Efficacy and Safety of Subcutaneous Belimumab in Anti-Double-Stranded DNA-Positive, Hypocomplementemic Patients With Systemic Lupus Erythematosus.

OBJECTIVE: To investigate the efficacy and safety of belimumab, a human immunoglobulin monoclonal antibody against B lymphocyte stimulator, in a subset of patients with systemic lupus erythematosus (SLE) who were hypocomplementemic (C3 <90 mg/dl and/or C4 <10 mg/dl) and anti-double-stranded DNA (anti-dsDNA) positive (≥30 IU/ml) at baseline. METHODS: In this phase III, double-blind, placebo-controlled study (BEL112341; ClinicalTrials.gov identifier: NCT01484496), patients with moderate to severe SLE (Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index [SELENA-SLEDAI] score ≥8) were randomized (2:1) to receive weekly subcutaneous (SC) belimumab 200 mg or placebo, plus standard SLE therapy, for 52 weeks. The primary end point was SLE Responder Index 4 (SRI-4) response rate at week 52. Secondary end points were time to severe flare and reduction in corticosteroid dose (weeks 40-52). Safety was assessed throughout. RESULTS: Of the 836 patients in the intent-to-treat (ITT) population, 356 were hypocomplementemic and anti-dsDNA positive at baseline (108 in the placebo group and 248 in the SC belimumab 200 mg group). Compared with placebo, the belimumab group contained more SRI-4 responders (47.2% versus 64.6%; P = 0.0014), had a lower incidence of severe flare according to the SELENA-SLEDAI flare index (31.5% versus 14.1%), and had a greater percentage of patients who reduced corticosteroid dosage by ≥25% to ≤7.5 mg/day during weeks 40-52 (11.4% versus 20.7%; P = 0.0844). Adverse events (AEs) were similar between treatment groups. CONCLUSION: Our findings indicate that in hypocomplementemic, anti-dsDNA-positive SLE patients, weekly SC belimumab 200 mg significantly improves SRI-4 response, decreases severe flare incidence, and reduces corticosteroid use versus placebo; a trend toward greater benefit compared with the overall ITT population was observed. AEs were consistent with the known safety profile of belimumab.

Elevated BLyS levels in patients with systemic lupus erythematosus: Associated factors and responses to belimumab.

INTRODUCTION: Patients with systemic lupus erythematosus (SLE) with B-lymphocyte stimulator (BLyS) levels ≥ 2 ng/mL are at increased risk of flare. A regression analysis was undertaken to identify routine clinical measures that correlate with BLyS ≥ 2 ng/mL. Efficacy and safety of belimumab 10 mg/kg were examined in patients with BLyS ≥ 2 ng/mL and < 2 ng/mL. METHODS: Data from BLISS-52 and -76 (N = 1684) were pooled post hoc. A univariate logistic regression was employed to identify factors predictive of baseline BLyS ≥ 2 ng/mL. Factors significant at the 0.05 level then entered a stepwise logistic regression as covariates. Efficacy endpoints included SLE responder index (SRI), ≥ 4-point reduction in Safety of Estrogens in Lupus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) and risk of severe flare over 52 weeks. Adverse events (AEs) were analyzed for each treatment arm and BLyS subgroup. RESULTS: Baseline predictors of BLyS ≥ 2 ng/mL included positive anti-Smith (≥ 15 U/mL), low complement (C) 3 (< 900 mg/L), anti-double-stranded DNA (anti-dsDNA) 80-200 and ≥ 200 IU/mL, immunosuppressant usage, proteinuria, elevated C-reactive protein (CRP), and low total lymphocyte count for all patients. Belimumab 10 mg/kg led to significantly greater SRI responses over 52 weeks versus placebo in both BLyS subgroups, though treatment differences were numerically greater at Week 52 in the BLyS ≥ 2 ng/mL group (24.1%, p < 0.0001) compared with BLyS < 2 ng/mL (8.2%, p = 0.0158). Results were similar for ≥ 4-point reduction in SELENA-SLEDAI. Risk of severe flare over 52 weeks was significantly reduced with belimumab 10 mg/kg versus placebo in the BLyS ≥ 2 ng/mL group (p = 0.0002). AEs were similar across treatment arms and BLyS subgroups. CONCLUSIONS: Positive anti-Smith, low C3, anti-dsDNA ≥ 80 IU/mL, immunosuppressant usage, proteinuria, elevated CRP, and low total lymphocyte count were predictors of BLyS ≥ 2 ng/mL. Monitoring these factors could identify patients with BLyS ≥ 2 ng/mL who are at risk of flare.

Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures.

OBJECTIVE: To evaluate the efficacy and tolerability of adjunctive lamotrigine in primary generalized tonic-clonic (PGTC) seizures in a randomized, double-blind, placebo-controlled trial. METHODS: Patients with a diagnosis of epilepsy with PGTC seizures who were receiving one or two antiepileptic drugs at study entry were eligible. Patients with partial seizures were excluded on the basis of seizure history and screening EEGs. The study comprised a baseline phase, an escalation phase during which study medication was titrated to a target dose, and a 12-week maintenance phase during which doses of lamotrigine/placebo and concomitant antiepileptic drugs were maintained. RESULTS: Of the 121 randomized patients ages 2 to 55 years, 117 (58 lamotrigine, 59 placebo) entered the escalation phase and received study medication. During the escalation and maintenance phases combined, median percent reduction in PGTC seizure frequency was 66.5% with lamotrigine compared with 34.2% with placebo (p = 0.006). The corresponding numbers for lamotrigine and placebo were 60.6% and 32.8% (p = 0.038) during the escalation phase and 81.9% and 43.0% (p = 0.006) during the maintenance phase. During the maintenance phase, 72% of lamotrigine-treated patients compared with 49% of placebo-treated patients experienced a > or = 50% reduction in frequency of PGTC seizures (p = 0.014). A similar pattern of results was observed for all generalized seizures. The most common drug-related adverse events were dizziness (5% lamotrigine, 2% placebo), somnolence (5% lamotrigine, 2% placebo), and nausea (5% lamotrigine, 3% placebo). CONCLUSIONS: Adjunctive lamotrigine is effective in the treatment of primary generalized tonic-clonic seizures and has a favorable tolerability profile.

Lamotrigine as adjunctive therapy in patients with refractory epilepsy and mental retardation.

This study evaluated the effects of lamotrigine as adjunctive therapy for refractory epilepsy in patients with mental retardation. Patients with epilepsy and mental retardation having uncontrolled seizures despite treatment with other antiepileptic drugs were eligible (n=67). The open-label study comprised a Baseline Phase, an Escalation Phase during which lamotrigine was titrated to a target dose, an 8-week Maintenance Phase during which doses of lamotrigine and concomitant antiepileptic drugs were maintained, and a 12-week Optimization Phase during which doses of lamotrigine and other antiepileptic drugs could be adjusted. Almost half (44%) of patients experienced a 50% reduction in seizure frequency during the Maintenance Phase after addition of lamotrigine; 15% of patients became seizure-free. A similar pattern of results was reported for the Optimization Phase. Investigator-rated clinical status was improved relative to baseline in 66 and 74% of patients at the end of the Maintenance and Optimization Phases, respectively. Most patients experienced improvements in seizure frequency, duration, and intensity during the Maintenance Phase (62 to 72%) and the Optimization Phase (65 to 74%). Many patients were rated as having improved social functioning during the Maintenance Phase (42%) and the Optimization Phase (46%). The Aberrant Behavior Checklist score for lethargy and the mean Habilitative Improvement Scale score were improved at the ends of the Maintenance and Optimization Phases relative to baseline (P< or =0.04). One limitation of this study is its open-label design, which limits the ability definitively to attribute the clinical improvements to lamotrigine. Adjunctive lamotrigine in patients with refractory epilepsy and mental retardation appears to decrease seizure frequency and improve behavior while permitting a reduction in dose of concomitant antiepileptic drugs.

Lamotrigine for HIV-associated painful sensory neuropathies: a placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and tolerability of lamotrigine (LTG) for the treatment of pain in HIV-associated sensory neuropathies. METHODS: In a randomized, double-blind study, patients with HIV-associated distal sensory polyneuropathy (DSP) received LTG or placebo during a 7-week dose escalation phase followed by a 4-week maintenance phase. Randomization was stratified according to whether or not patients were currently using neurotoxic antiretroviral therapy (ART). RESULTS: The number of patients randomized was 92 (62 LTG, 30 placebo) in the stratum receiving neurotoxic ART and 135 (88 LTG, 47 placebo) in the stratum not receiving neurotoxic ART. Mean change from baseline in Gracely Pain Scale score for average pain was not different between LTG and placebo at the end of the maintenance phase in either stratum, but the slope of the change in Gracely Pain Scale score for average pain reflected greater improvement with LTG than with placebo in the stratum receiving neurotoxic ART (p = 0.004), as did the mean change from baseline scores on the Visual Analogue Scale for Pain Intensity and the McGill Pain Assessment Scale and patient and clinician ratings of global impression of change in pain (p

The tolerability of lamotrigine in elderly patients with epilepsy.

OBJECTIVE: To determine the tolerability of lamotrigine in elderly patients with epilepsy. DESIGN: Pooled data from 13 lamotrigine clinical trials. SETTING: Multicentre clinical trials conducted in primary care and neurology practices. PARTICIPANTS: 208 elderly patients (aged > or = 65 years) were identified: 146 lamotrigine-treated patients, 53 carbamazepine-treated patients and 9 phenytoin-treated patients. INTERVENTIONS: Extent of exposure, incidence of drug-related adverse events, serious adverse events and study withdrawals were examined. RESULTS: The median duration of exposure for lamotrigine monotherapy and add-on therapy was 24.1 and 47.4 weeks, respectively. The median daily dosage of lamotrigine was 100 mg for monotherapy (range 75 to 500 mg) and 300 mg for add-on therapy (range 25 to 700 mg). Overall, the incidence of drug-related adverse events was lower for lamotrigine than comparator drugs: 49% (72/146) for lamotrigine compared with 72% (38/53) for carbamazepine (p = 0.006), and 89% (8/9) for phenytoin (p = 0.035) although patient numbers in each treatment group were not comparable. Patients receiving lamotrigine reported incidences of somnolence (p = 0.012), rash (p = 0.034), and headache (nonsignificant) that were one-half the incidence reported with carbamazepine monotherapy. Rash was the most common reason for study withdrawal: 4% (6/146) lamotrigine, 17% (9/53) carbamazepine and 0% phenytoin. Seven (5%, 7/146) lamotrigine-treated patients, 4 (8%, 4/53) carbamazepine-treated patients and 1 (11%, 1/9) phenytoin-treated patient experienced drug-related serious adverse events. CONCLUSION: Lamotrigine, used in the currently prescribed adult dosage regimen, was well tolerated in elderly patients with epilepsy.

Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy.

OBJECTIVE: To compare the incidence and magnitude of change in body weight associated with lamotrigine or divalproex sodium monotherapy in patients with epilepsy. METHODS: A randomized, double-blind study with 8-week escalation phase and 24-week maintenance phase was conducted. Target maintenance dosage was 200 mg/day (lamotrigine) and 20 mg/kg/day (valproic acid), with adjustment from 100 to 500 mg/day (lamotrigine) and 10 to 60 mg/kg/day (valproate) based on investigators' judgment. Eligible patients were > or = 12 years old with new-onset or previously diagnosed partial or generalized seizures. Weight change was primary and seizure frequency and tolerance were secondary outcome measures. RESULTS: For the lamotrigine group, 65 patients (mean age 34.5 years) were investigated; for the valproate group, 68 patients (mean age 30.1 years) were investigated. Weight remained stable in lamotrigine-treated patients. Significant weight gain occurred in valproate-treated patients by the 10th week of treatment; weight continued to increase throughout the study. After 32 weeks of treatment, mean weight gain was significantly higher in valproate-treated (12.8 +/- 9.3 lb) than lamotrigine-treated (1.3 +/- 11.9 lb) patients. Similar proportions of patients in lamotrigine (29%) and valproate (26%) groups were seizure-free. Overall frequency of adverse events was similar between the two treatment groups. Mean time to withdrawal from the study due to adverse events was 103 +/- 70 days for the lamotrigine group and 79 +/- 48 days for the valproate group. CONCLUSION: Valproate monotherapy was associated with significantly greater weight gain than lamotrigine monotherapy. Weight gain associated with valproate was significant within 10 weeks after initiating therapy and continued throughout the study. Efficacy of lamotrigine was comparable with that of valproate; lamotrigine tended to be better tolerated.