Pipamperone/Citalopram (PNB01) Versus Citalopram (CIT) and Versus Pipamperone (PIP) in Major Depressive Disorder (MDD)

• Change from baseline in total MADRS score at Week 6 [ Time Frame: From Baseline (Day 1) to (end of) Week 6 ] [ Designated as safety issue: No ]
  Change from baseline in total score on the Montgomery-Asberg Depression Rating Scale (MADRS) after 6 weeks of study treatment as assessed by the patient using an Interactive Voice Response System (IVRS) via telephone
• Change from baseline in total SDS score at Week 6 [ Time Frame: From Baseline (Day 1) to (end of) Week 6 visit ] [ Designated as safety issue: No ]
  Change from baseline in total score on the Sheehan Disability Scale (SDS) after 6 weeks of study treatment as assessed by the patient using an Interactive Voice Response System (IVRS) via telephone

The overall objective of this trial is to demonstrate clinically relevant superior antidepressant efficacy of the fixed dose combination PNB01 (low dose pipamperone and citalopram) over reference antidepressant treatment with citalopram alone, and a low dose of psychoactive pipamperone alone in patients with moderate to severe Major Depressive Disorder.

This study was specifically designed to assess patient related outcome (PRO) parameters using an Interactive Voice Response System (IVRS) via telephone.

This is an international, double-blind, centrally randomized (stratified), multicenter study in 555 patients suffering from moderate to severe MDD in up to 40 sites in the USA, Germany and Canada. Eligible out-patients will be treated once daily (QD) with a fixed dose of either PNB01 (PIP 15 mg / CIT 20 mg (Week 1) - PIP 15 mg / CIT 40 mg (Week 2-10)), CIT alone (CIT 20 mg (Week 1) - CIT 40 mg (Week 2-10) or PIP 15 mg alone (Week 1-10) in a 1:1:1 ratio in a double-blind fashion for 10 weeks. Study visits will be conducted 1, 2, 3, 4, 6, 8 and 10 weeks after study treatment initiation. Possible withdrawal effects will be assessed 1 week after study treatment withdrawal.

A blood sample for pharmacokinetic analysis will be collected when drawing blood for routine biochemistry. Patients who provided written informed consent to participate to the study will be asked to provide their consent to participate also to the non-mandatory pharmacogenetic study.

Patient related outcomes will be collected electronically (ePRO) at study visits prior to visiting the investigator by using an Interactive Voice Response System (IVRS) via telephone. Patients wishing or choosing to discontinue the study treatment prematurely will be encouraged to continue to provide their scores, safety data and medications taken, up to the scheduled study end, by telephone.

• Drug: PNB01 fixed dose combination of pipamperone and citalopram
  oral once daily administration
• Drug: Citalopram
  oral once daily administration
• Drug: Pipamperone
  oral once daily administration

• Experimental: PNB01
  Intervention: Drug: PNB01 fixed dose combination of pipamperone and citalopram
• Active Comparator: citalopram
  Intervention: Drug: Citalopram
• Sham Comparator: pipamperone
  Intervention: Drug: Pipamperone

Inclusion Criteria:

1. Patient is informed and given ample time and opportunity to think about her/his participation and has given her/his written informed consent.
2. Patient understands the investigational nature of the trial and is willing and able to comply with the trial requirements.
3. Patient is male or female, aged ≥ 18 years.
4. Patient has MDD according to the DSM IV-R criteria with an existence of depressed mood (DSM-IV-R Crit. A1) and loss of interest/anhedonia (DSM-IV-R Crit. A2) as confirmed by the MINI, lasting for at least 4 weeks and no longer than 18 months (78 weeks) for the current episode, and causing significant functional impairment (DSM-IV-R MDD C- criterion).
5. CGI-S rating of at least 4 and a minimum MADRS total score of 26 using IVRS ePRO at Baseline.

Exclusion Criteria:

1. Patient is pregnant, nursing, or is a woman of child-bearing potential who is not surgically sterile, 2 years postmenopausal, or who does not consistently use 2 combined effective methods of contraception (including at least 1 barrier method), unless sexually abstinent.
2. Existence of Mood Disorder with psychotic features and/or high suicidality risk, as confirmed by MINI.
3. Concomitant diagnosis of any additional primary Axis I disorder and presence of any of the following co-morbid disorders: (Hypo)manic episode, Panic Disorder (limited symptom attacks allowed), Obsessive Compulsive Disorder, Post-traumatic Stress Disorder, Alcohol dependence, any other Substance abuse and/or dependence, Psychotic Disorder, Eating Disorder, or General Anxiety Disorder, as confirmed by MINI.
4. Concomitant diagnosis of any primary Axis II disorder.
5. Patient is hospitalized.
6. Patient has a clinically relevant renal dysfunction (e.g. GFR <60mL/min).
7. Patient has hepatic dysfunction (total bilirubin >2.0mg/dL or alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) greater than 2 times the upper limit of the reference range).
8. Patient has a malignant neoplastic disease, a documented history of epilepsy (juvenile convulsions excepted) or a documented, in the opinion of the investigator, clinically relevant risk of bleeding (eg. severe bleeding disorder, treatment with warfarin, …).
9. Patient with a documented history or concomitant diagnosis or significant risk of cardiac arrhythmia or dysrhythmia, including a QTc interval of ≥500 ms at Baseline.
10. Patient has any other medical or psychiatric condition, which in the opinion of the investigator, can jeopardize or would compromise the patient's ability to participate in this trial or that would interfere with trial assessments.
11. Patient with documented alcohol or drug abuse, or having a positive standard screen for alcohol or drugs (including benzodiazepines and opioids).
12. Patient received, in the past 7 days treatment with any psychoactive drug prior to randomization, including typical and atypical antipsychotics, hypnotics, antidepressants, anxiolytic drugs, anticonvulsive therapy, opioids, monoamine oxidase (MAO) inhibitors, sedative antihistamines, psychostimulants or amphetamines, dopamine D2 receptor antagonists, butyrophenones, metoclopramide, lithium, anticonvulsants, benzodiazepines, or barbiturates. If patient has received such therapy, a washout period of at least 7 days prior to baseline is required before inclusion in this trial (except fluoxetine: 4 weeks, and St John's Wort or MAO inhibitors: within 2 weeks).
13. Concomitant treatment with diuretics, QT prolongation drugs, or dopamine agonists.
14. Resistant depression defined as having failed to respond to either: a/ 2 previous antidepressants at an adequate dose administered for at least 4 weeks during the current episode; b/ augmentation therapy with any atypical antipsychotic drug
15. Electroconvulsive therapy (ECT) or repetitive Transcranial Magnetic Stimulation therapy (rTMS) within the last 6 months; Vagus Nerve Stimulation (VNS) or Deep Brain Stimulation (DBS) ever.
16. Formal psychotherapy or alternative treatment for 1 week prior to or during the study.
17. Patient has participated in another trial of an investigational agent (including medical device) within the last 3 months prior to baseline or is currently participating in another trial of an investigational drug.
18. Known hypersensitivity to any of the study drugs