A Phase 3 Trial to Assess CYB003 in Major Depressive Disorder

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Cybin IRL Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

Trial duration

30 Oct 2025 → ongoing

Decision date (initial)

2026-01-23

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Cybin IRL Limited

External identifiers

EU CT number

2024-519270-40-00

ClinicalTrials.gov

NCT06793397

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Safety, Efficacy

To assess the efficacy of 2 administrations of IP compared to placebo in treating symptoms of MDD in adult participants.

Secondary objectives 3

1. To assess longer-term efficacy of 2 administrations of IP compared to placebo in treating symptoms of MDD in adult participants.
2. To further assess the efficacy of IP compared to placebo.
3. To determine the effect of 2 administrations of IP compared to placebo on symptoms of depression, as assessed by participants; global disease severity, anxiety, and quality of life.

Conditions and MedDRA coding

Major Depressive Disorder

Study design 3 periods

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Aged 18 to 85 years inclusive, at Screening.
2. 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 that includes confirmation with the Mini International Neuropsychiatric Interview [MINI, Version 7.0.2]). The first MDD episode must have occurred prior to age 60 by participant report or preferably medical records when available.
3. Depression is of moderate to severe degree as indicated by a score of ≥24 on the MADRS at Screening, independently confirmed by the Massachusetts General Hospital Clinical Trials Network and Institute SAFER (State versus trait; Assessability; Face validity; Ecological validity; and Rule of Three Ps [pervasive, persistent, and pathological]) assessment, and Clinical Global Impressions-Severity score of ≥4.
4. Participant has no more than a 25% decrease in the total MADRS score between Screening and the Baseline Visit (Day 1).
5. Participant has been on a stable dose of antidepressant medication (see Section 6.2.3.1 for permitted antidepressant medications and Section 6.2.2 for prohibited medications) 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 SAFER interview.
6. If the participant is engaged in a psychotherapeutic relationship, it must be stable and consistent for at least 12 weeks prior to Screening. No changes in the frequency or the setting are to be made throughout the trial.
7. Participant has a body mass index (BMI) of 40 kg/m2 or less (BMI ≤40 kg/m2), inclusive, at Screening.
8. Participant is able to refrain from nicotine use during the dosing session (up to 8 hours), as determined by a score of ≤4 on the Fagerström Test for Nicotine Dependence.
9. Registered with a healthcare professional who can confirm the diagnosis and previous treatments received by the participant. Confirmation may be noted in the form of email, telephone contact, written report, or pharmacy records.
10. Participants capable of producing sperm must use a condom plus spermicide (where publicly available) during the trial and for 12 weeks after their final dose of trial medication, if their partner is a person of childbearing potential.
11. 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 [see Appendix 14.1]) 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.
12. Female participants who were capable of producing eggs (ova), agree that the only exclusion from the requirement for contraception during the trial is to be postmenopausal or permanently sterile following hysterectomy, bilateral salpingectomy or bilateral oophorectomy. Postmenopausal is defined as spontaneous amenorrhea for at least 12 months, and a serum follicle stimulating hormone level in the menopausal range (refer to ACM Lab Ranges), unless the participant is taking hormone replacement therapy or is using hormonal contraception.
13. Participant has provided written informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form.

Exclusion criteria 31

1. 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 (as determined by MINI with Borderline Personality Disorder Module Version 7.0.2 at Screening).
2. Family history of schizophrenia, schizoaffective disorder, or bipolar disorder type 1 (first-degree relatives).
3. Significant suicide risk as defined by (a) suicidal ideation as endorsed on items 4 or 5 on the Columbia-Suicide Severity Rating Scale 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-injurious behavior within 12 months of Screening.
4. 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 (label specified) for an adequate duration as judged by the Investigator and SAFER interview.
5. Has had electroconvulsive treatment, transcranial magnetic stimulation, deep brain stimulation, or vagal nerve stimulation for any episode of MDD in the last 6 months.
6. Currently receiving a monoamine oxidase inhibitor, tricyclic antidepressant, mirtazapine, trazodone, moclobemide, buspirone, ketamine or S-ketamine, or an antipsychotic or mood stabilizer for MDD.
7. Participant report of (or if available in medical record) exposure to psilocin or 5HT-2a 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.
8. Participant report of (or if available in medical record) treatment with ketamine or S-ketamine use within 12 months prior to Screening.
9. 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).
10. Participants with renal insufficiency (estimated glomerular filtration rate ≤59 mL/min/1.73m2).
11. Has hypothyroidism or hyperthyroidism, unless controlled on appropriate medication with no change in dosage for at least 12 weeks prior to Screening. Participants must meet 1 of the following criteria in order to be enrolled: a. Thyroid-stimulating hormone (TSH) levels within normal reference range at Screening (refer to ACM Lab Ranges); OR b. TSH ≥0.75 × the lower limit of normal and ≤1.25 × upper limit of normal (ULN) AND with no clinical signs/symptoms of thyroid disease AND normal free triiodothyronine (T3) and free thyroxine (T4).
12. Current diagnosis of uncontrolled hypertension or an arrhythmia, or clinically abnormal results for heart rate (resting supine heart rate (HR) >100 beats per minute or blood pressure (BP) (resting supine systolic BP >139 mmHg or diastolic BP >89 mmHg) at Screening. Participants with well controlled hypertension and who have been on a stable dose of either 1 or 2 allowable antihypertensive medications for ≥4 weeks prior to Screening are permitted.
13. QT interval corrected for heart rate using Fridericia’s formula >450 msec for males and >470 msec for females at Screening, following triplicate electrocardiogram (ECG) readings.
14. Presence of clinically significant ECG abnormalities at the Screening Visit, as defined by Investigator judgment.
15. 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.
16. 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).
17. Aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase or total bilirubin levels ≥1.5 × the ULN at Screening. These laboratory evaluations may be repeated once at the discretion of the Investigator. If the repeat test is within the reference range, the participant may be included only if the Investigator considers that the previous finding will not introduce additional risk factors and will not interfere with interpretation of safety data.
18. Positive urine test for drugs of abuse or alcohol breath test at Screening or at Day 1 or Day 22 prior to dosing. A positive test for cannabinoids (e.g., marijuana) at Screening may not exclude a participant if after discussion with and evaluation by the Investigator, the participant agrees not to use any marijuana or other cannabinoid products during the trial, and if allowed to participate, the participant must test negative for cannabinoids on Day 1 and Day 22.
19. History of substance use disorder (excepting caffeine and tobacco-related disorders) within the last year, as assessed by a structured clinical interview (MINI, Version 7.0.2) or determined by self-report, or intake of 21 units of alcohol weekly, and the inability to refrain from alcohol use from 48 hours before Screening and each scheduled visit until discharge from the trial site. One unit is equivalent to a 285 mL glass of full-strength beer or 1 (30 mL) measure of spirits or 1 glass (100 mL) of wine.
20. Known sensitivity to psilocin and/or any excipients present in the formulation.
21. Use of a prescription medicine other than stable chronic dose of antidepressant medication(s) with the exception of those permitted during the trial (refer to Sections 6.2.3 and 6.2.3.1 of the protocol) or over-the-counter (OTC) medicines during 14 days before dosing. The Investigator and trial team may review medication on a case-by-case basis to determine if its use would compromise participant’s safety or interfere with trial procedures or data interpretation in discussion with the Medical Monitor and/or Sponsor.
22. Participant is taking or has taken any drugs known to inhibit monoamine oxidase within 14 days prior to trial medication administration.
23. Participant is taking or has taken OTC doses of 5 hydroxytryptophan or St John’s Wort within 14 days prior to trial medication administration.
24. Strenuous exercise within 48 hours prior to each clinic visit.
25. Any other concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the trial as outlined in this protocol, or that would, in the opinion of the Investigator, pose an unacceptable risk to the participant in this trial.
26. Other eligibility considerations (e.g., 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 psilocin), as judged by the Investigator.
27. The participant has participated in a clinical trial and has received a medication or a new chemical entity within 12 weeks prior to dosing with the current trial medication.
28. Participants capable of producing sperm who will not abstain from sperm donation between first dosing and 12 weeks after final dosing.
29. 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.
30. History of serotonin syndrome.
31. Unwilling to consent to audio and video recording of psychological support and dosing sessions.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from Baseline (Day -1) to Day 42 in MADRS total score.

Secondary endpoints 10

1. Change from Baseline (Day -1) to Day 84 in MADRS total score.
2. Proportion of participants with response defined as a ≥50% decrease in MADRS total score from Baseline (Day -1) to Day 84. Response will also be assessed after each dosing session (Day 2 and Day 23) and through Day 84.
3. Proportion of participants in remission defined as MADRS total score ≤10 at Day 84. Remission will also be assessed after each dosing session (Day 2 and Day 23) and through Day 84.
4. Proportion of responders with a sustained response (sustained defined as those meeting response criteria on or before Day 42 and sustained through Day 84 with one score greater than that for the response criterion permitted).
5. Proportion of participants with a sustained remission (sustained defined as those meeting remission criteria on or before Day 42 and sustained through Day 84 with one score greater than that for the remission criterion permitted).
6. Change from Baseline to each timepoint assessed in BDI-II.
7. Change from Baseline to each timepoint assessed in CGI-S score.
8. CGI-I score at each timepoint to assess change since Baseline (Day -1).
9. Change from Baseline to each timepoint assessed in GAD-7 total score.
10. Change from Baseline to each timepoint assessed in Q-LES-Q-SF total score.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Cybin IRL Limited

Sponsor organisation

Cybin IRL Limited

Address

One Spencer Dock, North Wall Quay North Wall Quay

City

Dublin 1

Postcode

DO1 X9R7

Country

Ireland

Scientific contact point

Organisation

Cybin IRL Limited

Contact name

Atul Mahableshwarkar

Public contact point

Organisation

Cybin IRL Limited

Contact name

Rochelle Suffern

Third parties 15

Locations

5 EU/EEA countries · 18 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 122 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications