Boosting recovery through excitation of arousal and awareness in comatose patients: Dose finding study (BREA2KTHROUGH DOSEFINDER)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Rigshospitalet

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

26 Feb 2025 → ongoing

Decision date (initial)

2024-05-28

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety

To do a dose escalation study to establish the safety of utilizing apomorphine and psilocybin in unresponsive ICU patients with acute brain injury. This is a prospective, open-label, phase 1b, dose escalation study (n=80 patients, i.e., 26 patients with 1 mg psilocybin, 27 patients with 10 mg, and 27 patients with 25 mg psilocybin; all 80 patients receive apomorphine 1-2h after psilocybin administration). The study is authorized and registered as EU-CT 2023-503617-30-02 and is currently recruiting patients as of June 2026. NB: The earlier version EU-CT 2023-503617-30-01 referred to under “Justification for trial category” was subsequently modified after request from the Ethics committee.

Secondary objectives 1

1. To investigate for somatic and neuropsychiatric adverse events

Conditions and MedDRA coding

Coma and other disorders of consciousness due to acute traumatic and non-traumatic brain injury

Regulatory references

Plan to share IPD

No

IPD plan description

N/A

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Age ≥ 18 years
2. Fluent in Danish or English language
3. Admission to ICU for severe acute brain injury after trauma, a cerebrovascular accident or anoxic-ischemic/metabolic injury (typically after cardiac arrest) causing coma or another acute DoC (i.e., UWS/VS, MCS), diagnosed by trained investigators
4. Unconsciousness is expected by the attending physicians to last for ≥3 days
5. Written informed consent for trial participation from both the trial guardian and next-of-kin

Exclusion criteria 12

1. Ongoing infusion of sedatives/continuous pharmacological sedation (We aim for unsedated patients during neurological examinations, pupillometry and NIRS-EEG, but if patients cannot fully be weaned from sedation, dosages are reduced to the lowest possible level.)
2. Expected survival <7 days
3. Known severe psychotic disorder (e.g., schizophrenia, psychosis after drug abuse, psychotic major depression, current major depression, bipolar disease, but previous history of major depression without psychosis allowed) or a history of a first-degree relative with such a disorder
4. Deafness, blindness, or bilateral eye surgery before the onset of brain injury
5. Ongoing use of dopamine agonists or antagonists within 6 half-lives of the drug
6. Ongoing or previous use of psychoactive or psychotropic substances (including, but not limited to monoamine oxidase inhibitors or medications that are known as uridine diphosphate glucuronosyltransferase enzyme modulators; and ongoing treatments with selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitors medications because of the potential to increase the risk of serotonin syndrome) 2 weeks prior examination or within 6 half-lives of the drug
7. Cardiac valvular disease and pulmonal hypertension (for a theoretical concern that serotonergic agents might aggravate these conditions)
8. Recovery of the ability to follow commands consistently prior to enrolment
9. Females of childbearing potential, unless negative HCG test is
10. Lack of Danish or English language proficiency
11. Lack of next-of-kin consent
12. Residency outside of Denmark

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Time to awakening within 30 days (overall safety)

Secondary endpoints 6

1. Number of participants with one or more SARs/SAEs at day 30
2. Any neuropsychiatric side effects until day 50 (e.g., hallucinations, anxiety, suicidality, signs of other psychological distress) after receiving psilocybin that warrants medical attention by the attending physicians using standard clinical care like application of sedatives/benzodiazepines and/or neuroleptic medication and non-pharmacological interventions
3. Improvement of conscious state after administration of psylocibin (at three different doses) and apomorphine, as measured by FOUR (≥2 points) and/or SECONDs (≥1 point) scores, at day 1 (exploratory endpoint)
4. Improvement of conscious state after administration of apomorphine plus 1 mg, 10 mg or 25 mg psylocibin, as measured by clinical outcome at day 1 (improvement across DoC categories, e.g., from VS/UWS to MCS-), FOUR (≥2 points) and/or SECONDs (≥1 point) scores at day 7, and as measured by GOS-E (≥1 point) at day 90 (exploratory endpoint)
5. Significantly larger median pupillary size during passive and active paradigms compared to the immediate rest periods prior and after administration of psilocybin and apomorphine, as measured by automated pupillometer (exploratory endpoint)
6. Neurovascular coupling (NIRS-EEG) measures combined with EEG features from our machine learning algorithm following administration of psylocibin and apomorphine, and cortical activation during tongue mental imagery paradigm (exploratory endpoint)

Investigational products

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

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Rigshospitalet

Sponsor organisation

Rigshospitalet

Address

Blegdamsvej 9

City

Copenhagen Oe

Postcode

2100

Country

Denmark

Scientific contact point

Organisation

Rigshospitalet

Contact name

Daniel Kondziella

Public contact point

Organisation

Rigshospitalet

Contact name

Daniel Kondziella

Third parties 1

Locations

1 EU/EEA country · 3 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 13 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