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CD005376

The evidence from randomised controlled trials for the treatment of IgG or IgA paraproteinaemic neuropathy is currently inadequate. More randomised controlled trials of treatments are required. These should have adequate follow-up periods and contain larger numbers of participants, perhaps through multicentre collaboration, considering the relative infrequency of this condition. Observational or open trial data provide limited support for the use of treatments such as plasma exchange, cyclophosphamide combined with prednisolone, intravenous immunoglobulin and corticosteroids. These show potential therapeutic promise but the potential benefits must be weighed against adverse effects. Their optimal use and the long-term benefits need to be considered and validated with well-designed randomised controlled trials.

Plasma exchange in polyneuropathy associated with monoclonal gammopathy of undetermined significance.

Polyneuropathy associated with monoclonal gammopathy of undetermined significance (MGUS) has been treated with plasma exchange, intravenous immune globulin, and chemotherapy, but the effectiveness of these treatments remains uncertain. We randomly assigned 39 patients with stable or worsening neuropathy and MGUS of the IgG, IgA, or IgM type to receive either plasma exchange twice weekly for three weeks or sham plasma exchange, in a double-blind trial. The patients who initially underwent sham plasma exchange subsequently underwent plasma exchange in an open trial. In the double-blind trial, the average neuropathy disability score improved by 2 points from base line (from 62.5 to 60.5) in the sham-exchange group and by 12 points (from 58.3 to 46.3) in the plasma-exchange group (P = 0.06). A similar difference was observed in the weakness score, a component of the neuropathy disability score (improvement, 1 and 10 points, respectively; P = 0.07). After treatment the summed compound muscle action potentials of motor nerves were 1.2 mV lower (worse) than at base line in the sham-exchange group and 0.4 mV higher (better) in the plasma-exchange group (P = 0.07). The greater degree of improvement with plasma exchange was equal in magnitude to or greater than the difference between not being able to walk on the heels or toes and being able to perform these activities. Changes in the vibratory detection threshold, summed motor-nerve conduction velocity, and sensory-nerve action potentials did not differ significantly between the treatment groups. In the open trial, in which patients who initially underwent sham exchange were treated with plasma exchange, the neuropathy disability score (P = 0.04), weakness score (P = 0.07), and summed compound muscle action potentials (P = 0.07) improved more with plasma exchange than they had with sham exchange. In both the double-blind and the open trial, those with IgG or IgA gammopathy had a better response to plasma exchange than those with IgM gammopathy. Plasma exchange appears to be efficacious in neuropathy associated with MGUS, especially of the IgG or IgA type.

CD009497

On the basis of one randomised trial which did not describe its methodology in sufficient detail to assess risk of bias and quality, excluded 27% of patients after randomisation due to various reasons, and is probably not free from selective outcome reporting bias, there is insufficient evidence to conclude that in patients with colonic cancer liver metastases, electro-coagulation alone brings any significant benefit in terms of survival or recurrence compared with the control. In addition, there is insufficient evidence for the effectiveness of adding allopurinol or dimethyl sulphoxide to electro-coagulation. The probability for selective outcome reporting bias in the trial is high. More randomised trials are needed in order to sufficiently validate electro-coagulation with or without co-interventions.

Scavengers of oxygen-derived free radicals prolong survival in advanced colonic cancer. A new approach.

The influence of oxygen-derived free radicals on survival in advanced colonic cancer was assessed in a prospective randomized controlled double-blind trial using the radical scavengers dimethyl sulphoxide (DMSO) and allopurinol. Following palliative sigmoid colectomy for carcinoma at Dukes' stage D, 306 patients were randomized to the control group or to electrocoagulation of liver secondaries alone or with allopurinol (50 mg by mouth 4 times a day) or DMSO (500 mg by mouth 4 times a day). In 193 fully evaluable patients who were studied for 5 years, allopurinol and DMSO incurred a significant (p < 0.05) survival advantage over the whole period of study. The similarity in efficacy between allopurinol and DMSO and the fact that the only action they share is scavenging oxyradicals, suggest that these radicals mediate the detrimental effects of malignancy and that removing them incurs a survival advantage for patients with advanced colonic cancer.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging--measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group.

Two prior double-blind, placebo-controlled, randomized trials demonstrated that glatiramer acetate (GA) reduces relapse rates in patients with relapsing remitting multiple sclerosis (RRMS). This study was designed to determine the effect, onset, and durability of any effect of GA on disease activity monitored with magnetic resonance imaging (MRI) in patients with RRMS. Two hundred thirty-nine eligible patients were randomized to receive either 20 mg GA (n = 119) or placebo (n = 120) by daily subcutaneous injection. Eligibility required one or more relapses in the 2 years before entry and at least one enhancing lesion on a screening MRI. The study was a randomized, double-blind, placebo-controlled phase during which all patients studied underwent monthly MRI scans and clinical assessments over 9 months. The primary outcome measure was the total number of enhancing lesions on T1-weighted images. Secondary outcome measures included the proportion of patients with enhancing lesions, the number of new enhancing lesions and change in their volume; the number of new lesions detected on T2-weighted images and change in their volume, and the change in volume of hypointense lesions seen on unenhanced T1-weighted images. Clinical measures of disease activity were also evaluated. The active treatment and placebo groups were comparable at entry for all demographic, clinical, and MRI variables. Treatment with GA showed a significant reduction in the total number of enhancing lesions compared with placebo (-10.8, 95% confidence interval -18.0 to -3.7; p = 0.003). Consistent differences favoring treatment with GA were seen for almost all secondary end points examined: number of new enhancing lesions (p < 0.003), monthly change in the volume of enhancing lesions (p = 0.01), and change in volume (p = 0.006) and number of new lesions seen on T2-weighted images (p < 0.003). The relapse rate was also significantly reduced by 33% for GA-treated patients (p = 0.012). All effects increased over time. Glatiramer acetate significantly reduced MRI-measured disease activity and burden.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

A single-center, randomized, double-blind, placebo-controlled study of interferon beta-1b on primary progressive and transitional multiple sclerosis.

Inflammation and neurodegeneration may have differential impacts on disease evolution in the different forms of multiple sclerosis. However, a beneficial effect of immunomodulatory drugs should not be ruled out in primary progressive multiple sclerosis. Our aim is to investigate the safety and efficacy of interferon beta-1b in primary progressive multiple sclerosis. We conducted a double-blind, stratified, randomized, parallel group, phase II pilot study where patients with primary progressive multiple sclerosis or 'transitional' forms of multiple sclerosis received interferon beta-1b at doses of 8 MIU or placebo for 24 months. The main objective of the study was to investigate the safety and tolerability of interferon beta-1b. The primary efficacy variable was the time to neurological deterioration (Expanded Disability Status Scale) confirmed at 3 months. Seventy-three patients were included and three dropped out the study. More patients in the treatment arm had at least one related adverse event (94.4% versus 45.9%; p < 0.001); no other significant differences in safety endpoints were observed. Time to neurological deterioration was not different between trial arms (log-rank test, p = 0.3135). Statistically significant differences favoring treatment were observed for the Multiple Sclerosis Functional Composite score at several timepoints, T1 and T2 lesion volume changes at 12 and 24 months, mean number of active lesions and proportion of patients with active lesions at 24 months. We conclude that interferon beta-1b is safe and well tolerated in patients with primary progressive multiple sclerosis and transitional multiple sclerosis. Positive effects of interferon beta on secondary clinical and magnetic resonance imaging outcomes were observed, but a beneficial effect on Expanded Disability Status Scale progression was not demonstrated.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Interferon beta-1a in primary progressive MS: an exploratory, randomized, controlled trial.

Patients with primary progressive MS have atypical clinical and MRI characteristics and have been excluded from most therapeutic trials. The authors report a randomized, controlled trial restricted to primary progressive MS. Fifty subjects were randomized to weekly IM interferon beta-1a 30 microg, 60 microg, or placebo for 2 years. The primary endpoint was time to sustained progression in disability. Secondary outcomes included the timed 10-meter walk, nine-hole peg test, and on MRI, T2 and T1 brain lesion loads and brain and spinal cord atrophy. The 30- microg dose of interferon beta-1a was well tolerated, but the 60- microg dose caused severe flulike reactions and raised liver enzymes. No treatment effect was seen on the primary endpoint. Subjects on interferon beta-1a 30 microg had a lower rate of accumulation of T2 lesion load than controls (p = 0.025); subjects on 60 microg had a greater rate of ventricular enlargement than controls (p = 0.025). This study has demonstrated that interferon beta-1a 30 microg was well tolerated, identified useful outcome measures, but showed no efficacy on the primary outcome measure or on most of the secondary outcome measures.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial.

Several double-blind placebo-controlled trials of relapsing-remitting multiple sclerosis have shown beneficial effects of intravenous immunoglobulin (IVIG) on relapse rate and disability. The European Study on Intravenous Immunoglobulin in Multiple Sclerosis set out to test IVIG in the secondary progressive phase of the disease. 318 patients with clinically definite secondary progressive multiple sclerosis (mean age 44 years [SD 7]) were randomly assigned IVIG 1 g/kg per month (n=159) or an equivalent volume of placebo (albumin 0.1%; n=159) for 27 months. After baseline investigation, clinical assessments were made every 3 months and MRI was repeated after 12 months and 24 months. The primary outcome was confirmed worsening of disability as defined by the time to first confirmed progression on the expanded disability status scale (EDSS). Analyses were by intention to treat. 19 patients in the IVIG group and 39 in the placebo group terminated study treatment prematurely but were included in the analyses. IVIG treatment had no beneficial effect on time to confirmed EDSS progression (hazard ratio 1.11 [95% CI 0.80-1.53] for IVIG versus placebo). The annual relapse rate was 0.46 in both groups. No significant differences between the treatment groups were found in any of the other clinical outcome measures or in the change of T2-lesion load over time. The treatment was generally well tolerated, although deep venous thrombosis, pulmonary embolism, or both occurred in seven patients with risk factors for thromboembolism (IVIG six, placebo one). Treatment with IVIG in this study did not show any clinical benefit and therefore cannot be recommended for patients with secondary progressive multiple sclerosis.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria.

To evaluate the efficiency of mitoxantrone in multiple sclerosis. Forty two patients with confirmed multiple sclerosis, selected as having a very active disease on clinical and MRI criteria were randomised to receive either mitoxantrone (20 mg intravenously (IV) monthly) and methylprednisolone (1 g iv monthly) or methylprednisolone alone over six months. In the steroid alone group five patients dropped out due to severe exacerbation. Blinded analysis of MRI data showed significantly more patients with no new enhancing lesions in the mitoxantrone group compared with the steroid alone group, (90% v 31%, P < 0.001). In the mitoxantrone group there was a month by month decrease almost to zero in the number of new enhancing lesions, and in the total number of enhancing lesions, whereas both remained high in the steroid alone group. The differences were significant for both indices at all months from 1-6. Unblinded clinical assessments showed a significant improvement in change in EDSS at months 2-6 in the mitoxantrone group, with a final mean improvement of more than one point (-1.1 v + 0.3; P < 0.001). There was a significant reduction in the number of relapses (7 v 31; P < 0.01), and an increase in the number of patients free of exacerbation (14 v 7; P < 0.05). In this selected group of patients with multiple sclerosis with very active disease, mitoxantrone combined with methylprednisolone was effective in improving both clinical and MRI indices of disease activity over a period of six months whereas methylprednisolone alone was not. Further double blinded long term studies are needed to properly evaluate the effect of mitoxantrone on progression in disability.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial.

Treatment options for patients with secondary progressive multiple sclerosis are few. Encouraging results in open-label studies prompted this randomised trial of mitoxantrone in such patients. 194 patients with worsening relapsing-remitting or secondary progressive multiple sclerosis were assigned placebo or mitoxantrone (5 mg/m(2) [exploratory group] or 12 mg/m(2) intravenously) every 3 months for 24 months. Clinical assessments were made every 3 months for 24 months. The primary endpoint was a multivariate analysis of five clinical measures. Analyses of mitoxantrone 12 mg/m(2) versus placebo were based on patients who received at least one dose and returned for at least one assessment of efficacy. Of 194 patients enrolled, 188 were able to be assessed at 24 months. There were no drug-related serious adverse events or evidence of clinically significant cardiac dysfunction. At 24 months, the mitoxantrone group experienced benefits compared with the placebo group for the primary outcome (difference 0.30 [95% CI 0.17-0.44]; p<0.0001) and the preplanned univariate analyses of those measures: change in expanded disability status scale (0.24 [0.04-0.44]; p=0.0194), change in ambulation index (0.21 [0.02-0.40]; p=0.0306), adjusted total number of treated relapses (0.38 [0.18-0.59]; p=0.0002), time to first treated relapse (0.44 [0.20-0.69]; p=0.0004), and change in standardised neurological status (0.23 [0.03-0.43]; p=0.0268). Mitoxantrone 12 mg/m(2) was generally well tolerated and reduced progression of disability and clinical exacerbations. Further studies are needed to identify the patients with these forms of multiple sclerosis who are most likely to respond to therapy, the best treatment protocols, and the frequency of long-term drug-related side-effects.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group.

Previous trials of interferon beta in multiple sclerosis (MS) have shown efficacy, but the degree of clinical benefit remains uncertain, and the optimum dose is not known. We undertook a double-blind, placebo-controlled study in relapsing/remitting MS to investigate the effects of subcutaneous interferon beta-1a. 560 patients with Kurtzke expanded disability status scale (EDSS) scores of 0-5.0, from 22 centres in nine countries, were randomly assigned subcutaneous recombinant interferon beta-1a 22 microg (n=189), or 44 microg (n=184), or placebo (n=187) three times a week for 2 years. Neurological examinations were done every 3 months. All patients had MRI twice yearly and 205 had monthly scans in the first 9 months of treatment. Analysis was by intention to treat. Clinical data on 533 (95%) patients were available at 2 years. The relapse rate was significantly lower at 1 and 2 years with both doses of interferon beta-1a than with placebo (mean number per patient 1.82 for 22 microg group, 1.73 for 44 microg group vs 2.56 for placebo group: risk reductions 27% [95% CI 14-39] and 33 [21-44]). Time to first relapse was prolonged by 3 and 5 months in the 22 microg and 44 microg groups respectively, and the proportion of relapse-free patients was significantly increased (p<0.05). Interferon beta-1a delayed progression in disability, and decreased accumulated disability during the study. The accumulation of burden of disease and number of active lesions on MRI was lower in both treatment groups than in the placebo group. Subcutaneous interferon beta-1a is an effective treatment for relapsing/remitting MS in terms of relapse rate, defined disability, and all MRI outcome measures in a dose-related manner, and it is well tolerated. Longer-term benefits may become clearer with further follow-up and investigation.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis.

A randomized, double-blinded, placebo-controlled, clinical trial of low-dose, weekly, oral methotrexate was performed in 60 patients with clinically definite chronic progressive multiple sclerosis (MS) attending a referral-based outpatient MS clinic. Study patients were 21 to 60 years old with a disease duration of longer than 1 year. Patients' Expanded Disability Status Scale scores were 3.0 to 6.5 (ambulatory with moderate disability). Patients were first stratified by Expanded Disability Status Scale scores, 3.0 to 5.5 and 6.0 to 6.5, and then were randomized to receive methotrexate or placebo treatment. Treatment consisted of weekly, oral, low-dose (7.5 mg) methotrexate or identical placebo for 2 years, followed by observation for as long as 1 year. A composite outcome measurement instrument was used and consisted of (1) Expanded Disability Status Scale, (2) ambulation index, (3) Box and Block Test, and (4) 9-Hole Peg Test. Failure of therapy was indicated by a designated change that was sustained for more than 2 months in one or more components of this composite measure. Significantly less progression of impairment as measured by validated tests of upper-extremity function was observed in the methotrexate treatment group in the absence of clinically significant toxicity. We conclude that low-dose, weekly, oral methotrexate offers a new, relatively nontoxic treatment option for patients with chronic progressive MS.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Systemic recombinant human interferon-beta treatment of relapsing-remitting multiple sclerosis: pilot study analysis and six-year follow-up.

A pilot study was undertaken to test the safety and establish the side effect profile of recombinant human interferon-beta 1b (Betaseron, Berlex Laboratories, Richmond, CA), in patients with relapsing-remitting multiple sclerosis (RRMS). During the initial dose finding period (24 weeks), five groups of 6 patients each were treated by subcutaneous injection three times each week with either 0.8, 4, 8, or 16 million units (mU) of Betaseron or placebo (WHO Standard). Although some side effects were noted in all groups, a dose-related trend in reduction of exacerbation frequency and side-effect profile was noted. Patients given 16 mU had no exacerbations during the initial dosing period, but associated side effects led to dose reduction or dropout. An 8 mU dose was selected for further study after 24 weeks, and continuous dosing at 8 mU in 15 patients has now exceeded 6 years. Side effects abated over time. Neutralizing antibody developed in most patients, but titers were variable, fluctuated independently of clinical course, and tended to fall with prolonged treatment. A dose-dependent rise in neopterin levels was observed during the initial dosing period. This pilot study has demonstrated responsiveness to Betaseron, shown a stable safety profile over time, and established guidelines for a dosing regimen to evaluate and optimize further the efficacy of Betaseron in RRMS.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis.

Interferon (IFN) beta has repeatedly shown benefit in multiple sclerosis (MS) in reducing the rate of relapse, the disease activity as shown with magnetic resonance imaging and, to some degree, the progression of disability; however, it is unknown how much the therapeutic response depends on the dose, the subgroup involved, and the disease stage. This multicentre, double blind, placebo controlled study explored the dose-response curve by examining the clinical benefit of low dose IFN beta-1a (Rebif), 22 micro g subcutaneously once weekly, in patients with secondary progressive MS. A total of 371 patients with clinically definite SPMS were randomised to receive either placebo or subcutaneous IFN beta-1a, 22 micro g once weekly, for 3 years. Clinical assessments were performed every 6 months. The primary outcome was time to sustained disability, as defined by time to first confirmed 1.0 point increase on the Expanded Disability Status Scale (EDSS). Secondary outcomes included a sensitive disability measure and relapse rate. Treatment had no beneficial effect on time to confirmed progression on either the EDSS (hazard ratio (HR) = 1.13; 95% confidence interval (CI) 0.82 to 1.57; p = 0.45 for 22 micro g v placebo) or the Regional Functional Status Scale (HR = 0.93; 95% CI 0.68 to 1.28; p = 0.67). Other disability measures were also not significantly affected by treatment. Annual relapse rate was 0.27 with placebo and 0.25 with IFN (rate ratio = 0.90; 95% CI 0.64 to 1.27; p = 0.55). The drug was well tolerated with no new safety concerns identified. No significant gender differences were noted. This patient population was less clinically active than SPMS populations studied in other trials. Treatment with low dose, IFN beta-1a (Rebif) once weekly did not show any benefit in this study for either disability or relapse outcomes, including a subgroup with preceding relapses. These results add a point at one extreme of the dose-response spectrum of IFN beta therapy in MS, indicating that relapses in this phase may need treatment with higher doses than in the initial phases.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN).

The three interferon beta preparations approved for treatment of relapsing-remitting multiple sclerosis (MS) differ in dose and frequency of administration. Interferon beta-1a 30 microg is administered once a week, interferon beta-1a 22 microg or 44 microg is given three times a week, and interferon beta-1b 250 microg is administered on alternate days. No clinical study directly comparing the different regimens has been published. The INCOMIN study was designed to compare the clinical and magnetic resonance imaging (MRI) benefits of on-alternate-day interferon beta-1b 250 microg with once-weekly interferon beta-1a 30 microg. INCOMIN was a 2-year, prospective, randomised, multicentre study. 188 patients with relapsing-remitting MS were assigned to interferon beta-1b (n=96) or interferon beta-1a (n=92). Primary outcome measures were the proportion of patients free from relapses and that of patients free from new proton density/T2 lesions at MRI assessment. Several secondary outcome measures were also assessed. Analysis was by intention to treat. Over 2 years, 49 (51%) individuals administered interferon beta-1b remained relapse-free compared with 33 (36%) given interferon beta-1a relative risk of relapse 0.76; 95% CI 0.59-0.9; p=0.03); and 42 (55%) compared with 19 (26%), respectively, remained free from new T2 lesions at MRI (relative risk of new T2 lesion 0.6; 0.45-0.8; p<0.0003). In both groups, the differences between the two treatments increased during the second year. There were also significant differences in favour of interferon beta-1b in most of the secondary outcome measures, including delay of confirmed disease progression. High-dose interferon beta-1b administered every other day is more effective than interferon beta-1a given once a week.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial.

To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis. A total of 943 patients with primary progressive multiple sclerosis were randomized to GA or placebo (PBO) in this 3-year, double-blind trial. The primary end point was an intention-to-treat analysis of time to 1- (entry expanded disability status scale, 3.0-5.0) or 0.5-point expanded disability status scale change (entry expanded disability status scale, 5.5-6.5) sustained for 3 months. The trial was stopped after an interim analysis by an independent data safety monitoring board indicated no discernible treatment effect on the primary outcome. Intention-to-treat analyses of disability and magnetic resonance imaging end points were performed. There was a nonsignificant delay in time to sustained accumulated disability in GA- versus PBO-treated patients (hazard ratio, 0.87 [95% confidence interval, 0.71-1.07]; p = 0.1753), with significant decreases in enhancing lesions in year 1 and smaller increases in T2 lesion volumes in years 2 and 3 versus PBO. Post hoc analysis showed that survival curves for GA-treated male patients diverged early from PBO-treated male subjects (hazard ratio, 0.71 [95% confidence interval, 0.53-0.95]; p = 0.0193). The trial failed to demonstrate a treatment effect of GA on primary progressive multiple sclerosis. Both the unanticipated low event rate and premature discontinuation of study medication decreased the power to detect a treatment effect. Post hoc analysis suggests GA may have slowed clinical progression in male patients who showed more rapid progression when untreated.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Benefit of interferon beta-1a on MSFC progression in secondary progressive MS.

Interferon beta-1a (IFNbeta-1a, Avonex) is efficacious in relapsing forms of MS. Studies of other IFNbeta preparations in secondary progressive MS (SPMS) yielded conflicting results. This study was undertaken to determine whether IFNbeta-1a slowed disease progression in SP-MS. A total of 436 subjects with SPMS and Expanded Disability Status Scale (EDSS) score 3.5 to 6.5 were randomized to receive IFNbeta-1a (60 micro g) or placebo by weekly intramuscular injection for 2 years. The primary outcome measure, used for the first time in a large-scale MS trial, was baseline to month 24 change in the MS Functional Composite (MSFC), comprising quantitative tests of ambulation (Timed 25-Foot Walk), arm function (Nine-Hole Peg Test [9HPT]), and cognition (Paced Auditory Serial Addition Test [PASAT]). Median MSFC Z-score change was reduced 40.4% in IFNbeta-1a subjects (-0.096 vs -0.161 in placebo subjects, p = 0.033), an effect driven mainly by the 9HPT and PASAT. There was no discernible benefit on the EDSS, which in this range principally reflects walking ability. IFNbeta-1a subjects had 33% fewer relapses (p = 0.008). There was significant benefit on eight of 11 MS Quality of Life Inventory subscales. New or enlarging T2-hyperintense brain MRI lesions and gadolinium-enhancing lesions were reduced at months 12 and 24 (both p < 0.001). IFNbeta-1a was well tolerated by the majority of subjects. Neutralizing antibodies developed in 3.3% of IFNbeta-1a-treated subjects. IFNbeta-1a demonstrated benefit on MSFC progression, relapses, quality of life, and MRI activity in SPMS.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study.

To evaluate the efficacy and safety of interferon beta-1b (IFNbeta-1b) in subjects with secondary progressive multiple sclerosis (SPMS). This 3-year, multicenter, double-blind, placebo-controlled, randomized trial of IFNbeta-1b included 939 subjects from the United States and Canada with SPMS and Expanded Disability Status Scale (EDSS) scores ranging from 3.0 to 6.5. Subjects were randomly assigned to receive either placebo or IFNbeta-1b (250 microg or 160 microg/m2 body surface area), administered subcutaneously every other day. The primary outcome was time to progression by > or =1.0 EDSS point (0.5 point if EDSS score was 6.0 to 6.5 at entry) confirmed at 6 months. Secondary outcomes included mean change in EDSS score from baseline, relapse-related measures, MRI activity, and a standardized neuropsychological function test. There was no significant difference in time to confirmed progression of EDSS scores between placebo-treated patients and either of the IFNbeta-1b treatment groups. However, IFNbeta-1b treatment resulted in improvement on secondary outcome measures involving clinical relapses, newly active MRI lesions, and accumulated burden of disease on T2-weighted MRI. Effects were similar for both IFNbeta-1b treatment groups. Neutralizing antibodies to IFNbeta-1b were detected in 23% of 250-microg and 32% of 160-microg/m2 recipients, but their presence did not consistently affect clinical or MRI outcomes. IFNbeta-1b was also well tolerated at both doses. Although no treatment benefit was seen on the time to confirmed progression of disability, relapse- and MRI-related outcomes showed significant benefit with both dosing regimens tested, a result consistent with the outcomes of earlier clinical trials.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group.

We studied copolymer 1 (Copaxone) in a multicenter (11-university) phase III trial of patients with relapsing-remitting multiple sclerosis (MS). Two hundred fifty-one patients were randomized to receive copolymer 1 (n = 125) or placebo (n = 126) at a dosage of 20 mg by daily subcutaneous injection for 2 years. The primary end point was a difference in the MS relapse rate. The final 2-year relapse rate was 1.19 +/- 0.13 for patients receiving copolymer 1 and 1.68 +/- 0.13 for those receiving placebo, a 29% reduction in favor of copolymer 1 (p = 0.007) (annualized rates = 0.59 for copolymer 1 and 0.84 for placebo). Trends in the proportion of relapse-free patients and median time to first relapse favored copolymer 1. Disability was measured by the Expanded Disability Status Scale (EDSS), using a two-neurologist (examining and treating) protocol. When the proportion of patients who improved, were unchanged, or worsened by > or = 1 EDSS step from baseline to conclusion (2 years) was evaluated, significantly more patients receiving copolymer 1 were found to have improved and more receiving placebo worsened (p = 0.037). Patient withdrawals were 19 (15.2%) from the copolymer 1 group and 17 (13.5%) from the placebo group at approximately the same intervals. The treatment was well tolerated. The most common adverse experience was an injection-site reaction. Rarely, a transient self-limited systemic reaction followed the injection in 15.2% of those receiving copolymer 1 and 3.2% of those receiving placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

A placebo-controlled, double-blind, randomized, two-center, pilot trial of Cop 1 in chronic progressive multiple sclerosis.

We found Cop 1 to be effective and relatively safe in a previous (exacerbating-remitting) clinical trial. This current trial involves 106 chronic-progressive patients. The major end point, confirmed progression of 1.0 or 1.5 units (depending on baseline disability) on the Kurtzke Expanded Disability Status Scale, was observed in nine (17.6%) treated and 14 (25.5%) control patients. The differences between the overall survival curves were not significant. Progression rates at 12 and 24 months were higher for the placebo group (p = 0.088) with 2-year probabilities of progressing of 20.4% for Cop 1 and 29.5% for placebo. We found a significant difference at 24 months between placebo and Cop 1 at one but not the other center. Two-year progression rates for two secondary end points, unconfirmed progression, and progression of 0.5 EDSS units, (p = 0.03) are significant.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

A placebo-controlled, randomized, double-masked, variable dosage, clinical trial of azathioprine with and without methylprednisolone in multiple sclerosis.

Ninety-eight patients with multiple sclerosis (MS) in the chronic progression phase entered a 3-year clinical trial to determine if azathioprine (AZ) alone or with adrenal cortical steroids stabilizes the course of MS. In group AM, the patients took AZ throughout and methylprednisolone (MP) for the first 36 weeks. Group AP received AZ and placebo instead of MP. Group PP took placebos for both drugs. We adjusted the AZ to maintain the total white blood cell count within 3,000 to 4,000/mm3; we gave the MP in a fixed dose "pulse" and alternate-day regimen. The "intent-to-treat" groups had no statistically significant differences in the rates of progression among the 3 treatments. Subgroup analysis suggests that patients in the AM group who completed treatment exactly according to protocol did statistically significantly better than the placebo recipients using the sum of Standard Neurological Examination scores, slightly better using the quantitative neuro-performance tests, but no better using Mickey's Illness Severity Scores or Kurtzke's Disability Status Scale. Also, the AZ-treated groups had half the relapse rate of the placebo-treated group. Adverse reactions to AZ accounted for most withdrawals. Hematologic and hepatic abnormalities were significantly associated with AZ, but serious non-MS abnormalities were uncommon and were equally distributed among the 3 groups. Addition of MP to the AZ slightly improved the efficacy of the treatment, but also increased the adverse effects. The benefits of AZ with or without steroids did not outweigh the risks, and therefore we do not recommend this treatment for patients with chronic progressive MS.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study.

The aim of the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) trial was to compare the efficacy, safety, and tolerability of 250 microg or 500 microg interferon beta-1b with glatiramer acetate for treating relapsing-remitting multiple sclerosis. Between November, 2003, and June, 2005, 2447 patients with relapsing-remitting multiple sclerosis were screened and 2244 patients were enrolled in this prospective, multicentre, randomised trial. Patients were randomly assigned 2:2:1 by block randomisation with regional stratification to receive one of two doses of interferon beta-1b (250 microg or 500 microg) subcutaneously every other day or 20 mg glatiramer acetate subcutaneously every day. The primary outcome was relapse risk, defined as new or recurrent neurological symptoms separated by at least 30 days from the preceding event and that lasted at least 24 h. Secondary outcomes were progression on the expanded disability status scale (EDSS) and change in T1-hypointense lesion volume. Clinical outcomes were assessed quarterly for 2.0-3.5 years; MRI was done at screening and annually thereafter. Analysis was by per protocol. This study is registered, number NCT00099502. We found no differences in relapse risk, EDSS progression, T1-hypointense lesion volume, or normalised brain volume among treatment groups. Flu-like symptoms were more common in patients treated with interferon beta-1b (p<0.0001), whereas injection-site reactions were more common in patients treated with glatiramer acetate (p=0.0005). Patient attrition rates were 17% (153 of 888) on 250 microg interferon beta-1b, 26% (227 of 887) on 500 microg interferon beta-1b, and 21% (93 of 445) for glatiramer acetate. 500 microg interferon beta-1b was not more effective than the standard 250 microg dose, and both doses had similar clinical effects to glatiramer acetate. Although interferon beta-1b and glatiramer acetate had different adverse event profiles, the overall tolerability to both drugs was similar. Bayer HealthCare Pharmaceuticals.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Intense immunosuppression in chronic progressive multiple sclerosis: the Kaiser study.

The value of a short course of intensive immunosuppression with cyclophosphamide in stabilising chronic progressive multiple sclerosis (MS) was examined in a randomised single-blinded, placebo-controlled clinical trial. Forty two patients, from the Kaiser Permanente Medical Care Program, Northern California, were studied. Twenty two patients received a short course of cyclophosphamide in an outpatient neurology clinic until their leucocyte counts fell below 4000/mm3, and 20 patients received folic acid. Level of disability, impairment of functional systems, and performance of social roles were assessed before randomisation and reassessed 12, 18, and 24 months after therapy. In both the cyclophosphamide and folic acid groups, the mean level of disability increased from the baseline examination to the 12 month follow up examination (the primary endpoint) by 0.5 on Kurtzke's Expanded Disability Status Scale, indicating similar disease progression in the two groups. Although immunosuppression therapy can be safely administered to MS patients in an outpatient clinic, evidence of substantial benefits was not found.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Full results of the Evidence of Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: a multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon beta-1a for relapsing multiple sclerosis.

Interferon (IFN)-beta therapy represents an important advance in the management of relapsing multiple sclerosis (MS), but information about the relative benefits and risks of available preparations is limited. This report describes the full results of the Evidence of Interferon Dose-response-European North American Comparative Efficacy (EVIDENCE) study, combining analyses that were previously reported in separate publications for different phases of the study. The EVIDENCE study was a multicenter, randomized, assessor-blinded comparison of 2 IFN-beta dosing regimens. In the study, patients with relapsing MS were randomly assigned to SC IFN-beta1a 44 lag TIW (Rebif, Serono Inc., Geneva, Switzerland) or IM IFN-betala 30 mug QW (Avonex, Biogen Idec, Cambridge, Massachusetts) for 1 to 2 years. The primary clinical end point during the comparative phase was the proportion of patients who remained free from relapses; secondary and tertiary clinical end points included the annualized relapse rate and time to first relapse, re- spectively. All clinical and magnetic resonance imaging (MRI) evaluations were performed by blinded assessors. In the crossover phase of the study, patients who were originally randomized to low-dose QW treatment switched to the high-dose TIW treatment for an additional 8 months. Adverse events were determined by spontaneous reporting and monthly laboratory testing during the comparative phase. A total of 677 patients were enrolled in the study and evenly randomized to treatment; 605 patients completed the comparative phase and 439 completed the crossover phase. During the comparative phase, a significantly higher proportion of patients in the high-dose TIW treatment group remained free from relapses when compared with patients in the low-dose QW treatment group (adjusted odds ratio, 1.5; 95% CI, 1.1-2.0; P = 0.023). The high-dose TIW regimen was also associated with a significant reduction in the annualized relapse rate (-17%; P = 0.033) and a prolonged time to first relapse (hazard ratio, 0.70; P = 0.002). MRI measures of disease activity were significantly reduced in the high-dose TIW group compared with the low-dose QW treatment. During the crossover phase, a 50% reduction in mean relapse rates was observed in patients who converted from low-dose QW treatment to high-dose TIW treatment (P < 0.001), with significant concomitant reductions in MRI activity. Injection-site reactions were significantly more common with high-dose TIW treatment than with low-dose QW treatment (85% vs 33%; P < 0.001). Neutralizing antibody formation was more common with high-dose TIW treatment than with low-dose QW treatment (26% vs 3%; P < 0.001). The comparative phase of the EVIDENCE study found that treatment of MS with SC IFN-beta1a 44 microg TIW was associated with a significant reduction in clinical and imaging measures of disease activity over 1 to 2 years, when compared with IM IFN-betala 30 microg QW treatment. The crossover phase found that patients who changed from low-dose QW treatment to high-dose TIW treatment experienced enhanced benefits of treatment without a substantial increase in adverse events.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Intravenous immunoglobulin in primary and secondary chronic progressive multiple sclerosis: a randomized placebo controlled multicentre study.

In patients with relapsing-remitting multiple sclerosis (MS), IVIG was shown to reduce the relapse rate and progression of disability. In patients with chronic progressive MS, a beneficial effect of IVIG was not documented in placebo controlled studies. This trial investigated the influence of IVIG in primary (PPMS) and secondary (SPMS) chronic progressive MS. Two-hundred and thirty-one patients stratified for PPMS (n=34) and SPMS (n=197) were randomly assigned to IVIG 0.4 g/kg per month or to placebo for 24 months. Primary endpoints were 1) the time to sustained progression of disease identified as worsening of the expanded disability status scale (EDSS) sustained for 3 months, and 2) the improvement of neurological functions defined by a patient's best EDSS score. Secondary endpoints were the proportion of patients with sustained progression, the relapse rate, the assessment of fine motor skills, visual evoked potentials, contrast sensitivity, depression and quality of life. Analysis of the intention-to-treat (ITT) population of combined PPMS and SPMS patients showed that the mean time to sustained progression was 74 weeks in the IVIG compared with 62 weeks in the placebo group (P=0.0406). When PPMS and SPMS patients were analysed separately, the time to sustained progression was also longer in the IVIG group, but the difference was not significant. There was no IVIG-mediated improvement in neurological functions. In the combined per protocol (PP) treated patients, IVIG treatment prolonged time to sustained progression by 13 weeks (P=0.0396). PPMS patients, but not SPMS patients showed a slight favourable IVIG effect on the best EDSS score. In the combined ITT population there were less patients with sustained progression in the IVIG than in the placebo group (P=0.028). The difference was significant in PPMS (P=0.016), but not in SPMS patients. In the combined PP population, there was a trend for a favorable IVIG effect on the rates of patients with sustained progression. In patients with PPMS, this IVIG effect reached significance (P=0.036). Other secondary endpoints did not show significant differences between treatment groups. Eighteen patients with PPMS and 102 patients with SPMS withdrew from the study for various reasons. Treatment was generally well tolerated. It was concluded that monthly IVIG infusion could delay progression of disease in patients with PPMS, and that there was a trend in favour of IVIG treatment in patients with SPMS.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial.

Interferon beta-1a and glatiramer acetate are commonly prescribed for relapsing-remitting multiple sclerosis (RRMS), but no published randomised trials have directly compared these two drugs. Our aim in the REGARD (REbif vs Glatiramer Acetate in Relapsing MS Disease) study was to compare interferon beta-1a with glatiramer acetate in patients with RRMS. In this multicentre, randomised, comparative, parallel-group, open-label study, patients with RRMS diagnosed with the McDonald criteria who had had at least one relapse within the previous 12 months were randomised to receive 44 mug subcutaneous interferon beta-1a three times per week or 20 mg subcutaneous glatiramer acetate once per day for 96 weeks to assess the time to first relapse. A subpopulation of 460 patients (230 from each group) also had serial MRI scans to assess T2-weighted and gadolinium-enhancing lesion number and volume. Treatments were assigned by a computer-generated randomisation list that was stratified by centre. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00078338. Between February and December, 2004, 764 patients were randomly assigned: 386 to interferon beta-1a and 378 to glatiramer acetate. After 96 weeks, there was no significant difference between groups in time to first relapse (hazard ratio 0.94, 95% CI 0.74 to 1.21; p=0.64). Relapse rates were lower than expected: 258 patients (126 in the interferon beta-1a group and 132 in the glatiramer acetate group) had one or more relapses (the expected number was 460). For secondary outcomes, there were no significant differences for the number and change in volume of T2 active lesions or for the change in the volume of gadolinium-enhancing lesions, although patients treated with interferon beta-1a had significantly fewer gadolinium-enhancing lesions (0.24 vs 0.41 lesions per patient per scan, 95% CI -0.4 to 0.1; p=0.0002). Safety and tolerability profiles were consistent with the known profiles for both compounds. The overall number and severity of adverse events were similar between the treatments and were not an important cause for discontinuation of the trial during the 96 weeks. There was no significant difference between interferon beta-1a and glatiramer acetate in the primary outcome. The ability to predict clinical superiority on the basis of results from previous studies might be limited by a trial population with low disease activity, which is an important consideration for ongoing and future trials in patients with RRMS.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome.

We designed a randomized, placebo-controlled, multicentre trial involving 51 relapsing-remitting multiple sclerosis patients to determine the clinical efficacy of mitoxantrone treatment over 2 years. Patients were allocated either to the mitoxantrone group (27 patients receiving I.V. infusion of mitoxantrone every month for 1 year at the dosage of 8 mg/m2) or to the placebo group (24 patients, receiving I.V. infusion of saline every month for 1 year) using a centralized randomization system. Disability at entry and at 12-24 months was evaluated by four blinded neurologists trained in the application of the Kurtzke Expanded Disability Scale (EDSS). In addition, the number and clinical characteristics of the exacerbations over the 24 months were recorded by the local investigators. MRI, at 0, 12 and 24 months, was performed with a 0.2 T permanent unit. MRI data were analysed by two blinded neuroradiologists. All patients underwent a clinical evaluation. A statistically significant difference in the mean number of exacerbations was observed between the mitoxantrone group and placebo group both during the 1st and the 2nd year. Although there was no statistically significant benefit in terms of mean EDSS progression over 2 years, the proportion of patients with confirmed progression of the disease, as measured by a one point increase on the EDSS scale, was significantly reduced at the 2nd year evaluation in the mitoxantrone group. Forty-two (23 mitoxantrone, 19 placebo) patients underwent all MRI examinations during the 24-month period. We observed a trend towards a reduction in the number of new lesions on T2-weighted images in the mitoxantrone group. Our study suggests that mitoxantrone might be effective in reducing disease activity, both by decreasing the mean number of exacerbations and by slowing the clinical progression sustained by most patients after 1 year from the end of treatment.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Austrian Immunoglobulin in Multiple Sclerosis Study Group.

Multiple sclerosis is an autoimmune disorder characterised by the repeated occurrence of demyelinating lesions within the central nervous system. Uncontrolled studies and experimental evidence suggest beneficial effects of repeated administration of intravenous immunoglobulin (IVIg) by immunomodulating mechanisms and induction or remyelination. We aimed to investigate the efficacy of IVIg in a randomised double-blind multicentre study. Patients with relapsing-remitting multiple sclerosis were randomly assigned a monthly dose of IVIg (0.15-0.2 g/kg bodyweight) or placebo. Duration of treatment was 2 years. The primary outcome measures were the effect of treatment on clinical disability-measured by the absolute change in Kurtzke's expanded disability status scale (EDSS) score- and the proportion of patients with improved, stable, or worse clinical disability (> or = 1.0 grade on EDSS score). Of the 243 patients screened, 150 met our eligibility criteria and were randomly assigned to IVIg or placebo. Before the start of treatment two patients in the placebo group dropped out, so there were 75 patients in the IVIg group and 73 in the placebo group. Intention-to-treat analysis showed that IVIg treatment had a beneficial effect on the course of clinical disability. The EDSS score decreased in the IVIg-treated patients and increased in the placebo group (-0.23 [95% CI -0.43 to -0.03] vs 0.12 [-0.13 to 0.37], p = 0.008). In the IVIg group, the numbers of patients with improved, stable, or worse clinical disability were 23 (31%), 40 (53%), and 12 (16%) compared with ten (14%), 46 (63%), and 17 (23%) in the placebo group. Side-effects were reported in three (4%) IVIg-treated patients and in four (5%) placebo-group patients, but were not directly linked to study medication. Monthly IVIg is an effective and well-tolerated treatment for patients with relapsing-remitting multiple sclerosis.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

A randomized study of two interferon-beta treatments in relapsing-remitting multiple sclerosis.

To investigate whether the efficacy of interferon-beta (IFNbeta) treatment of relapsing-remitting MS (RR-MS) was influenced by type, dose, and frequency of administration. From June 1996 through October 1997, the authors offered participation to all Danish RR-MS patients who met the following criteria: definite MS, at least two relapses within 2 years, age 18 to 55, and an Expanded Disability Status Scale (EDSS) score of < or = 5.5. The study was multicenter, controlled, open-label, randomized, head-to-head comparing IFNbeta-1a 22 microg once a week (n = 143) with IFNbeta-1b 250 microg every other day (n = 158), both subcutaneously, for 24 months. Patients who declined randomization were offered treatment with IFNbeta-1b 250 microg every other day (n = 120). The primary end-points were the annualized relapse rate, the time to first relapse, and neutralizing antibody formation. The secondary endpoint was time to sustained progression. The annual relapse rates were virtually equal in the two arms of the randomized study (IFNbeta-1a: 0.70; IFNbeta-1b: 0.71); so were the time to first relapse and the time to sustained progression. In the nonrandomized patients (IFNbeta-1b), the annual relapse rate was not significantly different, but the time to progression was shorter. In this study, 250 microg interferon-beta-1b administered every other day did not prove clinically superior to once-a-week administration of 22 microg interferon-beta-1a.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Natalizumab plus interferon beta-1a for relapsing multiple sclerosis.

Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an alpha4 integrin antagonist, appeared to be safe and effective alone and when added to interferon beta-1a in preliminary studies. We randomly assigned 1171 patients who, despite interferon beta-1a therapy, had had at least one relapse during the 12-month period before randomization to receive continued interferon beta-1a in combination with 300 mg of natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks. The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years. Combination therapy resulted in a 24 percent reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P=0.02). Kaplan-Meier estimates of the cumulative probability of progression at two years were 23 percent with combination therapy and 29 percent with interferon beta-1a alone. Combination therapy was associated with a lower annualized rate of relapse over a two-year period than was interferon beta-1a alone (0.34 vs. 0.75, P<0.001) and with fewer new or enlarging lesions on T(2)-weighted magnetic resonance imaging (0.9 vs. 5.4, P<0.001). Adverse events associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema. Two cases of progressive multifocal leukoencephalopathy, one of which was fatal, were diagnosed in natalizumab-treated patients. Natalizumab added to interferon beta-1a was significantly more effective than interferon beta-1a alone in patients with relapsing multiple sclerosis. Additional research is needed to elucidate the benefits and risks of this combination treatment. (ClinicalTrials.gov number, NCT00030966.). Copyright 2006 Massachusetts Medical Society.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: a dose-finding trial.

Several studies have reported a reduction of relapses after the long-term administration of IV immunoglobulin (IVIG) to patients with relapsing-remitting multiple sclerosis (RRMS), but they were mostly small and differed in terms of predefined outcome variables and treatment regimen. We therefore set out to test two different doses of a new formulation of immunoglobulin termed IGIV-C 10% for suppression of both clinical and MRI disease activity as well as safety. One hundred twenty-seven patients with RRMS participated in this multicenter, randomized, double-blind, placebo-controlled trial. Forty-four and 42 patients received treatment with 0.2 and 0.4 g/kg of IGIV-C 10%, and 41 patients received an equal volume of placebo (0.1% albumin) every 4 weeks for 48 weeks. The primary endpoint was the proportion of relapse-free patients. The main secondary endpoint was lesion activity assessed by 6-weekly MRI. Baseline variables were similar in IVIG- and placebo-treated groups. After 1 year, the proportion of relapse-free patients did not differ statistically according to treatment (IVIG 0.2 g/kg: 57%; IVIG 0.4 g/kg: 60%; placebo: 68%), and there was no difference regarding the cumulative number of unique newly active MRI lesions (median numbers: IVIG 0.2 g/kg: 8.0; IVIG 0.4 g/kg: 5.0; placebo: 7.2) after 48 weeks. There were no significant between-group differences in the rates of adverse events. Although IV immunoglobulin (IVIG) treatment was well tolerated, this study did not substantiate a beneficial effect of IVIG in doses ranging from 0.2 to 0.4 g/kg. This result seriously questions the utility of IVIG for the treatment of relapsing-remitting multiple sclerosis.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

No difference in efficacy of two different doses of intravenous immunoglobulins in MS: clinical and MRI assessment.

We performed a double-blind, placebo-controlled study to evaluate the efficacy of low and high dose of intravenous immunoglobulins (IVIG) in relapsing/remitting (RR) multiple sclerosis (MS). Patients (n = 49) with clinical definite RR MS were randomly allocated to three groups and treated with 0.2 g/kg (n = 17) or 0.4 g/kg (n = 15) once a month of IVIG and placebo (n = 17) for 12 months. Clinical data were assessed monthly and magnetic resonance imaging (MRI) was performed every 3 months during the study period. Annual relapse rate (ARR) and change of the mean Expanded Disability Status Scale (EDSS) and Neurological Rating Scale Score (NRSS) from baseline to study conclusion were used as the clinical end-points. For MRI activity total lesion volume on T2-weighted image (T2WI), new lesions and gadolinium (Gd)-enhanced lesions on T1WI were analysed. ARR in both IVIG groups (0.88 for 0.2 g/kg and 0.86 for 0.4 g/kg) was reduced compared with placebo (1.24) during treatment period. Neurological disability measured with EDSS decreased slightly in both the IVIG groups (0.029 and 0.066, respectively) and increased by 0.29 in placebo (P = 0.0117). The neurologic impairment measured by NRSS showed similar trend. The total lesion volume on T2WI increased by 13.56% in placebo whereas in the 0.4 g/kg IVIG group decreased by -3.95% and in the 0.2 g/kg IVIG group increased by 3.6%. The cumulative numbers of Gd-enhancing lesions and new T2WI lesions in the IVIG groups were reduced in comparison with the placebo group. Our findings suggest that the dose 0.2 g/kg of IVIG is equally effective as 0.4 g/kg in reducing MS activity.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Comparison of Betaferon, Avonex, and Rebif in treatment of relapsing-remitting multiple sclerosis.

To compare the relative efficacies of Betaferon, Avonex, and Rebif in the treatment of relapsing-remitting multiple sclerosis (RRMS). Ninety patients with RRMS were randomly allocated to the three treatment groups. The first group received Betaferon, the second group received Avonex, and the third group received Rebif for 24 months. Response to treatment was assessed at 6, 12, and 24 months after start of therapy. Of the 30 patients treated with Betaferon, the mean (standard deviation, SD) of relapse rate decreased from 2.2 (0.7) to 0.7 (0.7) episodes. Correspondingly, in the 30 patients treated with Avonex, the mean (SD) of relapse rate decreased from 2.0 (1.2) to 1.2 (0.9) (P < 0.001). In the 30 patients treated with Rebif, the mean (SD) of relapse rate decreased from 2.4 (1.0) to 0.6 (0.9) (P < 0. 01). After 2 years, 43.3% of patients receiving Betaferon and 56.7% of patients receiving Rebif remained relapse-free compared with 20% of those given Avonex. Expanded Disability Status Scale (EDSS) decreased by 0.7 U in Betaferon-treated patients (P < 0.001), 0.3 U in Rebif-treated patients (P < 0.05), and remained stable in Avonex patients. Treatment with Betaferon, Avenox, and Rebif significantly reduce relapse rate and EDSS score in patients with RRMS.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG)

The accepted standard treatment of relapsing multiple sclerosis consists of medications for disease symptoms, including treatment for acute exacerbations. However, currently there is no therapy that alters the progression of physical disability associated with this disease. The purpose of this study was to determine whether interferon beta-1a could slow the progressive, irreversible, neurological disability of relapsing multiple sclerosis. Three hundred one patients with relapsing multiple sclerosis were randomized into a double-blinded, placebo-controlled, multicenter phase III trial of interferon beta-1a. Interferon beta-1a, 6.0 million units (30 micrograms¿, was administered by intramuscular injection weekly. The primary outcome variable was time to sustained disability progression of at least 1.0 point on the Kurtzke Expanded Disability Status Scale (EDSS). Interferon beta-1a treatment produced a significant delay in time to sustained EDSS progression (p = 0.02). The Kaplan-Meier estimate of the proportion of patients progressing by the end of 104 weeks was 34.9% in the placebo group and 21.9% in the interferon beta-1a-treated group. Patients treated with interferon beta-1a also had significantly fewer exacerbations (p = 0.03) and a significantly lower number and volume of gadolinium-enhanced brain lesions on magnetic resonance images (p-values ranging between 0.02 and 0.05). Over 2 years, the annual exacerbation rate was 0.90 in placebo-treated patients versus 0.61 in interferon beta-1a-treated patients. There were no major adverse events related to treatment. Interferon beta-1a had a significant beneficial impact in relapsing multiple sclerosis patients by reducing the accumulation of permanent physical disability, exacerbation frequency, and disease activity measured by gadolinium-enhanced lesions on brain magnetic resonance images. This treatment may alter the fundamental course of relapsing multiple sclerosis.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

A double blind study on azathioprine efficacy in multiple sclerosis: final report.

Forty patients, affected by multiple sclerosis with remitting-relapsing or progressive course, were included in a double blind study of treatment with azathioprine (2 mg/kg/day) lasting 3 years. The mean changes on the Expanded Disability Status Scale and in the survival analysis show a trend in favour of azathioprine both in slowing disease progression and reducing relapse frequency. These findings, repeatedly observed in similar trials, indicate that azathioprine should be used in the treatment of multiple sclerosis.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Multiple sclerosis. Trials of maintenance treatment with prednisolone and soluble aspirin.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.

Natalizumab is the first alpha4 integrin antagonist in a new class of selective adhesion-molecule inhibitors. We report the results of a two-year phase 3 trial of natalizumab in patients with relapsing multiple sclerosis. Of a total of 942 patients, 627 were randomly assigned to receive natalizumab (at a dose of 300 mg) and 315 to receive placebo by intravenous infusion every four weeks for more than two years. The primary end points were the rate of clinical relapse at one year and the rate of sustained progression of disability, as measured by the Expanded Disability Status Scale, at two years. Natalizumab reduced the risk of sustained progression of disability by 42 percent over two years (hazard ratio, 0.58; 95 percent confidence interval, 0.43 to 0.77; P<0.001). The cumulative probability of progression (on the basis of Kaplan-Meier analysis) was 17 percent in the natalizumab group and 29 percent in the placebo group. Natalizumab reduced the rate of clinical relapse at one year by 68 percent (P<0.001) and led to an 83 percent reduction in the accumulation of new or enlarging hyperintense lesions, as detected by T2-weighted magnetic resonance imaging (MRI), over two years (mean numbers of lesions, 1.9 with natalizumab and 11.0 with placebo; P<0.001). There were 92 percent fewer lesions (as detected by gadolinium-enhanced MRI) in the natalizumab group than in the placebo group at both one and two years (P<0.001). The adverse events that were significantly more frequent in the natalizumab group than in the placebo group were fatigue (27 percent vs. 21 percent, P=0.048) and allergic reaction (9 percent vs. 4 percent, P=0.012). Hypersensitivity reactions of any kind occurred in 25 patients receiving natalizumab (4 percent), and serious hypersensitivity reactions occurred in 8 patients (1 percent). Natalizumab reduced the risk of the sustained progression of disability and the rate of clinical relapse in patients with relapsing multiple sclerosis. Adhesion-molecule inhibitors hold promise as an effective treatment for relapsing multiple sclerosis. (ClinicalTrials.gov number, NCT00027300.). Copyright 2006 Massachusetts Medical Society.

CD008933

Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis.

Cop 1 is a random polymer (molecular weight, 14,000 to 23,000) simulating myelin basic protein. It is synthesized by polymerizing L-alanine, L-glutamic acid, L-lysine, and L-tyrosine. It suppresses but does not induce experimental allergic encephalomyelitis, an animal model of multiple sclerosis. It is not toxic in animals. In a double-blind, randomized, placebo-controlled pilot trial, we studied 50 patients with the exacerbating-remitting form of multiple sclerosis, who self-injected either 20 mg of Cop 1 dissolved in 1 ml of saline or saline alone daily for two years. Six of 23 patients in the placebo group (26 percent) and 14 of 25 patients in the Cop 1 group (56 percent) had no exacerbations (P = 0.045). There were 62 exacerbations in the placebo group and 16 in the Cop 1 group, yielding two-year averages of 2.7 and 0.6 per patient, respectively. Among patients who were less disabled on entry (Kurtzke disability score, 0 to 2), there were 2.7 exacerbations in the placebo group and 0.3 in the Cop 1 group over two years. Among patients who were more affected (Kurtzke disability score, 3 to 6), there was an average of 2.7 exacerbations in the placebo group and 1.0 in the Cop 1 group. Over two years, less disabled patients taking Cop 1 improved an average of 0.5 Kurtzke units; those taking placebo worsened an average of 1.2 Kurtzke units. More disabled patients worsened by 0.3 (Cop 1 group) and 0.4 (placebo group) unit. Irritation at injection sites and rare, transient vasomotor responses were observed as side effects. These results suggest that Cop 1 may be beneficial in patients with the exacerbating-remitting form of multiple sclerosis, but we emphasize that the study is a preliminary one and our data require confirmation by a more extensive clinical trial.

CD005451

Carbamazepine is effective in chronic neuropathic pain, with caveats. No trial was longer than four weeks, of good reporting quality, using outcomes equivalent to at least moderate clinical benefit. In these circumstances, caution is needed in interpretation, and meaningful comparison with other interventions is not possible.

Do corticosteroids prevent post-herpetic neuralgia?

Forty otherwise healthy patients over 50 years of age with early, severe painful herpes zoster were randomly allocated to two groups for treatment. Twenty patients received prednisolone 40 mg daily with gradual reduction over a period of 4 weeks, whilst the other twenty patients received carbamazepine 100 mg four times daily. Thirteen of the twenty patients (65%) in the carbamazepine treated group developed post-herpetic neuralgia lasting up to 2 years, whilst only three of the twenty prednisolone treated patients (15%) had post-herpetic neuralgia lasting up to 6 months only. Thus the incidence and duration of post-herpetic neuralgia were considerably redudced in the prednisolone treated group. In neither group did disseminated zoster or other complications occur.

CD005451

Carbamazepine is effective in chronic neuropathic pain, with caveats. No trial was longer than four weeks, of good reporting quality, using outcomes equivalent to at least moderate clinical benefit. In these circumstances, caution is needed in interpretation, and meaningful comparison with other interventions is not possible.

A four year double-blind study of tegretol in facial pain.

CD005451

Carbamazepine is effective in chronic neuropathic pain, with caveats. No trial was longer than four weeks, of good reporting quality, using outcomes equivalent to at least moderate clinical benefit. In these circumstances, caution is needed in interpretation, and meaningful comparison with other interventions is not possible.

Tegretol in the treatment of diabetic neuropathy.

CD005451

Carbamazepine is effective in chronic neuropathic pain, with caveats. No trial was longer than four weeks, of good reporting quality, using outcomes equivalent to at least moderate clinical benefit. In these circumstances, caution is needed in interpretation, and meaningful comparison with other interventions is not possible.

Facial pain treated with carbamazepin (Tegretol).

CD005451

Carbamazepine is effective in chronic neuropathic pain, with caveats. No trial was longer than four weeks, of good reporting quality, using outcomes equivalent to at least moderate clinical benefit. In these circumstances, caution is needed in interpretation, and meaningful comparison with other interventions is not possible.

Clinical trial of carbazepine (tegretol) in trigeminal neuralgia.

CD005451

Carbamazepine is effective in chronic neuropathic pain, with caveats. No trial was longer than four weeks, of good reporting quality, using outcomes equivalent to at least moderate clinical benefit. In these circumstances, caution is needed in interpretation, and meaningful comparison with other interventions is not possible.

Tizanidine in the management of trigeminal neuralgia.

In a double-blind study the efficacy and tolerability of tizanidine was compared with those of carbamazepine in the management of trigeminal neuralgia. Six patients were allocated to treatment with tizanidine and six to carbamazepine. After individual titration the maximum daily doses were 18 mg and 900 mg, respectively. Among the efficacy factors used, the visual analog scale (VAS) and the overall efficacy as assessed by patients and investigator turned out to be the most appropriate. The results indicate that tizanidine was well tolerated, but the effects, if any, were inferior to those of carbamazepine.

CD005451

Carbamazepine is effective in chronic neuropathic pain, with caveats. No trial was longer than four weeks, of good reporting quality, using outcomes equivalent to at least moderate clinical benefit. In these circumstances, caution is needed in interpretation, and meaningful comparison with other interventions is not possible.

Nortriptyline-fluphenazine vs. carbamazepine in the symptomatic treatment of diabetic neuropathy.

We compared the efficacy and tolerance of the combination of nortriptyline-fluphenazine (NF) vs. carbamazepine (CMZ) in the symptomatic therapy of patients with severe, distal, symmetrical, predominantly sensitive diabetic polyneuropathy (DPN). We followed a double blind, crossover, randomized and double placebo design. Sixteen patients with severe DPN participated in the study. Patients received either NF (1 tablet three times a day (tid)), for 2 weeks and 2 tablets tid for the next 2 weeks or CMZ 1/2 tablet tid for 2 weeks and 1 tablet tid for the next 2 weeks. After this, patients received placebos of both drugs (wash-out period), until symptoms returned to baseline levels (100%), then they were crossed over to receive the other comparing drug schedule. A visual analogue scale was used to evaluate the percent changes in pain and paresthesia. HbA1, fasting serum glucose, and safety tests were performed at 2- and 4-week intervals, respectively. Both therapies produced significant improvement of both pain and paresthesia. No statistically significant differences were observed between both therapies for either pain or paresthesia. No significant biochemical changes were observed with any of the two therapies. Side effects were mild and more frequent in the NF period. In this study no superiority of either drug schedule was demonstrated; therefore, the decision to use any of them should be made according to the associated pathology and potential side effects of each drug.

CD005451

Carbamazepine is effective in chronic neuropathic pain, with caveats. No trial was longer than four weeks, of good reporting quality, using outcomes equivalent to at least moderate clinical benefit. In these circumstances, caution is needed in interpretation, and meaningful comparison with other interventions is not possible.

Studies on the concomitant use of carbamazepine and clomipramine for the relief of post-herpetic neuralgia.

CD005451

Carbamazepine is effective in chronic neuropathic pain, with caveats. No trial was longer than four weeks, of good reporting quality, using outcomes equivalent to at least moderate clinical benefit. In these circumstances, caution is needed in interpretation, and meaningful comparison with other interventions is not possible.

Controlled sequential trials of carbamazepine in trigeminal neuralgia.

CD005451

Carbamazepine is effective in chronic neuropathic pain, with caveats. No trial was longer than four weeks, of good reporting quality, using outcomes equivalent to at least moderate clinical benefit. In these circumstances, caution is needed in interpretation, and meaningful comparison with other interventions is not possible.

Symptomatic treatment of peripheral diabetic neuropathy with carbamazepine (Tegretol): double blind crossover trial.

CD005451

Carbamazepine is effective in chronic neuropathic pain, with caveats. No trial was longer than four weeks, of good reporting quality, using outcomes equivalent to at least moderate clinical benefit. In these circumstances, caution is needed in interpretation, and meaningful comparison with other interventions is not possible.

Central post-stroke pain--a controlled trial of amitriptyline and carbamazepine.

A double-blind, 3-phase, cross-over, placebo-controlled trial of the pain-relieving effect of amitriptyline and carbamazepine was carried out in 15 patients with central post-stroke pain (CPSP) but without signs of depression. Treatment was given, in randomized order, for periods of 4 weeks, separated by 1 week wash-out. The final doses were 75 and 800 mg/day, respectively, for amitriptyline and carbamazepine. The treatment effects were assessed by daily ratings of pain intensity on a 10-step verbal scale and at the end of each treatment period by a global rating of the analgesic effect on a 5-step verbal scale. For the assessment of depression the Comprehensive Psychopathological Rating Scale (CPRS) was used. Amitriptyline produced a statistically significant reduction of pain when compared to placebo. According to the global rating, 10 of the 15 patients were responders to this drug. The effect could already be noticed during the second treatment week and it appeared to be correlated to the plasma concentration, since the median total ami- and nortriptyline concentrations were 497 and 247 nmol/l, respectively, for responders and non-responders. The early onset, together with the fact that the patients were not depressed, nor did they obtain reduced scores on ratings of depressive symptoms and signs, provides strong support for the conclusion that the pain relief was not caused by an antidepressive effect. Five of the 14 patients treated with carbamazepine reported some pain relief, but the effect did not reach statistical significance when compared to placebo. No correlation was found between effect and plasma concentration. In general, the patients tolerated the planned final dose of amitriptyline well. No final dose reduction was necessary. Carbamazepine caused more side effects and the final dose had to be reduced in 4 patients. However, only 1 patient had to be taken off medication, on day 25, due to drug interaction.

CD005451

Carbamazepine is effective in chronic neuropathic pain, with caveats. No trial was longer than four weeks, of good reporting quality, using outcomes equivalent to at least moderate clinical benefit. In these circumstances, caution is needed in interpretation, and meaningful comparison with other interventions is not possible.

Carbamazepine in the treatment of neuralgia. Use of side effects.

CD005451

Carbamazepine is effective in chronic neuropathic pain, with caveats. No trial was longer than four weeks, of good reporting quality, using outcomes equivalent to at least moderate clinical benefit. In these circumstances, caution is needed in interpretation, and meaningful comparison with other interventions is not possible.

The analgesic effect of tocainide in trigeminal neuralgia.

Tocainide is a derivative of lidocaine with anti-arrhythmic action and, unlike lidocaine, can be used for oral treatment. Tocainide was alternatively with carbamazepine given to 12 patients with trigeminal neuralgia in a double-blind cross-over study for 2 weeks. The analgesic effect was estimated each day by the patients using a 0-10-point scale summarizing the frequency and severity of the attacks. The similarity in analgesic effect of the two drugs was striking. A possible analgesic mechanism could be that tocainide blocks the sodium channels in the hyperexcitable nerve membranes in the pain-producing foci in trigeminal neuralgia.

CD005451

Carbamazepine is effective in chronic neuropathic pain, with caveats. No trial was longer than four weeks, of good reporting quality, using outcomes equivalent to at least moderate clinical benefit. In these circumstances, caution is needed in interpretation, and meaningful comparison with other interventions is not possible.

Pimozide therapy for trigeminal neuralgia.

Pimozide was compared with carbamazepine in a double-blind crossover trial in 48 patients with trigeminal neuralgia who were refractory to medical therapy. Pimozide treatment produced greater reduction in trigeminal neuralgia symptoms than carbamazepine treatment. All of the pimozide-treated patients improved, while only 56% of carbamazepine-treated patients were relieved of their pain. Although both drugs provoked some adverse effects, it was not necessary to interrupt the trial in any case. After this 24-week trial, all patients began receiving pimozide and were followed up according to an open-label study design. In all cases, the pimozide dosage was progressively reduced until the minimal effective dose was reached. Central and peripheral mechanisms that may underlie pimozide-induced improvement are discussed.

CD000459

Limited data from small studies using neuroleptic reduction or specific neuroleptic drugs as treatments for TD did not provide any convincing evidence of the value of these approaches. There is a need for larger trials of a longer duration in order to fully investigate this area.

The effects of a 50% reduction of cis(z)-flupenthixol decanoate in chronic schizophrenic patients maintained on a high dose regime.

Eighteen chronic schizophrenic patients who had shown improvement from increased maintenance dosages of cis(z)-flupenthixol decanoate were entered into a double-blind study in which half of the patients were randomly allocated to be maintained on 50% of their pre-trial dosage. During the 44 week study the reduced dosage group showed increased morbidity and one-third of these patients had a schizophrenic relapse. The greatest deterioration occurred in patients reduced from above to below 200 mg cis(z)-flupenthixol decanoate biweekly. A review of all the patients entered into the study showed a relationship between deterioration of schizophrenic and depressive features and cis(z)-flupenthixol plasma levels which reflected the administered dosage. Prolactin levels in general did not reflect control of schizophrenic symptoms. Side-effects were few, and there was no emergence of tardive dyskinesia. A multicentre trial is needed for further evaluation.

CD000459

Limited data from small studies using neuroleptic reduction or specific neuroleptic drugs as treatments for TD did not provide any convincing evidence of the value of these approaches. There is a need for larger trials of a longer duration in order to fully investigate this area.

Low-dose neuroleptic treatment of outpatient schizophrenics. I. Preliminary results for relapse rates.

In an attempt to begin to establish minimum effective dosage requirements for the maintenance treatment of schizophrenia, we undertook a double-blind comparison of low-dose fluphenazine decanoate (1.25 to 5.0 mg/2 wk) with the standard-dose regimen (12.5 to 50.0 mg/2 wk) in outpatient schizophrenics. For the first 126 patients studied, cumulative relapse rates at one year for the low dose were 56% and for the standard dose 7%, a significant difference. Despite the fact that very little dyskinetic symptomatology developed in the sample as a whole, the low-dose treatment appeared to have a significant advantage in producing fewer early signs of tardive dyskinesia. Severity of relapse and total cumulative dosage were also considered.

CD000459

Limited data from small studies using neuroleptic reduction or specific neuroleptic drugs as treatments for TD did not provide any convincing evidence of the value of these approaches. There is a need for larger trials of a longer duration in order to fully investigate this area.

A single-blind, randomized trial comparing quetiapine and haloperidol in the treatment of tardive dyskinesia.

While the atypical antipsychotics should ultimately reduce the prevalence of tardive dyskinesia, it is likely to remain a significant clinical problem for a long time to come. No strategy has clearly emerged as the treatment of choice for tardive dyskinesia. Atypical antipsychotics have reduced propensities for producing acute extrapyramidal symptoms (EPS) and possibly tardive dyskinesia and may be effective in treating patients with established tardive dyskinesia. This 12-month, randomized, investigator-blinded study compared the efficacy of quetiapine (N = 22) and haloperidol (N = 23) in treating patients with DSM-IV schizophrenia or schizoaffective disorder and established tardive dyskinesia. Dyskinesia was assessed using the Extrapyramidal Symptom Rating Scale (ESRS) dyskinesia subscale scores and the Clinical Global Impression (CGI) dyskinesia scores. Other EPS, weight, serum prolactin level, and glycosylated hemoglobin level were also assessed. Subjects were enrolled in the study between April 2000 and March 2002. Mean endpoint doses were 400 mg/day of quetiapine and 8.5 mg/day of haloperidol. Compared with the haloperidol group, the quetiapine group showed significantly greater improvements in ESRS dyskinesia (6 and 9 months [p <or=.01]) and CGI dyskinesia (from 6 months onward [p <.05] and with repeated-measures analysis [p =.002]). Response rate (>or= 50% symptom reduction) was greater with quetiapine than haloperidol (64% [9/14] and 37% [6/16] at 6 months; 55% [6/11] and 28% [4/14] at 12 months). Other EPS decreased significantly with quetiapine at 3 (p =.01), 6 (p =.01), and 9 (p =.002) months. Serum prolactin levels decreased with quetiapine but increased with haloperidol, differing significantly between the groups at endpoint (p =.005). No significant changes in weight or glucose metabolism were recorded in either group. Quetiapine effectively reduces the severity of tardive dyskinesia and is well tolerated in patients with established tardive dyskinesia.

CD000459

Limited data from small studies using neuroleptic reduction or specific neuroleptic drugs as treatments for TD did not provide any convincing evidence of the value of these approaches. There is a need for larger trials of a longer duration in order to fully investigate this area.

A comparison of masking effects of haloperidol versus molindone in tardive dyskinesia.

An experimental method was utilized to compare the masking effects of two neuroleptic agents--molindone and haloperidol--on 18 neuroleptic-treated schizophrenic patients exhibiting operationally defined withdrawal-exacerbated tardive dyskinesia. After a week on one of these two medications at preestablished doses equivalent to that of the pre-study neuroleptic, molindone-masked total AIMS scores by significantly less (12%) than haloperidol (27%). Similarly, during a second week when the dose of these neuroleptics was equivalent to 200% that of the pre-study dose, molindone masked the total AIMS score significantly less (23%) as compared to haloperidol (53%). Several interpretations of this finding are considered. This study demonstrates the feasibility of a method that may offer a model for understanding pharmacological differences among neuroleptic medications.

CD000459

Limited data from small studies using neuroleptic reduction or specific neuroleptic drugs as treatments for TD did not provide any convincing evidence of the value of these approaches. There is a need for larger trials of a longer duration in order to fully investigate this area.

Treatment of tardive dyskinesia. II. Short-term efficacy of dopamine-blocking agents haloperidol and thiopropazate.

CD000025

Magnesium sulphate more than halves the risk of eclampsia, and probably reduces maternal death. There is no clear effect on outcome after discharge from hospital. A quarter of women report side effects with magnesium sulphate.

[Anticonvulsant treatment in severe preeclampsia. Comparison between diazepam and magnesium sulfate].

The objective was to compare the materno-fetal effects between Diazepam and Magnesium sulfate used as anticonvulsivant therapy in cases of severe pre-eclampsia. The study was prospective, comparative, longitudinal, randomized clinical trial. The study was done at Centro Medico Nacional Instituto Mexicano del Seguro Social. Division of Obstetrics and Gynecology, Torreon, Coah, Mexico. The patients were all the women admitted to the labor and delivery ward with diagnosis of severe pre-eclampsia and viable conceptus were assigned at random to receive either Diazepam (Group A, n = 19) or Magnesium sulfate (group B, n = 19). There were no significant differences between both groups. All of the patients remained alert, conscious and well oriented. None of the newborns showed hiporreflexia, flaccidity or neonatal respiratory distress that could be implicated to the anticonvulsivant therapy. It is concluded that Diazepam and Magnesium sulfate are good alternatives as anticonvulsivant therapy in cases of severe pre-eclampsia.

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Magnesium sulphate more than halves the risk of eclampsia, and probably reduces maternal death. There is no clear effect on outcome after discharge from hospital. A quarter of women report side effects with magnesium sulphate.

A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia.

Magnesium sulfate is used widely to prevent eclamptic seizures in pregnant women with hypertension, but few studies have compared the efficacy of magnesium sulfate with that of other drugs. Anticonvulsant prophylaxis with phenytoin for eclampsia has been recommended, but there are virtually no data to support its efficacy. Our objective was to compare magnesium sulfate with phenytoin in preventing seizures in hypertensive women during labor. We randomly assigned women with hypertension who were admitted for delivery to receive either magnesium sulfate or phenytoin. The magnesium sulfate regimen consisted of a 10-g intramuscular loading dose followed by a maintenance dose of 5 g given intramuscularly every four hours. For women with severe preeclampsia, an additional 4-g loading dose was given intravenously. The phenytoin regimen included a 1000-mg loading dose infused over a period of 1 hour, followed by a 500-mg oral dose 10 hours later. With either regimen, anticonvulsant therapy was continued for 24 hours post partum. Ten of 1089 women randomly assigned to the phenytoin regimen had eclamptic convulsions, as compared with none of 1049 women randomly assigned to magnesium sulfate (P = 0.004). There were no significant differences in any risk factors for eclampsia between the two study groups. Maternal and infant outcomes were also similar in the two study groups. Magnesium sulfate is superior to phenytoin for the prevention of eclampsia in hypertensive pregnant women. These results validate the long-practiced use of magnesium sulfate in the prevention of eclampsia.

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Magnesium sulphate more than halves the risk of eclampsia, and probably reduces maternal death. There is no clear effect on outcome after discharge from hospital. A quarter of women report side effects with magnesium sulphate.

Comparison of magnesium and methyldopa for the control of blood pressure in pregnancies complicated with hypertension.

Although magnesium is now the drug of choice for the prevention of eclamptic seizures only few studies have evaluated whether magnesium may reduce blood pressure in pregnancies complicated with hypertension. A total of 33 patients with pregnancy-induced hypertension were randomized to either magnesium or methyldopa treatment. Of these 16 received magnesium and 17 methyldopa. The treatment comprised a 48-hour magnesium infusion followed by oral magnesium tablets until 3 days after delivery or 250 mg methyldopa 4 times a day in a similar period. Patients treated with magnesium had 1 day after inclusion a statistically significantly lower systolic blood pressure compared to the level in the methyldopa group (138.1 +/- 11 vs. 147.6 +/- 11 mm Hg; p < 0.05), but no difference was observed in diastolic blood pressure (92.0 +/- 6.6 vs. 96.0 +/- 10.1 mm Hg; NS). From the 5th day of inclusion and until delivery both systolic and diastolic blood pressure were significantly lower in the magnesium group (p < 0.05). Including all blood pressure measurements in a single analysis showed that both systolic (138 +/- 13 vs. 148 +/- 15 mm Hg; p < 0.0001) and diastolic (92 +/- 10 vs. 94 +/- 10 mm Hg; p < 0.05) blood pressure were lower in the magnesium group compared to the methyldopa group. There was no difference between the two groups regarding gestational age at delivery, birth weight, Apgar scores and pH in umbilical cord blood. This preliminary study demonstrates that magnesium treatment lowers blood pressure in pregnancies complicated with hypertension. The effect is without any adverse effect on maternal and neonatal well-being. Copyright 2000 S. Karger AG, Basel

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Magnesium sulphate more than halves the risk of eclampsia, and probably reduces maternal death. There is no clear effect on outcome after discharge from hospital. A quarter of women report side effects with magnesium sulphate.

The effect of magnesium sulfate therapy on the duration of labor in women with mild preeclampsia at term: a randomized, double-blind, placebo-controlled trial.

The primary outcome was to determine whether magnesium sulfate therapy prolongs the duration of labor in women with mild preeclampsia. Secondary outcomes were to assess the side effects associated with magnesium sulfate therapy: hours and maximum dose of oxytocin, incidence of progression to severe preeclampsia, incidence of cesarean delivery, change in maternal hematocrit, incidence of postpartum hemorrhage, incidence of maternal infection, and Apgar scores. Women with a diagnosis of mild preeclampsia at term were randomized to receive standard therapy during labor and for 12 hours post partum with either magnesium sulfate (n = 67) or a matching placebo solution (n = 68). There was no difference between magnesium sulfate and placebo with respect to the primary outcome variables: total length of labor (median 17.8 hours vs 16.5 hours, p = 0.7) and length of the active phase of labor (median 5.4 hours vs 6.0 hours, p = 0.5). In addition, no difference was observed in the secondary outcome variables: hours of oxytocin use, change in hematocrit, frequency of maternal infection, progression to severe preeclampsia, incidence of cesarean delivery, and Apgar scores. Although not statistically significant, the incidence of postpartum hemorrhage was approximately fourfold greater in the magnesium sulfate group (relative risk 4.1, 95% confidence interval 0.5 to 35.4). There was a significant difference in the maximum dose of oxytocin used (13.9 +/- 8.6 mU/min with magnesium sulfate vs 11.0 +/- 7.6 mU/min with placebo, p = 0.036). The use of magnesium sulfate during labor in women with mild preeclampsia at term does not affect any component of labor but did necessitate a higher dose of oxytocin.

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Magnesium sulphate more than halves the risk of eclampsia, and probably reduces maternal death. There is no clear effect on outcome after discharge from hospital. A quarter of women report side effects with magnesium sulphate.

Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial.

Anticonvulsants are used for pre-eclampsia in the belief they prevent eclamptic convulsions, and so improve outcome. Evidence supported magnesium sulphate as the drug to evaluate. Eligible women (n=10141) had not given birth or were 24 h or less postpartum; blood pressure of 140/90 mm Hg or more, and proteinuria of 1+ (30 mg/dL) or more; and there was clinical uncertainty about magnesium sulphate. Women were randomised in 33 countries to either magnesium sulphate (n=5071) or placebo (n=5070). Primary outcomes were eclampsia and, for women randomised before delivery, death of the baby. Follow up was until discharge from hospital after delivery. Analyses were by intention to treat. Follow-up data were available for 10,110 (99.7%) women, 9992 (99%) of whom received the allocated treatment. 1201 of 4999 (24%) women given magnesium sulphate reported side-effects versus 228 of 4993 (5%) given placebo. Women allocated magnesium sulphate had a 58% lower risk of eclampsia (95% CI 40-71) than those allocated placebo (40, 0.8%, vs 96, 1.9%; 11 fewer women with eclampsia per 1000 women). Maternal mortality was also lower among women allocated magnesium sulphate (relative risk 0.55, 0.26-1.14). For women randomised before delivery, there was no clear difference in the risk of the baby dying (576, 12.7%, vs 558, 12.4%; relative risk 1.02, 99% CI 0.92-1.14). The only notable difference in maternal or neonatal morbidity was for placental abruption (relative risk 0.67, 99% CI 0.45-0.89). Magnesium sulphate halves the risk of eclampsia, and probably reduces the risk of maternal death. There do not appear to be substantive harmful effects to mother or baby in the short term.

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Magnesium sulphate more than halves the risk of eclampsia, and probably reduces maternal death. There is no clear effect on outcome after discharge from hospital. A quarter of women report side effects with magnesium sulphate.

Does magnesium sulfate affect the length of labor induction in women with pregnancy-associated hypertension?

Our purpose was to determine whether seizure prophylaxis with magnesium sulfate prolongs induction of labor in women with pregnancy-associated hypertension. Women with a singleton pregnancy in vertex presentation between 32 and 42 weeks' gestation who required induction of labor for either preeclampsia, preeclampsia superimposed on chronic hypertension, or transient hypertension were randomized to receive either magnesium sulfate or phenytoin (Dilantin) for seizure prophylaxis. Women with rupture of the membranes, spontaneous contractions resulting in cervical change, or an initial cervical examination showing > 2 cm dilatation and 50% effacement were excluded. Fifty-four women were randomized to receive either magnesium sulfate (n = 28) or phenytoin (n = 26). The two groups were similar for selected maternal antepartum, intrapartum, and postpartum characteristics that have been associated with a prolongation or failure of labor induction. The two groups were also similar for the interval from the start of induction to (1) the first examination > or = 5 cm cervical dilatation and (2) delivery and in the frequency of women requiring cesarean delivery. Compared with phenytoin, magnesium sulfate seizure prophylaxis in women with pregnancy-associated hypertension does not prolong the induction of labor nor does it result in an increase in cesarean deliveries.

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Magnesium sulphate more than halves the risk of eclampsia, and probably reduces maternal death. There is no clear effect on outcome after discharge from hospital. A quarter of women report side effects with magnesium sulphate.

Magnesium sulfate in women with mild preeclampsia: a randomized controlled trial.

To determine whether magnesium sulfate prevents disease progression in women with mild preeclampsia. A total of 222 women with mild preeclampsia were randomized to receive intravenous magnesium sulfate (n = 109) or matched placebo (n = 113). Mild preeclampsia was defined as blood pressure of at least 140/90 mm Hg taken on two occasions in the presence of new-onset proteinuria. Patients with chronic hypertension or severe preeclampsia were excluded. Patients were considered to have disease progression if they developed signs or symptoms of severe preeclampsia, eclampsia, or laboratory abnormalities of full or partial HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. The groups were similar with respect to maternal age, ethnicity, gestational age, parity, and maternal weight at enrollment. Fourteen women (12.8%) in the magnesium group and 19 (16.8%) in the placebo group developed severe preeclampsia after randomization (relative risk = 0.8, 95% confidence interval 0.4, 1.5, P =.41). None in either group developed eclampsia or thrombocytopenia. Women assigned magnesium had similar rates of cesarean delivery (30% versus 25%), chorioamnionitis (3% versus 2.7%), endometritis (5.3% versus 4.3%), and postpartum hemorrhage (1% versus 0.9%), compared to those assigned placebo. Neonates born to women assigned magnesium had similar mean Apgar scores at 1 and 5 minutes as those born to women assigned placebo (7.7 +/- 1.5 versus 7.8 +/- 1.6 and 8.7 +/- 0.7 versus 8.8 +/- 0.6, respectively). Magnesium sulfate does not have a major impact on disease progression in women with mild preeclampsia. Magnesium use does not seem to increase rates of cesarean delivery, infectious morbidity, obstetric hemorrhage, or neonatal depression.

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Magnesium sulphate more than halves the risk of eclampsia, and probably reduces maternal death. There is no clear effect on outcome after discharge from hospital. A quarter of women report side effects with magnesium sulphate.

A randomised controlled trial of intravenous magnesium sulphate versus placebo in the management of women with severe pre-eclampsia.

To determine whether the administration of prophylactic intravenous magnesium sulphate reduces the occurrence of eclampsia in women with severe pre-eclampsia. Randomised controlled trial. A tertiary referral obstetric unit. Eight hundred and twenty-two women with severe pre-eclampsia requiring termination of pregnancy by induction of labour or caesarean section. The women were randomised to receive either placebo (saline) or magnesium sulphate intravenously. The investigators were blinded to the contents of the pre-mixed solutions. The occurrence of eclampsia in the two groups. The data of 699 women were evaluated. Fourteen were withdrawn after randomisation. The overall incidence of eclampsia was 1.8%. Of 345 women who received magnesium sulphate, one developed eclampsia (0.3%); in the placebo group, 11/340 women (3.2%) developed eclampsia (relative risk 0.09; 95% confidence interval 0.01-0.69; P = 0.003). The use of intravenous magnesium sulphate in the management of women with severe pre-eclampsia significantly reduced the development of eclampsia.

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Magnesium sulphate more than halves the risk of eclampsia, and probably reduces maternal death. There is no clear effect on outcome after discharge from hospital. A quarter of women report side effects with magnesium sulphate.

Phenytoin versus magnesium sulfate in preeclampsia: a pilot study.

A randomized clinical trial was designed to determine whether there are clinically demonstrable advantages of phenytoin over magnesium sulfate in preeclamptic patients because of the latter drug's uterine relaxant properties. An intravenous infusion, immediately after randomization, of either phenytoin or magnesium sulfate, with subsequent measurement of serum concentrations and maintenance of therapeutic levels was given to 103 preeclamptic and two eclamptic women. Observed were the rate of cervical dilation during active labor and change in hematocrit between predelivery and 24-hour postdelivery values and the incidence of side effects ascertained by interview. Compared with those receiving magnesium sulfate, patients receiving phenytoin had more rapid cervical dilation (3.3 cm/hr versus 1.5 cm/hr, p = 0.016) and a smaller fall in hematocrit after delivery (-4.7% versus -7.6%, p = 0.034). A significantly lower incidence of hot flushes (15% versus 46%, p < 0.005) and a trend toward less dyspnea and weakness were reported by phenytoin-treated patients. Our phenytoin regimen produced acceptable serum phenytoin levels (10 to 25 micrograms/ml) in 96% of patients.

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Magnesium sulphate more than halves the risk of eclampsia, and probably reduces maternal death. There is no clear effect on outcome after discharge from hospital. A quarter of women report side effects with magnesium sulphate.

Expectant management in severe preeclampsia: does magnesium sulfate prevent the development of eclampsia?

Although magnesium sulfate has been traditional or standard treatment for severe preeclampsia and eclampsia to prevent convulsions, its efficiency has always been in doubt and its induced side-effects also make it controversial for use. In this study, 64 patients, diagnosed with severe preeclampsia, were randomized into group I (34 patients) managed with MgSO4, and group II (30 patients) managed without MgSO4. There were no occurrences of eclampsia in either group. Although there was no statistical significance in the final delivery method, group I had a higher rate in cesarean section, in which most were significantly due to fetal distress (p < 0.05). Furthermore, group I had significantly more babies with poor apgar score than group II (p = 0.019). During the treatment period for those with a gestational age of less than 34 weeks, there were two patients with abruptio placentae in group I and the treatment periods were noted to be longer in group II than in group I. From the results of monitoring serum magnesium level in group I, when therapeutic level was achieved, magnesium sulfate induced great discomfort which might have led to the deterioration of the patients' condition. According to this study, magnesium sulfate's minimal efficiency, and its adverse side-effects, also make magnesium sulfate a poor choice in the management of preeclampsia. Therefore, because of our poor understanding of the etiology of preeclampsia, suitable management should be undertaken without magnesium sulfate. Improvement of the patient's pathophysiological condition or termination of pregnancy as early as possible, is recommended.

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Magnesium sulphate more than halves the risk of eclampsia, and probably reduces maternal death. There is no clear effect on outcome after discharge from hospital. A quarter of women report side effects with magnesium sulphate.

A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia.

Magnesium sulfate may prevent eclampsia by reducing cerebral vasoconstriction and ischemia. Nimodipine is a calcium-channel blocker with specific cerebral vasodilator activity. Our objective was to determine whether nimodipine is more effective than magnesium sulfate for seizure prophylaxis in women with severe preeclampsia. We conducted an unblinded, multicenter trial in which 1650 women with severe preeclampsia were randomly assigned to receive either nimodipine (60 mg orally every 4 hours) or intravenous magnesium sulfate (given according to the institutional protocol) from enrollment until 24 hours post partum. High blood pressure was controlled with intravenous hydralazine as needed. The primary outcome measure was the development of eclampsia, as defined by a witnessed tonic-clonic seizure. Demographic and clinical characteristics were similar in the two groups. The women who received nimodipine were more likely to have a seizure than those who received magnesium sulfate (21 of 819 [2.6 percent] vs. 7 of 831 [0.8 percent], P=0.01). The adjusted risk ratio for eclampsia associated with nimodipine, as compared with magnesium sulfate, was 3.2 (95 percent confidence interval, 1.1 to 9.1). The antepartum seizure rates did not differ significantly between groups, but the nimodipine group had a higher rate of postpartum seizures (9 of 819 [1.1 percent] vs. 0 of 831, P=0.01). There were no significant differences in neonatal outcome between the two groups. More women in the magnesium sulfate group than in the nimodipine group needed hydralazine to control blood pressure (54.3 percent vs. 45.7 percent, P<0.001). Magnesium sulfate is more effective than nimodipine for prophylaxis against seizures in women with severe preeclampsia. Copyright 2003 Massachusetts Medical Society

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Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

Improving the outcome of infants born at <30 weeks' gestation--a randomized controlled trial of preventative care at home.

Early developmental interventions to prevent the high rate of neurodevelopmental problems in very preterm children, including cognitive, motor and behavioral impairments, are urgently needed. These interventions should be multi-faceted and include modules for caregivers given their high rates of mental health problems. We have designed a randomized controlled trial to assess the effectiveness of a preventative care program delivered at home over the first 12 months of life for infants born very preterm (<30 weeks of gestational age) and their families, compared with standard medical follow-up. The aim of the program, delivered over nine sessions by a team comprising a physiotherapist and psychologist, is to improve infant development (cognitive, motor and language), behavioral regulation, caregiver-child interactions and caregiver mental health at 24 months' corrected age. The infants will be stratified by severity of brain white matter injury (assessed by magnetic resonance imaging) at term equivalent age, and then randomized. At 12 months' corrected age interim outcome measures will include motor development assessed using the Alberta Infant Motor Scale and the Neurological Sensory Motor Developmental Assessment. Caregivers will also complete a questionnaire at this time to obtain information on behavior, parenting, caregiver mental health, and social support. The primary outcomes are at 24 months' corrected age and include cognitive, motor and language development assessed with the Bayley Scales of Infant and Toddler Development (Bayley-III). Secondary outcomes at 24 months include caregiver-child interaction measured using an observational task, and infant behavior, parenting, caregiver mental health and social support measured via standardized parental questionnaires. This paper presents the background, study design and protocol for a randomized controlled trial in very preterm infants utilizing a preventative care program in the first year after discharge home designed to improve cognitive, motor and behavioral outcomes of very preterm children and caregiver mental health at two-years' corrected age. ACTRN12605000492651.

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Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

Minimizing adverse effects of low birthweight: four-year results of an early intervention program.

The outcome of an early intervention program for low-birthweight (LBW) infants was examined in this study. The intervention consisted of 11 sessions, beginning during the final week of hospitalization and extending into the home over a 3-month period. The program aimed to facilitate maternal adjustment to the care of a LBW infant, and, indirectly, to enhance the child's development. Neonates weighing less than 2,200 grams and under 37 weeks gestational age were randomly assigned to experimental or control conditions. A full-term, normal birthweight (NBW) group served as a second control. 6-month analyses of dyads who completed all assessments over a 4-year period (N's = 25 LBW experimental, 29 LBW control, and 28 NBW infant-mother dyads) showed that the experimental group mothers reported significantly greater self-confidence and satisfaction with mothering, as well as more favorable perception of infant temperament than LBW control group mothers. A progressive divergence between the LBW experimental and LBW control children on cognitive scores culminated in significant group differences on the McCarthy GCI at ages 36 and 48 months, when the LBW experimental group caught up to the NBW group. Possible explanations for the observed delay in the emergence of intervention effects on cognitive development and the mediating role of favorable mother-infant transactional patterns are discussed in light of recent evidence from the literature.

CD005495

Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

Randomised trial of parental support for families with very preterm children. Avon Premature Infant Project.

To test the effectiveness of a home based developmental education programme in very preterm children. A randomised controlled trial was conducted of developmental or social support intervention, started at discharge for up to 2 years, in 309 consecutive survivors of 32 weeks gestation or less, born to mothers resident in greater Bristol between December 1990 and July 1993. Home visits were made by research nurses trained in either Portage (a developmental education programme) or in nondirectional counselling (parent adviser scheme). Interventions were also provided to appropriate primary care and community support for disability. Griffiths Mental Development Scales were used to assess outcome at 2 years. Mean (SEM) Griffiths quotients (GQ) were: Portage 96.8 (1.6); parent adviser 95.9 (1.6); preterm control 92.9 (2.0). Despite randomisation, social variables significantly confounded these results. Using linear regression analysis, intervention was associated with improved scores: Portage: +4.3 GQ points (95% CI 1.6 to 7.0); parent adviser: +3.4 GQ points (1.4 to 6.1). The effect of Portage was greatest in those children with birthweights < 1250 g (+5.3 GQ points (0.2 to 10.4) and in those with an abnormal neonatal cerebral ultrasound scan (+7.3 GQ points (1.6 to 13.0). Primary analysis showed no developmental benefit from long term family support after preterm birth. Secondary analysis controlling for the presence of adverse social markers showed similar small advantage for both intervention groups. In the smallest infants and those with brain injuries, a structured developmental programme may offer advantage over social support intervention.

CD005495

Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

Teenage, lower-class, black mothers and their preterm infants: an intervention and developmental follow-up.

To assess the combined risks of being born preterm and to a teenage mother, and to evaluate the effects of an early intervention, preterm infants born to lower-class, black, teenage mothers were provided a home-based, parent-training intervention, and their development was then compared with that of nonintervention controls, of term infants of teenage mothers, and of term and preterm infants of adult mothers. Despite equivalence on prenatal care, factors which placed the preterm infant of the teenage mother at greater risk at birth were the small-for-date size of the infant and the less realistic developmental milestones and child rearing attitudes expressed by the mother. The preterm infants of teenage mothers who received intervention showed more optimal growth, Denver scores, and face-to-face interactions at 4 months. Their mothers rated their infants' temperaments more optimally, expressed more realistic developmental milestones and child-rearing attitudes, and received higher ratings on face-to-face interactions. At 8 months, the intervention group received superior Bayley mental, Caldwell, and infant temperament scores.

CD005495

Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

Early intervention promotes intellectual development of premature infants: a preliminary report. Early Intervention of Premature Infants Cooperative Research Group.

To evaluate the effect of early intervention on the intellectual development of the premature infants. Premature infants at gestational age of 28-36.9 weeks were randomly divided into two groups: intervention and conventional care groups. Normal newborn infants during the same period were included in the control group (routine care). Up to March 1996, 156 cases were over the age 1.5-2 years (corrected age), 52 in the intervention group, 51 in the conventional care group and 53 in the normal control group. Parents were taught to carry out the 0-2 year intervention program, which included motor, cognitive, speech development and social behavior. Every three months, height, weight and head circumference were measured. At the age of one and a half and two years, all infants in the three groups received infant development tests of Child Development Center of China (CDCC) scale. The examiner did not know which infant had received intervention. There was no significant difference in biological factors among the two premature groups and in cultural and social factors among the three groups. Intelligence tests at the age of one and a half and two years showed that the average mental development index (MDI) in the intervention group was 13.8 and 14.6 higher than those in the conventional care group and the differences were significant. The psychomotor development index (PDI) was 5.2 and 4.7 higher but the differences were not significant. The MDI and PDI in the intervention group and normal control were quite close, but at two years, the MDI and PDI in the intervention group were 5.7 and 7.3 higher than those in the normal control and the differences were significant (P < 0.05). Compared with the normal control, the MDI in conventional care group at one and a half and two years of age were 11.5 and 8.9 lower. The difference was very significant. There were four cases of mental retardation, whose mental development index (MDI) was less then 70 in the conventional care group, but none in the intervention group. Early intervention can promote intellectual development of the premature infants and may be beneficial to the prevention of mental retardation. Early and intensive intervention can produce better results. Bringing parent's initiative into full play through deepening their understanding of the importance of early intervention is the key to success.

CD005495

Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

Low birth weight and home intervention strategies: preterm infants.

We investigated the effects of a 1-year home intervention on premature infants with low (less than 1500 g) and higher (1500-2000 g) birth weights. Infants from each weight condition were block randomly assigned to a control or to one of two treatment groups. One treatment group focused on the development of the infant; the other treatment group focused on the parent-infant interaction. The low birth weight infants obtained significantly lower Bayley mental and motor scores, and were more passive and less intense than the higher birth weight infants. However, the low birth weight infants and their parents were more responsive to the home intervention than were the higher birth weight infants, as demonstrated by changes in the Bayley mental scores and the Home Observation for Measurement of the Environment (HOME) inventory. These findings exemplify the reciprocal relationship between the child's characteristics and parental responding. The importance of selecting the most high-risk premature infants for early home intervention is outlined.

CD005495

Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

Early physiotherapy intervention in premature infants.

Preterm infants are more likely to have disabling cerebral palsy (CP) than term infants. It has been reported that early therapeutic approaches may be appropriate for infants at risk of neuromotor dysfunction, to minimize the degree of future handicaps. Two hundred and twenty-nine infants born at less than 34 weeks' gestation, with birth weight < or = 2,000 g, cared for in the neonatal intensive care unit of Hacettepe University Hospital between January 1997-June 1999 were included in this study. Of the 229 infants initially included, 39 (17%) were dropped from the study within the first 12 months' assessment, due to lack of participation from the families. Thirty of the remaining 190 infants were found to have perinatal hypoxia or abnormal neurosonography, and were taken as the group at risk of development of CP, thus receiving early intervention therapy; these are listed as "premature at risk". The study group consisted of 160 infants not considered at risk. These were randomly paired into two groups of 80 infants, one that was given early interventional therapy, and the control group that received no program. Eleven of the 30 infants at risk, 2 of the 80 infants from the intervention group, and 4 of the 80 from the control group were diagnosed as having CP within the first six months of life. There was no difference in the age of loss or acquisition of reflexes and general abilities between the intervention and control groups. There was no difference in the prevalence of CP between the intervention and control groups. In conclusion this study showed no effect of early intervention in premature babies without risk of CP other than prematurity.

CD005495

Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

Effect of a developmental program on motor performance in infants born preterm.

A randomised controlled trial was conducted to evaluate the effect of a motor developmental program in improving motor performance in Thai infants born preterm. Eighty-four preterm born infants were randomly assigned to either a control or intervention group. Additionally, 27 low-risk preterm infants were included forming a comparative group for this study. From term equivalent age to four months adjusted age, all infants had their motor performance assessed monthly with the Test of Infant Motor Performance by one of the physiotherapist research assistants blind to group assignment and infants' adjusted age. In addition, the intervention infants received a developmental program at each monthly visit. Motor performance for each group plotted against age revealed linear trends of progression. The intervention group showed the greatest improvement. Two-way repeated measures ANOVA revealed significant differences across age and among groups. Scheffé comparisons indicated that the mean differences between each pair of the three groups were significant and supported the finding of greater improvement of the intervention infants over the control group. Thus the results suggest that the intervention program is likely to have beneficial effects when offered to a similar population of preterm born infants.

CD005495

Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

Effect of early neurodevelopmental therapy in normal and at-risk survivors of neonatal intensive care.

At a corrected age of 3 months, 80 low birth-weight infants were assigned to normal or at-risk groups on the basis of a neurodevelopmental assessment scale. Both groups were further divided into intervention and non-intervention sub-groups (20 infants in each). Intervention consisted of monthly hospital-based neurodevelopmental therapy in addition to a home exercise programme. Infants were re-assessed by a physiotherapist at 6, 9, and 12 months, and were tested at 12 months by an independent psychologist blinded for infant group. Mean birthweight and gestational age were similar for normal and at-risk groups. At-risk infants had higher mean neurodevelopmental scores throughout the study period and lower 1-year development quotients (DQ) than normals. In neither normal nor at-risk groups did neurodevelopmental therapy alter the pattern of development or the outcome.

CD005495

Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

Randomized trial of a parenting intervention for very preterm infants: outcome at 2 years.

To determine the efficacy of a neonatal parenting intervention for improving development in very preterm infants. A cluster-randomized, controlled trial with a cross-over design and washout period was conducted in 6 neonatal centers. Two hundred thirty-three babies <32 weeks' gestation were recruited (intervention = 112; control = 121). Intervention families received weekly Parent Baby Interaction Programme (PBIP) sessions during neonatal intensive care unit admission and up to 6 weeks after discharge. Control families received standard care. All 195 infants remaining in the study at 24 months' corrected age were assessed by psychologists blinded to group allocation. There was no significant difference in Mental Development Index (-0.9 points; 95% CI, -5.0, 3.2) or Psychomotor Development Index (2.5; -3.3, 8.4) scores between the intervention and control groups and no significant effect of intervention on Mental Development Index or Psychomotor Development Index scores for subgroups dichotomized by gestational age (<28 weeks/> or =28 weeks), parity (1st/other child) or mother's cohabiting status (supported/unsupported). There was no effect of PBIP on infant development at 2 years' corrected age. Parenting interventions may be better delivered after discharge or targeted for preterm infants with high biological and social risk.

CD005495

Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

The effects of an early developmental mother-child intervention program on neurodevelopment outcome in very low birth weight infants: a pilot study.

Several studies report increased minor neurodevelopment dysfunctions in children born very low birth weight (VLBW). Usefulness of preventive early intervention programs to improve neurodevelopment outcome of VLBW infants is still under investigation. To evaluate the effects of an early post-discharge developmental mother-child intervention program on neurodevelopment outcome at 36 months in VLBW infants. Prospective study. 36 VLBW infants ([mean (S.D.)] birthweight=864 g (204 g); gestational age=27.9 weeks (2.4 weeks)), consecutively born January-August 2001, randomized in intervention and control groups. Neurodevelopment assessment at 36 months of chronological age with use of the Griffiths Mental Development Scale and related subscales. At 36 months of chronological age, as compared to controls, children in intervention group exhibited higher scores in personal-social subscales ([mean (S.D.)]=101.4 (9.3) vs. 92.9 (12.1), P=0.02), eye-hand coordination (92.7 (4.5) vs. 87.1 (9.9), P=0.041), practical reasoning (98.6 (8.2) vs. 89.4 (10.1), P=0.01). Development Scale were 97.6 (5.5) and 92.4 (9.9), respectively, in intervention and control groups (P=0.074). Early post-discharge developmental mother-child intervention program may have a positive effect on later neurodevelopment outcome of VLBW children.

CD005495

Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

One-year outcome of auditory-tactile-visual-vestibular intervention in the neonatal intensive care unit: effects of severe prematurity and central nervous system injury.

Thirty-seven infants with severe central nervous system injury or extreme prematurity were randomly assigned to a multisensory (auditory-tactile-visual-vestibular) intervention or control group. Intervention began in the hospital at 33 weeks' postconceptional age and continued twice daily in the home until 2 months' corrected age. Mother-infant interactions during feedings were videotaped, and the Bayley Scales of Infant Development were administered. Control mothers stimulated their infants more during feeding, but these significant differences dissipated by 4 months. The presence of periventricular leukomalacia was associated with significantly poorer mental development, regardless of group assignment. Experimental infants tended to exhibit better motor and mental performance and had 23% fewer cerebral palsy diagnoses at 1 year, but these trends were not statistically significant. The type of brain injury was more important in determining 1-year developmental outcome than type of postnatal experience, suggesting that periventricular leukomalacia presents a major challenge for infant development.

CD005495

Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

Improving cognitive development of low-birth-weight premature infants with the COPE program: a pilot study of the benefit of early NICU intervention with mothers.

The purpose of this pilot study was to evaluate the effectiveness of a parent-focused intervention program (COPE) on infant cognitive development and maternal coping. A randomized clinical trial was conducted with 42 mothers of low-birth-weight (LBW) premature infants hospitalized in a neonatal intensive care unit (NICU), with follow-up at 3 months' and 6 months' corrected ages. COPE mothers received the four-phase educational-behavioral program that began 2-4 days postbirth and continued through 1 week following discharge from the NICU. Comparison mothers received audiotaped information during the same four time frames. Results indicated that COPE infants had significantly higher mental development scores at a 3 months' corrected age (M = 100.3) than did the comparison infants (M = 93.9), and this difference widened at 6 months' corrected age, with COPE infants scoring 14 points higher. COPE mothers were significantly less stressed by the NICU sights and sounds and had significantly stronger beliefs about what behaviors and characteristics to expect from their premature infants. Findings from this study support the need for further testing of early NICU interventions with parents to determine their effectiveness on parental coping and infant developmental outcomes. Copyright 2001 John Wiley & Sons, Inc.

CD005495

Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

The effects of an early physical therapy intervention for very preterm, very low birth weight infants: a randomized controlled clinical trial.

A randomized controlled clinical trial was used to investigate effects of physical therapy (PT) intervention on motor outcome of infants born very preterm with very low birth weight (VLBW). Seventy-two infants born very preterm with VLBW were randomly assigned to a nontreatment (NT) (n = 38) or treatment (T) (n = 34) group. The T group received developmental PT from birth until four months corrected age (CA) weekdays during the infant's neonatal stay and on a needs- and problem-orientated basis thereafter. The NT group received no intervention. Both groups were assessed at four months CA using the Alberta Infant Motor Scale (AIMS) as was a control group of 14 infants born full term. Parental compliance was measured using a parent questionnaire. PT intervention had no significant effect on the T group's motor performance. However, no T group subjects had abnormal motor development at four months CA when compared to the NT group (16%) and the control group (14%) (p = 0.09). The T group subjects with high levels of parental compliance had better scores on the AIMS than those with lower parental compliance (p = 0.05). PT intervention does not significantly affect motor performance of infants born very preterm with VLBW at four months CA. Parental compliance and intervention frequency may have influenced the outcome. Preliminary evidence suggests that neonatal and early PT may reduce the incidence of motor delay among infants born very preterm with VLBW. Follow-up of this group is recommended to ascertain the long-term benefits of this type of early PT.

CD005495

Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

A randomized controlled trial of an early intervention program in low birth weight children: outcome at 2 years.

Preterm infants are at increased risk of cognitive, motor and behavioral problems. Different intervention programs have been designed in an attempt to improve outcome, but the results are conflicting. To examine the effects of an early intervention program on cognitive, motor and behavioral problems and parenting stress among low birth weight children at 2 years corrected age. A randomized controlled trial was conducted including infants with a birth weight <2000 g treated at the University Hospital of North Norway, to examine the effects of a modified version of the Mother-Infant Transaction Program on cognitive, motor and behavioral outcomes and parenting stress. The children were assessed with the Bayley Scales of Infant Development and the Child Behavior Checklist/2-3 (CBCL) and the Parenting Stress Index were administered to the parents at 2 years corrected age. Sixty-nine children in the intervention group and 67 in the control group were assessed at 2 years. There were no differences between the groups in cognitive or motor outcomes. The intervention group scored consistently lower on all CBCL syndrome scales, but no difference was significant. The mothers in the intervention group reported significantly lower parental stress in both child and parent domain, whereas the fathers reported lower stress in child domain compared to the control group. This early intervention program does not improve cognitive, motor or behavioral outcomes at 2 years. There was a significant reduction in parenting stress reported by both mothers and fathers in the intervention group.

CD005495

Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

The Infant Behavioral Assessment and Intervention Program for very low birth weight infants at 6 months corrected age.

To determine whether the Infant Behavioral Assessment and Intervention Program (IBAIP), designed to support and enhance infants' self-regulatory competence, improved developmental and neurobehavioral outcomes in very low birth weight (VLBW) infants. We randomized 86 infants to 1 intervention before discharge and to 6 to 8 home interventions until 6 months corrected age, and 90 control infants received standard care. Developmental and behavioral outcomes were evaluated at 6 months corrected age with the Bayley Scales of Infant Development-II (BSID-II). Neurobehavioral functioning was evaluated with the Infant Behavioral Assessment (IBA) at baseline and at 6 months corrected age. Despite randomization, some differences in neonatal characteristics were found between the intervention and control infants. After adjustment, intervention effects of 7.2 points (+/- standard error 3.1) on the Mental Developmental Index and 6.4 +/- 2.4 points on the Psychomotor Developmental Index favored the intervention infants. The Behavioral Rating Scale of the BSID-II (P = .000) and the IBA (more approach [P = .003] and less stress [P = .001] over time) also favored the intervention infants. The IBAIP improved the mental, motor, and behavioral outcomes of VLBW infants at 6 months corrected age.

CD005495

Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

The effectiveness of early intervention: examining risk factors and pathways to enhanced development.

In this paper we examine the effectiveness of early intervention, especially vis-à-vis (a) child and family risk factors and (b) the pathways to enhanced child and family development. To address these issues we draw on findings from the Infant Health and Development Program (IHDP) for low-birth-weight premature infants. The data we present reveal the considerable effectiveness of the IHDP intervention in enhancing several aspects of early and later child and family development. The findings also illustrate the importance of looking beyond intervention group differences to examine the extent to which early intervention effects are more pronounced for some children and families than others and to examine the processes underlying intervention effects (e.g., exactly how do early interventions change children and families?). For example, both initial and longer-term IHDP intervention effects varied by both characteristics of the children and characteristics of their families. Our data also provide some insight into the processes by which intervention effects may have occurred. We conclude our consideration of these many complexities with suggestions for practice, social policy, and future research.

CD005495

Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

The effects of the Rice infant sensorimotor stimulation treatment on the development of high-risk infants.

The Rice Infant Sensorimotor Stimulation (RISS) treatment was given to 15 premature infants to determine effects on neurophysiological development. The mothers of the infants were trained to administer the treatment for 15 minutes, 4 times a day, for 1 month, beginning the day the infant arrived home from the hospital. When each infant in the study (15 experimental and 14 control) was 4 months postnatal age, he/she was examined by a pediatrician, a psychologist, and a pediatric nurse who had no knowledge of which infant was experimental or control. The results indicated the experimental infants made significant gains in neurological development (p less than .001), weight gain (p less than .04), and mental development (p less than .05). The findings of this research indicate that early and systematic stimulation of the nerve pathways of the skin and of the vestibular nerve cells can accelerate growth and development of premature infants.

CD005495

Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

Neurodevelopment until the adjusted age of 2 years in extremely low birth weight infants after early intervention--a case-control study.

A total of 104 infants with birth weights of less than 1000 grams were enrolled in this prospective case-control study in order to examine the effect of occupational therapy based on sensory integration (SI) and neurodevelopmental therapy (NDT) on neurological development. The children were grouped as matched pairs on the basis of a set of developmental risks assessed at the age of 3 months. The intervention children had a weekly session of 60 minutes of occupational therapy from the corrected age of 6 months up to 12 months. All the children were examined at the corrected age of 3, 6, 9, 12, 18 and 24 months. The neurodevelopment of the cases and the controls did not differ essentially and the only significant difference was found in the social development of the children at the age of 12 months to the advantage of the intervention group. It is concluded that this amount of occupational therapy in at-risk children does not have a relevant effect on neurological development.

CD005495

Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

Developmental intervention program for high-risk premature infants: effects on development and parent-infant interactions.

Developmental follow-up studies have documented that low birth weight infants are at high risk for mental and physical disabilities, despite recent advances in neonatal intensive care. Moreover, parent-infant bonding is hampered by the barriers created by technical equipment. This study evaluated a program of hospital and home-based developmental interventions designed to enhance the development of high-risk, preterm infants and the quality of communication between infants and their caregivers. Treatment and contrast groups consisted of 41 premature infants weighing less than 1800 g at birth. Treatment took a preventive approach, consisting of daily multimodal interventions in-hospital and twice-monthly interventions by child development specialists in the child's home, through 12 months adjusted age. Infants in the contrast group received traditional, remedially oriented care. The Bayley Scales of Infant Development were used to measure mental and psychomotor development, and the Greenspan-Lieberman Observations System (GLOS) was used to analyze the behavioral characteristics of infant-caregiver interactions. Developmental interventions had positive, significant effects on mental development and on the quality of caregiver-infant interactions. Changes in mental development were not independent of changes in the GLOS.

CD005495

Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into pre-school age. There is a great deal of heterogeneity between studies due to the variety of early developmental intervention programmes trialled and gestational ages of the preterm infants included, which limits the comparisons of intervention programmes. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programmes.

Effect of an early intervention programme on low birthweight infants with cerebral injuries.

To determine the effect of an early intervention programme (EIP) on low birthweight infants with cerebral injuries. Subjects were 23 high-risk low birthweight infants (periventricular leukomalacia 15, intraventricular haemorrhage 5, both 3) receiving care in the neonatal intensive care unit (NICU) at Nagasaki University Hospital. Subjects were randomly assigned to the EIP group (n = 12) or the control group (n = 11). Participants in the EIP group received a Neonatal Behavioral Assessment scale (NBAS)-based intervention combined with developmental support designed to enhance the infants' development and the quality of the parent-infant relationship. The control group received routine medical nursing care without the EIP. The EIP began prior to discharge from the NICU and lasted until 6 months of corrected age. All children were examined on the NBAS preintervention and again at 44 weeks postconceptional age. Maternal anxiety status (STAI) and maternal feelings of confidence in dealing with her baby (LCC) were measured pre and postintervention. Mental and motor development was assessed postintervention using the Bayley Scale of Infant Development. Orientation and State Regulation of infant behavioural profiles, the STAI and LCC scores significantly improved in the EIP group (mean difference (95% CI): Orientation 0.7 (0.4, 1.1), State Regulation 0.9 (0.3, 1.5), STAI -5.5 (- 9.1, -1.9, LCC 5.3 (4.2, 6.5)), but not in the control group. Bayley mental developmental index (MDI) score in the EIP group was higher than in the control group, but there was no significant difference between the two groups (mean difference (95% CI): MDI 8.5 (- 0.8, 17.8), PDI 6.7 (- 1.9, 15.4)). The EIP has beneficial effects on neonatal neurobehavioural development and maternal mental health of low birthweight infants with cerebral injuries. This evidence suggests that short-term changes in maternal mental health and infant neurobehaviour promoted by an EIP may serve to initiate a positive interaction between parents and infants.

CD004168

In order to eliminate potential selection bias, more RCTs need to be conducted in this area so that effectiveness, as well as efficacy, can be ascertained. The interlock programme appears to be effective while the device is installed in the vehicle of the offender. Studies need to address ways of improving recidivism rates in the long term, as the major challenges are participation rates, compliance and durability.

Evaluation of a program to motivate impaired driving offenders to install ignition interlocks.

Approximately 30,000 alcohol ignition interlocks, which are designed to prevent the operation of a vehicle if the driver has been drinking, are in use in the US and Canada. Ignition interlock programs are also being initiated in Sweden and Australia. The best-controlled studies that are currently available suggest that ignition interlocks are effective in reducing impaired driving recidivism while on the vehicle. However, in the US, the practical effectiveness of these devices is limited because only a small number of offenders are willing to install them in order to drive legally. This paper reports on a study of a court policy that created a strong incentive for impaired driving offenders to install interlocks by making traditional penalties, such as jail or electronically monitored house arrest, the alternative to participation in an interlock program. Comparison of the recidivism rates of offenders subject to this policy with offenders in similar, nearby courts, not using interlocks, indicated that the policy was producing substantial reductions in DUI recidivism.

CD004168

In order to eliminate potential selection bias, more RCTs need to be conducted in this area so that effectiveness, as well as efficacy, can be ascertained. The interlock programme appears to be effective while the device is installed in the vehicle of the offender. Studies need to address ways of improving recidivism rates in the long term, as the major challenges are participation rates, compliance and durability.

The Alberta Interlock Program: the evaluation of a province-wide program on DUI recidivism.

This study was designed to determine the efficacy of alcohol safety interlocks in reducing recidivism among first and second driving-under-the-influence (DUI) offenders. It also evaluates the overall effectiveness of interlock programs where typically only a small portion of DUI offenders elect to install interlocks. The driving records of DUI offenders participating in interlock programs for 6 months for first offenders and 2 years for second offenders were compared with similar offenders who chose not to participate. A province-wide program in Alberta, Canada. Records of 35,132 drivers convicted of DUI between 1 July 1998 and 30 September 1996 were analyzed Repeat DUI offenses during and after the interlock period. While the offenders had interlocks on their vehicles, DUI recidivism was substantially reduced. Once the interlock had been removed and the participants had been reinstated, their DUI rate was the same as other offenders indicating that the interlock reduced recidivism while in place. Because only 8.9% of eligible drivers elected to participate in the interlock program, the program did not significantly increase the overall effectiveness of the province's management of DUI offenders. Interlocks are associated with a major reduction in DUI recidivism while on the vehicle of the offender. However, because few offenders elect to participate, the program produces only a small (5.9%) overall reduction in the recidivism rate of all DUI offenders.

CD004168

In order to eliminate potential selection bias, more RCTs need to be conducted in this area so that effectiveness, as well as efficacy, can be ascertained. The interlock programme appears to be effective while the device is installed in the vehicle of the offender. Studies need to address ways of improving recidivism rates in the long term, as the major challenges are participation rates, compliance and durability.

Effects of ignition interlock license restrictions on drivers with multiple alcohol offenses: a randomized trial in Maryland.

This investigation sought to test the effectiveness of a statewide ignition interlock license restriction program for drivers with multiple alcohol-related traffic offenses. A total of 1387 multiple offenders eligible for license reinstatement were randomly assigned to participate in an ignition interlock program (experimental group) or in the conventional postlicensing treatment program (control group). The arrest rates of these 2 groups for alcohol traffic offenses were compared for 1 year during the ignition interlock license restriction program and for 1 year after unrestricted driving privileges were returned. Participation in the interlock program reduced offenders' risk of committing an alcohol traffic violation within the first year by about 65%. The alcohol traffic violation rate during the first year was significantly less for participants in the interlock program (2.4%) than for those in the control group (6.7%). However, there was no statistically significant difference between these groups in the second year, after the interlock license restriction was lifted. Ignition interlock license restriction programs are effective at reducing recidivism among drivers with multiple alcohol offenses, at least while the restriction is in effect.

CD004602

A single dose of paracetamol provides effective analgesia for about half of patients with acute postoperative pain, for a period of about four hours, and is associated with few, mainly mild, adverse events.

The efficacy of ketoprofen and paracetamol (acetaminophen) in postoperative pain after third molar surgery.

1. A placebo-controlled, double-blind, randomized trial was carried out to evaluate the efficacy of single doses of racemic ketoprofen 12.5 and 25 mg and paracetamol 500 and 1000 mg in patients with post-operative pain after third molar surgery over a 6 h investigation period. 2. Outcome variables included overall pain scores (AUC(0,360 min), maximum pain relief, pain relief at 1 h after dosage and the number of patients taking escape analgesics. 3. Overall pain scores (AUC(0,360 min) were significantly lower for all active treatments when compared to placebo (P < 0.01). 4. Both ketoprofen treatments and patients treated with paracetamol 1000 mg reported significantly greater pain relief (P < 0.01) and a later time to taking escape analgesics (P < 0.01) than patients medicated with placebo. 5. At 1 h after dosage, pain scores were significantly less (P < 0.01) after both doses of ketoprofen when compared with placebo. 6. Single doses of ketoprofen 12.5 and 25 mg, together with paracetamol 1000 mg are effective analgesics for treating post-operative pain after third molar surgery. These treatments provide up to 4 h of pain relief after this surgical procedure.

CD004602

A single dose of paracetamol provides effective analgesia for about half of patients with acute postoperative pain, for a period of about four hours, and is associated with few, mainly mild, adverse events.

The additive analgesic efficacy of acetaminophen, 1000 mg, and codeine, 60 mg, in dental pain.

In a double-blind, randomized, single-dose trial the analgesic contribution of acetaminophen, 1000 mg, and codeine, 60 mg, was determined. The study was a 2 X 2 factorial experiment in which 120 patients suffering from pain as a result of oral surgery rated their pain intensity and pain relief for up to 5 hours after a single dose of one of: 1000 mg acetaminophen, 60 mg codeine, 1000 mg acetaminophen plus 60 mg codeine, or placebo. The factorial analysis showed that both 1000 mg acetaminophen and 60 mg codeine made a statistically significant (P less than 0.05) contribution to the analgesic effectiveness of the combination on all measures of efficacy (sum of pain intensity differences, largest pain intensity difference, total pain relief, largest pain relief, and time to remedication). The incidence of adverse effects did not appear to differ among the treatments, including placebo.

CD004602

A single dose of paracetamol provides effective analgesia for about half of patients with acute postoperative pain, for a period of about four hours, and is associated with few, mainly mild, adverse events.

[Treatment of postoperative wound pain with suprofen].

The present randomized double-blind study was performed to investigate the analgesic effects of single doses of suprofen (alpha-methyl-4-(2-thienylcarbonyl)benzene acetic acid; Suprol) 200 mg, suprofen 400 mg paracetamol (APAP, acetaminophen) 650 mg, and combination suprofen 100 mg + APAP 650 mg versus placebo. The five treatment groups were homogeneous as to their demographic features and comprised 28--32 subjects each. Data for a total of 146 patients were evaluated. There were statistically significant differences between the therapeutic effect of the test preparations containing active substance on the one hand and placebo and the other hand. Of the active substances, the best results were obtained with the combination suprofen 100 mg + APAP 650 mg, followed by suprofen 400 mg and APAP 650 mg; there were hardly any differences in the results obtained with the two latter substances. Suprofen 200 mg ranked third. Statistical significance was only seen for the parameter pain intensity (SPID) on comparison of suprofen 100 mg + APAP 650 mg versus suprofen 200 mg. Side effects, homogeneously distributed over the treatment groups, were observed in four cases.

CD004602

A single dose of paracetamol provides effective analgesia for about half of patients with acute postoperative pain, for a period of about four hours, and is associated with few, mainly mild, adverse events.

Double-blind comparison of meclofenamate sodium with acetaminophen, acetaminophen with codeine and placebo for relief of postsurgical dental pain.

CD004602

A single dose of paracetamol provides effective analgesia for about half of patients with acute postoperative pain, for a period of about four hours, and is associated with few, mainly mild, adverse events.

Ibuprofen and acetaminophen in the relief of acute pain: a randomized, double-blind, placebo-controlled study.

To determine the relative analgesic efficacy of ibuprofen 400 mg and acetaminophen 1000 mg, we conducted a single-dose, double-blind, placebo-controlled, randomized clinical trial using a standard assay for analgesic agents, the dental pain model. At regular intervals over 6 hours, 184 patients who had undergone dental impaction surgery rated pain intensity and relief on categorical scales and pain half-gone on a dichotomous nominal scale; a categorical overall evaluation was completed at the end of 6 hours. Both active agents were effective compared to placebo. Ibuprofen 400 mg was more effective than acetaminophen 1000 mg for Sum Pain Intensity Difference (SPID), Total Pain Relief (TOTPAR), sum pain half-gone, and overall evaluation (P less than .05 to P less than .001). The time-effect curves demonstrated a greater peak effect and longer duration of action for ibuprofen 400 mg compared to acetaminophen 1000 mg. Side effects were reported in five ibuprofen patients, 11 acetaminophen-treated patients, and seven placebo patients. Based on the results of this clinical study, we conclude that ibuprofen 400 mg is a safe and more effective analgesic than acetaminophen 1000 mg for patients with acute pain.

CD004602

A single dose of paracetamol provides effective analgesia for about half of patients with acute postoperative pain, for a period of about four hours, and is associated with few, mainly mild, adverse events.

Ibuprofen liquigel for oral surgery pain.

Ibuprofen liquigel is a solubilized potassium ibuprofen 200-mg gelatin capsule formulation that was approved for over-the-counter use in 1995. This study compared the analgesic efficacy and tolerability of ibuprofen liquigel 200 mg, ibuprofen liquigel 400 mg, acetaminophen caplets 1000 mg, and placebo in patients experiencing moderate or severe pain after surgical removal of impacted third molars. This randomized, double-blind, parallel-group, 6-hour study was conducted in 210 patients experiencing moderate or severe postoperative pain. Ratings of pain intensity and pain relief were recorded every 15 minutes for the first hour, at 90 and 120 minutes, and then hourly through hour 6. The onsets of first perceptible relief and meaningful relief were recorded using 2 stopwatches. An analysis of variance model was employed to test for significant differences (P < or = 0.05) between treatment groups with respect to pain relief, pain intensity difference, total pain relief (TOTPAR), and summed pain intensity difference (SPID). Stopwatch measures were analyzed using the Cox proportional hazards model. Drug tolerability was assessed by monitoring the occurrence of adverse events. During the first 2 hours of the study (TOTPAR 2 and SPID 2), all active treatments were significantly more efficacious than placebo (P < 0.001), with ibuprofen liquigel 200 and 400 mg significantly more efficacious than acetaminophen 1000 mg (P < 0.05 and P < 0.01, respectively). For the entire duration of the study (TOTPAR 6 and SPID 6), only the 2 doses of ibuprofen liquigel were significantly more efficacious than placebo (P < 0.001). Ibuprofen liquigel 200 and 400 mg were also significantly more efficacious than acetaminophen 1000 mg on the summary measures TOTPAR 6 and SPID 6 (P < 0.01 and P < 0.001, respectively). Analysis of the stopwatch data revealed that all active treatments displayed significantly more rapid onsets to confirmed first perceptible relief (P < 0.001 to < 0.05) and meaningful relief (P < 0.001 to < 0.01) than did placebo, with ibuprofen liquigel 400 mg displaying a significantly more rapid onset to meaningful relief than acetaminophen 1000 mg (P < 0.05) and a significantly more rapid onset to confirmed first perceptible relief than acetaminophen 1000 mg (P < 0.001) and ibuprofen liquigel 200 mg (P < 0.01). All adverse events were considered mild or moderate, with an overall incidence of 11.5% in the ibuprofen liquigel 200-mg group, 6.8% in the ibuprofen liquigel 400-mg group, 19.0% in the acetaminophen 1000-mg group, and 25.9% in the placebo group. Ibuprofen liquigel provided greater peak and overall analgesic effects and a more rapid onset to analgesia than did acetaminophen 1000 mg.

CD004602

A single dose of paracetamol provides effective analgesia for about half of patients with acute postoperative pain, for a period of about four hours, and is associated with few, mainly mild, adverse events.

Multicenter clinical trial of ibuprofen and acetaminophen in the treatment of postoperative dental pain.

Pharmacological management of pain for acute and chronic conditions has been guided by a scientific understanding of peripheral and central acting mechanisms for the control of inflammation as well as pain. Oral surgery pain is a reliable model to reference the effectiveness of commonly used analgesics such as ibuprofen and acetaminophen. A total of 706 patients who were experiencing moderate to severe pain received a single dose of ibuprofen, acetaminophen, or placebo. After 6 hours, the degree of pain relief and tolerance was assessed. Ibuprofen has important implications for postoperative pain in clinical practice.

CD004602

A single dose of paracetamol provides effective analgesia for about half of patients with acute postoperative pain, for a period of about four hours, and is associated with few, mainly mild, adverse events.

A comparison of four analgesics in post-episiotomy pain.

This study was conducted to compare the analgesic efficacy of four commonly used analgesics namely ibuprofen, analgin, paracetamol and aspirin in post-episiotomy pain. The subjects were healthy postpartum women on the obstetric service of Goa Medical College, each of whom received only one experimental medication. Subjective reports were used as indices of pain intensity or relief. Ibuprofen was found to be the most effective analgesic in post-episiotomy pain followed by analgin and paracetamol in that order. Surprisingly, aspirin was found to be no better than placebo.

CD004602

A single dose of paracetamol provides effective analgesia for about half of patients with acute postoperative pain, for a period of about four hours, and is associated with few, mainly mild, adverse events.

Onset of acetaminophen analgesia: comparison of oral and intravenous routes after third molar surgery.

The purpose of this randomized double-blind study was to compare the efficacy and safety of propacetamol 2 g (an i.v. acetaminophen 1 g formulation) administered as a 2-min bolus injection (n=50) or a 15-min infusion (n=50) with oral acetaminophen 1 g (n=50) or placebo (n=25) for analgesia after third molar surgery in patients with moderate to severe pain after impacted third molar removal. All patients were evaluated for efficacy during the initial 6 h period after treatment administration (T(0)) and for safety during the entire week after T(0). The onset of analgesia after propacetamol was shorter (3 min for bolus administration, 5 min for 15-min infusion) than after oral acetaminophen (11 min). Active treatments were significantly better for all parameters (pain relief, pain intensity, patient's global evaluation, duration of analgesia) than placebo (P<0.05). Adverse events were more frequent after propacetamol, especially pain at the injection site. Propacetamol bolus resulted in a much higher incidence of local adverse events than the infusion (propacetamol bolus 90% vs propacetamol infusion 52%) with no clinically significant benefits in terms of analgesic efficacy. I.V. propacetamol, administered as a 15-min infusion, is a fast-acting analgesic agent. It is more effective in terms of onset of analgesia than a similar dose of oral acetaminophen.

CD004602

A single dose of paracetamol provides effective analgesia for about half of patients with acute postoperative pain, for a period of about four hours, and is associated with few, mainly mild, adverse events.

The relative efficacy of indoprofen compared with opioid-analgesic combinations.

This double-blind, parallel-design study used postsurgical dental outpatients as subjects. The patients self-administered a single dose of one of the study medications when they estimated their pain to be of moderate or severe intensity. The study medications were 200 mg of indoprofen, 650 mg of acetaminophen, 650 of acetaminophen with 60 mg of codeine, 650 mg of acetaminophen with 100 mg of d-propoxyphene N, and a placebo. On a report form, data were recorded on baseline pain and then hourly for four hours, intensity of pain, relief of pain, and side effects were reported. Also, an overall evaluation was recorded. Data were analyzed with the use of analysis of variance and Duncan's Multiple Range test. All four active treatments were statistically superior to placebo for sum pain intensity difference, total relief of pain, and overall evaluation parameters. Both opioid-analgesic combinations showed small additive effects over acetaminophen alone, and indoprofen was superior to both combination treatments and acetaminophen alone.