Clinical trial NCT03870776: RESIST : Administration of MAP4343 in Antidepressant Non-Responders Patients Experiencing a Major Depressive Episode
Official title: Double-blind,Controlled,Randomized Phase 2 Study of Efficacy,Safety,Pharmacokinetics& Pharmacodynamics of Daily Oral Administration of MAP4343 During 6 Weeks in Antidepressant Non-responders Patients Experiencing a Major Depressive Episode
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Depression
Keywords: Depression
Resistant depression
Lead sponsor: Mapreg
Sponsor class: INDUSTRY
Collaborators: name: Eurofins Optimed
First posted: 2019-03-12
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: There are 3 groups :

* Placebo group will receive placebo during 42 days with antidepressant treatment in add-on.
* Dose 1 during 42 days with antidepressant treatment in add-on. Upon IDMC recommendation after the first futility analysis (IDMC#5 13-Jun-2022), Dose 1 was stopped from the 17-Jun-2022.
* Dose 2 during 42 days with antidepressant treatment in add-on.
Primary purpose: TREATMENT

Brief summary: The study is a phase II, double-blind, randomized, placebo controlled, parallel, multicentric study in 110 patients with drug resistant depression.

Detailed description: This is a phase II, versus placebo, multicentre, double blind, randomized, parallel study in male or female patients with drug resistant depression.

This study targets the antidepressant non-responders' patients who have already experienced at least 2 antidepressant treatments with no success. It is estimated that about 2/3 of the patients treated with antidepressant drugs do not respond partially or completely to the actual conventional treatments (Selective Serotonin Reuptake Inhibitor and Serotonin and Norepinephrine Reuptake Inhibitor).

110 patients with drug resistant depression episode, aged 18 to 80 will be included in the study. They will be recruited from psychiatric consultations in the centers participating to the study.

Eligibility criteria: Inclusion Criteria:

1. TRD level from to 2 to 4 inclusive according to the Thase \& Rush classification;
2. Patient experiencing a Major Depressive Episode (MDE) according to DSM-5 criteria. MDE can be isolated or recurrent. The diagnosis is based on Mini-International Neuropsychiatric Interview (MINI) test;
3. Patient who received a previous antidepressant treatment (AD-Y) in monotherapy with vortioxetine, duloxetine or venlafaxine) at optimized dosages during 6 weeks prior to randomization, associated or not to AD-potentiator (quetiapine), are eligible.
4. Hamilton Depression Rating Scale (HDRS) score \> 21;
5. Clinical Global Impressions scale (CGI) ≥ 4;
6. Male or female patient, aged 18 to 80 years inclusive;
7. Females of childbearing potential/Sexually active males with partner of childbearing potential: commitment to consistently and correctly use an acceptable method of birth control (oral, transdermal, systemic or implant contraception birth control, intrauterine devices, diaphragm or condoms) for the duration of the trial and for 4 months after the last study drug administration; Females of non-childbearing potential: either surgically sterilized or at least 1 year postmenopausal (amenorrhea duration at least 12 months);
8. Negative pregnancy test at screening baseline;
9. Body Mass Index (BMI) between 18 and 32 kg/m2 inclusive;
10. Laboratory parameters within the normal range of the laboratory (hematological, blood chemistry tests, urinalysis, hormonology). Individual values out of the normal range can be accepted if judged clinically non relevant by the Investigator;
11. Normal ECG recording on a 12-lead ECG at the screening visit:

    * 120 \< PR \< 210 ms
    * QRS \< 120 ms
    * QTcF ≤ 430 ms for male and \< 450 ms for female,
    * No sign of any trouble of sinusal automatism,
    * Or considered NCs by investigators;
12. Normal Blood Pressure (BP) and Heart Rate (HR) at the screening visit after 10 minutes in supine position:

    * 95 mmHg ≤ Systolic Blood Pressure (SBP) ≤ 140 mmHg,
    * 50 mmHg ≤ Diastolic Blood Pressure (DBP) ≤ 90 mmHg,
    * 50 bpm ≤ HR ≤ 80 bpm,
    * Or considered NCs by investigators;
13. Signing a written informed consent prior to selection;
14. Covered by Health Insurance System and/or in compliance with the recommendations of National Law in force relating to biomedical research.

Exclusion Criteria:

1. MDE with mood congruent or not congruent psychotic characteristics;
2. Patient hospitalized following the procedures: Psychiatric care at the request of another person (soins psychiatriques à la demande d'un tiers) or Psychiatric care at the request of the state representative (soins psychiatriques sur décision du représentant de l'Etat);
3. Suicidal risk in the last month before randomization (C-SSRS: answer yes to the item 3 and/or answer yes to section suicidal behavior; MINI 5.00; suicidal risk section or item 3 of HDRS ≥ 3);
4. History of other psychiatric disorder than DME except global anxiety, social phobia, panic troubles that should be accepted. In particular, patients who experienced a depressive state in bipolar disorder 1 or 2, schizophrenic or schizoaffective disorder should not be included;
5. Presence or history of drug hypersensitivity, or certain allergic-prone condition diagnosed that could represent a risk factor for an allergic shock;
6. Presence or history of hypersensitivity to vortioxetine, duloxetine, venlafaxine or one of their excipients;
7. Any history or presence of severe hepatic insufficiency and/or of hepatic disease which could lead to hepatic insufficiency;
8. Patients who are pregnant or breastfeeding. Patients should not be enrolled if they plan to become pregnant during the time of study participation;
9. Any drug intake during the last month prior to the first administration except treatments for concomitant pathologies which are stable since at least 3 months; Benzodiazepine-type anxiolytics, hydroxyzine chlorhydrate, and add-on treatments are authorized within limits described in Section 5.3; For the previous drug intake, the investigator should consider the time needed to sufficiently eliminate a drug from body system, e.g. 5 half-lives of the drug;
10. Subjects who received MAOI in monotherapy right before the selection (as ttX);
11. General anesthesia within 3 months before administration;
12. Major surgery within 28 days prior to randomization or major surgery planned during the next 6 months;
13. Positive HBs antigen or anti HCV antibody, or positive results for HIV 1 or 2 tests;
14. Significant renal disease, defined as a history of chronic renal failure requiring dialysis or kidney transplant, calculated creatinine clearance ≤ 60 mL/min;
15. Blood donation (including in the frame of a clinical trial) within 2 months before administration;
16. Subject who, in the judgment of the Investigator, is likely to be non-compliant or uncooperative during the study, or unable to cooperate because of a language problem, poor mental development;
17. Medical history which in the opinion of the investigator would make the patient unsuitable for participation in the study (including, but not limited, to patients with coronary insufficiency, thromboembolism diseases);
18. Exclusion period of a previous study;
19. No possibility of contact in case of emergency;
20. History or presence of drug or alcohol abuse (alcohol consumption \> 40 g/day);
21. Administrative or legal supervision.

Primary outcomes:
measure: Hamilton Depression Rating Scale score evolution between baseline and D43
timeFrame: 43 days
Secondary outcomes:
measure: Efficacy of treatment assessed by psychopathological evaluations with Hamilton Depression Rating Scale
timeFrame: 43 days
measure: Efficacy of treatment assessed by psychopathological evaluations with Montgomery and Asberg Depression rating Scale
timeFrame: 43 days
measure: Efficacy of treatment assessed by psychopathological evaluations with Brief Anxiety Scale
timeFrame: 43 days
measure: Efficacy of treatment assessed by psychopathological evaluations with Scale of Global Clinical Impressions
timeFrame: 43 days
measure: Efficacy of treatment assessed by psychopathological evaluations with Quick Inventory of Depressive Symptoms
timeFrame: 43 days
measure: Efficacy of treatment assessed by psychopathological evaluations with General Assessment Functioning
timeFrame: 43 days
measure: Pharmacokinetic assessments with observed maximum plasma concentration (Cmax);
timeFrame: 127 days
measure: Pharmacokinetic assessments with first time to reach Cmax (tmax);
timeFrame: 127 days
measure: Pharmacokinetic assessments with elimination rate constant (Kel);
timeFrame: 127 days
measure: Pharmacokinetic assessments with plasma elimination half-life (t1/2);
timeFrame: 127 days
measure: Pharmacokinetic assessments with plasma area under the plasma concentration-time curve from administration up to infinity with extrapolation of the terminal phase (AUCinf);
timeFrame: 127 days
measure: Pharmacokinetic assessments with percentage of extrapolated AUCinf (%AUCextra);
timeFrame: 127 days
measure: Pharmacokinetic assessments with volumn of distribution (Vd/F);
timeFrame: 127 days
measure: Pharmacokinetic assessments with Clearance (Cl/F);
timeFrame: 127 days
measure: Pharmacokinetic assessments with accumulation ratio (R);
timeFrame: 127 days
measure: Safety parameters assessed by the number of adverse events (AE)
timeFrame: 127 days
measure: Safety parameters assessed - Heart rate
timeFrame: 127 days
measure: Safety parameters assessed by blood pressure
timeFrame: 127 days
measure: Safety parameters assessed - 12-lead Electrocardiogramm
timeFrame: 127 days
measure: Safety parameters assessed - 12-lead ElectrocardiogrammPR;
timeFrame: 127 days
measure: Safety parameters assessed -12-lead Electrocardiogramm : QT
timeFrame: 127 days
measure: Safety parameters assessed - 12-lead Electrocardiogramm : QTc
timeFrame: 127 days
measure: Safety parameters assessed by hematology parameters : Haemoglobin
timeFrame: 127 days
measure: Safety parameters assessed by hematology parameters: Haematocrit
timeFrame: 127 days
measure: Safety parameters assessed by hematology parameters: Red blood cells
timeFrame: 127 days
measure: Safety parameters assessed by hematology parameters: White blood cells
timeFrame: 127 days
measure: Safety parameters assessed by hematology parameters:Neutrophils
timeFrame: 127 days
measure: Safety parameters assessed by hematology parameters: Eosinophils
timeFrame: 127 days
measure: Safety parameters assessed by hematology parameters: Basophils
timeFrame: 127 days
measure: Safety parameters assessed by hematology parameters: Lymphocytes
timeFrame: 127 days
measure: Safety parameters assessed by hematology parameters: Monocytes
timeFrame: 127 days
measure: Safety parameters assessed by hematology parameters: Platelets
timeFrame: 127 days
measure: Safety parameters assessed by hematology parameters: Reticulocytes;
timeFrame: 127 days
measure: Safety parameters assessed by red blood cells indices
timeFrame: 127 days
measure: Safety parameters assessed by hemostasis parameters
timeFrame: 127 days
measure: Safety parameters assessed by serology parameters
timeFrame: 127 days
measure: Safety parameters assessed by biochemistry parameters : Glucose
timeFrame: 127 days
measure: Safety parameters assessed by biochemistry parameters: Creatinine
timeFrame: 127 days
measure: Safety parameters assessed by biochemistry parameters: SGOT/ASAT
timeFrame: 127 days
measure: Safety parameters assessed by biochemistry parameters: SGOT/ALAT
timeFrame: 127 days
measure: Safety parameters assessed by biochemistry parameters:GGT
timeFrame: 127 days
measure: Safety parameters assessed by biochemistry parameters: Alkalin phosphatase
timeFrame: 127 days
measure: Safety parameters assessed by biochemistry parameters: CPK
timeFrame: 127 days
measure: Safety parameters assessed by biochemistry parameters: Total bilirubin
timeFrame: 127 days
measure: Safety parameters assessed by biochemistry parameters: Conjugated bilirubin
timeFrame: 127 days
measure: Safety parameters assessed by biochemistry parameters: Uric Acid
timeFrame: 127 days
measure: Safety parameters assessed by biochemistry parameters: Cholesterol
timeFrame: 127 days
measure: Safety parameters assessed by biochemistry parameters: Triglycerides
timeFrame: 127 days
measure: Safety parameters assessed by biochemistry parameters: Sodium
timeFrame: 127 days
measure: Safety parameters assessed by biochemistry parameters: Potassium
timeFrame: 127 days
measure: Safety parameters assessed by biochemistry parameters: Chlore
timeFrame: 127 days
measure: Safety parameters assessed by biochemistry parameters:Calcium
timeFrame: 127 days
measure: Safety parameters assessed by biochemistry parameters:Total protein
timeFrame: 127 days
measure: Safety parameters assessed by biochemistry parameters:Albumin
timeFrame: 127 days
measure: Safety parameters assessed by hormonology parameters
timeFrame: 127 days
measure: Safety parameters assessed by weight measurement
timeFrame: 127 days
measure: Safety parameters assessed by height measurement
timeFrame: 127 days
measure: Battery of cognitive tasks
timeFrame: 43 days
measure: Plasmatic quantification of inflammatory biomarkers concentration (CRPs)
timeFrame: 43 days
measure: Plasmatic quantification of inflammatory biomarkers concentration (Interleukins1, 6 and 10)
timeFrame: 43 days
measure: Blood quantification of gut microbiome
timeFrame: 43
Other outcomes:
Locations:
city: Angers
country: France
facility: CHU Angers
city: Besançon
country: France
facility: CHU Besançon
city: La Roche-sur-Yon
country: France
facility: CHD Vendée
city: Lille
country: France
facility: Hôpital Fontan 1
city: Nantes
country: France
facility: CHU Nantes
city: Paris
country: France
facility: APHP Hôpital La Pitié Salpétrière - Prinicipal investigator center
city: Paris
country: France
facility: Hôpital Ste Anne
city: Poitiers
country: France
facility: CHU Henri Laborit
city: Tours
country: France
facility: CHRU Tours
city: Élancourt
country: France
facility: Cabinet Médical Ambroise Paré
Study officials:
affiliation: Mapreg
name: Isabelle VILLEY, PhD, MBA
role: STUDY_DIRECTOR
References: