A Study of a N, N-dimethyltryptamine (DMT) Analog (CYB004) in Participants With Generalized Anxiety Disorder (GAD) With Depressive Symptoms

Study Overview
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Brief Summary
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The purpose of this proof-of-concept study is to determine the safety, tolerability, and preliminary clinical efficacy of CYB004 participants with GAD with depressive symptoms.

Official Title
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A Phase 1b/2a, Randomized, Double-Blind, Active Controlled Study to Assess the Preliminary Clinical Efficacy, Safety, Tolerability, and Pharmacokinetics, of CYB004 in Participants With Generalized Anxiety Disorder (GAD) With Depressive Symptoms

Conditions
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Generalized Anxiety Disorder

Intervention / Treatment
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* Drug: CYB004
* Behavioral: Psychotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged between 21 to 65 years, inclusive, at Screening. Has a diagnosis of GAD (as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition [DSM-V] of moderate to severe degree), established through a full psychiatric work up. Has co-occurring symptoms of moderate to severe depression. Has a BMI of 18 to 37.5 kg/m2, inclusive at Screening. Is ≥60 kg. Is a non-smoker for at least the past 3 months prior to Screening. Has been on a stable dose of antidepressant/anxiolytic medication (no more than 50% change) in the last month prior to Screening and has had an inadequate response, as judged by the Investigator. Is willing to refrain from taking any benzodiazepines or buspirone (or other 5-HT1A agonist) during the 24 hours preceding each dosing visit. Is willing to refrain from taking monoamine oxidase inhibitors for 3 weeks prior to Screening, if applicable. Is negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test at Screening and at Day -1. Provision of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. Exclusion Criteria: Has a primary DSM-5 psychiatric diagnosis other than GAD within the past 6 months established through a full psychiatric work-up. A secondary diagnosis of MDD may be permissible. Current or previously diagnosed schizophrenia spectrum or other psychotic disorders, including schizophrenia, schizoaffective disorder, schizotypal disorder, schizophreniform disorder or brief psychotic disorder; current or previous history of bipolar disorder, or current personality disorder. Current or previous diagnosis of treatment-resistant MDD, defined as failure to respond to 2 or more antidepressant treatments given at an adequate dose for an adequate duration. Currently receiving a monoamine oxidase inhibitor, tricyclic antidepressant, mirtazapine, or a mood stabilizer or has taken any of these medications in the last 3 weeks. Currently taking antipsychotic medication which are 5-HT2 antagonists or has taken such medication in the last 3 weeks. Clinically significant risk of suicidality, as determined through a comprehensive psychiatric interview. Clinically relevant history of abnormal physical health interfering with the study as determined by medical history and physical examinations obtained during Screening as judged by the Investigator (including [but not limited to], neurological, endocrine, cardiovascular, respiratory, gastrointestinal, hepatic, or renal disorder). Diagnosis of hypertension or an arrhythmia. History of hypothyroidism and/or current abnormal thyroid function tests. Clinically relevant abnormal laboratory results. Positive test for hepatitis B surface antigen (HBsAg), anti-hepatitis C antibody (anti- HCV) or human immunodeficiency virus I and II (anti-HIV I/II) at Screening. History or clinical evidence of any disease and/or existence of any surgical or medical condition which might interfere with the absorption, distribution, metabolism or excretion of the study drug. Any other concomitant disease or condition that could interfere with, or for which the treatment might interfere with the conduct of the study, or that would, in the opinion of the Investigator, pose an unacceptable risk to the participant in this study. Has a presence or relevant history of any of the following medical conditions: organic brain disorders (e.g., epilepsy, seizure, intracranial hypertension, intracranial bleed and aneurysmal disease, brain tumor or other medical conditions associated with seizures or convulsions). Consumes excessive amounts of caffeine (e.g., coffee, tea, caffeinated sodas) or methylxanthines (e.g., chocolate) based on the Investigator's determination and discretion. Has participated in a clinical study and has received a medication or a new chemical entity within 3 months prior to dosing of current study medication. Known sensitivity to DMT or ayahuasca. Is taking a prescription medicine (except for stable chronic dose of antidepressant medication(s), sedatives/hypnotics, and hormonal contraceptives, if applicable), certain herbal supplements (to be reviewed by the Investigator), or over-the-counter (OTC) medicine during the 28 days before dosing. Is taking or has taken over the counter (OTC) doses of 5-hydroxytryptophan or St John's Wort within 28 days prior to receiving the study drug. Donation of blood or plasma of >400 mL within 1 month prior to first dosing until 4 weeks after final dosing. For participants capable of producing sperm: Is not willing to abstain from sperm donation between first dosing and 3 months after final dosing. For participants capable: Is pregnant, breastfeeding or planning to conceive. Known difficulty with obtaining intravenous (IV) access. Not fluent in the English language. Other eligibility considerations (i.e., participant personal circumstances, behavior, and/or any current problem that might interfere with participation or that is incompatible with establishment of rapport or safe exposure to the study drug), as judged by the Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Active<br>Arm A participants will receive a full dose of CYB004 in 2 of 2 medicine sessions, approximately three weeks apart. All participants will receive supportive EMBARK psychotherapy throughout the study. | Drug: CYB004<br>* CYB004 is a synthetic deuterated N, N-Dimethyltryptamine (DMT) analog.<br>Behavioral: Psychotherapy<br>* Manualized psychotherapy (called EMBARK) performed by facilitators<br>|
| Active Comparator: Arm B: Control<br>Arm B participants will receive a low dose of CYB004 in 2 of 2 medicine sessions, approximately three weeks apart. All participants will receive supportive EMBARK psychotherapy throughout the study. | Drug: CYB004<br>* CYB004 is a synthetic deuterated N, N-Dimethyltryptamine (DMT) analog.<br>Behavioral: Psychotherapy<br>* Manualized psychotherapy (called EMBARK) performed by facilitators<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hamilton Anxiety Rating Scale (HAM-A) | The HAM-A is a 14-item scale that is used to rate the severity of symptoms of anxiety. Each of the 14 items is defined by a series of symptoms and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Items are scored from 0 (not present) to 4 (very severe), for a total score ranging from 0 to 56. Scores <17 indicate mild anxiety, scores of 18 to 24 indicate mild to moderate anxiety, and scores of 25 to 30 or higher indicate moderate to severe anxiety. | Screening (Day-28 and Day-1), Day 1, Day 8, Day 15, Day 21, Day 23, Day 43, Day 64, Day 85, Day 106, Day Day 127, Day 148, and End of Treatment (Day 169) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hamilton Depression Scale (HAM-D) | The HAM-D is a validated 17-item questionnaire administered by the clinician used to assess severity of, and change in, depressive symptoms in the past week. The questionnaire assesses core symptoms of depression, anxiety, and side effects of drug treatment on a scale of 0 to 50 with higher scores indicating more severe depression. Scores of 0-7 are considered normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression (Zimmerman et al., 2013); the maximum score being 52 on the 17-point scale. | Screening (Day-28 and Day-1), Day 1, Day 8, Day 15, Day 21, Day 23, Day 43, Day 64, Day 85, Day 106, Day Day 127, Day 148, and End of Treatment (Day 169) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Generalized Anxiety Disorder, GAD, Depression, CYB004, CYB004-001, Psychedelic, DMT, N, N-dimethyltryptamine