Phase 1 SAD/MAD Study of CVN766 in Healthy Volunteers

Study Overview
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Brief Summary
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Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability, and Pharmacokinetic Study of Escalating Single and Multiple Doses of CVN766 in Healthy Subjects

Detailed Description
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Study Design: This is a Phase 1, randomized, double-blind, placebo-controlled, single- and multiple-dose ascending study in healthy subjects with concurrent PK sampling from blood plasma, urine, and cerebrospinal fluid. The overall study design is outlined below: Part 1: Single-Dose Regimen and Fasted-Fed Crossover For the single-dose regimen, approximately 40 healthy male or female subjects will be enrolled in 1 of 5 single-dose cohorts (designated as S1 through S5, respectively) in an ascending fashion. Each cohort will consist of 8 subjects randomized to CVN766 or placebo, whereby 6 subjects will receive a single oral dose of CVN766 suspension, and 2 subjects will receive a matching placebo suspension under overnight fasted conditions. Subjects will remain fasted for 4 hours post-dose. Consumption of water is permitted as desired except for 1 hour before and after administration of Study Drug. Sentinel dosing (1 subject to receive CVN766 and 1 subject to receive placebo) will be used in each cohort to ensure adequate safety and tolerability evaluation prior to administering CVN766 or placebo to the remainder of subjects within the cohort. After blinded review by the Safety Review Group (SRG) of 24-hour, post-dose safety and tolerability data from the sentinel group, the remaining 6 subjects of each cohort may be dosed provided that the adverse event (AE) profile in the first 2 subjects is considered acceptable. To accommodate the lumbar puncture in the S3 fasted cohort, after the sentinel group, the remaining 6 subjects dosing may be staggered every two days. The planned dose levels will be 5, 15, 45, 125, and 250 mg CVN766. The SRG will review all available blinded safety, tolerability, clinical laboratory results (minimally including samples collected from subjects through 72-hours post-dose), and pharmacokinetic (PK) data after each cohort and before subsequent dose escalation. Each following dose level may be higher, lower, or remain the same as the preceding cohort, dependent on the recommendation of the SRG. Additional cohort(s) may be added if deemed necessary by the SRG to fully characterize the safety and tolerability of CVN766. For example, if the maximum tolerated dose (MTD) is not reached with cohort S5, additional cohorts with higher dose levels may be considered. Such additional cohorts will follow the same schedule of events as for cohorts S1 through S5. Additional/Alternative PK timepoints may be implemented if the SRG determines this is necessary to fully characterize the PK profile of CVN766. To assess the effect of food on CVN766 bioavailability in suspension formulation, single-dose administration will be repeated in a single cohort (S3) after ingestion of a standardized high-fat, high-calorie meal according to FDA Guidance for Industry (Food-effect bioavailability and fed bioequivalence studies, Dec 2002). Once the safety of the S3 cohort dose level has been assessed, the S3 cohort subjects will return to the clinic (no sooner than 14 days after their prior dose, or at least 4 half-lives, has lapsed based on preliminary PK data, whichever is longer). They will receive the same dose as before, administered after ingesting a standardized breakfast. Subjects will finish the entire content of their breakfast within 25 minutes and will receive an investigational product 30 minutes (± 5 minutes) after beginning the meal. Sentinel dosing will not be required for subjects returning to the clinic for the fed regimen. If the CVN766 PK parameters in the fasted S3 cohort reveal poor absorption with inconclusive results, the fed cohort will be deferred until a higher dose level. Subjects for all cohorts will be admitted to the study unit 1 day prior to dosing and remain in the unit for safety and PK assessments. On Day 1, subjects will undergo safety monitoring and PK sampling from blood plasma through 72 hours post-dose and, for cohort S3 (fasted) only, from CSF via lumbar puncture at 3 hours post-dose. The total confinement period will be 4 nights, unless extended at the discretion of the Investigator, e.g., for monitoring and/or management of AEs. Follow-up assessments will occur on approximately Days 8 and 14 and +21 and +28 for cohort S3. Part 2: Multiple-Dose Regimen For the multiple-dose regimen, approximately 24 healthy male and female subjects age 18 to 50 years old will be enrolled in 1 of the 3 multiple-dose cohorts (designated as M1 through M3, respectively) in an ascending fashion. The dose levels planned to be studied in the multiple-dose regimen are 45, 125, and 250 mg CVN766 for multiple-dose cohorts M1 through M3, respectively. Each multiple-dose cohort will consist of 8 subjects randomized to CVN766 or placebo, whereby 6 subjects will receive a daily oral dose of CVN766, and 2 subjects will receive a matching placebo for 7 days. Dosing will be administered in the fasting state; this can be changed by the SRG if exposure is found to be higher in the fed state. The planned dosing duration for the multiple-dose cohorts is 7 days. However, the duration may be increased to ≤14 days at the discretion of the SRG if preliminary PK data suggests steady-state will not be achieved within 6 days of daily dosing. For each dose on intensive PK sampling days (first and last days of dosing, e.g., Days 1 and 7), subjects will remain fasted for 4 hours post-dose. On other dosing days (Days 2-6), subjects will remain fasted for 1-hour post-dose. Consumption of water is permitted as desired except for 1 hour before and after administration of Study Drug. Unlike the single-dose regimen, sentinel dosing within cohorts is not required in the multiple-dose regimen. Initiation of the multiple-dose regimen will only occur after a full blinded review of all safety, tolerability, and clinical laboratory results for the fasting drug administration to single-dose Cohort S3 (minimally including samples collected through Day 4) and available PK data. For each multiple-dose cohort after the first, the actual choice of dose level may be modified by the SRG after the available blinded safety, tolerability, clinical laboratory results, and PK data in the preceding multiple-dose and corresponding single-dose cohorts (i.e., multiple-dose Cohort M2 will not initiate until the data review for multiple-dose Cohort M1 and single-dose cohort S4 is complete). Each subsequent dose level may be higher, lower, or remain the same as the preceding. Additional multiple-dose cohort(s) may be added if deemed necessary by the SRG to fully characterize the safety and tolerability of CVN766. Such additional cohorts will follow the same schedule of events as for prior multiple-dose cohorts. Additional/Alternative PK timepoints may be implemented if the SRG determines this is necessary to fully characterize the PK profile of CVN766. Subjects for all multiple-dose cohorts will be admitted to the study unit 1 day prior to dosing and remain in the unit for the duration of the dosing period and for at least 48 hours after the last dose for safety and PK assessments before discharge. On treatment Days 1 and 7, subjects will undergo safety monitoring and PK sampling from blood plasma through 48 hours post-dose and, in cohort M1 only, from urine through 24 hours post-dose. In cohorts M1 and M2, on treatment Day 7 (or last day of dosing, if extended beyond Day 7), subjects will additionally undergo PK sampling from CSF via lumbar puncture at 3 hours post-dose. If needed to resolve questions arising from prior cohorts' data, subjects in cohort M3 also may, at SRG discretion, undergo PK sampling from CSF via lumbar puncture, the choice of day (e.g., Day 1 or Day 7) and sampling time to be decided by SRG. Subjects in MAD cohorts may be asked to return to the clinic for an additional PK sample 3 days after the last dose (e.g., Day 10) depending on emerging PK data, i.e., t½). The total confinement period will be 9 nights unless extended for additional dosing days or management of AEs. Follow-up assessments will occur approximately 7 and 14 days after the final dose.

Official Title
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A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability, and Pharmacokinetic Study of Escalating Single and Multiple Doses of CVN766 in Healthy Subjects

Conditions
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Safety Issues, Tolerance

Intervention / Treatment
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* Drug: CVN766


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject eligibility is determined according to the following criteria prior to entry into the study: In the investigator's opinion, the subject can understand and sign the Informed Consent Form and comply with all protocol requirements. The subject is a healthy male or female adult who is 18 to 55 years of age, inclusive at the time of ICF. Subject weighs at least 45 kg (99 lbs) and has a BMI between 18.0 and 32.0 kg/m2, inclusive at Screening. A male subject who is nonsterilized* and sexually active with a female partner of childbearing potential* agrees to use adequate contraception* from signing the ICF throughout the study and for 12 weeks after the last dose. *Definitions and acceptable methods of contraception are defined in Section 9.1.9 Contraception and Pregnancy Avoidance Procedure, and reporting responsibilities are defined in Section 9.1.10 Pregnancy. A female subject of childbearing potential who complies with contraception requirements* or a female with no childbearing potential, defined as the subject has been surgically sterilized (hysterectomy, bilateral oophorectomy, or tubal ligation) or who are postmenopausal (defined as continuous amenorrhea of at least 2 years and FSH>40 IU/L). Exclusion Criteria:Any subject who meets any of the following criteria will not qualify for entry into the study: Subject has received any investigational compound within 30 days prior to the first dose of study medication or within 5 half-lives, whichever is greater. Subject is a study site employee or an immediate family member of a study site employee. Subject has evidence of CS neurologic, cardiovascular, pulmonary, hepatic, hematopoietic disease, renal, metabolic, gastrointestinal, urologic, immunologic, endocrine disease, serious allergy, full-body allergic skin rash (including hives), psychiatric disorder, or other abnormality that may impact the ability of the subject to participate or potentially confound the study results. There is any finding in the subject's medical history, physical examination, or safety laboratory tests giving reasonable suspicion of a disease that would contraindicate taking CVN766 or a similar drug in the same class or that might interfere with the conduct of the study Subject has a known hypersensitivity to any component of the formulation of CVN766. Subject has a positive urine result for drugs of abuse at Screening or Inpatient Check-in (Day -1). Subject has a history of drug abuse or a history of alcohol abuse (more than 14 units/week) within 1 year prior to the Screening Visit or is unwilling to agree to abstain from alcohol and drugs throughout the study. Subject has taken any excluded medication, supplements, or food products listed in the Excluded Medications and Dietary Products table as listed in Table 3: Excluded Medications and Dietary Products. Male subjects who do not agree to all the following rules: when sexually active with a female partner(s) of childbearing potential during the study, and for 12 weeks after the last dose of study drug: a) must use an acceptable method of birth control (condom or surgical sterilization) and b) refrain from sexual activity with female partners who do not use an acceptable method of birth control. Barrier contraception (condom) must be used by all-male subjects who were not surgically sterilized at least 90 days prior to screening. Male subjects must also agree to refrain from sperm donation during the study and until 12 weeks after the last dose of study drug. Female subjects who are pregnant or breastfeeding or plan to become pregnant or donate ova during the study or 30 days after the last dose of the study drug. Women of childbearing potential must agree to practice an acceptable method of birth control (e.g., oral or parenteral contraceptives, intrauterine device, barrier, abstinence). *Definitions and acceptable methods of contraception are defined in Section 9.1.9, Contraception and Pregnancy Avoidance Procedure, and reporting responsibilities are defined in Section 9.1.10, Pregnancy. Subject has previously had a seizure or convulsion (lifetime, with the exception of febrile seizures), including absence seizure. Subject has current o recent (within 6 months) gastrointestinal disease that would be expected to influence the absorption of drugs (i.e., a history of malabsorption, any surgical intervention known to impact absorption [e.g., bariatric surgery or bowel resection], esophageal reflux, peptic ulcer disease, erosive esophagitis, or frequent [i.e., more than once per week] occurrence of heartburn). Subject has a history of cancer or other malignancy, except for basal cell carcinoma or squamous cell carcinoma that has been in remission for at least 3 years prior to Day 1. Subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or a human immunodeficiency virus infection at Screening. Subject who regularly use nicotine-containing products (including but not limited to cigarettes, electronic cigarettes, pipes, cigars, chewing tobacco, nicotine patch, or nicotine gum). Casual user may participate but must agree to refrain from the time of Screening for the duration of the study or a positive urine cotinine test at Inpatient Check-in (Day 1). Subject has poor peripheral venous access (defined as more than three failed attempts to cannulate. Subject has donated or lost 450 mL or more of their blood volume (including plasmapheresis) or had a transfusion of any blood product within 45 days prior to Day 1. Subject has an abnormal (CS) ECG at Screening or Inpatient Check-in (Day -1). Entry of any subject with an abnormal (NCS) ECG must be approved and documented by signature by the Investigator or medically qualified sub-investigator. Subject has a supine blood pressure outside the ranges of 90 to 140 mm Hg for systolic and 40 to 90 mm Hg for diastolic, confirmed with repeat per PI discretion, at the Screening Visit or Inpatient Check-in (Day -1). Subject has a resting heart rate outside the range of 40 to 100 bpm, confirmed with repeat per PI discretion, at the Screening Visit or Inpatient Check-in (Day -1). Subject has a QT interval with Fridericia's correction method (QTcF) >450 ms (males) or >470 ms (females) or PR outside the range of 120 to 220 ms, confirmed with one repeat testing at the Screening Visit or Inpatient Check-in (Day -1) Visit. Subject has abnormal Screening or Inpatient Check-in (Day -1) laboratory values that suggest a CS underlying disease or subject with the following lab abnormalities: ALT and/or AST >1.5 the ULN, confirmed with one repeat testing. Subject has a risk of suicide according to the investigator's clinical judgment or has made a suicide attempt in the previous 2 years. 7.3 Excluded Medications and Dietary Products -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: For the single-dose regimen, approximately 40 healthy male or female subjects will be enrolled in 1 of 5 single-dose cohorts (designated as S1 through S5, respectively) in an ascending fashion. Each cohort will consist of 8 subjects randomized to CVN766 or placebo, whereby 6 subjects will receive a single oral dose of CVN766 suspension, and 2 subjects will receive a matching placebo suspension under overnight fasted conditions. For the multiple-dose regimen, approximately 24 healthy male and female subjects age 18 to 50 years old will be enrolled in 1 of the 3 multiple-dose cohorts (designated as M1 through M3, respectively) in an ascending fashion. The dose levels planned to be studied in the multiple-dose regimen are 45, 125, and 250 mg CVN766 for multiple-dose cohorts M1 through M3, respectively.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: SAD Cohort 1<br>Each dose cohort: 8 subjects (6 active:2 placebo). 5 mg | Drug: CVN766<br>* highly selective orexin-1 receptor (Ox1R) antagonist<br>|
| Active Comparator: SAD Cohort 2<br>Each dose cohort: 8 subjects (6 active:2 placebo). 15 mg. | Drug: CVN766<br>* highly selective orexin-1 receptor (Ox1R) antagonist<br>|
| Active Comparator: SAD Cohort 3<br>Each dose cohort: 8 subjects (6 active:2 placebo). 45 mg. | Drug: CVN766<br>* highly selective orexin-1 receptor (Ox1R) antagonist<br>|
| Active Comparator: SAD Cohort 4<br>Each dose cohort: 8 subjects (6 active:2 placebo). 125 mg | Drug: CVN766<br>* highly selective orexin-1 receptor (Ox1R) antagonist<br>|
| Placebo Comparator: SAD Cohort 5<br>Each dose cohort: 8 subjects (6 active:2 placebo). 250 mg. | Drug: CVN766<br>* highly selective orexin-1 receptor (Ox1R) antagonist<br>|
| Active Comparator: MAD Cohort 1<br>Each dose cohort: 8 subjects (6 active:2 placebo). 45mg | Drug: CVN766<br>* highly selective orexin-1 receptor (Ox1R) antagonist<br>|
| Placebo Comparator: MAD Cohort 2<br>Each dose cohort: 8 subjects (6 active:2 placebo). 125 mg. | Drug: CVN766<br>* highly selective orexin-1 receptor (Ox1R) antagonist<br>|
| Placebo Comparator: MAD Cohort 3<br>Each dose cohort: 8 subjects (6 active:2 placebo). 250 mg. | Drug: CVN766<br>* highly selective orexin-1 receptor (Ox1R) antagonist<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of Adverse Events | Occurrence of all adverse events from signing of informed consent through end of study treatment. | Baseline through 14 days post final dose | 
| Evaluation of Hematology | RBC | Baseline through 14 days post final dose | 
| Evaluation of Vital Signs | typanic body temperature | Baseline through 14 days post final dose | 
| Evaluation of Electrocardiograms | Standard 12-lead ECG - QT interval | Baseline through 14 days post final dose | 
| Evaluation of BMI | Weight and Height will be combined to calculate BMI using the following formula: BMI = weight (kg)/[height (m)]2 | Baseline through 14 days post final dose | 
| Evaluation Serum Chemistry | ALT | Baseline through 14 days post final dose | 
| Evaluation of Urinalysis | pH | Baseline through 14 days post final dose | 
| Evaluation of Vital Signs | Respiration Rate | Baseline through 14 days post final dose | 
| Evaluation of Vital Signs | Pulse Rate | Baseline through 14 days post final dose | 
| Evaluation of Vital Signs | Blood Pressure (both systolic and diastolic) | Baseline through 14 days post final dose | 
| Evaluation of Hematology | WBC with differential | Baseline through 14 days post final dose | 
| Evaluation of Hematology | Hemoglobin | Baseline through 14 days post final dose | 
| Evaluation of Hematology | Hematocrit | Baseline through 14 days post final dose | 
| Evaluation of Hematology | PT/INR | Baseline through 14 days post final dose | 
| Evaluation of Hematology | Platelets | Baseline through 14 days post final dose | 
| Evaluation of Electrocardiograms | Standard 12-lead ECG - QTc | Baseline through 14 days post final dose | 
| Evaluation of Electrocardiograms | Standard 12-lead ECG - PR | Baseline through 14 days post final dose | 
| Evaluation of Electrocardiograms | Standard 12-lead ECG - RR | Baseline through 14 days post final dose | 
| Evaluation of Electrocardiograms | Standard 12-lead ECG - QRS | Baseline through 14 days post final dose | 
| Evaluation of Electrocardiograms | Standard 12-lead ECG - QT | Baseline through 14 days post final dose | 
| Evaluation of Electrocardiograms | Standard 12-lead ECG - QTcF | Baseline through 14 days post final dose | 
| Evaluation of Electrocardiograms | Standard 12-lead ECG - QTcB | Baseline through 14 days post final dose | 
| Evaluation of Serum Chemistry | Albumin | Baseline through 14 days post final dose | 
| Evaluation of Serum Chemistry | Alkaline phosphatase | Baseline through 14 days post final dose | 
| Evaluation of Serum Chemistry | Lipase | Baseline through 14 days post final dose | 
| Evaluation of Serum Chemistry | AST | Baseline through 14 days post final dose | 
| Evaluation of Serum Chemistry | Total bilirubin | Baseline through 14 days post final dose | 
| Evaluation of Serum Chemistry | Direct bilirubin | Baseline through 14 days post final dose | 
| Evaluation of Serum Chemistry | Total Protein | Baseline through 14 days post final dose | 
| Evaluation of Serum Chemistry | Creatinine | Baseline through 14 days post final dose | 
| Evaluation of Serum Chemistry | Blood urea nitrogen | Baseline through 14 days post final dose | 
| Evaluation of Serum Chemistry | Creatine kinase | Baseline through 14 days post final dose | 
| Evaluation of Serum Chemistry | GGT | Baseline through 14 days post final dose | 
| Evaluation of Serum Chemistry | Potassium | Baseline through 14 days post final dose | 
| Evaluation of Serum Chemistry | Sodium | Baseline through 14 days post final dose | 
| Evaluation of Serum Chemistry | Glucose | Baseline through 14 days post final dose | 
| Evaluation of Serum Chemistry | Chloride | Baseline through 14 days post final dose | 
| Evaluation of Serum Chemistry | Bicarbonate | Baseline through 14 days post final dose | 
| Evaluation of Serum Chemistry | Calcium | Baseline through 14 days post final dose | 
| Evaluation of Urinalysis | specific gravity | Baseline through 14 days post final dose | 
| Evaluation of Urinalysis | protein | Baseline through 14 days post final dose | 
| Evaluation of Urinalysis | glucose | Baseline through 14 days post final dose | 
| Evaluation of Urinalysis | blood | Baseline through 14 days post final dose | 
| Evaluation of Urinalysis | nitrite | Baseline through 14 days post final dose | 
| Evaluation of Urinalysis | Microscopic Analysis (only if positive dipstick results): RBC/high power field, WBC/high power field, Epithelial cells, casts | Baseline through 14 days post final dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentration (AUC) of CVN766 | To evaluate the pharmacokinetics of single and multiple doses of CVN766 Pharmacokinetic parameters including, but not limited to area under the plasma concentration-time curve (AUC) from 0 to 24hours (AUC0-24) | SAD: PK Collection on Day 1-4, and early termination (up to 8 days); MAD: PK Collection on Day 1-10, and early termination (up to 14 days) | 
| Plasma Concentration (Cmax) of CVN766 | To evaluate the pharmacokinetics of single and multiple doses of CVN766. Pharmacokinetic parameters including, but not limited to maximum plasma concentration (Cmax) | SAD: PK Collection on Day 1-4, and early termination (up to 8 days); MAD: PK Collection on Day 1-10, and early termination (up to 14 days) | 
| Food effect by measurement of plasma PK (Cmax) | Assess the effect of food on the bioavailability in the current formulation after digesting a high caloric meal. | Baseline through 14 days post-dose | 
| Food effect by measurement of plasma PK (AUC) | Assess the effect of food on the bioavailability in the current formulation after digesting a high caloric meal. | Baseline through 14 days post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PK, Efficacy