| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Major Depressive Disorder |
|
| MedDRA Classification |
| 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 antidepressant efficacy of radafaxine ER compared to placebo. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of radafaxine ER compared to placebo on:
- depression symptoms, and
- disability.
• To evaluate the safety and tolerability of radafaxine ER and placebo.
• To characterize the population pharmacokinetics (PK) of radafaxine ER.
• To evaluate the PK-pharmacodynamic (PD) relationship between radafaxine ER exposure and efficacy, safety and tolerability.
• To potentially investigate pharmacogenetic relationships between genetic variants and radafaxine ER. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Subject currently meets the diagnosis for MDD (without psychotic features), single episode or recurrent, as defined in the DSM-IV-TR diagnosed with a comprehensive psychiatric evaluation incorporating the Mini International Neuropsychiatric Interview (MINI) [Sheehan et al., 1998], as assessed* by a physician with adequate training in psychiatry (e.g., Board Certification in psychiatry in the US; Certificate of Completion of Specialist training in psychiatry in the EU).
* Assessment by a physician with adequate training in psychiatry must include a face-to-face evaluation of the subject, but may be aided by subject evaluation conducted by a healthcare professional with a clinically relevant qualification (e.g., psychiatric nurse or psychologist) and a minimum of two years of documented experience assessing patients with MDD.
2. Subject must, in the investigator’s opinion based on clinical history, have met DSM-IV-TR criteria for their current major depressive episode for at least 12 weeks but no greater than 24 months.
3. Subjects must exhibit moderate to severe levels of depression as defined by:
• a MADRS total score ≥22 at the Screening visit,
• a CGI-S score of ≥4 at the Screening visit, and
• meeting or exceeding an undisclosed pre-defined threshold for the HAMD-17 administered via IVRS at the Screening and Randomisation visits.
4. Subject must have the ability to comprehend the key components of the consent form and provide informed consent.
5. Subject must read and write at a level sufficient to complete study-related assessments.
6. Subject must be a male or female outpatient between the ages of 18 and 64 years, inclusive.
7. A female subject is eligible to enter and participate in the study if she is of:
a. non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is pre-menarchal or post-menopausal); or,
b. child-bearing potential, has a negative pregnancy test at the Screening and Randomisation visits, and agrees to satisfying one of the following requirements:
• Complete abstinence from intercourse from two weeks prior to administration of the investigational product, throughout the Double-Blind and Single-Blind Phases, and for a minimum of one week after premature discontinuation from the investigational product. Abstinence is appropriate only when it is an ongoing practice rather than a temporary measure for entering the study.
• Consistent and correct use of an acceptable method of birth control listed below:
• Female sterilization; or
• Sterilization of her male partner(s); or
• Implants of levonorgestrel; or
• Injectable progesterone; or
• Oral contraceptive (combined or progestogen only); or
• Double-barrier contraception, specifically, a spermicide plus a mechanical barrier (e.g., spermicide plus a male condom or a female diaphragm); or
• Any intrauterine device (IUD) with published data showing that the highest expected failure rate is less than 1% per year (not all IUD’s meet this criterion); or
• Any other method of contraception with data documented in the product labeling as approved by regulatory agencies, or in the absence of approved labeling, in peer reviewed studies, showing that the highest expected failure rate for that method is less than 1% per year.
|
|
| E.4 | Principal exclusion criteria |
- Subject has an unstable medical disorder; or a disorder that would interfere with the action, absorption, distribution, metabolism, or excretion of radafaxine or may pose a safety concern, or interfere with the accurate assessment of safety or efficacy.
- Subject has a history of infectious hepatitis (other than Hepatitis A, which is permissible provided that the infection fully resolved at least 12 months prior to the Screening visit).
- Subject has a positive urine test at the Screening visit for illicit drug use, a history of alcohol or substance abuse or dependence within the past 12 months or a blood alcohol level of ≥15mg/dl (0.015 %) at the Screening visit. Note – subjects must be told to avoid consumption of alcoholic beverages for at least eight hours prior to their Screening visit. The use of alcohol by subjects participating in the study is not recommended.
- Subject, who, in the investigator’s judgment, poses a homicidal or serious suicidal risk, has made a suicide attempt within the six months preceding the Screening visit or who has ever been homicidal.
- Subject has any laboratory or medical abnormality that in the investigator’s judgment is considered to be clinically significant and could potentially affect subject safety or study outcome.
- Female subject is pregnant, lactating, or does not agree to use contraceptive method(s) specified in the protocol to avoid pregnancy during the study.
- Subject has a current or past history of seizure (except for an isolated febrile seizure in childhood), or has a condition which, in the opinion of the investigator, predisposes the subject to seizures.
• Examples of such conditions include, but are not limited to, brain injury (traumatic or disease related) or concomitant medications known to appreciably lower the seizure threshold.
- Subject has a systolic blood pressure (SBP) >140mmHg or a diastolic blood pressure (DBP) >90mmHg at the Screening or Randomisation visit.
- Subject has:
a. taken any psychotropic drug within two weeks prior to the Randomisation visit, including all antidepressants (for example, but not limited to, monoamine oxidase inhibitors [MAOIs], tricyclic antidepressants [TCAs], serotonin and norepinephrine reuptake inhibitors [SNRIs], norepinephrine and dopamine reuptake inhibitors [NDRIs], noradrenergic reuptake inhibitors [NRIs], and selective serotonin reuptake inhibitors [SSRIs]) with the exception of fluoxetine, for which the time period is four weeks prior to the Randomisation visit (Week 0); or
b. taken any psychoactive herbal treatment (e.g., St. John's Wort, SAM-e) within two weeks prior to the Randomisation visit; or
c. taken any of the following medications within one week prior to the Randomisation visit due to potential for PK interaction: ketoconazole, itraconazole, and ritonavir (potent CYP450 SA4 inhibitors) or beta-blockers primarily metabolized by CYP450 2D6 (e.g., bisoprolol, metoprolol and timolol); or
d. initiated treatment with or had a change in dose of any permitted beta-blocker within two months prior to the Randomisation visit.
A subject shall not be withdrawn from his or her current treatment regimen for the primary purpose of enrolling into this trial.
Note: Following the Randomisation visit and through Day 10 of the Double-Blind Phase, zolpidem tartrate and zaleplon at the recommended dosage, and nonprescription sleep aids may be used for night-time sedation.
- Subject has ECG or clinical evidence of any of the following:
a. atrial or ventricular hypertrophy;
b. intraventricular conduction defects (excluding incomplete right bundle branch block in the absence of clinical evidence of heart disease);
c. symptomatic coronary artery disease (or any symptomatic cardiac disease);
d. myocardial strain, ischemia, or infarct;
e. atrial or ventricular arrhythmia (must be in normal sinus rhythm);
f. second- or third-degree AV block;
g. congestive heart failure;
h. cor pulmonale;
i. any cardiac condition or ECG evidence that the investigator feels may predispose the subject to ischemia or arrhythmia; or
j. any ECG abnormality that in the investigator’s judgment may pose a potential safety concern.
- Subject has a history of myocardial infarction, cardiac bypass surgery or angioplasty.
- Subject has a history of cerebrovascular accident or transient ischemic attack.
- Subject has a history of allergic reaction to, or a medically significant adverse effect from the investigational products or their excipients, or closely related compounds (e.g., bupropion). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Change from randomisation in the Montgomery-Asberg Depression Rating Scale (MADRS) total score for radafaxine ER compared to placebo at the end of the double-blind Treatment Phase (Double-Blind Phase) (Week 8). |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| 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 | No |
| 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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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