The main purposes of this study are: * to investigate the safety and tolerability of ACI-19764 when it is administered to healthy participants and participants with cardiovascular risk factors * to determine how quickly and to what extent ACI-19764 is absorbed, transported, metabolized, and excreted by the body (fasted and after a meal) * to determine the effect of ACI-19764 on specific markers in the blood that are part of the immune system The effects of ACI-19764 will be compared with the effects of a placebo. ACI-19764 is a brain-penetrant NLRP3 inhibitor. The study consists of 3 parts, Part A (SAD, single ascending dose) and Part B (MAD, multiple ascending doses) in healthy participants, and Part C (one multiple-dose level) in participants with cardiovascular risk factors. Participants in Part A will receive the study compound once, and participants in Part B and Part C will receive the study compound multiple times (daily over 14 and 28 days, respectively). Parts A and B will be divided into different groups of participants to test different doses of ACI-19764.
In study Part A (SAD part), up to 6 dose levels with 8 male participants in each are planned (6 participants on ACI-19764 and 2 on placebo). Each cohort has a screening period followed by admission to the site for administration of ACI-19764 or placebo. Participants remain onsite for observation for 3 days. Participants may need to return for additional visits for 2 days after discharge to check the blood levels of the drug. A safety follow up call is planned approximately 3 weeks after discharge. In one of the higher dose cohorts, the effect of food on drug levels in the blood will also be explored with an additional admission. There may be fewer than 6 cohorts. In study Part B (MAD part), up to 3 dose levels with 10 participants (8 on active and 2 on placebo) in each are planned. Each dose level will be investigated in a separate cohort of 10 healthy male and female participants (with 4 participants of each sex on active treatment and 1 of each sex on placebo). Each cohort has a screening period followed by admission to the site for 17 days (14-day treatment and 3 days observation). Depending on the blood levels of the drug, participants may have to return to the site for additional blood tests for the 2 days following discharge. A safety phone call is planned approximately 3 weeks after discharge. In study Part C, a single cohort of 36 participants (18 on active and 18 on placebo) with cardiovascular risk factors is planned, including males and females. After the screening period, ACI-19764 or placebo will be administered orally once daily for 4 weeks (i.e., from Day 1 up to and including Day 28). Study participants will be confined to the study site from Day -1 up to Day 2 and from Day 28 to Day 29. In between, they will return to the study site for ambulatory visits on Day 10 and Day 17. When not on site, participants will take ACI-19764 or placebo daily at home. Participants will return to the study site on Day 31 for an ambulatory visit for blood collection. Depending on the blood levels of the drug, participants may have to return to the site on Day 35 for additional blood tests. A safety phone call is planned approximately 3 weeks after discharge.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
114
Placebo capsules matching ACI-19764 capsules
ACI-19764 capsules at dose A1
ACI-19764 capsules at dose A2
ACI-19764 capsules at dose A3
ACI-19764 capsules at dose A4
ACI-19764 capsules at dose A5
ACI-19764 capsules at dose A6
ACI-19764 capsules at dose B1
ACI-19764 capsules at dose B2
ACI-19764 capsules at dose B3
ACI-19764 capsules at dose C1
ICON
Groningen, Netherlands
RECRUITINGFrequency of Adverse Events (AEs) and Serious Adverse Events (SAEs) assessed by intensity (mild, moderate or severe) and causal relationship (unrelated, unlikely related, possibly related or probably related)
Time frame: From first study treatment administration up to the end of the safety follow-up (i.e. 21 to 24 days after Day 4 for study Part A, 21 to 24 days after Day 17 for study Part B, and 21 to 24 days after Day 29 for study Part C)
Vital signs: Change from baseline in blood pressure
Time frame: From baseline up to the end of the treatment and observation period for Parts A and B (i.e. Day 4 for study Part A and Day 17 for study Part B), and up to the end of the safety follow-up for Part C (i.e. 21 to 24 days after Day 29)
Vital signs: Change from baseline in respiratory rate
Time frame: From baseline up to the end of the treatment and observation period for Parts A and B (i.e. Day 4 for study Part A and Day 17 for study Part B), and up to the end of the safety follow-up for Part C (i.e. 21 to 24 days after Day 29)
Vital signs: Change from baseline in pulse rate
Time frame: From baseline up to the end of the treatment and observation period for Parts A and B (i.e. Day 4 for study Part A and Day 17 for study Part B), and up to the end of the safety follow-up for Part C (i.e. 21 to 24 days after Day 29)
Vital signs: Change from baseline in body temperature
Time frame: From baseline up to the end of the treatment and observation period for Parts A and B (i.e. Day 4 for study Part A and Day 17 for study Part B), and up to the end of the safety follow-up for Part C (i.e. 21 to 24 days after Day 29)
ECG: Change from baseline in heart rate
Time frame: From baseline up to the end of the treatment and observation period for Parts A and B (i.e. Day 4 for study Part A and Day 17 for study Part B), and up to the end of the safety follow-up for Part C (i.e. 21 to 24 days after Day 29)
ECG: Change from baseline in PR interval
Time frame: From baseline up to the end of the treatment and observation period for Parts A and B (i.e. Day 4 for study Part A and Day 17 for study Part B), and up to the end of the safety follow-up for Part C (i.e. 21 to 24 days after Day 29)
ECG: Change from baseline in QRS interval
Time frame: From baseline up to the end of the treatment and observation period for Parts A and B (i.e. Day 4 for study Part A and Day 17 for study Part B), and up to the end of the safety follow-up for Part C (i.e. 21 to 24 days after Day 29)
ECG: Change from baseline in QT interval
Time frame: From baseline up to the end of the treatment and observation period for Parts A and B (i.e. Day 4 for study Part A and Day 17 for study Part B), and up to the end of the safety follow-up for Part C (i.e. 21 to 24 days after Day 29)
ECG: Change from baseline in QTcF interval
Time frame: From baseline up to the end of the treatment and observation period for Parts A and B (i.e. Day 4 for study Part A and Day 17 for study Part B), and up to the end of the safety follow-up for Part C (i.e. 21 to 24 days after Day 29)
ECG: Change from baseline in QTcB interval
Time frame: From baseline up to the end of the treatment and observation period for Parts A and B (i.e. Day 4 for study Part A and Day 17 for study Part B), and up to the end of the safety follow-up for Part C (i.e. 21 to 24 days after Day 29)
Number of participants reporting suicidal ideation or behavior using Columbia-Suicide Severity Rating Scale (C-SSRS)
Applicable to study Parts B and C only
Time frame: From baseline up to the end of the treatment and observation period (i.e. Day 17 for study Part B and Day 28 for study Part C)
Pharmacokinetic (PK) in plasma: Maximum observed concentration (Cmax), stratified by sex
Time frame: From baseline to up to the end of the treatment and observation period (i.e. Day 4 for study Part A, Day 17 for study Part B, and Day 28 for study Part C)
Pharmacokinetic (PK) in plasma: Time to reach Cmax (tmax), stratified by sex
Time frame: From baseline to up to the end of the treatment and observation period (i.e. Day 4 for study Part A, Day 17 for study Part B, and Day 28 for study Part C)
Pharmacokinetic (PK) in plasma: Area under the curve (AUC) from time zero to the last measured concentration above the limit of quantification (AUC 0-last)
Applicable to study Part A only
Time frame: From baseline to up to the end of the treatment and observation period (i.e. Day 4)
Pharmacokinetic (PK) in plasma: AUC from time zero to infinity (AUC 0-infinity)
Applicable to study Part A only
Time frame: From baseline to up to the end of the treatment and observation period (i.e. Day 4)
Pharmacokinetic (PK) in plasma: Terminal elimination half-life (t½)
Applicable to study Part A only
Time frame: From baseline to up to the end of the treatment and observation period (i.e. Day 4)
Pharmacokinetic (PK) in plasma: Dose proportionality for Cmax and AUC 0-infinity
Applicable to study Part A only
Time frame: From baseline to up to the end of the treatment and observation period (i.e. Day 4)
Pharmacokinetic (PK) in plasma: AUCtau (AUC of one dosing interval) after first and last study treatment administration, stratified by sex
Applicable to study Parts B and C only
Time frame: From baseline to up to the end of the treatment period (i.e. Day 15 for study Part B and Day 29 for study Part C)
Pharmacokinetic (PK) in plasma: Terminal elimination half-life (t½) after last study treatment administration, stratified by sex
Applicable to study Parts B and C only
Time frame: From baseline to up to the last timepoint measured (i.e. Day 19 for study Part B and 21 to 24 days after Day 29 for study Part C)
Pharmacokinetic (PK) in plasma: Average plasma concentration at steady state (Cavg,ss) during the last dosing interval, stratified by sex
Applicable to study Parts B and C only
Time frame: From baseline to up to the end of the treatment period (i.e. Day 14 for study Part B and D28 for study Part C)
Pharmacokinetic (PK) in plasma: Minimum plasma concentration at steady state (Cmin,ss) during the last dosing interval, stratified by sex
Applicable to study Parts B and C only
Time frame: From baseline to up to the end of the treatment period (i.e. Day 14 for study Part B and D28 for study Part C)
Pharmacokinetic (PK) in plasma: Trough (pre-dose) plasma concentrations (Ctrough), stratified by sex
Applicable to study Parts B and C only
Time frame: From baseline to up to the end of the treatment period (i.e. Day 14 for study Part B and D28 for study Part C)
Pharmacokinetic (PK) in plasma: Accumulation index (AI) for Cmax and AUCtau, stratified by sex
Applicable to study Parts B and C only
Time frame: From baseline to up to the end of the treatment period (i.e. Day 14 for study Part B and D28 for study Part C)
Pharmacokinetic (PK) in CSF: Drug concentration at steady state (trough level capturing Cmin), stratified by sex
Applicable to study Part B2 and B3 only
Time frame: From baseline to Day 13
Pharmacokinetic (PK) in plasma: Maximum observed concentration (Cmax) in fed state
Applicable to study Part A Food Effect group only
Time frame: From baseline up to the end of the treatment and observation period (i.e. Day 4) of the 2nd study period for the Food Effect group
Pharmacokinetic (PK) in plasma: Time to reach Cmax (tmax) in fed state
Applicable to study Part A Food Effect group only
Time frame: From baseline up to the end of the treatment and observation period (i.e. Day 4) of the 2nd study period for the Food Effect group
Pharmacokinetic (PK) in plasma: Area under the curve (AUC) from time zero to the last measured concentration above the limit of quantification (AUC 0-last), in fed state
Applicable to study Part A Food Effect group only
Time frame: From baseline up to the end of the treatment and observation period (i.e. Day 4) of the 2nd study period for the Food Effect group
Pharmacokinetic (PK) in plasma: AUC from time zero to infinity (AUC 0-infinity) in fed state
Applicable to study Part A Food Effect group only
Time frame: From baseline up to the end of the treatment and observation period (i.e. Day 4) of the 2nd study period for the Food Effect group
Pharmacokinetic (PK) in plasma: Terminal elimination half-life (t½) in fed state
Applicable to study Part A Food Effect group only
Time frame: From baseline up to the end of the treatment and observation period (i.e. Day 4) of the 2nd study period for the Food Effect group
Pharmacokinetic (PK) in plasma: Dose proportionality for Cmax and AUC 0-infinity in fed state
Applicable to study Part A Food Effect group only
Time frame: From baseline up to the end of the treatment and observation period (i.e. Day 4) of the 2nd study period for the Food Effect group
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Pharmacodynamic (PD) effect of ACI-19764 (target engagement [TE]) after SAD and MAD administration of ACI-19764 in healthy participants and of one multiple-dose level in participants with cardiovascular risk factors, stratified by sex
Change from baseline in PD parameters. Given as % of target engagement in whole blood assay (i.e. Inhibition of IL-1β release after ex vivo LPS and ATP stimulation)
Time frame: From baseline up to the last timepoint measured (i.e. Day 4 for study Part A, Day 19 for study Part B, and 21 to 24 days after Day 29 for study Part C)
Peripheral Pharmacodynamic (PD) effect of ACI-19764 in participants with cardiovascular risk factors
Proportion of participants with serum C-reactive protein (CRP) \<2 mg/L after 4 weeks of treatment. Applicable to study Part C only
Time frame: From baseline up to the end of the 4-weeks treatment period (i.e. Day 28)
Peripheral Pharmacodynamic (PD) effect of ACI-19764 in participants with cardiovascular risk factors
Proportion of participants with serum C-reactive protein (CRP) \<1 mg/L after 4 weeks of treatment. Applicable to study Part C only
Time frame: From baseline up to the end of the 4-weeks treatment period (i.e. Day 28)
Peripheral Pharmacodynamic (PD) effect of ACI-19764 in participants with cardiovascular risk factors
Percentage change from baseline in serum C-reactive protein (CRP) after 4 weeks of treatment. Applicable to study Part C only
Time frame: From baseline up to the end of the 4-weeks treatment period (i.e. Day 28)
Peripheral Pharmacodynamic (PD) effect of ACI-19764 in participants with cardiovascular risk factors
Absolute change from baseline in serum C-reactive protein (CRP) after 4 weeks of treatment. Applicable to study Part C only
Time frame: From baseline up to the end of the 4-weeks treatment period (i.e. Day 28)