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Patients with chronic kidney disease may develop new or more severe anemia when treated with antiplatelet agents due to blood loss in conjunction with impaired erythropoiesis. Because anemia independently predicts limb amputation and mortality among patients with peripheral artery disease (PAD), we evaluated the relationship between estimated glomerular filtration rate (eGFR) and hemoglobin (Hb) levels in the EUCLID trial in which patients with symptomatic PAD were randomized to ticagrelor or clopidogrel. At baseline, 9025, 1870, and 1000 patients had eGFR ⩾ 60, 45–59, and < 45 mL/min/1.73 m2, respectively. The mean fall in Hb during the trial was 0.46 ± 1.68 g/dL and did not differ by baseline eGFR category, although Hb fall ⩾ 10% was more frequent among patients with lower eGFR ( p for trend < 0.0001). On-study treatment with iron, erythropoiesis-stimulating agents, and/or red blood cell transfusion was reported for 479 (5.3%), 165 (8.8%), and 129 (12.9%) patients in the three eGFR categories, respectively ( p for trend < 0.0001). After adjustment for baseline and post-randomization effects, those not receiving anemia treatment had a smaller reduction in Hb from baseline than those receiving anemia treatment ( p < 0.0001). Other determinants of Hb reduction included absence of on-study myocardial infarction, coronary or peripheral revascularization, residence outside North America, male sex, and baseline eGFR. We conclude that among patients with PAD treated with P2Y12 inhibitors, lower baseline eGFR was associated with a greater reduction in Hb. ClinicalTrials.gov Identifier: NCT01732822

Background The Paediatric Asthma Team previously ran faceto- face group clinics and when the Covid-19 meant that outpatient appointments moved to telephone and we wanted to see if Video Group Clinics were more time efficient for the clinicians and provided positive learning opportunities to parents managing wheeze. Objectives Our objective were to see if VGCs improved the following: For Patients . Allow families to learn from each others experiences . Allow more time for teaching and questions . Increase confidence of parents and children managing wheeze at home . Improve convenience by having No travel time and therefore reduce WNB rate For Clinicians . Improve time efficiency . Reduce repetition with teaching . Allow time to cover questions . Add variety in working week Methods . 2 hour training . Wrote and edited appointment letters and pre-clinic questionnaires . Developed a consent and confidentiality agreement specific to online groups . Information Governance permission to use Microsoft Teams . Called patients to get their email addresses to send out information pre clinic . Practice runs . Prepare Power Points on VIW/Asthma/Transition . With the initial high WNB rate we contacted the parents who DNA'd to get feedback and as a result changed our letter to email and forms online, provided a leaflet on discharge from the ward and increased the numbers we invited. . We tried different patient groups 5y new, 5 new and transition clinic. . We kept a record all patients that were invited, those that attended, cancelled and DNA'd . Patients filled out an online feedback form Results . 11 clinics . Over 6 months (July-December 2020) . 62 patients booked . 31 patients attended . 8 cancelled . 23 WNB - 37% WNB rate VGC Negative: . Our administrator typically spends more time contacting parents before the clinic compared with a 1:1 VGC Positives: . Time efficient for clinician (1.5 hours for 4-8 patients vs 3.5 hours for 5 in individual face to face clinic). . More time for teaching/peer learning compared with a 1:1 appointment . Positive experience for the clinicians . Positive feedback: 'Much easier to attend than a walk in appointment' 'No travel was a bonus' 'It was really helpful to be in a group setting and hear experiences from other parents of kids with asthma.' 'I found it useful to hear other people's experiences and how they cope with some of the difficulties encountered.' 'The session was very well facilitated and space felt completely safe.' 'Also some of them asked relevant questions that i might not have thought of on my own' Helpful 'Thank you so much for all the support with my little princess, it was very helpful for me' Conclusions After the initial set up challenges we found the VGC worked best for follow up of 'new' patients with preschool wheeze requiring A+E or hospital admission;we found the time spent for education and recognising wheeze was hugely beneficial. We had consistent positive feedback from parents about the benefits of a group clinic and how much they learnt from peers, we also found it time efficient as a clinician. We will be continuing VGCs beyond the Covid-19 pandemic.

BACKGROUND: Patients with peripheral artery disease (PAD) have a higher risk of major adverse cardiovascular events (MACE) compared with those without PAD.OBJECTIVES: The aim of this post hoc analysis was to evaluate sex-specific differences in MACE and limb events in the EUCLID (Examining Use of Ticagrelor in PAD) trial.METHODS: Cox proportional hazards models were used to compare time-to-event outcomes stratified by sex. Covariates were introduced after adjusted model selection.RESULTS: EUCLID enrolled 13,885 patients with PAD (28% women [n = 3,888]). PAD severity and medical treatment were comparable between sexes, whereas prior lower extremity revascularization was reported less frequently in women (54.8% vs. 57.3%; p = 0.006). Women were older (mean ± SD age: 67.8 ± 8.9 vs. 66.1 ± 8.2 years; p < 0.001) and more likely to have diabetes mellitus (p = 0.004), hypertension, hyperlipidemia, and chronic kidney disease (all p < 0.001). Over a mean follow-up of 30 months, women had a lower risk of MACE (9.5% vs. 11.2%; adjusted hazard ratio: 0.77; 95% confidence interval: 0.68 to 0.88; p < 0.001) and all-cause-mortality (7.6% vs. 9.7%; adjusted hazard ratio: 0.61; 95% confidence interval: 0.53 to 0.71; p < 0.001). In contrast, risk for major adverse limb events (2.6% vs. 3.0%) and hospitalization for acute limb ischemia (1.6% vs. 1.7%) were not different by sex.CONCLUSIONS: Although women with PAD are at lower risk for MACE and all-cause mortality, risk for limb events was similar between sexes over a mean follow-up of 30 months. Understanding sex-specific differences and dissociation between baseline cardiovascular risk and subsequent cardiovascular events requires further investigation. (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease [EUCLID]; NCT01732822).

Background: A reduced ankle-brachial index (ABI) is a measure of atherosclerosis and is associated with ischemic risk in the general population. Whether this relationship is maintained in peripheral artery disease after lower extremity revascularization (LER), which can modify ABI, is unknown. Methods: The EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) enrolled 13 885 patients with symptomatic peripheral artery disease; 57% with prior LER, and 43% with ABI ≤0.80. The primary major adverse cardiovascular events (MACE) outcome was a composite of cardiovascular death, myocardial infarction, or ischemic stroke. Major adverse limb events (MALE) included acute limb ischemia and major amputation. An adjusted Cox proportional hazards model demonstrated a nonlinear relationship between ABI and outcomes. A restricted cubic spline model with 4 knots was developed to identify the best fitting model to describe the relationship between ABI and MACE and MALE risk. Results: Baseline ABI (mean±SD) was 0.77±0.21 in participants with prior LER and 0.63±0.14 in those without prior LER ( P P P P =0.0004) and MALE (hazard ratio, 1.27 [95% CI, 1.08–1.49]; P =0.003). Conclusions: Patients with established peripheral artery disease, particularly those with prior LER, have an increased risk of MACE and MALE. The ABI remains a strong predictor of MACE and MALE ischemic events with an inverse relationship below an ABI threshold for patients with and without prior LER. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01732822.

Background/Introduction: Amputation is a major morbidity of peripheral artery disease (PAD). Although traditionally attributed to ischemia, the multifactorial nature is increasingly recognized, particularly in those with concomitant diabetes mellitus (DM). Elucidating the drivers of amputation in PAD with and without DM may be important in developing strategies for prevention. Purpose: To elucidate the primary drivers of amputations in patients with PAD with and without DM. Methods: EUCLID randomized 13,885 patients with PAD. Investigators prospectively reported all amputations. In this post-hoc analysis, amputations (major – ankle and above, minor – distal to ankle) were retrospectively adjudicated using safety data when available to characterize the drivers including infection, ischemia, or multifactorial. Etiologies were evaluated by DM status at baseline. Results: A total of 415 patients (3% of total) underwent 533 (260 major and 263 minor) amputations over a median of 30 months. Of these, 360 (68%) occurred in the 5,345 patients with DM (n/N of 6.7%) and 173 (32%) occurred in the 8,450 patients without DM (n/N of 2.0%). There were 172 non-traumatic amputations with sufficient documentation to determine drivers. Ischemia was the primary driver overall (51%) followed by infection (27%) and multifactorial (22%). The primary driver, however, varied by DM status with the dominant driver in those with DM being infection (59%) and in those without DM, ischemia (82%) ( Fig. 1 ). The etiology varied for major and minor with the former driven by ischemia (65%) and the latter driven by infection (59%). Conclusions: Amputations in PAD appear to have different primary drivers depending on concomitant DM. Infection may have a larger role in those with DM and ischemia in those without DM. Further research to elucidate the pathobiology and predictors of these outcomes may help in the development of strategies for prevention.

Background: Current guidelines recommend aggressive management of hypertension. Recent evidence suggested potential harm with low blood pressure targets in patients with peripheral artery disease. We investigated the association of a history of hypertension and office systolic blood pressure (SBP) with major adverse cardiovascular events (MACEs) and major adverse limb events (MALEs). Methods and Results: The EUCLID trial (Examining the Use of Ticagrelor in Peripheral Artery Disease) included 13 885 participants with symptomatic peripheral artery disease; median follow-up was 30 months. Cox proportional hazards regression was used to calculate hazard ratios (HRs) for any MACE, MALE, and MALE including lower extremity revascularization. A clinical history of arterial hypertension was present in 10 857 (78%) participants, and these participants were older and more likely to be female when compared with the 3026 (22%) patients without hypertension. In patients with a history of hypertension, the adjusted hazard ratio for MACE was 0.94, 95% CI, 0.82–1.08; P =0.39, and the adjusted hazard ratio for MALE was 1.08, 95% CI, 0.96–1.23; P =0.21. During follow-up, average SBP was 135 mm Hg (125–145). Every 10 mmHg increase in SBP>125 mmHg was associated with an increased risk of MACE (HR, 1.10 [95% CI, 1.06–1.14]; P P =0.062), and an increased risk of MALE/lower extremity revascularization (HR, 1.08 [95% CI, 1.04–1.11]; P P P =0.824; HR, 1.04 [95% CI, 0.95–1.13], P =0.392, respectively). Conclusions: History of hypertension was not associated with higher hazard for MACE or MALE in patients with peripheral artery disease. In contrast, there was a higher hazard of MACE in patients with out-of-target low and high SBP. High but not low SBP was associated with an increased risk of ischemic limb events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01732822.

Amputation remains a frequent and feared outcome in patients with peripheral artery disease (PAD). Although typically characterized as major or minor on the extent of tissue loss, the etiologies and outcomes after amputation by extent are not well-understood. In addition, emerging data suggest that the drivers and outcomes of amputation in patients with PAD may differ in those with and without diabetes mellitus (DM).The EUCLID trial randomized 13,885 patients with symptomatic PAD, including 5345 with concomitant diabetes, to ticagrelor or clopidogrel and followed them for long-term outcomes. Amputations were prospectively reported by trial investigators. Their primary and contributing drivers were adjudicated using safety data, including infection, ischemia, or multifactorial etiologies. Outcomes following major and minor amputations were analyzed, including recurrent amputation, major adverse limb events, adverse cardiovascular events, and mortality. Multivariable logistic regression models were used to identify independent predictors of minor amputations. Analyses were performed overall and stratified by the presence or absence of DM at baseline.Of the patients randomized, 398 (2.9%) underwent at least one lower extremity nontraumatic amputation, for a total of 511 amputations (255 major and 256 minor) over a median of 30 months. A history of minor amputation was the strongest independent predictor for a subsequent minor amputation (odds ratio, 7.29; 95% confidence interval, 5.17-10.30; P .001) followed by comorbid DM (odds ratio, 4.60; 95% confidence interval, 3.16-6.69; P .001). Compared with patients who had a major amputation, those with a minor amputation had similar rates of subsequent major amputation (12.2% vs 13.6%), major adverse limb events (15.1% vs 14.9%), and major adverse cardiovascular events (17.6% vs 16.3%). Ischemia alone was the primary driver of amputation (51%), followed by infection alone (27%), and multifactorial etiologies (22%); however, infection was the most frequent driver in those with DM (58%) but not in those without DM (15%).Outcomes after amputation remain poor regardless of whether they are categorized as major or minor. The pattern of amputation drivers in PAD differs by history of DM, with infection being the dominant etiology in those with DM and ischemia in those without DM. Greater focus is needed on the prognostic importance of minor amputation and of the multifactorial etiologies of amputation in PAD. Nomenclature with anatomical description of amputations and eliminating terms "major" or "minor" would seem appropriate.

In patients with symptomatic peripheral artery disease (PAD), the impact of chronic kidney disease (CKD) on major adverse cardiovascular events has not been fully evaluated. The Examining Use of Ticagrelor In PAD (EUCLID) trial randomized 13,885 patients with PAD to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. This post hoc analysis compared the incidence of the primary composite endpoint (cardiovascular death, myocardial infarction (MI), or ischemic stroke) in patients with CKD (eGFR < 60 mL/min/1.73 m2) with those without CKD (eGFR ⩾ 60 mL/min/1.73 m2). The primary safety endpoint was thrombolysis in MI (TIMI) major bleeding. A total of 13,483 patients were included; 3332 (25%) had CKD, of whom 237 had stage 4/5 disease. Median follow-up was approximately 30 months. After statistical adjustment, patients with CKD had a higher rate of the primary endpoint compared with those without CKD (6.75 vs 3.72 events/100 patient-years; adjusted hazard ratio (HR) 1.45, 95% CI 1.30–1.63). CKD was not associated with increased risk of hospitalization for acute limb ischemia (ALI) (adjusted HR 0.96, 95% CI 0.69–1.34) or major amputation (adjusted HR 0.92, 95% CI 0.66–1.28). CKD was not associated with a significantly increased risk of major bleeding (adjusted HR 1.21, 95% CI 0.89–1.64), but minor bleeding was significantly increased (adjusted HR 1.51, 95% CI 1.07–2.15). In conclusion, patients with PAD and CKD had higher rates of cardiovascular death, MI, and ischemic stroke, but similar rates of ALI, major amputation, and TIMI major bleeding when compared with patients without CKD. ClinicalTrials.gov Identifier: NCT01732822

BackgroundOnasemnogene abeparvovec (AVXS-101) is a gene-replacement therapy that treats the genetic root cause of SMA, biallelic survival motor neuron 1 gene (SMN1) deletion/mutation. In a phase 1 study, AVXS-101 improved survival and motor function of symptomatic SMA type 1 patients. In SPR1NT (NCT03505099), AVXS-101 is being evaluated in presymptomatic newborns with SMA.MethodsSPR1NT is a multicenter, open-label, phase 3 study enrolling ≥27 SMA patients with 2xSMN2or 3xSMN2. Asymptomatic infants aged ≤6 weeks receive a one-time, intravenous AVXS-101 infusion. Safety and efficacy are assessed through 18 or 24 months for patients with 2x or 3xSMN2, respectively. Primary outcomes are independent sitting ≥30 seconds (2xSMN2) or assisted standing (3xSMN2).ResultsAs of 8 March 2019, 18 infants aged 8–40 days received AVXS-101 (11 female; 8 with 2xSMN2; 9 with 3xSMN2; 1 with 4xSMN2). Among patients with 2xSMN2, mean CHOP-INTEND at baseline was 44.0 points, which increased by 14.4 points at 3 months (n=7); 6/8 patients scored ≥60 points; 3/8 reached maximum score. 4/8 patients sat unassisted; all ages of sitting milestone achievements were within the WHO range (1st–99th percentile: 3.8–9.2 months).ConclusionsPreliminary data from SPR1NT show rapid motor function improvements in presymptomatic SMA patients.

Objective To compare the efficacy of high-dose (3,600 mg/day) vs low-dose (1,200 mg/day) oral gabapentin enacarbil (GEn) on pain intensity in adults with postherpetic neuralgia (PHN) and a history of inadequate response to ≥1,800 mg/day gabapentin. Design Multicenter, randomized, double-blind, crossover study ([NCT00617461][1]). Setting Thirty-five outpatient centers in Germany and the United States. Subjects Subjects aged ≥18 years with a diagnosis of PHN. Methods During a 2-week baseline period, subjects received open-label treatment with 1,800 mg/day gabapentin. Subjects who had a mean 24-hour average pain intensity score ≥4 during the last 7 days of the baseline period were randomized to receive GEn (1,200 or 3,600 mg/day) for treatment period 1 (28 days), followed by GEn 2,400 mg/day (4 days), and the alternate GEn dose for treatment period 2 (28 days). Results There was a modest but significant improvement in pain intensity scores with GEn 3,600 mg vs 1,200 mg (adjusted mean [90% confidence interval] treatment difference, −0.29 [−0.48 to −0.10]; P = 0.013). The difference in efficacy between doses was observed primarily in subjects who received the higher dose during treatment period 2; certain aspects of the study design may have contributed to this outcome. Plasma steady-state gabapentin exposure during GEn treatment was as expected and consistent between treatment periods. No new safety signals or adverse event trends relating to GEn exposure were identified. Conclusions While the overall results demonstrated efficacy in a PHN population, the differences between treatment periods confound the interpretation. These findings could provide insight into future trial designs. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00617461&atom=%2Fpainmedicine%2F14%2F12%2F1918.atom

Gabapentin enacarbil (GEn) is an actively transported prodrug of gabapentin that provides sustained, dose-proportional exposure to gabapentin. This randomized, double-blind, parallel-group, placebo-controlled study evaluated the safety and efficacy of 3 different maintenance doses of oral GEn in subjects with postherpetic neuralgia. Adults with a 24-hour average pain intensity score of ≥4.0 received GEn 1,200 mg, 2,400 mg, 3,600 mg, or placebo for 14 weeks (including a 1-week up-titration, 12-week maintenance, and 1-week taper). The primary endpoint was change from baseline to end of maintenance treatment in mean 24-hour average pain intensity score. The intent-to-treat population consisted of 371 subjects (GEn 1,200 mg = 107, 2,400 mg = 82, 3,600 mg = 87, placebo = 95). With regard to the primary endpoint, all 3 GEn treatment groups demonstrated a statistically significant difference relative to placebo. The adjusted mean change from baseline for the treatment groups ranged from −2.36 to −2.72 versus −1.66 for the placebo group. Exposure-response modeling suggested an ED50 around 1,200 mg/day, which was consistent with historical findings reported for gabapentin. The most commonly reported adverse events were dizziness and somnolence. All studied doses of GEn significantly improved pain associated with postherpetic neuralgia as compared to placebo and were well tolerated. Perspective GEn provides clinically important pain relief with doses from 1,200 mg to 3,600 mg and is generally well tolerated and efficacious. As an actively transported prodrug of gabapentin, it provides dose-proportional and extended exposure to gabapentin.

Background Gabapentin enacarbil (GEn), a transported prodrug of gabapentin, provides sustained, dose-proportional gabapentin exposure. The purpose of this study was to investigate the dose response of GEn to select the optimal dose(s) for clinical use in subsequent diabetic peripheral neuropathy (DPN) trials. Methods This was a multicenter, randomized, double-blind, double-dummy, parallel group, placebo-controlled trial with a study duration of approximately 20 weeks (Clinicaltrials.gov database, Identifier ! NCT00643760). Pregabalin (PGB) (Lyrica(®) ; Pfizer Inc.) was used as an active control to provide assay sensitivity of the trial. A total of 421 adult subjects with DPN were randomized in a ratio of 2:1:1:1:2 to receive oral GEn 3,600 mg/day, GEn 2,400 mg/day, GEn 1,200 mg/day, PGB 300 mg/day, or matching placebo, respectively. The primary efficacy endpoint was change from baseline to end of maintenance treatment with respect to the mean 24-hour average pain intensity score based on an 11-point Pain Intensity Numerical Rating Scale (PI-NRS). Safety and tolerability assessments included treatment-emergent adverse events (TEAEs), laboratory evaluations, vital signs, electrocardiograms (ECG), neurological examination, and pedal edema. Results The adjusted mean difference vs. placebo at the end of maintenance treatment with respect to the mean 24-hour average PI-NRS pain intensity score for GEn 1,200 mg (-0.35; [95% CI: -1.02, 0.31]; P = 0.295), GEn 2,400 mg (-0.02; [95% CI: -0.71, 0.66]; P = 0.946), and GEn 3,600 mg (-0.55; [95% CI: -1.10, 0.01]; P = 0.105) was not statistically significant. The active control, PGB (300 mg/day), did not differentiate from placebo. Conclusion Overall, none of the GEn treatment groups differentiated from placebo. Analyses of the secondary endpoints showed comparable results across treatment groups. However, the majority of the endpoints, including all of the pain endpoints, showed the largest numerical treatment difference was between GEn 3,600 mg and placebo. The active control, PGB (300 mg/day), did not differentiate from placebo.

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 1800mg, 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.

CATIE-AD was a multicenter effectiveness trial of atypical antipsychotics in patients with agitation and psychosis associated with AD who resided in the community. The study enrolled 421 participants. In this paper we present and discuss baseline characteristics of participants (demographics, cognitive, behavioral, and functional assessments), caregivers (demographics and caregiver burden) and settings at randomization. Those enrolled suffered from a wide range of cognitive impairment, were medically complex and experienced acute psychopathology requiring intervention with atypical antipsychotics. Family members providing the equivalent of institutional care experienced significant depression and caregiver burden. With the increasing prevalence of AD, clinicians and health care planners should look into future needs of those AD sufferers who are residing in community.

Richard K Bogan,1 Aaron Ellenbogen,2 Philip M Becker,3 Clete Kushida,4 Eric Ball,5 William G Ondo,6 Christine K Caivano,7 Sarah Kavanagh71SleepMed, Columbia, SC, 2Quest Research Institute, Farmington Hills, MI, 3Sleep Medicine Associates of Texas, Dallas, TX, 4Division of Sleep Medicine, Department of Psychiatry and Behavioral Sciences, Stanford Center for Human Sleep Research, Stanford, CA, 5Walla Walla Clinic, Walla Walla, WA, 6University of Texas Health Science Center, Houston, TX, 7Global Regulatory Affairs (CKC)* and Neurosciences MDC (SK), GlaxoSmithKline, Research Triangle Park, NC, USA*Development Sciences department at the time of the analysisPurpose: The aim of the study reported here was assessment of subjective and novel sleep endpoints, according to sleep disturbance severity at baseline, in adult subjects with moderate to severe primary restless legs syndrome (RLS) treated with gabapentin enacarbil (GEn) 1200 mg or placebo.Methods: Integrated analysis of two 12-week randomized trials in subjects with RLS was undertaken. Sleep outcomes from the Medical Outcomes Study (MOS) Sleep Scale and the Post Sleep Questionnaire were evaluated. Novel sleep endpoints derived from the 24-Hour RLS Symptom Diary were compared with similar endpoints derived from the Pittsburgh Sleep Diary (PghSD). Subjects were divided into two subgroups based on their level of sleep disturbance (responses to item 4 of the International Restless Legs Scale) at baseline. Data were analyzed using a last observation carried forward approach.Results: The modified intent-to-treat population comprised 427 subjects (GEn 1200 mg, n = 223; placebo, n = 204). GEn significantly improved all MOS Sleep Scale domain scores from baseline compared with placebo (P < 0.05) in both subgroups. Compared with placebo, GEn-treated subjects with very severe to severe sleep disturbance reported higher overall sleep quality, fewer nighttime awakenings, and fewer hours awake per night due to RLS symptoms at Week 12 on the Post Sleep Questionnaire (all P < 0.001, distribution of responses); sleep quality was the only significant item in those with moderate to no sleep disturbance (P < 0.0001). Evaluation of sleep endpoints derived from the 24-Hour RLS Symptom Diary and PghSD yielded similar results.Conclusion: Once-daily GEn 1200 mg significantly improves subjective sleep outcomes compared with placebo in subjects with RLS, regardless of the severity of sleep disturbance at baseline, although a greater improvement in sleep assessments may be observed in subjects with very severe to severe sleep disturbance than in those with moderate to no disturbance. Similar patterns were observed between treatment groups when comparing sleep endpoints derived from the PghSD and the novel sleep endpoints derived from the 24-Hour RLS Symptom Diary.Keywords: 24-Hour RLS Symptom Diary, Pittsburgh Sleep Diary, Medical Outcomes Study Sleep Scale, Post Sleep Questionnaire