RESIST : Administration of MAP4343 in Antidepressant Non-Responders Patients Experiencing a Major Depressive Episode

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

Detailed Description
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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.

Official Title
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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

Conditions
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Depression

Intervention / Treatment
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* Drug: MAP4343
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: TRD level from to 2 to 4 inclusive according to the Thase & Rush classification; 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; 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. Hamilton Depression Rating Scale (HDRS) score > 21; Clinical Global Impressions scale (CGI) ≥ 4; Male or female patient, aged 18 to 80 years inclusive; 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); Negative pregnancy test at screening baseline; Body Mass Index (BMI) between 18 and 32 kg/m2 inclusive; 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; 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; 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; Signing a written informed consent prior to selection; Covered by Health Insurance System and/or in compliance with the recommendations of National Law in force relating to biomedical research. Exclusion Criteria: MDE with mood congruent or not congruent psychotic characteristics; 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); 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); 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; Presence or history of drug hypersensitivity, or certain allergic-prone condition diagnosed that could represent a risk factor for an allergic shock; Presence or history of hypersensitivity to vortioxetine, duloxetine, venlafaxine or one of their excipients; Any history or presence of severe hepatic insufficiency and/or of hepatic disease which could lead to hepatic insufficiency; Patients who are pregnant or breastfeeding. Patients should not be enrolled if they plan to become pregnant during the time of study participation; 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; Subjects who received MAOI in monotherapy right before the selection (as ttX); General anesthesia within 3 months before administration; Major surgery within 28 days prior to randomization or major surgery planned during the next 6 months; Positive HBs antigen or anti HCV antibody, or positive results for HIV 1 or 2 tests; Significant renal disease, defined as a history of chronic renal failure requiring dialysis or kidney transplant, calculated creatinine clearance ≤ 60 mL/min; Blood donation (including in the frame of a clinical trial) within 2 months before administration; 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; 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); Exclusion period of a previous study; No possibility of contact in case of emergency; History or presence of drug or alcohol abuse (alcohol consumption > 40 g/day); Administrative or legal supervision.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional 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. Dose 2 during 42 days with antidepressant treatment in add-on.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Patients will receive the placebo during 42 days. | Drug: Placebo<br>* Daily oral administration of Placebo<br>|
| Experimental: MAP4343 group B<br>Patients will receive daily dose 1 during 42 days. | Drug: MAP4343<br>* Daily oral administration of MAP4343<br>Drug: Placebo<br>* Daily oral administration of Placebo<br>|
| Experimental: MAP4343 group C<br>Patients will receive daily dose 2 during 42 days. | Drug: MAP4343<br>* Daily oral administration of MAP4343<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hamilton Depression Rating Scale score evolution between baseline and D43 | Assessment of HDRS score with 17 items with sides 0 to 2 or 0 to 4. The scores from 0 to 4 correspond respectively to symptoms: absent, doubtful or insignificant, light, moderate, important, those ranging from 0 to 2 to symptoms: absent, doubtful or slight, overt or severe. The total score consists of the addition of the individual scores. | 43 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of treatment assessed by psychopathological evaluations with Hamilton Depression Rating Scale | psychopathological evaluations at each study visit: Hamilton Depression Rating Scale (17 items with sides 0 to 2 or 0 to 4. The scores from 0 to 4 correspond respectively to symptoms: absent, doubtful or insignificant, light, moderate, important, those ranging from 0 to 2 to symptoms: absent, doubtful or slight, overt or severe. The total score consists of the addition of the individual scores) | 43 days | 
| Efficacy of treatment assessed by psychopathological evaluations with Montgomery and Asberg Depression rating Scale | psychopathological evaluations at each study visit:Montgomery and Asberg Depression rating Scale used to quatify the intensity of depressive symptomatology | 43 days | 
| Efficacy of treatment assessed by psychopathological evaluations with Brief Anxiety Scale | psychopathological evaluations at each study visit: Brief Anxiety Scale, a dimensional measure of generalized anxiety with 8 items | 43 days | 
| Efficacy of treatment assessed by psychopathological evaluations with Scale of Global Clinical Impressions | psychopathological evaluations at each study visit: Scale of Global Clinical Impressions which includes 2 items rated from 1 to 7 (first item is a measurement of the overall measurement of patient's condition; 2nd item evaluates the overall improvementof patient compared to his condition at the admission to the research | 43 days | 
| Efficacy of treatment assessed by psychopathological evaluations with Quick Inventory of Depressive Symptoms | psychopathological evaluations at each study visit: Quick Inventory of Depressive Symptoms is a questionnaire allowing the assessment of the degree of depression by the patient himself. | 43 days | 
| Efficacy of treatment assessed by psychopathological evaluations with General Assessment Functioning | psychopathological evaluations at each study visit: General Assessment Functioning. The score is ranged on a hypothetical continuum from 1, the value representing the sickest individual, to 90, a value representing an individual without or with very minimal symptoms and functioning satisfactorily in his social environment or his family. The scale is divided into 9 equal intervals ranging from 1 to 10, 11 to 20, 21 to 30, etc. | 43 days | 
| Pharmacokinetic assessments with observed maximum plasma concentration (Cmax); | Cmax for MAP4343 in plasma at each study visit. | 127 days | 
| Pharmacokinetic assessments with first time to reach Cmax (tmax); | tmax for MAP4343 in plasma at each study visit. | 127 days | 
| Pharmacokinetic assessments with elimination rate constant (Kel); | Kel for MAP4343 in plasma at each study visit. | 127 days | 
| Pharmacokinetic assessments with plasma elimination half-life (t1/2); | t1/2 for MAP4343 in plasma at each study visit | 127 days | 
| Pharmacokinetic assessments with plasma area under the plasma concentration-time curve from administration up to infinity with extrapolation of the terminal phase (AUCinf); | AUCinf for MAP4343 in plasma at each study visit | 127 days | 
| Pharmacokinetic assessments with percentage of extrapolated AUCinf (%AUCextra); | %AUCextra for MAP4343 in plasma at each study visit | 127 days | 
| Pharmacokinetic assessments with volumn of distribution (Vd/F); | Vd/F for MAP4343 in plasma at each study visit. | 127 days | 
| Pharmacokinetic assessments with Clearance (Cl/F); | Cl/F for MAP4343 in plasma at each study visit | 127 days | 
| Pharmacokinetic assessments with accumulation ratio (R); | R for MAP4343 in plasma at each study visit. | 127 days | 
| Safety parameters assessed by the number of adverse events (AE) | AE evaluation | 127 days | 
| Safety parameters assessed - Heart rate | Vital signs assessed by heart rate measurement (beats per minute) | 127 days | 
| Safety parameters assessed by blood pressure | Vital signs assessed by systolic and diastolic blood pressure measurement (mmHg) | 127 days | 
| Safety parameters assessed - 12-lead Electrocardiogramm | Heart Rate; Electrocardiogramm measure during 12 hours (12-lead ECG) : heart rate (beats per minute) | 127 days | 
| Safety parameters assessed - 12-lead ElectrocardiogrammPR; | Electrocardiogramm measure during 12 hours (12-lead ECG) : PR interval (milliseconds) | 127 days | 
| Safety parameters assessed -12-lead Electrocardiogramm : QT | Electrocardiogramm measure during 12 hours (12-lead ECG) : QT interval (milliseconds) | 127 days | 
| Safety parameters assessed - 12-lead Electrocardiogramm : QTc | Electrocardiogramm measure during 12 hours (12-lead ECG) : QTc with automatic correction (milliseconds) | 127 days | 
| Safety parameters assessed by hematology parameters : Haemoglobin | Laboratory exams : hematology parameters (Haemoglobin in g/L) | 127 days | 
| Safety parameters assessed by hematology parameters: Haematocrit | Laboratory exams : hematology parameters (Haematocrit in %) | 127 days | 
| Safety parameters assessed by hematology parameters: Red blood cells | Laboratory exams : hematology parameters (Red blood cells in Tera/L) | 127 days | 
| Safety parameters assessed by hematology parameters: White blood cells | Laboratory exams : hematology parameters (White blood cells in Giga/L) | 127 days | 
| Safety parameters assessed by hematology parameters:Neutrophils | Laboratory exams : hematology parameters (Neutrophils in Giga/L | 127 days | 
| Safety parameters assessed by hematology parameters: Eosinophils | Laboratory exams : hematology parameters (Eosinophils in Giga/L) | 127 days | 
| Safety parameters assessed by hematology parameters: Basophils | Laboratory exams : hematology parameters (Basophils in Giga/L) | 127 days | 
| Safety parameters assessed by hematology parameters: Lymphocytes | Laboratory exams : hematology parameters (Lymphocytes in Giga/L) | 127 days | 
| Safety parameters assessed by hematology parameters: Monocytes | Laboratory exams : hematology parameters (Monocytes in Giga/L) | 127 days | 
| Safety parameters assessed by hematology parameters: Platelets | Laboratory exams : hematology parameters (Platelets in Giga/L) | 127 days | 
| Safety parameters assessed by hematology parameters: Reticulocytes; | Laboratory exams : hematology parameters (Reticulocytes in Giga/L) | 127 days | 
| Safety parameters assessed by red blood cells indices | MCV; Red blood cells indices : MCV (in picograms) MCH; Red blood cells indices : MCH (in picograms) MCHC; Red blood cells indices : MCHC (in picograms) | 127 days | 
| Safety parameters assessed by hemostasis parameters | INR measurement; Laboratory exams : hemostasis parameters (INR) Prothrombin time; Laboratory exams : hemostasis parameters (Prothrombin time in seconds) APTT; Laboratory exams : hemostasis parameters (APTT in seconds) APTT reference; Laboratory exams : hemostasis parameters (APTT reference in seconds) | 127 days | 
| Safety parameters assessed by serology parameters | P24 antigen; Laboratory exams : serology (P24 antigen detection) HIV; Laboratory exams : serology (HIV 1/2 antibodies detection) HCV; Laboratory exams : serology (HCV antibodies detection) HBs; Laboratory exams : serology (HBs antigen detection) | 127 days | 
| Safety parameters assessed by biochemistry parameters : Glucose | Lab exams: biochem(Glucose in mmol/L) | 127 days | 
| Safety parameters assessed by biochemistry parameters: Creatinine | Lab exams: biochem( in μmol/L) | 127 days | 
| Safety parameters assessed by biochemistry parameters: SGOT/ASAT | Lab exams : biochem(in IU/L) | 127 days | 
| Safety parameters assessed by biochemistry parameters: SGOT/ALAT | Lab exams: biochem(in IU/L) | 127 days | 
| Safety parameters assessed by biochemistry parameters:GGT | Lab exams: biochem(IU/L) | 127 days | 
| Safety parameters assessed by biochemistry parameters: Alkalin phosphatase | Lab exams: biochem(IU/L) | 127 days | 
| Safety parameters assessed by biochemistry parameters: CPK | Lab exams: biochem(IU/L) | 127 days | 
| Safety parameters assessed by biochemistry parameters: Total bilirubin | Lab exams: biochem(μmol/L) | 127 days | 
| Safety parameters assessed by biochemistry parameters: Conjugated bilirubin | Lab exams: biochem(μmol/L) | 127 days | 
| Safety parameters assessed by biochemistry parameters: Uric Acid | Lab exams: biochem(μmol/L) | 127 days | 
| Safety parameters assessed by biochemistry parameters: Cholesterol | Lab exams: biochem(in mmol/L) | 127 days | 
| Safety parameters assessed by biochemistry parameters: Triglycerides | Lab exams: biochem(in mmol/L) | 127 days | 
| Safety parameters assessed by biochemistry parameters: Sodium | Lab exams: biochem(in mmol/L) | 127 days | 
| Safety parameters assessed by biochemistry parameters: Potassium | Lab exams: biochem(in mmol/L) | 127 days | 
| Safety parameters assessed by biochemistry parameters: Chlore | Lab exams: biochem( in mmol/L) | 127 days | 
| Safety parameters assessed by biochemistry parameters:Calcium | Lab exams: biochem(in mmol/L) | 127 days | 
| Safety parameters assessed by biochemistry parameters:Total protein | Lab exams: biochem(in g/L) | 127 days | 
| Safety parameters assessed by biochemistry parameters:Albumin | Lab exams: biochem(in g/L) | 127 days | 
| Safety parameters assessed by hormonology parameters | Laboratory exams : hormonology (Β-HCG) | 127 days | 
| Safety parameters assessed by weight measurement | Physical exams : weight measurement in kilograms | 127 days | 
| Safety parameters assessed by height measurement | Physical exams : height measurement in centimeters | 127 days | 
| Battery of cognitive tasks | Cognitive evaluation | 43 days | 
| Plasmatic quantification of inflammatory biomarkers concentration (CRPs) | Plasmatic quantification of concentration CRPs. | 43 days | 
| Plasmatic quantification of inflammatory biomarkers concentration (Interleukins1, 6 and 10) | Plasmatic quantification of concentration of Interleukins 1, 6 and 10 | 43 days | 
| Blood quantification of gut microbiome | Metagenomic study of blood markers of gut mircrobiome | 43 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Depression, Resistant depression