Relative Bioavailability of Cenobamate Administered as a Crushed Tablet, Either Orally or via Nasogastric Tube, versus an Intact Whole Tablet.

Cenobamate is approved for the treatment of focal seizures in adults and is currently available as an oral tablet. Alternative methods of drug administration are needed for patients who are unable to swallow whole intact tablets. This phase 1, open-label, randomized, single-dose, three-way crossover (3-period, 3-treatment, 6-sequence) study (NCT05572255), conducted in healthy volunteers, assessed the relative bioavailability of a crushed 200-mg cenobamate tablet administered orally or via nasogastric (NG) tube compared with an intact 200-mg tablet. Each treatment was separated by a 13-day washout period. Plasma samples for cenobamate concentration analysis were collected pre-dose and at multiple time points up to 264 h post-dose. Standard bioequivalence study criteria were applied to the relative bioavailability assessments. All 90% confidence intervals of test-to-reference geometric mean ratios for cenobamate pharmacokinetic parameters (Cmax, AUClast, and AUCinf) were within 85-110% (predefined limit, 80-125%), suggesting no difference in cenobamate exposures following administration of an intact tablet orally or a crushed tablet orally or via NG tube. All treatment-emergent adverse events (TEAEs) were classified as mild and resolved. There were no deaths or other serious AEs (SAEs), and no TEAEs led to discontinuation. Our results indicate that the administration of cenobamate as a crushed tablet taken orally or via an NG tube can provide additional flexibility when patients cannot swallow intact tablets. Based on the results of this study, cenobamate is now approved by FDA to be taken whole or the tablets can be crushed. The crushed tablet can be mixed with water and either administered by mouth as an oral suspension or administered via a nasogastric tube.

Pharmacokinetics of cenobamate as monotherapy compared with adjunctive therapy.

OBJECTIVE: Cenobamate was approved by the US Food and Drug Administration (FDA) based on studies of adjunctive therapy in patients with focal epilepsy. To support the use of cenobamate monotherapy, this pharmacokinetic (PK)-based simulation analysis evaluated the predicted PK exposure of cenobamate when used as monotherapy versus adjunctive therapy. METHODS: A population pharmacokinetic (PopPK) model of cenobamate was developed using pooled human data from eight phase 1 studies in healthy subjects or special populations, and three phase 2 and 3 studies in patients with focal seizures (N = 960). Concomitant antiseizure medications (ASMs) with a statistically significant effect on the apparent systemic clearance (CL/F) of cenobamate in the PopPK model were used to compare simulated patient plasma exposures (area under the plasma concentration vs time curve [AUC]) following monotherapy versus adjunctive therapy. Treatment equivalence between monotherapy and adjunctive therapy was concluded if the 90% confidence interval (CI) of the geometric mean AUC ratio was within 0.8-1.25. RESULTS: In the PopPK model, statistically significant effects on cenobamate CL/F were shown for clobazam (decreased cenobamate CL/F by 19%) and carbamazepine (increased cenobamate CL/F by 15%); these differences were not considered clinically meaningful. Other ASMs (lacosamide, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and valproate) when coadministered with cenobamate did not have significant effects on the disposition (ie, PK or efficacy) of cenobamate. The geometric mean ratio (90% CIs) of cenobamate AUC for adjunctive therapy/monotherapy was 0.87 (0.816-0.925) for adjunctive carbamazepine and 1.24 (1.147-1.339) for adjunctive clobazam. The 90% CI was within the no-effect limits (90% CIs 0.8-1.25) for adjunctive carbamazepine and partially exceeding no-effect limits for adjunctive clobazam. CONCLUSIONS: Based on the results from this PopPK analysis, cenobamate monotherapy can be expected to result in comparable exposures to those that have been demonstrated to be safe and effective when used as adjunctive therapy for the treatment of focal seizures, supporting the use of cenobamate as monotherapy in these patients.

Efficacy of cenobamate by focal seizure subtypes: Post-hoc analysis of a phase 3, multicenter, open-label study.

PURPOSE: To report post-hoc efficacy data by focal seizure subtypes from 10 US study sites from a large, global, open-label, phase 3 study of adjunctive cenobamate. METHODS: Patients 18-70 years old with uncontrolled focal seizures taking stable doses of 1-3 antiseizure medications were administered increasing daily doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) at 2-week intervals (target dose 200 mg/day). Further increases to 400 mg/day by 50-mg/day increments every other week were allowed. RESULTS: 240 patients were evaluated; 27 (11.3%), 224 (93.3%), and 56 (23.3%) patients had focal aware motor (FAM), focal impaired awareness (FIA), and focal to bilateral tonic-clonic (FBTC) seizures, respectively (patients may have had ≥ 1 seizure subtype). Median baseline seizure frequencies/28 days were 10.5, 2.3, and 0.9 for FAM, FIA, and FBTC seizure subtypes. Reductions in median percent seizure frequency/28 days from baseline were observed during Months 1-3 (55.0%, 52.4%, and 94.1% for FAM, FIA, and FBTC). Greater reductions were observed during Months 4-5 (88.2%, 81.0%, and 100%) and during Months 25-27 (98.1%, 100%, and 100%). The percentage of patients achieving 100% seizure reduction in the FAM, FIA, and FBTC seizure subtypes was 22.2% (6/27), 21.5% (48/223), and 50% (28/56) during Months 1-3 and increased to 47.8% (11/23), 54.3% (88/162), and 90.5% (38/42) during Months 25-27, respectively. The most common treatment-emergent adverse events (≥ 20%) were fatigue, dizziness, and somnolence. No cases of DRESS were reported. CONCLUSIONS: Seizure reductions occurred in all focal seizure subtypes with cenobamate over time through Months 25-27, with the earliest onset in the FBTC group. Results from this subset analysis of the phase 3 study support the long-term efficacy of cenobamate across focal seizure types.

A Phase 1 Clinical Study Evaluating the Effects of Cenobamate on the QT Interval.

Cenobamate is an antiseizure medication for uncontrolled focal seizures. This thorough QT study assessed the effects of therapeutic and supratherapeutic cenobamate doses (maximum recommended dose, 400 mg/day) on correct QT interval (QTc) in healthy adults (N = 108) randomly assigned to 1 of 3 treatments: (A) cenobamate (days 1-63) up-titrated by 50-mg increments weekly to a 200 mg/day therapeutic dose (day 35) and then by 100 mg weekly to a 500 mg/day supratherapeutic dose (day 63), with placebo-moxifloxacin (days -1 and 64); (B) moxifloxacin 400 mg (day -1; positive control), placebo-cenobamate (days 1-63), and placebo-moxifloxacin (day 64); and (C) placebo-moxifloxacin (day -1), placebo-cenobamate (days 1-64), and moxifloxacin 400 mg (day 64). The primary end point was baseline-adjusted, placebo-corrected QTc (ΔΔQTcF; corrected for heart rate [HR] by Fridericia's method) with cenobamate 200 and 500 mg/day. Baseline electrocardiographic parameters were balanced across groups. Mean ΔΔQTcF was negative throughout for cenobamate doses (largest: day 35, -10.8 milliseconds; day 63, -18.4 milliseconds). Based on concentration-QTc analysis, ∆∆QTcF effect was predicted as -9.85 and -17.14 milliseconds at mean peak plasma levels of therapeutic (200 mg/day; 23.06 µg/mL) and supratherapeutic (500 mg/day; 63.96 µg/mL) doses. Cenobamate had no clinically relevant prolonging effect on electrocardiographic parameters (eg, PR, QRS); HR effects were similar to placebo. Cenobamate showed slight dose-related shortening of QTc, but to a degree not known to be clinically relevant (no reductions ≤340 milliseconds). Cenobamate had no clinically relevant effects on HR or electrocardiographic parameters and no QTc-prolonging effect at therapeutic/supratherapeutic doses. Cenobamate is contraindicated in patients with short-QT syndrome and caution should be used when coadministering with drugs that shorten QT interval.

Effect of cenobamate on the single-dose pharmacokinetics of multiple cytochrome P450 probes using a cocktail approach in healthy subjects.

This study was designed to evaluate the effects of cenobamate, an antiseizure medication for focal seizures, on the pharmacokinetics of cytochrome P450 probes (bupropion, CYP2B6; midazolam, CYP3A4/5; warfarin, CYP2C9; and omeprazole, CYP2C19) in healthy subjects. Probes were administered alone on days 1 (bupropion) and 7 (midazolam/warfarin/omeprazole), and with cenobamate 100 mg/day on day 69 (midazolam) and cenobamate 200 mg/day on days 99 (bupropion) and 105 (midazolam/warfarin/omeprazole). No significant interaction was concluded if 90% confidence intervals (CIs) for geometric mean ratios (GMRs) for area under the curve (AUC) and maximum concentration of CYP substrates and/or their metabolites were within the no-effect interval (0.80-1.25). When co-administered with cenobamate 100 mg/day, AUC from time of administration up to the time of the last quantifiable concentration (AUC0-last ) GMR (90% CIs) for midazolam was 0.734 (0.647-0.832). When co-administered with cenobamate 200 mg/day, AUC0-last GMRs (90% CI) for midazolam, bupropion, S-warfarin, and omeprazole were 0.277 (0.238-0.323), 0.615 (0.522-0.724), 1.14 (1.10-1.18), and 2.07 (1.44-2.98), respectively. Co-administration of cenobamate with midazolam and bupropion probes led to values that were outside and below the no effect boundary, indicating that cenobamate induces the CYP3A4/5 and CYP2B6 enzymes. Co-administration of cenobamate led to omeprazole values which were outside and above the no-effect boundary, but with high variability, suggesting that cenobamate may moderately inhibit CYP2C19 activity. No effect on CYP2C9 was observed with the cenobamate and warfarin combination. Co-administration of cenobamate with these probes drugs was well-tolerated. In this study, 200 mg/day cenobamate moderately induced CYP3A4/5 (dose-dependently; 100 mg/day was a weak inducer), was a weak inducer of CYP2B6, moderately inhibited CYP2C19, and had a negligible effect on CYP2C9.

Long-term safety of adjunctive cenobamate in patients with uncontrolled focal seizures: Open-label extension of a randomized clinical study.

OBJECTIVE: This study was undertaken to examine long-term (up to 7.8 years) retention rate, safety, and tolerability of the antiseizure medication (ASM) cenobamate as adjunctive treatment in the open-label extension (OLE) of study YKP3089C013 (C013; ClinicalTrials.gov: NCT01397968). METHODS: Patients who completed the 12-week, multicenter, multinational, double-blind, randomized, placebo-controlled C013 study, which examined adjunctive cenobamate treatment of adults with uncontrolled focal seizures, were eligible to enroll in the OLE. During the OLE, dose adjustments of cenobamate and concomitant ASMs were allowed. Safety assessments included frequency of treatment-emergent adverse events (TEAEs) and serious TEAEs, TEAE severity, and TEAEs leading to discontinuation. Probability of patient continuation in the OLE was examined using a Kaplan-Meier analysis. RESULTS: One hundred forty-nine patients entered the OLE (median duration of cenobamate treatment = 6.25 years). As of the data cutoff, 57% of patients (85/149) remained in the OLE (median treatment duration = 6.8 years, range = 6.4-7.8 years). The median modal daily cenobamate dose was 200 mg (range = 50-400 mg). The probability of treatment continuation at 1-6 years of cenobamate treatment was 73%, 67%, 63%, 61%, 60%, and 59%, respectively. Among patients who continued at 1 year (n = 107), the probability of continuing at Years 2-5 was 92%, 87%, 83%, and 82%. The most common discontinuation reasons were patient withdrawal (19.5%, 29/149), adverse event (10.1%, 15/149), and lack of efficacy (5.4%, 8/149). TEAEs leading to discontinuation in 1% or more of patients were fatigue (1.3%, 2/149), ataxia (1.3%, 2/149), and memory impairment or amnesia (1.3%, 2/149). Dizziness (32.9%, 49/149), headache (26.8%, 40/149), and somnolence (21.5%, 32/149) were the most frequently reported TEAEs and were primarily mild or moderate in severity. SIGNIFICANCE: Long-term retention in the C013 OLE study demonstrated sustained safety and tolerability of adjunctive cenobamate treatment up to 7.8 years in adults with treatment-resistant focal seizures taking one to three ASMs.

Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, phase 3, multicenter, open-label safety study.

OBJECTIVE: During the development of cenobamate, an antiseizure medication (ASM) for focal seizures, three cases of drug reaction with eosinophilia and systemic symptoms (DRESS) occurred. To mitigate the rate of DRESS, a start-low, go-slow approach was studied in an ongoing, open-label, multicenter study. Also examined were long-term safety of cenobamate and a method for managing the pharmacokinetic interaction between cenobamate, a 2C19 inhibitor, and concomitant phenytoin or phenobarbital. METHODS: Patients 18-70 years old with uncontrolled focal seizures taking stable doses of one to three ASMs were enrolled. Cenobamate 12.5 mg/d was initiated and increased at 2-week intervals to 25, 50, 100, 150, and 200 mg/d. Additional biweekly 50 mg/d increases to 400 mg/d were allowed. During titration, patients taking phenytoin or phenobarbital could not have their cenobamate titration rate or other concomitant ASMs adjusted; phenytoin/phenobarbital doses could be decreased by 25%-33%. RESULTS: At data cutoff (median treatment duration = 9 months), 1347 patients were enrolled, of whom 269 (20.0%) discontinued, most commonly due to adverse events (n = 137) and consent withdrawn for reason other than adverse event (n = 74); 1339 patients received ≥1 treatment dose (median modal dose = 200 mg). The most common treatment-emergent adverse events (TEAEs) were somnolence (28.1%), dizziness (23.6%), and fatigue (16.6%). Serious TEAEs occurred in 108 patients (8.1%), most commonly seizure (n = 14), epilepsy (n = 5), and pneumonia, fall, and dizziness (n = 4 each). No cases of DRESS were identified. In the phenytoin/phenobarbital groups, 43.4% (36/114) and 29.7% (11/51) of patients, respectively, had their doses decreased. At the end of titration, mean plasma phenytoin/phenobarbital levels were generally comparable to baseline. SIGNIFICANCE: No cases of DRESS were identified in 1339 patients exposed to cenobamate using a start-low (12.5 mg/d), go-slow titration approach. Cenobamate was generally well tolerated in the long term, with no new safety issues found. Phenytoin/phenobarbital dose reductions (25%-33%), when needed during cenobamate titration, maintained stable plasma levels.

Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures.

OBJECTIVE: To evaluate the efficacy and safety of adjunctive cenobamate 200 mg/d in patients with uncontrolled focal (partial-onset) seizures despite treatment with 1 to 3 antiepileptic drugs. METHODS: In this multicenter, double-blind, placebo-controlled study, adults 18 to 65 years of age with focal seizures were randomized 1:1 (cenobamate:placebo) after an 8-week baseline period. The 12-week double-blind treatment period consisted of a 6-week titration phase and a 6-week maintenance phase. The primary outcome was percent change in seizure frequency (from baseline) per 28 days during double-blind treatment. RESULTS: Two hundred twenty-two patients were randomized; 113 received cenobamate and 109 received placebo; and 90.3% and 90.8% of patients, respectively, completed double-blind treatment. Median baseline seizure frequency was 6.5 in 28 days (range 0-237). Compared to placebo, cenobamate conferred a greater median percent seizure reduction (55.6% vs 21.5%; p < 0.0001) The responder rate (≥50% reduction in seizure frequency) was 50.4% for cenobamate and 22.2% for placebo (p < 0.0001). Focal seizures with motor component, impaired awareness, and focal to bilateral tonic-clonic seizures were significantly reduced with cenobamate vs placebo. During maintenance, 28.3% of cenobamate-treated and 8.8% of placebo-treated patients were seizure-free. Treatment-emergent adverse events reported in >10% in either group (cenobamate vs placebo) were somnolence (22.1% vs 11.9%), dizziness (22.1% vs 16.5%), headache (12.4% vs 12.8%), nausea (11.5% vs 4.6%), and fatigue (10.6% vs 6.4%). CONCLUSION: Adjunctive treatment with cenobamate 200 mg/d significantly improved seizure control in adults with uncontrolled focal seizures and was well tolerated. CLINICALTRIALSGOV IDENTIFIER: NCT01397968. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, for patients with uncontrolled focal seizures, adjunctive cenobamate reduces seizures.

Pharmacokinetics of Cenobamate: Results From Single and Multiple Oral Ascending-Dose Studies in Healthy Subjects.

Cenobamate (YKP3089) is an antiepileptic drug recently approved by the Food and Drug Administration for the treatment of focal (partial-onset) seizures in adults. The objectives of a first-in-human single-ascending-dose study and 3 multiple-ascending-dose studies were to characterize the pharmacokinetics, safety, and tolerability of cenobamate after single-dose and multiple-dose administration in healthy subjects. The 4 randomized, placebo-controlled, double-blind studies were conducted in 210 healthy subjects receiving single (5 to 750 mg) or multiple (50 to 600 mg/day) oral doses of cenobamate or placebo using capsule formulation. Safety assessments included treatment-emergent adverse events (TEAEs) and laboratory evaluations. Maximum plasma concentrations of cenobamate were observed between 0.8 and 4.0 hours after oral administration. Cmax increased in a dose-proportional manner for single- and multiple-dose administration across all tested doses. Although the AUC of cenobamate increased in a more than dose-proportional manner after single-dose administration, a dose-proportional increase in cenobamate AUCτ was observed after multiple dosing from 50 to 500 mg/day. Cenobamate exhibited low oral clearance (decreasing from approximately 1.4 to 0.50 L/h with dose increase) and long terminal half-life (range, approximately 30 to 76 hours with increasing dose). Steady-state was attained after approximately 2 weeks, and the accumulation ratio was approximately 5 over the 50 to 300 mg/day range. The pharmacokinetic characteristics of cenobamate are consistent with once-daily dosing. Most TEAEs were mild in severity, 2 serious TEAEs were reported, and no deaths occurred across all studies. Except for multiple daily doses of 600 mg, all doses were generally well tolerated.

Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial.

BACKGROUND: More than a third of patients with epilepsy are treatment resistant, and thus new, more effective therapies to achieve seizure freedom are needed. Cenobamate (YKP3089), an investigational antiepileptic drug, has shown broad-spectrum anticonvulsant activity in preclinical studies and seizure models. We aimed to evaluate the safety, efficacy, and tolerability of adjunctive cenobamate in patients with uncontrolled focal (partial)-onset epilepsy. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled, dose-response study at 107 epilepsy and neurology centres in 16 countries. Adult patients (aged 18-70 years) with focal seizures despite treatment with 1-3 antiepileptic drugs were randomly assigned (1:1:1:1) via an interactive web response system, by block sizes of 4 within each country, to adjuvant once daily oral cenobamate at dose groups of 100 mg, 200 mg, or 400 mg, or placebo following an 8-week baseline assessment. Patients, investigators, and study personnel were masked to treatment assignment. The study included a 6-week titration phase and 12-week maintenance phase. The primary efficacy outcomes were percentage change in 28-day focal seizure frequency (focal aware motor, focal impaired awareness, or focal to bilateral tonic-clonic seizures) from baseline analysed in the modified intention-to-treat population (≥1 dose and any post-baseline seizure data) and responder rates (≥50% reduction) analysed in the maintenance phase population (≥1 dose in the maintenance phase and any maintenance phase seizure data). The primary efficacy outcomes were analysed using a hierarchal step-down procedure comparing 200 mg versus placebo, 400 mg versus placebo, then 100 mg versus placebo. Safety and tolerability were compared descriptively across treatment groups for all randomised patients. This study is registered with ClinicalTrials.gov, number NCT01866111. FINDINGS: Between July 31, 2013, and June 22, 2015, 437 patients were randomly assigned to either placebo (n=108) or cenobamate 100 mg (n=108), 200 mg (n=110), or 400 mg (n=111). Of these patients, 434 (106 [98%] in placebo group, 108 [100%] in 100 mg group, 109 [99%] in 200 mg group, and 111 [100%] in 400 mg group) were included in the modified intention-to-treat population, and 397 (102 [94%] in placebo group, 102 [94%] in 100 mg group, 98 [89%] in 200 mg group, and 95 [86%] in 400 mg group) were included in the modified intention-to-treat maintenance phase population. Median percentage changes in seizure frequency were -24·0% (IQR -45·0 to -7·0%) for the placebo group compared with -35·5% (-62·5 to -15·0%; p=0·0071) for the 100 mg dose group, -55·0% (-73·0 to -23·0%; p<0·0001) for the 200 mg dose group, and -55·0% (-85·0 to -28·0%; p<0·0001) for the 400 mg dose group. Responder rates during the maintenance phase were 25% (26 of 102 patients) for the placebo group compared with 40% (41 of 102; odds ratio 1·97, 95% CI 1·08-3·56; p=0·0365) for the 100 mg dose group, 56% (55 of 98; 3·74, 2·06-6·80; p<0·0001) for the 200 mg dose group, and 64% (61 of 95; 5·24, 2·84-9·67; p<0·0001) for the 400 mg dose group. Treatment-emergent adverse events occurred in 76 (70%) of 108 patients in the placebo group, 70 (65%) of 108 in the 100 mg group, 84 (76%) of 110 in the 200 mg group, and 100 (90%) of 111 in the 400 mg group. Treatment-emergent adverse events led to discontinuation in five (5%) patients in the placebo group, 11 (10%) in the 100 mg dose group, 15 (14%) in the 200 mg dose group, and 22 (20%) in the 400 mg dose group. One serious case of drug reaction with eosinophilia and systemic symptoms occurred in the 200 mg cenobamate group. No deaths were reported. INTERPRETATION: Adjunctive cenobamate reduced focal (partial)-onset seizure frequency, in a dose-related fashion. Treatment-emergent adverse events were most frequent in the highest dose group. Cenobamate appears to be an effective treatment option in patients with uncontrolled focal seizures. FUNDING: SK Life Science.

Initiation of epoetin-alpha therapy at a starting dose of 120,000 units once every 3 weeks in patients with cancer receiving chemotherapy: an open-label, multicenter study with randomized and nonrandomized treatment arms.

BACKGROUND: Epoetin-alpha initiated once weekly, followed by once-every-3-weeks maintenance, was effective and well tolerated for chemotherapy-induced anemia. This study evaluated a starting dose of epoetin-alpha 120,000 U once every 3 weeks for chemotherapy-induced anemia using early and late initiation regimens. METHODS: Patients with baseline hemoglobin 11.0-12.0 g/dL were randomly assigned to early intervention with immediate epoetin-alpha (n = 68) or to standard intervention with epoetin-alpha when hemoglobin decreased to <11 g/dL (n = 68). A third group of patients with baseline hemoglobin <11 g/dL (n = 50) were enrolled but not randomized; epoetin-alpha was initiated immediately. The primary endpoint was mean proportion of hemoglobin values within the target range (11.0-13.0 g/dL) among randomized patients. RESULTS: The mean proportion of hemoglobin values in range through week 16 was 60% in each randomized group. Mean hemoglobin by week showed similar increases over the study. Blood transfusions were administered in 9%, 8%, and 24% of patients in the early, standard, and nonrandomized groups. Mean epoetin-alpha doses were similar between treatment groups. Dose reductions and withholds were more common in the early intervention group. Adverse events (eg, diarrhea, fatigue, nausea) were consistent with the safety profile for epoetin-alpha . Clinically relevant thrombotic vascular events (regardless of relationship to study treatment) were reported for 9%, 12%, and 12% of patients in the early, standard, and nonrandomized groups. CONCLUSIONS: Early and standard intervention with epoetin-alpha, administered once every 3 weeks, increased and maintained hemoglobin levels within 11.0-13.0 g/dL in patients with chemotherapy-induced anemia.

A randomized study of extended dosing regimens for initiation of epoetin alfa treatment for anemia of chronic kidney disease.

BACKGROUND AND OBJECTIVES: Although epoetin alfa is commonly initiated weekly (QW) in anemic chronic kidney disease (CKD) patients, recent evidence indicates that it can be initiated every 2 wk (Q2W) and used in maintenance therapy every 4 wk (Q4W). This study examined the feasibility of initiating epoetin alfa Q4W in anemic CKD patients not receiving dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This open-label study randomized subjects (1:2:2:2) to treatment with epoetin alfa 10,000 IU QW, 20,000 IU Q2W, 20,000 IU Q4W, or 40,000 IU Q4W for 16 wk. Subjects were > or =18 yr, had hemoglobin <11 g/dl, a glomerular filtration rate of 15 to 90 ml/min per 1.73 m(2), and had not received erythropoietic therapy within 8 wk. The primary analysis was a noninferiority comparison of the 40,000 IU Q4W to the 20,000 IU Q2W group in the per-protocol population with respect to hemoglobin change from baseline to the end of study. RESULTS: Of 262 subjects randomized, 229 comprised the per-protocol population. Mean hemoglobin change from baseline for the 40,000 IU Q4W group (1.24 g/dl) was not inferior to the 20,000 IU Q2W group (1.11 g/dl) with the lower limit of 95% CI, -0.21 g/dl. In the QW, 20,000 IU Q2W, 20,000 IU Q4W, and 40,000 IU Q4W groups, 90%, 87%, 75%, and 86% of subjects, respectively, achieved a hemoglobin increase > or =1 g/dl. Serious adverse events were similar across all groups. CONCLUSIONS: Epoetin alfa can be initiated Q4W in anemic CKD subjects.

Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in adolescent females with anorexia nervosa: a double-blind, placebo-controlled study.

PURPOSE: To evaluate the effect of an oral contraceptive (OC) on bone mineral density (BMD) in adolescent females with anorexia nervosa (AN) or eating disorder not otherwise specified (EDNOS). METHODS: Females 11-17 years of age with AN or EDNOS entered the study. Subjects were randomized equally to treatment with a triphasic OC containing norgestimate (NGM) 180-250 microg and ethinyl estradiol (EE) 35 microg or placebo for 13 28-day cycles. Dual energy x-ray absorptiometry scans (DXA) of the lumbosacral spine (LS) and hip were obtained at baseline and after 6 and 13 cycles. RESULTS: Demographic characteristics of the 112 subjects (NGM/EE 53; Placebo 59) who received study drug and had at least one on-treatment DXA were similar between groups for age (mean: 15 years in each group) and body mass index (mean: NGM/EE 17.9 kg/m2; Placebo 17.6 kg/m2). At the end of Cycle 6, there was a significant increase in the mean LS BMD in the NGM/EE group compared with placebo (.020 g/cm2 vs. .008 g/cm2; p = .021); however, at the end of Cycle 13 the mean increase in LS BMD in the NGM/EE group compared with placebo was no longer significant (.026 g/cm2 vs. .019 g/cm2, p = .244). There was no significant difference in change in hip BMD between groups. The incidence of adverse events was similar between groups. CONCLUSIONS: In a group of adolescent females with AN or EDNOS, treatment with a triphasic OC for 13 cycles did not have a statistically significant effect on LS or hip BMD.

Efficacy and tolerability of topiramate 200 mg/d in the prevention of migraine with/without aura in adults: a randomized, placebo-controlled, double-blind, 12-week pilot study.

BACKGROUND: Several large, randomized, double-blind, placebo-controlled trials have found topiramate (TPM) to be effective and generally well tolerated as a preventive therapy for migraine. OBJECTIVE: This paper evaluates efficacy and safety data from a pilot study of TPM 200 mg/d as preventive therapy in adult subjects with a history of migraine with or without aura. METHODS: The pilot study had a randomized, double-blind, placebo-controlled design. Subjects were randomized in a 2:1 ratio to receive TPM 200 mg/d or placebo. The double-blind treatment phase consisted of an 8-week titration period (25 mg/d for the first week, followed by weekly increases of 25 mg) and a 12-week maintenance period. The primary efficacy measure was the change in mean monthly migraine frequency. Additional measures were the median percent reduction in monthly migraine frequency and the proportion of responders (those with > or =50%, > or =75%, or 100% reduction in monthly migraine frequency). RESULTS: The intent-to-treat (ITT) population included 211 subjects (138 TPM, 73 placebo; mean [SD] mean weight, 76.7 [18.7] kg). Of 45 subjects who discontinued the study in the TPM group, 21 discontinued during the titration period, compared with 3 of 13 subjects who discontinued in the placebo group. When the efficacy data were assessed using the per-protocol, analysis-of-covariance model, TPM 200 mg/d was not associated with a significant reduction in mean monthly migraine frequency compared with placebo. A post hoc analysis using a Poisson regression model in the ITT population suggested that TPM significantly reduced mean monthly migraine frequency compared with placebo (P=0.04). A significantly larger proportion of TPM-treated subjects had a > or =75% reduction in monthly migraine frequency compared with placebo (P=0.03). At least 1 adverse event was reported by 90.0% and 69.9% of the TPM and placebo groups, respectively. Treatment-emergent adverse events (AEs) occurring in > or =10% of subjects in the TPM group were paresthesia (45%), dizziness (16%), fatigue (16%), nausea (14%), and weight loss (14%). Most treatment-emergent AEs were rated mild or moderate in severity. Of 3 serious AEs (depression, abdominal pain, leg pain) occurring during the trial, none were considered related to either TPM or placebo. CONCLUSION: In this pilot study, mean monthly migraine frequency did not differ significantly between TPM and placebo.

Effect of cotherapy reduction on tolerability of epilepsy add-on therapy: a randomized controlled trial.

BACKGROUND: Adverse effects are the most common cause for failure of an antiepileptic drug (AED), especially when an AED is added to existing therapy. With the increased drug load, it may not be possible to titrate the newly added AED to effective doses. Reducing the dosage of AED cotherapy as the new drug is introduced may improve tolerability. OBJECTIVE: To evaluate reduction of AED cotherapy as a strategy to improve tolerability and patient retention when a new AED is added to existing therapy. METHODS: In a 20-week, randomized, open-label study, topiramate was initiated as add-on therapy in adults and adolescents (> or =12 y of age) with inadequately controlled partial-onset seizures. Patients were randomized to receive treatment in which adverse events could be managed by adjustments in AED cotherapy (flex-dose group) or treatment in which AED cotherapy dosages remained fixed (fixed-dose group). Topiramate could be adjusted as needed in both groups. In the flex-dose group, patients exited randomized treatment when topiramate was discontinued. In the fixed-dose group, patients exited when AED cotherapy was reduced due to adverse events or when topiramate was discontinued. The primary study outcome was the percentage of patients exiting randomized treatment due to adverse events. RESULTS: The flex-dose group comprised 297 patients; 302 patients were in the fixed-dose group. Significantly fewer patients in the flex-dose group exited the study due to adverse events (16% vs 23% in the fixed-dose group; p = 0.02). In the flex-dose group, 10% (17 of 168) of patients discontinued topiramate due to adverse events after AED cotherapy was reduced versus 22% (29 of 129) when AED cotherapy was not reduced. CONCLUSIONS: Reduction of AED cotherapy is a useful strategy to improve tolerability and retention when topiramate is initiated as adjunctive therapy.

Tramadol/acetaminophen tablets in the treatment of postsurgical orthopedic pain.

Tramadol/acetaminophen (APAP) combination tablets were shown effective and safe for postsurgical orthopedic pain in a 6-day, multicenter, randomized, double-blind, active- and placebo-controlled study. Of 305 intent-to-treat (ITT) postsurgical patients, 153 patients undergoing arthroscopy who had at least moderate pain were randomized to receive either tramadol 37.5 mg/APAP 325 mg (mean, 4.3 tablets), or codeine 30 mg/APAP 300 mg (mean, 4.6 tablets), or placebo. Tramadol/APAP was superior to placebo for the following outcome variables: total pain relief (TOTPAR, P = .013), sum of pain intensity differences (SPID, P = .049), sum of total pain relief and sum of pain intensity differences (SPRID, P = .018), and average daily pain relief (P = .031). Similar incidence of adverse events for tramadol/APAP and codeine/APAP was found, except for constipation (0% vs 10.9%) and vomiting (8.2% vs 16.4%).

Analgesic efficacy and safety of tramadol/ acetaminophen combination tablets (Ultracet) in treatment of chronic low back pain: a multicenter, outpatient, randomized, double blind, placebo controlled trial.

OBJECTIVE: To evaluate the analgesic efficacy and safety of tramadol 37.5 mg/acetaminophen 325 mg (tramadol/APAP) combination tablets for treatment of chronic low back pain (LBP). METHODS: This 91 day, multicenter, outpatient, randomized, double blind, placebo controlled study enrolled 338 patients with chronic LBP requiring daily medication for > or = 3 months. Patients with at least moderate pain [pain visual analog scale (VAS) with scores > or = 40/100 mm] after washout were randomized to tramadol/APAP or placebo. After a 10 day titration, patients received 1 or 2 tablets QID. Primary outcome measure was final pain VAS score. Secondary measures included pain relief, quality of life and physical functioning, efficacy failure, and overall medication assessments. RESULTS: In total, 336 intent-to-treat patients received tramadol/APAP (n = 167) or placebo (n = 169). Mean baseline pain VAS score was 67.8. Intent-to-treat analysis showed significantly better mean final pain VAS scores (47.4 vs 62.9; p < 0.001) and mean final pain relief scores (1.8 vs 0.7; p < 0.001) for tramadol/APAP than for placebo. Roland Disability Questionnaire scores and physical-related subcategories of the McGill Pain Questionnaire and the Medical Outcome Study Short Form-36 Health Survey were significantly better for tramadol/APAP patients. More patients rated tramadol/APAP as "very good" or "good" than placebo (63.6 vs 25.2%; p < 0.001). Kaplan-Meier estimates of cumulative discontinuation rates due to efficacy failures were 22.9% (tramadol/APAP) vs 54.7% (placebo; p < 0.001). The most common treatment related adverse events with tramadol/APAP were nausea (12.0%), dizziness (10.8%), and constipation (10.2%). Average daily dose of tramadol/APAP was 4.2 tablets (tramadol 158 mg/APAP 1369 mg). CONCLUSION: Tramadol 37.5 mg/APAP 325 mg combination tablets show efficacy in pain reduction, in measures of physical functioning and quality of life, and in overall medication assessments, with a tolerability profile comparable with other opioids used for the treatment of chronic LBP.

Combination tramadol plus acetaminophen for postsurgical pain.

BACKGROUND: This multicenter, randomized, double-blind, active- and placebo-controlled trial evaluated tramadol plus acetaminophen (APAP) for orthopedic (n = 153) and abdominal (n = 152) postsurgical pain. METHODS: Patients with moderate pain or greater were randomized to an initial two tablets of 37.5 mg tramadol plus 325 mg APAP (n = 98), codeine 30 mg plus APAP 300 mg (n = 109), or placebo (n = 98); thereafter, they received 1 to 2 tablets every 4 to 6 hours as needed for pain for 6 days. Outcome measures were pain relief and pain intensity, total pain relief, sum of pain intensity differences, and sum of pain relief and pain intensity differences during 4 hours and the daily averages. RESULTS: Tramadol plus APAP was superior to placebo for total pain relief, sum of pain intensity differences, and sum of pain relief and pain intensity differences (P < or =0.015); tramadol plus APAP and codeine plus APAP did not separate (P > or=0.281). For average daily pain relief, average daily pain intensity, and overall medication assessment, tramadol plus APAP was superior to placebo (P < or =0.038); codeine plus APAP did not separate from placebo (P > or =0.125). Discontinuation because of adverse events occurred in 8.2% of tramadol plus APAP, 10.1% of codeine plus APAP, and 3.0% of placebo patients. Except for constipation (4.1% tramadol plus APAP vs 10.1% codeine plus APAP) and vomiting (9.2% vs 14.7%, respectively), adverse events were similar for active treatments. CONCLUSIONS: Tramadol plus APAP (mean dose 4.4 tablets) was effective and well tolerated for postsurgical pain and showed better tolerability than did codeine plus APAP.