scholarly journals Phase 1, Randomized, Double-Blind, Placebo-Controlled Studies on the Safety, Tolerability, and Pharmacokinetics of Naldemedine in Healthy Volunteers

2017 ◽  
Vol 7 (5) ◽  
pp. 474-483 ◽  
Author(s):  
Kazuya Fukumura ◽  
Takaaki Yokota ◽  
Yuko Baba ◽  
Juan Camilo Arjona Ferreira
Keyword(s):  
Healthy Volunteers ◽  
Phase 1 ◽  
Double Blind ◽  
Double Blind Placebo

scholarly journals A Double-Blind, Placebo Controlled, Randomized Phase 1 Cross-Over Study with ALLN-177, an Orally Administered Oxalate Degrading Enzyme

2016 ◽  
Vol 44 (2) ◽  
pp. 150-158 ◽  
Author(s):  
Craig B. Langman ◽  
Danica Grujic ◽  
Rita M. Pease ◽  
Linda Easter ◽  
Jennifer Nezzer ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Healthy Volunteers ◽  
Treatment Period ◽  
Phase 1 ◽  
Urinary Oxalate ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Oxalate Excretion ◽  
Urinary Oxalate Excretion ◽  
Dietary Oxalate

Background: Hyperoxaluria may result from increased endogenous production or overabsorption of dietary oxalate in the gastrointestinal tract leading to nephrolithiasis and, in some, to oxalate nephropathy and chronic kidney disease. ALLN-177 is an oral formulation of a recombinant, oxalate specific, microbial enzyme oxalate decarboxylase intended to treat secondary hyperoxaluria by degrading dietary oxalate in the gastrointestinal tract, thereby reducing its absorption and subsequent excretion in the urine. Methods: This double-blind, placebo controlled, randomized, cross-over, phase 1 study of ALLN-177 evaluated the tolerability of ALLN-177 and its effect on urinary oxalate excretion in 30 healthy volunteers with hyperoxaluria induced by ingestion of a high oxalate, low calcium (HOLC) diet. The primary end point was the difference in the mean 24-hour urinary oxalate excretion during the ALLN-177 treatment period compared with the placebo treatment period. Results: The daily urinary oxalate excretion increased in the study population from 27.2 ± 9.5 mg/day during screening to 80.8 ± 24.1 mg/day (mean ± SD) on the HOLC diet before introducing ALLN-177 or placebo therapy for 7 days. Compared to placebo, ALLN-177 treatment reduced urinary oxalate by 11.6 ± 2.7 mg/day, p = 0.0002 (least squares mean ± SD). Conclusions: In healthy volunteers, with diet-induced hyperoxaluria treatment with ALLN-177, when compared to placebo, significantly reduced urinary oxalate excretion by degrading dietary oxalate in the gastrointestinal tract and thereby reducing its absorption. ALLN-177 may represent a new approach for managing secondary hyperoxaluria and its complications.

Randomized, double-blind, placebo-controlled, dose-escalation study: Investigation of the safety, pharmacokinetics, and antihyperalgesic activity of L-4-chlorokynurenine in healthy volunteers

2017 ◽  
Vol 17 (1) ◽  
pp. 243-251 ◽  
Author(s):  
Mark Wallace ◽  
Alexander White ◽  
Kathy A. Grako ◽  
Randal Lane ◽  
Allen (Jo) Cato ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Healthy Volunteers ◽  
Phase 1 ◽  
Spontaneous Pain ◽  
Two Phase ◽  
Double Blind ◽  
Pain Model ◽  
Double Blind Placebo ◽  
Oral Prodrug ◽  
Heat Hyperalgesia

AbstractBackground and aimsNeuropathic pain is a significant medical problem needing more effective treatments with fewer side effects. Overactive glutamatergic transmission viaN-methyl-D-aspartate receptors (NMDARs) are known to play a role in central sensitization and neuropathic pain. Although ketamine, a NMDAR channel-blocking antagonist, is often used for neuropathic pain, its side-effect profile and abusive potential has prompted the search for a safer effective oral analgesic. A novel oral prodrug, AV-101 (L-4 chlorokynurenine), which, in the brain, is converted into one of the most potent and selective GlyB site antagonists of the NMDAR, has been demonstrated to be active in animal models of neuropathic pain. The two Phase 1 studies reported herein were designed to assess the safety and pharmacokinetics of AV-101, over a wide dose range, after daily dosing for 14-days. As secondary endpoints, AV-101 was evaluated in the capsaicin-induced pain model.MethodsThe Phase 1A study was a single-site, randomized, double-blind, placebo-controlled, single oral ascending dose (30–1800 mg) study involving 36 normal healthy volunteers. The Phase 1B study was a single-site randomized, double-blind, placebo-controlled, study of multiple ascending doses (360, 1080, and 1440mg/day) of AV-101 involving 50 normal healthy volunteers, to whom AV-101 or placebo were administered orally daily for 14 consecutive days. Subjects underwent PK blood analyses, laboratory assessments, physical examination, 12-lead ECG, ophthalmological examination, and various neurocognitive assessments. The effect of AV-101 was evaluated in the intradermally capsaicin-induced pain model (ClinicalTrials.gov Identifier: NCT01483846).ResultsTwo Phase 1, with an aggregate of 86 subjects, demonstrated that up to 14 days of oral AV-101, up to 1440mg per day, was safe and very well tolerated with AEs quantitively and qualitatively like those observed with placebo. Mean half-life values of AV-101 were consistent across doses, ranging with an average of 1.73 h, with the highestCmax(64.4 μg/mL) and AUC0-t(196 μgh/mL) values for AV-101 occurring in the 1440-mg dose group. In the capsaicin induce-pain model, there was no significant change in the area under the pain time curve (AUPC) for the spontaneous pain assessment between the treatment and the placebo groups on Day 1 or 14 (the primary endpoint). In contrast, there were consistent reductions at 60–180 min on Day 1 after dosing for allodynia, mechanical hyperalgesia, heat hyperalgesia, and spontaneous pain, and on Day 14 after dosing for heat hyperalgesia.ConclusionsAlthough, AV-101 did not reach statistical significance in reducing pain, there were consistent reductions, for allodynia pain and mechanical and heat hyperalgesia. Given the excellent safety profile and PK characteristics demonstrated by this study, future clinical trials of AV-101 in neuropathic pain are justified.ImplicationsThis article presents the safety and PK of AV-101, a novel oral prodrug producing a potent and selective GlyB site antagonist of the NMDA receptor. These data indicate that AV-101 has excellent safety and PK characteristics providing support for advancing AV-101 into Phase 2 studies in neuropathic pain, and even provides data suggesting that AV-101 may have a role in treating depression.

Su1596 Phase 1, Randomized, Double-Blind, Placebo-Controlled Studies of the Safety, Tolerability and Pharmacokinetics of Naldemedine in Healthy Volunteers

2016 ◽  
Vol 150 (4) ◽  
pp. S537-S538 ◽  
Author(s):  
Kazuya Fukumura ◽  
Takaaki Yokota ◽  
Yuko Baba ◽  
Juan Camilo Arjona Ferreira
Keyword(s):  
Healthy Volunteers ◽  
Phase 1 ◽  
Double Blind ◽  
Double Blind Placebo

P4-381: A Two-Part, Double-Blind, Placebo-Controlled, Phase 1 Study of the Safety and Pharmacokinetics of Single and Multiple Ascending Doses of CT1812 in Healthy Volunteers

2016 ◽  
Vol 12 ◽  
pp. P1183-P1184
Author(s):  
Susan Catalano ◽  
Michael Grundman ◽  
Lon S. Schneider ◽  
Steven DeKosky ◽  
Roger Morgan ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Double Blind ◽  
Double Blind Placebo
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