A Study of a Psilocybin Analog (CYB003) in Humans With Major Depressive Disorder (APPROACH)
This Phase III randomised, double-blind, placebo-controlled trial (n=220) will study the efficacy, safety, and tolerability of CYB003 (16mg), a synthetic psilocybin analogue, compared to placebo as an adjunctive treatment for major depressive disorder (MDD).
Randomised, quadruple-blind, parallel-group Phase III study (n≈220) comparing CYB003 16 mg given in two dosing sessions ~3 weeks apart versus matching placebo, adjunctive to a stable antidepressant and manualised psychological support.
Primary aim is to assess efficacy, safety, and tolerability in participants with moderate-to-severe MDD; key eligibility includes BMI ≤40 kg/m2 and exclusion for psychotic/bipolar disorders, recent high suicide risk, and recent psychedelic use.
Study Protocol
Preparation
sessions
Dosing
2 sessions
Locations
Scottsdale Research Institute — Phoenix, Arizona, United States
Mountain Clinical Trials — Phoenix, Arizona, United States
Noble Clinical Research — Tucson, Arizona, United States
Del Sol Research Management — Tucson, Arizona, United States
CenExel CIT (Clinical Innovations, Inc) — Bellflower, California, United States
Kadima Neuropsychiatry Institute — La Jolla, California, United States
Bespoke Treatment/Lipov Medical Group — Los Angeles, California, United States
Catalina Research Institute — Montclair, California, United States
Excell Research, Inc — Oceanside, California, United States
Open Mind Collective/UCSF Medical Center Mount Zion — San Francisco, California, United States
Inland Psychiatric Medical Group Inc — San Juan Capistrano, California, United States
Mountain View Clinical Research — Denver, Colorado, United States
Starlight Clinical Research — Evergreen, Colorado, United States
Research Centers of America — Hollywood, Florida, United States
K2 Medical Research-Maitland — Maitland, Florida, United States
Floridian Neuroscience Institute
Integration
sessions
Therapeutic Protocol
support
Study Arms & Interventions
CYB003
experimental
CYB003 16 mg in 2 dosing sessions ~3 weeks apart; adjunctive to stable antidepressant with manualised psychological support.
Interventions
Psilocybin16 mg
via Oral• two sessions• 2 doses total
Deuterated psilocin analog; adjunctive to ongoing antidepressant therapy.
Compound
via Other• throughout study
Manualised psychological support performed by facilitators.
Placebo
inactive
Matching placebo in 2 dosing sessions; manualised psychological support; non-responders eligible for extension.
Interventions
Placebo
via Oral• two sessions• 2 doses total
Matching placebo.
Compound
via Other• throughout study
Manualised psychological support performed by facilitators.
Participants
Ages
18 – 75
Sexes
Male & Female
BMI
0 - 40
Psychosis History
Excluded
Inclusion Criteria
Inclusion Criteria:
Participants must meet all the following criteria to be included in the trial:
Aged 18 to 85 years inclusive, at Screening
Participant has a diagnosis of MDD (single or recurrent episode as defined by DSM-5 TR [if single episode, duration of ≥4 weeks and ≤24 months] and established as per evaluation by the Investigator. The first MDD episode must have occurred prior to age 60.
Depression is of moderate to severe degree at Screening, independently confirmed by additional clinical assessments
Participant has been on a stable dose of a single antidepressant medication at an adequate dose (label specified) for an adequate duration in the last 4 weeks prior to Screening and has had an inadequate response (less than 50% improvement), as judged by the Investigator and clinical interviews.
Participant has a body mass index (BMI) of 40 kg/m2 or less (BMI ≤ 40 kg/m2), inclusive, at Screening.
Participant is able to refrain from nicotine use during the dosing session (up to 8 hours)
Registered with a healthcare professional who can confirm the diagnosis and previous treatments received by the participant.
Participants capable of producing sperm must use a condom during the trial and for 12 weeks after their final dose of trial medication, if their partner is a person of childbearing potential. In addition, their partner of childbearing potential must use a highly effective method of contraception (i.e., failure rate less than 1% when used consistently and correctly) from first dosing until 12 weeks following final dosing.
Participants of childbearing potential who have a partner capable of producing sperm must agree to use a highly effective method of contraception (i.e., failure rate less than 1% when used consistently and correctly) in combination with the use of a condom plus spermicide during the trial and for 12 weeks after their final dose of trial medication. Such participants must have a negative pregnancy test at Screening and Day -1 prior to dosing.
Female participants who were capable of producing eggs (ova) must be postmenopausal or permanently sterile following hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Postmenopausal is defined as spontaneous amenorrhea for at least 12 months, and a serum follicle-stimulating hormone level in the menopausal range, unless the participant is taking hormone replacement therapy or is using hormonal contraception.
Participant has provided written informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form.
Exclusion Criteria
Exclusion Criteria:
Participants with any of the following characteristics/conditions will be excluded from trial participation:
Current or previously diagnosed schizophrenia spectrum or other psychotic disorders, including schizophrenia, schizoaffective disorder, schizotypal disorder, schizophreniform disorder, brief psychotic disorder, attention deficit hyperactivity disorder, current or previous history of bipolar disorder, or current borderline personality disorder.
Family history of schizophrenia, schizoaffective disorder, or bipolar disorder type 1 (first degree relatives).
Significant suicide risk within the past 6 months, during the Screening Period, or at Baseline; or (b) suicidal behaviors within 12 months of Screening; or (c) clinical assessment of significant suicidal risk during clinical interview; or (d) non-suicidal self-injury within 12 months of Screening.
Current or previous diagnosis of treatment-resistant MDD, defined as failure to respond to 2 or more antidepressant treatments of 2 different classes given at an adequate dose for an adequate duration as judged by the Investigator and clinical interview.
Has had electroconvulsive treatment, transcranial magnetic stimulation, deep brain stimulation, or vagal nerve stimulation for any episode of MDD in the last 6 months.
Currently receiving a monoamine oxidase inhibitor, tricyclic antidepressant, mirtazapine, trazodone, moclobemide, buspirone, ketamine or S-ketamine, or an antipsychotic or mood stabilizer for MDD.
Participant report of (or if available in medical record) exposure to psilocin, or 5-HT2a receptor agonists, or any other psychedelics, such as ayahuasca, mescaline, lysergic acid diethylamide, peyote, or 3,4-methylenedioxymethamphetamine, more than 4 times over the participant's lifetime or any psychedelic use within 12 months prior to Screening.
Clinically relevant history of abnormal physical health interfering with the trial as determined by medical history and physical examinations obtained during Screening as judged by the Investigator (including but not limited to, neurological, cardiovascular, respiratory, gastrointestinal [including dyspepsia or gastroesophageal reflux disease], hepatic, or renal disorder).
Participants with renal insufficiency.
Has hypothyroidism or hyperthyroidism, unless controlled on appropriate medication with no change in dosage for at least 12 weeks prior to Screening.
Innovative Clinical Research, INC — North Miami, Florida, United States
Clinical Neuroscience Solutions, Inc — Orlando, Florida, United States
Charter Research — Orlando, Florida, United States
Combined Research Orlando Phase I-IV — Orlando, Florida, United States
K2 Medical Research - Tampa — Tampa, Florida, United States
Atlanta Center for Medical Research, CenExel — Atlanta, Georgia, United States
CenExel iResearch Atlanta — Decatur, Georgia, United States
CenExel iResearch Savannah — Savannah, Georgia, United States
Great Lakes Clinical Trials, DBA Flourish Research — Chicago, Illinois, United States
Uptown Research Institute — Chicago, Illinois, United States
Psychiatric Medicine Associates, LLC — Skokie, Illinois, United States
DelRicht Research — New Orleans, Louisiana, United States
Sunstone Medical, PC — Rockville, Maryland, United States
Adams Clinical Boston — Boston, Massachusetts, United States
Adams Clinical — Boston, Massachusetts, United States
Elixia Health — Springfield, Massachusetts, United States
Redbird Research, LLC — Las Vegas, Nevada, United States
Oasis Clinical Trials — Las Vegas, Nevada, United States
Global Medical Institutes, Princeton Medical Institute — Princeton, New Jersey, United States
Adams Clinical Harlem — New York, New York, United States
Adams Clinical Bronx — The Bronx, New York, United States
Monroe Biomedical Research — Monroe, North Carolina, United States
Neurobehavioral Clinical Research — North Canton, Ohio, United States
Clinical Neuroscience Solutions, CNS Healthcare — Memphis, Tennessee, United States
InSite Clinical Research, LLC — DeSota, Texas, United States
Zillan Clinical Research — Houston, Texas, United States
AIM Trials — Plano, Texas, United States
Cedar Clinical Research — Murray, Utah, United States
Inner Space Research, LLC — Orem, Utah, United States
Current diagnosis of uncontrolled hypertension or an arrhythmia, or clinically relevant abnormal results for heart rate or blood pressure
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 trial medication.
Participant has a presence or relevant history of 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).
Known sensitivity to psilocin and/or any excipients present in the formulation.
Participant is taking or has taken OTC doses of 5 hydroxytryptophan or St John's Wort within 45 days prior to trial medication administration.
Strenuous exercise within 48 hours prior to each clinic visit.
The participant has participated in a clinical trial and has received a medication or a new chemical entity within 12 weeks prior to dosing of current trial medication.
Participants capable of producing sperm who will not abstain from sperm donation between first dosing and 12 weeks after final dosing.
Participants of childbearing potential who are pregnant, breastfeeding, planning to conceive or unwilling to abstain from egg (ova) donation between first dosing and 12 weeks after final dosing.
History of serotonin syndrome.
Unwilling to consent to audio and video recording of psychological support and dosing sessions.