprazole; to determine the incidence of positive, as well as negative, side-effects; to elicit patients' opinions on changing medication within a class, and on the importance of certain characteristics of medication. The design was a double-blind, double-dummy, randomised, crossover trial, set in five general practice research centres in the UK and Ireland. 240 eligible patients were randomised to receive daily treatment, first for 4 weeks with omeprazole 20 mg/day, and then for reverse order. Each phase of 4 weeks was separately assessed by patients through questionnaires and by non-directed questioning about positive and negative side-effects. At the end of the 8 weeks, patients compared the two medications in seven treatment characteristics. Patients were further asked their attitude to changing medication within a class. Data were collected by a web-based electronic data capture system. Results showed that the majority of patients could be switched to another PPI therapy, predictably without noticeable difference in maintenance of primary symptom control. About one-quarter to one-half of patients were able to express a preference for one or other of the treatments dependent on the variable assessed. For 'absence of unwanted side-effects' and 'presence of positive side-effects' a statistically significant difference in favour of rabeprazole was detected (p = 0.0467 and p = 0.0188, respectively). In terms of the total treatment preference score, the primary outcome variable, there was no statistically significant difference between the two PPIs (p = 0.0754). This finding is mainly attributable to the two PPIs providing similar relief of primary mask the findings for the other variables assessed. However, there were numerically more patients (10 vs. 3) who reported 'marked' positive side-effects on rabeprazole. On direct questioning, patients indicated that tablets (rabeprazole) were more easily swallowed than capsules (omeprazole) (p < 0.0001), but less easily handled than capsules (p = 0.0003). These analyses may however have been confounded by the fact that the omeprazole medication had to be over-encapsulated to allow blinding for this double-dummy, blinded study. There was no difference in tolerability between rabeprazole and omeprazole, with 52.6% and 51% of patients reporting at least one adverse event, respectively. Of the patients controlled and maintained on omeprazole before the study, 33.9% reported adverse events on omeprazole during the study and seven discontinued the study for that reason. Patients thought the most important drug characteristics for treating this condition were rapid and lasting control of pain. Most (83.6%) would be willing to try an alternative medication within a drug class. In conclusion, most patients already controlled by a PPI would be willing to try another. An individual patient may have a strong preference for one PPI over another, and this difference may be important if treatment is to be long term.

Clinical experience of galantamine in dementia: a series of case reports.

OBJECTIVE: To use case studies to add the benefit of personal experience with galantamine to published literature and to demonstrate the type of patients that may benefit from this treatment. METHODS: We describe eleven patients, aged 57-90 years, fulfilling the consensus diagnostic criteria for probable Alzheimer's disease, mixed dementia, vascular dementia, Lewy body dementia or Parkinson's dementia. All patients were treated with galantamine that may enhance cholinergic function in the brain by inhibiting acetylcholinesterase and potentiating the effects of acetylcholine at nicotinic acetylcholine receptors. Clinical features were rated according to eight assessment scales in old age psychiatry and additional information was obtained from family and other carers. In some cases caregiver distress was measured. RESULTS: All patients described showed a general improvement in cognition and neuropsychiatric symptoms, although observed improvements and effects were not always reflected by the results of formal assessments. Several patients became more independent, particularly in their activities of daily living, and treatment was felt to have helped maintain independence in their home environment, either alone or with their family or carers. One man continued in employment. Adverse events included nausea and vomiting. CONCLUSIONS: Outcomes in this case series indicate that galantamine is well tolerated and highlight aspects of the different side-effect profiles of the anticholinesterase inhibitors. Subjective benefits were not always apparent from objective measures. These case studies demonstrate the type of patients that may benefit from galantamine.

Clinical experience with the long-acting injectable formulation of the atypical antipsychotic, risperidone.

BACKGROUND: To detail specific effects of long-acting risperidone on individuals with schizophrenia and their way of life in a series of four cases. METHOD: Four patients with schizophrenia were selected from four different psychiatric centres. Patients were established on an oral dose of risperidone (1-4 mg/day) for 2 weeks. Based on their oral dose, they then received intramuscular injections of 25 mg or 50 mg of long-acting risperidone every 2 weeks, which could be adjusted according to clinical response. Assessments of efficacy (Positive And Negative Syndrome Scale, Clinical Global Impression-Severity) and safety (Extrapyramidal Symptom Rating Scale) were made at intervals throughout a 1-year period. RESULTS: Patients demonstrated a variety of reasons for receiving a long-acting injectable antipsychotic drug, including insufficient control of symptoms, adverse events and convenience. After 1 year of treatment with long-acting risperidone, all patients showed improvements in their symptoms of schizophrenia over their original stable condition, and benefited from a considerable reduction or total disappearance of pre-existing extrapyramidal symptoms. Patients were more socially interactive, with no signs of sedation, fatigue, confusion, depression or anxiety, and none were considered to have relapsed or to require hospitalisation. Three of the four patients were considered to have had no signs of illness after 1 year, one of whom had returned to college and another to work. They demonstrate that patients can be switched from oral and depot medications without problems. There was little pain or discomfort and no inflammatory response experienced at the injection site. CONCLUSION: The cases demonstrate the suitability of long-acting risperidone in patients benefiting from long-term treatment and suggest its potential in all patients who are at risk of relapse.

The rationale and use of topiramate for treating neuropathic pain.

OBJECTIVE: To outline the modes of action of topiramate and to examine the theoretical reasons as to why topiramate may alleviate neuropathic pain. Results of animal and human studies in the use of topiramate for treating pain are reviewed, together with case studies describing situations where topiramate was effective when other treatments have failed. CONCLUSIONS: Topiramate acts on neuronal transmission in at least five ways: by modulating voltage-gated sodium ion channels, potentiating gamma-aminobutyric acid inhibition, blocking excitatory glutamate neurotransmission, modulating voltage-gated calcium ion channels, and by inhibiting carbonic anhydrase. This review suggests that there are good theoretical reasons for a trial of topiramate in patients with neuropathic pain where conventional medical treatments have failed. Although not currently licensed for treating pain, topiramate should be considered before invasive methods of pain relief are contemplated. Most of the side effects of topiramate are dose dependent, but by starting medication with a low dose (

Treatment outcome in patients with chronic schizophrenia during long-term administration with risperidone.

Treatment outcome was evaluated in outpatients with chronic schizophrenia during long-term administration of risperidone in a study reflecting clinical practice. This UK multicenter, noncomparative, open trial was conducted in 79 patients. Risperidone treatment for 52 weeks commenced at 2 mg/d, with the option to titrate to 6 mg/d. The primary efficacy variable was study failure (study discontinuation for relapse, adverse events, insufficient response, withdrawn consent, lost to follow-up, or noncompliance). The most common dosage was 6 mg/d. Of the 79 patients in the intent-to-treat analysis, 38 completed the study (sustained treatment success), 29 were classified as treatment failure, and 12 were "not evaluable." When the intent-to-treat population was reclassified into study success or study failure, there were 40 study successes (38 treatment successes and 2 ineligible to continue) and 39 study failures (29 treatment failures, 3 lost to follow-up, and 7 noncompliant). Among patients considered to be treatment failures, only 10 had relapse and 10 had adverse events, 2 had insufficient response, and 7 withdrew consent. Raw mean time to treatment failure was 101.7 +/- 90.9 days, and median time was 77 days (range 7 to 284). From Kaplan-Meier curves, mean time to treatment failure was 213.3 +/- 12.2 days; the median was longer than the study period. There was significant improvement (reduction in severity of symptoms) for the intent-to-treat population in total and all Positive and Negative Syndrome Scale subscale scores (P < or =0.0119), Clinical Global Impression Severity (P = 0.0003), cognitive function "letter fluency totals" (P = 0.0044), Abnormal Involuntary Movement Scale (P < 0.0001), and Targeting Abnormal Kinetic Effects scale (measures abnormal kinetic effects; P < 0.0001) at study end point. Most patients considered the treatment at least "acceptable" during the study, and mean change at study end corresponded to between "acceptable" and "quite acceptable." After 1 year of risperidone treatment in a naturalistic setting reflecting usual UK clinical practice, patients with chronic schizophrenia showed improvement in symptoms and reduction in disease severity, and only 10 of 79 had relapse; 48.1% of patients were considered to be sustained treatment successes, 36.7% as treatment failures, and 15.2% as not "evaluable." Fifty-one percent of patients were considered to be study successes and 49% as study failures.

Risperidone for the treatment of delusional disorder.

INTRODUCTION: The overlap between diagnostic criteria for schizophrenia and delusional disorder (DD) may cause diagnostic confusion. This is important if response to treatment differs. Risperidone, an atypical antipsychotic, is established in the treatment of schizophrenia, although less so in other psychotic conditions. METHOD: We report the case of a woman who developed DD, persecutory type, at the age of 50 years. Treatment with sulpiride 200-800 mg daily caused side-effects of drowsiness and 'hangover' and, consequently, non-compliance. Written informed consent was gained for a 24-week, randomized, double-blind, placebo-controlled, crossover trial of risperidone, initiated at 1 mg daily and increasing to 2 mg daily. RESULTS: Significant improvement was found, as assessed by the Brief Psychiatric Rating Scale, Positive and Negative Symptom Schedule and Maudsley Assessment of Delusions Schedule. CONCLUSION: We believe that this is the first case study reporting the resolution of persecutory DD with risperidone. A controlled clinical trial of risperidone in the treatment of patients with DD is warranted. (Int J Psych Clin Pract 2002; 6: 113-116).