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

Pipamperone/Citalopram (PNB01) Versus Citalopram (CIT) and Versus Pipamperone (PIP) in the Treatment of Moderate to Severe Major Depressive Disorder (MDD): a Randomized, Double-blind Phase III Study of 10 Weeks

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.

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Drug: PNB01 fixed dose combination of pipamperone and citalopram; Drug: Citalopram; Drug: Pipamperone

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 555
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Kelowna, British Columbia, Canada
      • Site 201
    • Penticton, British Columbia, Canada
      • Site 202
  • Ontario
    • Chatham, Ontario, Canada
      • Site 205
    • Mississauga, Ontario, Canada
      • Site 203
    • Mississauga, Ontario, Canada
      • Site 204
• United States
  • California
    • Glendale, California, United States
      • Site 103
    • National City, California, United States
      • Site 101
    • Riverside, California, United States
      • Site 113
    • San Diego, California, United States
      • Site 106
    • San Diego, California, United States
      • Site 116
  • Florida
    • Fort Myers, Florida, United States
      • Site 112
    • Miami, Florida, United States
      • Site 135
    • Winter Park, Florida, United States
      • Site 108
  • Georgia
    • Atlanta, Georgia, United States
      • Site 133
    • Smyrna, Georgia, United States
      • Site 128
  • Illinois
    • Libertyville, Illinois, United States
      • Site 132
    • Schaumburg, Illinois, United States
      • Site 117
  • Maryland
    • Baltimore, Maryland, United States
      • Site 110
  • Mississippi
    • Flowood, Mississippi, United States
      • Site 109
  • New York
    • New York, New York, United States
      • Site 115
  • Ohio
    • Beachwood, Ohio, United States
      • Site 126
    • Cincinnati, Ohio, United States
      • Site 127
    • Middleburg Heights, Ohio, United States
      • Site 124
  • Pennsylvania
    • Allentown, Pennsylvania, United States
      • Site 105
    • Media, Pennsylvania, United States
      • Site 123
    • Philadelphia, Pennsylvania, United States
      • Site 122
  • Texas
    • Austin, Texas, United States
      • Site 119
    • Dallas, Texas, United States
      • Site 104
    • Wichita Falls, Texas, United States
      • Site 102
  • Washington
    • Kirkland, Washington, United States
      • Site 107
    • Seattle, Washington, United States
      • Site 134

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PNB01; oral, once daily administration	Drug: PNB01 fixed dose combination of pipamperone and citalopram; oral once daily administration
Active Comparator: citalopram; oral, once daily administration	Drug: Citalopram; oral once daily administration
Sham Comparator: pipamperone; oral, once daily administration	Drug: Pipamperone; oral once daily administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early and Sustained (Antidepressant) Response (ESR) Rate	Early and Sustained Response (ESR) is defined as a MADRS total score reduction from Baseline of 50% or more and a MADRS total score ≤16 at Week 2, Week 3, Week 4, and Week 6.	From (end of) Week 2 visit to (end of) Week 6 visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Total MADRS Score at Week 6	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 The MADRS scale is a widely used and well-validated 10-item diagnostic questionnaire designed to measure the severity of depressive episodes in patients with mood disorders. The 10 items are all rated on a scale from 0 to 6 (resulting in a maximum total score of 60 points) and include 'apparent sadness', 'reported sadness', 'inner tension', 'reduced sleep', 'reduced appetite', 'concentration difficulties', 'lassitude', 'inability to feel', 'pessimistic thoughts' and 'suicidal thoughts'. Higher scores indicative of greater depressive symptomology.	From Baseline (Day 1) to (end of) Week 6
Change From Baseline in Total SDS Score at Week 6	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 SDS is a generic brief self-report tool that was developed to assess functional impairment in three inter-related domains; 1) work or school, 2) social life and 3) family life. The patient rates the extent to which work/school, social life and home life or family responsibilities are impaired by his or her symptoms on a 10-point visual analog scale. Total scores range from a minimum of 0 to a maximum of 30 (0 unimpaired, 30 highly impaired).	From Baseline (Day 1) to (end of) Week 6 visit

Collaborators and Investigators

• Sponsor: PharmaNeuroBoost N.V.
• Investigators: Study Chair: Michael E Thase, MD, Director, Mood and Anxiety Section; 3535 Market Street, Suite 670; Philadelphia, PA 19104-3309, United States of America; Study Chair: Max Schmauss, MD, Bezirkskrankenhaus Augsburg Klinik für Psychiatrie, Psychotherapie und Psychosomatik Dr.-Mack-Straße 1 D-86156 Augsburg, Germany; Study Director: Philippe Lemmens, PhD, Pharmaneuroboost N.V. Alkerstraat 30A B-3570 Alken, Belgium

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Actual): November 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: March 8, 2011
• First Submitted That Met QC Criteria: March 10, 2011
• First Posted (Estimate): March 11, 2011

Study Record Updates

• Last Update Posted (Actual): April 7, 2022
• Last Update Submitted That Met QC Criteria: March 14, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Serotonin Antagonists; Antidepressive Agents, Second-Generation; Antiparkinson Agents; Anti-Dyskinesia Agents; Citalopram; Dexetimide; Pipamperone
• Other Study ID Numbers: PNB01-C301; 2011-001190-11 (EudraCT Number)