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

Sponsor
PharmaNeuroBoost N.V. (Industry)
Overall Status
Completed
CT.gov ID
NCT01312922
Collaborator
(none)
555
31
3
15
17.9
1.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
Phase 3

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 Design

Study Type:
Interventional
Actual Enrollment :
555 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
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
Study Start Date :
Sep 1, 2011
Actual Primary Completion Date :
Nov 1, 2012
Actual Study Completion Date :
Dec 1, 2012

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

  1. Early and Sustained (Antidepressant) Response (ESR) Rate [From (end of) Week 2 visit to (end of) Week 6 visit]

    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.

Secondary Outcome Measures

  1. Change From Baseline in Total MADRS Score at Week 6 [From Baseline (Day 1) to (end of) 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.

  2. Change From Baseline in Total SDS Score at Week 6 [From Baseline (Day 1) to (end of) Week 6 visit]

    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).

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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

Contacts and Locations

Locations

Site City State Country Postal Code
1 Site 103 Glendale California United States
2 Site 101 National City California United States
3 Site 113 Riverside California United States
4 Site 106 San Diego California United States
5 Site 116 San Diego California United States
6 Site 112 Fort Myers Florida United States
7 Site 135 Miami Florida United States
8 Site 108 Winter Park Florida United States
9 Site 133 Atlanta Georgia United States
10 Site 128 Smyrna Georgia United States
11 Site 132 Libertyville Illinois United States
12 Site 117 Schaumburg Illinois United States
13 Site 110 Baltimore Maryland United States
14 Site 109 Flowood Mississippi United States
15 Site 115 New York New York United States
16 Site 126 Beachwood Ohio United States
17 Site 127 Cincinnati Ohio United States
18 Site 124 Middleburg Heights Ohio United States
19 Site 105 Allentown Pennsylvania United States
20 Site 123 Media Pennsylvania United States
21 Site 122 Philadelphia Pennsylvania United States
22 Site 119 Austin Texas United States
23 Site 104 Dallas Texas United States
24 Site 102 Wichita Falls Texas United States
25 Site 107 Kirkland Washington United States
26 Site 134 Seattle Washington United States
27 Site 201 Kelowna British Columbia Canada
28 Site 202 Penticton British Columbia Canada
29 Site 205 Chatham Ontario Canada
30 Site 203 Mississauga Ontario Canada
31 Site 204 Mississauga Ontario Canada

Sponsors and Collaborators

  • 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 Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
PharmaNeuroBoost N.V.
ClinicalTrials.gov Identifier:
NCT01312922
Other Study ID Numbers:
  • PNB01-C301
  • 2011-001190-11
First Posted:
Mar 11, 2011
Last Update Posted:
Apr 7, 2022
Last Verified:
Mar 1, 2022

Study Results

Participant Flow

Recruitment Details This was a centrally randomized (stratified), double-blind, multicenter study in up to 40 sites in the U.S. and Canada.
Pre-assignment Detail A total of 555 eligible patients were planned and randomized in the study
Arm/Group Title PNB01 Citalopram Pipamperone
Arm/Group Description oral, once daily administration PNB01 fixed dose combination of pipamperone and citalopram: oral once daily administration oral, once daily administration Citalopram: oral once daily administration oral, once daily administration Pipamperone: oral once daily administration
Period Title: Overall Study
STARTED 185 185 185
COMPLETED 117 131 135
NOT COMPLETED 68 54 50

Baseline Characteristics

Arm/Group Title PNB01 Citalopram Pipamperone Total
Arm/Group Description oral, once daily administration PNB01 fixed dose combination of pipamperone and citalopram: oral once daily administration oral, once daily administration Citalopram: oral once daily administration oral, once daily administration Pipamperone: oral once daily administration Total of all reporting groups
Overall Participants 185 185 185 555
Age, Customized (Count of Participants)
18 - 60 years
184
99.5%
182
98.4%
179
96.8%
545
98.2%
> 60 years
1
0.5%
3
1.6%
6
3.2%
10
1.8%
Sex: Female, Male (Count of Participants)
Female
111
60%
104
56.2%
114
61.6%
329
59.3%
Male
74
40%
81
43.8%
71
38.4%
226
40.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
5
2.7%
1
0.5%
1
0.5%
7
1.3%
Asian
5
2.7%
6
3.2%
4
2.2%
15
2.7%
Native Hawaiian or Other Pacific Islander
1
0.5%
0
0%
1
0.5%
2
0.4%
Black or African American
53
28.6%
54
29.2%
54
29.2%
161
29%
White
116
62.7%
119
64.3%
120
64.9%
355
64%
More than one race
0
0%
0
0%
0
0%
0
0%
Unknown or Not Reported
5
2.7%
5
2.7%
5
2.7%
15
2.7%

Outcome Measures

1. Primary Outcome
Title Early and Sustained (Antidepressant) Response (ESR) Rate
Description 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.
Time Frame From (end of) Week 2 visit to (end of) Week 6 visit

Outcome Measure Data

Analysis Population Description
Full Analysis Set (FAS): The FAS consists of all patients who are randomized and were administered at least one dose of trial medication, as assessed from pill counting. Patients will be analyzed according to the treatment group to which they were randomized (intention-to-treat principle), irrespective of the study treatment received.
Arm/Group Title PNB01 Citalopram Pipamperone
Arm/Group Description oral, once daily administration PNB01 fixed dose combination of pipamperone and citalopram: oral once daily administration oral, once daily administration Citalopram: oral once daily administration oral, once daily administration Pipamperone: oral once daily administration
Measure Participants 176 174 181
Count of Participants [Participants]
17
9.2%
17
9.2%
17
9.2%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection PNB01, Citalopram
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 1.000
Comments
Method Fisher Exact
Comments
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.987
Confidence Interval (2-Sided) 95%
0.456 to 2.140
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection PNB01, Pipamperone
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 1.000
Comments
Method Fisher Exact
Comments
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.031
Confidence Interval (2-Sided) 95%
0.476 to 2.233
Parameter Dispersion Type:
Value:
Estimation Comments
2. Secondary Outcome
Title Change From Baseline in Total MADRS Score at Week 6
Description 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.
Time Frame From Baseline (Day 1) to (end of) Week 6

Outcome Measure Data

Analysis Population Description
Secondary Outcome Measures were pre-specified to be completed based on significance of the Primary Outcome Measure. Secondary Outcome Measures were therefore not completed.
Arm/Group Title PNB01 Citalopram Pipamperone
Arm/Group Description oral, once daily administration PNB01 fixed dose combination of pipamperone and citalopram: oral once daily administration oral, once daily administration Citalopram: oral once daily administration oral, once daily administration Pipamperone: oral once daily administration
Measure Participants 0 0 0
3. Secondary Outcome
Title Change From Baseline in Total SDS Score at Week 6
Description 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).
Time Frame From Baseline (Day 1) to (end of) Week 6 visit

Outcome Measure Data

Analysis Population Description
Secondary Outcome Measures were pre-specified to be completed based on significance of the Primary Outcome Measure. Secondary Outcome Measures were therefore not completed.
Arm/Group Title PNB01 Citalopram Pipamperone
Arm/Group Description oral, once daily administration PNB01 fixed dose combination of pipamperone and citalopram: oral once daily administration oral, once daily administration Citalopram: oral once daily administration oral, once daily administration Pipamperone: oral once daily administration
Measure Participants 0 0 0

Adverse Events

Time Frame 10 weeks + follow-up 1 week
Adverse Event Reporting Description Safety Set (SS): The SS consists of all patients who are randomized and were administered at least 1 dose of trial medication, as assessed from pill counting. Patients will be analyzed according to the treatment group of the study treatment that was actually received.
Arm/Group Title PNB01 Citalopram Pipamperone
Arm/Group Description oral, once daily administration PNB01 fixed dose combination of pipamperone and citalopram: oral once daily administration oral, once daily administration Citalopram: oral once daily administration oral, once daily administration Pipamperone: oral once daily administration
All Cause Mortality
PNB01 Citalopram Pipamperone
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/185 (0%) 0/185 (0%) 0/185 (0%)
Serious Adverse Events
PNB01 Citalopram Pipamperone
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 3/185 (1.6%) 4/185 (2.2%) 1/185 (0.5%)
Gastrointestinal disorders
gastric ulcer 0/185 (0%) 0 1/185 (0.5%) 1 0/185 (0%) 0
Oesophagitis 0/185 (0%) 0 1/185 (0.5%) 1 0/185 (0%) 0
Hepatobiliary disorders
Cholelithiasis 1/185 (0.5%) 1 0/185 (0%) 0 0/185 (0%) 0
Injury, poisoning and procedural complications
Radius fracture 0/185 (0%) 0 1/185 (0.5%) 1 0/185 (0%) 0
Ulna Fracture 0/185 (0%) 0 1/185 (0.5%) 1 0/185 (0%) 0
Metabolism and nutrition disorders
dehydratation 1/185 (0.5%) 1 0/185 (0%) 0 0/185 (0%) 0
Musculoskeletal and connective tissue disorders
Back Pain 1/185 (0.5%) 1 0/185 (0%) 0 0/185 (0%) 0
Nervous system disorders
Syncope 0/185 (0%) 0 1/185 (0.5%) 1 0/185 (0%) 0
Psychiatric disorders
Depression 0/185 (0%) 0 1/185 (0.5%) 1 0/185 (0%) 0
suicidal ideation 0/185 (0%) 0 1/185 (0.5%) 1 0/185 (0%) 0
Suicide attempt 0/185 (0%) 0 0/185 (0%) 0 1/185 (0.5%) 1
Respiratory, thoracic and mediastinal disorders
Dyspnoea 1/185 (0.5%) 1 0/185 (0%) 0 0/185 (0%) 0
Other (Not Including Serious) Adverse Events
PNB01 Citalopram Pipamperone
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 127/185 (68.6%) 131/185 (70.8%) 118/185 (63.8%)
Gastrointestinal disorders
Diarrhoea 9/185 (4.9%) 11 17/185 (9.2%) 19 1/185 (0.5%) 1
Dry Mouth 18/185 (9.7%) 18 10/185 (5.4%) 11 16/185 (8.6%) 17
Nausea 16/185 (8.6%) 17 28/185 (15.1%) 30 14/185 (7.6%) 16
General disorders
Fatigue 6/185 (3.2%) 7 9/185 (4.9%) 10 5/185 (2.7%) 6
Infections and infestations
Nasopharyngitis 8/185 (4.3%) 8 10/185 (5.4%) 10 6/185 (3.2%) 6
Investigations
Weight Increase 9/185 (4.9%) 10 2/185 (1.1%) 2 15/185 (8.1%) 15
Metabolism and nutrition disorders
Decreased Appetitie 4/185 (2.2%) 5 10/185 (5.4%) 11 3/185 (1.6%) 3
Nervous system disorders
Dizziness 10/185 (5.4%) 13 12/185 (6.5%) 14 10/185 (5.4%) 11
Headache 20/185 (10.8%) 20 20/185 (10.8%) 25 19/185 (10.3%) 21
Sedation 4/185 (2.2%) 5 7/185 (3.8%) 7 8/185 (4.3%) 8
Somnolence 29/185 (15.7%) 29 20/185 (10.8%) 23 12/185 (6.5%) 13
Psychiatric disorders
Insomnia 11/185 (5.9%) 12 20/185 (10.8%) 20 9/185 (4.9%) 10

Limitations/Caveats

To avoid limited risk of concluding efficacy when there is no effect, hierarchical testing was implemented with following order of confirmatory tests: 1) Patient-ESR rates of PNB01vs citalopram 2) If above testing is sig., repeat patient-ESR testing for PNB01vs pipamperone 3) In case in 1 of these 2 tests PNB01 does not have sig. higher ESR rate, trial is considered negative, & no following sec. confirmatory tests are to be executed. Secondary Outcome Measures were therefore not completed

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title Dr. E. Buntinx, MD
Organization ANeuroTech
Phone +32 (0) 473 861 079
Email erik.buntinx@aneurotech.com
Responsible Party:
PharmaNeuroBoost N.V.
ClinicalTrials.gov Identifier:
NCT01312922
Other Study ID Numbers:
  • PNB01-C301
  • 2011-001190-11
First Posted:
Mar 11, 2011
Last Update Posted:
Apr 7, 2022
Last Verified:
Mar 1, 2022