Inclisiran and cardiovascular events: a patient-level analysis of phase III trials.

BACKGROUND: Inclisiran, an siRNA administered twice-yearly, significantly reduced LDL cholesterol (LDL-C) in Phase III trials. Whether lowering LDL-C with inclisiran translates into a lower risk of cardiovascular (CV) events is not yet established. METHODS AND RESULTS: Patient-level, pooled analysis of ORION-9, -10 and -11, included patients with heterozygous familial hypercholesterolaemia, atherosclerotic CV disease (ASCVD), or ASCVD risk equivalent on maximally tolerated statin-therapy, randomized 1:1 to receive 284 mg inclisiran or placebo on Days 1, 90, and 6-monthly thereafter for 18 months. Prespecified exploratory endpoint of major cardiovascular events (MACEs) included non-adjudicated CV death, cardiac arrest, non-fatal myocardial infarction (MI), and fatal and non-fatal stroke, evaluated as part of safety assessments using a standard Medical Dictionary for Regulatory Activities basket. Although not prespecified, total fatal and non-fatal MI, and stroke were also evaluated. Mean LDL-C at baseline was 2.88 mmol/L. At Day 90, the placebo-corrected percentage reduction in LDL-C with inclisiran was 50.6%, corresponding to an absolute reduction of 1.37 mmol/L (both P < 0.0001). Among 3655 patients over 18 months, 303 (8.3%) experienced MACE, including 74 (2.0%) fatal and non-fatal MIs, and 28 (0.8%) fatal and non-fatal strokes. Inclisiran significantly reduced composite MACE [OR (95% CI): 0.74 (0.58-0.94)], but not fatal and non-fatal MIs [OR (95% CI): 0.80 (0.50-1.27)] or fatal and non-fatal stroke [OR (95% CI): 0.86 (0.41-1.81)]. CONCLUSION: This analysis offers early insights into the potential CV benefits of lowering LDL-C with inclisiran and suggests potential benefits for MACE reduction. These findings await confirmation in the larger CV outcomes trials of longer duration.

Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia is characterized by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. Monoclonal antibodies directed against proprotein convertase subtilisin-kexin type 9 (PCSK9) have been shown to reduce LDL cholesterol levels by more than 50% but require administration every 2 to 4 weeks. In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia. METHODS: In this phase 3, double-blind trial, we randomly assigned, in a 1:1 ratio, 482 adults who had heterozygous familial hypercholesterolemia to receive subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450. The two primary end points were the percent change from baseline in the LDL cholesterol level on day 510 and the time-adjusted percent change from baseline in the LDL cholesterol level between day 90 and day 540. RESULTS: The median age of the patients was 56 years, and 47% were men; the mean baseline level of LDL cholesterol was 153 mg per deciliter. At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% confidence interval [CI], -43.7 to -35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of -47.9 percentage points (95% CI, -53.5 to -42.3; P<0.001). The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% (95% CI, -41.1 to -35.1) in the inclisiran group and an increase of 6.2% (95% CI, 3.3 to 9.2) in the placebo group, for a between-group difference of -44.3 percentage points (95% CI, -48.5 to -40.1; P<0.001). There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia. Adverse events and serious adverse events were similar in the two groups. CONCLUSIONS: Among adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile. (Funded by the Medicines Company; ORION-9 ClinicalTrials.gov number, NCT03397121.).

Effect of inclisiran on lipids in primary prevention: the ORION-11 trial.

AIMS: Patients often require combination therapies to achieve LDL cholesterol (LDL-C) targets for the primary prevention of atherosclerotic cardiovascular disease. This study investigates the effect of inclisiran, a small interfering ribonucleic acid targeting hepatic proprotein convertase subtilisin/kexin type 9 production, in primary prevention patients with elevated LDL-C despite statins. METHODS AND RESULTS: This pre-specified analysis of the placebo-controlled, randomized ORION-11 trial included 203 individuals at risk of, but without prior, cardiovascular events and LDL-C ≥2.6 mmol/L, despite maximally tolerated statins. Inclisiran 284 mg or placebo was administered on Days 1, 90, and thereafter every 6 months up to 540 days. Co-primary endpoints were percentage LDL-C change from baseline to Day 510 and time-adjusted change from baseline after Day 90 and up to Day 540. Key secondary endpoints included percentage and absolute changes in atherogenic lipoproteins. Safety was assessed over 540 days. The mean baseline (SD) LDL-C was 3.6 (1.5) mmol/L. At Day 510, the placebo-corrected LDL-C change with inclisiran was -43.7% [95% confidence interval (CI): -52.8 to -34.6] with a corresponding time-adjusted change of -41.0% (95% CI: -47.8 to -34.2); (P < 0.0001). The placebo-corrected absolute change in LDL-C at Day 510 with inclisiran was -1.5 mmol/L (95% CI: -1.8 to -1.2), with a respective time-adjusted change of -1.3 mmol/L (95% CI: -1.6 to -1.1). Inclisiran significantly lowered non-HDL cholesterol and apolipoprotein B (apoB) at Day 510 vs. placebo (P < 0.0001 for both), with a greater likelihood of attaining lipoprotein and apoB goals, and was well-tolerated except for mainly mild, treatment-emergent adverse events at the injection site. CONCLUSION: Inclisiran was generally well-tolerated in primary prevention patients with elevated LDL-C, who derived significant reductions in atherogenic lipoprotein levels with twice-yearly maintenance dosing.

NGM282 Improves Liver Fibrosis and Histology in 12 Weeks in Patients With Nonalcoholic Steatohepatitis.

NGM282, an engineered fibroblast growth factor 19 analogue, rapidly and significantly reduced liver fat content in a multicenter, randomized, double-blind, placebo-controlled study in patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH). However, it is unclear whether these changes would be accompanied by histological improvement. In this open-label study, we assessed the histological efficacy of NGM282 in patients with biopsy-confirmed nonalcoholic steatohepatitis. Paired liver biopsies from 43 patients who received subcutaneous NGM282 (1 mg, n = 24; 3 mg, n = 19) once daily for 12 weeks were evaluated blinded to time point, subject, and clinical information. At week 12, NGM282 significantly reduced nonalcoholic fatty liver disease activity score (NAS; -1.9; 95% confidence interval, -2.6 to -1.2; P < 0.001 in the 1 mg group; -2.2, -3.1 to -1.3; P < 0.001 in the 3 mg group) and fibrosis (-0.5; -0.9 to 0; P = 0.035 in the 3 mg group) scores. Overall, 50% and 63% of the patients receiving NGM282 1 mg or 3 mg, respectively, improved NAS by 2 or more points without fibrosis worsening. Of the patients receiving NGM282 1 mg or 3 mg, 25% and 42%, respectively, improved liver fibrosis by one stage or more without worsening of steatohepatitis. Treatment with NGM282 led to relative reductions in liver fat content (-58% and -67% in the 1 mg and 3 mg groups, respectively), corrected T1 (cT1; -8% and -9%), alanine aminotransferase (ALT) (-67% and -60%), aspartate aminotransferase (-57% and -52%), and fibrogenesis biomarkers neoepitope-specific N-terminal propeptide of type III collagen (Pro-C3; -22% and -33%) and enhanced liver fibrosis score (ELF; -3% and -6%) at week 12. Greater reductions in Pro-C3, ELF, and cT1, but not in liver fat content, 7alpha-hydroxy-4-cholesten-3-one, or ALT, were observed in histological responders than in nonresponders. Conclusion: In this open-label study, NGM282 improved the histological features of NASH in 12 weeks with significant reductions in NAS and fibrosis scores, accompanied by improvements in noninvasive imaging and serum markers.

Rosuvastatin improves the FGF19 analogue NGM282-associated lipid changes in patients with non-alcoholic steatohepatitis.

BACKGROUND: NGM282, an engineered analogue of the gut hormone FGF19, improves hepatic steatosis and fibrosis biomarkers in patients with non-alcoholic steatohepatitis (NASH). However, NGM282 increases serum cholesterol levels by inhibiting CYP7A1, which encodes the rate-limiting enzyme in the conversion of cholesterol to bile acids. Herein, we investigate whether administration of a statin can manage the cholesterol increase seen in patients with NASH receiving treatment with NGM282. METHODS: In this phase II, open-label, multicenter study, patients with biopsy-confirmed NASH were treated with subcutaneous NGM282 once daily for 12 weeks. After 2 weeks, rosuvastatin was added in stepwise, biweekly incremental doses to a maximum of 40 mg daily. Both drugs were continued until the end of treatment at week 12. We evaluated plasma lipids, lipoprotein particles and liver fat content. RESULTS: In 66 patients who received NGM282 0.3 mg (n = 23), NGM282 1 mg (n = 21), or NGM282 3 mg (n = 22), circulating cholesterol increased from baseline at week 2. Initiation of rosuvastatin resulted in rapid decline in plasma levels of total cholesterol and low-density lipoprotein cholesterol. At week 12, reductions from baseline in total cholesterol levels of up to 18% (p <0.001), low-density lipoprotein cholesterol of up to 28% (p <0.001), triglycerides of up to 34% (p <0.001) and an increase in high-density lipoprotein cholesterol of up to 16% (p <0.001), with similar changes in lipoprotein particles, were observed in these patients. Robust decreases from baseline in 7alpha-hydroxy-4-cholesten-3-one (p <0.001) and liver fat content (p <0.001) were also observed. Rosuvastatin was safe and well-tolerated when co-administered with NGM282 in patients with NASH. CONCLUSIONS: In this multicenter study, NGM282-associated elevation of cholesterol was effectively managed with rosuvastatin. Co-administration of rosuvastatin with NGM282 may be a reasonable strategy to optimize the cardiovascular risk profile in patients with NASH. LAY SUMMARY: Non-alcoholic steatohepatitis (NASH) represents a large and growing public health concern with no approved therapy. NGM282, an engineered analogue of the gut hormone FGF19, reduces liver fat, liver injury and inflammation in patients with NASH. However, NGM282 increases cholesterol levels. Here we show that co-administration of a statin can manage the cholesterol increase seen in patients with NASH receiving treatment with NGM282, producing a favorable overall lipid profile.

Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: A multicenter, randomized, double-blind, placebo-controlled phase II trial.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an inflammatory, cholestatic and progressively fibrotic liver disease devoid of effective medical intervention. NGM282, an engineered, non-tumorigenic FGF19 analogue, potently regulates CYP7A1-mediated bile acid homeostasis. We assessed the activity and safety of NGM282 in patients with PSC. METHODS: In this double-blind, placebo-controlled phase II trial, 62 patients who had PSC confirmed by cholangiography or biopsy and an elevated alkaline phosphatase (ALP) >1.5 × the upper limit of normal were randomly assigned 1:1:1 to receive NGM282 1 mg, 3 mg or placebo once daily for 12 weeks. The primary outcome was the change in ALP from baseline to week 12. Secondary and exploratory outcomes included changes in serum biomarkers of bile acid metabolism and fibrosis. Efficacy analysis was by intention-to-treat. RESULTS: At 12 weeks, there were no significant differences in the mean change from baseline in ALP between the NGM282 and placebo groups, and therefore, the primary endpoint was not met. However, NGM282 significantly reduced levels of 7alpha-hydroxy-4-cholesten-3-one (a marker of hepatic CYP7A1 activity, LS mean differences -6.2 ng/ml (95% CI -10.7 to -1.7; p = 0.008) and -9.4 ng/ml (-14.0 to -4.9; p <0.001) in the NGM282 1 mg and 3 mg groups, respectively, compared with placebo) and bile acids. Importantly, fibrosis biomarkers that predict transplant-free survival, including Enhanced Liver Fibrosis score and Pro-C3, were significantly improved following NGM282 treatment. Most adverse events were mild to moderate in severity, with gastrointestinal symptoms more frequent in the NGM282 treatment groups. CONCLUSIONS: In patients with PSC, NGM282 potently inhibited bile acid synthesis and decreased fibrosis markers, without significantly affecting ALP levels. LAY SUMMARY: We present for the first time, the clinical and laboratory effects of a first-in-class, engineered analogue of the endocrine hormone FGF19 in patients with primary sclerosing cholangitis (PSC). By incorporating non-invasive markers of fibrosis, beyond standard liver injury markers, we show that NGM282 impacted on fibrosis turnover and hepatic inflammation without changing alkaline phosphatase. Our findings demonstrate the complexities of using highly potent rational agents in PSC, and furthermore challenge the dogma about what the appropriate endpoints should be for trials in PSC.

NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Non-alcoholic steatohepatitis is a chronic liver disease characterised by the presence of hepatic steatosis, inflammation, and hepatocellular injury, for which no Food and Drug Administration (FDA)-approved treatment exists. FGF19 is a hormone that regulates bile acid synthesis and glucose homoeostasis. We aimed to assess the safety and efficacy of NGM282, an engineered FGF19 analogue, for the treatment of non-alcoholic steatohepatitis. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 study, we recruited patients aged 18-75 years with biopsy-confirmed non-alcoholic steatohepatitis as defined by the non-alcoholic steatohepatitis clinical research network histological scoring system, from hospitals and gastroenterology and liver clinics in Australia and the USA. Key eligibility criteria included a non-alcoholic fatty liver disease activity score of 4 or higher, stage 1-3 fibrosis, and at least 8% liver fat content. Patients were randomly assigned (1:1:1) via a web-based system and stratified by diabetic status to receive either 3 mg or 6 mg subcutaneous NGM282 or placebo. The primary endpoint was the absolute change from baseline to week 12 in liver fat content. Responders were patients who achieved a 5% or larger reduction in absolute liver fat content as measured by MRI-proton density fat fraction. Efficacy analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02443116. FINDINGS: Between July 14, 2015, and Aug 30, 2016, 166 patients were screened across 18 sites in Australia and the USA. 82 patients were randomly assigned to receive 3 mg NGM282 (n=27), 6 mg NGM282 (n=28), or placebo (n=27). At 12 weeks, 20 (74%) patients in the 3 mg dose group and 22 (79%) in the 6 mg dose group achieved at least a 5% reduction in absolute liver fat content from baseline (relative risk 10·0 [95% CI 2·6-38·7] vs 11·4 [3·0-43·8], respectively; p<0·0001 for both comparisons) versus two (7%) in the placebo group. Overall, 76 (93%) of 82 patients experienced at least one adverse event, most of which were grade 1 (55 [67%]), and only five (6%) were grade 3 or worse. The most commonly (≥10%) reported adverse events were injection site reactions (28 [34%]), diarrhoea (27 [33%]), abdominal pain (15 [18%]), and nausea (14 [17%]). These adverse events were reported more frequently in the NGM282 groups compared with the placebo group. No life-threatening events or patient deaths occurred during the study. INTERPRETATION: NGM282 produced rapid and significant reductions in liver fat content with an acceptable safety profile in patients with non-alcoholic steatohepatitis. Further study of NGM282 is warranted in this patient population. FUNDING: NGM Biopharmaceuticals.

Impact of Data Imputation Methodology on Pain Assessment over 24 Hours in a Randomized, Placebo-Controlled Study of Gabapentin Enacarbil in Patients with Neuropathic Pain Associated with Postherpetic Neuralgia.

OBJECTIVE: To assess the impact of gabapentin enacarbil on primary and secondary pain endpoints using three data imputation methodologies in a randomized phase II study of adult patients with postherpetic neuralgia. METHODS: The primary endpoint was change from baseline to end of maintenance treatment in mean 24-hour average pain intensity score. Secondary endpoints (daytime/nighttime average pain intensity score, daytime/nighttime current pain intensity score, and daytime/nighttime worst pain intensity score) were based on daily electronic diary assessments. Comparisons of each gabapentin enacarbil dose with placebo were performed using three different statistical methodologies: last observation carried forward, baseline observation carried forward, and mixed-effect model for repeated measures. RESULTS: Of the 376 randomized patients, 371 were in the intent-to-treat population (gabapentin enacarbil 1,200 mg, 107; 2,400 mg, 82; 3,600 mg, 87; placebo, 95). For mean 24-hour average pain intensity score, there were statistically significant improvements from baseline to end of maintenance treatment for all gabapentin enacarbil groups vs placebo using the three analysis methods. Significant improvements were also observed for all secondary endpoints with gabapentin enacarbil 1,200 mg using the three analysis methods. Most secondary endpoints also showed improvements following treatment with gabapentin enacarbil 2,400 mg or 3,600 mg compared with placebo. CONCLUSIONS: Gabapentin enacarbil (1,200 mg, 2,400 mg, and 3,600 mg) was effective and well tolerated in patients with postherpetic neuralgia compared with placebo, as confirmed by three different and robust statistical methodologies.

Safety of Once-Daily Oxymetazoline HCl Ophthalmic Solution, 0.1% in Patients with Acquired Blepharoptosis: Results from Four Randomized, Double-Masked Clinical Trials.

PURPOSE: An oxymetazoline 0.1% ophthalmic solution was recently approved for treatment of acquired blepharoptosis in adults. This study's objective was to evaluate the safety profile of oxymetazoline 0.1% when administered once daily for 14-84 days. PATIENTS AND METHODS: Pooled analysis examined safety outcomes from four randomized, double-masked, placebo-controlled clinical trials conducted at 6, 16, 27, and 35 sites, respectively, in the United States. In total, 568 participants with acquired blepharoptosis were evaluated. Median age was 66 years and 74.8% of participants were female. Overall, 375 participants self-administered oxymetazoline 0.1% to both eyes once/day and 193 self-administered placebo (vehicle) daily. Treatment-emergent adverse event (TEAE) rates, severity, and causality were evaluated in the overall population and within participant subgroups defined based on age, race, and ethnicity. Vital signs and ophthalmic findings were evaluated at predefined study visits. Patient-reported treatment tolerability was recorded at study end. RESULTS: TEAE incidence was similar among participants using oxymetazoline 0.1% (31.2%) or vehicle (30.6%). Nearly all TEAEs were mild-to-moderate, and most were not suspected of being treatment related. Serious TEAEs occurred in four participants receiving oxymetazoline 0.1% and one participant receiving vehicle. Nine and two participants in the oxymetazoline 0.1% and vehicle groups, respectively, discontinued due to a TEAE. Ocular TEAEs occurring in ≥2% of participants receiving oxymetazoline 0.1% were punctate keratitis, conjunctival hyperemia, dry eye, blurred vision, instillation site pain, and corneal vital dye staining, with none occurring in >3.5% of participants. TEAE rates were similar across subgroups based on age, race, and ethnicity. No clinically significant mean changes in vital signs or ophthalmologic findings occurred, and >98% of participants rated oxymetazoline 0.1% as causing no/mild discomfort. CONCLUSION: Once-daily oxymetazoline 0.1% was safe and well tolerated in participants with acquired blepharoptosis when used for 14-84 days. Safety did not appear to differ based on age, race, or ethnicity.

Predictors of clinical response in a double-blind placebo controlled crossover trial of gabapentin enacarbil for restless legs syndrome.

OBJECTIVES: Restless Legs Syndrome (RLS) is a sensory-motor disorder which produces sleep disturbance. Using data from a large clinical trial of gabapentin enacarbil (GEn) we sought to assess the ability of baseline, and changes from baseline, in clinical trial endpoints to predict treatment response. METHODS: Data were derived from a randomized, double-blind, placebo-controlled, crossover polysomnography study of gabapentin enacarbil 1200 mg (n = 121) or placebo (n = 123). Efficacy evaluations included: sleep measures from polysomnography, subjective sleep measures, Suggested Immobilization Test (SIT) measures, and International Restless Legs Severity Scale (IRLS) and Clinical Global Impression-Improvement (CGI-I). Correlations were evaluated using Spearman's rank correlation coefficients. Predictors of treatment response were separately assessed for GEn and placebo using categorical IRLS and CGI-I outcomes. Stepwise logistic regression models ascertained which combination of baseline and change from baseline variables predicted response. RESULTS: Moderate to large correlations were observed between changes in the IRLS and changes in subjective sleep for both GEn and placebo, substantially larger for GEn than placebo. Small to moderate correlations were present between the change in IRLS and the change in SIT-discomfort for both GEn and placebo. In the stepwise regression, for both GEn and placebo, baseline and change from baseline SIT discomfort, as well as change in sleep quality, were strong predictors of response. CONCLUSIONS: Changes in sleep quality, and baseline and changes in SIT discomfort were prominent predictors of treatment response for GEn and placebo. Predictors of treatment response may allow for more targeted enrollment in future clinical trials and may provide insights into the efficacy of RLS treatments.

The Effect of Gabapentin Enacarbil on Quality of Life and Mood Outcomes in a Pooled Population of Adult Patients with Moderate-to-Severe Primary Restless Legs Syndrome.

OBJECTIVE: The aim was to assess gabapentin enacarbil (GEn) treatment effects on quality of life (QOL) and mood in adults with moderate-to-severe primary restless legs syndrome (RLS). METHODS: Data were pooled from three placebo-controlled, randomized, double-blind, 12-week trials for adults receiving GEn (600 mg or 1200 mg) or placebo once daily. QOL was assessed with the RLS QOL questionnaire in two studies. Mood was examined with the Profile of Mood States Brief Form (POMS-B), and as an exploratory analysis with International Restless Legs Scale (IRLS) item 9 (daily affairs) and item 10 (mood disturbance) across all three studies. Mood and QOL were secondary endpoints in the individual clinical trials. No adjustments for multiplicity were applied. RESULTS: The QOL analysis modified intent-to-treat (MITT) population included 541 adults (placebo, n = 204; GEn 600 mg, n = 114; GEn 1200 mg, n = 223). Both GEn doses significantly improved QOL versus placebo (week 12; p < 0.01). The mood analysis MITT population included 671 adults (placebo, n = 244; GEn 600 mg, n = 161; GEn 1200 mg, n = 266). GEn 600 mg significantly improved POMS vigor-activity versus placebo (week 12; p < 0.05); other POMS criteria were not significantly affected. GEn 1200 mg significantly improved POMS scores for total mood disturbance, depression-dejection, fatigue-inertia, vigor-activity, and confusion-bewilderment versus placebo at week 12 (p < 0.05); tension-anxiety and anger-hostility were not significantly affected. Both GEn doses significantly improved IRLS item 9 and item 10 versus placebo at week 12 (p < 0.05). The most frequent treatment-emergent adverse events with GEn were somnolence and dizziness. CONCLUSIONS: GEn (600 mg and 1200 mg) once daily significantly improved QOL in adults with moderate-to-severe primary RLS at all time points examined. While the only POMS item significantly improved by GEn 600 mg versus placebo at week 12 was vigor-activity, GEn 1200 mg significantly improved total mood disturbance and several other POMS items versus placebo at week 12. Both QOL and mood improvements were numerically greater with GEn 1200 mg versus 600 mg. TRIAL REGISTRATIONS: Clinicaltrials.gov identifiers NCT00298623, NCT00365352, NCT01332305.

The Effect of Gabapentin Enacarbil on Pain Associated with Moderate-to-Severe Primary Restless Legs Syndrome in Adults: Pooled Analyses from Three Randomized Controlled Trials.

BACKGROUND: Adults with moderate-to-severe primary restless legs syndrome (RLS) often experience painful dysesthesias, which may lead to impaired quality of life. OBJECTIVES: The aim of this study was to assess the effects of gabapentin enacarbil (GEn) on pain associated with moderate-to-severe primary RLS in adults. METHODS: Data were pooled from three double-blind, randomized, placebo-controlled, 12-week trials (NCT00298623, NCT00365352, NCT01332305) for adults receiving GEn or placebo once daily. Change in average daily RLS pain score and a combined International Restless Legs Scale (IRLS)-pain response were examined. RESULTS: The modified intention-to-treat population included 671 adults (placebo, n = 244; GEn 600 mg, n = 161; GEn 1200 mg, n = 266). Both GEn doses significantly improved average daily RLS pain score at week 12 (p < 0.001 for GEn 600 mg vs. placebo and GEn 1200 mg vs. placebo). The combined IRLS-pain response subanalysis included 366 patients with a baseline IRLS total score ≥15 and pain score ≥4 (placebo, n = 133; GEn 600 mg, n = 86; GEn 1200 mg, n = 147). Most patients were both IRLS and pain responders (placebo, 40 %; GEn 600 mg, 70 %; GEn 1200 mg, 67 %). Spearman rank correlations between IRLS total and pain score (change from baseline to week 12) were moderate or strong. The most frequent treatment-emergent adverse events were somnolence (placebo, 5 %; GEn 600 mg, 20 %; GEn 1200 mg, 23 %) and dizziness (placebo, 4 %; GEn 600 mg, 13 %; GEn 1200 mg, 22 %). CONCLUSIONS: This post hoc pooled analysis suggests that GEn (600 and 1200 mg) once daily significantly improved pain associated with moderate-to-severe primary RLS in adults; however, the analysis was not powered to detect statistical differences between the two GEn doses. Numerically, more GEn-treated patients had a combined IRLS-pain response than placebo-treated patients.

Effect of Gabapentin Enacarbil on Individual Items of the International Restless Legs Study Group Rating Scale and Post-sleep Questionnaire in Adults with Moderate-to-Severe Primary Restless Legs Syndrome: Pooled Analysis of 3 Randomized Trials.

PURPOSE: Few studies have investigated restless legs syndrome (RLS) treatment effects on individual International RLS Study Group Rating Scale (IRLS) items. We assessed the effects of gabapentin enacarbil (GEn) on individual IRLS items and their correlation with sleep disturbances in adults with moderate-to-severe primary RLS. METHODS: Data were pooled from the randomized, double-blind, placebo-controlled, 12-week studies of XP052, XP053, and XP081 for adults who received GEn (600 or 1200 mg) or placebo once daily. Adults had primary RLS, IRLS total score ≥15, and RLS symptoms >15 days during the month before screening and for ≥4 of the 7 consecutive evenings at baseline. End points included mean change from baseline to week 12 in individual IRLS and post-sleep questionnaire (PSQ) items. For IRLS items, least squares mean treatment differences were calculated from a mixed model for repeated measures. For PSQ items, Cochran-Mantel-Haenszel row mean scores tests with integer scoring were used. Correlations between IRLS and PSQ items were assessed by Spearman's rank coefficients. Safety profile outcomes included treatment-emergent adverse events (TEAEs) and serious TEAEs. FINDINGS: The modified intent-to-treat population included 671 patients (GEn 600 mg = 161; GEn 1200 mg = 266; placebo = 244). GEn significantly improved mean [SE] differences versus placebo for all IRLS items at week 12, including severity of sleep disturbance (GEn 600 mg, -0.4 [0.10]; GEn 1200 mg, -0.4 [0.09]), daytime tiredness (-0.4 [0.09]; -0.4 [0.08]), RLS severity (-0.4 [0.10]; -0.3 [0.08]), impact on daily affairs (-0.3 [0.07]; -0.3 [0.07]), and mood disturbance (-0.2 [0.07]; -0.3 [0.06]); all P<0.001). For PSQ items, significant (P<0.01) improvements occurred with both GEn doses versus placebo at week 12. The correlations between IRLS and PSQ items for change from baseline to week 12 were moderate to strong, and all correlations were significant (P<0.001). The most frequent TEAEs were somnolence (GEn 600 mg, 20%; GEn 1200 mg, 23%; placebo, 5%) and dizziness (GEn 600 mg, 14%; GEn 1200 mg, 22%; placebo, 5%). IMPLICATIONS: GEn significantly improved individual IRLS items and sleep disturbance versus placebo. Correlations between IRLS and PSQ items were moderate to strong. This was not a formal meta-analysis and was not powered to compare the GEn doses. Nevertheless, our study finds that the benefits of GEn extend to individual IRLS items and supports the importance of sleep quality in RLS treatment. ClinicalTrials.gov identifiers: NCT00298623, NCT00365352, and NCT01332305.

Efficacy of gabapentin enacarbil in adult patients with severe primary restless legs syndrome.

AIM: Assess efficacy and tolerability of gabapentin enacarbil (GEn) in adults with severe primary restless legs syndrome (RLS). METHODS: We pooled data from three 12-week, double-blind, placebo-controlled, randomized trials (NCT00298623, NCT00365352, NCT01332305) across GEn 600-mg, GEn 1200-mg, and placebo treatment groups for severe primary RLS (baseline International Restless Legs Scale (IRLS) total score ≥24). Co-primary end points at week 12 were mean change from baseline in IRLS total score and proportion of responders ("much"/very much" improved) on the investigator-rated Clinical Global Impression - Improvement (CGI-I) Scale. Outcomes for individual IRLS items (eg, sleep, mood, quality of life, pain, safety) were assessed. RESULTS: A total of 309 patients had severe primary RLS (placebo, n = 110; GEn 600 mg, n = 80; GEn 1200 mg, n = 119). GEn 600 mg and 1200 mg significantly improved least-squares mean IRLS total scores versus placebo at week 12 (placebo, -12.3; GEn 600 mg, -16.3; GEn 1200 mg, -18.0; treatment difference vs. placebo, both p <0.01). Significantly more patients with severe primary RLS treated with GEn 600 mg (64%) and 1200 mg (74%) were CGI-I responders at week 12 versus placebo (42%; p <0.01 for both GEn doses). Both GEn doses led to significant improvements in the other outcomes explored versus placebo at week 12. The most frequent treatment-emergent adverse events (TEAEs) were somnolence (GEn, 21-24%; placebo, 3%) and dizziness (GEn, 14-19%; placebo, 3%). CONCLUSIONS: GEn (600 mg or 1200 mg) once daily significantly improved RLS symptoms and consequences of these symptoms in severe primary RLS. The most frequent TEAEs were somnolence and dizziness.

Treatment response to sleep, pain, and mood disturbance and their correlation with sleep disturbance in adult patients with moderate-to-severe primary restless legs syndrome: Pooled analyses from 3 trials of gabapentin enacarbil.

INTRODUCTION: This pooled analysis investigated the effects of gabapentin enacarbil (GEn) on clinical correlates of sleep disturbance in adults with moderate-to-severe primary restless legs syndrome (RLS) and no-to-moderate or severe-to-very severe baseline sleep disturbance. METHODS: Co-primary end-points were mean change from baseline to week 12 in International Restless Legs Scale (IRLS) total score and proportion of responders ('much'/'very much' improved) on the investigator-rated Clinical Global Impression-Improvement (CGI-I) scale (week 12). Pain, mood, individual IRLS items, and safety were assessed. RESULTS: The modified intent-to-treat population was 671 adults randomized to GEn 600 mg (n = 161), GEn 1200 mg (n = 266), or placebo (n = 244). GEn significantly improved least squares mean change in IRLS total score from baseline versus placebo for no-to-moderate (GEn 600 mg,- 12.3; 1200 mg, - 11.3; placebo, - 7.7) and severe-to-very severe (- 16.6; - 17.0; - 12.7) groups (all P < 0.01). Significantly more GEn-treated patients (both doses) were CGI-I responders (week 12) versus placebo in both sleep subgroups (all P < 0.01). GEn substantially improved mood and pain scores for both sleep subgroups versus placebo. The most frequent treatment-emergent adverse events were somnolence and dizziness. CONCLUSION: GEn (600 mg and 1200 mg) was effective and well tolerated in adults with moderate-to-severe primary RLS regardless of baseline sleep disturbance level.

Effect of prior exposure to dopamine agonists on treatment with gabapentin enacarbil in adults with moderate-to-severe primary restless legs syndrome: pooled analyses from 3 randomized trials.

BACKGROUND: Dopamine agonists (DAs) are a first-line therapy for moderate-to-severe restless legs syndrome (RLS), but these treatments may lead to complications, such as augmentation and impulse control disorders, requiring switching to another therapeutic class. Here we assess efficacy and tolerability of gabapentin enacarbil (GEn) in adults with moderate-to-severe primary RLS, with or without prior DA exposure. METHODS: Data from 3 trials were pooled. Patients were identified as DA-naive or DA-exposed, based on prior treatment with ropinirole, pramipexole, rotigotine, or pergolide mesylate, and the dopamine precursor levodopa. Details on prior treatment duration and dose were unavailable. Patients with a history of augmentation were excluded. Within DA-naive/DA-exposed patients we investigated the co-primary end points from the pivotal trials: mean change from baseline to week 12 in International RLS (IRLS) Rating Scale total score and proportion of responders ("much"/"very much" improved) on the investigator-rated Clinical Global Impression-Improvement (CGI-I) scale. Safety was also assessed. RESULTS: 671 patients were randomized (DA-naive: placebo, n = 194; GEn 600 mg, n = 131; GEn 1200 mg, n = 214; DA-exposed: placebo, n = 50; GEn 600 mg, n = 30; GEn 1200 mg, n = 52). Across treatment arms, no significant differences between DA-naive and DA-exposed subgroups in IRLS Rating Scale total score change from baseline at any visit were seen, except week 1 in the placebo group (-6.1 DA-naive vs -3.4 DA-exposed, P = .020). No significant differences in the odds of CGI-I response at week 12 between DA-naive vs DA-exposed patients in any treatment group were seen; however, with placebo there was a nonsignificant trend toward fewer responders among DA-exposed (34.0%) vs DA-naive (44.3%) patients. Both GEn doses significantly improved the IRLS Rating Scale total score change from baseline and CGI-I response vs placebo, regardless of prior DA exposure. The most common treatment-emergent adverse events were dizziness and somnolence. CONCLUSIONS: Prior DA exposure had no significant effect on efficacy or tolerability of GEn (600 or 1200 mg) in this pooled analysis of adults with moderate-to-severe primary RLS. These data support the use of GEn in DA-exposed and DA-naive patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00298623, NCT00365352, and NCT01332305.

Efficacy and safety of low-dose submicron diclofenac for the treatment of osteoarthritis pain: a 12 week, phase 3 study.

OBJECTIVE: NSAIDs, such as diclofenac, are the most commonly used medications to treat osteoarthritis (OA), but they are associated with dose-related adverse events (AEs). Low-dose submicron diclofenac was developed using a new, proprietary dry milling process that creates submicron drug particles (SoluMatrix Fine Particle Technology * ), enabling effective treatment at lower doses than other commercially available diclofenac drug products. This phase 3 study evaluated the efficacy and safety of low-dose submicron diclofenac 35 mg three times daily (tid) and twice daily (bid) in patients with OA pain. RESEARCH DESIGN AND METHODS: This double-blind study enrolled patients ≥40 years of age with clinically and radiographically confirmed (Kellgren-Lawrence grade II-III) hip or knee OA. Eligible patients were chronic NSAID and/or acetaminophen (APAP) users with baseline Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) pain subscale scores ≥40 mm by visual analog scale and an OA flare (≥15 mm increase in WOMAC pain subscale score following discontinuation of NSAIDs/APAP at screening). Patients were randomized to submicron diclofenac 35 mg tid, submicron diclofenac 35 mg bid, or placebo for 12 weeks. ClinicalTrials.gov identifier: NCT01461369. MAIN OUTCOME MEASURES: Efficacy parameters included mean change from baseline in WOMAC pain subscale score at week 12 (primary efficacy parameter) and in average total WOMAC score over 12 weeks. RESULTS: Submicron diclofenac 35 mg tid significantly improved WOMAC pain subscale scores from baseline at 12 weeks (-44.1; p = 0.0024) compared with placebo (-32.5). Submicron diclofenac 35 mg bid provided numerical improvement in pain at week 12 that did not reach statistical significance (-39.0; p = 0.0795) compared with placebo. Submicron diclofenac 35 mg tid (-35.9; p = 0.0002) and 35 mg bid (-30.3; p = 0.0363) improved the average total WOMAC score in treated patients over 12 weeks compared with placebo (-23.2). The most frequent AEs in the submicron diclofenac-treated groups were diarrhea, headache, nausea, and constipation. The inclusion of patients with a documented requirement for analgesic therapy (OA 'flare') at baseline and the high rates of rescue medication usage in the placebo group may have impacted the study outcome for the submicron diclofenac treatment groups. CONCLUSIONS: Low-dose submicron diclofenac is an effective therapeutic option for the treatment of OA pain.