Monotherapy Trials of New Antiepileptic Drugs

Summary: A number of clinical trials that test the efficacy and safety of the newer antiepileptic drugs (AEDs) have recently been concluded. Two dose-response trials in inpatients with refractory partial seizures and outpatients with newly diagnosed partial epilepsy established the efficacy of gabapentin as monotherapy. Lamotrigine was found to have efficacy similar to that of phenytoin and carbamazepine (CBZ) and to be better tolerated than CBZ in patients with newly diagnosed epilepsy. It was also shown to have efficacy as monotherapy in partial seizures, based on the results of an active controlled trial, and in the treatment of absence seizures, based on the results of a responder-enriched study. Topiramate as monotherapy was found to be efficacious for treatment of partial-onset seizures, based on the results of a single-center dose-response trial. A dose-response trial that tested the efficacy of tiagabine monotherapy in patients with refractory partial epilepsy was uninformative. Oxcarbazepine was found to be safe and efficacious in four comparative trials in patients with newly diagnosed epilepsy as well as in one placebo-controlled inpatient trial in patients with refractory partial seizures.     

Vigabatrin Versus ACTH as First-Line Treatment for Infantile Spasms: A Randomized, Prospective Study

Summary: Purpose: To compare the efficacy and tolerability of vigabatrin (VGB) and adrenocorticotrophic hormone (ACTH) as first-line therapy in infantile spasms. Methods: Forty-two infants (22 males, 20 females) aged 2–9 months with newly diagnosed infantile spasms, were included in the trial. Patients were randomized to receive VGB 100–150 mg/kg/day or Depot ACTH 10 IU/day. The alternative drug was given if spasms were not controlled within 20 days or in cases of intolerance to initial therapy. Twenty-three patients (7 cryptogenic, 16 symptomatic) received VGB as first-line therapy; 19 patients (8 cryptogenic, 11 symptomatic) received ACTH as the first drug. Results: Cessation of spasms was observed in 11 (48%) of the patients randomized to VGB and in 14 (74%) of those randomized to ACTH. Response to VGB was observed within 1–14 days, but two-thirds of patients (7/11) responded within 3 days. In the group treated with VGB, side effects such as drowsiness, hypotonia and irritability were observed in 13% of patients, compared with 37% in the group treated with ACTH. VGB was more effective than ACTH as treatment for cerebral malformations or tuberous sclerosis, whereas ACTH proved more effective in perinatal hypoxic/ischemic injury. The efficacy of the two drugs was similar in cryptogenic cases. Disappearance of interictal EEG abnormalities occurred sooner in patients randomized to ACTH than in those who received VGB as initial therapy. During the second phase, the alternative drug was given to the resistant patients. Spasms ceased in 2 of 5 patients treated with VGB and in 11 of 12 patients treated with ACTH. After 3 months, relapses of spasms were observed in 6 patients treated with ACTH and in 1 treated with VGB. VGB produced a therapeutic response in nearly half the patients receiving this drug. Conclusions: Our data lend further support to the view that VGB may be considered a first-choice drug in the treatment of IS.     

Australian tertiary care outcomes of entecavir monotherapy in treatment naive patients with chronic hepatitis B

AIM:To evaluate the long-term treatment outcomes of entecavir monotherapy in treatment naive patients in an Australian tertiary care setting. METHODS:A retrospective analysis of treatment naive patients receiving entecavir monotherapy through Westmead Hospital was performed.Patients were excluded if they had received previous treatment with another nucleoside or nucleotide analogue,were pregnant or less than 18 years old. RESULTS:Out of 336 patients,163 patients fulfilled the selection criteria.Range of follow up was 3-46 mo (mean 26 mo).134 patients(82.2%)had pre-treatment biopsies,with 26 patients(16.0%)demonstrating F3-4 fibrosis.In total,153 patients(93.9%)achieved at least Partial Virological Suppression(PVS),with 134 patients (82.2%)achieving complete virological suppression. The cumulative CVS and PVS rates at 36 mo were 82.1%and 96.4%,respectively.3 patients(1.8%)failed to achieve PVS,while 5 patients(3.0%)developed virological rebound.128 patients(78.5%)maintained CVS throughout follow up.Predictors of CVS included lower baseline DNA level(P=0.001),hepatitis B virus e antigen negative status(P=0.001)and increasing age at treatment(log rank 0.001).No significant adverse effects were reported necessitating cessation of entecavir. CONCLUSION:Entecavir monotherapy is efficacious and safe in an Australian tertiary care setting.Resistance and rebound rates are very low.This is similar to data from controlled and uncontrolled trials around the world.     

Real-world effectiveness of select biologic and DMARD monotherapy and combination therapy in the treatment of rheumatoid arthritis: results from the RADIUS observational registry

ABSTRACT

Objective:?To evaluate the effectiveness of select biologics, methotrexate (MTX), and other disease-modifying anti-rheumatic drugs (DMARDs) in the management of adult rheumatoid arthritis (RA) in routine clinical practice.

Research design and methods:?RADIUS (Rheumatoid Arthritis DMARD Intervention and Utilization Study) comprises two prospective, 5‐year, observational registries of over 10?000 patients. Over 4600 patients who initiated MTX or a biologic regimen (etanercept [ETN], infliximab [INF], ETN + MTX, and INF + MTX) and who had at least one on-regimen, follow-up evaluation, were included in this analysis. Adalimumab was not included because it had not yet received FDA approval at RADIUS initiation. Other common DMARD regimens (?N = 762) were also compared with MTX. Patients who initiated less commonly used regimens, such as anakinra or cyclosporine, and those who did not have at least one on-regimen, follow-up evaluation, were not eligible for this analysis. Because ESR/CRP measurements were often not available, a modified ACR20 response (mACR20), defined as three out of four response criteria excluding ESR/CRP, was used to assess response at 12 months. Logistic regression analysis was performed to control for baseline covariates that may affect outcomes.

Main outcome measures:?The primary endpoint was the proportion of patients who achieved a mACR20 response at 12 months post-RADIUS entry.

Results:?After adjusting for baseline covariates, patients receiving either ETN + MTX or ETN monotherapy were more likely to achieve a mACR20 response at 12 months than patients receiving MTX alone (odds ratio [OR] 1.29, 95% confidence interval [CI] 1.09–1.52; p < 0.01 and OR 1.23, 95% CI 1.02–1.47; p < 0.05, respectively). Conversely, patients treated with MTX + leflunomide (LEF) were less likely to achieve a mACR20 response than those receiving MTX alone (OR 0.68, 95% CI 0.48–0.96; p < 0.05). Significant differences were not observed between patients receiving MTX alone and either INF + MTX, MTX + hydroxychloroquine, MTX + hydroxychloroquine + sulfasalazine, INF monotherapy, or LEF monotherapy.

Conclusion:?These data from routine rheumatology clinical practice settings highlight the effectiveness of common biologic and DMARD therapies, and provide additional data beyond those of randomized, controlled trials.     

Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes

ABSTRACT

Objective: To evaluate the efficacy and safety of once-daily saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes (T2D) and inadequate glycemic control.

Research design and methods: This study included a main treatment cohort (MTC) with 401 patients (HbA_1c?≥?7% and ≤10%) randomized and treated with oral saxagliptin 2.5, 5, or 10?mg once daily or placebo for 24 weeks and a separate open-label cohort (OLC) with 66 patients (HbA_1c?>?10% and ≤12%) who received saxagliptin 10?mg once daily for 24 weeks. Primary endpoint was HbA_1c change from baseline to week 24. Secondary endpoints included change from baseline to week 24?in fasting plasma glucose (FPG), proportion of patients achieving HbA_1c?<?7%, and changes in postprandial glucose area-under-the-curve (PPG-AUC). Efficacy analyses for continuous variables were performed using an ANCOVA model with last-observation-carried-forward methodology.

Results: In the MTC, saxagliptin demonstrated statistically significant decreases in adjusted mean HbA_1c changes from baseline (mean, 7.9%) to week 24 (?0.43%, ?0.46%, ?0.54%) for saxagliptin 2.5, 5, and 10?mg, respectively, vs. +0.19% for placebo (all p?<?0.0001). Adjusted mean FPG was significantly reduced from baseline (?15, ?9, ?17?mg/dL) for saxagliptin 2.5, 5, and 10?mg, respectively, vs. +6?mg/dL for placebo (p?=?0.0002, p?=?0.0074, p?<?0.0001, respectively). More saxagliptin-treated patients achieved HbA_1c?<?7% at week 24 (35% [p?=?NS], 38% [p?=?0.0443], 41% [p?=?0.0133]) for saxagliptin 2.5, 5, and 10?mg, respectively, than placebo (24%). PPG-AUC was reduced for saxagliptin 2.5, 5, and 10?mg (?6868, ?6896, ?8084?mg·min/dL, respectively) vs. placebo (?647?mg·min/dL) with statistical significance demonstrated for saxagliptin 5?mg (p?=?0.0002) and 10?mg (p?<?0.0001). HbA_1c, FPG, and PPG-AUC reductions were also observed in the OLC at 24 weeks. In the MTC, adverse event frequency was similar across all study arms. No cases of confirmed hypoglycemia (symptoms, with fingerstick glucose ≤50?mg/dL) were observed in either cohort. Saxagliptin was not associated with weight gain. Study limitations included the lack of a control group for the OLC and the use of prespecified rescue criteria, which limited the exposure time during which patients could remain on their originally randomized medication without the introduction of additional antihyperglycemic rescue treatment.

Conclusions: Once-daily saxagliptin monotherapy for 24 weeks was generally well tolerated and demonstrated clinically meaningful reductions in key parameters of glycemic control vs. placebo.

Trial Registration: Clinical Trials NCT00121641     

Dosimetric analysis of urethral strictures following HDR 192Ir brachytherapy as monotherapy for intermediate- and high-risk prostate cancer

Background and purposeTo evaluate dosimetric parameters related to urethral strictures following high dose-rate brachytherapy (HDRBT) alone for prostate cancer.Material and methodsTen strictures were identified in 213 patients treated with HDRBT alone receiving 34 Gy in four fractions, 36 Gy in four fractions, 31.5 Gy in 3 fractions or 26 Gy in 2 fractions. A matched-pair analysis used 2 controls for each case matched for dose fractionation schedule, pre-treatment IPSS score, number of needles used and clinical target volume. The urethra was divided into membranous urethra and inferior, mid and superior thirds of the prostatic urethra.ResultsStricture rates were 3% in the 34 Gy group, 4% in the 36 Gy group, 6% in the 31.5 Gy group and 4% in the 26 Gy group. The median time to stricture formation was 26 months (range 8–40). The dosimetric parameters investigated were not statistically different between cases and controls. No correlation was seen between stricture rate and fractionation schedule.ConclusionsUrethral stricture is an infrequent complication of prostate HDRBT when used to deliver high doses as sole treatment, with an overall incidence in this cohort of 10/213 (4.7%). In a matched pair analysis no association with dose schedule or urethral dosimetry was identified, but the small number of events limits definitive conclusions.     

Quality of life and employment status are correlated with antiepileptic monotherapy versus polytherapy and not with use of "newer" versus "classic" drugs: results of the "Compliant 2006" survey in 907 patients

"Classic" and "newer" antiepileptic drugs (AEDs) were compared in an epidemiological survey regarding patient's acceptance of AEDs, quality of life (QoL), and employment. Data from 907 outpatients, 45.9% female (mean age: 44.8 ± 17.9 years), were evaluated by 90 neurologists in private practices, who were also involved in a non-interventional study by Sanofi-Aventis Deutschland GmbH, regarding medication, seizure type, illness duration, employment, patients' acceptance of AEDs (4-point scale where 1=very good), and QoL (6-point scale where 1=very good). Among the patients, 69.7% were on monotherapy, 25.4% were taking two AEDs, and 4.9% were taking more than two AEDs. Patient's acceptance of AEDs (mean ± SD=1.65 ± 0.62) and QoL (2.34 ± 0.89) were "good." Among patients aged 18-65 years, 68.6% were employed. QoL and acceptance were lower with polytherapy. Older age and polytherapy were associated with lower probability of employment. No differences emerged between "classic" and "newer" AED monotherapy. Polytherapy-associated lower QoL could be due to severity of illness or adverse effects of treatment.     

Comparison of the cognitive effects of tiagabine and carbamazepine as monotherapy in newly diagnosed adult patients with partial epilepsy: pooled analysis of two long-term, randomized, follow-up studies

PURPOSE: Patients with epilepsy are at greater risk for cognitive impairment than are age- and education-matched controls. Cognitive decline is a significant adverse event associated with many first-generation anticonvulsant drugs (AEDs); however, the past decade has seen the introduction of several new AEDs with more-favorable cognitive profiles. Tiagabine (TGB) is indicated as adjunctive therapy for the treatment of partial seizures. The cognitive effects of TGB and carbamazepine (CBZ) monotherapy were evaluated in adult epilepsy patients with partial seizures. METHODS: This analysis pooled data from two randomized studies with similar populations, dosing, and cognitive assessments. TGB was titrated to 20-30 mg/day and CBZ to 400-800 mg/day over a 6-week period. A control or no-drug group of untreated patients with a single epileptic seizure was included for comparison. Cognitive function was assessed at baseline and 52 weeks. RESULTS: Of the 105 epilepsy patients enrolled, 79 completed the 52 weeks of monotherapy (TGB, 74%; CBZ, 77%). Altogether, 19 untreated patients composed the no-drug group. During the 52-week follow-up, only one statistically significant difference was found between the treatment groups and the no-drug group [verbal fluency task: F(2, 92) = 3.16; p = 0.047]. On further analysis, it was determined that this statistical difference was solely based on the patients receiving CBZ performing worse than the control group (p = 0.048). Statistically significant improvements (p < 0.05) were found on six (26%) of 23 variables with TGB and CBZ, as well as the no-drug group, although the variables differed between the groups. Significant worsening in the test scores was not seen in any of the study groups. CONCLUSIONS: The results of this 52-week, follow-up study show that successful TGB monotherapy with 20-30 mg/day has a cognitive profile similar to that of successful long-term CBZ monotherapy with 400-800 mg/day in newly diagnosed patients with epilepsy and to that of untreated patients with a single seizure. We observed no significant decline in cognitive scores associated with TGB monotherapy.