A Trial of the Effect of CVL-865 on Panic Symptoms Induced by Carbon Dioxide Inhalation in Healthy Subjects

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine anxiolytic effect of multiple doses of CVL-865 using an experimental medicine model of carbon dioxide (CO2) inhalation in healthy volunteers.

Official Title
-----------------
A Randomized, Double-blind, Placebo- and Active Comparator-controlled, Crossover Trial to Examine the Effect of Multiple Doses of CVL-865 on Panic Symptoms Induced by Carbon Dioxide Inhalation in Healthy Subject

Conditions
-----------------
Panic Disorder

Intervention / Treatment
-----------------
* Drug: CVL-865 High dose
* Drug: Alprazolam 1mg XR
* Drug: Placebo
* Drug: CVL-865 low dose


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy male and female subjects, ages 18 to 55 years, inclusive, at the time of signing the ICF. Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and heart rate measurement, 12-lead ECG, and clinical laboratory tests, as evaluated by the investigator. Body mass index of 18.5 to 30.0 kg/m2, inclusive, and a total body weight >50 kg (110 lbs) A female subject of childbearing potential who is sexually active with a nonsterilized male partner must agree to use a highly effective method of contraception from signing of informed consent and for 30 days post last dose. A male subject with a pregnant or a nonpregnant partner of childbearing potential must agree to use condom during treatment and until the end of relevant systemic exposure in the male subject for 94 days following the last dose with IMP. Capable of giving signed informed consent Ability, in the opinion of the investigator, to understand the nature of the trial and comply with protocol requirements, including the prescribed dosage regimens, scheduled visits, laboratory tests, and other trial procedures. Defined as sensitive to the anxiogenic effects of double-breath CO2 inhalation Exclusion Criteria: Subjects with a current history of clinically significant cardiovascular pulmonary, gastrointestinal, renal, hepatic, metabolic, hematological, immunological, or neurological disease. Subjects with a current or past history of clinically significant respiratory conditions Subject with a personal or family history of sickle cell anemia Subject with a personal or family history of cerebral aneurysm Subjects with a clinically significant current or past personal or family history of any psychiatric disorder as classified by DSM-4 or DSM-5 criteria Subjects with epilepsy or a history of seizures except for a single seizure episode Subjects with a history of substance or alcohol-use disorder (DSM-5 criteria) Subjects who answer Yes on the C-SSRS Suicidal Ideation Item 4, 5 and whose most recent episode meeting criteria for this C-SSRS Item 4, 5 occurred within the last 6 months Subjects who, in the opinion of the investigator, present a serious risk of suicide Subjects with human immunodeficiency virus seropositive status or acquired immunodeficiency syndrome, chronic hepatitis B or C (defined as positive serology and aspartate aminotransferase or alanine aminotransferase elevated to >2 × ULN) Subject with a positive drug screen for illicit drugs Subjects with a 12-lead ECG demonstrating either of the following: QT interval corrected for heart rate using Fridericia's formula >450 msec (average of 3 ECGs obtained at the Screening Visit) QRS interval >120 msec at the Screening Visit Subjects with any of the following abnormalities in clinical laboratory tests at the Screening Visit, as assessed by the local laboratory and confirmed by a single repeat measurement, if deemed necessary: AST or ALT ≥2 × ULN Total bilirubin ≥1.5 × ULN. Subjects with a history of Gilbert's syndrome may be eligible provided the direct bilirubin is <ULN Females: Hemoglobin <11 g/dL; Males: hemoglobin <12 g/dL White blood cell count <3.0 × 109/L Neutrophil count <2.0 × 109/L Platelet count <150 × 109/L Subjects with other abnormal laboratory test results, vital sign results, or ECG findings unless, based on the investigator's judgment, the findings are not medically significant Systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg at Screening or Day -1 Subjects taking prohibited medication or who would be likely to require prohibited concomitant therapy Subject has a current or past history of BZD abuse and/or dependence Female subjects who are breastfeeding and/or who have a positive pregnancy test result prior to receiving IMP Subjects who currently use or have used tobacco or nicotine-containing products within 30 days prior to signing the ICF. Subjects who test positive for urine cotinine Subjects who has a history of consuming foods or beverages containing >8 units of methylxanthines per day and refuses to abstain from consumption of methylxanthine containing food and beverages while in the clinic. Subjects with any condition possibly affecting drug absorption Subjects with difficulty swallowing Subjects who are known to be allergic or hypersensitive to the IMP or any of its components Subjects with a known sensitivity or contraindication to alprazolam Subjects who have participated in any clinical trial within 90 days prior to signing the ICF. Subjects who have demonstrated a non-response to 35% CO2 double inhalation challenge in a previous trial. Any subject who, in the opinion of the sponsor, investigator, or medical monitor, should not participate in the trial Subjects with a positive SARS-CoV-2 quantitative PCR test result at Day -1, Period 1 are excluded. Results from subjects reporting a positive SARS-CoV-2 quantitative PCR test result prior to Day -1, Period need to be discussed with the sponsor/medical monitor prior to enrolment of the subject into the trial

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CVL-865<br>High dose CVL-865 (25mg) Low dose CVL-865 (7.5mg) | Drug: CVL-865 High dose<br>* High dose CVL-865: Will be administered as 5mg BID for 2 days followed by 12.5mg BID for another 2 days during the Titration Phase. 25mg will be administered during the Maintenance Phase (3 days of BID and morning dose only on the 4th day)<br>Drug: CVL-865 low dose<br>* Low dose CVL-865, oral tablets. Will be administered as 2.5mg BID for 2 days followed by 5mg BID for another 2 days during the Titration Phase. 7.5mg BID will be administered during the Maintenance Phase (3 days of BID and morning dose only on 4th day)<br>|
| Active Comparator: Alprazolam<br>Active Comparator Alprazolam with extended release oral tablets; 1 tablet BID | Drug: Alprazolam 1mg XR<br>* Alprazolam 1mg XR will be administered for 8 days BID (morning dose only on 8th day)<br>|
| Placebo Comparator: Placebo<br>Placebo Comparator matching oral tablets for CVL-865, capsule for Alprazolam | Drug: Placebo<br>* Placebo, oral tablet/capsule will be administered for 8 days BID (morning dose only on 8th day)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSL-IV score | Change in Panic Symptom List -IV (PSL-IV), a questionnaire including 13 symptoms, each with intensity rating from 0 (not at all) to 4 (very intense), from pre-CO2 to Post CO2 challenge value | up to Day 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| VAS Fear score | Change in Visual Analog Scale (VAS) value for fear, consisting of a horizontal line 100 mm in length with 0 corresponding to no fear and 100 corresponding to the most fear possible, from pre-CO2 to Post CO2 challenge | up to Day 8 | 
| CO2 challenge | Change from pre-CO2 to post-CO2 challenge values in Finapres NanoCore Physiological Measurements | Screening, Day 1, Day 8 | 
| Treatment-emergent AEs | Treatment-emergent AEs | From screening to Follow-up Visit | 
| Suicidality assessed using Columbia - Suicide Severity Rating Scale (C-SSRS) | Suicidality assessed using Columbia - Suicide Severity Rating Scale (C-SSRS) with no/yes (0/1) to each interview question on the occurrence of suicide events or ideation. | Screening, Day -1, Day 8 | 
| CVL-865 (and alprazolam, if appropriate) concentrations |  | Day 8 | 
| Change From Baseline in NeuroCart test battery Score | Psychodynamic effects of CVL-865 will be assessed by means of the NeuroCart test battery (including saccadic eye movements, adaptive tracking, body sway, Quantitative EEG) | Screening, Day 1, Day 8 | 
| Change from Baseline in Bond & Lader Visual Analogue Scale (VAS) | Visual Analogue Scale (VAS) is made up of 16 pairs of alternative descriptors of mood and attention at either end. The Bond-Lader of a 10 cm line. Participants will rate their feelings at the time of assessment by indicating the point on the line which best represent their mood. Each item is scored by measuring the position relative to the left hand end of the line and levels of anxiety, sedation, and dysphoria are then calculated from the combined scores of selected items. The score ranges from 0 to 100, with a high score reflecting a high level of anxiety, sedation or dysphoria. | Day 1, Day 8 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Anxiety, Panic, CVL-865, PF-06372865, Hypercapnia, CO2 challenge, Healthy Subjects