Stanley Cohan

A phase III trial of intramuscular recombinant interferon beta as treatment for exacerbating-remitting multiple sclerosis: design and conduct of study and baseline characteristics of patients

The design and conduct of a randomized, double-blinded, placebo-controlled, multicenter, phase III study of recombinant interferon beta-1a (IFN-β-1a) as treatment for exacerbating-remitting MS are described, as are baseline characteristics of the study population. The purpose of the study was to determine if 6.0 × 106 IU (30 μg) of IFN-β-1a, administered by weekly intramuscular (i.m.) injections, was effective in delaying the onset of sustained disability. The primary outcome measure was time to onset of treatment failure, defined as a worsening on the Kurtzke Expanded Disability Status Scale (EDSS) of greater than or equal to 1.0 point compared with baseline, persisting for at least 6 months. An intent-to-treat design was used. The primary outcome measure was analyzed using the Mantel-Cox log-rank statistic and Kaplan-Meier survival curves. Secondary outcomes included quantitative measures of upper and lower extremity function, neuropsychological test performance, functional and quality of life assessments and several measures derived from annual brain MRI studies. Entry criteria included prestudy exacerbation rates of at least 0.67 per year and EDSS scores of 1.0–3.5. A total of 301 MS patients were randomly assigned to receive weekly i.m. injections of IFN-β-1a or placebo. The average age of the study population at entry was 37 years; 92% were Caucasian and 73% were women. The mean prestudy disease duration was 6.5 years, mean prestudy exacerbation rate was 1.2 per year and the mean EDSS score was 2.3. The randomization yielded well-balanced treatment arms. Various aspects of the study are discussed, including: (1) the decision to focus study design on sustained disability; (2) the rationale for the treatment regimen; (3) measures taken to assure the reliability of the primary outcome measure; and (4) a description of the secondary outcome measures.

Cerebrospinal fluid abnormalities in a phase III trial of Avonex® (IFNβ-1a) for relapsing multiple sclerosis

Abstract Background and objective : This report provides results of CSF analyses done in a subset of relapsing remitting MS patients participating in a placebo-controlled, double-blind, phase III clinical trial of IFNβ-Studies supported by the National Multiple Sclerosis Society (grants RG2019, RG2827),a (Avonex®, Biogen). The clinical trial demonstrated that IFNβ-1a treatment resulted in significantly reduced disability progression, annual relapse rate, and new brain lesions visualized by cranial magnetic resonance imaging. The objectives of the current study were to determine: (a) whether CSF abnormalities in MS patients correlated with disease or MRI characteristics, and (b) effects of IFNβ-1a therapy on these CSF abnormalities. Methods : CSF was analyzed from 262 (87%) of the 301 study subjects at entry into the clinical trial, and a second CSF sample was analyzed from 137 of these 262 subjects after 2 years of therapy. CSF cell counts, oligoclonal bands (OCB), IgG index, and free kappa light chains were measured using standard assays. Baseline CSF results were compared with demographic, disease, and MRI parameters. Differences in on-study relapse rate, gadolinium enhancement, and EDSS change according to baseline CSF status was used to determine the predictive value of CSF for subsequent clinical and MRI disease activity. Change in CSF parameters after 104 weeks were used to determine the effects of treatment. Results : (1) At study baseline, 37% of the subjects had abnormal CSF WBC counts, 61% had abnormal levels of CSF free kappa light chains, 84% had abnormal IgG index values, and 90% were positive for OCB. (2) Baseline IgG index, kappa light chains, and OCB showed weakly positive, statistically significant correlations with Gd-enhanced lesion volume and T2 lesion volume. WBC showed a statistically significant correlation with Gd-enhancing lesion volume but was uncorrelated with T2 lesion volume. (3) There was an associated between baseline CSF WBC counts and on-study clinical and MRI disease activity in placebo recipients. (4) IFNβ-1a treatment resulted in significantly reduced CSF WBC counts, but there was no treatment-related change in CSF IgG index, kappa light chains, or OCB, which remained relatively stable over time in both patient groups. Conclusions : The current study documents significant reductions in CSF WBC counts in patients treated with IFNβ-1a for 104 weeks. This finding is considered relevant to the therapeutic response, since CSF WBC counts were found to be positively correlated with subsequent clinical and MRI disease activity in placebo-treated relapsing MS patients.BACKGROUND AND OBJECTIVE This report provides results of CSF analyses done in a subset of relapsing remitting MS patients participating in a placebo-controlled, double-blind, phase III clinical trial of IFNbeta-Studies supported by the National Multiple Sclerosis Society (grants RG2019, RG2827),a (Avonex , Biogen). The clinical trial demonstrated that IFNbeta-1a treatment resulted in significantly reduced disability progression, annual relapse rate, and new brain lesions visualized by cranial magnetic resonance imaging. The objectives of the current study were to determine: (a) whether CSF abnormalities in MS patients correlated with disease or MRI characteristics, and (b) effects of IFNbeta-1a therapy on these CSF abnormalities. METHODS CSF was analyzed from 262 (87%) of the 301 study subjects at entry into the clinical trial, and a second CSF sample was analyzed from 137 of these 262 subjects after 2 years of therapy. CSF cell counts, oligoclonal bands (OCB), IgG index, and free kappa light chains were measured using standard assays. Baseline CSF results were compared with demographic, disease, and MRI parameters. Differences in on-study relapse rate, gadolinium enhancement, and EDSS change according to baseline CSF status was used to determine the predictive value of CSF for subsequent clinical and MRI disease activity. Change in CSF parameters after 104 weeks were used to determine the effects of treatment. RESULTS (1) At study baseline, 37% of the subjects had abnormal CSF WBC counts, 61% had abnormal levels of CSF free kappa light chains, 84% had abnormal IgG index values, and 90% were positive for OCB. (2) Baseline IgG index, kappa light chains, and OCB showed weakly positive, statistically significant correlations with Gd-enhanced lesion volume and T2 lesion volume. WBC showed a statistically significant correlation with Gd-enhancing lesion volume but was uncorrelated with T2 lesion volume. (3) There was an associated between baseline CSF WBC counts and on-study clinical and MRI disease activity in placebo recipients. (4) IFNbeta-1a treatment resulted in significantly reduced CSF WBC counts, but there was no treatment-related change in CSF IgG index, kappa light chains, or OCB, which remained relatively stable over time in both patient groups. CONCLUSIONS The current study documents significant reductions in CSF WBC counts in patients treated with IFNbeta-1a for 104 weeks. This finding is considered relevant to the therapeutic response, since CSF WBC counts were found to be positively correlated with subsequent clinical and MRI disease activity in placebo-treated relapsing MS patients.

Eight-year immunogenicity and safety of interferon beta-1a-Avonex treatment in patients with multiple sclerosis.

An open-label extension study of the phase III trial of intramuscular interferon beta-1a (IFNβ-1a-Avonex) was conducted to evaluate the immunogenicity and safety of IFNβ-1a-Avonex over six years in patients with relapsing multiple sclerosis (MS). Patients who participated in the pivotal phase III study were offered enrolment; entry was also open to patients who had not participated. All patients received IFNβ-1a-Avonex 30 mg intramuscularly once weekly for six years, for a treatment duration of up to eight years in patients who received IFNβ-1a-Avonex in the phase III trial. Serum levels of IFNβ antibodies were measured every six months using a screening enzyme-linked immunosorbent assay (ELISA) followed by an antiviral cytopathic effect assay to detect neutralizing antibodies (NAbs) in serum samples positive on ELISA. The incidence of adverse events and laboratory test results assessed safety. Of 382 total patients, 218 had participated in the phase III study (103 placebo, 115 IFNβ-1a-Avonex) and 164 had not participated; 24 of the 164 were IFNβ-naïve. At baseline, 281 patients were negative for IFNβ antibodies (NAb-). NAbs (titre≥ 20) developed at any time over six years in 5% of these patients. Of 140 patients who had been on IFNβ-1b-Betaseron, 49 were positive for NAbs (NAb+) at baseline; 11 of 115 who had been on IFNβ-1a-Avonex were NAb+ at baseline. Thirty-nine of 49 patients who had been on Betaseron and were NAb+ had titres <100; 36 of these 39 seroconverted to NAb-while on IFNβ-1a-Avonex, with a median time of approximately six months. Ten patients who had been on Betaseron had NAb titres ≥ 100; five remained NAb+ during six years on IFNβ-1a-Avonex and five seroconverted to NAb-, but only after at least two years. Five patients who had been on IFNβ-1a-Avonex during the clinical trial were NAb+ with titres <100 at baseline; four seroconverted to NAb-, with a median time of two to three years. Six patients who had been on IFNβ-1a-Avonex had NAb titres ≥100; five of these remained NAb+ at six years. No patient with a NAb titre >1000 seroconverted to NAb-, whether initially treated with IFNβ-1a-Avonex or -Betaseron. Adverse events were similar to those observed in the pivotal phase III trial. Results from this trial indicated that IFNβ-1a-Avonex was associated with a low incidence of NAbs and was well tolerated for up to eight years. Further, the results indicate that persistence of NAbs is dependent on titre and IFNβ product.

Comprehensive toxicology screening in the emergency department: An aid to clinical diagnosis

An audit of 2,641 toxicology requests from the Georgetown University Hospital Emergency Department from 1981 through 1984 was conducted to assess the contribution of toxicology laboratory results to the clinical evaluation of the intoxicated patient. Positive findings were obtained in 80% of the patients tested. Ethanol was the most common intoxicant, accounting for 48% of all positive results and an average serum concentration of 250 mg/dl. Multiple drug use was documented in 28% of the patients with positive results; some ingested as many as six substances. Women were more likely than men to be polydrug users. A comparison of laboratory findings with diagnosis based on history and examination for 76 patients revealed that the laboratory provided additional information on the nature of the intoxication two-thirds of the time. Our conclusion is that the toxicology laboratory offering a broadly based screening service when properly utilized by the emergency department staff can aid in establishing an accurate diagnosis and provide a guide to therapy in the intoxicated patient.

Cytomegalovirus encephalitis associated with episodic neurologic deficits and OKT-8+ pleocytosis

After 3 days of symptoms suggesting a viral illness, a 35-year-old man experienced three episodes of aphasia, right-sided sensory symptoms, and bifrontal headache. Each lasted several hours. CSF examination revealed a moderate lymphocytosis consisting of 80% OKT-8+ cells. Serum anti-cytomegalovirus (anti-CMV) antibody titer was elevated at 1:1,024 and subsequently fell to 1:64. Episodic symptoms recurred 5 months later, at which time the anti-CMV titer peaked at 1:8,192. A trial of inhaled oxygen aborted two episodes after several minutes each.

Simplified detection of quaternary ammonium compounds by gas chromatography.

An analytical method for the measurement of quaternary ammonium compounds in biological fluids has been developed. Samples are prepared by forming the corresponding iodides, which are extracted and isolated. The residue is taken into n-hexane or into water and part of the solution obtained is injected onto the gas chromatograph where thermal degradation takes place. The methyl iodide released is measured by a 63Ni electron capture detector. This method is quite sensitive and detects with good reliability and reproducibility as little as 10(-14) mole quaternary ammonium compound.

Comparing the ability of various compositive outcomes to discriminate treatment effects in MS clinical trials

We compared the ability of the Kurtzke Expanded Disability Status Scale (EDSS) and a composite outcome of non-physician-based measures of time to ambulate 25 feet (TA) and manual dexterity (the Box and Block Test [BBT], and 9-Hole Peg Test [9HPT]) to discriminate treatment effects in the Phase III study of interferon beta-1a. A log-rank comparison of Kaplan-Meier curves by treatment group showed the non-physicianbased composite of BBT, 9HPT, and TA was of comparable sensitivity (P=0.013) in discriminating sustained treatment failure as the EDSS alone (P=0.029). The composite of BBT, 9HPT, TA, and EDSS was more sensitive (P=0.009) in discriminating sustained treatment failure than the EDSS alone. Compositive outcomes of the EDSS and non-physician-based measures of manual dexterity and timed ambulation provide an appealing strategy to reduce the number of patients required to discriminate treatment effects in MS clinical trials.

Computed tomography in patients with homonymous visual field defects—A. Clinico-radiologic correlation

Abstract CT Scans were obtained in 39 patients with homonymous visual field defects and analyzed in conjunction with the results of neurologic and neuro-ophthalmologic examination. Nineteen patients had infarcts involving the optic radiations or the occipital lobes. The CT scan findings correlated with the age, size and location of the infarct. Large hemispheric infarcts were associated with dense homonymous hemianopsias. Six patients in this series had primary or metastasic neoplasm, CT again demonstrated a close correlation between the location of the lesions and the resulting field defects. Six patients had arterio-venous malformations of the occipital lobe. In three of them, CT scans identified an occipital lobe hematoma and separated these patients from those with cerebral infarction.

Pharmacology of Calcium Antagonists: Clinical Relevance in Neurology

Calcium antagonists are of potential value in preventing neuronal death following cerebral ischemia or anoxia. Prevention of calcium influx into neurons, not just preservation of cerebral blood flow, is necessary if these agents are to be protective. To be of value clinically in humans, these agents must be effective even if administered after the ischemic insult has occurred. Experimental studies suggest that flunarizine, which inhibits calcium influx following brain anoxia, prolongs clinical survival and prevents neuronal death even when administered after the ischemic event, has no known significant toxic effects in humans following acute administration, has important potential value in the treatment of stroke, and should be evaluated in controlled clinical trials of patients with acute stroke.

Flunarizine Blocks Elevation of Free Cytosolic Calcium in Synaptosomes Following Sustained Depolarization

Gerbil cerebral cortical synaptosomes loaded with the fluorescent calcium probe FURA-2 were used to study depolarization-induced presynaptic cytosolic free calcium concentration, as an in vitro model of cerebral ischemia. The depolarization-induced increase in intrasynaptosomal cytosolic free calcium concentration is not sodium-dependent or sodium channel-dependent and may be due to an influx of extrasynaptosomal calcium resulting from a cadmium- and omega-conotoxin-sensitive, nickel-, nifedipine-, and nimodipine-insensitive voltage-regulated channel. The depolarization-induced increase in intrasynaptosomal free cytosolic calcium concentration is also inhibited by flunarizine, a calcium antagonist that has protective effects in animal models of cerebral anoxia and ischemia. Our results suggest that presynaptic calcium uptake following depolarization may be mediated in part by an N-type channel. Flunarizine may block presynaptic calcium accumulation, in part, by blocking this N-type channel; this blockade may be just one of several mechanisms by which flunarizine exerts protective effects following cerebral ischemia.