CombiChronoS - Effectiveness of a Combination of Chronotherapeutics for the Treatment of Major Depressive Episode (MDE) with Insomnia: A Multicenter, Randomized, Double-Blind, Placebo-Controlled 2x2 Factorial Trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

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

Trial duration

28 Jan 2026 → ongoing

Decision date (initial)

2025-05-12

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

DGOS - Ministry of Health

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To evaluate the effectiveness of two chronotherapeutics, either alone or in combination, on the reduction of depressive symptoms after 8 weeks of treatment in patients with Major Depressive Episode (MDE): active light therapy for 8 weeks and 2 mg prolonged-release melatonin for 8 weeks.

Secondary objectives 9

1. To evaluate the effectiveness of two chronotherapeutics, either alone or in combination, on:
2. 1. The reduction of depressive symptoms at 1, 4, 8 weeks, and 3 months of treatment, using the MADRS scale.
3. 2. Therapeutic response at 1, 4, 8 weeks, and 3 months of treatment, using the MADRS scale.
4. 3. Remission of depressive symptoms at 4, 8 weeks, and 3 months of treatment, using the MADRS scale.
5. 4. Improvement in sleep and circadian rhythms at 1, 4, 8 weeks, and 3 months of treatment, based on sleep and sleep-wake rhythm self-questionnaires and objective actigraphy parameters.
6. 5. The longitudinal evolution of the MADRS score over time from baseline to 8 weeks (measured at 1, 4, and 8 weeks) and from baseline to 3 months.
7. 6. Time to therapeutic response from baseline to 3 months of treatment, using the MADRS scale.
8. 7. The safety and tolerance of different combinations of chronotherapeutics
9. 8. Patient's mood state and overall functioning at 1, 4, 8 weeks, and 3 months of treatment

Conditions and MedDRA coding

insomnia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. 1-Aged 18 to 65 years.
2. 2- Diagnosed with Major Depressive Episode (MDE) in the context of a unipolar disorder (DSM-5 criteria) and a MADRS score ≥20 (threshold validated for moderate MDE).
3. 3- Comorbid insomnia (DSM-5 criteria) with an ISI score ≥8 (threshold validated for mild and clinically significant insomnia).
4. 4- Not exposed to antidepressants of any class in the month prior to inclusion
5. 5- Not exposed to light therapy in the month prior to inclusion.
6. 6- Patients receiving outpatient or inpatient care for a treatment duration of 8 weeks
7. 7- Ability to understand and sign the informed consent.

Exclusion criteria 12

1. 1- Subjects under guardianship or deprived of liberty.
2. 2- Ophthalmic diseases (cataracts, glaucoma, age-related macular degeneration, etc.) or diseases affecting the retina (retinitis pigmentosa, diabetes, herpes, etc.).
3. 3- The following disorders (according to DSM-5): Schizophrenia and other psychotic disorders; Bipolar disorder, particularly (hypo)manic episodes (YMRS score ≥ 12); Other unstable mental disorders, such as substance use disorders, including alcohol and tobacco
4. 4- Other unstable general medical conditions.
5. 5- Pregnant or breastfeeding women.
6. 6- Hypersomnia with prolonged total sleep time secondary to MDE according to ICSD-3 criteria.
7. 7- Therapeutic resistance of the current MDE (2 antidepressants from different classes).
8. 8- Presence of a high suicide risk, assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS, score ≥ 4).
9. 9- Treatment with melatonin at the time of inclusion.
10. 10- Participation in another interventional study during the course of the trial
11. 11- Known hypersensitivity to melatonin.
12. 12- Contraindication to selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Montgomery-Åsberg Depression Rating Scale (MADRS) score at 8 weeks (Week 8, Visit 3 – clinical evaluation visit) adjusted for the baseline score (Week 0, Visit 0 – inclusion and randomization visit) in each of the four treatment arms

Secondary endpoints 8

1. 1. MADRS score at 1, 4, 8 weeks, and 3 months: o Therapeutic response (50% reduction in MADRS score). o Remission (MADRS score ≤ 10).
2. 2. Subjective sleep quality at 1, 4, 8 weeks, and 3 months: sleep and sleep-wake rhythm self-questionnaires
3. 3. Objective actigraphy parameters at 1, 4, and 8 weeks: o Sleep parameters: total sleep time, nocturnal awakenings (WASO), fragmentation index, sleep efficiency (total sleep time/total time in bed), time spent in bed. o Rhythm parameters: relative amplitude, stability, and variability of sleep-wake rhythms, L5 and M10 phase markers (onset of the least active 5 hours and most active 10 hours).
4. 4. Subjective sleep diary parameters at 1, 4, and 8 weeks.
5. 5. Slope of longitudinal evolution of the MADRS score
6. 6. Time (in days) to therapeutic response (maximum assessment at 3 months).
7. 7. Side effects questionnaire (PRISE-M) at 1, 4, and 8 weeks
8. 8. Mood state and overall functioning questionnaires (YMRS, C-SSRS, QIDS-SR, GAG7, CGI) at 1, 4, 8 weeks, and 3 months

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr. Pierre Alexis GEOFFROY

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr. Pierre Alexis GEOFFROY

Locations

1 EU/EEA country · 5 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 18 files

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

Application history

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