| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Major Depressive Disorder |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025453 |
| E.1.2 | Term | Major depressive disorder NOS |
| E.1.2 | System Organ Class | 100000004873 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the efficacy, safety, and tolerability of cariprazine 1.5
mg/day and 3 mg/day compared with placebo as an adjunctive
treatment to ongoing antidepressant therapy (ADT) in patients with
major depressive disorder (MDD) who have had an inadequate response
to antidepressants alone |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Written informed consent has been obtained
2.Written documentation has been obtained in accordance with the
relevant country and local privacy requirements, where applicable (eg,
Written Authorization for Use and Release of Health and Research Study
Information [US sites] and written Data Protection consent [EU sites])
3.Patient is male or female 18 to 65 years of age, inclusive, at the time
of consent
4.Patient must be an outpatient at the time of Visit 1 (Screening)
5.Patient meets the DSM-5 criteria for MDD based on SCID-5, with a
current major depressive episode of at least 8 weeks to less than 24
months in duration at Visit 1/Screening. A diagnosis of MDD with
psychotic features will be acceptable
6.Diagnosis of MDD confirmed through a formal adjudication process
(see Section 6.1)
7.Patient demonstrates ability to follow study instructions and likely to
complete all required visits
8.In the current depressive episode, patient must have an inadequate
response (< 50%improvement) to 1 to 3 antidepressants of adequate
dose and adequate duration, as measured by the modified ATRQ.
Adequate dose is defined as a dose above the minimum labeled dose
(per package insert). Adequate duration is defined as continuous ADT
treatment for at least 6 weeks, with a minimum of 3 of 6 weeks above
the minimal dose.
9.Only one antidepressant (of sufficient dose per package insert and
taken for at least 6 weeks) will be allowed at randomization and patients
must agree to continue taking the same ADT dosing regimen through
completion of Visit 6/ET. Patients who are taking more than one
antidepressant at Screening, regardless of the indication, will need to
discontinue all other antidepressants prior to Baseline (Visit 2)
10.Patient must have a minimum score of 22 on the rater-administered
Hamilton Depression Rating Scale–17 items (HAMD-17) at both
Screening (Visit 1) and Baseline (Visit 2)
11.Patient has a score of 2 or higher on Item 1 of the HAMD-17 rating
scale at Visits 1 and 2
12.Patient has normal physical examination findings, clinical laboratory
test results, and electrocardiogram (ECG) results from Screening (Visit
1), or abnormal results that are judged to be clinically insignificant by
the investigator
13.Male and female patients must agree to use a medically acceptable
and highly effective method of birth control during the course of the
entire study and for 12 weeks after the last dose of investigational
product, as defined in Section 4.5.1.1 of protocol.
14.Women of childbearing potential (only) must have a negative
qualitative serum β-human chorionic gonadotropin pregnancy test prior
to Visit 2 |
|
| E.4 | Principal exclusion criteria |
1.Diagnosis of any current psychiatric diagnosis other than MDD
(including those with current intellectual development disability) with the exception of specific phobias
2.History of manic or hypomanic episodes
3.Patients with a YMRS score ≥ 12
4.Patient has a history of meeting DSM-5 diagnosis for any substancerelated disorders (ie, use disorders except caffeine- and tobacco-related)
within the 3 months before Visit 1 (Screening)
5. Patient had a positive result at Visit 1 (Screening) from the urine drug screen (UDS) for any prohibited drugs. Exception: patients with a
positive UDS at Visit 1 for opiates, cannabinoids, amphetamines, barbiturates, or benzodiazepines may be allowed in the study provided:
a.The drug was used for a legitimate medical purpose;
b.The drug can be discontinued prior to further participation in the study (except for benzodiazepines which may be continued if the patient has
been taking a stable dose [ie, lorazepam up to 2 mg/day or its benzodiazepine equivalent] for at least 1 month prior to Visit 1
(Screening) or if used as rescue during washout); and
c. A repeat UDS must be performed prior to Visit 2 and must be negative, except benzodiazepine use as described in 4(b) and Section 4.5.3
6.The patient represents a suicide risk, as determined by meeting any of the following criteria:
a. Patient made a suicide attempt within the past year prior to Visit 1 (Screening)
b.Patient had a score of 4 or greater on Item 10 of the MADRS at Visit 1 (Screening) or Visit 2 (Baseline)
c. Patient had a score of 3 or greater on Item 3 of the HAMD-17 at Visit 1 (Screening) or Visit 2 (Baseline)
d. Patient is at significant risk, as judged by the investigator, based on the psychiatric interview or information collected in the Columbia–
Suicide Severity Rating Scale (C-SSRS) at Visit 1 (Screening) or Visit 2 (Baseline)
7. Patient is at imminent risk of injuring self or others or causing significant damage to property, as judged by the investigator
8. Patient has a history of intolerance or hypersensitivity to cariprazine or other drugs of the same class or to rescue medications
Treatment-Related Criteria:
9. Per ATRQ, patient failed to respond to > 3 trials of ADTs given at an adequate dose (as defined by the ADT package insert) and duration of ≥
6 weeks during the present episode
10. Patient was treated with monoamine oxidase inhibitors in the current episode
11. Patient has history of treatment with clozapine > 50 mg/day or any depot antipsychotic at any time prior to Visit 1 (Screening)
12. Patient has history of treatment with esketamine, electroconvulsive therapy, vagus nerve stimulation, transcranial magnetic stimulation, or
any experimental central nervous system treatment during the current episode or in the 6 months before Visit 1 (whichever is longer) or
previous lack of response to treatment with esketamine, electroconvulsive therapy, vagus nerve stimulation, or transcranial magnetic stimulation
13.Patients who require concomitant treatment with moderate or strong cytochrome P450 3A4 (CYP3A4) inhibitors or any CYP3A4 inducers. If
applicable, these treatments must be discontinued at least 10 days prior to Visit 2 (Baseline)
14.Patient requires concomitant treatment with any prohibited medication, supplement, or herbal product including any psychotropic
drug or any drug with psychotropic activity or with a potentially psychotropic component (for exceptions allowed for concomitant
treatments, refer to Sections 4.5.2 and 4.5.3)
15.Participation in any clinical study, involving experimental or investigational drugs or devices during the study or within 3 months
before Visit 1 (or at least 5 half-lives of the drug, whichever is longer)
16.Initiation or termination of psychotherapy for depression within the 3 months preceding Visit 1 (Screening), or plans to initiate, terminate, or
change such therapy during the course of the study
Other Medical Criteria:
17.Female patients who are pregnant, planning to become pregnant during the course of the study, or are currently lactating
18.Any concurrent medical condition that, in the judgment of the investigator, might interfere with the conduct of the study, confound the
interpretation of the study results, or endanger the patient's well-being
19.Any cardiovascular disease that is clinically significant, unstable, or decompensated including history of congenital QTc prolongation or QTc
prolongation (screening ECG with QTcF ≥ 450 msec for men and QTcF ≥ 470 msec for women)
20.Any disease (eg, hypertension) that is clinically unstable or decompensated, based on the investigator's judgment
21.Newly diagnosed or clinically uncontrolled hypo- or hyperthyroidism as evident on clinical laboratory test results at Visit 1 (Screening).
Patients diagnosed previously with hypo- or hyperthyroidism have to be stabilized on appropriate pharmacotherapy with no change in dosage for
at least 1 month before Visit 1 (Screening). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy parameter will be the change from baseline to Week 6 in the MADRS total score. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline (Visit 2) to Week 6 (Visit 6) or early patient
discontinuation from the study (Early Termination visit) |
|
| E.5.2 | Secondary end point(s) |
Additional efficacy parameters will include the following:
- Change from baseline in the CGI-S score
- CGI-I score
- CGI-I response (CGI-I score ≤ 2)
- MADRS response (≥ 50% reduction from baseline in MADRS total
score)
- MADRS remission (MADRS total score ≤ 10)
- Change from baseline in the HAMD-17 total score
- Change from baseline in the HAM-A total score |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Postbaseline visits described in the Table 1 of the protocol. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Adjunt to antidepressant treatment of Major Depressive Disorder |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Czech Republic |
| Finland |
| Poland |
| Serbia |
| Slovakia |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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