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

Depression Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03870776
• Other study ID #: MAP4343 / OP103617.MAP
• Status: Recruiting
• Phase: Phase 2
• Start date: June 1, 2019
• Est. completion date: March 1, 2025

Study information

• Verified date: April 2024
• Source: Mapreg
• Contact: Isabelle VILLEY, PhD, MBA
• Phone: + 33 1 49 59 18 71
• Email: isabelle.villey[@]mapreg.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 110
• Est. completion date: March 1, 2025
• Est. primary completion date: December 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Depression

Intervention

Drug:
• MAP4343
Daily oral administration of MAP4343
• Placebo
Daily oral administration of Placebo

Locations

Country	Name	City	State
France	CHU Angers	Angers
France	CHU Besançon	Besançon
France	Centre Hospitalier Cholet	Cholet
France	Cabinet Médical Ambroise Paré	Élancourt
France	CHD Vendée	La Roche-sur-Yon
France	Hôpital Fontan 1	Lille
France	CHU Nantes	Nantes
France	APHP Hôpital La Pitié Salpétrière - Prinicipal investigator center	Paris
France	Hôpital Ste Anne	Paris
France	CHU Henri Laborit	Poitiers
France	CHRU Tours	Tours

Sponsors (2)

Lead Sponsor	Collaborator
Mapreg	Eurofins Optimed

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Pharmacokinetic assessments with observed maximum plasma concentration (Cmax);	Cmax for MAP4343 in plasma at each study visit.	127 days
Secondary	Pharmacokinetic assessments with first time to reach Cmax (tmax);	tmax for MAP4343 in plasma at each study visit.	127 days
Secondary	Pharmacokinetic assessments with elimination rate constant (Kel);	Kel for MAP4343 in plasma at each study visit.	127 days
Secondary	Pharmacokinetic assessments with plasma elimination half-life (t1/2);	t1/2 for MAP4343 in plasma at each study visit	127 days
Secondary	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
Secondary	Pharmacokinetic assessments with percentage of extrapolated AUCinf (%AUCextra);	%AUCextra for MAP4343 in plasma at each study visit	127 days
Secondary	Pharmacokinetic assessments with volumn of distribution (Vd/F);	Vd/F for MAP4343 in plasma at each study visit.	127 days
Secondary	Pharmacokinetic assessments with Clearance (Cl/F);	Cl/F for MAP4343 in plasma at each study visit	127 days
Secondary	Pharmacokinetic assessments with accumulation ratio (R);	R for MAP4343 in plasma at each study visit.	127 days
Secondary	Safety parameters assessed by the number of adverse events (AE)	AE evaluation	127 days
Secondary	Safety parameters assessed - Heart rate	Vital signs assessed by heart rate measurement (beats per minute)	127 days
Secondary	Safety parameters assessed by blood pressure	Vital signs assessed by systolic and diastolic blood pressure measurement (mmHg)	127 days
Secondary	Safety parameters assessed - 12-lead Electrocardiogramm	Heart Rate; Electrocardiogramm measure during 12 hours (12-lead ECG) : heart rate (beats per minute)	127 days
Secondary	Safety parameters assessed - 12-lead ElectrocardiogrammPR;	Electrocardiogramm measure during 12 hours (12-lead ECG) : PR interval (milliseconds)	127 days
Secondary	Safety parameters assessed -12-lead Electrocardiogramm : QT	Electrocardiogramm measure during 12 hours (12-lead ECG) : QT interval (milliseconds)	127 days
Secondary	Safety parameters assessed - 12-lead Electrocardiogramm : QTc	Electrocardiogramm measure during 12 hours (12-lead ECG) : QTc with automatic correction (milliseconds)	127 days
Secondary	Safety parameters assessed by hematology parameters : Haemoglobin	Laboratory exams : hematology parameters (Haemoglobin in g/L)	127 days
Secondary	Safety parameters assessed by hematology parameters: Haematocrit	Laboratory exams : hematology parameters (Haematocrit in %)	127 days
Secondary	Safety parameters assessed by hematology parameters: Red blood cells	Laboratory exams : hematology parameters (Red blood cells in Tera/L)	127 days
Secondary	Safety parameters assessed by hematology parameters: White blood cells	Laboratory exams : hematology parameters (White blood cells in Giga/L)	127 days
Secondary	Safety parameters assessed by hematology parameters:Neutrophils	Laboratory exams : hematology parameters (Neutrophils in Giga/L	127 days
Secondary	Safety parameters assessed by hematology parameters: Eosinophils	Laboratory exams : hematology parameters (Eosinophils in Giga/L)	127 days
Secondary	Safety parameters assessed by hematology parameters: Basophils	Laboratory exams : hematology parameters (Basophils in Giga/L)	127 days
Secondary	Safety parameters assessed by hematology parameters: Lymphocytes	Laboratory exams : hematology parameters (Lymphocytes in Giga/L)	127 days
Secondary	Safety parameters assessed by hematology parameters: Monocytes	Laboratory exams : hematology parameters (Monocytes in Giga/L)	127 days
Secondary	Safety parameters assessed by hematology parameters: Platelets	Laboratory exams : hematology parameters (Platelets in Giga/L)	127 days
Secondary	Safety parameters assessed by hematology parameters: Reticulocytes;	Laboratory exams : hematology parameters (Reticulocytes in Giga/L)	127 days
Secondary	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
Secondary	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
Secondary	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
Secondary	Safety parameters assessed by biochemistry parameters : Glucose	Lab exams: biochem(Glucose in mmol/L)	127 days
Secondary	Safety parameters assessed by biochemistry parameters: Creatinine	Lab exams: biochem( in µmol/L)	127 days
Secondary	Safety parameters assessed by biochemistry parameters: SGOT/ASAT	Lab exams : biochem(in IU/L)	127 days
Secondary	Safety parameters assessed by biochemistry parameters: SGOT/ALAT	Lab exams: biochem(in IU/L)	127 days
Secondary	Safety parameters assessed by biochemistry parameters:GGT	Lab exams: biochem(IU/L)	127 days
Secondary	Safety parameters assessed by biochemistry parameters: Alkalin phosphatase	Lab exams: biochem(IU/L)	127 days
Secondary	Safety parameters assessed by biochemistry parameters: CPK	Lab exams: biochem(IU/L)	127 days
Secondary	Safety parameters assessed by biochemistry parameters: Total bilirubin	Lab exams: biochem(µmol/L)	127 days
Secondary	Safety parameters assessed by biochemistry parameters: Conjugated bilirubin	Lab exams: biochem(µmol/L)	127 days
Secondary	Safety parameters assessed by biochemistry parameters: Uric Acid	Lab exams: biochem(µmol/L)	127 days
Secondary	Safety parameters assessed by biochemistry parameters: Cholesterol	Lab exams: biochem(in mmol/L)	127 days
Secondary	Safety parameters assessed by biochemistry parameters: Triglycerides	Lab exams: biochem(in mmol/L)	127 days
Secondary	Safety parameters assessed by biochemistry parameters: Sodium	Lab exams: biochem(in mmol/L)	127 days
Secondary	Safety parameters assessed by biochemistry parameters: Potassium	Lab exams: biochem(in mmol/L)	127 days
Secondary	Safety parameters assessed by biochemistry parameters: Chlore	Lab exams: biochem( in mmol/L)	127 days
Secondary	Safety parameters assessed by biochemistry parameters:Calcium	Lab exams: biochem(in mmol/L)	127 days
Secondary	Safety parameters assessed by biochemistry parameters:Total protein	Lab exams: biochem(in g/L)	127 days
Secondary	Safety parameters assessed by biochemistry parameters:Albumin	Lab exams: biochem(in g/L)	127 days
Secondary	Safety parameters assessed by hormonology parameters	Laboratory exams : hormonology (?-HCG)	127 days
Secondary	Safety parameters assessed by weight measurement	Physical exams : weight measurement in kilograms	127 days
Secondary	Safety parameters assessed by height measurement	Physical exams : height measurement in centimeters	127 days
Secondary	Battery of cognitive tasks	Cognitive evaluation	43 days
Secondary	Plasmatic quantification of inflammatory biomarkers concentration (CRPs)	Plasmatic quantification of concentration CRPs.	43 days
Secondary	Plasmatic quantification of inflammatory biomarkers concentration (Interleukins1, 6 and 10)	Plasmatic quantification of concentration of Interleukins 1, 6 and 10	43 days
Secondary	Blood quantification of gut microbiome	Metagenomic study of blood markers of gut mircrobiome	43