Pipamperone/Citalopram (PNB01) Versus Citalopram (CIT) and Versus Pipamperone (PIP) in Major Depressive Disorder (MDD)
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
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
- 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
- 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.
- 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
Inclusion Criteria:
-
Patient is informed and given ample time and opportunity to think about her/his participation and has given her/his written informed consent.
-
Patient understands the investigational nature of the trial and is willing and able to comply with the trial requirements.
-
Patient is male or female, aged ≥ 18 years.
-
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).
-
CGI-S rating of at least 4 and a minimum MADRS total score of 26 using IVRS ePRO at Baseline.
Exclusion Criteria:
-
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.
-
Existence of Mood Disorder with psychotic features and/or high suicidality risk, as confirmed by MINI.
-
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.
-
Concomitant diagnosis of any primary Axis II disorder.
-
Patient is hospitalized.
-
Patient has a clinically relevant renal dysfunction (e.g. GFR <60mL/min).
-
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).
-
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, …).
-
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.
-
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.
-
Patient with documented alcohol or drug abuse, or having a positive standard screen for alcohol or drugs (including benzodiazepines and opioids).
-
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).
-
Concomitant treatment with diuretics, QT prolongation drugs, or dopamine agonists.
-
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
-
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.
-
Formal psychotherapy or alternative treatment for 1 week prior to or during the study.
-
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.
-
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.- PNB01-C301
- 2011-001190-11
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
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 |
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 |
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
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 |
erik.buntinx@aneurotech.com |
- PNB01-C301
- 2011-001190-11