| 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 | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025458 |
| E.1.2 | Term | Major depressive disorder, recurrent episode, moderate degree |
| 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 demonstrate that the antidepressant activity of Viotra™ is not inferior to amitriptyline in subjects who have an unsatisfactory response
to / are resistant to treatment with SSRIs. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety and tolerability of Viotra™. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed informed consent.
2. Male or female.
3. Age 18-65 years inclusive.
4. Subjects with a current episode of moderate to severe Major Depressive Disorder meeting the criteria of DSM IV -TR and documented using the brief structured interview Mini International Neuropsychiatric Interview (MINI) version 5.0 and with a minimum duration of two weeks and a maximum of twelve months.
5. Minimum Hamilton Depression Scale (HAM-D) 17 items total score of 18 at screening and ≥12 at the end of the lead-in phase prior to randomisation.
6. Female subjects of childbearing potential must have a negative pregnancy test at the Screening Visit and must use an acceptable method of contraception throughout the study and for 30 days after. The following contraceptive methods are acceptable: hormonal (e.g. oral, injection, transdermal patch, implant, cervical ring), barrier (e.g. condom or diaphragm with spermicidal agent), intrauterine system (IUS) or intrauterine device (IUD). If hormonal contraceptives are used by female subjects they must be established for 6 weeks before the first administration of test product. Male sterilisation is considered an acceptable form of contraception if the appropriate post-vasectomy documentation (absence of sperm) is provided. Sexual abstinence is considered acceptable if this is in line with the preferred and usual lifestyle of the subject; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. To be considered „not of child-bearing potential “ female subjects must be surgically sterilized or post-menopausal (defined as no menses for one year or an FSH value >40 IU/L). Male subjects with female partners of child-bearing potential must use an acceptable method of contraception throughout the study and for 30 days after.
7. Able to understand and comply with the requirements of the study as judged by the investigator. |
|
| E.4 | Principal exclusion criteria |
1. Considered by the investigator to be at significant risk of suicide or scoring 5 or more on the Montgomery Asberg Depression Rating Scale (c) question 10.
2. Significant other psychiatric illness which would interfere with trial assessments – co-morbid generalised anxiety disorder (GAD) and panic disorder will be permitted where MDD is considered the primary diagnosis.
3. Significant physical illness which would interfere with trial assessments.
4. Recent (within 1 week of screening) antidepressants (except for fluoxetine [within 4 weeks of screening] and St John’s Wort or MAOI’s [within 14 days of screening]).
5. Benzodiazepine or any other psychotropic medication including lithium or other mood stabilisers within 1 week of screening. Propranolol is permitted where a stable dose (minimum 30 days) has been prescribed for non-psychotropic reasons e.g. high blood pressure.
6. Oral anticoagulant therapy within one month of screening.
7. Formal psychotherapy or alternative treatments for one week prior to screening or during the study defined as that administered by a specialist healthcare professional, using formal structured techniques.
8. Reduced hepatic function defined as liver enzyme levels ≥2.5 times upper limit of normal.
9. Renal insufficiency defined as creatinine clearance <30 mL/min.
10. Epilepsy – Patients with epilepsy or those susceptible to seizures should not be included. Where it has not been possible to exclude an underlying susceptibility greater than that of the general study patient population with sufficient confidence and/or an old condition cannot be regarded as resolved, then the patient should not be included.
11. Uncontrolled Hypothyroidism.
12. Uncontrolled Hypertension.
13. Acute porphyria.
14. Urinary retention, prostatic hypertrophy, narrow angle glaucoma or increased intraocular pressure or any other clinically relevant contraindication stated in the SMPCs for citalopram, tramadol or amitriptyline (See Appendix 5).
15. History of significant cardiac dysrhythmia or history of myocardial infarction within 1 year prior to screening.
16. Significant history of alcohol or substance abuse.
17. Regular alcohol intake above the recommended UK guideline of 4 units per day for males or 3 units per day for females.
18. Pregnant or lactating women.
19. Known hepatitis B or C or human immunodeficiency virus (HIV) or syphilis seropositivity. Note: testing for hepatitis, syphilis or HIV will not be performed as part of the screening procedures.
20. A corrected QT interval of >470ms for female subjects of >450ms for male subjects, calculated using the QTcB correction formula, or second degree or higher heart block on an ECG recording, at screening.
21. Allergy to the study drugs or excipients.
22. Treatment with another investigational medicinal product within the 30 days prior to screening.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The mean difference in baseline-adjusted MADRS score at the end of treatment (week 8). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• The mean difference in baseline-adjusted MADRS score at weeks 1, 2, 4 and 6.
• Percentage of subjects with remission defined as ≤ 10 on the MADRS at the end of treatment (week 8).
• Percentage of responders defined as ≥ 50% decrease from baseline in the MADRS at the end of treatment (week 8).
• The mean difference in baseline-adjusted CGI severity at week 8.
• The mean difference in CGI improvement at weeks 1, 2, 4, 6, and 8. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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) | 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 | No |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.3.1 | Comparator description |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| The study ends with the last telephone follow-up (4 weeks after Visit 8) of the last subject participating in 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 | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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