Fatty Acid Amide Hydrolase Inhibitor Treatment in Men With Chronic Prostatitis/Chronic Pelvic Pain Syndrome: An Adaptive Double-blind, Randomized Controlled Trial

Wagenlehner, Florian M. E.; Till, J. W. Olivier van; Houbiers, J. G. A.; Martina, Reynaldo; Cerneus, Dirk; Melis, Joost; Majek, Antoni; Vjaters, Egils; Urban, Mi­chael; Ramonas, Henrikas; Shoskes, Daniel A.; Nickel, J. Curtis

doi:10.1016/j.urology.2017.02.029

Cited by 48 publications

(39 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, there are also issues associated with the uniform prior and care should be exercised when choosing a prior distribution. In this study, the Bayesian posterior mean and variance were similar to those from the Frequentist analyses (Wagenlehner et al., ), indicating the chosen prior distributions were reasonable.…”

Section: Discussionsupporting

confidence: 74%

“…This was a randomized double blind response adaptive trial to investigate PoC, that is does the drug work in these patients, and to determine the dose response relationship of the drug (Wagenlehner et al., ). Five doses were investigated: placebo, 25 mg twice daily (bid), 75 mg (bid), 150 mg once daily (qd), 150 mg (bid), and 300 mg (bid).…”

Section: Methodsmentioning

confidence: 99%

“…The Phase II study described in this manuscript was a combined PoC and DF study to investigate efficacy and the effective dose range of a drug with a novel model of action in a patient population that is difficult to recruit, using a Bayesian adaptive allocation procedure (Wagenlehner et al., ). Adaptive designs are being applied more often than not in the exploratory phase of drug development.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A combined proof of concept and dose finding study with multiple endpoints: A Bayesian adaptive design in chronic prostatitis/chronic pelvic pain syndrome

et al. 2018

View full text Add to dashboard Cite

There is a need for identifying effective drugs or terminating ineffective drugs as early as possible to optimize efficient and cost effective drug development. The aim of the proposed trial was to simultaneously establish Proof of Concept (PoC) and dose finding (DF) for a new drug with a novel mode of action in a new indication. We simulated and executed an adaptive allocation design to investigate the effects of a drug on male patients suffering from chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). This manuscript describes the clinical trial simulations and primary analysis results. A Bayesian adaptive allocation procedure was employed to allocate patients to treatment using a normal dynamic linear model. The study was to stop early for efficacy if the probability of a clinically significant difference between an experimental arm and placebo was at least 90%. The study was to stop for futility if the probability that the maximum effective dose was better than placebo by at least the futility difference was less than 20%. During the execution phase the study was stopped early, that is 32% less than planned maximum sample size, due to futility. The final results confirmed that the predefined stopping rules were met. In conclusion, the simulations showed that, if the drug was effective, this adaptive design could accomplish both the goals of PoC and DF. However, the study stopped early for futility in line with the simulation predictions for stopping. This resulted in the early stopping of a trial recruiting patients on ineffective treatment.

show abstract

Section: Discussionsupporting

confidence: 74%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A combined proof of concept and dose finding study with multiple endpoints: A Bayesian adaptive design in chronic prostatitis/chronic pelvic pain syndrome

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Although an enormous body of preclinical research has provided convincing evidence of the anti-nociceptive effects of peripherally restricted CB1 receptor agonists, selective CB2 receptor agonists and endocannabinoid degrading enzyme inhibitors, clinical translation of these compounds for pain relief has remained elusive. Some FAAH inhibitors and selective CB1 and CB2 agonists have been tested in clinical studies but failed to produce sufficient anti-nociceptive effects, although some compounds were well tolerated and showed minimal or no adverse events [275][276][277]. A potent and selective FAAH inhibitor, PF04457845, did not produce better anti-nociceptive effects than the placebo when investigated in a randomized placebo controlled clinical trial in patients with osteoarthritis [275].…”

Section: Clinical Perspectivementioning

confidence: 99%

Targeting Peripherally Restricted Cannabinoid Receptor 1, Cannabinoid Receptor 2, and Endocannabinoid-Degrading Enzymes for the Treatment of Neuropathic Pain Including Neuropathic Orofacial Pain

Hossain

Ando

Unno

2020

IJMS

View full text Add to dashboard Cite

Neuropathic pain conditions including neuropathic orofacial pain (NOP) are difficult to treat. Contemporary therapeutic agents for neuropathic pain are often ineffective in relieving pain and are associated with various adverse effects. Finding new options for treating neuropathic pain is a major priority in pain-related research. Cannabinoid-based therapeutic strategies have emerged as promising new options. Cannabinoids mainly act on cannabinoid 1 (CB1) and 2 (CB2) receptors, and the former is widely distributed in the brain. The therapeutic significance of cannabinoids is masked by their adverse effects including sedation, motor impairment, addiction and cognitive impairment, which are thought to be mediated by CB1 receptors in the brain. Alternative approaches have been developed to overcome this problem by selectively targeting CB2 receptors, peripherally restricted CB1 receptors and endocannabinoids that may be locally synthesized on demand at sites where their actions are pertinent. Many preclinical studies have reported that these strategies are effective for treating neuropathic pain and produce no or minimal side effects. Recently, we observed that inhibition of degradation of a major endocannabinoid, 2-arachydonoylglycerol, can attenuate NOP following trigeminal nerve injury in mice. This review will discuss the above-mentioned alternative approaches that show potential for treating neuropathic pain including NOP.

show abstract

“…Both TRPV1-and CB1R-antagonists ablated this pro-nociceptive phenotype, and the authors acknowledged the gaps in knowledge surrounding the range of active lipid signaling molecules that are metabolized by FAAH, with these data suggesting potential limitations of FAAH inhibition based on pain type [221]. Further, it is of value to acknowledge that attempts to examine systemic FAAH-inhibition in the setting of chronic pain have generated conflicting findings [222,223], including a drug candidate (PF-04457845, Pfizer) that was dropped after clearing Phase II clinical trials due to poor efficacy [224]. Several new FAAH inhibitors with improved efficacy are in development; however, this development was placed on hold pending an investigation of the pharmaceutical company Bial's agent, 10-2474, which led to the development of severe neurological disorders during a phase I clinical trial in 5 of 6 subjects, with 1 death [225].…”

Section: Novel Approaches To Modulate the Ocular Ecs: Cannabinoid Recmentioning

confidence: 99%

Potential for endocannabinoid system modulation in ocular pain and inflammation: filling the gaps in current pharmacological options

Lafreniere

Kelly

2018

Neuronal Signaling

View full text Add to dashboard Cite

Challenges in the management of ocular pain are an underappreciated topic. Currently available therapeutics lack both efficacy and clear guidelines for their use, with many also possessing unacceptable side effects. Promising novel agents would offer analgesic, anti-inflammatory, and possibly neuroprotective actions; have favorable ocular safety profiles; and show potential in managing neuropathic pain. Growing evidence supports a link between the endocannabinoid system (ECS) and a range of physiological and disease processes, notably those involving inflammation and pain. Both preclinical and clinical data suggest analgesic and anti-inflammatory actions of cannabinoids and ECS-modifying drugs in chronic pain conditions, including those of neuropathic origin. This review will examine existing evidence for the anatomical and physiological basis of ocular pain, specifically, ocular surface disease and the development of chronic ocular pain. The mechanism of action, efficacy, and limitations of currently available treatments will be discussed, and current knowledge related to ECS-modulation of ocular pain and inflammatory disease will be summarized. A perspective will be provided on the future directions of ECS research in terms of developing cannabinoid therapeutics for ocular pain.

show abstract

Fatty Acid Amide Hydrolase Inhibitor Treatment in Men With Chronic Prostatitis/Chronic Pelvic Pain Syndrome: An Adaptive Double-blind, Randomized Controlled Trial

Cited by 48 publications

References 23 publications

A combined proof of concept and dose finding study with multiple endpoints: A Bayesian adaptive design in chronic prostatitis/chronic pelvic pain syndrome

A combined proof of concept and dose finding study with multiple endpoints: A Bayesian adaptive design in chronic prostatitis/chronic pelvic pain syndrome

Targeting Peripherally Restricted Cannabinoid Receptor 1, Cannabinoid Receptor 2, and Endocannabinoid-Degrading Enzymes for the Treatment of Neuropathic Pain Including Neuropathic Orofacial Pain

Potential for endocannabinoid system modulation in ocular pain and inflammation: filling the gaps in current pharmacological options

Contact Info

Product

Resources

About