Futility studies: spending a little to save a lot.
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Clinical Trials as Topic↗
Biomedical subjects
Steven R Schwid
Publications and source records attributed to Steven R Schwid.
Effects of tyramine administration in Parkinson's disease patients treated with selective MAO-B inhibitor rasagiline.
Rasagiline is a novel, potent, and selective MAO-B inhibitor shown to be effective for Parkinson's disease. Traditional nonselective MAO inhibitors have been associated with dietary tyramine interactions that can induce hypertensive reactions. To test safety, tyramine challenges (50-75 mg) were performed in 72 rasagiline-treated and 38 placebo-treated Parkinson's disease (PD) patients at the end of two double-blind placebo-controlled trials of rasagiline. An abnormal pressor response was prespecified as three consecutive measurements of systolic blood pressure (BP) increases of >or= 30 mm Hg and/or bradycardia of < 40 beats/min. In the first study involving 55 patients with early PD on rasagiline monotherapy, no patients randomized to rasagiline (1 mg/2 mg; n = 38) or placebo (n = 17) developed systolic BP (SBP) or heart rate changes indicative of a tyramine reaction. In the second trial involving 55 levodopa-treated patients, 3 of 22 subjects on rasagiline 0.5 mg/day and 1 of 21 subjects on placebo developed asymptomatic, self-limiting SBP elevations >or= 30 mm Hg on three measurements. No subject on 1 mg/day rasagiline (0/12) experienced significant BP or heart rate changes following tyramine ingestion. These data demonstrate that rasagiline 0.5 to 2 mg daily is not associated with clinically significant tyramine reactions and can be used as monotherapy or adjunct to levodopa in PD patients without specific dietary tyramine restriction.
Administration, Oral↗
Immune response to influenza vaccine is maintained in patients with multiple sclerosis receiving interferon beta-1a.
Immunologic response was assessed prospectively using influenza vaccine in 86 patients with multiple sclerosis (MS) who were taking interferon beta-1a and 77 patients who were not taking interferon. Blood samples were assayed for hemagglutination inhibition (HI) titers 0, 21, and 28 days after immunization. The two groups were similar in the proportion of patients achieving an HI titer of 40 or greater, the prespecified primary end point and on all secondary indicators of immune response.
Adjuvants, Immunologic↗
Treating fatigue in patients with MS: one step forward, one step back.
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Amantadine↗
Enhanced benefit of increasing interferon beta-1a dose and frequency in relapsing multiple sclerosis: the EVIDENCE Study.
BACKGROUND: The EVIDENCE (Evidence of Interferon Dose-Response: European North American Comparative Efficacy) Study demonstrated that patients with multiple sclerosis (MS) who initiate interferon beta-1a therapy with 44 microg 3 times weekly (TIW) were less likely to have a relapse or activity on magnetic resonance imaging (MRI) compared with those who initiate therapy at a dosage of 30 microg 1 time weekly (QW). OBJECTIVE: To determine the effect of changing the dosage from 30 microg QW to 44 microg TIW in this extension of the EVIDENCE Study. DESIGN/PATIENTS: Patients with relapsing MS originally randomized to interferon beta-1a, 30 microg QW, during the comparative phase of the study changed to 44 microg TIW, whereas patients originally randomized to 44 microg TIW continued that regimen. Patients were followed up, on average, for an additional 32 weeks. MAIN OUTCOME MEASURE: The within-patient pretransition to post-transition change in relapse rate. RESULTS: At the transition visit, 223 (73%) of 306 patients receiving 30 microg QW converted to 44 microg TIW, and 272 (91%) of 299 receiving 44-microg TIW continued the same therapy. The post-transition annualized relapse rate decreased from 0.64 to 0.32 for patients increasing the dose (P<.001) and from 0.46 to 0.34 for patients continuing 44-microg TIW (P = .03). The change was greater in those increasing dose and frequency (P = .047). Patients converting to the 44-mug TIW regimen had fewer active lesions on T2-weighted MRI compared with before the transition (P = .02), whereas those continuing the 44-microg TIW regimen had no significant change in T2 active lesions. Patients who converted to high-dose/high-frequency interferon beta-1a therapy had increased rates of adverse events and treatment terminations consistent with the initiation of high-dose subcutaneous interferon therapy. CONCLUSIONS: Patients receiving interferon beta-1a improved on clinical and MRI disease measures when they changed from 30 microg QW to 44 microg TIW.
Adjuvants, Immunologic↗
A randomized controlled study of the acute and chronic effects of cooling therapy for MS.
BACKGROUND: Cooling demyelinated nerves can reduce conduction block, potentially improving symptoms of MS. The therapeutic effects of cooling in patients with MS have not been convincingly demonstrated because prior studies were limited by uncontrolled designs, unblinded evaluations, reliance on subjective outcome measures, and small sample sizes. OBJECTIVE: To determine the effects of a single acute dose of cooling therapy using objective measures of neurologic function in a controlled, double-blinded setting, and to determine whether effects are sustained during daily cooling garment use. METHODS: Patients (n = 84) with definite MS, mild to moderate disability (Expanded Disability Status Scale score < 6.0), and self-reported heat sensitivity were randomized into a multicenter, sham-treatment controlled, double-blind crossover study. Patients had the MS Functional Composite (MSFC) and measures of visual acuity/contrast sensitivity assessed before and after high-dose or low-dose cooling for 1 hour with a liquid cooling garment. One week later, patients had identical assessments before and after the alternate treatment. Patients were then re-randomized to use the cooling garment 1 hour each day for a month or to have observation only. They completed self-rated assessments of fatigue, strength, and cognition during this time, and underwent another acute cooling session at the end of the period. After 1 week of rest, they had identical assessments during the alternate treatment. RESULTS: Body temperature declined during both high-dose and low-dose cooling, but high-dose produced a greater reduction (p < 0.0001). High-dose cooling produced a small improvement in the MSFC (0.076 +/- 0.66, p = 0.007), whereas low-dose cooling produced only a trend toward improvement (0.053 +/- 0.031, p = 0.09), but the difference between conditions was not significant. Timed gait testing and visual acuity/contrast sensitivity improved in both conditions as well. When patients underwent acute cooling following a month of daily cooling, treatment effects were similar. Patients reported less fatigue during the month of daily cooling, concurrently on the Rochester Fatigue Diary and retrospectively on the Modified Fatigue Impact Scale. CONCLUSIONS: Cooling therapy was associated with objectively measurable but modest improvements in motor and visual function as well as persistent subjective benefits.
Adolescent↗
Cognitive fatigue during a test requiring sustained attention: a pilot study.
BACKGROUND: Fatigue is common in multiple sclerosis (MS), but difficulty quantifying fatigue severity has impeded studies of its characteristics, mechanisms, and therapeutics. Motor fatigue can be objectively measured as the decline in strength occurring during sustained contractions. Analogous declines in cognitive performance occur during tasks requiring sustained attention. OBJECTIVE: To objectively measure cognitive fatigue as a decline in performance during tests requiring sustained attention. DESIGN/METHODS: Patients with clinically stable MS (n = 20) and healthy controls (n = 21) with comparable age, gender, and education completed the Paced Auditory Serial Addition Test (PASAT) and the Digit Ordering Test (DOT) at two identical test sessions separated by 4-10 days, within a month after two practice sessions. Cognitive fatigue was quantified with two pre-specified methods for each test. The reliability of cognitive fatigue assessments was evaluated with intraclass correlation coefficients (ICCs) and construct validity was evaluated using correlations with measures of self-reported fatigue, cognition, and overall impairment/disability. RESULTS: MS patients had an average of 18.7 items correct on the first 20 items of the PASATand 17.8 correct on the last 20 items, quantified as 5.3-5.8% declines in performance using the different measurement methods (P = 0.01, rejecting the null hypothesis of zero mean decline). Although MS patients as a group demonstrated a similar decline at both sessions, ICCs were relatively low. Control patients did not demonstrate significant declines in performance during PASAT administration, but tests comparing declines in MS patients and controls did not demonstrate significant differences. Fatigue was not demonstrated using the DOT, and test-retest reliability was very poor. CONCLUSIONS: MS patients have objectively measurable cognitive fatigue during administration of the PASAT.
Adolescent↗
Multiple sclerosis, depression, and the risk of suicide.
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Depression↗
Fatigue in multiple sclerosis: current understanding and future directions.
Fatigue is a very common symptom of multiple sclerosis (MS). Theoretically, fatigue may be related to neuromodulation by soluble products of the autoimmune process or by disruption of central nervous system pathways necessary for sustained activity, but little empirical evidence supports these possibilities. Amantadine, pemoline, and modafanil improved fatigue in placebo-controlled clinical trials, but these studies all had significant limitations. Difficulty measuring fatigue has impeded studies of its characteristics, mechanisms, and therapeutics. Most studies have relied on self-report questionnaires. These may be inappropriate, however, because they can be easily confounded by other symptoms of MS, they are entirely subjective, and they require patients to make difficult retrospective assessments. Studies of fatigue would be improved by including measures of more rigorously defined, quantifiable components of fatigue. For example, motor fatigue can be measured as the decline in strength during sustained muscle contractions. Cognitive fatigue can be measured as the analogous decline in cognitive performance during tasks requiring sustained attention. Lassitude is defined as a subjective sense of reduced energy, and it can be measured with the use of a visual analog diary. These measures provide reproducible results and demonstrate significant differences between MS patients and healthy controls. Dividing fatigue into these components can provide objective assessments that are less likely to be confounded by other symptoms of MS, such as weakness, spasticity, cognitive impairment, and depressed mood.
Evidence-Based Medicine↗