Moderate Treatment-emergent Adverse Events Research Articles

First-in-human study of alpibectir (BVL-GSK098), a novel potent anti-TB drug.

The clinical candidate alpibectir augments the activity of, and overcomes resistance to, the anti-TB drug ethionamide in vitro and in vivo. A Phase 1, double-blind, randomized, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics (PK) and food effect of alpibectir administered as single and multiple oral doses in healthy volunteers (NCT04654143). Eighty participants were randomized. In single ascending dose (SAD), a total of six dose levels of alpibectir (0.5 to 40 mg) were tested under fasted and fed (10 mg) conditions as single daily doses in sequential cohorts. In multiple ascending dose (MAD), repeat doses (5 to 30 mg) were administered once daily for 7 days in three sequential cohorts. No serious adverse event was reported. Thirteen participants across groups experienced a total of 13 mild or moderate treatment-emergent adverse events. Alpibectir showed rapid absorption after single dose (mean Tmax range of 0.88 to 1.53 h). Food affected the PK of alpibectir, characterized by a slower absorption (mean Tmax 3.87 h), a lower Cmax (-17.7%) and increased AUC0-t (+19.6%) compared with the fasted condition. Following repeat dosing, dose proportionality was shown for both Cmax and AUC0-tau. Accumulation of alpibectir was observed across all doses, with a more profound effect on AUC during a dosing interval (AUC0-tau) compared with Cmax (1.8- and 1.3-fold on average), respectively. Steady state was considered to have been achieved by Day 7 of dosing. Alpibectir was generally well tolerated, and no clinically relevant safety findings were identified in the participants treated during SAD or MAD. The PK is dose-proportional and affected by food.

KP104, a Bifunctional C5 Antibody/Factor H Fusion Protein, Effectively Controls Both Intravascular and Extravascular Hemolysis: Interim Results from a Phase 2 Study in Complement Inhibitor-Naïve PNH Patients

Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematologic disease characterized by intravascular and extravascular hemolysis (IVH and EVH) mediated by complement activation through both the terminal and alternative pathways (TP and AP). The current treatment options for PNH are limited to addressing only a single complement pathway, resulting in either unresolved EVH with TP inhibitors or potentially exposing patients to the risk of life-threatening breakthrough hemolysis with AP inhibitors (Notaro et al. N Engl J Med 2022;387:160-6). KP104 is an innovative fusion protein comprised of a humanized anti-C5 mAb and the functional domain of complement regulator factor H to inhibit both TP and AP activation. We report here the interim results from a phase 2 study of KP104 in complement inhibitor-naïve PNH patients. Methods This open-label Phase 2 clinical trial (NCT05476887) aims to assess the efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of KP104 in patients diagnosed with PNH who have not received prior complement inhibitors. The primary objectives of the study are to evaluate key clinical markers including lactate dehydrogenase (LDH) and hemoglobin (Hgb) levels, transfusion requirements, and FACIT-fatigue scores. The first part of the study consists of three cohorts, with an enrollment of 6 patients per cohort. The study includes an initial treatment period of 12 or 13 weeks of KP104 dosing regimen, followed by a 9-month extension treatment period. The specific dosing regimens for each cohort are as follows: Cohort 1: 1,200 mg IV (Day 1) + 720 mg SC QW (starting Day 8) Cohort 2: 2,400 mg IV (Day 1) + 1,920 mg SC Q2W (starting Day 8) Cohort 3: 3,600 mg IV (Day 1) + 2,880 mg SC Q2W (starting Day 8) Results Interim results include data from 15 patients who completed 16/17 weeks of treatment (6 patients each from Cohort 1 and 2, and 3 from Cohort 3), as of the data cutoff on July 12 th, 2023. Among these patients (4 males and 11 females, mean (±SD) age 33(±12) years, a median of 3 transfusions were required 12 months prior to the study and 9 patients were previously diagnosed with aplastic anemia. Baseline mean (SD) Hgb and LDH levels were 7.0 (±1.5) g/dL and 1,824 (±512) U/L, respectively. By week 16/17, all 15 patients demonstrated positive clinical improvements. Mean (SD) Hgb levels increased by 4.9 (±1.7) g/dL, 5.8 (±1.6) g/dL, and 5.8 (±2.8) g/dL over baseline, and mean (SD) LDH levels reduced by 88.0 (±3.67) %, 83.5 (±7.45) %, and 89.5 (±4.05) % over baseline for Cohort 1, 2 and 3, respectively. Additionally, 9/15 (60%) patients achieved hemoglobin levels ≥12 g/dL (3/6, 5/6 and 1/3 for Cohort 1, 2 and 3, respectively), and all 15 patients had LDH levels below 1.5xULN. None of the 15 patients required transfusions or encountered any thromboembolic events after receiving KP104 treatment. Positive changes were observed in absolute reticulocyte count and bilirubin levels, along with significant enhancements in FACIT-fatigue scores seen in all 3 cohorts, with mean (SD) increases of 13.8 (±7.91), 12.8 (±9.15), and 9.3 (±10.69) for Cohorts 1, 2, and 3, respectively. Dose-dependent reductions in two PD biomarkers, C3b deposition and free C5 levels, further confirmed KP104's dual mechanism of AP and TP inhibition. KP104 was well tolerated, with no serious adverse events or treatment-emergent adverse events (TEAEs) that led to drug discontinuation or study withdrawal. 10/15 (67%) patients reported at least one mild or moderate TEAE, with no observed dose dependency. The most frequently reported TEAEs included transient injection site induration, headache, and COVID-19 infection, all of which were promptly or duly resolved. A single occurrence of clinical breakthrough hemolysis, observed in the lowest dose cohort and concurrent with an episode of gastroenteritis, was quickly resolved after an extra dose. Conclusion The interim results of this phase 2 study demonstrate the safety and efficacy of KP104 in effectively controlling IVH and EVH in complement inhibitor-naïve PNH patients. The findings provide compelling clinical evidence that a bifunctional inhibitor targeting the AP and TP can properly address the current treatment gaps associated with single complement pathway inhibitors, potentially eliminating the need for cumbersome and costly combination therapies (Notaro et al. N Engl J Med 2022;387:160-6).

Safety, Tolerability, and Pharmacokinetics of IMU-935, a Novel Inverse Agonist of Retinoic Acid Receptor-Related Orphan Nuclear Receptor γt: Results From a Double-Blind, Placebo-Controlled, First-in-Human Phase 1 Study.

Retinoic acid receptor-related orphan nuclear receptor (ROR)γt regulates the transcription of interleukin-17 and other cytokines implicated in inflammatory and autoimmune diseases. We assessed the safety, tolerability, and pharmacokinetics (PK) of IMU-935, an inverse agonist of RORγt, in a first-in-human phase 1 study. This was a double-blind, placebo-controlled trial that randomly assigned healthy subjects single ascending doses (25-400mg) or multiple ascending doses (150mg once or twice daily for 14days) of IMU-935 or placebo. Dose escalation was determined by the safety, tolerability, and PK. Twenty-four and 70 subjects received placebo or IMU-935, respectively. Of the 70 subjects who received IMU-935, 59 received a single dose and 11 received multiple doses. Treatment-emergent adverse events (TEAEs) occurred in 21 subjects (88%) and 58 (83%) given any dose of placebo or IMU-935, respectively. Treatment-related TEAEs occurred in 6 (30%) and 25 (42%) subjects given a single dose of placebo and IMU-935, respectively. All treatment-related TEAEs were mild except for 2 moderate TEAEs and 1 moderate TEAE in the IMU-935 group and placebo group, respectively. No treatment-related discontinuations or serious adverse events occurred. The PK of IMU-935 were dose proportional with a half-life of ≈24hours. In conclusion, IMU-935 was safe with no dose-limiting toxicities and had a PK profile that supports once-daily dosing.

Safety and Efficacy of Damoctocog Alfa Pegol Prophylaxis in Patients with Severe Hemophilia A: Interim Results of a Post-Marketing, Interventional Study

BackgroundDamoctocog alfa pegol (BAY 94-9027, Jivi®) is an approved factor (F)VIII treatment indicated for use in previously treated patients with hemophilia A aged ≥12 years, based on its safety and efficacy profile as demonstrated in the PROTECT VIII trial (NCT01580293).Here, we report preliminary results of a post-marketing interventional study of damoctocog alfa pegol prophylaxis in previously FVIII-treated patients with severe hemophilia A aged ≥18 years.MethodsThis is an ongoing, multicenter, single group, uncontrolled, open-label, post-marketing, interventional, phase IV trial (NCT04085458) of damoctocog alfa pegol in previously FVIII-treated patients with severe hemophilia A, aged ≥18 years (Figure 1). Eligible patients receive prophylaxis with damoctocog alfa pegol for 100 exposure days (EDs), starting with 45 IU/kg every 5 days (E5D) (recommended dose) or 40 IU/kg twice-weekly (2×W) until their next planned visit (Visit 3 after 10-15 EDs). At Visit 3, patients can either continue with the same regimen, increase their dose, or switch regimen to 2×W, E5D, or every 7 days (E7D), based on their needs as judged by the investigator. Patients who switched prophylaxis regimen after their third visit were assigned to a variable frequency (VAR) group. Patients with ≥1 infusion of damoctocog alfa pegol and bleeding data for ≥3 months were eligible for inclusion in the modified intent-to-treat cohort and are included in this interim analysis.Primary endpoint is FVIII inhibitor development (titer ≥0.6 Bethesda units). Secondary endpoints include treatment emergent adverse events (TEAE), anti-PEG (polyethylene glycol) antibody development and annualized bleeding rate (ABR). Bleeds and study drug consumption were recorded using an electronic patient diary. All analyses are exploratory.ResultsBy June 1, 2021, 32 patients have been enrolled. Of these, 30 patients have had ≥1 infusion of damoctocog alfa pegol and bleeding data for ≥3 months, and are thus included in this analysis (2×W, n = 7; E5D, n = 8; E7D, n = 9; VAR, n = 6). Median (range) age at start of FVIII treatment was 5.0 (0-15.0) years, with the majority (n = 24; 80.0%) starting with an on-demand regimen. Median (range) age for starting prophylaxis was 32.0 (0-64) years. At data cutoff, median (range) total time in study was 422 (112-554) days and 87 (30-114) EDs. Safety data are presented in Table 1. No patients developed FVIII inhibitors, PEG antibodies or anti-drug antibodies. Sixteen (53.3%) patients developed TEAE, with the majority being mild in severity (n = 12, 40.0%). Three (10.0%) patients experienced mild or moderate TEAEs, which were considered study drug-related by the investigator. At data cutoff, median (quartile, [Q]1; Q3) total and joint ABRs were 1.82 (0.7; 5.5) and 0.37 (0.0; 2.6), respectively. Of 20 patients who were treated for ≥12 months, 30% (n = 6) had zero total bleeds and 60% (n = 12) had zero joint bleeds in their last year of treatment.ConclusionsPreliminary results from 30 patients observed for up to 80 weeks show that individualized prophylaxis regimens of damoctocog alfa pegol were well tolerated in this post-marketing study. No immunogenicity concerns were observed, with no patients developing FVIII inhibitors, anti-PEG or anti-drug antibodies. Despite many patients starting prophylaxis late, ABRs were low and a large proportion achieved zero bleeds. These data support the favorable safety and efficacy profile of damoctocog alfa pegol prophylaxis in routine clinical use. [Display omitted] DisclosuresHolme: Bayer, Octapharma, Pfizer and Shire: Research Funding; Bayer, Novo Nordisk, Octapharma, Pfizer, Shire and Sobi: Consultancy. Hvitfeldt Poulsen: Pfizer: Research Funding; Bayer, Novo Nordisk, Sobi, Pfizer, Octapharma: Other: Congress Support. Tueckmantel: Bayer: Current Employment. Alvarez Roman: Amgen, Bayer, CSL Behring, Novartis, Novo Nordisk, Shire/Takeda, Sobi, Roche: Speakers Bureau; Shire/Takeda: Research Funding. De Cristofaro: Shire/Takeda: Research Funding; Bayer, Takeda: Consultancy; Bayer: Other: Congress Support; Sobi: Consultancy.

An Oral Formulation of the Probiotic, Bacillus subtilis HU58, Was Safe and Well Tolerated in a Pilot Study of Patients with Hepatic Encephalopathy.

Background Hepatic encephalopathy often results in high blood ammonia levels because of inefficient ammonia processing by the liver. Lactulose treatment promotes the growth of urease-producing gut bacteria and a reduced colon pH, thus reducing blood ammonia absorption. It is thought that probiotics as an add-on therapy may be beneficial. Patients and Methods. Bacillus subtilis HU58 was tested for safety and tolerability in patients with hepatic encephalopathy taking lactulose in this double-bind, placebo-controlled, 4-week pilot study. Study participants received one dose of B. subtilis HU58 or placebo (orally) for the first five days and two daily doses thereafter. Participants were monitored for safety and blood ammonia levels. Results Forty patients participated (placebo, 11; probiotic, 29). Baseline characteristics were generally comparable; the mean baseline blood ammonia level was somewhat higher in the probiotic group. Mild or moderate treatment-emergent adverse events (TEAEs) were reported in 27.3% and 17.2% of patients in the placebo and probiotic groups, respectively; no severe TEAEs were reported. One patient (9.1%) taking placebo and two (6.9%) taking the probiotic experienced serious TEAEs (SAEs); none resulted in study discontinuation and all were considered to have no/unlikely relationship to the study product. There were no significant differences in the mean percent change (MPC) of blood ammonia levels between groups, though the probiotic group exhibited a trend toward a milder increase. Stratification of the probiotic group by baseline blood ammonia level (>60 μg/dL and ≤60 μg/dL) resulted in a significantly reduced MPC in the >60 μg/dL subgroup (MPC (SD); ≤60 μg/dL (n = 14), 35.3% (73.3); >60 μg/dL (n = 14), −26.5% (24.4); p = 0.0087). Conclusions Daily treatment with oral B. subtilis HU58 was safe and well tolerated over a 4-week period in patients with hepatic encephalopathy, and a significantly reduced MPC of blood ammonia level was observed in patients with a baseline level >60 µg/dL.

561 Development and first-in-human characterization of a potent oral CCR4 antagonist for the treatment of atopic dermatitis

Atopic dermatitis (AD) is predominantly driven by T helper type 2 cells (Th2). Accumulation of Th2 cells depends on CCR4-mediated recruitment of Th2 cells by the CCR4 ligands CCL17 and CCL22. Both are elevated in inflamed tissue, and levels correlate with disease activity and severity. Here, we describe RPT193, a novel, highly potent and specific oral CCR4 antagonist. In multiple preclinical mouse models of allergic skin inflammation, we demonstrated efficacy and reduction of Th2 cytokines with once daily dosing of RPT193 that is comparable to antibodies specific to IL-4 receptor and IL-13. The safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of escalating single and multiple oral (once daily for 7 days) doses of RPT193 are currently being evaluated in healthy adults. The study has enrolled healthy subjects into 4 single and 4 multiple dose cohorts (randomized 3:1 to receive RPT193 ranging from 50-400 mg or placebo). As of an ad hoc interim analysis, 64 healthy subjects have received single or multiple doses of RPT193 or placebo. Blinded safety review suggests RPT193 has acceptable safety and tolerability with only mild or moderate treatment-emergent adverse events after single or multiple doses. No stopping criteria were met at any dose tested. RPT193 demonstrated linear PK, a terminal half-life of ∼24 hours, and accumulation upon multiple dosing. CCR4 receptor occupancy of >80% at 24 hours post-dose was attained in most subjects receiving single doses and all subjects receiving multiple doses of RPT193. In summary, preclinical data indicate that CCR4 antagonism with RPT193 inhibits allergic skin inflammation in mice akin to targeting IL-13 or the IL-4 receptor. Clinical experience thus far indicates encouraging safety, PK consistent with once daily dosing, and desired target coverage. The data warrant further investigation of RPT193 in patients with AD and potentially other allergic immune conditions.

144 Efficacy and Safety of NER1006 Versus Standard Bowel Preparations: A Meta-Analysis of Randomized Phase 3 Clinical Trials

INTRODUCTION: The efficacy of bowel cleansing is essential for a quality colonoscopy, especially in the setting of colorectal cancer screening. Unfortunately, suboptimal bowel preparation is still observed in 25% of procedures. Recently, a very low-volume 1L PEG solution (NER1006) has been introduced on the evidence of three phase 3 randomized controlled trials. We conducted a meta-analysis to explore cleansing success, adenoma detection rate (ADR), and safety profile of NER1006 versus standard bowel preparations. METHODS: PubMed/Medline and Embase were systematically searched through April 2019 by two independent reviewers (M.M. and F.S.M.) for randomized phase 3 clinical trials comparing the effectiveness of NER1006 versus standard bowel preparations. RESULTS: Three RCTs (four arms, 2151 participants) met the inclusion criteria and were included in the meta-analysis (Table 1). The analysis showed a significant higher overall cleansing success for patients receiving NER1006 compared with standard preparations both using the Harefield Cleansing Scale (HCS) (OR 1.29; 95% CI 1.02–1.61; P = 0.031, I2 = 0%, 2151 participants) and the Boston Bowel Preparation Scale (BBPS) (OR 1.43; 95% CI 1.15–1.78; P = 0.001, I2 = 0%, 2151 participants) (Figure 1a,b), as well as a significant greater high-quality cleansing of the right colon both when assessed with the HCS (OR 2.26; 95% CI 1.44–3.54; P < 0.001, I2 = 70%, 2151 participants) and with the BBPS (OR 1.74; 95% CI 1.09–2.79; P = 0.021, I2 = 66%, 2151 participants) (Figure 1c,d). The pooled estimate of the NER1006 effect on ADR showed no significant difference in terms of overall ADR (OR 1.03; 95% CI 0.85–1.24; P = 0.773, I2 = 0%, 2151 participants), and a higher, although not significant, ADR of the right colon (OR 1.24; 95% CI 0.85–1.79; P = 0.262, I2 = 38%, 2151 participants) (Figure 2a,b). When considering the impact of NER1006 on mild to moderate treatment-emergent adverse events (TEAEs), we observed a significant pooled estimate of number of TEAEs (OR 2.25; 95% CI 1.81–2.80; P < 0.001, I2 = 0%, 2060 participants) and of patients with TEAEs (OR 1.80; 95% CI 1.36–2.38; P < 0.001, I2 = 0%, 2060 participants) (Figure 2c,d). No serious adverse events occurred. CONCLUSION: Compared with standard bowel preparations, NER1006 showed a higher overall cleansing success, a greater high-quality cleansing of the right colon and a higher, although not significant, ADR of the right colon. NER1006 showed a higher incidence of mild to moderate TEAEs, in the absence of serious adverse events.

Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial

Post-partum depression is a serious mood disorder in women that might be triggered by peripartum fluctuations in reproductive hormones. This phase 2 study investigated brexanolone (USAN; formerly SAGE-547 injection), an intravenous formulation of allopregnanolone, a positive allosteric modulator of γ-aminobutyric acid (GABAA) receptors, for the treatment of post-partum depression. For this double-blind, randomised, placebo-controlled trial, we enrolled self-referred or physician-referred female inpatients (≤6 months post partum) with severe post-partum depression (Hamilton Rating Scale for Depression [HAM-D] total score ≥26) in four hospitals in the USA. Eligible women were randomly assigned (1:1), via a computer-generated randomisation program, to receive either a single, continuous intravenous dose of brexanolone or placebo for 60 h. Patients and investigators were masked to treatment assignments. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all randomised patients who started infusion of study drug or placebo and who had a completed baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Patients were followed up until day 30. This trial is registered with ClinicalTrials.gov, number NCT02614547. This trial was done between Dec 15, 2015 (first enrolment), and May 19, 2016 (final visit of the last enrolled patient). 21 women were randomly assigned to the brexanolone (n=10) and placebo (n=11) groups. At 60 h, mean reduction in HAM-D total score from baseline was 21·0 points (SE 2·9) in the brexanolone group compared with 8·8 points (SE 2·8) in the placebo group (difference -12·2, 95% CI -20·77 to -3·67; p=0·0075; effect size 1·2). No deaths, serious adverse events, or discontinuations because of adverse events were reported in either group. Four of ten patients in the brexanolone group had adverse events compared with eight of 11 in the placebo group. The most frequently reported adverse events in the brexanolone group were dizziness (two patients in the brexanolone group vs three patients in the placebo group) and somnolence (two vs none). Moderate treatment-emergent adverse events were reported in two patients in the brexanolone group (sinus tachycardia, n=1; somnolence, n=1) and in two patients in the placebo group (infusion site pain, n=1; tension headache, n=1); one patient in the placebo group had a severe treatment-emergent adverse event (insomnia). In women with severe post-partum depression, infusion of brexanolone resulted in a significant and clinically meaningful reduction in HAM-D total score, compared with placebo. Our results support the rationale for targeting synaptic and extrasynaptic GABAA receptors in the development of therapies for patients with post-partum depression. A pivotal clinical programme for the investigation of brexanolone in patients with post-partum depression is in progress. Sage Therapeutics, Inc.

Prospective Open-Label, Single-Arm, Multicenter, Safety, Tolerability, and Pharmacokinetic Studies of Intravenous Levetiracetam in Children With Epilepsy

Levetiracetam given via intravenous administration has been shown to be an effective alternative in adults with epilepsy when oral administration is not feasible. This study was a prospective single-arm, multicenter study to assess tolerability, safety, and pharmacokinetics of intravenous levetiracetam in children with epilepsy. Children with epilepsy ages 1month to 16 years requiring intravenous levetiracetam were enrolled. Assessments included vital signs, electrocardiogram, hematology, chemistry, plasma concentrations of antiepileptic medications, weight, physical/neurological examinations, and pharmacokinetics. A total of 52 patients were enrolled. Mild to moderate treatment-emergent adverse events occurred in 63%, the most frequent being pyrexia and dry mouth. Most other treatment-emergent adverse events were considered unrelated to intravenous levetiracetam administration. Therefore, intravenous levetiracetam in the acute setting was overall well tolerated in children 1month to 16 years.

Effects of Guanfacine Extended Release on Oppositional Symptoms in Children Aged 6–12 Years with Attention-Deficit Hyperactivity Disorder and Oppositional Symptoms

To evaluate the efficacy and safety of guanfacine extended release (XR, Intuniv; Shire Development Inc., Wayne, PA, USA) in the treatment of oppositional symptoms in children aged 6-12 years with a diagnosis of attention-deficit hyperactivity disorder (ADHD) and the presence of oppositional symptoms. In this randomized, double-blind, placebo-controlled, multicentre, flexible-dose, dose-optimization study, children aged 6-12 years were randomized to receive guanfacine XR (1-4 mg/day) or placebo for 9 weeks. Screening and washout periods were followed by a 5-week dose-optimization period, a 3-week dose-maintenance period and a 1-week tapering period. The primary efficacy measure was change from baseline to endpoint in the oppositional subscale of the Conners' Parent Rating Scale-Revised: Long Form (CPRS-R:L) score. Change in ADHD Rating Scale IV (ADHD-RS-IV) total score was a secondary efficacy measure. Safety assessments included adverse events (AEs), vital signs, ECG readings and laboratory studies. A total of 217 children were enrolled: 138 were randomized to receive guanfacine XR and 79 to receive placebo. Least-squares mean reductions from baseline to endpoint in CPRS-R:L oppositional subscale scores were 10.9 in the guanfacine XR group compared with 6.8 in the placebo group (p < 0.001; effect size = 0.59). A significantly greater reduction in ADHD-RS-IV total score from baseline to endpoint was also seen in the guanfacine-treated group compared with the placebo group (23.8 vs 11.5, respectively; p < 0.001; effect size = 0.92). A post hoc correlation analysis between percentage reduction from baseline to endpoint in CPRS-R:L oppositional subscale and ADHD-RS-IV total scores indicated that the decreases in oppositional symptoms and ADHD symptoms were highly correlated (r = 0.74). The most commonly reported, treatment-emergent AEs (TEAEs) in the guanfacine XR group were somnolence (50.7%), headache (22.1%), sedation (13.2%), upper abdominal pain (11.8%) and fatigue (11.0%) and most were mild or moderate in severity. TEAEs of sedation, somnolence or hypersomnia were experienced by 62.5% of subjects in the guanfacine XR group. These events were most common during the dose-titration period but most (63.5%) resolved prior to the taper period. TEAEs of fatigue, lethargy and asthenia were reported in 11.0%, 3.7% and 0.0% of subjects in the guanfacine XR group, respectively. Most subjects receiving guanfacine XR demonstrated modest changes in blood pressure, pulse rate and ECG readings that were not considered clinically significant. In this population of children aged 6-12 years with ADHD and the presence of oppositional symptoms, significant reductions in CPRS-R:L oppositional subscale and ADHD-RS-IV total scores were observed with guanfacine XR treatment compared with placebo. Treatment with guanfacine XR at optimized doses was associated with mostly mild or moderate TEAEs. The findings of this study support the efficacy of guanfacine XR in the treatment of children with ADHD and the presence of oppositional symptoms. NCT00367835.

Exploratory Polysomnographic Evaluation of Pregabalin on Sleep Disturbance in Patients with Epilepsy

To evaluate the effects of adjunctive pregabalin 300 mg/day versus placebo on polysomnographic (PSG) variables in patients with well controlled partial seizures and subjectively reported sleep disturbance. An exploratory, 4-week, double-blind, randomized study in patients with well controlled partial seizures on AED monotherapy and subjective sleep disturbance over the previous 6 months. Mean changes from baseline to endpoint in PSG and subjective sleep variables (MOS Sleep Scale, Groningen Sleep Questionnaire) in patients on adjunctive pregabalin 300 mg/day (n=8) were compared with patients on placebo (n=7). Baseline PSGs showed sleep fragmentation. Mean sleep efficiency improved significantly in both treatment groups in the mean baseline to endpoint change; there was no significant between-group difference. Pregabalin treatment was associated with a significant reduction in number of awakenings (p = 0.02), and improvement in wake time after sleep onset approached significance (p = 0.055), suggesting improvement in sleep continuity that was not observed in the placebo group. Pregabalin was also associated with significant improvements in the MOS sleep disturbance and sleep quantity subscales compared with placebo (p < or =0.03). There were no changes in self-reported seizure control. This exploratory pilot study suggests that pregabalin may improve sleep continuity in patients with clinically relevant sleep disturbance. The effect on disturbed sleep appears independent of seizure control. The effects of pregabalin on disturbed sleep and seizures and their interrelationships warrant further study.

A randomized, double‐blind trial demonstrating bioequivalence of the current recombinant activated factor VII formulation and a new robust 25°C stable formulation

Recombinant activated factor VIIa (rFVIIa) is a well-established treatment for bleeding episodes in patients with congenital or acquired haemophilia A or B with inhibitors to factors VIII and IX and patients with FVII deficiency. The aim of this trial was to demonstrate bioequivalence between the currently marketed (rFVIIa/NovoSeven) and a new rFVIIa formulation (VII25) stable at up to 25 degrees C. Furthermore, short-term safety and tolerability of VII25 and pharmacokinetics of both formulations were investigated. In this single-centre, randomized, double-blind, two-way cross-over trial, healthy male subjects received one intravenous bolus injection of rFVIIa and one of VII25, both at 90 microg kg(-1), in a randomized order 2-3 weeks apart. Mean VII25/rFVIIa ratio for area under the plasma activity-time curve from time 0 to last quantifiable activity (primary bioequivalence endpoint), was 0.93, 90% confidence interval (CI) (0.89-0.96), within the predefined bioequivalence range (0.80-1.25). Secondary pharmacokinetic parameters were comparable between formulations. No serious adverse events were observed. Six mild or moderate treatment-emergent adverse events were reported in five subjects. Coagulation-related parameter profiles were similar between rFVIIa and VII25. No clinically abnormal changes were observed for laboratory parameters and no subjects developed FVIIa antibodies. This trial demonstrated bioequivalence between the currently available rFVIIa and VII25 stable at up to 25 degrees C. VII25's 'user-friendly' formulation removes the inconvenience of storing/transporting at 2-8 degrees C, and as the drug substance is the same, the activity and safety established for rFVIIa is maintained.

A Randomized, Double-blind, Placebo-controlled Study of Citalopram in Adolescents With Major Depressive Disorder

In a European, multicenter, double-blind study, 244 adolescents, 13 to 18 years old, with major depression were randomized to treatment with citalopram (n = 124) or placebo (n = 120). One third of the patients in both groups withdrew from the study. No significant differences in improvement of scores from baseline to week 12 between citalopram and placebo were found. The response rate was 59% to 61% in both groups according to the Schedule for Affective Disorders and Schizophrenia for school-aged children-Present episode version (Kiddie-SADS-P) (depression and anhedonia scores < or =2) and Montgomery Asberg Depression Rating Scale (MADRS) (> or =50% reduction). Remission (MADRS score < or =12) was achieved by 51% of patients with citalopram and 53% with placebo. A post hoc analysis revealed that more than two thirds of all patients received psychotherapy during this study. For those patients not receiving psychotherapy, there was a higher percentage of Kiddie-SADS-P responders with citalopram (41%) versus placebo (25%) and a significantly higher percentage of MADRS responders and remitters with citalopram (52% and 45%, respectively) versus placebo (22% and 19%, respectively). Mild to moderate treatment-emergent adverse events were reported in 75% citalopram and 71% of placebo patients, most commonly headache, nausea, and insomnia. Serious adverse events occurred in 14% to 15% in both groups. Suicide attempts, including suicidal thoughts and tendencies, were reported by 5 patients in the placebo group and by 14 patients in the citalopram group (not significant) with no pattern with respect to duration of treatment, time of onset, or dosage. In contrast, the suicidal ideation (Kiddie-SADS-P) single item showed worsening more frequently in the placebo (18%) than in the citalopram group (8%).