Safety, Tolerability and Pharmacokinetic and Pharmacodynamic Learnings from a Double-Blind, Randomized, Placebo-Controlled, Sequential Group First-in-Human Study of the TRPV1 Antagonist, JNJ-38893777, in Healthy Men
Manitpisitkul P.,Janssen Research & Development LLC |
Mayorga A.,Janssen Research & Development LLC |
Shalayda K.,Janssen Research & Development LLC |
De Meulder M.,Janssen Research & Development |
And 3 more authors.
Clinical Drug Investigation | Year: 2015
Background and Objective: Nociceptive and neuropathic pain, one of common reasons of disability and loss of quality life, are often undertreated due to safety concerns with current therapies. This study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of JNJ-38893777, a potent and selective transient receptor potential vanilloid 1 (TRPV1) channel antagonist in healthy men. Methods: In a single-center, double-blind, placebo-controlled, sequential group, single-ascending-dose phase 1 study, 80 healthy men (18–45 years old; body mass index 18.5 to <30 kg/m2), randomized to two groups, received either JNJ-38893777 (n = 6) or placebo (n = 2) in a dose-escalation manner. The study was designed in two parts: Part 1, an early tablet formulation was administered under fasting conditions at 5, 15, 45, 125, 250, or 500 mg; Part 2, a new tablet formulation was administered in a fasting state (250 mg) and a high-fat fed state (250 mg, 375 mg, or 500 mg). Serial plasma and urine samples (collected over 120 h post-dose) were analyzed using LC–MS/MS for pharmacokinetic evaluations. Results: JNJ-38893777 concentrations peaked from 3.0 to 5.5 h (median) post-administration, and then declined multi-exponentially with a prolonged terminal phase. Renal clearance was negligible. Maximum concentration (Cmax) and area under the concentration–time curve from time zero to infinity (AUC∞) of the early formulation increased with increasing doses but less than dose-proportionally over 5–500 mg (fasted) doses. The new tablet formulation showed no improvements in the fasting state but showed an 11- to 22-fold increase in JNJ-38893777 exposure; interindividual variability reduced from 73–85 % to 23–24 %, and a significant increase (P < 0.05) in heat pain detection threshold (~3 °C) was observed in the fed state. Mild to moderate adverse events were observed, with no evidence of exposure dependence up to 500 mg (fed). Concentration-related increases in body temperature or changes in Fridericia-corrected QT interval (QTcF) were not observed. Conclusion: JNJ-38893777 was tolerated at single doses up to 500 mg (fed) and is suitable for further clinical development. © 2015, Springer International Publishing Switzerland.
Fulcher G.,University of Sydney |
Matthews D.R.,Oxford Center for Diabetes |
Perkovic V.,University of Sydney |
de Zeeuw D.,University of Groningen |
And 8 more authors.
Diabetes Therapy | Year: 2015
Introduction: The efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, was evaluated in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on sulfonylurea monotherapy. Methods: The CANagliflozin cardioVascular Assessment Study (CANVAS) is a double-blind, placebo-controlled cardiovascular outcomes study that randomized participants to placebo or canagliflozin 100 or 300 mg once daily in addition to routine therapy. Participants in the CANVAS trial are men and women aged ≥30 years with T2DM and a history or high risk of cardiovascular disease, and inadequate glycemic control (glycated hemoglobin [HbA1c] ≥7.0% and ≤10.5%) on current antihyperglycemic therapies. The primary objective of this prespecified substudy was to assess change from baseline to 18 weeks in HbA1c among patients on sulfonylurea monotherapy. Results: Of the 4330 patients enrolled in CANVAS, 127 met the entry criteria for the sulfonylurea monotherapy substudy (placebo, n = 45; canagliflozin 100 mg, n = 42; canagliflozin 300 mg, n = 40). At 18 weeks, placebo-subtracted changes (95% confidence interval) in HbA1c were −0.74% (−1.15, −0.33; P < 0.001) and −0.83% (−1.24, −0.42; P < 0.001) with canagliflozin 100 and 300 mg, respectively. Relative to placebo, canagliflozin 100 and 300 mg also decreased fasting plasma glucose (FPG; −2.1 mmol/L [−3.0, −1.2] and −2.7 mmol/L [−3.6, −1.7], respectively). Body weight was lower with canagliflozin 300 mg (–1.8% [−3.2, −0.4]; P = 0.014) but unchanged with canagliflozin 100 mg (−0.4% [−1.8, 1.0]; P = 0.557). Canagliflozin 300 mg increased hypoglycemia episodes compared to canagliflozin 100 mg and placebo (15%, 0%, and 4.4%, respectively). Adverse events (AEs) of male and female genital mycotic infections, pollakiuria, and thirst were more common with canagliflozin. Conclusions: Canagliflozin added to ongoing sulfonylurea monotherapy produced improvements in HbA1c, FPG, and body weight, with an increased incidence of AEs consistent with the mechanism of action of SGLT2 inhibition. Funding: Janssen Research & Development, LLC. Clinical trial registration: ClinicalTrials.gov NCT01032629. © 2015, The Author(s).
Schwartz S.,Cetero Research |
Etropolski M.S.,Janssen Research & Development LLC |
Shapiro D.Y.,Janssen Research & Development LLC |
Rauschkolb C.,Janssen Research & Development LLC |
And 5 more authors.
Clinical Drug Investigation | Year: 2014
Background and Objective: Data from two similarly designed studies of tapentadol extended release (ER) for managing neuropathic pain associated with diabetic peripheral neuropathy (DPN; NCT00455520, NCT01041859) in adults were pooled for this analysis, allowing a detailed evaluation of efficacy in patient subgroups and secondary endpoints. Methods: In each study, patients were titrated to their optimal dose of open-label tapentadol ER [100–250 mg twice daily (bid)] over 3 weeks. Patients with ≥1-point improvement in average pain intensity [11-point numerical rating scale (NRS)] were randomized (1:1) to receive placebo or tapentadol ER during a 12-week, double-blind maintenance period. Results: Mean (standard deviation [SD]) changes in pain intensity from baseline to week 12 of maintenance in the placebo (n = 343) and tapentadol ER (n = 360) groups, respectively, were 1.28 (2.41) and 0.08 (1.87) [least squares mean difference (LSMD): −1.14 (95 % confidence interval [CI]: −1.435, −0.838); P < 0.001, in favour of tapentadol ER]. Significant between-group differences were also observed in changes from the start of the double-blind treatment period to the double-blind endpoint for the Short Form-36 physical functioning, role-physical, bodily pain, social functioning and role-emotional subscale and physical component summary scores, and the EuroQol 5-Dimension health status index (all P < 0.05, in favour of tapentadol ER). No clinically relevant differences were observed in the efficacy of tapentadol ER across patient subgroups divided by age, sex, race, opioid experience and pain intensity. Incidences of treatment-emergent adverse events were 56.0 % (192/343) with placebo and 74.7 % (269/360) with tapentadol ER during maintenance. Conclusion: Results of this pooled analysis indicate that tapentadol ER was effective for managing DPN-related pain, and provided consistent analgesic efficacy across different patient subgroups. © 2014, The Author(s).
Liu Y.,Janssen Research & Development |
Liu Y.,Janssen Research & Development LLC
Journal of Biopharmaceutical Statistics | Year: 2016
In a controlled clinical trial comparing an experimental drug to a control using time to event analysis, the logrank test is normally used to test against the equality between two survival curves when the proportional hazard rate assumption is held, which of course requires non-informative censoring. The authors used an example from a randomized, double-blind, parallel group, low-dose active controlled study comparing the safety and efficacy of two doses (400 mg/day versus 50 mg/day) of study medication used as monotherapy for the treatment of newly diagnosed or recurrent epilepsy. This analysis imputes the event time of subjects considered to have problematic informative censoring to demonstrate the impact of violations in necessary assumptions, and assesses robustness of the p-value as calculated from imputed data as compared with un-imputed data. Assuming a parametric distribution for time to event, had these subjects resulted in an event in the trial after withdrawal, the expected additional time to event is formulated and calculated using methods developed in this article. Combining the imputed informative censoring subjects with the remainder of the original data, new p-values are obtained using the log-rank test and compared to the original p-value. KM plots are also compared. © 2016 Taylor & Francis
News Article | September 2, 2016
The National Institute of Mental Health announced a $15.4 million initiative that will bring academia and industry together using induced pluripotent stem cell (iPSC) technology to delve into the cellular underpinnings of schizophrenia and bipolar disorder and identify or develop drugs to treat the illnesses. Hongjun Song, Ph.D. of Johns Hopkins University School of Medicine and Rusty Gage Ph.D., of the Salk Institute for Biological studies, will co-lead the consortium, which is made up of four academic institutes and two industry partners. The two other academic partners are the University of Michigan and Conrad Prebys Center for Chemical Genomics at the Sanford Burnham Prebys Medical Discovery Institute. The industry partners are Janssen Research & Development and Cellular Dynamics International. According to the announcement, one of the major goals of the project will be to improve the quality of iPSC technology, by creating standards and a reliable, scalable, and reproducible test system for quickly screening libraries of drugs that may be effective against the disorders. “There has been a bottleneck in stem cell research,” Song, professor of neurology and neuroscience at Johns Hopkins said in a prepared statement. “Every lab uses different protocols and cells from different patients, so it’s really hard to compare results. This collaboration gathers the resources needed to create robust, reproducible tests that can be used to develop new drugs for mental health disorders. The research groups hope to take into account a large variety of genetic differences by using iPSCs created from more than 50 patients with bipolar disorder or schizophrenia. The teams will generate four different types of brain cells using iPCs to see which types of cells are influenced by certain genetic differences and at what stage in development those effects occur. After characteristics of each disease are determined at a cellular level, the industry partners will use the system to help determine or develop drugs that can treat these illnesses. “This exciting new research has great potential to expedite drug discovery by using human cells from individuals who suffer from these devastating illnesses,” Husseini K. Manji, M.D., the global therapeutic area head of neuroscience for Janssen Research & Development said in the statement. “Starting with a deeper understanding of each disorder should enable the biopharmaceutical industry to design drug discovery strategies that are focused on molecular pathology.” The consortium hopes that the large amounts of data produced on the molecular and genetic differences between the two disorders will also provide insights for the study of many other mental illness that share some of the genetic variations as bipolar disorder and schizophrenia. The precompetitive agreement is funded by the National Cooperative Reprogrammed Cell Research Groups, which was created by the NIMH in 2013. Bipolar disorder is characterized by severe shifts in mood, energy, and activity levels, and affects about 5.7 million American adults, according to the National Institute of Mental Health. While there are medications that treat symptoms of schizophrenia, which is a disease that affects about 3.2 million Americans, the underlying causes are still unknown.