Completed Study design:
Part A: Single oral dose part in Japanese healthy male adults conducted as a randomized, double-blind, placebo-controlled, parallel-group, dose escalation, comparison study
Part B: Single oral dose part in Japanese elderly males and females conducted as an open-label study
Part C: Multiple oral dose part in Japanese healthy male adults conducted as a randomized, double-blind, placebo-controlled, parallel-group, comparison study Number of participants:
Part A: 32 (4 cohorts, 8 participants in each cohort [6 in the ONO-2808 group and 2 in the placebo group])
Part B: 6 (1 cohort, 3 male and 3 female participants in the ONO-2808 group)
Part C: 16 (2 cohorts, 8 participants in each cohort [6 in the ONO-2808 group and 2 in the placebo group])
In Part A, AEs were observed in 2/6 participants (33.3%) in the ONO-2808 30 mg group, 1/6 participants (16.7%) in the 100 mg fasted group, 1/6 participants (16.7%) in the 100 mg fed group, and 1/6 participants (16.7%) in the 200 mg group. All these AEs were assessed as adverse reactions.
In Part B, AEs were observed in 2/6 participants (33.3%) among overall elderly participants in the ONO-2808 100 mg group, including 1/3 participants (33.3%) in the male group and 1/3 participants (33.3%) in the female group. All these AEs were assessed as adverse reactions.
In Part C, AEs were observed in 2/6 participants (33.3%) in the ONO-2808 20 mg group and 1/6 participants (16.7%) in the 60 mg group. Of these, AEs observed in 1/6 participants (16.7%) in the 20 mg group and 1/6 participants (16.7%) in the 60 mg group were assessed as adverse reactions.
There were no reports of serious adverse events or deaths in any parts. Furthermore, there were no reports of AEs leading to the study intervention discontinuation in Part C (multiple-dose part).
Part A: Adverse events observed in Part A were as follows: head discomfort, diarrhoea, and dizziness in 1/6 participants (16.7%) each in the ONO-2808 30 mg group, stomatitis in 1/6 participants (16.7%) in the 100 mg fasted group, head discomfort in 1/6 participants (16.7%) in the fed group, and constipation in 1/6 participants (16.7%) in the 200 mg group. All these events were Grade 1 in severity and resolved without interventions. All these adverse events were assessed as adverse reactions. When the point estimates (95% confidence interval) for B (slope) in the regression formula of a power model were calculated to investigate the dose proportionality of plasma ONO-2808 pharmacokinetic parameters, Cmax and AUCinf were 1.03 (0.959-1.11) and 1.10 (1.04-1.16), respectively, whereas Cmax and AUCinf generally increased dose-proportionally. When the ratio (90% confidence interval) of pharmacokinetic parameter geometric means in the fed state to the fasted state was calculated to investigate the effect of food on the pharmacokinetics of ONO-2808 in plasma following the administration of ONO-2808 100 mg, Cmax and AUCinf were 0.95 (0.78-1.16) and 1.00 (0.91-1.10), respectively, showing no apparent difference between the fasted and fed states. The urinary excretion of ONO-2808 in the ONO-2808 100 and 200 mg fasted administration groups became almost constant from 120 hours post-dose, and approximately 50% of the dose was excreted as an unchanged drug in the urine.
Part B: In Part B, adverse events were observed in 2/6 participants (33.3%) among overall elderly participants in the ONO-2808 100 mg group, including atrial fibrillation in 1/3 participants (33.3%) in the male group and vomiting in 1/3 participants (33.3%) in the female group. All these events were Grade 1 in severity and resolved without interventions. All these adverse events were assessed as adverse reactions. The ratio (90% confidence interval) of Cmax and AUCinf geometric means in Japanese elderly males and females to Japanese healthy male adults was 1.32 (1.04-1.68) and 0.97 (0.77-1.22), respectively, showing that the ratio of Cmax geometric means in Japanese elderly males and females was approximately 1.3 times higher than that in Japanese healthy adult males, but no apparent difference was found in AUCinf. The ratio (90% confidence interval) of Cmax and AUCinf geometric means in Japanese elderly females to Japanese elderly males was 0.91(0.54-1.54) and 1.15(0.60-2.24), respectively, no apparent difference was noted in the exposure (Cmax and AUCinf) between Japanese elderly males and Japanese elderly females. The urinary excretion rate of ONO-2808 became almost constant from 120 hours post-dose, and approximately 60% of the dose was excreted as an unchanged drug in the urine.
Part C: Adverse events observed in Part C were as follows: calculus urinary and alanine aminotransferase increased in 1/6 participants (16.7%) each in the ONO-2808 20 mg group and drug-induced liver injury in 1/6 participants (16.7%) in the 60 mg group. In the participant who experienced drug-induced liver injury, ALT increased and AST increased were confirmed on laboratory tests. Based on the changes in other laboratory test values and findings of liver biopsy, these findings were assessed as drug-induced liver injury. Drug-induced liver injury was Grade 2 in severity and other events were all Grade 1, all resolved without interventions. Of these, alanine aminotransferase increased observed in 1/6 participants (16.7%) in the 20 mg group and drug-induced liver injury observed in 1/6 participants (16.7%) in the 60 mg group were assessed as adverse reactions. The geometric means (95% confidence intervals) of Cmax (Robs) and AUC24h (Robs) on Day 14 to Day 1 of multiple-dose administration of ONO-2808 were 2.41 (1.97-2.94) and 2.95 (2.58-3.38), respectively, in the ONO-2808 20 mg group and 2.65 (2.14-3.27) and 3.09 (2.52-3.78), respectively, in the 60 mg group. The plasma ONO-2808 trough concentration reached the steady-state approximately on Day 8 in both the 20 and 60 mg groups. Both Cmax and AUC24h of Robs (accumulation coefficient) on Day 14 of multiple-dose administration were approximately two to three times higher than those on Day 1. At 24 hours after the last dose of ONO-2808, ONO-2808 was transferred from plasma to the cerebrospinal fluid (CSF) at a concentration ratio of about 10%.
When ONO-2808 was administered, no safety problems were observed and tolerability was favorable. Meanwhile, when ONO-2808 was orally administered as a multiple-dose, Grade 2 drug-induced liver injury was observed in 1 participant.
AUCinf increased slightly more than dose-proportionally. Cmax in the elderly was approximately 1.3 times higher than that in healthy adult males.The concentration was reached the steady-state approximately on Day 8. Accumulation coefficient was approximately two to three times.
<Japanese healthy adult males and elderly males/females>
1) Japanese healthy adult male subjects, Japanese elderly male or female subjects
2) Age at the time of informed consent: 20 to 45 (Healthy adults), 65 to 74 (Elderly males/Elderly females)
3) BMI (at screening): 18.5 kg/m2 to less than 25.0 kg/m2
1) Subjects who are on a treatment for or with a history of respiratory, cardiovascular, psychiatric, neurologic, gastrointestinal, immunologic, hepatic, renal, hematopoietic or endocrine and/or other disease.
2) Subjects with current or with a history of severe allergy to drugs or foods
3) Subjects with current or with a history of drug or alcohol abuse
1) Part A: Single Japanese Part
A single-dose, dose-escalation, placebo-controlled, double-blind, randomized, parallel-group study in healthy Japanese adult male subjects.
2) Part B (Japanese elderly single dose part)
A single-dose, uncontrolled, open-label study in elderly Japanese men and women.
3) Part C (Japanese Multiple dose part)
A multiple-dose, placebo-controlled, double-blind, randomized, parallel-group study in healthy Japanese adult male subjects.
介入コード / Code
介入キーワード /Keyword
主たる評価項目 / Primary Outcome(s)
安全性評価(全パート)、薬物動態評価(全パート)、脳脊髄液中化合物濃度評価(パートCのみ)
Safety (All Part), Pharmacokinetic (All Part), Compound concentration in cerebrospinal fluid (Part C only)