JNJ-73763989 and bersacapavir treatment in nucleos(t)ide analog suppressed patients with chronic hepatitis B: REEF-2.

BACKGROUND & AIMS: Functional cure (FC) for chronic hepatitis B (CHB) requires finite treatment. Two agents under investigation aimed at achieving FC are small interfering RNA JNJ-73763989 (JNJ-3989) and capsid assembly modulator JNJ-56136379 (JNJ-6379; bersacapavir). METHODS: REEF-2, a phase 2b, double-blind, placebo-controlled, randomized study (ClinicalTrials.gov Identifier: NCT04129554), enrolled 130 nucleos(t)ide analog (NA)-suppressed hepatitis B e-antigen (HBeAg)-negative CHB patients who received JNJ-3989 (200 mg subcutaneously every 4 weeks)+JNJ-6379 (250 mg oral daily)+NA (oral daily; active arm) or placebos for JNJ-3989 and JNJ-6379 + active NA (control arm) for 48 weeks followed by 48 weeks off-treatment follow-up. RESULTS: At Follow-up Week 24, no patients achieved the primary endpoint of FC (off-treatment hepatitis B surface antigen [HBsAg] seroclearance). No patients achieved FC at Follow-up Week 48. There was pronounced on-treatment reduction in mean HBsAg from baseline at Week 48 in the active arm versus no decline in the control arm (1.89 vs 0.06 log10 IU/mL; P = 0.001). At Follow-up Week 48, reductions from baseline were >1 log10 IU/mL in 81.5% versus 12.5% of patients in the active and control arms, respectively, and 38/81 (46.9%) patients in the active arm achieved HBsAg <100 IU/mL versus 6/40 (15.0%) patients in the control arm. Off-treatment HBV DNA relapse and alanine aminotransferase (ALT) increases were less frequent in the active arm with 7/77 (9.1%) and 11/41 (26.8%) patients in the active and control arms, respectively, restarting NA during follow-up. CONCLUSIONS: Finite 48-week treatment with JNJ-3989+JNJ-6379+NA resulted in fewer and less severe posttreatment HBV DNA increases and ALT flares, and a higher proportion of patients with off-treatment HBV DNA suppression, with or without HBsAg suppression, but did not result in FC. GOV IDENTIFIER: NCT04129554.

Efficacy and safety of the siRNA JNJ-73763989 and the capsid assembly modulator JNJ-56136379 (bersacapavir) with nucleos(t)ide analogues for the treatment of chronic hepatitis B virus infection (REEF-1): a multicentre, double-blind, active-controlled, randomised, phase 2b trial.

BACKGROUND: JNJ-73763989 (JNJ-3989), a small interfering RNA, targets all hepatitis B virus (HBV) RNAs, reducing all HBV proteins. JNJ-56136379 (JNJ-6379; also known as bersacapavir), a capsid assembly modulator, inhibits HBV replication. We aimed to evaluate the efficacy (ie, antiviral activity) and safety of these therapeutics in combination with nucleos(t)ide analogues in patients with chronic hepatitis B. METHODS: The REEF-1 multicentre, double-blind, active-controlled, randomised, phase 2b study was done at 108 hospitals or outpatient centres across 19 countries in Asia, Europe, and North and South America. We included patients aged 18-65 years with chronic hepatitis B (defined as HBsAg positivity at screening and at least 6 months before screening or alternative markers of chronicity [eg, HBV DNA]), including those not currently treated, virologically suppressed, HBeAg positive, and HBeAg negative. Patients were randomly assigned (1:1:2:2:2:2) via permuted block randomisation according to a computer-generated schedule to receive oral nucleos(t)ide analogues once per day plus placebo (control group); oral JNJ-6379 250 mg daily plus nucleos(t)ide analogues (JNJ-6379 dual group); nucleos(t)ide analogues plus subcutaneously injected JNJ-3989 at doses of 40 mg (JNJ-3989 dual 40 mg group), 100 mg (JNJ-3989 dual 100 mg group), or 200 mg (JNJ-3989 dual 200 mg group) every 4 weeks; or JNJ-6379 250 mg plus JNJ-3989 100 mg every 4 weeks plus nucleos(t)ide analogues (triple group) for 48 weeks followed by a follow-up phase. An interactive web response system provided concealed treatment allocation, and investigators remained masked to the intervention groups until the primary analysis at week 48. The primary endpoint was the proportion of patients meeting predefined nucleos(t)ide analogue-stopping criteria (alanine aminotransferase <3 × upper limit of normal, HBV DNA below the lower limit of quantitation, HBeAg negative, and HBsAg <10 IU/mL) at week 48. All patients who received at least one dose of study drug were included in the analysis population used for primary efficacy assessment, excluding those who withdrew because of COVID-19-related reasons, withdrew before week 44, or had no efficacy data (ie, the modified intention-to-treat population). Safety was assessed in all participants who received at least one dose of study drugs. This trial is registered with ClinicalTrials.gov, NCT03982186. The study has been completed. FINDINGS: Between Aug 1, 2019, and April 26, 2022, 470 patients (310 [66%] male and 244 [52%] White) were randomly assigned: 45 to the control group, 48 to the JNJ-6379 dual group, 93 to the JNJ-3989 dual 40 mg group, 93 to the JNJ-3989 dual 100 mg group, 96 to the JNJ-3989 dual 200 mg group, and 95 to the triple group. At week 48, five (5%; 90% CI 2-11) of 91 patients in the JNJ-3989 dual 40 mg group, 15 (16%; 10-24) of 92 in the JNJ-3989 dual 100 mg group, 18 (19%; 13-27) of 94 in the JNJ-3989 dual 200 mg group, eight (9%; 4-15) of 94 in the triple group, and one (2%; 0-10) of 45 in the control group met nucleos(t)ide analogue stopping criteria. No patients in the JNJ-6379 dual group met stopping criteria. 38 (81%) patients who met nucleos(t)ide analogue-stopping criteria at week 48 were virologically suppressed and HBeAg negative at baseline. Ten (2%) of 470 patients had serious adverse events during the treatment phase, and two patients (one each from the JNJ-3989 dual 200 mg group [exercise-related rhabdomyolysis] and the triple group [increase in ALT or AST]) had serious adverse events related to study treatment. During follow-up, 12 (3%) of 460 patients had a serious adverse event; one (<1%), a gastric ulcer, was considered to be related to nucleos(t)ide analogues and occurred in a patient from the JNJ-3989 dual 200 mg group. 29 (6%) of 460 patients in the treatment phase and in ten (2%) of 460 patients in the follow-up phase had grade 3 or 4 adverse events. Five (1%) of 470 patients discontinued treatment due to adverse events, and there were no deaths. INTERPRETATION: Although treatment with JNJ-3989 led to a dose-dependent response for meeting nucleos(t)ide analogue-stopping criteria, it rarely led to HBsAg seroclearance. However, most patients treated with JNJ-3989 had clinically meaningful reductions in HBsAg that might contribute to a liver environment conducive to better immune control and, in turn, might improve the response to immune-modulating therapies. FUNDING: Janssen Research and Development.

Planning for the Next Pandemic: Ethics and Innovation Today for Improved Clinical Trials Tomorrow.

The coronavirus pandemic has brought public attention to the steps required to produce valid scientific clinical research in drug development. Traditional ethical principles that guide clinical research remain the guiding compass for physicians, patients, public health officials, investigators, drug developers and the public. Accelerating the process of delivering safe and effective treatments and vaccines against COVID-19 is a moral imperative. The apparent clash between the regulated system of phased randomized clinical trials and urgent public health need requires leveraging innovation with ethical scientific rigor. We reflect on the Belmont principles of autonomy, beneficence and justice as the pandemic unfolds, and illustrate the role of innovative clinical trial designs in alleviating pandemic challenges. Our discussion highlights selected types of innovative trial design and correlates them with ethical parameters and public health benefits. Details are provided for platform trials and other innovative designs such as basket and umbrella trials, designs leveraging external data sources, multi-stage seamless trials, preplanned control arm data sharing between larger trials, and higher order systems of linked trials coordinated more broadly between individual trials and phases of development, recently introduced conceptually as "PIPELINEs."

Efficacy and safety of canagliflozin in patients with type 2 diabetes and stage 3 nephropathy.

BACKGROUND/AIMS: Some sodium glucose co-transporter 2 (SGLT2) inhibitors are approved for the treatment of patients with type 2 diabetes mellitus (T2DM) with an estimated glomerular filtration rate (eGFR) of ≥45 ml/min/1.73 m(2). The efficacy and safety of canagliflozin, an approved SGLT2 inhibitor, was evaluated in patients with stage 3 chronic kidney disease (CKD; eGFR ≥30 to <60 ml/min/1.73 m(2)). METHODS: This analysis used integrated data from four randomized, placebo-controlled, phase 3 studies that enrolled patients with T2DM and stage 3 CKD. RESULTS are presented for the overall population as well as subgroups with stage 3a CKD (eGFR ≥45 and <60 ml/min/1.73 m(2)) and stage 3b CKD (eGFR ≥30 and <45 ml/min/1.73 m(2)). RESULTS: Among all subjects studied with stage 3 CKD, placebo-subtracted reductions in HbA1c (-0.38 and -0.47%; p < 0.001), body weight (-1.6 and -1.9%; p < 0.001), and systolic blood pressure (-2.8 and -4.4 mm Hg; p < 0.01) were seen with canagliflozin 100 and 300 mg, respectively. Decreases in HbA1c, body weight, and systolic blood pressure were examined in the stage 3a and 3b CKD subgroups, with greater decreases in HbA1c, -0.47% (-0.61, -0.32) and body weight in subjects in stage 3a CKD, -1.8% (-2.3, -1.2) with canagliflozin 100 mg. Initial declines in eGFR were seen early following treatment initiation with canagliflozin, but trended towards baseline over time. The most common adverse events with canagliflozin included genital mycotic infections and adverse events related to reduced intravascular volume likely secondary to osmotic diuresis. CONCLUSION: In subjects with T2DM and stage 3 CKD, canagliflozin reduced HbA1c, body weight, and blood pressure, and was generally well tolerated.

Safety and tolerability of canagliflozin in patients with type 2 diabetes mellitus: pooled analysis of phase 3 study results.

BACKGROUND: Canagliflozin is a sodium glucose cotransporter 2 inhibitor developed for treating type 2 diabetes mellitus (T2DM). METHODS: The safety/tolerability profile of canagliflozin 100 and 300 mg over 26 weeks was assessed using an integrated analysis of data pooled from 4 placebo-controlled, phase 3 studies representing a broad range of patients with T2DM (N = 2313; mean age, 56.0 years; glycated hemoglobin [HbA1c], 8.0%; body mass index, 32.1 kg/m2; estimated glomerular filtration rate, 88.1 mL/min/1.73 m2) on various prespecified background diabetes mellitus treatments. Safety/tolerability evaluations included adverse event (AE) reporting, with additional data collection prespecified for selected AEs, and assessments of renal-related, lipid, and other safety laboratory parameters. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01081834; NCT01106625; NCT01106677; NCT01106690. RESULTS: The overall incidence of AEs was similar with canagliflozin 100 and 300 mg and placebo; incidences of serious AEs and AEs leading to study discontinuation were low across groups. Canagliflozin was associated with higher incidences than placebo of genital mycotic infections and osmotic diuresis-related AEs; these were generally considered by the investigator to be mild to moderate in intensity and infrequently led to discontinuation. Canagliflozin was associated with transient reductions in estimated glomerular filtration rate that trended toward baseline over the assessment period; incidences of renal-related AEs were low across groups. Dose-related increases in the incidence of hypoglycemia episodes were seen with canagliflozin versus placebo in patients on background sulfonylurea; incidences of severe hypoglycemia were low across groups. Hypoglycemia incidence was low overall in patients not on background sulfonylurea, but slightly higher with canagliflozin versus placebo. Relative to placebo, favorable changes in high-density lipoprotein cholesterol and triglycerides were seen with canagliflozin; increases in low-density lipoprotein cholesterol were also seen. Canagliflozin was associated with small changes in other safety laboratory parameters that were not clinically meaningful. CONCLUSIONS: Canagliflozin as monotherapy and as combination therapy was generally well tolerated in patients with T2DM inadequately controlled on their current diabetes mellitus treatment.

Efficacy and safety of canagliflozin compared with placebo in older patients with type 2 diabetes mellitus: a pooled analysis of clinical studies.

BACKGROUND: Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). The efficacy and safety of canagliflozin were evaluated in patients with T2DM <65 and ≥65 years of age. METHODS: Pooled data from 4 randomised, placebo-controlled, 26-week, Phase 3 studies (N = 2,313) evaluating canagliflozin 100 and 300 mg were analysed by age: <65 years (n = 1,868; mean age, 52.8 years) or ≥65 years (n = 445; mean age, 69.3 years). Efficacy evaluations included change from baseline in glycaemic parameters and systolic blood pressure (BP), and percent change from baseline in body weight. Assessment of safety/tolerability included adverse event (AE) reports, incidence of documented hypoglycaemia, and percent change from baseline in fasting plasma lipids. RESULTS: Canagliflozin 100 and 300 mg reduced HbA1c and fasting plasma glucose relative to placebo in patients <65 and ≥65 years of age. Both canagliflozin doses reduced body weight and systolic BP relative to placebo in patients <65 and ≥65 years of age. Incidence of overall AEs was similar across all treatment groups in patients <65 and ≥65 years of age. Incidences of serious AEs and AE-related discontinuations were similar across all treatment groups in patients <65 years of age and higher with canagliflozin 100 mg than other groups in patients ≥65 years of age. As in patients <65 years of age, incidences of genital mycotic infections and osmotic diuresis-related AEs were higher with canagliflozin relative to placebo in those ≥65 years of age. Incidences of urinary tract infections (UTIs), renal-related AEs, AEs related to volume depletion, and documented hypoglycaemia episodes were similar across all treatment groups in patients ≥65 years of age; no notable trends were observed with canagliflozin 100 and 300 mg relative to placebo in these AEs among patients <65 years of age. Changes in lipid parameters with canagliflozin were similar in both age subsets. CONCLUSIONS: Canagliflozin improved glycaemic control, body weight, and systolic BP, and was generally well tolerated in older patients with T2DM. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01081834; NCT01106677; NCT01106625; NCT01106690.

Genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus: a pooled analysis of clinical studies.

OBJECTIVE: To characterize genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) using pooled data from Phase 3 studies. RESEARCH DESIGN AND METHODS: Genital mycotic infections with canagliflozin 100 and 300 mg were evaluated in Population 1 (N = 2313; mean exposure [weeks]: canagliflozin, 24.3; placebo, 23.8), including patients from four placebo-controlled studies, and Population 2 (N = 9439; mean exposure [weeks]: canagliflozin, 68.1; control, 64.4), including patients from eight placebo/active-controlled studies (including older patients and those with renal impairment or high cardiovascular disease risk). CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01081834; NCT01106625; NCT01106677; NCT01106690; NCT01032629; NCT01064414; NCT01106651; NCT00968812. MAIN OUTCOME MEASURES: Adverse events suggestive of genital mycotic infections were recorded, with additional information collected using supplemental electronic case report forms. RESULTS: In Population 1, genital mycotic infection incidence was higher with canagliflozin 100 and 300 mg than placebo (95% confidence intervals excluded zero) in females (10.4%, 11.4%, 3.2%) and males (4.2%, 3.7%, 0.6%). These were generally mild to moderate in intensity, none were serious, and few led to discontinuation. Most events with canagliflozin were treated with antifungal therapies, and median symptom duration following treatment initiation was similar across groups; few patients had >1 event (females, 2.3%; males, 0.9%). Findings with canagliflozin 100 and 300 mg versus control were similar in Population 2 (females: 14.7%, 13.9%, 3.1%; males: 7.3%, 9.3%, 1.6%); a low proportion of males underwent circumcision across groups. Most events with canagliflozin occurred within the first 4 months in females and first year in males; no consistent evidence of dose dependence was observed. Key limitations included lack of laboratory confirmation for most events and variable treatment methods. CONCLUSIONS: Genital mycotic infection incidences were higher with canagliflozin than control in patients with T2DM; events were generally mild to moderate in intensity and responded to standard treatments.

Randomized clinical study of a histamine H3 receptor antagonist for the treatment of adults with attention-deficit hyperactivity disorder.

BACKGROUND: Psychostimulants, including methylphenidate and amphetamine preparations, are commonly prescribed for the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adults. Histamine H3 receptors reside on non-histamine neurons and regulate other neurotransmitters (e.g. acetylcholine, noradrenaline [norepinephrine]) suggesting that H3 antagonists have the potential to improve attention and impulsivity. Research indicates that H3 receptor antagonists due to their novel mechanism of action may have a unique treatment effect offering an important alternative for the treatment of ADHD. Bavisant (JNJ-31001074) is a highly selective, orally active antagonist of the human H3 receptor with a novel mechanism of action, involving wakefulness and cognition, with potential as a treatment for ADHD. OBJECTIVE: The objective of this study was to evaluate the efficacy, safety and tolerability of three dosages of bavisant compared with placebo in adults with ADHD. STUDY DESIGN: This randomized, double-blind, placebo- and active-controlled, parallel-group, multicentre study evaluated three dosages of bavisant (1 mg/day, 3 mg/day or 10 mg/day) and two active controls in adults with ADHD. The study consisted of a screening phase of up to 14 days, a 42-day double-blind treatment phase and a 7-day post-treatment follow-up phase. Efficacy and safety assessments were performed. SETTING: The study was conducted at 37 study centres in the US from April 2009 through January 2010. PARTICIPANTS: Men and women aged 18-55 years with an established diagnosis of ADHD as confirmed by clinician and self-report diagnostic measures were enrolled. INTERVENTION: Participants were randomly assigned equally to one of six treatment groups: placebo, bavisant 1 mg/day, 3 mg/day or 10 mg/day, atomoxetine hydrochloride 80 mg/day or osmotic-release oral system (OROS) methylphenidate hydrochloride 54 mg/day. MAIN OUTCOME MEASURE: The primary efficacy endpoint was the change in the Attention Deficit Hyperactivity Disorder Rating Scale, Version IV (ADHD-RS-IV) total score from baseline (day 1) to the end of the treatment phase (day 42), and included all randomized participants who received one or more doses of study drug and had baseline and one or more post-baseline assessments (intent-to-treat [ITT] population). Safety assessments included treatment-emergent adverse events (TEAEs), laboratory tests and ECG readings. RESULTS: 430 participants were randomized, 424 received one or more doses of study medication and 335 (78%) of those randomized completed the study. Study participants had a mean age of 33.9 years and were predominantly White men. Mean treatment duration ranged from 31.4 to 38.8 days across groups. Mean change from baseline in the total ADHD-RS-IV score at day 42 (primary efficacy endpoint) was -8.8 in the placebo group versus -9.3, -11.2 and -12.2 in the bavisant 1 mg/day, 3 mg/day and 10 mg/day groups, respectively; the change in the 10 mg/day group was not statistically superior to placebo (p=0.161), and hence statistical comparisons of the 1 mg/day and 3 mg/day groups with placebo based on a step-down closed testing procedure were not performed. Mean change from baseline in the total ADHD-RS-IV score at day 42 was superior to placebo in the atomoxetine (-15.3) and OROS methylphenidate (-15.7) groups (p<0.005). Secondary efficacy assessments demonstrated a similar pattern with a non-significant trend towards improvement in the bavisant groups. The two lower dosages showed a good tolerability profile, but the higher dosage of bavisant was less well tolerated, as evidenced by the incidence of total TEAEs (61.8%, 82.4%, 89.0%), and discontinuations due to TEAEs (4.4%, 7.4%, 19.2%) in the bavisant 1 mg/day, 3 mg/day and 10 mg/day groups, respectively, compared with 58.9% and 2.7%, respectively on placebo. In the atomoxetine and OROS methylphenidate groups, the incidence of total TEAEs was 83.8% and 82.4% and discontinuations due to TEAEs was 10.8% and 8.8%, respectively. CONCLUSION: Bavisant, a highly selective, wakefulness-promoting H3 antagonist, did not display significant clinical effectiveness in the treatment of adults with ADHD. CLINICAL TRIAL REGISTRATION NUMBER: NCT00880217.

A randomized trial of paliperidone palmitate and risperidone long-acting injectable in schizophrenia.

Paliperidone palmitate (PP) is a recently (USA) approved injectable new-generation antipsychotic. This 53-wk, Phase-III double-blind study was designed to assess the non-inferiority of PP to risperidone long-acting injectable (RIS-LAI) in schizophrenia treatment. Acutely symptomatic patients (n=749), with a Positive and Negative Syndrome Scale (PANSS) total score between 60 and 120 were randomly allocated to gluteal injections of either (a) PP: 50 mg eq. on days 1 and 8, and flexible dosing [25-100 mg eq. (i.e. 39-156 mg USA dosing)] once-monthly; or (b) RIS-LAI: bi-weekly injections of 25 mg on days 8 and 22, and flexible dosing (25-50 mg) starting from day 36, with allowed oral supplementation. Patients (n=747) were 59% men, 92% white, mean (s.d.) age of 41 (11.95) yr and 45% (n=339) completed the study. Mean (s.d.) change from baseline to endpoint in PANSS total score was: -11.6 (21.22) PP; and -14.4 (19.76) RIS-LAI (per-protocol analysis set, primary measure); least-squares means difference was -2.6 (95% CI -5.84 to 0.61), with a prespecified 5-point non-inferiority margin. PP's suboptimal dosing regimen (<150 mg eq. initial dose) resulted in lower median plasma levels of the active moiety in PP-treated vs. RIS-LAI-treated patients. Insomnia was the most common treatment-emergent adverse event, with a similar incidence in both groups (15%). PP did not demonstrate comparable efficacy to RIS-LAI, which may be attributable to the initiation dosing strategy employed. Tolerability of both treatments was comparable to previous studies, with no new safety signals detected.

Dosing and switching strategies for paliperidone palmitate: based on population pharmacokinetic modelling and clinical trial data.

Paliperidone palmitate is a second-generation, long-acting injectable (LAI) antipsychotic recently approved by the US FDA and European Medicines Agency for use in patients with schizophrenia. This article reviews the recommended dosing regimens for initiation and maintenance treatment with paliperidone palmitate in adult patients with schizophrenia. We also address issues of switching to paliperidone palmitate from other antipsychotics, managing missed doses and dosing in special patient populations. The dosing recommendations that were approved by the FDA and other regulatory agencies around the world are based on the results of population pharmacokinetic (PK) simulations and data from clinical trials that are presented in this review. A one-compartment disposition model with zero/first-order absorption best described the PK of paliperidone palmitate. Population PK models for extended-release paliperidone and long-acting risperidone were also developed and we report the results from these models. The PK profiles for 5000 patients were simulated after paliperidone palmitate injections. The population median and 90% prediction intervals of the simulated plasma concentration versus time profiles after multiple doses are graphically displayed in this review. Based on the data from model-based PK simulations, the approved recommended initiation regimen for paliperidone palmitate is 150 mg equivalent (mg eq.) paliperidone (paliperidone palmitate 234 mg) on day 1 followed by 100 mg eq. paliperidone (paliperidone palmitate 156 mg) on day 8, each administered into the deltoid muscle, using a 1-inch 23-gauge needle in those weighing <90 kg and a 1.5-inch 22-gauge needle in those weighing ≥90 kg. No oral supplementation is required. Monthly maintenance dosing is in the range of 25-150 mg eq. paliperidone (paliperidone palmitate 39-234 mg; recommended dose of 75 mg eq. paliperidone [paliperidone palmitate 117 mg]) injected into the deltoid (needle size is weight adjusted) or gluteal (using a 1.5-inch 22-gauge needle) muscle. The day 8 dose may be administered ±2 days and monthly doses ±7 days, without a clinically significant impact on plasma concentrations. The re-initiation schedule in patients whose last maintenance dose was >6 weeks previously is dependent upon the duration of time since the last paliperidone palmitate injection. In patients with mild renal impairment (creatinine clearance [CL(CR)]: 50-80 mL/min), dosage should be adjusted. No dose adjustment is required in patients with mild or moderate hepatic impairment; no data currently exist regarding severe hepatic impairment. Elderly patients with normal renal function should receive the same dosage as younger adult patients with normal renal function. In the event of an age-related decline in CL(CR), dosage should be adjusted accordingly. Paliperidone palmitate can be initiated the day after discontinuing previous oral antipsychotic treatment. In patients switching from other LAIs (including long-acting risperidone), paliperidone palmitate dosing should be initiated at the time of what would have been the next scheduled injection of the previous LAI, and continued monthly thereafter. In summary, following initiation dosing, paliperidone palmitate is administered on a monthly basis. It is the first of the second-generation antipsychotics to be available and approved with this dosing regimen. Population PK modelling presented in this review has helped provide practical guidance for administering this novel LAI antipsychotic.

A double-blind study of paliperidone palmitate and risperidone long-acting injectable in adults with schizophrenia.

This 13-week double-blind study was designed to assess noninferiority of the recently approved (in the U.S.) injectable atypical antipsychotic paliperidone palmitate (PP) versus risperidone long-acting injectable (RIS-LAI) in adult patients with schizophrenia. Patients (N=1220) were randomized (1:1) to either a) PP: deltoid injections on day 1 (150 mg eq.), day 8 (100 mg eq.), and once-monthly flexible dosing as deltoid or gluteal injections on day 36 (50 mg eq. or 100 mg eq.) and day 64 (50 mg eq. or 100 mg eq. or 150 mg eq.) or b) RIS-LAI: gluteal injections days 8 and 22 (25mg), days 36, 50 (25 or 37.5mg) and days 64, 78 (25, 37.5 or 50mg). RIS-LAI-treated patients received oral supplementation with RIS 1-6 mg/day (days 1 to 28), and PP-treated patients received oral placebo. The safety analysis set (n=1214) included 58% men, 78% white, with mean (SD) baseline PANSS total score: PP, 84.1 (12.09); and RIS-LAI, 83.6 (11.28). Mean (SD) change from baseline to endpoint in PANSS total score decreased similarly in both groups; PP (-18.6 [15.45]) and RIS-LAI (-17.9 [14.24]). PP treatment was noninferior to RIS-LAI (point estimate [95% CI]: 0.4 [-1.62;2.38], per-protocol analysis set [primary analysis]). The tolerability and safety of PP was generally similar to RIS-LAI with no new safety or tolerability findings.

A controlled, evidence-based trial of paliperidone palmitate, a long-acting injectable antipsychotic, in schizophrenia.

Paliperidone palmitate is a long-acting injectable antipsychotic agent. This 13-week, multicenter, randomized (1 : 1 : 1 : 1), double-blind, parallel-group study evaluated the efficacy, safety, and tolerability of fixed 25, 50, and 100 milligram equivalent (mg equiv.) doses of paliperidone palmitate vs placebo administered as gluteal injections on days 1 and 8, then every 4 weeks (days 36 and 64) in 518 adult patients with schizophrenia. The intent-to-treat analysis set (N=514) was 67% men and 67% White, with a mean age of 41 years. All paliperidone palmitate dose groups showed significant improvement vs placebo in the Positive and Negative Syndrome Scale (PANSS) total score (primary efficacy measure; 25 and 50 mg equiv., p=0.02; 100 mg equiv., p<0.001), as well as Clinical Global Impression Severity scores (p< or =0.006) and PANSS negative and positive symptom Marder factor scores (p< or =0.04). The Personal and Social Performance scale showed no significant difference between treatment groups. The overall incidence of treatment-emergent adverse events was similar between groups. Parkinsonism, the most frequently reported extrapyramidal symptom, was reported at similar rates for placebo (5%) and paliperidone palmitate (5-6% across doses). The mean body mass index and mean weight showed relatively small dose-related increases during paliperidone palmitate treatment. Investigator-evaluated injection-site pain, swelling, redness, and induration were similar across treatment groups; scores for patient-evaluated injection-site pain (visual analog scale) were similar across groups and diminished with time. All doses of once-monthly paliperidone palmitate were efficacious and generally tolerated, both locally and systemically. Paliperidone palmitate offers the potential to improve outcomes in adults with symptomatic schizophrenia.

Efficacy and safety of paliperidone palmitate in adult patients with acutely symptomatic schizophrenia: a randomized, double-blind, placebo-controlled, dose-response study.

This 13-week, double-blind study evaluated the efficacy and safety of the atypical antipsychotic paliperidone palmitate (recently approved in the United States) versus placebo administered as monthly gluteal injections (after two initial doses given 1 week apart) in acutely symptomatic patients with schizophrenia. Patients (N=388) were randomly assigned (1 : 1 : 1 : 1) to paliperidone palmitate 50, 100, or 150 mg eq. or placebo. As the 150 mg eq. dose was administered to fewer patients (n=30) than planned, meaningful and definitive conclusions cannot be drawn from the results of this group. The change from baseline in Positive and Negative Syndrome Scale total score at endpoint showed improvement in both paliperidone palmitate 50 and 100 mg eq. groups but was significant only in the 100 mg eq. group (P=0.019). The paliperidone palmitate 50 (P=0.004) and 100 mg eq. (P<0.001) groups showed significant improvement in the Personal and Social Performance score from baseline to endpoint versus placebo. Common adverse events (in >or=2% of patients in any group) more frequent with paliperidone palmitate 50 or 100 mg eq. than placebo (>or=5% difference) were headache, vomiting, extremity pain, and injection site pain. Treatment with paliperidone palmitate (100 mg eq.) was efficacious and all doses tested were tolerable.

Safety and tolerability of oral paliperidone extended-release tablets in elderly patients with schizophrenia: a double-blind, placebo-controlled study with six-month open-label extension.

OBJECTIVE: The objective of this multicenter, international study was to evaluate safety and tolerability of paliperidone extended-release (ER) tablets in elderly (age > or =65 years) patients with schizophrenia. The authors conducted a 6-week, double-blind, randomized, placebo-controlled, optional 24-week open-label extension study. Interventions consisted of flexible, once-daily doses of paliperidone ER (3-12 mg/day; 6-mg starting dose, adjusted in 3-mg dose increments) or placebo (2:1) during double-blind treatment and paliperidone ER only during open-label treatment. Measurements included adverse events, laboratory tests, physical examinations, 12-lead electrocardiograms, movement disorder rating scales, Positive and Negative Syndrome Scale, and Clinical Global Impression scale. The study was not powered to show statistical differences. RESULTS: Patients (N = 114) were predominantly female (73%); mean age was 70 years (double-blind phase). Concomitant disease presence was consistent with that of an older population. During the double-blind phase, discontinuation rates resulting from adverse events were similar between groups (paliperidone ER: 7%, placebo: 8%) as were incidences of treatment-emergent adverse events (paliperidone ER: 67%, placebo: 71%). Serious adverse events occurred in 3% of the paliperidone ER- and 8% of the placebo-treated patients. Elevated prolactin levels occurred in approximately one half of patients. No prolactin- or glucose treatment-related adverse events or noteworthy mean changes in body weight (0 kg [standard deviation: 2.1] and 0 kg [standard deviation: 2.3] for paliperidone ER and placebo, respectively) were observed. Safety and tolerability results in the extension were consistent with the shorter-term results. Efficacy measures did not show consistent statistical improvement between treatment groups. CONCLUSION: Paliperidone ER (3-12 mg/day) treatment over a 30-week period was generally well-tolerated and may improve symptom severity in elderly patients with schizophrenia.

A double-blind, placebo-controlled, randomized study evaluating the effect of paliperidone extended-release tablets on sleep architecture in patients with schizophrenia.

The effects of paliperidone extended-release on sleep architecture in patients with schizophrenia-related insomnia were evaluated in this multicenter, double-blind, randomized, placebo-controlled study. Patients received paliperidone extended-release 9 mg/day or matching placebo during the 14-day double-blind phase. Sleep architecture and sleep continuity were evaluated using polysomnograms. Subjective sleep measures were evaluated daily using the Leeds Sleep Evaluation Questionnaire. Efficacy and safety were also assessed. Thirty-six patients (17 on paliperidone extended-release, 19 on placebo; mean age 32.2 years) completed the study. Paliperidone extended-release treatment vs. placebo resulted in clinically and statistically significant differences in sleep measurements from baseline to endpoint including a reduction in: persistent sleep latency (41 min), sleep onset latency (35 min), number of awakenings after sleep onset (7), time awake in bed (50 min), and stage 1 sleep duration (12 min); prolongation in: total sleep time (53 min), sleep period time (42 min), stage 2 sleep duration (51 min), and rapid eye movement sleep duration (18 min); and an increase in sleep efficiency index (11%). Paliperidone extended-release, compared with placebo, did not exacerbate daytime somnolence and improved symptoms of schizophrenia. Paliperidone extended-release was well tolerated and improved sleep architecture and sleep continuity in patients diagnosed with schizophrenia and concomitant insomnia.

Prevalence and predictors of epoetin hyporesponsiveness in chronic kidney disease patients.

BACKGROUND: The required erythropoiesis-stimulating agent (ESA) dose varies when correcting anaemia in chronic kidney disease (CKD) patients. This analysis was performed to identify the prevalence of and factors associated with ESA hyporesponsiveness. METHODS: This analysis was a post hoc evaluation of epoetin alfa dosage requirements in a subgroup of patients from the Effect of early Correction of Anemia on the Progression of CKD study. The patients in this subgroup were randomly assigned to the high haemoglobin target group (14-15 g/dl for men and 13-14 g/dl for women) and completed a 4-month haemoglobin stabilization phase with complete epoetin dosage data. The relationship of demographics, disease characteristics and laboratory measures with epoetin dosage were evaluated using Pearson's correlation, association measures and analysis of covariance (ANCOVA) models. RESULTS: Of the 93 patients evaluated in this subgroup analysis, 14 (15%) were hyporesponsive to epoetin (maximum dosage >100 IU/kg/week during stabilization). An ANCOVA analysis showed that 52% of the observed variability in epoetin dosage at completion of the stabilization phase could be accounted for by diabetes as the primary cause of kidney disease, angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) use, proteinuria, transferrin saturation, age, pre-treatment haemoglobin, geographical region, serum iron and body mass index (BMI). Unidentified patient characteristics accounted for an additional 16% of the dosage variance. CONCLUSIONS: Older age, higher BMI, anaemia, ACE inhibitor/ARB use and diabetes as the primary cause of kidney disease are associated with increased epoetin requirements when normalizing haemoglobin in anaemic CKD patients.

Effect of early correction of anemia on the progression of CKD.

BACKGROUND: This study is designed to assess the effect of early and complete correction of anemia by using recombinant human erythropoietin (epoetin) alfa on the progression of chronic kidney disease (CKD). METHODS: Patients were randomly assigned to achieve high (13 to 15 g/dL [130 to 150 g/L]) or low (11 to 12 g/dL [110 to 120 g/L]) hemoglobin-level targets during 4 months of stabilization, followed by 36 months of maintenance. Glomerular filtration rate (GFR) decrease was measured by using iohexol clearance. Quality of life, nutrition, and safety also were monitored. RESULTS: Because of labeling changes for subcutaneous administration of epoetin alfa (Eprex; Johnson and Johnson, Schaffhausen, Switzerland), the study was terminated prematurely. There were 195 patients enrolled in each group; 108 high-hemoglobin and 133 low-hemoglobin patients entered the maintenance phase. Mean maintenance duration was 7.4 months for the high-hemoglobin group and 8.3 months for the low-hemoglobin group. GFR decrease was numerically, but not statistically significantly, lower with the high-hemoglobin group (0.058 versus 0.081 mL/min/1.73 m2/mo [< 0.01 mL/s/1.73 m2/mo]). Physical quality-of-life measures showed trends (Role-Physical, P = 0.055; Physical Function, P = 0.083) or statistically significant improvement (Vitality, P = 0.042) with high hemoglobin levels at the end of the stabilization phase. Adverse events were similar between groups. Cardiovascular adverse events occurred in 25% of the high-hemoglobin and 18% of the low-hemoglobin patients (P = 0.137). Neither epoetin dosage nor hemoglobin level was associated with cardiovascular adverse events or death. CONCLUSION: These data suggest that normalization of hemoglobin levels in patients with CKD is safe. Longer duration studies are needed to clarify efficacy benefits with high hemoglobin levels.