| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Major depressive disorder |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025453 |
| E.1.2 | Term | Major depressive disorder NOS |
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| 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 with symptoms of decreased pleasure, interest and energy as measured by the Inventory of Depressive Symptoms (Self Report).. |
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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 with symptoms of decreased pleasure, interest and energy.
•To characterize the population pharmacokinetics (PK) of GSK372475 in subjects with MDD with symptoms of decreased pleasure, interest and energy.
•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 with symptoms of decreased pleasure, interest and energy.
•To evaluate the effects of GSK372475 on motivation (physical, mental, and social) and energy.
•To evaluate the effects of GSK37245 on sexual functioning.
•To evaluate the efficacy of paroxetine compared to placebo in patients with MDD with symptoms of decreased energy, pleasure, and interest.
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| E.2.3 | Trial contains a sub-study | No |
| 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 investigator’s 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 25 at the Screening and Randomization Visits.
5.In addition, subjects should exhibit symptoms of decreased energy, pleasure, and interest as measured by a score of at least one on four of the five items (item 19 (General interest/involvement), item 20 (Energy/fatiguability), item 21 (Pleasure/Enjoyment), item 22 (Sexual interest), item 30 (Leaden paralysis/physical energy), and a total of at least 7 on the 5-item sub-scale of the IDS-SR at Screening and Randomization.
6.Subjects must have a CGI-S score of 4 at the Randomization Visit.
7.Subject must have the ability to comprehend the key components of the consent form and provide informed consent.
8.Subject must read and write at a level sufficient to complete study-related assessments.
9.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 subject’s 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.Subject’s IVRS IDS-SR assessment increases or decreases by more than 25% between the Screening (Week -1) and Randomization (Week 0) visits or subject’s IDS 5-item subscale score falls to <7 (items 19, 20, 21, 22, 30).
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 investigator’s 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).
*Major depressive disorder should be the condition that precipitates the evaluation (principal diagnosis) and the condition that best accounts for the clinical presentation (primary diagnosis). Secondary diagnoses of other anxiety disorders such as generalized anxiety disorder, posttraumatic stress disorder, social anxiety disorder, acute stress disorder, and obsessive-compulsive disorder are permissible.
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 no contact with an adult on a daily basis (i.e., subjects who are not living with at least one other adult or subjects who do not have an adult who contacts them on a daily basis). This criterion only applies to sites in Canada, Mexico, Central and South America.
5.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.
6.Subject has received electroconvulsive therapy or transcranial magnetic stimulation within the six months prior to the Screening (Week –1) visit.
7.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.
8.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.
9.Subject, who, in the investigator’s 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.
10.Subject has any laboratory abnormality that in the investigator’s judgement is considered to be clinically significant and could potentially affect subject safety or study outcome.
11.Female subject is pregnant, lactating, or does not agree to use contraceptive method(s) specified in the protocol to avoid pregnancy during the study.
12.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.
13.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.
14.Subject has chronic hepatitis B and C, as evidenced by positive Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody.
*Please refer to protocol for complete list |
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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 10) in the MADRS total score.
•Change from randomization at the end of the Treatment Phase (Week 10) in the 6-item Bech scale extracted from the HAMD-17.
•Change from randomization at the end of the Treatment Phase (Week 10) in the Inventory of Depressive Symptomatology – Clinician-Rated version (IDS-CR) total score.
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| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Information not present in EudraCT |
| 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 | 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.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 | 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
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| 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 | 20 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 20 |
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