Titration Period Research Articles

Tolerability of lacosamide rapid dose titration: A randomized, multicenter, prospective, open-label study

ObjectiveCurrently recommended dosing of lacosamide often necessitates long titration periods. However, the use of a regimen consisting of initial loading dose of 200 mg followed by a maintenance dose of 200 mg/day in practice suggests tolerability of more rapid titration schedules. We aimed to clarify whether the shortened titration schedule affects tolerability of lacosamide. MethodsWe evaluated the safety of two rapid titration protocols designed to reach the target dose of 400 mg/day within 1 week, and the conventional weekly titration protocol (reaching the target dose of 400 mg/day in three weeks). The ≥50% responder rate and steady-state plasma concentration of lacosamide were also analyzed. Adverse events were assessed at 1 week and 5 weeks after reaching the target dose. ResultsSeventy-five patients with epilepsy were enrolled and evenly distributed to three titration protocols, from which 5 patients were lost to follow-up and excluded from the safety analysis. Discontinuation of lacosamide or dose reductions due to adverse events occurred in 32 patients (46%), of whom a large majority (74%) had experienced adverse events after reaching 400 mg/day, demonstrating apparent dose-dependency. There was no difference in safety outcomes among the three titration groups. Concomitant use of sodium channel blockers significantly increased the risk of adverse events. ConclusionRapid titration protocols for lacosamide were not associated with an increased risk of adverse events compared to the conventional weekly titration protocol. Uptitration of lacosamide at shorter intervals to an effective target dosage may be feasible in appropriate clinical situations.

Durability of Initial Platelet Count Response in Patients Treated with Avatrombopag for Immune Thrombocytopenia (ITP): Post-Hoc Results from a Phase 3 Clinical Study

Background: The clinical management of ITP has been evolving. Thrombopoietin receptor agonists (TPO-RAs) have become widely utilized as subsequent treatments, and the 2019 ASH guidelines recommend their use over rituximab to achieve a durable response. TPO-RAs eltrombopag (ELT) and romiplostim (ROMI) have been FDA approved for over a decade with a well demonstrated efficacy profile. ELT, an oral medication, must be administered two hours prior to or four hours after meals containing polyvalent cations such as calcium or magnesium to mitigate clinically relevant effects on the pharmacokinetic profile (ELT prescribing information). Additionally, ELT carries a boxed warning for hepatoxicity that requires monitoring. ROMI, an injectable, is typically administered in a health care practitioner's office weekly which may be challenging for some patients (Pts). Avatrombopag (AVA) is an oral TPO-RA approved in 2019 for Pts with ITP. In clinical trials, AVA rapidly increased platelet count (PC) (5 days) and maintained it in the target range (50 to 150×109/L) with chronic dosing. Further, it has an exposure-adjusted safety profile generally comparable to placebo with no boxed warning for hepatotoxicity. AVA does not chelate polyvalent cations; therefore, it is administered with food and without restrictions regarding meal composition. A high proportion of Pts (~90%) respond to AVA; but limited information is available regarding the durability of response over time utilizing clinically relevant loss of response definitions. Aims: To understand the duration of initial response with AVA and the overall percent of treatment days a response level PC was achieved in responding Pts. Methods: A 6-month, multicenter, randomized, double-blind, Phase 3 study enrolled 32 AVA and 17 placebo-treated Pts with ITP. The study design included a 6-week study drug titration period, 12-week concomitant ITP medication reduction period, and an 8-week maintenance period. The primary endpoint was the median number of cumulative weeks of PC response (PC ≥50,000/µL) over the course of the study without rescue medication. Pts receiving rescue medication during the study were deemed to be non-responders for the remainder of the study. For this post-hoc analysis, we analyzed how many days it took for responding AVA Pts (n=29) to experience their first loss of response (LOR) or reach core study conclusion. After the initial PC ≥50,000/µL was noted, we also examined the percentage of remaining treatment time that initial response was maintained. Response was defined as the first time achieving a PC ≥50,000/µL. LOR was defined as a Pt experiencing a PC <30,000/µL for 4 consecutive weeks (LOR-4wk), or in a more conservative manner, Pts experiencing a PC <30,000/µL on 2 consecutive scheduled visits (LOR-2vis) [visits were weekly or biweekly depending on the phase of the study with 21 visits occurring over 26 weeks]. When a LOR was observed, the date of the first PC <30,000/µL was used for subsequent calculations with a return of response defined as a PC exceeding ≥30,000/µL again. Pts who required rescue therapy (n=6) were included in the analyses and the first date of administration was used for the LOR date. Pts requiring either corticosteroids (n=4) or IVIg (n=1) as rescue therapy were considered non-responders for a minimum of 8 weeks and Pts receiving a platelet transfusion (n=1) for a minimum of 1 week. Results: 72.4% (21/29) and 55.2% (16/29) of AVA responsive Pts never experienced a LOR-4wk or LOR-2vis, respectively. The median number of days until responding Pts experienced their first LOR-4wk, discontinued treatment, or completed the 6-month study was 170 (mean 134.7) and 146 (mean 119.1) for the LOR-2vis analysis. Pts maintained their initial response on average for 87.7% (median 100%) of their remaining time in the study for LOR-4wk and 84.5% (median 100%) for LOR-2vis analyses, with Pts often losing response only briefly when noted. Pts requiring rescue therapy often returned to a response level PC and remained in the 6-month study for approximately 5 months following their initial response. Conclusions: These data suggest that the initial response to AVA is stable and durable with up to 72.4% of Pts never experiencing a LOR, even with the planned objective of reducing the use of baseline concomitant ITP medications during the study. In those pts experiencing a LOR, many ended up achieving response level PCs again without a subsequent LOR. Disclosures Wojdyla: Dova Pharmaceuticals: Current Employment. Vredenburg:Dova Pharmaceuticals: Current Employment. Jamieson:Dova Pharmaceuticals: Current Employment. Gernsheimer:Amgen Corporation: Consultancy, Honoraria; Novartis: Consultancy; Cellphire: Consultancy; Rigel Corporation: Consultancy, Research Funding; Principia: Research Funding; Sanofi: Consultancy; Vertex: Consultancy; Dova Pharmaceuticals: Consultancy.

Efficacy and safety of calcium, magnesium, potassium, and sodium oxybates (lower-sodium oxybate [LXB]; JZP-258) in a placebo-controlled, double-blind, randomized withdrawal study in adults with narcolepsy with cataplexy.

Study ObjectivesEvaluate efficacy and safety of lower-sodium oxybate (LXB), a novel oxybate medication with 92% less sodium than sodium oxybate (SXB).MethodsAdults aged 18–70 years with narcolepsy with cataplexy were eligible. The study included a ≤30-day screening period; a 12-week, open-label, optimized treatment and titration period to transition to LXB from previous medications for the treatment of cataplexy; a 2-week stable-dose period (SDP); a 2-week, double-blind, randomized withdrawal period (DBRWP); and a 2-week safety follow-up. During DBRWP, participants were randomized 1:1 to placebo or to continue LXB treatment.ResultsEfficacy was assessed in 134 participants who received randomized treatment, and safety was assessed in all enrolled participants (N = 201). Statistically significant worsening of symptoms was observed in participants randomized to placebo, with median (first quartile [Q1], third quartile [Q3]) change in weekly number of cataplexy attacks from SDP to DBRWP (primary efficacy endpoint) in the placebo group of 2.35 (0.00, 11.61) versus 0.00 (−0.49, 1.75) in the LXB group (p < 0.0001; mean [standard deviation, SD] change: 11.46 [24.751] vs 0.12 [5.772]), and median (Q1, Q3) change in Epworth Sleepiness Scale score (key secondary efficacy endpoint) of 2.0 (0.0, 5.0) in the placebo group versus 0.0 (−1.0, 1.0) in the LXB group (p < 0.0001; mean [SD] change: 3.0 [4.68] vs 0.0 [2.90]). The most common treatment-emergent adverse events with LXB were headache (20.4%), nausea (12.9%), and dizziness (10.4%).ConclusionsEfficacy of LXB for the treatment of cataplexy and excessive daytime sleepiness was demonstrated. The safety profile of LXB was consistent with SXB.Clinical trial registrationNCT03030599.

Long-term efficacy and safety of cannabidiol (CBD) in children with treatment-resistant epilepsy: Results from a state-based expanded access program

IntroductionAn intermediate-sized, multicenter, expanded-access study was opened in 2015 through the support of the State of Georgia. This study provided children with treatment-resistant epilepsy (TRE) access to plant-derived highly purified cannabidiol (CBD; Epidiolex® in the US; Epidyolex® in the EU; 100 mg/mL oral solution). These children had failed to achieve seizure freedom with available treatment options and were ineligible to participate in randomized controlled trials that only included patients with Lennox–Gastaut and Dravet syndromes. MethodsCannabidiol safety, changes in seizure type, frequency, and seizure-free days were evaluated for children aged 1–18 years (at time of consent) as an adjunctive treatment for 36 months. The study consisted of a two-month baseline period, a titration period, treatment period, and optional titration period, which occurred after ≥26 weeks of treatment. Cannabidiol treatment was administered up to a targeted dose of 25 mg/kg/day, with an optional secondary treatment up to 50 mg/kg/day. Daily seizure type, seizure frequency, and seizure-free days were recorded in a Web-based diary, and changes in these outcomes were recorded and analyzed for the duration of the study. The occurrence of adverse events (AEs) was also recorded. ResultsThe median percentage change in seizures for 45 patients in Months 3, 6, 12, 18, 24, and 36 showed a statistically significant (p < 0.001) reduction in major seizures (ranging from 54 to 72% at various time points) and all seizures (61–70%) compared with baseline. A mean increase in seizure-free days per 28 days was >5 in all treatment periods after Month 2, and an average increase of 7.52 (p < 0.001) seizure-free days per 28 days was observed at the end of follow-up compared with baseline. All patients experienced ≥1 AE. Children who transitioned to the optional secondary treatment (high-dose group) reported more AEs before increasing their dose to >25.0 mg/kg/day compared with the low-dose group. However, the average rate of AEs was significantly lower after moving to a high-dose regimen (p = 0.004). Twelve children reported 20 serious AEs, none of which were considered related to CBD. ConclusionsThis study supports CBD as an adjunctive treatment for children with TRE. Treatment was well tolerated in doses up to 50 mg/kg/day. Patients who did not achieve desired results at a dose of ≤25.0 mg/kg/day reported more AEs when CBD dose increased to >25.0 mg/kg/day. Decreases in major seizure frequency and an increase in seizure-free days compared with baseline were reported during treatment. This supports the efficacy and tolerability of CBD for mixed seizure etiologies.

Effects of emixustat hydrochloride in patients with proliferative diabetic retinopathy: a randomized, placebo-controlled phase 2 study

PurposeTo evaluate the effects of oral emixustat hydrochloride on pro-angiogenic and inflammatory cytokines in the aqueous humor, as well as other ophthalmic parameters, in subjects with proliferative diabetic retinopathy (PDR).MethodsTwenty-three patients with PDR, with or without diabetic macular edema (DME), were assigned to emixustat or placebo in daily oral doses ranging from 5 to 40 mg over a step-up titration period, for 84 days. The main outcome measures included levels of IL-1β, IL-6, IL-8, TGFβ-1, and VEGF in the aqueous humor.ResultsSeven of 12 subjects (58%) who were randomized to emixustat and 11 of 12 subjects (92%) who were randomized to placebo completed the study. No statistically significant differences between treatment groups were observed for changes in any of the aqueous humor cytokines tested. However, median VEGF levels were slightly reduced in the emixustat but not the placebo group (− 70.0 pg/mL versus + 42.7 pg/mL, or − 11.8% versus + 6.7%). In a post hoc analysis of all subjects (with or without DME), statistically significant differences between treatment arms in mean changes from baseline in central subfield thickness (CST; emixustat − 11.9 μm, placebo + 36.2 μm; P = 0.076) and total macular volume (TMV; emixustat − 0.13 mm3, placebo + 0.23 mm3; P = 0.026) were observed, both favoring emixustat. Emixustat’s safety profile was consistent with prior studies (i.e., the adverse events of delayed dark adaptation and visual impairment were more common in subjects treated with emixustat).ConclusionAlthough this pilot study did not demonstrate statistically significant differences in changes in aqueous humor cytokine levels between the emixustat and placebo groups, VEGF levels were slightly reduced in the emixustat but not in the placebo group. In addition, statistically significant differences favoring the emixustat group were observed in CST and TMV among all subjects. These data warrant further investigation of emixustat’s potential therapeutic effects in diabetic retinopathy.Trial registrationClinicalTrials.gov identifier: NCT02753400 (April 2016)

STW5 (Iberogast®) for constipation in Parkinson's disease.

Chronic constipation is one of the most frequent non-motor symptoms in Parkinson's disease (PD), and impairs patients' quality of life. The aim of this pilot study was to assess the efficacy and the tolerability of STW5, a phytotherapeutic agent composed of nine plant extracts, for the treatment of constipation in patients with PD. We carried out an open monocentric study of STW5 in the treatment of constipation in parkinsonian patients. Forty-four PD patients with a mean age of 66.4±7.3 years (range, 35-78), a mean disease duration of 12.6±5.4 years (range, 3-27) and with constipation defined by Rome III criteria for functional constipation were included. Following a two-week laxative-free baseline period, all the patients were treated with 20 drops STW5 t.i.d for 28 days, after a seven-day titration period. Treatment efficacy was defined as marked improvement of stool frequency with an increase of three exonerations during the last week of treatment when compared to the week before the initiation of treatment. Responder rate for stool frequency was estimated at 29/45 patients. An increase of stool frequency≥three eliminations/week was observed in only four out of 44 patients (9.0%) at the end of the study. The only significant difference observed before and after treatment was a decrease in stool consistency (P=0.0272). Our results suggest that STW5 has a safety profile but is not effective as a phytotherapeutic agent in constipation related to Parkinson's disease.

Lower risk of severe hypoglycaemia with insulin glargine 300 U/mL versus glargine 100 U/mL in participants with type 1 diabetes: A meta-analysis of 6-month phase 3 clinical trials.

Severe hypoglycaemia (SH) remains a challenge to people with type 1 diabetes (T1DM), and new‐generation basal insulins may improve patient outcomes. This post hoc meta‐analysis explored the risk of SH with insulin glargine 300 U/mL (Gla‐300) versus glargine 100 U/mL (Gla‐100) in a pooled population with T1DM from three randomized, multicentre, 6‐month similarly designed phase 3 trials: EDITION 4, EDITION JP 1 and EDITION JUNIOR. Endpoints included incidence and time to first occurrence of SH. Among 629 and 626 participants randomized to Gla‐300 and Gla‐100, respectively, glycated haemoglobin reductions were similar. Fewer participants experienced ≥1 SH event with Gla‐300 (6.2%) than with Gla‐100 (9.3%). From baseline to month 6, the risk of a first SH event was lower with Gla‐300: hazard ratio 0.65 [95% confidence interval (CI) 0.44–0.98; stratified log‐rank test P = 0.038]. SH event rates were numerically lower with Gla‐300 versus Gla‐100 from baseline to month 6 [relative risk (RR) 0.80 (95% CI 0.49–1.29); P = 0.356] and baseline to week 8 [RR 0.73 (95% CI 0.37–1.44); P = 0.369]. Thus, Gla‐300 demonstrated similar glycaemic control with lower risk of SH versus Gla‐100, particularly during the titration period.

Efficacy and safety of ambrisentan in Chinese patients with connective tissue disease-pulmonary arterial hypertension: a post-hoc analysis

BackgroundThe efficacy and safety of ambrisentan has been previously evaluated in Chinese patients with pulmonary arterial hypertension (PAH). This post-hoc analysis assessed the efficacy and safety of ambrisentan in a subgroup of connective tissue disease (CTD) patients with PAH.MethodsIn this open-label, single-arm study, patients received ambrisentan 5 mg once daily for 12 weeks, followed by 12-week dose titration period (dose up to 10 mg). Efficacy endpoints included change from baseline in exercise capacity (measured by 6-min walk test [6MWT]), N-terminal pro B type natriuretic peptide (NT-proBNP) plasma levels, WHO Functional Class (FC) and Borg Dyspnoea Index (BDI) scores from baseline to weeks 12 and 24. Safety endpoints included time to clinical worsening and incidence of adverse events (AEs).ResultsIn total, 71 Chinese patients with CTD-PAH were included in this analysis. Ambrisentan treatment significantly improved exercise capacity (6MWT) from baseline (mean: 366.4 m) to week 12 (63.8 m, p < 0.001) and week 24 (73.2 m, p < 0.001). A significant reduction in NT-proBNP levels was observed from baseline (mean: 1837.5 ng/L) to week 12 (− 1156.8 ng/L, p < 0.001) and week 24 (− 1095.5 ng/L, p < 0.001). BDI scores decreased significantly at week 12 (− 0.6, p < 0.001) and week 24 (− 0.4, p = 0.002) from baseline (mean: 2.7). The WHO FC improved in 29 (40.8%) and 34 (47.9%) patients at weeks 12 and 24, respectively. Adverse events were reported in 52 (73.2%) patients. One patient (1.4%) experienced clinical worsening at week 24.ConclusionAmbrisentan showed significant improvement in exercise capacity and no clinical worsening in the majority of Chinese patients with CTD-PAH in the 24-week treatment period. The AEs observed in the CTD-PAH subgroup were consistent with the known safety profile of ambrisentan in the overall Chinese PAH population.Trial registrationClinicalTrial.gov Identifier, https://clinicaltrials.gov/, NCT01808313 Registration date (first time): February 28, 2013.

Prognostic importance of long-term SBP variability in high-risk hypertension

In addition to high blood pressure variability (BPV), low BPV was associated with adverse cardiovascular prognosis in selected high-risk patients. We explored this issue in the Systolic Blood Pressure Intervention Trial (SPRINT) using a nonlinear approach with BPV as a continuous variable. Long-term systolic BPV (SBPV) (coefficient of variation, CoV %) was calculated on quarterly visits until a fatal/nonfatal cardiovascular event or all-cause mortality, excluding titration period and patients with missing visits. We used Cox proportional hazard models with penalized smoothing splines to shape the risk of outcomes against the continuum of SBPV (independent variable). Adjusted hazard ratios (aHR, 95% CI) were calculated using the reference range derived from the nonlinear model. Sensitivity analysis based on propensity score matching (PSM) was performed. The association of SBPV with fatal/nonfatal cardiovascular events was J-shaped, whereas that with all-cause mortality was linear. After multivariate adjustment, however, the only significant associations remained that of low SBPV (CoV <5%) with cardiovascular events (hazard ratio 1.85, 95% CI 1.24-2.75, P = 0.003), and of high SBPV (CoV >10%) with the composite of cardiovascular events and all-cause mortality (hazard ratio 1.35, 95% CI 1.02-1.80; P = 0.037). Low SBPV was associated with ischemic heart disease (hazard ratio 2.76, 95% CI 1.55-4.91; P < 0.001). There was a significant U-shaped association of SBPV with cardiovascular events in the PSM cohort. Nonlinear modeling indicates that low and high long-term SBPV have prognostic relevance in high-risk hypertensive individuals from SPRINT. Randomized trials are needed to test these findings and their potential therapeutic implications.

Safety and acceptability of clozapine and risperidone in progressive multiple sclerosis: a phase I, randomised, blinded, placebo-controlled trial

ObjectiveBecause clozapine and risperidone have been shown to reduce neuroinflammation in humans and mice, the Clozapine and Risperidone in Progressive Multiple Sclerosis (CRISP) trial was conducted to determine whether clozapine...

The Efficacy and Safety of Piribedil Relative to Pramipexole for the Treatment of Early Parkinson Disease: A Systematic Literature Review and Network Meta-Analysis.

Patients with early Parkinson disease (PD) frequently defer initiation of levodopa treatment to minimize long-term complications. Nonergoline dopamine agonists, such as pramipexole and piribedil, are frequent first-line therapies for early PD patients, yet limited head-to-head randomized controlled trial (RCT) evidence exists for dopamine agonists in this population. We therefore conducted a systematic literature review and network meta-analysis. MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were systematically searched (until January 7, 2020), identifying RCTs assessing the efficacy of piribedil or pramipexole in early PD. Eligible trial data were incorporated into fixed- and random-effects Bayesian network meta-analyses. No RCTs were identified directly comparing piribedil with pramipexole, but 6 trials provided data for pramipexole versus placebo and 2 compared piribedil versus placebo, facilitating indirect comparisons. Across all time points assessed, no significant differences were found between pramipexole and piribedil for change in the Unified Parkinson's Disease Rating Scale (UPDRS) score from baseline. Piribedil and pramipexole demonstrated superiority relative to placebo for UPDRS II/III change at weeks 22 to 30. No significant differences were noted between the treatments at weeks 20 to 35 for anxiety, constipation, hypotension, nausea, and somnolence. Sensitivity analyses on adjustment for dose titration periods and baseline risk yielded the same pattern of results. No significant differences were found for pramipexole versus piribedil in the UPDRS II/III scores from baseline in early PD, with similar safety profiles.

EQUIDopa: A responsive web application for the levodopa equivalent dose calculator

Background and objectiveLevodopa/carbidopa intestinal gel infusion is a treatment option for patients of advanced stage of Parkinson's disease. This treatment requires the time-consuming and error-prone conversion of orally taken antiparkinson drugs into an equivalent replacing dose of levodopa/carbidopa, which is delivered via pump. In order to facilitate and speed up this conversion process, we developed a specific user-friendly application that would be available online or as a standalone mobile application. Such an application has now been written and designed in collaboration with a computer scientist and physician, who is also intended to be the final user. MethodsThe levodopa equivalent dose calculations are based on previous studies and data reported in the literature. Two related on-line conversion applications were analyzed and evaluated. The primary objectives of the application were determined, and basic functionalities were outlined. The application was implemented using modern development tools and frameworks. ResultsThe application has proven to be effective and easy to use in our clinical setting. It can serve as a control for manual calculations made by medical staff. It can also be applied as a useful tool in levodopa/carbidopa intestinal gel infusion courses for the advanced treatment of Parkinson's disease. ConclusionThe presented application could replace the tedious and error-prone levodopa equivalent dose conversion of antiparkinson drugs efficiently. In comparison to related on-line conversion applications, this specific application provides more functionality, reduces the risk of user errors, and can be run on a variety of devices. The conversion value provided by the application is only an estimate. The effect of the drugs is specific for each individual patient, which could not be considered in the calculations. Therefore, the responsibility of using the results of the application rests with the clinical judgment of the user. Nevertheless, the application can give us a good starting point for the initial pump setting, which would be adjusted further during the titration period, according to the patient's response.

Efficacy and safety of perampanel monotherapy in patients with focal-onset seizures with newly diagnosed epilepsy or recurrence of epilepsy after a period of remission: The open-label Study 342 (FREEDOM Study).

ObjectiveOur study assessed perampanel monotherapy in patients (aged ≥12 years) with focal‐onset seizures (FOS) with or without focal to bilateral tonic‐clonic seizures (FBTCS) in Japan and South Korea.MethodsStudy 342 (NCT03201900; FREEDOM) is a single‐arm, open‐label, Phase III study. Patients initially received perampanel in a 32‐week 4‐mg/d Treatment Phase (6‐week Titration; 26‐week Maintenance Periods). If they experienced a seizure during the 4‐mg/d Maintenance Period, they could be up‐titrated to 8 mg/d across an additional 30‐week Treatment Phase (4‐week Titration; 26‐week Maintenance Periods). Primary endpoint was the seizure‐freedom rate during the Maintenance Period (4 mg/d and last evaluated dose [4 or 8 mg/d]). Secondary endpoints included time to first seizure onset and to withdrawal during Maintenance. Treatment‐emergent adverse events (TEAEs) were monitored.ResultsAt data cutoff (February 28, 2019), 89 patients with FOS (84 [94.4%] with newly diagnosed epilepsy and 5 [5.6%] with recurrence of epilepsy after a period of remission) had received ≥1 perampanel dose; 16 patients discontinued during the 4‐mg/d Titration Period, meaning 73 patients entered the 4‐mg/d Maintenance Period and were included in the primary analysis set for efficacy. Seizure‐freedom rate in the 26‐week Maintenance Period was 46/73 (63.0%; 95% confidence interval [CI]: 50.9‐74.0) at 4 mg/d and 54/73 (74.0%; 95% CI: 62.4‐83.5) at 4 or 8 mg/d. Cumulative probability of seizure‐onset and withdrawal rates during Maintenance was 30.8% (95% CI: 21.5‐43.0) and 23.7% (95% CI: 15.4‐35.3) at 4 mg/d, and 18.2% (95% CI: 11.0‐29.3) and 23.3% (95% CI: 15.2‐34.8) at 4 or 8 mg/d. Perampanel was generally well tolerated, and the most common TEAE was dizziness.SignificancePerampanel monotherapy (4 to 8 mg/d) was efficacious and consistent with the known safety profile up to 26 weeks in patients (≥12 years) with primarily newly diagnosed FOS with or without FBTCS.

SO050DIFFERENT FERRIC CITRATE DOSE REGIMENS IN THE TREATMENT OF IRON DEFICIENCY ANAEMIA IN PATIENTS WITH NON-DIALYSIS-DEPENDENT CKD: THE COMPASS TRIAL

Abstract Background and Aims Ferric citrate (FC) is approved in the US as oral iron replacement for the treatment of iron deficiency anaemia (IDA) in adult patients with non-dialysis dependent (NDD) chronic kidney disease (CKD) and for the treatment of hyperphosphatemia in adult patients with dialysis dependent CKD. For IDA, a starting dose FC of 1 tablet three times daily (TID) is recommended with titration to maintain haemoglobin (Hb) at goal. This study was designed to investigate the possibility of dosing FC twice daily (BID) for flexibility in clinical practice. The efficacy and safety of different FC dosing regimens for the treatment of IDA were examined in adults with NDD-CKD. Method In this 48-wk, Phase 4, randomized, open-label, multicentre study, subjects with IDA of NDD-CKD (stage 3-5) were randomized 1:1 to receive 1 FC tablet (1gm containing 210mg ferric iron) TID or 2 tablets BID. At wk 12, subjects whose Hb increased &amp;lt;0.5 g/dL from baseline (BL) or was &amp;lt;10 g/dL had their dose increased to either 2 tablets TID or 3 tablets BID consistent with their original dosing regimen. This prespecified analysis reports data through wk 24. The primary endpoint was mean change in Hb from BL to wk 24. Secondary endpoints included mean change in transferrin saturation (TSAT), ferritin, and phosphate to wk 24. Results 206 subjects were randomized, 183 were included in this analysis after completing the 24-wk dose titration period. Groups were well matched with mean age of 69.5 +/- 10.32 years, 64% female and 54% had diabetes as a cause of CKD. Mean BL eGFR was 33.6 +/- 10.85 ml/min/1.73m2 and Hb 10.45 +/-0.744 g/dL. In subjects who did not require an increase in the FC dose at wk 12, mean changes in Hb at wk 24 were 1.05 and 1.24 g/dL in the 1 tablet TID and 2 tablet BID dosage groups, respectively. In subjects who required an increase in the FC dose at wk 12, mean changes in Hb at wk 24 were 0.41 and 0.13 g/dL in the 2 tablet TID and 3 tablet BID groups, respectively. Mean changes in TSAT, ferritin and phosphate are presented in the Table. The incidence of TEAEs was 78.2% and 75.0% in the BID and TID groups, respectively. The most common AEs reported were diarrhoea, stool discoloration and constipation. The incidence of SAEs was 13.9% and 17.3% in the BID and TID groups, respectively. Five deaths were reported, none were deemed related to FC per the investigator. Conclusion FC was effective and generally well tolerated in the treatment of IDA in this NDD-CKD population. Subjects who had per protocol FC dose increases at wk 12 had less pronounced iron deficiency at BL and smaller increases in Hb suggesting an additional underlying cause of anaemia. Mean changes in Hb, TSAT, ferritin, and phosphate and AE profiles were similar in the BID and TID regimens as well as in 3 g/day and 4 g/day dosing groups supporting the potential for dosing flexibility with FC. Clinicaltrials.gov identifier NCT03236246 Funding provided by Akebia Therapeutics, Inc.

114-LB: An Exploratory Study to Evaluate the Glycemic Variability by Continuous Glucose Monitoring (CGM) with Insulin Glargine 300 U/mL vs. Glargine 100 U/mL in Patients with Type 2 Diabetes

Decreasing glycemic variability (GV) is become a criterion of glycemic control and important goal in the treatment of diabetes. Despite this importance there are only a few reports on GV using continuous glucose monitoring (CGM) patients with T2D on basal insulin. The aim of this exploratory study was to compare the GV after 12 weeks of treatment on Glargine-100U (Glar-100) or Glargine-300U (Glar-300) in T2D patients. Methods: This is 12-week, randomized with parallel arms. Ninety-four T2D subjects &amp;gt;18 y old with HbA1c between 7.5% -11% (9.2±0.9%) on NPH insulin ÷ OAD, were randomized to Glar-100 or Glar-300. A blinded CGM was inserted in a baseline (run-in) and after 12-week patient- driven titration period. The CGM parameter included TIR (70-180mg/dl), MAGE, CV, time in hypoglycemia and in hyperglycemia ranges were uploaded by carelink software and the GV parameters were analyzed by Glyculator software. Results: No differences between groups was found in any analysed GV parameter. The final HbA1c were similar to Glar-100 and Glar-300(8.0±1.12 and 8.15±1.04), however there were a significant difference regarding on total hypoglycemic events verified by self-monitoring blood glucose (SMBG) Glar-100 and Glar-300 groups (0.44±0.43 vs. 0.25± 0.42 episodes/patient/year respectively, p= 0.007). In exploratory analysis in the quartile that reached the HbA1c &amp;lt;7.4% TIR for Glar-300 group was 75.43% and 65.62% for Glar-100 (NS). Conclusion: In this exploratory study, even when we could not detect differences between GV parameters (probably due to not reaching target glycemic control), the lower risk of hypoglycemia with Glar-300 compared to Glar-100 can still be clearly shown. A tendency for longer TIR stay in the Glar-300 group vs. in the Glar-100 group was seen in the subgroup of those who reached close-to-target A1c values. Disclosure D.R. Franco: Advisory Panel; Self; Abbott, Medtronic, Novo Nordisk A/S, Sanofi. Research Support; Self; Sanofi. Speaker’s Bureau; Self; Abbott, AstraZeneca, Medtronic. G.D. Visconti: None. C. Feder: None. J. Baptista: None. A.G. Vianna: Board Member; Self; Abbott, Medtronic, Novo Nordisk A/S. Research Support; Self; Sanofi. Speaker’s Bureau; Self; Lilly Diabetes. M.T. Guimarães: None. F.V. Souza: None. L.A. Tagata: None. F. Eliaschewitz: Advisory Panel; Self; AstraZeneca, Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Bayer AG, GlaxoSmithKline plc., Novo Nordisk A/S, Sanofi-Aventis. Speaker’s Bureau; Self; Eli Lilly and Company. Funding Sanofi

0740 Quality of Life in Phase 3, Placebo-Controlled, Double-Blind, Randomized Withdrawal Study of JZP-258 in Adults with Narcolepsy with Cataplexy

Abstract Introduction Narcolepsy negatively impacts health-related quality of life (HRQoL). Sodium oxybate is a standard of care for the treatment of cataplexy and excessive daytime sleepiness in narcolepsy. JZP-258 is an oxybate product candidate with 92% less sodium. Efficacy and safety of JZP-258 were established in a double-blind randomized withdrawal study in adults with narcolepsy with cataplexy. Methods Participants 18-70 years of age began JZP-258 treatment during a 12-week, open-label, optimized treatment and titration period, followed by a 2-week stable-dose period (SDP). Participants were then randomized to receive placebo or continue JZP-258 treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). HRQoL assessments included the 36-Item Short Form Health Survey Version 2 (SF-36) and 5-level EuroQoL 5-Dimensions Self-Report Questionnaire (EQ-5D-5L). Results 201 participants enrolled; 134 were randomized and received at least 1 dose of double-blind study medication (efficacy population; placebo, n=65; JZP-258, n=69). Decreased scores (worsening) were observed in participants randomized to placebo compared with participants randomized to continue JZP-258 treatment for the SF-36 physical component summary (median [Q1, Q3], −1.92 [−3.46, 1.73] for placebo and −0.03 [−2.07, 2.41] for JZP-258; nominal P=0.02), SF-36 mental component summary (−1.92 [−6.28, 1.34] for placebo and 1.55 [−1.88, 3.78] for JZP-258; nominal P=0.03), and EQ-5D-5L visual analog scale (−5.00 [−10.0, 5.00] for placebo and 0 [0, 5.00] for JZP-258; nominal P=0.01). No change was observed in the EQ-5D-5L crosswalk index (0 [−0.05, 0.03] for placebo and 0 [−0.01, 0.03] for JZP-258; nominal P=0.39). The overall safety profile of JZP-258 was similar to sodium oxybate. Conclusion HRQoL worsened in those randomized to placebo during DBRWP but remained stable in participants who continued JZP-258 treatment. Support Jazz Pharmaceuticals

0753 Cataplexy-Free Days in a Phase 3, Placebo-Controlled, Double-Blind, Randomized Withdrawal Study of JZP-258 in Adults With Narcolepsy With Cataplexy

Abstract Introduction Sodium oxybate (SXB) is a standard of care for the treatment of cataplexy and excessive daytime sleepiness in narcolepsy. JZP-258 is an oxybate product candidate with 92% less sodium. This analysis evaluated cataplexy-free days/week, as a measure of treatment impact, in a placebo-controlled randomized withdrawal study of JZP-258 treatment in patients with narcolepsy. Methods Treatment for cataplexy at study entry included 1) SXB (SXB-only); 2) SXB plus other anticataplectics (SXB+other); 3) anticataplectics other than SXB (other anticataplectics); or 4) cataplexy treatment-naive (anticataplectic-naive). Participants (aged 18-70 years with narcolepsy with cataplexy) began JZP-258 treatment during a 12-week, open-label, optimized treatment and titration period (OLOTTP), followed by a 2-week stable-dose period (SDP). Participants were randomized to receive placebo or continue JZP-258 treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). Results Of 201 enrolled participants, 134 comprised the efficacy population (placebo, n=65; JZP-258, n=69). Median (Q1, Q3) cataplexy-free days/week at first week of OLOTTP (while initiating JZP-258) by prior treatment were SXB-only, 5.8 (2.0, 7.0); SXB+other, 6.4 (5.0, 7.0); other anticataplectics, 4.0 (1.8, 6.0); anticataplectic-naive, 3.5 (0, 5.8). At end of SDP (on stable dose of JZP-258), median (Q1, Q3) cataplexy-free days/week were 6.0 (3.5, 7.0), 6.1 (1.4, 7.0), 6.0 (2.6, 7.0), and 6.2 (4.0, 7.0), respectively. Prior to randomization, there was no difference in median cataplexy-free days/week between participants to be randomized to placebo (6.0 [3.5, 7.0]) or JZP-258 treatment (6.0 [3.0, 7.0]); during DBRWP, median cataplexy-free days/week decreased in participants randomized to placebo (3.5 [0, 5.83]) but remained similar in participants randomized to continue JZP-258 treatment (5.6 [2.8, 7.0]). The overall safety profile of JZP-258 was similar to SXB. Conclusion Number of cataplexy-free days/week increased with JZP-258 treatment in participants previously naive to oxybate. Number of cataplexy-free days/week decreased during placebo exposure in participants randomized to placebo. Support Jazz Pharmaceuticals

0752 JZP-258 Dose Titration and Transition from Sodium Oxybate in a Placebo-Controlled, Double-Blind, Randomized Withdrawal Study in Adult Participants With Narcolepsy With Cataplexy

Abstract Introduction Sodium oxybate (SXB) is a standard of care for the treatment of cataplexy and excessive daytime sleepiness in narcolepsy. JZP-258 is an oxybate product candidate (at same concentration as SXB) with 92% less sodium. JZP-258 dose adjustment during titration was evaluated. Methods At study entry, participants were taking SXB only, SXB+other anticataplectics, anticataplectics other than SXB, or were cataplexy treatment-naive. JZP-258 treatment began during a 12-week, open-label optimized treatment and titration period. Participants taking SXB only or SXB+other anticataplectics transitioned to JZP-258 at the same gram-for-gram dose as SXB and titrated to an efficacious and tolerable (optimal) dose from weeks 3-12. Participants taking other anticataplectics or who were anticataplectic-naive initiated JZP-258 at 4.5 g/night and were titrated to an optimal dose at 1-1.5 g/night/week (maximum total dose, 9 g/night). A 2-week stable-dose period and 2-week, double-blind, randomized withdrawal period followed. Results During the stable-dose period, total nightly JZP-258 dose (median [range]) was higher in participants taking SXB at study entry (SXB-only, 7.5 g [4.5-9.0], n=45; SXB+other anticataplectics, 9.0 g [6.0-9.0], n=14) compared with those not taking SXB (other anticataplectics, 7.5 g [4.5-9.0], n=23; anticataplectic-naive, 7.0 g [3.0-9.0], n=67), and dose adjustments were fewer. In most (69%) participants taking SXB at study entry who entered the stable-dose period, no change in dose was required (median [range] number of adjustments was 0 ([0-8]); for those with a change in dose, most changes were within one titration step (1.5 g/night). In participants not taking SXB at study entry, the median (range) number of adjustments was 3.0 (0-7). Conclusion Most participants taking SXB at study entry transitioned to JZP-258 treatment at the same dose with retained effectiveness. Participants not previously taking SXB achieved a tolerable and efficacious dose of JZP-258 after a median of 3 adjustments. Support Jazz Pharmaceuticals

0478 A Multicenter Pilot Study to Evaluate Next-Dose Transition from Zolpidem to Lemborexant for the Treatment of Insomnia

Abstract Introduction Switching of medications for insomnia occurs often in clinical practice based on a variety of reasons. However, few clinical studies have examined methods for transitioning patients between different insomnia medications. This is especially important to consider when the classes of drugs are different (e.g., GABA-ergic agonism vs orexin receptor antagonism); thus, clinical guidance would be valuable. The safety and efficacy of the dual orexin receptor antagonist lemborexant (LEM) for the treatment of insomnia was confirmed in two Phase 3 studies, SUNRISE-1 (NCT02783729, E2006-G000-304) and SUNRISE-2 (NCT02952820, E2006-G000-303). This pilot study (NCT04009577, E2006-A001-312) was designed to assess pre-specified dosing approaches for directly transitioning from the sedative-hypnotic zolpidem (ZOL), a commonly prescribed sleep aid, to LEM. Methods This multicenter pilot study has enrolled subjects age ≥18 years with an insomnia diagnosis (DSM-5 criteria), who used ZOL (intermittently or frequently) as their only insomnia treatment. Following a 3-week Screening period, eligible subjects enter the Treatment Phase (2-week titration period: assigned to 1 of 3 treatment arms based on ZOL use during Screening), and then the Extension Phase (maintenance period up to 12 weeks). During both the Treatment and Extension Phases, the dose of LEM is flexible between 5 and 10 mg, depending on efficacy and tolerability. The primary endpoint is to evaluate the proportion of subjects taking ZOL who successfully transition to LEM (lemborexant 5 mg [LEM5] or lemborexant 10 mg [LEM10]) after 2 weeks of LEM treatment. Results Enrollment began July 15, 2019. It was initially projected that approximately 110 subjects would be screened to provide about 60 subjects for randomization across 3 treatment arms. Interim data will be presented (planned cutoff date Jan 08, 2020). Conclusion This pilot study will help inform on dosing guidance when transitioning a patient from a GABA-ergic drug to an orexin receptor antagonist. Support Eisai Inc.

0477 Characteristics of Insomnia Subjects Screened for Transitioning from Zolpidem Tartrate to Lemborexant in a Multicenter Pilot Study

Abstract Introduction Patients who take insomnia medication may change medications for reasons including lack of efficacy, adverse events, and dependence concerns. A pilot study (NCT04009577, E2006-A001-312) assessed a dosing approach for transitioning patients from zolpidem tartrate (ZOL; immediate or extended-release) to lemborexant, a dual orexin receptor antagonist. Here we describe characteristics of subjects who entered the study Screening Period and their reasons for wanting to change medications. Methods This multicenter pilot study was conducted in the U.S. and enrolled subjects age ≥18y with insomnia diagnosed per DSM-5 criteria, and who used ZOL (self-reported intermittently [3-4 nights/week] or frequently [≥5 nights/week]) as their only insomnia treatment. Subjects entered a 3-week Screening Period, during which frequency/dose of ZOL taken was recorded; subjects also wore an actigraph continuously. Eligible subjects thereafter entered the Treatment Phase to determine lemborexant dosing (5 or 10mg during a 2-week Titration Period with assignment to 1 of 3 treatment schedules based on ZOL usage frequency during Screening), followed by a 12-week Extension (Maintenance) Phase and a 4-week Follow-up Period. Results Forty-nine subjects entered the Screening period and completed the Chief Complaint Form through November 2019; mean(SD) age was 57.1(13.8)y, 67.3% were female, 69.4% were white, and 28.6% were black. 31 subjects reported using ZOL frequently and 15 reported using ZOL intermittently (3 missing). The most common sleep complaint was waking up too early (n=33), followed by difficulty staying asleep (n=13), and difficulty falling asleep (n=3). Reasons for wanting to switch from ZOL included: ZOL not working (n=19), concerns about taking ZOL (n=14), wanting to try something new/potentially better (n=6), side effects (n=5), and residual daytime sleepiness (n=4). 43/49 subjects completed screening through this period. Conclusion This study offers the opportunity to understand patients’ current use of insomnia medication and their motivation for wanting to change insomnia medications. Support Eisai Inc.