Long-term, open-label, safety study of once-daily ropinirole extended/prolonged release in early and advanced Parkinson's disease.

Long-term safety of once-daily ropinirole extended/prolonged release (ropinirole XL/PR) was evaluated in subjects with early and advanced Parkinson's disease (PD) in this study, 101468/248. Subjects (n = 419) who completed one of three prior studies evaluating ropinirole XL/PR for the treatment of PD were enrolled in this open-label, multicenter, extension study, and were to be followed for up to 73 months. Ropinirole XL/PR was titrated/continued, and adjusted as appropriate during the maintenance phase (maximum 24 mg/d). Levodopa (L-dopa) and other nondopamine agonist PD medications were permitted. Safety outcomes that were investigated included frequency of adverse events (AEs). Subjects' preference regarding once daily versus three times daily study medication regimens was also investigated in a subset of the study population. The median duration of ropinirole XL/PR exposure was 1275 d. Most subjects (87%) reported at least one AE, with the most common (≥ 10%) AEs being, back pain (14%), hallucinations (13%), somnolence (11%) and peripheral edema (11%). Twenty-five percent of subjects discontinued the study prematurely due to an AE during the treatment period. Long-term treatment with ropinirole XL/PR was not associated with any new or unexpected safety concerns in patients with early and advanced PD, and a majority of subjects preferred the once-daily dosing regimen.

Pharmacokinetics and Safety of a 1:1 Mixture of Doxecitine and Doxribtimine: Open-label Phase 1 Single Ascending Dose and Food Effect Studies in Healthy Adults.

PURPOSE: Doxecitine (deoxycytidine [dC]) and doxribtimine (deoxythymidine [dT]) powder for oral solution is a 1:1 mixture consisting of equal weights 2'-deoxycytidine (dC) and 2'-deoxythymidine (dT). Doxecitine and doxribtimine (referred to as study drug) is being developed as treatment for people with thymidine kinase 2 deficiency (TK2d). TK2d is an ultra-rare mitochondrial DNA depletion and multiple deletion syndrome characterized by progressive muscle weakness and premature death. Here, we report the pharmacokinetics (PK), the effect of food, and the tolerability of 2 study drug formulations, evaluated in 2 studies (Study MT-1621-103 and Study MT-1621-105). METHODS: A sequential, ascending 1:1 dose ratio was used for both studies (n = 14 healthy volunteer adult participants/study). After a 28-day (Study MT-1621-103) or 35-day (Study MT-1621-105) screening period, participants fasted overnight and sequentially received 86.6, 173.4, and 266.6 mg/kg study drug with a 48-hour PK assessment period and 48-hour washout period between doses. After 48 additional hours, participants were fed a high-fat meal and received 266.6 mg/kg study drug. Plasma and urine were collected before dosing and throughout the 48-hour PK period. dC and dT concentrations were analyzed by validated liquid chromatography mass spectrometry methods. Safety was evaluated throughout the study and at 2-week follow-up. FINDINGS: Plasma levels of dC and dT increased rapidly and dose-dependently above endogenous levels for both formulations, with a median Tmax of 1 to 2 hours under fasting conditions. Post-dose plasma dC and dT concentrations declined to nearly pre-dose (baseline) concentrations after 8 to 12 hours, suggesting rapid elimination. Peak and extent of plasma exposure (baseline-corrected Cmax and AUC0-t) tended to increase less than dose-proportionally for plasma dC and greater than dose-proportionally for plasma dT. PK variability of dC and dT was moderate-to-high (>30%). Administration with food delayed Tmax to a median of 2 to 4 hours and increased plasma exposure: baseline-corrected plasma dC Cmax and AUC0-t increased by ∼79% to 96% and 137% to 250%, respectively, and dT Cmax and AUC0-t increased by 27% to 29% and 74% to 89%, respectively, indicating a significant food effect. Renal clearance played a minor role in the elimination of systemically available intact dC and dT (Fe<0.3%). The study drug was generally well tolerated; most frequent study-drug-related adverse events (AEs) were diarrhea (n = 4/29, 14%) and dizziness (n = 3/29, 10%). Most AEs were mild-to-moderate in severity. IMPLICATIONS: Doxecitine and doxribtimine are orally bioavailable in the intended clinical dose range. The PK profile supports a formulation consisting of equal doses of doxecitine and doxribtimine, a 3-times-daily dosing regimen, and administration with food.

Prevalence of Hepatic Encephalopathy from a Commercial Medical Claims Database in the United States.

INTRODUCTION: Hepatic encephalopathy (HE), a complication of cirrhosis, is associated with increased healthcare resource utilization and mortality, and impaired quality of life. Information on the prevalence of HE in the US general population is limited. METHODS: Prevalence of HE was estimated by sequential stepwise data analysis of the Symphony Health anonymized patient-level data (APLD) claims database. First, patients ≥ 18 years with International Classification of Diseases ninth/tenth edition, clinical modification (ICD-9/10-CM), and codes for cirrhosis from 2018 medical and hospital claims were used to estimate prevalence of cirrhosis within the data set and number of patients with cirrhosis in the US general population. Second, patients diagnosed with cirrhosis in the APLD data set from 2015-2016 with an HE ICD-9/10-CM code within 1 year of cirrhosis diagnosis were used to deduce the prevalence of HE within the data set and estimate the number of patients with HE in the US general population. Last, US DiagnosticSource data on serum ammonia level laboratory results measured within ±2 days of a confirmed HE event were merged with the APLD HE data set, then applied to the US general population. RESULTS: Medical and hospital claims data were available for 272,256 patients with cirrhosis in 2018. An estimated 536,856 US adults had a diagnosis of cirrhosis (prevalence of 0.21%) in 2018. This proportion applied to the estimated number of patients with cirrhosis in the United States resulted in a prevalence estimate of 201,858 cirrhosis patients with HE in 2018. When factoring in serum ammonia data, prevalence was conservatively estimated as approximately 196,000 cirrhosis patients with HE and serum ammonia levels > 21 µmol/L. CONCLUSIONS: In this longitudinal cohort-based study, it was estimated that ≈202,000 patients had HE in the United States in 2018, representing a considerable burden to society and payers.

Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study.

OBJECTIVE: To assess dose-response effects of the anti-CD20 monoclonal antibody ofatumumab on efficacy and safety outcomes in a phase 2b double-blind study of relapsing forms of multiple sclerosis (RMS). METHODS: Patients (n = 232) were randomized to ofatumumab 3, 30, or 60 mg every 12 weeks, ofatumumab 60 mg every 4 weeks, or placebo for a 24-week treatment period, with a primary endpoint of cumulative number of new gadolinium-enhancing lesions (per brain MRI) at week 12. Relapses and safety/tolerability were assessed, and CD19+ peripheral blood B-lymphocyte counts measured. Safety monitoring continued weeks 24 to 48 with subsequent individualized follow-up evaluating B-cell repletion. RESULTS: The cumulative number of new lesions was reduced by 65% for all ofatumumab dose groups vs placebo (p < 0.001). Post hoc analysis (excluding weeks 1-4) estimated a ≥90% lesion reduction vs placebo (week 12) for all cumulative ofatumumab doses ≥30 mg/12 wk. Dose-dependent CD19 B-cell depletion was observed. Notably, complete depletion was not necessary for a robust treatment effect. The most common adverse event was injection-related reactions (52% ofatumumab, 15% placebo), mild to moderate severity in 97%, most commonly associated with the first dose and diminishing on subsequent dosing. CONCLUSION: Imaging showed that all subcutaneous ofatumumab doses demonstrated efficacy (most robust: cumulative doses ≥30 mg/12 wk), with a safety profile consistent with existing ofatumumab data. This treatment effect also occurred with dosage regimens that only partially depleted circulating B cells. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with RMS, ofatumumab decreases the number of new MRI gadolinium-enhancing lesions 12 weeks after treatment initiation.

A fixed-dose, dose-response study of ropinirole prolonged release in early stage Parkinson's disease.

AIM: This Phase IV, double-blind, randomized, parallel-group study characterized the dose-response and tolerability of fixed doses of ropinirole prolonged release (PR). PATIENTS & METHODS: Subjects with early Parkinson's disease (PD) received placebo or ropinirole PR 2, 4, 8, 12 or 24 mg once daily, up-titrated to randomized or highest tolerated dose, maintained for 4 weeks. RESULTS: The primary end point was not met (change from baseline in Unified PD Rating Scale motor score). However, because the data were not normally distributed, prespecified nonparametric analysis of covariance suggested ropinirole PR (8 and 12 mg/day) was effective in treating motor symptoms. The adverse event profile was consistent with the known safety profile of ropinirole PR. There was no impulse control disorder reported. Although a higher than previously reported rate of sudden onset of sleep events was reported, these were not dose dependent and were likely to have been influenced by the method of data collection. CONCLUSION: The adverse event profile was consistent with the known safety profile of ropinirole PR and ropinirole PR (8 or 12 mg/day) improved motor symptoms of early PD.

A randomized, fixed-dose, dose-response study of ropinirole prolonged release in advanced Parkinson's disease.

AIM: This Phase IV, double-blind, randomized, parallel-group study characterized the dose-response and tolerability of fixed doses of ropinirole prolonged release (PR) in subjects with advanced Parkinson's disease. PATIENTS & METHODS: Subjects receiving concomitant l-dopa received once-daily ropinirole PR 4, 8, 12, 16 or 24 mg, or placebo, up-titrated for 13 weeks, maintained for 4 weeks. RESULTS: At maintenance period week 4, ropinirole PR significantly reduced total awake 'Off-time' (16 mg; p = 0.027); increased absolute awake time spent 'On' without troublesome dyskinesia from baseline versus placebo (8 mg; p = 0.036); improved Unified Parkinson's Disease Rating Scale motor scores versus placebo (all doses; p = 0.005-0.016). Incidence of adverse events was similar between treatment groups; no dose-related trends were observed. CONCLUSION: Ropinirole PR (16 mg) reduced 'Off-time' with 8 mg the likely lowest maximally effective dose, and the safety profile was consistent with previous studies.

Remission rates following antidepressant therapy with bupropion or selective serotonin reuptake inhibitors: a meta-analysis of original data from 7 randomized controlled trials.

BACKGROUND: Although it is widely believed that the various classes of antidepressants are equally effective, clinically meaningful differences may be obscured in individual studies because of a lack of statistical power. The present report describes a meta-analysis of original data from a complete set of studies comparing the norepinephrine/dopamine reuptake inhibitor (NDRI) bupropion with selective serotonin reuptake inhibitors (SSRIs; sertraline, fluoxetine, or paroxetine). METHOD: Individual patient data were pooled from a complete set of 7 randomized, double-blind studies comparing bupropion (N = 732) with SSRIs (fluoxetine, N = 339; sertraline, N = 343; paroxetine, N = 49) in outpatients with major depressive disorder (DSM-III-R or DSM-IV); 4 studies included placebo (N = 512). Response and remission rates were compared at week 8 or endpoint in both the intent-to-treat sample, using the last-observation-carried-forward (LOCF) method to account for attrition, and the observed cases. Tolerability data, including incidence of sexual side effects, were also compared. RESULTS: The LOCF response and remission rates for the bupropion (62% and 47%) and SSRI (63% and 47%) groups were similar; both active therapies were superior to placebo (51% and 36%; all comparisons, p < .001). The same pattern of results was demonstrated on the observed cases analyses. Although bupropion and SSRIs were generally well tolerated, SSRI therapy resulted in significantly higher rates of sexual side effects as compared to both bupropion and placebo. SSRIs were also associated with more somnolence and diarrhea, and bupropion was associated with more dry mouth. CONCLUSION: Bupropion and the SSRIs were equivalently effective and, overall, both treatments were well tolerated. The principal difference between these treatments was that sexual dysfunction commonly complicated SSRI therapy, whereas treatment with bupropion caused no more sexual dysfunction than placebo.

Challenges and opportunities in designing clinical trials for neuromyelitis optica.

Current management of neuromyelitis optica (NMO) is noncurative and only partially effective. Immunosuppressive or immunomodulatory agents are the mainstays of maintenance treatment. Safer, better-tolerated, and proven effective treatments are needed. The perceived rarity of NMO has impeded clinical trials for this disease. However, a diagnostic biomarker and recognition of a wider spectrum of NMO presentations has expanded the patient population from which study candidates might be recruited. Emerging insights into the pathogenesis of NMO have provided rationale for exploring new therapeutic targets. Academic, pharmaceutical, and regulatory communities are increasingly interested in meeting the unmet needs of patients with NMO. Clinical trials powered to yield unambiguous outcomes and designed to facilitate rapid evaluation of an expanding pipeline of experimental agents are needed. NMO-related disability occurs incrementally as a result of attacks; thus, limiting attack frequency and severity are critical treatment goals. Yet, the severity of NMO and perception that currently available agents are effective pose challenges to study design. We propose strategies for NMO clinical trials to evaluate agents targeting recovery from acute attacks and prevention of relapses, the 2 primary goals of NMO treatment. Aligning the interests of all stakeholders is an essential step to this end.

Dose response of Gabapentin Enacarbil versus placebo in subjects with moderate-to-severe primary restless legs syndrome: an integrated analysis of three 12-week studies.

BACKGROUND: The efficacy and tolerability of gabapentin enacarbil (Horizant®; GlaxoSmithKline, Brentford, UK) has been demonstrated in several restless legs syndrome (RLS) phase II and phase III clinical studies at various doses from 600 mg to 2400 mg. OBJECTIVE: The objective of this study was to evaluate key efficacy and safety outcomes in subjects with RLS treated with once-daily gabapentin enacarbil 600 mg, 1200 mg, 1800 mg and 2400 mg, providing supportive evidence of the efficacy of gabapentin enacarbil 600 mg compared with higher doses and placebo. STUDY DESIGN: Integrated post hoc analysis of three 12-week, randomized, double-blind, placebo-controlled trials in subjects with RLS. SETTING: The three studies were carried out at multiple centres in the US. PATIENTS: In total, 760 subjects were included in the pooled analysis (placebo, n = 245; gabapentin enacarbil 600 mg, n = 163; gabapentin enacarbil 1200 mg, n = 269; gabapentin enacarbil 1800 mg, n = 38; gabapentin enacarbil 2400 mg, n = 45). INTERVENTION: In all studies, gabapentin enacarbil or placebo was administered once daily at approximately 5 p.m. with food. Gabapentin enacarbil was initiated at a dose of 600 mg with subsequent titration in 600 mg increments every 3 days up to the randomized dose. MAIN OUTCOME MEASURE: The efficacy endpoints analysed for the purpose of this integrated analysis were change from baseline in International Restless Legs Scale (IRLS) total score and the proportion of responders (subjects rated as 'much' or 'very much' improved) on the investigator-rated Clinical Global Impression-Improvement (CGI-I) scale. Safety endpoints assessed were the incidence of treatment-emergent adverse events (AEs) and serious AEs. RESULTS: Gabapentin enacarbil 600 mg significantly improved IRLS total score compared with placebo (adjusted mean [standard error] change in IRLS total score from baseline to week 12 last observation carried forward: -13.6 [0.71] vs -9.3 [0.55]; adjusted mean treatment difference: -4.3; 95% CI -6.01, -2.52; p < 0.0001). A significantly higher proportion of subjects was rated as responders on the investigator-rated CGI-I scale with gabapentin enacarbil 600 mg compared with placebo (70.2% vs 42.2%; adjusted odds ratio 3.1; 95% CI 1.96, 4.89; p < 0.0001). Similar treatment benefits were seen with both efficacy endpoints for the three higher doses. The AEs reported most frequently were somnolence and dizziness; there was a dose-response relationship to these AEs. No new or unexpected safety issues were identified by this integrated analysis. CONCLUSION: The lowest dose of gabapentin enacarbil evaluated (600 mg) significantly improved RLS symptoms compared with placebo. The safety profile was consistent with that described previously in the literature.

Extended-release bupropion for patients with major depressive disorder presenting with symptoms of reduced energy, pleasure, and interest: findings from a randomized, double-blind, placebo-controlled study.

OBJECTIVE: This multicenter, double-blind, placebo-controlled study evaluated the efficacy and safety of extended-release bupropion (bupropion XL) in the treatment of major depressive disorder (MDD) with prominent symptoms of decreased energy, pleasure, and interest. METHOD: Eligible adult outpatients meeting DSM-IV criteria for MDD were randomly assigned to bupropion XL 300 to 450 mg/day (N = 135) or placebo (N = 139) for 8 weeks. The primary efficacy measure, change from baseline on the 30-item Inventory of Depressive Symptomatology-Self Report (IDS-IVR-30) total score, was obtained using interactive voice response (IVR) technology. Secondary measures included change from baseline on the 30-item Inventory of Depressive Symptomatology-Clinician-Rated (IDS-C-30) total score and change in domain subset scores for energy, pleasure, and interest; for insomnia; and for anxiety. Response and remission rates were also calculated. Safety was assessed by withdrawal rates, adverse events (AEs), body weight, and vital signs. The study was conducted from June 24, 2003, to June 30, 2004. RESULTS: Bupropion XL was superior to placebo at endpoint in reducing the IDS-IVR-30 total score (p = .018) and the energy, pleasure, and interest domain (p = .007) and the insomnia domain (p = .023) scores. IDS-C-30 outcomes were also significant (p < .001; p < .001, and p = .008, respectively). Clinician-rated remission rates were significantly higher with bupropion XL than placebo (32% vs. 18%, IDS-C-30; 41% vs. 27%, IDS-IVR-30), as were response rates (50% vs. 35%, IDS-C-30; 53% vs. 38%, Clinical Global Impressions-Improvement of Illness). Most AEs were mild or moderate. The incidence of a >or= 7% body weight loss was 3.7% with bupropion XL and 1.4% with placebo. CONCLUSION: Bupropion XL was effective and well tolerated in MDD patients with decreased energy, pleasure, and interest.