scholarly journals IMI2-PainCare-BioPain-RCT3: a randomized, double-blind, placebo-controlled, crossover, multi-center trial in healthy subjects to investigate the effects of lacosamide, pregabalin, and tapentadol on biomarkers of pain processing observed by electroencephalography (EEG)

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
André Mouraux ◽  
Petra Bloms-Funke ◽  
Irmgard Boesl ◽  
Ombretta Caspani ◽  
Sonya C. Chapman ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Healthy Subjects ◽  
Drug Exposure ◽  
Phase 1 ◽  
Double Blind ◽  
Brain Potentials ◽  
Analgesic Drugs ◽  
Nociceptive System ◽  
Evoked Brain Potentials ◽  
Patient Reported

Abstract Background IMI2-PainCare-BioPain-RCT3 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics, by providing a quantitative understanding between drug exposure and effects of the drug on nociceptive signal processing in human volunteers. IMI2-PainCare-BioPain-RCT3 will focus on biomarkers derived from non-invasive electroencephalographic (EEG) measures of brain activity. Methods This is a multisite single-dose, double-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD) and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from scalp EEG measurements (laser-evoked brain potentials [LEPs], pinprick-evoked brain potentials [PEPs], resting EEG) will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose in separate study periods. Medication effects will be assessed concurrently in a non-sensitized normal condition and a clinically relevant hyperalgesic condition (high-frequency electrical stimulation of the skin). Patient-reported outcomes will also be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split between LEP and PEP under tapentadol. Remaining treatment arm effects on LEP or PEP or effects on EEG are key secondary confirmatory analyses. Complex statistical analyses and PK-PD modeling are exploratory. Discussion LEPs and PEPs are brain responses related to the selective activation of thermonociceptors and mechanonociceptors. Their amplitudes are dependent on the responsiveness of these nociceptors and the state of the pathways relaying nociceptive input at the level of the spinal cord and brain. The magnitude of resting EEG oscillations is sensitive to changes in brain network function, and some modulations of oscillation magnitude can relate to perceived pain intensity, variations in vigilance, and attentional states. These oscillations can also be affected by analgesic drugs acting on the central nervous system. For these reasons, IMI2-PainCare-BioPain-RCT3 hypothesizes that EEG-derived measures can serve as biomarkers of target engagement of analgesic drugs for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification. Trial registration This trial was registered 25/06/2019 in EudraCT (2019%2D%2D001204-37).

A phase III, randomized, double-blind, multicenter trial comparing the investigational agent orteronel (TAK-700) plus prednisone (P) with placebo plus P in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or following docetaxel-based therapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4693-TPS4693 ◽  
Author(s):  
Robert Dreicer ◽  
David B. Agus ◽  
Joaquim Bellmunt ◽  
Johann Sebastian De Bono ◽  
Daniel Peter Petrylak ◽  
...  
Keyword(s):  
Disease Progression ◽  
Fusion Gene ◽  
Phase 1 ◽  
Objective Response ◽  
Specific Antigen ◽  
Phase Iii ◽  
Double Blind ◽  
Investigational Agent ◽  
Patient Reported ◽  
To Receive

TPS4693 Background: The investigational agent orteronel is a selective inhibitor of 17,20-lyase, a key enzyme in the testosterone synthesis pathway. In a phase 1/2 study in men with mCRPC, orteronel reduced prostate-specific antigen (PSA) levels, and inhibited testosterone and DHEA-S consistent with potent 17,20-lyase inhibition (Agus D, et al. J Clin Oncol 2012;30:s5 abst 98). Docetaxel-based chemotherapy is an effective but noncurative therapy for mCRPC that has progressed on hormonal therapy; new therapeutic options are needed. Methods: This double-blind, multicenter study is assessing orteronel + P vs placebo + P in men with mCRPC (NCT01193257; C21005). Patients must have evidence of disease progression during or after receiving a total of ≥360 mg/m2 docetaxel within a 6-mo period. Patients who are clearly intolerant to docetaxel or have progressive disease before receiving ≥360 mg/m2 are also eligible if they have received at least 225 mg/m2 of docetaxel within a 6-mo period and meet the other inclusion criteria. Other eligibility criteria include radiographically documented metastatic disease and baseline testosterone <50 ng/dL following surgical or medical castration. Prior adrenal-targeted therapies are not permitted. Men may have opioid-requiring bone pain. The planned sample size is 1083; men will be randomized 2:1 to receive orteronel 400 mg twice daily (BID) plus P 5 mg BID or placebo plus P. The primary endpoint is overall survival; other endpoints are radiographic progression-free survival, PSA decrease of ≥50% at 12 wks, pain response at 12 wks, safety, time to PSA progression, objective response by RECIST, circulating tumor cell and endocrine marker changes, and patient-reported outcomes. After disease progression, men may continue to receive study drug. Tumor specimens will be analyzed for biomarkers that may predict orteronel antitumor activity, including the TMPRSS2:ERG fusion gene. The same regimens are being evaluated in a concurrent phase 3 study in chemotherapy-naïve men with mCRPC (NCT01193244).

scholarly journals 0146 Efficacy and Safety of Single Dose of TS-142, a Novel and Potent Dual Orexin Receptor Antagonist, in Insomnia Patients

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A58-A58
Author(s):  
M Uchiyama ◽  
D Kambe ◽  
Y Imadera ◽  
H Sunaga ◽  
S Hasegawa ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Healthy Subjects ◽  
Phase 1 ◽  
Sleep Onset ◽  
Pharmacokinetic Profile ◽  
Residual Effects ◽  
Digit Symbol Substitution Test ◽  
Efficacy And Safety ◽  
Serious Adverse Events ◽  
Double Blind

Abstract Introduction TS-142 is a novel dual orexin receptor antagonist (DORA) developed for the treatment of insomnia. Here we report its pharmacokinetic profile in the healthy subjects and its efficacy and safety in patients with insomnia. Methods A phase1 study was conducted to clarify pharmacokinetic profile, in which various doses of TS-142 (1–30 mg) were orally administered once to thirty two healthy subjects. Subsequently, a phase 2a study utilizing polysomnography (PSG) was carried out in patients with primary insomnia, in which 5, 10, or 30 mg of TS-142, or placebo was randomly administered in a double-blind manner. Karolinska Sleepiness Scale (KSS) and Digit Symbol Substitution Test (DSST) were also examined in the morning after PSG. Results Following single administration of TS-142, plasma concentration of unchanged compound reached maximum within 2.50 h (median), and then eliminated rapidly, giving mean elimination half-life between 1.32 and 3.25 h. Twenty-three patients with insomnia completed the Phase2a study. Both latency to persistent sleep (LPS) and wake after sleep onset (WASO) were significantly improved with TS-142 at all doses, in comparison with placebo (-42, -42 and -45 for LPS [min] and -28, -35 and -55 for WASO [min] in 5, 10, 30 mg, respectively). KSS and DSST administered in the morning indicated no serious hangover effects. No serious adverse events were observed in these trials. Conclusion The phase 1 trial showed favorable pharmacokinetic profiles. The phase 2a trial demonstrated that TS-142 was efficacious in objective sleep onset and maintenance with minimal next-day residual effects. TS-142 was generally well tolerated in both studies. Support Taisho Pharmaceutical. Co., Ltd.

scholarly journals Clinical neurorestorative cell therapies: Developmental process, current state and future prospective

2020 ◽  
Vol 8 (2) ◽  
pp. 61-82
Author(s):  
Hongyun Huang
Keyword(s):  
Clinical Trials ◽  
Developmental Process ◽  
Phase 1 ◽  
The United States ◽  
Small Sample ◽  
Cellular Damage ◽  
Placebo Control ◽  
Double Blind ◽  
Cell Therapies ◽  
Current State

Clinical cell therapies (CTs) for neurological diseases and cellular damage have been explored for more than 2 decades. According to the United States Food and Drug Administration, there are 2 types of cell categories for therapy, namely stem cell-derived CT products and mature/functionally differentiated cell-derived CT products. However, regardless of the type of CT used, the majority of reports of clinical CTs from either small sample sizes based on single-center phase 1 or 2 unblinded trials or retrospective clinical studies showed effects on neurological improvement and the ability to either partially or temporarily thwart the deteriorating cellular processes of the neurodegenerative diseases. There have been only a few prospective, multicenter, randomized, double- blind placebo-control clinical trials of CTs so far in this developing novel area that have shown negative results, and more clinical trials are needed. This will expand our knowledge in exploring the type of cells that yield promising results and restore damaged neurological structure and functions of the central nervous system based on higher level evidence-based medical data. In this review, we briefly introduce the developmental process, current state, and future prospective for clinical neurorestorative CT.

SAFETY OF AMISELIMOD IN HEALTHY SUBJECTS: RESULTS FROM A PHASE 1 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY

2021 ◽  
Vol 160 (3) ◽  
pp. S1-S2
Author(s):  
Stephen Hanauer ◽  
Terry O’Reilly ◽  
Robert Lester ◽  
Neal Slatkin ◽  
Jimin Lee ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Phase 1 ◽  
Controlled Study ◽  
Double Blind ◽  
Double Blind Placebo

scholarly journals Pharmacokinetics, Safety, and Tolerability of GS-9851, a Nucleotide Analog Polymerase Inhibitor for Hepatitis C Virus, following Single Ascending Doses in Healthy Subjects

2012 ◽  
Vol 57 (3) ◽  
pp. 1201-1208 ◽  
Author(s):  
Jill Denning ◽  
Melanie Cornpropst ◽  
Stephen D. Flach ◽  
Michelle M. Berrey ◽  
William T. Symonds
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Maximum Concentration ◽  
Healthy Subjects ◽  
Drug Exposure ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Double Blind ◽  
Time Curve ◽  
Nucleotide Analog

ABSTRACTTo investigate the pharmacokinetics, safety, and tolerability of GS-9851 (formerly PSI-7851), a new nucleotide analog inhibitor of hepatitis C virus (HCV), we conducted a double-blind, parallel, placebo-controlled, randomized, single-ascending-dose study. Healthy subjects received oral doses of 25 to 800 mg GS-9851. Peak concentrations of GS-9851 in plasma were achieved more rapidly than those of the metabolites GS-566500 (formerly PSI-352707) and GS-331007 (formerly PSI-6206), with time to maximum concentration of drug in plasma (tmax) values of 1.0 to 1.8 h, 1.5 to 3.0 h, and 3.0 to 6.0 h, respectively. The majority of systemic drug exposure was from the nucleoside GS-331007, with maximum concentration of drug in plasma (Cmax) and area under the concentration-time curve to the last measurable concentration (AUC0–t) values at least 7- and 41-fold higher, respectively, than those obtained for GS-9851 after adjusting for differences in molecular weight. The terminal elimination half-life (t1/2) of GS-331007 increased with the dose, achieving at1/2of 25.7 h at 800 mg GS-9851. Dose proportionality was not observed for GS-331007. The majority of drug recovered in urine was in the form of GS-331007, with the percentage of this metabolite in urine samples ranging from 57% to 27% with increasing dose. GS-9851 was generally well tolerated, with no maximum tolerated dose identified. In conclusion, GS-9851 and its metabolites demonstrated a favorable pharmacokinetic profile consistent with once-daily dosing, and therefore, further clinical studies evaluating GS-9851 in HCV-infected patients are warranted.

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