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

• Sponsor: Mapreg (Industry)
• Overall Status: Unknown status
• CT.gov ID: NCT03870776
• Collaborator: (none)
• Enrollment: 110
• Location: 1
• Arms: 3
• Anticipated Duration (Months): 24
• Patients Per Site Per Month: 4.6

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Depression	Drug: MAP4343; Drug: Placebo	Phase 2

Detailed Description

This will be 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 65 will be included in the study. They will be recruited from psychiatric consultations in the centers participating to the study.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 110 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• 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. Dose 2 during 42 days with antidepressant treatment in add-on.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 (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Double-blind, Controlled, Randomized Phase 2 Study of Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of a Daily Oral Administration of MAP4343 During 6 Weeks in Antidepressant-non Responders Patients Experiencing a Major Depressive Episode
• Actual Study Start Date: Jun 1, 2019
• Anticipated Primary Completion Date: Jun 1, 2021
• Anticipated Study Completion Date: Jun 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Patients will receive the placebo during 42 days.	Drug: Placebo; Daily oral administration of Placebo
Experimental: MAP4343 group B Patients will receive daily dose 1 during 42 days.	Drug: MAP4343; Daily oral administration of MAP4343; Drug: Placebo; Daily oral administration of Placebo
Experimental: MAP4343 group C Patients will receive daily dose 2 during 42 days.	Drug: MAP4343; Daily oral administration of MAP4343

Outcome Measures

Primary Outcome Measures

1. Hamilton Depression Rating Scale score evolution between baseline and D43 [43 days]

   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.

Secondary Outcome Measures

1. Efficacy of treatment assessed by psychopathological evaluations with Hamilton Depression Rating Scale [43 days]

   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)

2. Efficacy of treatment assessed by psychopathological evaluations with Montgomery and Asberg Depression rating Scale [43 days]

   psychopathological evaluations at each study visit:Montgomery and Asberg Depression rating Scale used to quatify the intensity of depressive symptomatology

3. Efficacy of treatment assessed by psychopathological evaluations with Brief Anxiety Scale [43 days]

   psychopathological evaluations at each study visit: Brief Anxiety Scale, a dimensional measure of generalized anxiety with 8 items

4. Efficacy of treatment assessed by psychopathological evaluations with Scale of Global Clinical Impressions [43 days]

   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

5. Efficacy of treatment assessed by psychopathological evaluations with Quick Inventory of Depressive Symptoms [43 days]

   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.

6. Efficacy of treatment assessed by psychopathological evaluations with General Assessment Functioning [43 days]

   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.

7. Pharmacokinetic assessment with observed maximum plasma concentration (Cmax) [127 days]

   Cmax for MAP4343 in plasma at each study visit.

8. Pharmacokinetic assessment with first time to reach Cmax (tmax) [127 days]

   tmax for MAP4343 in plasma at each study visit.

9. Pharmacokinetic assessment with elimination rate constant (Kel) [127 days]

   Kel for MAP4343 in plasma at each study visit.

10. Pharmacokinetic assessment with plasma elimination half-life (t1/2) [127 days]

    t1/2 for MAP4343 in plasma at each study visit.

11. Pharmacokinetic assessment with plasma area under the plasma concentration-time curve from administration up to infinity with extrapolation of the terminal phase (AUCinf) [127 days]

    AUCinf for MAP4343 in plasma at each study visit.

12. Pharmacokinetic assessment with percentage of extrapolated AUCinf (%AUCextra) [127 days]

    %AUCextra for MAP4343 in plasma at each study visit.

13. Pharmacokinetic assessment with volum of distribution (Vd/F) [127 days]

    Vd/F for MAP4343 in plasma at each study visit.

14. Pharmacokinetic assessment with Clearance (Cl/F) [127 days]

    Cl/F for MAP4343 in plasma at each study visit.

15. Pharmacokinetic assessment with accumulation ratio (R) [127 days]

    R for MAP4343 in plasma at each study visit.

16. Safety parameters assessed by the number of adverse events (AE) [127 days]

    AE evaluation

17. Safety parameters assessed Heart rate [127 days]

    Vital signs assessed by heart rate measurement (beats per minute)

18. Safety parameters assessed by blood pressure [127 days]

    Vital signs assessed by systolic and diastolic blood pressure measurement (mmHg)

19. Safety parameters assessed 12-lead Electrocardiogramm : Heart Rate [127 days]

    Electrocardiogramm measure during 12 hours (12-lead ECG) : heart rate (beats per minute)

20. Safety parameters assessed 12-lead Electrocardiogramm : PR [127 days]

    Electrocardiogramm measure during 12 hours (12-lead ECG) : PR interval (milliseconds)

21. Safety parameters assessed 12-lead Electrocardiogramm : QT [127 days]

    Electrocardiogramm measure during 12 hours (12-lead ECG) : QT interval (milliseconds)

22. Safety parameters assessed 12-lead Electrocardiogramm : QTc [127 days]

    Electrocardiogramm measure during 12 hours (12-lead ECG) : QTc with automatic correction (milliseconds)

23. Safety parameters assessed by hematology parameters : Haemoglobin [127 days]

    Laboratory exams : hematology parameters (Haemoglobin in g/L)

24. Safety parameters assessed by hematology parameters : Haematocrit [127 days]

    Laboratory exams : hematology parameters (Haematocrit in %)

25. Safety parameters assessed by hematology parameters : Red blood cells [127 days]

    Laboratory exams : hematology parameters (Red blood cells in Tera/L)

26. Safety parameters assessed by hematology parameters : White blood cells [127 days]

    Laboratory exams : hematology parameters (White blood cells in Giga/L)

27. Safety parameters assessed by hematology parameters : Neutrophils [127 days]

    Laboratory exams : hematology parameters (Neutrophils in Giga/L)

28. Safety parameters assessed by hematology parameters : Eosinophils [127 days]

    Laboratory exams : hematology parameters (Eosinophils in Giga/L)

29. Safety parameters assessed by hematology parameters : Basophils [127 days]

    Laboratory exams : hematology parameters (Basophils in Giga/L)

30. Safety parameters assessed by hematology parameters : Lymphocytes [127 days]

    Laboratory exams : hematology parameters (Lymphocytes in Giga/L)

31. Safety parameters assessed by hematology parameters : Monocytes [127 days]

    Laboratory exams : hematology parameters (Monocytes in Giga/L)

32. Safety parameters assessed by hematology parameters : Platelets [127 days]

    Laboratory exams : hematology parameters (Platelets in Giga/L)

33. Safety parameters assessed by hematology parameters : Reticulocytes [127 days]

    Laboratory exams : hematology parameters (Reticulocytes in Giga/L)

34. Safety parameters assessed by red blood cells indices : MCV [127 days]

    Red blood cells indices : MCV (in picograms)

35. Safety parameters assessed by red blood cells indices : MCH [127 days]

    Red blood cells indices : MCH (in picograms)

36. Safety parameters assessed by red blood cells indices : MCHC [127 days]

    Red blood cells indices : MCHC (in picograms)

37. Safety parameters assessed by hemostasis parameters : INR measurement [127 days]

    Laboratory exams : hemostasis parameters (INR)

38. Safety parameters assessed by hemostasis parameters : Prothrombin level [127 days]

    Laboratory exams : hemostasis parameters (Prothrombin level in %)

39. Safety parameters assessed by hemostasis parameters : Prothrombin time [127 days]

    Laboratory exams : hemostasis parameters (Prothrombin time in seconds)

40. Safety parameters assessed by hemostasis parameters : APTT [127 days]

    Laboratory exams : hemostasis parameters (APTT in seconds)

41. Safety parameters assessed by hemostasis parameters : APTT reference [127 days]

    Laboratory exams : hemostasis parameters (APTT reference in seconds)

42. Safety parameters assessed by serology parameters : P24 antigen [127 days]

    Laboratory exams : serology (P24 antigen detection)

43. Safety parameters assessed by serology parameters : HIV [127 days]

    Laboratory exams : serology (HIV 1/2 antibodies detection)

44. Safety parameters assessed by serology parameters : HCV [127 days]

    Laboratory exams : serology (HCV antibodies detection)

45. Safety parameters assessed by serology parameters : HBs [127 days]

    Laboratory exams : serology (HBs antigen detection)

46. Safety parameters assessed by biochemistry parameters [127 days]

    Laboratory exams : biochemistry (Glucose in mmol/L)

47. Safety parameters assessed by biochemistry parameters : Creatinine [127 days]

    Laboratory exams : biochemistry (Creatinine in micromol/L)

48. Safety parameters assessed by biochemistry parameters : SGOT / ASAT [127 days]

    Laboratory exams : biochemistry (SGOT / ASAT in IU/L)

49. Safety parameters assessed by biochemistry parameters : SGOT / ALAT [127 days]

    Laboratory exams : biochemistry (SGPT / ALAT in IU/L)

50. Safety parameters assessed by biochemistry parameters : GGT [127 days]

    Laboratory exams : biochemistry (GGT in IU/L)

51. Safety parameters assessed by biochemistry parameters : Alkalin phosphatase [127 days]

    Laboratory exams : biochemistry (Alkalin phosphatase in IU/L)

52. Safety parameters assessed by biochemistry parameters : CPK [127 days]

    Laboratory exams : biochemistry (CPK in IU/L)

53. Safety parameters assessed by biochemistry parameters : Total bilirubin [127 days]

    Laboratory exams : biochemistry (Total bilirubin in micromol/L)

54. Safety parameters assessed by biochemistry parameters : Conjugated bilirubin [127 days]

    Laboratory exams : biochemistry (Conjugated bilirubin in micromol/L)

55. Safety parameters assessed by biochemistry parameters : Uric Acid [127 days]

    Laboratory exams : biochemistry (Uric Acid in micromol/L)

56. Safety parameters assessed by biochemistry parameters : Cholesterol [127 days]

    Laboratory exams : biochemistry (Cholesterol in mmol/L)

57. Safety parameters assessed by biochemistry parameters : Triglycerides [127 days]

    Laboratory exams : biochemistry (Triglycerides in mmol/L)

58. Safety parameters assessed by biochemistry parameters : Sodium [127 days]

    Laboratory exams : biochemistry (Sodium in mmol/L)

59. Safety parameters assessed by biochemistry parameters : Potassium [127 days]

    Laboratory exams : biochemistry (Potassium in mmol/L)

60. Safety parameters assessed by biochemistry parameters : Chlore [127 days]

    Laboratory exams : biochemistry (Chlore in mmol/L)

61. Safety parameters assessed by biochemistry parameters : Calcium [127 days]

    Laboratory exams : biochemistry (Calcium in mmol/L)

62. Safety parameters assessed by biochemistry parameters : Magnesium [127 days]

    Laboratory exams : biochemistry (Magnesium in mmol/L)

63. Safety parameters assessed by biochemistry parameters : Total protein [127 days]

    Laboratory exams : biochemistry (Total protein in g/L)

64. Safety parameters assessed by biochemistry parameters : Albumin [127 days]

    Laboratory exams : biochemistry (Albumin in g/L)

65. Safety parameters assessed by biochemistry parameters : Insulin [127 days]

    Laboratory exams : biochemistry (Insulin in mU/L)

66. Safety parameters assessed by hormonology parameters [127 days]

    Laboratory exams : hormonology (Β-HCG)

67. Safety parameters assessed by weight measurement [127 days]

    Physical exams : weight measurement in kilograms

68. Safety parameters assessed by height measurement [127 days]

    Physical exams : height measurement in centimeters

69. Pharmacodynamics parameters on brain morphology measured by MRI : Hippocampal volume [43 days]

    Hippocampal volume

70. Pharmacodynamics parameters on brain morphology measured by MRI : Self-referential memory task [43 days]

    Self-referential memory task

71. Pharmacodynamics parameters on brain morphology measured by MRI : Sensitivity to reward and punishment [43 days]

    Sensitivity to reward and punishment

72. Plasmatic quantification of biomarkers concentration (pregnenolone) [43 days]

    Plasmatic quantification of pregnenolone

73. Plasmatic quantification of biomarkers concentration (CRPs) [43 days]

    Plasmatic quantification of concentration CRPs

74. Plasmatic quantification of biomarkers concentration (Interleukins) [43 days]

    Plasmatic quantification of concentration of Interleukins 1, 6 and 10

75. Plasmatic quantification of biomarkers concentration (ELK-1) [43 days]

    Plasmatic quantification of concentration of ELK-1

76. Plasmatic quantification of biomarkers concentration (BDNF) [43 days]

    Plasmatic quantification of concentration of BDNF

77. Plasmatic quantification of concentration of VEGF [43 days]

    Plasmatic quantification of concentration of VEGF

78. Plasmatic quantification of concentration of tubulin isoforms acet and tyr [43 days]

    Plasmatic quantification of concentration of tubulin isoforms acet and tyr

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Antidepressant drug Resistance level from to 2 to 4 inclusive.

2. Patient experiencing a Major Depressive Episod (MDE) according to DSM-V criteria. MDE can be isolated or recurrent. The diagnosis is based on Mini-International Neuropsychiatric Interview (MINI) test.

3. Patient should have received a previous antidepressant treatment in monotherapy: IRSS, IRSNA, Tricyclique or other drug class prescribed at the maximal dose before the selection

4. Hamilton Depression Rating Scale (HDRS) scores >21

5. Global clinical Impressions scale (GCI) > 4

6. Male or female patient, aged 18 to 65 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 (amenorrhoea duration at least 12 months);

8. Negative pregnancy test at screening baseline;

9. Body Mass Index (BMI) between 18 and 30 kg/m2 inclusive;

10. Laboratory parameters within the normal range of the laboratory (hematological, hemostasis, 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;

1. 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;

1. Signing a written informed consent prior to selection;

2. 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 excepted global anxiety, social phoby, panic troubles that should be accepted. In particular, patients who experienced a depressive state in bipolar disorder 1 or 2, schizophrenic or schizo-affective disorder should not be included;

5. Presence or history of protein drug hypersensitivity, or allergic disease diagnosed and treated by a physician;

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 those defined 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 IMAO in monotherapy before the selection (as treatment X);

11. General anaesthesia 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 grams / day);

21. Administrative or legal supervision;

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	AHPH La Pitié Salpétrière	Paris		France

Sponsors and Collaborators

• Mapreg

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mapreg
• ClinicalTrials.gov Identifier: NCT03870776
• Other Study ID Numbers: MAP4343 / OP103617.MAP
• First Posted: Mar 12, 2019
• Last Update Posted: Oct 8, 2019
• Last Verified: Oct 1, 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Mapreg: Depression; Resistant depression
• Additional relevant MeSH terms: Depression

Study Results

No Results Posted as of Oct 8, 2019