| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Major Depressive Disorder (MDD) |
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| 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 GSK372475 compared to placebo in subjects diagnosed with MDD.
secondary objectives
To evaluate the safety and tolerability of GSK372475 compared to placebo in subjects diagnosed with MDD.
To characterize the population pharmacokinetics (PK) of GSK372475 in subjects with MDD.
To evaluate the PK-pharmacodynamic (PD) relationship between GSK372475 exposure and efficacy (i.e., primary and secondary efficacy endpoints) and safety and tolerability in subjects with MDD.
To evaluate the effects of GSK372475 on motivation (physical, mental, and social) and energy.
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| E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of GSK372475 compared to placebo in subjects diagnosed with MDD.
To characterize the population pharmacokinetics (PK) of GSK372475 in subjects with MDD.
To evaluate the PK-pharmacodynamic (PD) relationship between GSK372475 exposure and efficacy (i.e., primary and secondary efficacy endpoints) and safety and tolerability in subjects with MDD.
To evaluate the effects of GSK372475 on motivation (physical, mental, and social) and energy.
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria
apply:
1. Male or female outpatients aged 18-64 years, inclusive.
2. Subject currently meets the diagnosis for MDE associated with MDD, single episode or recurrent, according to DSM-IV-TR (296.2/296.3), diagnosed through a
comprehensive psychiatric evaluation (in conjunction with the Mini International Neuropsychiatric Interview (MINI), Clinician Rated Version 5.0 [Sheehan, 1998]),
as assessed by a physician with adequate training in psychiatry (e.g., Board
Certification in psychiatry in US; Certificate of Completion of Specialist training in
psychiatry in 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.
3. Subject must, in the investigators opinion based on clinical history, have met DSM-IV-TR criteria for their current MDE for at least 12 weeks but no greater than 24
months.
4. Subjects with an IVRS IDS-SR total score ≥33 at the Screening and randomization
Visits.
5. Subjects must have a CGI-S score of ≥4 at the Randomization Visit.
6. Subject must have the ability to comprehend the key components of the consent form and provide informed consent.
7. Subject must read and write at a level sufficient to complete study-related assessments.
8. 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)
• Post-menopausal females defined as being amenorrhoeic for greater than two years with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms). However, if indicated, this should be confirmed by estradiol and FSH levels consistent with menopause (according to local laboratory ranges). Women who have not been confirmed as post-menopausal should be advised to use contraception as outlined below.
• Pre-menopausal females with a documented (medical report verification) hysterectomy and/or bilateral oophorectomy only when reproductive status has been confirmed by hormone level assessment.
b. Child-bearing potential, has a negative pregnancy test at Screening and randomization, and agrees to satisfy one of the following requirements:
• Complete abstinence from intercourse from commencement of last normal menstrual period (2 weeks minimum) prior to administration of the first dose of study drug, throughout the Treatment Phase, and for a minimum of 8 weeks after completion or premature discontinuation from the study drug; or,
• Established use of acceptable methods of contraception from commencement of last normal menstrual period (3 weeks minimum) prior to administration of the first dose of study medication, throughout the Treatment Phase, and for a minimum of 8 weeks after completion or premature discontinuation from the study drug. Acceptable methods of birth control are listed below:
• Female sterilization (documented bilateral tubal ligation); or
• Sterilization (vasectomy) of male partner prior to commencement of female subjects last normal menstrual period prior to administration of the first dose of study medication, and the male partner is the sole partner for that female subject.; or
• Implants of levonorgestrel; or
• Injectable progesterone; or
• Oral contraceptive (combined or progestogen only) (must have been taking reliably through at least one full menstrual cycle period); or
• Documented placement of an intrauterine device (IUD) with published data showing that the highest expected failure rate is less than 1% per year (not all IUDs 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.
Because of the unacceptable failure rate of barrier (chemical and/or physical) methods, the barrier method of contraception must only be used in combination with other acceptable methods. Post-coital methods of contraception are not permitted.
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| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria
apply:
1. Subjects IVRS IDS-SR assessment increases or decreases by more than 25%
between the Screening (Week -1) and Randomization (Week 0) visits.
2. Subject has:
a. Symptoms of the presenting illness which are better accounted for by another
diagnosis*; or
b. A current DSM-IV-TR diagnosis of Panic Disorder; or
c. Symptoms of generalized anxiety or panic attacks that in the investigators
judgement could interfere with their ability to complete the trial; or
d. A current DSM-IV-TR diagnosis of Antisocial or Borderline Personality Disorder, Dementia, or another current DSM-IV-TR Axis II diagnosis that would suggest nonresponsiveness to pharmacotherapy or non-compliance with the protocol; or
e. A current (or within six months prior to the Screening visit) diagnosis of
anorexia nervosa or bulimia; or
f. A DSM-IV-TR diagnosis of Bipolar Disorder, Schizophrenia, or other psychotic
disorder(s).
3. Subject has an unstable medical disorder; or a disorder that would interfere with the action, absorption, distribution, metabolism, or excretion of GSK372475 or may
pose a safety concern, or interfere with the accurate assessment of safety or efficacy.
4. Subject has initiated psychotherapy within three months prior to the Screening
(Week 1) visit, or plans to initiate psychotherapy during the trial. Subjects who
present with their current MDD diagnosis despite longer-term psychotherapy (i.e.
greater than three months prior to the Screening visit) may be included.
5. Subject has received electroconvulsive therapy or transcranial magnetic stimulation within the six months prior to the Screening (Week 1) visit.
6. Subject has previously failed an adequate therapeutic course of pharmacotherapy for MDD (e.g., for ≥4 weeks) from two different classes of antidepressants or two
antidepressants within the same class.
7. Subject has a positive urine test at the Screening (Week 1) or Randomization (Week 0) visits for illicit drug use; a history of DSM diagnosed alcohol or substance abuse or dependence (other than nicotine) within the past 2 years or a blood alcohol level of ≥15mg/dl (0.015 %) at the Screening visit (Week 1). 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.
8. Subject, who, in the investigators judgement, poses a homicidal or serious suicidal risk, has had any previous suicide attempt, a family history of suicide attempts, or who has ever been homicidal.
9. Subject has any laboratory abnormality that in the investigators judgement is
considered to be clinically significant and could potentially affect subject safety or
study outcome.
10. Female subject is pregnant, lactating, or does not agree to use contraceptive
method(s) specified in the protocol to avoid pregnancy during the study.
11. Subject has a current or past history of seizure (except for febrile seizures in
childhood), or has a condition which, in the opinion of the investigator, predisposes
the subject to seizures.
12. Subject has a systolic blood pressure (SBP) >140mmHg or a diastolic blood pressure (DBP) ≥90mmHg at the Screening (Week 1) or Randomization (Week 0) visit.
13. Subject has taken:
a. any psychotropic drug within two weeks prior to the Randomization (Week 0)
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], and selective serotonin reuptake inhibitors [SSRIs]) with the exception of fluoxetine, for which the time period is four weeks prior to the Randomization visit (Week 0); or
b. any psychoactive herbal treatment (e.g., St. John's Wort, SAM-e) within two
weeks prior to the Randomization visit (Week 0);
None of these medications should be taken during the study. A subject shall not be
withdrawn from his or her current treatment regimen for the primary purpose of
enrolling into this trial.
14. Subjects who have taken other drugs known to inhibit P-glycoprotein or to inhibit or induce P450 enzymes within 14 days (or 5 half lives, whichever is longer) prior to the Randomization Visit.
*See protocol for further exclusion criteria
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from randomization at the end of the Treatment Phase (Week 8) in the MADRS total score. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| 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) | Yes |
| 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 |
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| 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 | |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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