Clinical trial NCT05334108: Drug-Drug Interaction Study to Evaluate the Effects of Ecopipam on the Pharmacokinetics of Multiple Substrates for Drug Metabolism and Transport
Official title: A Phase 1, Open-Label, Fixed Sequence, Drug-Drug Interaction Study to Evaluate the Effects of Repeat Titrated Doses of Ecopipam on the Pharmacokinetics of Multiple Substrates for Drug Metabolism and Transport in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Drug Interaction
Lead sponsor: Emalex Biosciences Inc.
Sponsor class: INDUSTRY
Collaborators: name: ICON Early Phase Services
name: Nuventra, Inc.
First posted: 2022-04-19
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: This is a single center, open-label, fixed sequence Phase 1, drug-drug interaction (DDI) study in healthy subjects.

Detailed description: Following a Screening period, eligible subjects will be enrolled sequentially to one of three cohorts to receive a single dose of probe substrate(s), followed by repeated titrated doses of ecopipam twice daily (BID) (with subjects in Cohort 3 also receiving a single dose of ecopipam and probe substrates on Day 4 prior to titration). After steady-state ecopipam dosing is reached, ecopipam will be co-administered with a single dose of probe substrate(s) (with continuation of ecopipam BID (every 12 h) dosing during the blood sampling period for the respective probe substrates), followed by an ecopipam tapering period and clinic discharge assessments.

Eligibility criteria: Inclusion Criteria:

* Male subjects or female subjects of non-childbearing potential
* ≥18 and \<55 years of age at the time of consent
* BMI \>18.5 and \<30 kg/m2 and a weight of ≥50 kg for males or ≥45 kg for females
* Subjects must be healthy, as determined by the Investigator, based on medical history, physical examination, ECG, and standard panel of blood and laboratory tests at Screening.
* Sexually active males must use a double barrier method of contraception during the study and for at least 90 days after the last dose of study drug
* Male subjects must be willing not to donate sperm until 90 days following the last study drug administration

Exclusion Criteria:

* Personal or family History of significant medical illness
* Clinically significant abnormalities on screening tests/exams
* History of or significant risk of committing suicide
* Donation of plasma within 7 days prior to dosing
* Donation or significant loss of blood within 30 days prior to the first dosing
* Major surgery within 3 months or minor surgery within 1 month prior to admission
* Use of prohibited prescription, over-the-counter medications or natural health products
* Alcohol-based products 24 hours prior to admission
* Female subjects who are currently pregnant or lactating
* Positive pregnancy test
* Use of tobacco or nicotine products within 3 months prior to Screening
* Significant alcohol consumption
* History of drug abuse within the previous 2 years, or a positive drug screen
* History of allergy to study medications
* Undergoing abrupt discontinuation of alcohol or sedatives
* Not suitable for study in the opinion of the Principal Investigator

Primary outcomes:
measure: Cmax of IV midazolam (and its 1'-hydroxymidazolam metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: Cmax of IV midazolam (and its 1'-hydroxymidazolam metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
measure: Cmax of oral midazolam (and its 1'-hydroxymidazolam metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: Cmax oral midazolam (and its 1'-hydroxymidazolam metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
measure: Cmax of dabigatran in the presence of ecopipam
timeFrame: Up to Day 22
measure: Cmax of dabigatran in the absence of ecopipam
timeFrame: Up to Day 22
measure: Cmax of pitavastatin (and its pitavastatin lactone metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: Cmax of pitavastatin (and its pitavastatin lactone metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
measure: Cmax of rosuvastatin in the presence of ecopipam
timeFrame: Up to Day 22
measure: Cmax of rosuvastatin in the absence of ecopipam
timeFrame: Up to Day 22
measure: Cmax of atorvastatin (and its 4'-hydroxy atorvastatin metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: Cmax of atorvastatin (and its 4'-hydroxy atorvastatin metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUCinf of IV midazolam (and its 1'-hydroxymidazolam metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUCinf of IV midazolam (and its 1'-hydroxymidazolam metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUCinf of oral midazolam (and its 1'-hydroxymidazolam metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUCinf of oral midazolam (and its 1'-hydroxymidazolam metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUCinf of dabigatran in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUCinf of dabigatran in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUCinf of pitavastatin (and its pitavastatin lactone metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUCinf of pitavastatin (and its pitavastatin lactone metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUCinf of rosuvastatin in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUCinf of rosuvastatin in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUCinf of atorvastatin (and its 4'-hydroxy atorvastatin metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUCinf of atorvastatin (and its 4'-hydroxy atorvastatin metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUClast of IV midazolam (and its 1'-hydroxymidazolam metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUClast of IV midazolam (and its 1'-hydroxymidazolam metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUClast of oral midazolam (and its 1'-hydroxymidazolam metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUClast of oral midazolam (and its 1'-hydroxymidazolam metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUClast of dabigatran in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUClast of dabigatran in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUClast of pitavastatin (and its pitavastatin lactone metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUClast of pitavastatin (and its pitavastatin lactone metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUClast of rosuvastatin in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUClast of rosuvastatin in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUClast of atorvastatin (and its 4'-hydroxy atorvastatin metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUClast of atorvastatin (and its 4'-hydroxy atorvastatin metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUC0-24 of oral midazolam (and its 1'-hydroxymidazolam metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUC0-24 of oral midazolam (and its 1'-hydroxymidazolam metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUC0-24 of dabigatran in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUC0-24 of dabigatran in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUC0-24 of pitavastatin (and its pitavastatin lactone metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUC0-24 of pitavastatin (and its pitavastatin lactone metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUC0-24 of rosuvastatin in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUC0-24 of rosuvastatin in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUC0-24 of atorvastatin (and its 4'-hydroxy atorvastatin metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUC0-24 of atorvastatin (and its 4'-hydroxy atorvastatin metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
Secondary outcomes:
measure: Cmax of bupropion (and its 4-hydroxybupropion metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: Cmax of bupropion (and its 4-hydroxybupropion metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
measure: Cmax omeprazole (and its 5'-hydroxy omeprazole metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: Cmax omeprazole (and its 5'-hydroxy omeprazole metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUCinf of bupropion (and its 4-hydroxybupropion metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUCinf of bupropion (and its 4-hydroxybupropion metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUCinf of omeprazole (and its 5'-hydroxy omeprazole metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUCinf of omeprazole (and its 5'-hydroxy omeprazole metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUClast of bupropion (and its 4-hydroxybupropion metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUClast of bupropion (and its 4-hydroxybupropion metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
measure: AUClast of omeprazole (and its 5'-hydroxy omeprazole metabolite) in the presence of ecopipam
timeFrame: Up to Day 22
measure: AUClast of omeprazole (and its 5'-hydroxy omeprazole metabolite) in the absence of ecopipam
timeFrame: Up to Day 22
measure: CL/F for dextromethorphan in the presence of ecopipam
timeFrame: Up to Day 22
measure: CL/F for dextromethorphan in the absence of ecopipam
timeFrame: Up to Day 22
measure: CL for IV midazolam in the presence of ecopipam
timeFrame: Up to Day 22
measure: CL for IV midazolam in the absence of ecopipam
timeFrame: Up to Day 22
measure: CL/F for oral midazolam in the presence of ecopipam
timeFrame: Up to Day 22
measure: CL/F for oral midazolam in the absence of ecopipam
timeFrame: Up to Day 22
measure: CL/F for dabigatran in the presence of ecopipam
timeFrame: Up to Day 22
measure: CL/F for dabigatran in the absence of ecopipam
timeFrame: Up to Day 22
measure: CL/F for pitavastatin in the presence of ecopipam
timeFrame: Up to Day 22
measure: CL/F for pitavastatin in the absence of ecopipam
timeFrame: Up to Day 22
measure: CL/F for rosuvastatin in the presence of ecopipam
timeFrame: Up to Day 22
measure: CL/F for rosuvastatin in the absence of ecopipam
timeFrame: Up to Day 22
measure: CL/F for atorvastatin in the presence of ecopipam
timeFrame: Up to Day 22
measure: CL/F for atorvastatin in the absence of ecopipam
timeFrame: Up to Day 22
measure: CL/F for bupropion in the presence of ecopipam
timeFrame: Up to Day 22
measure: CL/F for bupropion in the absence of ecopipam
timeFrame: Up to Day 22
measure: CL/F for caffeine in the presence of ecopipam
timeFrame: Up to Day 22
measure: CL/F for caffeine in the absence of ecopipam
timeFrame: Up to Day 22
measure: CL/F for omeprazole in the presence of ecopipam
timeFrame: Up to Day 22
measure: CL/F for omeprazole in the absence of ecopipam
timeFrame: Up to Day 22
measure: V/F for dextromethorphan in the presence of ecopipam
timeFrame: Up to Day 22
measure: V/F for dextromethorphan in the absence of ecopipam
timeFrame: Up to Day 22
measure: V for IV midazolam in the presence of ecopipam
timeFrame: Up to Day 22
measure: V for IV midazolam in the absence of ecopipam
timeFrame: Up to Day 22
measure: V/F for oral midazolam in the presence of ecopipam
timeFrame: Up to Day 22
measure: V/F for oral midazolam in the absence of ecopipam
timeFrame: Up to Day 22
measure: V/F for dabigatran in the presence of ecopipam
timeFrame: Up to Day 22
measure: V/F for dabigatran in the absence of ecopipam
timeFrame: Up to Day 22
measure: V/F for pitavastatin in the presence of ecopipam
timeFrame: Up to Day 22
measure: V/F for pitavastatin in the absence of ecopipam
timeFrame: Up to Day 22
measure: V/F for rosuvastatin in the presence of ecopipam
timeFrame: Up to Day 22
measure: V/F for rosuvastatin in the absence of ecopipam
timeFrame: Up to Day 22
measure: V/F for bupropion in the presence of ecopipam
timeFrame: Up to Day 22
measure: V/F for bupropion in the absence of ecopipam
timeFrame: Up to Day 22
measure: V/F for atorvastatin in the presence of ecopipam
timeFrame: Up to Day 22
measure: V/F for atorvastatin in the absence of ecopipam
timeFrame: Up to Day 22
measure: V/F for caffeine in the presence of ecopipam
timeFrame: Up to Day 22
measure: V/F for caffeine in the absence of ecopipam
timeFrame: Up to Day 22
measure: V/F for omeprazole in the presence of ecopipam
timeFrame: Up to Day 22
measure: V/F for omeprazole in the absence of ecopipam
timeFrame: Up to Day 22
measure: Total concentration of bilirubin in the presence of ecopipam
timeFrame: Up to Day 18
measure: Total concentration of bilirubin in the absence of ecopipam
timeFrame: Up to Day 18
measure: Unconjugated concentration of bilirubin in the presence of ecopipam
timeFrame: Up to Day 18
measure: Unconjugated concentration of bilirubin in the absence of ecopipam
timeFrame: Up to Day 18
measure: Conjugated concentration of bilirubin in the presence of ecopipam
timeFrame: Up to Day 18
measure: Conjugated concentration of bilirubin in the absence of ecopipam
timeFrame: Up to Day 18
measure: Average of the 6-hour plasma dextromethorphan: dextrorphan ratio in the presence of ecopipam
timeFrame: Up to Day 14
measure: Average of the 8-hour plasma dextromethorphan: dextrorphan ratio in the presence of ecopipam
timeFrame: Up to Day 14
measure: Average of the 12-hour plasma dextromethorphan: dextrorphan ratio in the presence of ecopipam
timeFrame: Up to Day 14
measure: Average of the 6-hour plasma dextromethorphan: dextrorphan ratio in the absence of ecopipam
timeFrame: Up to Day 14
measure: Average of the 8-hour plasma dextromethorphan: dextrorphan ratio in the absence of ecopipam
timeFrame: Up to Day 14
measure: Average of the 12-hour plasma dextromethorphan: dextrorphan ratio in the absence of ecopipam
timeFrame: Up to Day 14
measure: Average of the 6-hour plasma caffeine: paraxanthine metabolite ratio in the presence of ecopipam
timeFrame: Up to Day 14
measure: Average of the 8-hour plasma caffeine: paraxanthine metabolite ratio in the presence of ecopipam
timeFrame: Up to Day 14
measure: Average of the 12-hour plasma caffeine: paraxanthine metabolite ratio in the presence of ecopipam
timeFrame: Up to Day 14
measure: Average of the 6-hour plasma caffeine: paraxanthine metabolite ratio in the absence of ecopipam
timeFrame: Up to Day 14
measure: Average of the 8-hour plasma caffeine: paraxanthine metabolite ratio in the absence of ecopipam
timeFrame: Up to Day 14
measure: Average of the 12-hour plasma caffeine: paraxanthine metabolite ratio in the absence of ecopipam
timeFrame: Up to Day 14
measure: Safety and tolerability as demonstrated by the Modified Observer's Assessment of Alertness/Sedation (MOAA/S)
timeFrame: Up to Day 63
measure: Safety and tolerability as demonstrated by the Columbia Suicide Severity Rating Scale (C-SSRS)
timeFrame: Up to Day 63
measure: Number of participants requiring concomitant medications
timeFrame: Up to Day 63
measure: AEs with relatedness associated with dextromethorphan
timeFrame: Up to Day 63
measure: AEs with relatedness associated with IV midazolam
timeFrame: Up to Day 63
measure: AEs with relatedness associated with oral midazolam
timeFrame: Up to Day 63
measure: AEs with relatedness associated with dabigatran
timeFrame: Up to Day 63
measure: AEs with relatedness associated with pitavastatin
timeFrame: Up to Day 63
measure: AEs with relatedness associated with rosuvastatin
timeFrame: Up to Day 63
measure: AEs with relatedness associated with atorvastatin
timeFrame: Up to Day 63
measure: AEs with relatedness associated with bupropion
timeFrame: Up to Day 63
measure: AEs with relatedness associated with caffeine
timeFrame: Up to Day 63
measure: AEs with relatedness associated with omeprazole
timeFrame: Up to Day 63
measure: AEs with relatedness associated with ecopipam
timeFrame: Up to Day 63
measure: Absolute values of white blood cell (WBC), neutrophils, lymphocytes, monocytes, eosinophils, basophils and platelets (1000/mm3)
timeFrame: Up to Day 26
measure: Absolute values of hematocrit (percent)
timeFrame: Up to Day 26
measure: Absolute values of hemoglobin (g/dL)
timeFrame: Up to Day 26
measure: Absolute values of Red blood cell (RBC) count (M/mm3)
timeFrame: Up to Day 26
measure: Absolute values of sodium, potassium, chloride (mmol/L)
timeFrame: Up to Day 26
measure: Absolute values of magnesium, urea, phosphorus, calcium, glucose, and total, conjugated and unconjugated bilirubin (mg/dL)
timeFrame: Up to Day 26
measure: Absolute values of albumin and total protein (g/dL)
timeFrame: Up to Day 26
measure: Absolute values of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), creatinine phosphokinase (CPK), and creatinine (U/L)
timeFrame: Up to Day 26
measure: Absolute values of urine specific gravity
timeFrame: Up to Day 26
measure: Absolute values of urine pH
timeFrame: Up to Day 26
measure: Absolute values of urine glucose
timeFrame: Up to Day 26
measure: Absolute values of urine protein
timeFrame: Up to Day 26
measure: Absolute values of urine blood
timeFrame: Up to Day 26
measure: Absolute values of urine ketones
timeFrame: Up to Day 26
measure: Absolute values of urine bilirubin and nitrite
timeFrame: Up to Day 26
measure: Absolute values of urobilinogen (Eu/dL)
timeFrame: Up to Day 26
measure: Absolute values of urine leukocytes by dipstick
timeFrame: Up to Day 26
measure: Change from Day -1 to Day of Discharge white blood cell (WBC), neutrophils, lymphocytes, monocytes, eosinophils, basophils and platelets (1000/mm3)
timeFrame: Up to Day 26
measure: Change from Day -1 to Day of Discharge in hematocrit (percent)
timeFrame: Up to Day 26
measure: Change from Day -1 to Day of Discharge in hemoglobin (g/dL)
timeFrame: Up to Day 26
measure: Change from Day -1 to Day of Discharge in Red blood cell (RBC) count (M/mm3)
timeFrame: Up to Day 26
measure: Change from Day -1 to Day of Discharge in sodium, potassium, chloride (mmol/L)
timeFrame: Up to Day 26
measure: Change from Day -1 to Day of Discharge in magnesium, urea, phosphorus, calcium, glucose, and total, conjugated and unconjugated bilirubin (mg/dL)
timeFrame: Up to Day 26
measure: Change from Day -1 to Day of Discharge in albumin and total protein (g/dL)
timeFrame: Up to Day 26
measure: Change from Day -1 to Day of Discharge in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and creatinine phosphokinase (CPK), and creatinine (U/L)
timeFrame: Up to Day 26
measure: Change from Day -1 to Day of Discharge in urine specific gravity
timeFrame: Up to Day 26
measure: Change from Day -1 to Day of Discharge in urine pH
timeFrame: Up to Day 26
measure: Change from Day -1 to Day of Discharge in urine glucose
timeFrame: Up to Day 26
measure: Change from Day -1 to Day of Discharge in urine protein
timeFrame: Up to Day 26
measure: Change from Day -1 to Day of Discharge in urine blood
timeFrame: Up to Day 26
measure: Change from Day -1 to Day of Discharge in urine ketones
timeFrame: Up to Day 26
measure: Change from Day -1 to Day of Discharge in urine bilirubin and nitrite
timeFrame: Up to Day 26
measure: Change from Day -1 to Day of Discharge in urobilinogen (Eu/dL)
timeFrame: Up to Day 26
measure: Change from Day -1 to Day of Discharge in urine leukocytes by dipstick
timeFrame: Up to Day 26
measure: Absolute values of electrocardiogram (ECG) parameters: PR, QRS, QT, and QT interval corrected for heart rate using Fridericia's formula (QTcF) (Milliseconds)
timeFrame: Up to Day 26
measure: Change from pre-dose for the respective day in ECG parameters: PR, QRS, QT, and QTcF (Milliseconds)
timeFrame: Up to Day 26
measure: Absolute values of oral temperature (degrees Celsius)
timeFrame: Up to Day 26
measure: Change from pre-dose for the respective day in oral temperature (degrees Celsius)
timeFrame: Up to Day 26
measure: Absolute values of heart rate (beats/minute)
timeFrame: Up to Day 26
measure: Change from pre-dose for the respective day in heart rate (beats/minute)
timeFrame: Up to Day 26
measure: Absolute values of respiratory rate (breaths/minute)
timeFrame: Up to Day 26
measure: Absolute values of systolic blood pressure (SBP) and diastolic blood pressure (DBP) (mmHG)
timeFrame: Up to Day 26
measure: Change from pre-dose for the respective day in SBP and DBP (mmHG)
timeFrame: Up to Day 26
measure: Absolute values of mean corpuscular hemoglobin (MCH) (pg)
timeFrame: Up to Day 26
measure: Change from Day 1 to Day of Discharge of mean corpuscular hemoglobin (MCH) (pg)
timeFrame: Up to Day 26
measure: Absolute values of mean corpuscular volume (MCV) (fL)
timeFrame: Up to Day 26
measure: Change from Day 1 to Day of Discharge of mean corpuscular volume (MCV) (fL)
timeFrame: Up to Day 26
measure: Absolute values of mean corpuscular hemoglobin concentration (MCHC) (g/dL)
timeFrame: Up to Day 26
measure: Change from Day 1 to Day of Discharge of mean corpuscular hemoglobin concentration (MCHC) (g/dL)
timeFrame: Up to Day 26
Other outcomes:
Locations:
city: San Antonio
country: United States
facility: ICON Early Phase Services
state: Texas
Study officials:
References: