Long-term clinical experience with weekly interferon beta-1a in relapsing multiple sclerosis

Post-marketing surveillance studies are needed to assess the long-term safety, compliance and clinical efficacy of interferon beta-1a (IFN β -1a) therapy in multiple sclerosis (MS) patients. The goals of this study were to (i) assess the safety, compliance and clinical efficacy of long-term intramuscular (i.m.) IFN β -1a therapy in a large cohort of patients, and (ii) suggest possible predictors of therapeutic response. A total of 255 patients were included in the study. Mean time on therapy was 31.7 ± 19.3 months. Within 3 years, 31% of patients discontinued treatment, mainly for disease activity. No significant sustained blood analysis alteration was observed over time, apart from a decrease of cholesterol levels. After 3 years of treatment, mean Expanded Disability Status Scale (EDSS) scores increased by 0.4 points compared with baseline. The mean annual relapse rate was reduced compared with baseline. Patients with ≤2 relapses in the previous 2 years and with baseline EDSS scores of ≤2 had a longer estimated time to first relapse and to progression and first relapse, respectively. These results confirm the safety and suggest a sustained effectiveness of i.m. IFN β -1a, extending the reported follow-up period to 6.3 years, and hypothesize the presence of possible predictors of clinical outcome.     

Oral interferon beta-1a in relapsing-remitting multiple sclerosis: a double-blind randomized study

BACKGROUND: Interferon beta (IFNB) is available in parenteral formulations for treatment of multiple sclerosis (MS). The purpose of this study was to evaluate safety, tolerability and effects on MRI lesions of three different doses of oral IFNB-1a compared with placebo over six months in relapsing-remitting (RR) MS patients. METHODS: In this multicenter; double-blind randomized trial, RR-MS patients received 0.06, 0.6 or 6 million international units (MIU) IFNB-1a or placebo every other day for up to six months. Gadolinium DTPA-enhanced brain MRI scans were performed at screening and monthly during treatment. The primary variable was the cumulative number of newly active lesions. Secondary variables included volume of enhancing lesions on T1-weighted images each month and lesion volume on T2-weighted images at months three and six. Safety measures included adverse events, laboratory variables, vital signs, ECG, physical examination, EDSS and number of relapses. Neopterin was measured in 21 patients and neutralizing antibodies in 24 patients. RESULTS: Of 194 screened patients, 173 were randomized (42-44 patients per group) in 15 centers. Median cumulative numbers of newly active lesions over six months were 4.0 in the placebo and 0.6 MIU groups, compared with 7.5 and 9.0 in the 0.06 and 6 MIU groups (no significant differences). Secondary efficacy endpoints showed small and inconsistent differences between groups. Adverse events showed no notable group differences. Approximately two-thirds of patients in each group remained relapse free. No patients showed neutralizing antibodies. Neopterin levels were comparable between groups. CONCLUSION: Oral IFNB-1a showed neither beneficial effects in RRMS nor any systemic biological effects. Treatment was safe and well tolerated.     

A longitudinal study of T1 hypointense lesions in relapsing MS: MSCRG trial of interferon beta-1a. Multiple Sclerosis Collaborative Research Group

BACKGROUND: T1 hypointense lesions (T1 black holes) are focal areas of relatively severe CNS tissue damage detected by MRI in patients with MS. OBJECTIVE: To determine the natural history of T1 hypointense lesions in relapsing MS and the utility of T1 hypointense lesions as outcome measures in MS clinical trials. METHODS: MR studies were from the Multiple Sclerosis Collaborative Research Group trial. Longitudinal results are reported in 80 placebo- and 80 interferon beta-1a (IFNbeta-1a)-treated patients with mild to moderate disability relapsing-remitting MS. RESULTS: There was a small but significant correlation between T1 hypointense lesion volume and disability at baseline and on trial (r = 0.22, r = 0.28). In placebo patients there was a 29.2% increase in the mean volume of T1 hypointense lesions (median 124.5 mm3) over 2 years (p < 0.001 for change from baseline), as compared to an 11.8% increase (median 40 mm3) in the IFNbeta-1a-treated patients (change from baseline not significant). These treatment group comparisons did not quite reach significance. The most significant contributor to change in T1 hypointense lesions was the baseline number of enhancing lesions (model r2 = 0.554). Placebo patients with more active disease, defined by enhancing lesions at baseline, were the only group to show a significant increase in T1 hypointense lesion volume from baseline. CONCLUSION: The development of T1 hypointense lesions is strongly influenced by prior inflammatory disease activity, as indicated by enhancing lesions. These results suggest that treatment with once weekly IM IFNbeta-1a (30 mcg) slows the 2-year accumulation of these lesions in the brain.     

Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis

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 I11 trial of interferon beta-la. Interferon beta-la, 6.0 million units (30 μg), 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-la treatment produced a significant delay in time to sustained EDSS progression (p equals; 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-la-treated group. Patients treated with interferon beta-la also had significantly fewer exacerbations (p = 0.03) and a significantly lower number and volume of gadolinium-enhanced brain lesions on magnetic resonance images (pvalues 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-la-treated patients. There were no major adverse events related to treatment. Interferon beta- la 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 hndamen- tal course of relapsing multiple sclerosis.     

Clinical benefits of interferon beta-1a in relapsing-remitting MS: a phase IV study

OBJECTIVE: To evaluate the efficacy and safety of IFNbeta-1a (Avonex, Biogen, Inc., Cambridge, MA, USA) in patients with relapsing-remitting multiple sclerosis (MS). METHODS: In this multicenter, open-label, prospective clinical trial, 96 patients with relapsing-remitting MS received IFNbeta-1a 30 mcg intramuscularly once weekly for 2 years. Outcome variables included: change from baseline in mean number of exacerbations, proportion of exacerbation-free patients, and mean Expanded Disability Status Scale (EDSS) scores at Years 1 and 2. RESULTS: IFNbeta-1a significantly (P < 0.0001) reduced exacerbation rate at Years 1 and 2 of treatment. The percentage of exacerbation-free patients was 53% during Year 1 and 33% during Year 2. Mean EDSS scores were 2.96 +/- 1.26 at baseline, 2.89 +/- 1.42 at Year 1, and 3.00 +/- 1.62 at Year 2 (P = 0.116). EDSS scores improved in 35.4%, remained stable in 28.1%, and worsened in 36.5% of patients. IFNbeta-1a treatment was well tolerated. CONCLUSION: This study confirms and extends the beneficial clinical profile for IFNbeta-1a in relapsing MS.     

Relationship between serum levels of IL-10, MRI activity and interferon beta-1a therapy in patients with relapsing remitting MS

BACKGROUND: The purposes of this study were to: (1) compare monthly serum IL-10 in patients with relapsing remitting (RR) multiple sclerosis (MS) and healthy controls, (2) determine the relationship between IL-10 and MRI activity and (3) determine the effect of interferon beta-1a (IFNB-1a) treatment on IL-10 levels. RESULTS: Median serum IL-10 levels were lower in untreated RRMS (185.5 pg/ml) compared to controls (438.5 pg/ml) (P=0.19). Serum levels of IL-10 did not appear to predict the appearance of new gadolinium-enhancing (Gd+) lesions concurrently or 1 month thereafter. However, IL-10 levels were more likely to be elevated the month during which Gd+ lesions resolved (OR=3.14, P=0.01). Median IL-10 levels were lower during IFNB-1a treatment (P=0.01). CONCLUSIONS: These observations suggest a relationship between serum IL-10 levels and resolution of abnormal vascular permeability in new lesions.     

Comparing efficacy and side effects of a weekly intramuscular biogeneric/biosimilar interferon beta-1a with Avonex in relapsing remitting multiple sclerosis: a double blind randomized clinical trial

Objective

We compared the efficacy and safety of two biosimilar forms of interferon beta-1a in the treatment of multiple sclerosis: Avonex (Biogen Idec, USA) and CinnoVex (CinnaGen, Iran).

Methods

In a double blind randomized clinical trial study 84 patients with relapsing remitting multiple sclerosis (RRMS) with Expanded Disability Status Scale (EDSS) score of 0–5.5 were randomly allocated to two groups of 42 subjects.

Results

Twenty-four patients lost to follow-up. Finally, 31 patients (mean ± SD of age = 33.7 ± 7.0; 7 males and 24 females) in the Avonex and 29 patients (mean ± SD of age = 32.2 ± 9.2; 8 males and 21 females) in the CinnoVex group completed full 24 months of study period. Decrease in EDSS was 1.05 ± 0.24, p = 0.62 in the Avonex and 0.16 ± 0.88, p = 1.0 in the CinnoVex group after 12 months and 0.27 ± 1.05, p = 0.46 in the Avonex and 0.16 ± 1.06, p = 1.0 in the CinnoVex group after 24 months. There was no statistically significant difference in attack number between two groups (1.0 ± 1.2 in Avonex and 1.2 ± 1.3 in CinnoVex; p = 0.46). Volume of T2-weighted lesions on MRI showed a progressive significant increase in the 12th month (28056 ± 23693) in Avonex treated patients compared with first image (16353 ± 11172) (p = 0.01). But number of gadolinium-enhancing lesions in CinnoVex showed statistically significant decrease after 12 months (0.08 ± 0.28 vs. 1.00 ± 1.22; p = 0.03). However, there were no significant differences between groups after 24 months. There were no significant differences between 2 groups regarding frequency and duration of most considerable side effects, as well. Neutralizing antibodies were not positive in any patients.

Conclusion

CinnoVex can be used as a safe and effective alternative to Avonex in treatment of RRMS.     

Randomized,comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial

BACKGROUND: Interferon beta (IFNbeta) reduces relapses and MRI activity in relapsing-remitting MS (RRMS), with variable effects on disability. The most effective dose regimen remains controversial. METHODS: This randomized, controlled, multicenter trial compared the efficacy and safety of IFNbeta-1a (Rebif) 44 micro g subcutaneously three times weekly (tiw), and IFNbeta-1a (Avonex) 30 micro g IM once weekly (qw) in 677 patients with RRMS. Assessors blinded to treatment performed neurologic and MRI evaluations. The primary endpoint was the proportion of patients who were relapse free at 24 weeks; the principal MRI endpoint was the number of active lesions per patient per scan at 24 weeks. RESULTS: After 24 weeks, 74.9% (254/339) of patients receiving IFNbeta-1a 44 micro g tiw remained relapse free compared with 63.3% (214/338) of those given 30 micro g qw. The odds ratio for remaining relapse free was 1.9 (95% CI, 1.3 to 2.6; p = 0.0005) at 24 weeks and 1.5 (95% CI, 1.1 to 2.1; p = 0.009) at 48 weeks, favoring 44 micro g tiw. Patients receiving 44 micro g tiw had fewer active MRI lesions (p < 0.001 at 24 and 48 weeks) compared with those receiving 30 micro g qw. Injection-site reactions were more frequent with 44 micro g tiw (83% vs 28%, p < 0.001), as were asymptomatic abnormalities of liver enzymes (18% vs 9%, p = 0.002) and altered leukocyte counts (11% vs 5%, p = 0.003) compared with the 30 micro g qw dosage. Neutralizing antibodies developed in 25% of 44 micro g tiw patients and in 2% of patients receiving 30 micro g qw. CONCLUSIONS: IFNbeta-1a 44 micro g subcutaneously tiw was more effective than IFNbeta-1a 30 micro g IM qw on all primary and secondary outcomes investigated after 24 and 48 weeks of treatment.     

A randomized, double-blind, placebo-controlled study of oral hydrolytic enzymes in relapsing multiple sclerosis

Oral administration of hydrolytic enzymes (HE), such as bromelain, trypsin and rutosid, may have beneficial effects on the clinical course of neurological symptoms related to multiple sclerosis (MS). This is supported by a complete protection by HE from experimental allergic encephalomyelitis, an animal model related to MS. Three hundred and one patients with relapsing MS were enrolled in a double-blind, placebo-controlled trial. No treatment effect between the placebo and the HE groups was found either for clinical or MRI parameters.     

Prospective assessment of changing from placebo to IFN beta-1a in relapsing MS: the PRISMS study

The efficacy of interferon (IFN) beta has been shown in several placebo-controlled, parallel-group studies in relapsing-remitting multiple sclerosis (RRMS). PRISMS, the largest such study to date, clearly demonstrated the efficacy of IFN beta-1a on all outcome measures over 2 years during the placebo-controlled, parallel-group phase. However, this study's placebo-crossover design also provided us with a unique opportunity to conduct a prospective within-group assessment, eliminating the impact of inter-patient variability. At the start of year 3, patients receiving placebo during years 1-2 were re-randomized in a dose-blinded fashion to receive IFN beta-1a, 22 or 44 mcg subcutaneously three times weekly, during years 3 and 4. Clinic visits occurred 3-6 monthly and T2 MRI scans were obtained after 1 and 2 years on therapy. Comparison of the mean relapse count per patient over 2 years (the primary outcome measure) during time on placebo (years 1 and 2) with that during active treatment (years 3 and 4) revealed a decrease from 2.6 to 1.2 in both dose groups (54% relative reduction; p<0.001). Disability progression, T2 MRI lesion activity and accumulation of T2 lesion burden were also significantly improved with therapy (p<0.01). No new safety issues were noted. These data provide further support for IFN beta-1a's efficacy in RRMS. The ability to detect significant treatment effects with reduced patient numbers in this type of before/after analysis, may be due to the reduction in inter-patient variability.     

Randomized, double-blind, placebo-controlled study of subcutaneous interferon beta-1a in relapsing-remitting multiple sclerosis: a categorical disability trend analysis

The treatment effects of recent immunomodulatory therapies on disease progression in relapsing-remitting multiple sclerosis (MS) have been mostly established from 'confirmed progression' endpoints. However, the reliability of this outcome measure is poor and a significant proportion of patients may be erroneously classified. We previously proposed the area under disability/time curves to quantify in-trial disability changes, but although these have advantages, they lack information on the direction of change. We have therefore performed disease trend analyses and categorical classifications using serial Expanded Disability Status Scale (EDSS) scores from the 533 complete datasets in a double-blind, randomized, placebo-controlled, phase III trial of subcutaneous interferon beta-1a (IFNbeta-1a) (PRISMS study). We found significant treatment benefits for IFNbeta-1a on in-trial disability course (P=0.002). Therapeutic advantages remained when relapse-related assessments were excluded (P=0.018). Post hoc analyses demonstrated that IFNbeta-1a was mainly effective in both increasing the proportion of patients with a 'stable' course and reducing those with prolonged, disabling deteriorations. Baseline disease duration and EDSS levels, but not MRI lesion load, predicted the subsequent disability trends. Mean 'numbers needed to treat' (NNTs) to obtain preferred disability courses were reduced in patients with shorter disease duration. These results have important implications for the targeting of immunomodulatory therapies in MS.     

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

BACKGROUND: 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. METHODS: 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]). RESULTS: 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. CONCLUSIONS: IFNbeta-1a demonstrated benefit on MSFC progression, relapses, quality of life, and MRI activity in SPMS.     

Topiramate in older patients with partial-onset seizures: a pilot double-blind, dose-comparison study

Purpose: Pharmacokinetics of antiepileptic drugs (AEDs) can be altered by age-related changes in physiology, thereby altering clinical effects, especially tolerability, in older adults. We compared two dosages of topiramate (TPM) in a pilot study of patients ≥60 years of age with partial-onset seizures.
Methods: In this 24-week, double-blind, randomized, parallel-group study, patients with one or more seizures in previous 6 months were randomized to treatment with 50 or 200 mg/day TPM. TPM was initiated as monotherapy or added to one AED and titrated by 25 mg/day per week to target or maximum tolerated dose as the concomitant AED, if any, was withdrawn.
Results: Thirty-eight patients were randomized to the 50 mg/day TPM (mean age, 68 years) and 39–200 mg/day TPM (69 years). Seizure control was similar with the two dosages when TPM could be used as monotherapy, whereas 200 mg TPM was more effective than 50 mg in patients requiring adjunctive therapy. The overall incidence of adverse events was similar for the two dosages—66% with 50 mg and 62% with 200 mg TPM. Most common adverse events were somnolence (TPM 50, 13%; TPM 200, 8%), dizziness (13% vs. 8%), and headache (13% vs. 5%). Of 10 (13%) patients reporting a cognitive-related adverse event, six patients were assigned to the 50-mg group. A total of 14 patients (18%; seven in each group) discontinued TPM due to adverse events.
Conclusions: This pilot study supports the practice of using low-to-moderate dosages of AEDs in older adults.     

Cervene in acute ischemic stroke: Results of a double-blind, placebo-controlled, dose-comparison study.

Cervene (nalmefene), an opioid antagonist with relative kappa receptor selectivity, has shown neuroprotective effects in multiple experimental central nervous system injury and ischemic models. The agent already has a well-established safety profile in various clinical indications. Results from an earlier pilot study in 44 acute stroke patients suggest that Cervene administered by 24-hour maintenance infusion was safe and tolerable. The primary and secondary objectives of the current study were to assess the dose-related safety and preliminary efficacy of Cervene in patients with acute ischemic stroke. Methods: The present investigation was a Phase II, placebocontrolled, double-blind, randomized, dose-comparison, parallel-group study of a 24-hour administration of Cervene injection. Patients with acute ischemic stroke, onset of symptoms within 6 hours, and baseline score >/=4 on the National Institute of Health Stroke Scale (NIHSS) were randomized to 1 of 4 treatment groups: Cervene 6 mg, 20 mg, 60 mg or placebo. The primary efficacy outcome was the proportion of patients achieving a score of >/=60 on the Barthel Index and a rating of "moderate disability" or better on the Glasgow Outcome Scale at 12 weeks. Results: A total of 312 patients were randomized at 28 centers. All doses of Cervene were well tolerated. Overall, there was no significant difference in 3-month functional outcome for any dose of Cervene treatment compared with placebo. However, a prospective secondary analysis showed that both male and female patients less than age 70 years may have had an improved 3-month outcome. Conclusions: The results of this study indicate that the competitive kappa receptor opiate antagonist Cervene can be given safely to acute stroke patients at doses up to 60 mg/24 hr. Although overall there was no significant difference in the 3-month outcome, Cervene treatment may be associated with improved outcomes for patients younger than age 70.     

A randomized, double-blind, placebo-controlled MRI study of anti-herpes virus therapy in MS.

OBJECTIVE: To evaluate the effect of treatment with the antiherpes drug valacyclovir on MRI-evident lesions in patients with relapsing-remitting MS in a phase 2, randomized, double-blind, placebo-controlled study. BACKGROUND: It has been postulated from virologic studies that herpesvirus infection could play a role in the progression of MS. METHODS: Patients were eligible for the study if they had had two or more MS relapses in the 2-year period before enrollment. Seventy patients with Expanded Disability Status Scale scores of 0 to 5.5 were randomly assigned to receive 1 gram of valacyclovir (n = 36) or placebo (n = 34) three times daily for 24 weeks. Patients underwent MRI every fourth week for 32 weeks: twice during pretreatment, six times during treatment, and once after treatment. Scoring of neurologic disability was performed at the start and end of the treatment period. The primary endpoint was the number of new active MRI-evident lesions over 24 weeks of treatment. Secondary endpoints included other MRI measures and clinical endpoints. RESULTS: The mean number of new active lesions +/- SD per patient during 24 weeks of treatment with valacyclovir was 11.9 +/- 17.6 and that during placebo treatment was 14.5 +/- 21.4. A protocol-planned exploratory analysis stratified patients according to baseline activity; this analysis showed that patients with high levels of disease activity in the valacyclovir treatment group (n = 17) developed fewer new active lesions per scan than did those in the placebo treatment group (n = 11). The median number (Q(1), Q(3) range) of active lesions was 2.0 (1.38, 3.96) in the valacyclovir treatment group and 6.5 (2.63, 9.0) in the placebo treatment group. CONCLUSIONS: Valacyclovir treatment did not reduce the formation of active lesions in patients with relapsing-remitting MS who had two or more relapses during the previous 2-year period. In a subgroup of patients with high levels of disease activity who had more than one active MRI-evident lesion during 4 weeks, valacyclovir treatment was associated with a reduced number of new active MRI-evident lesions and with an increase in the number of scans free of new active lesions. The results of the exploratory subgroup analysis provide support for further studies of antiherpes therapy for patients with MS and high levels of MRI-evident disease activity.