| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Generalized Anxiety Disorder (GAD) |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10018105 |
| E.1.2 | Term | Generalized anxiety disorder |
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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 |
| The primary objective of this study is to evaluate the efficacy of pregabalin as compared to placebo as an adjunctive treatment in patients with GAD who partially responded to a standard GAD treatment. Efficacy will be measured by the improvement in the total Hamilton Anxiety Rating Scale (HAM A) scores from baseline (Visit 8, Week 0) observed following 8 weeks of double blind treatment (Visit 15, Week 8 or at earlier termination during the double blind treatment phase) and analyzed using a mixed linear model for repeated measures. |
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| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the trial:
1. Males and females 18 years of age or older.
2. Primary DSM IV diagnosis of GAD (DSM IV, 300.02), as confirmed by the MINI structured interview.
3. All patients must have a total HAM A score ≥22 at screening.
4. Patients who initiated GAD treatment prior to entering the study must have a CGI I ≥ 3 minimally improved or worse as determined by the physician’s assessment of a patient’s response to the treatment (escitalopram, paroxetine, or venlafaxine XR) at study enrollment (Visit 1).
5. Patients who initiated the GAD treatment at enrollment (Visit 1) must have a minimum score of CGI S ≥ 4 at Screening (Visit 0) and Enrollment (Visit 1).
6. Historical failure to respond optimally to a GAD treatment (CGI I ≥3 minimally improved or worse). This treatment must be a different treatment than the one used during the open label optimization phase of this study and must be included in the treatments listed in Table 1, Appendix 1 (in the protocol). GAD treatments not included in Table 1, Appendix 1 (in the protocol), but which the investigator considers to meet this criterion must be discussed with and approved by the sponsor in advance of enrolling the patient in the study.
7. Able to understand and cooperate with study procedures and to give informed consent.
8. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the trial.
9. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
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| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the trial:
1. Current* primary DSM IV diagnosis of major depressive disorder (MDD single episode, recurrent) with or without seasonal pattern, dysthymic disorder, depressive disorder NOS, social phobia, panic disorder with or without agoraphobia, post traumatic stress disorder (PTSD), dissociative disorder, borderline personality disorder, obsessive compulsive disorder, antisocial personality disorder, as defined in the DSM IV TR. If a subject has a past misdiagnosis of any of these disorders, the investigator will need to contact the sponsor prior to screening.
2. Past and/or current DSM IV diagnosis of schizophrenia, schizoaffective disorder, other psychotic disorders, bipolar disorders (I or II), factitious disorder or cognitive disorder (including delirium, dementia, and amnestic disorder).
3. DSM IV substance (except for nicotine and caffeine) dependence within the past 30 days.
4. Presence of comorbid personality disorders (Axis II) based on DSM IV criteria per the investigator’s clinical judgment.
5. Suicide risk by history, self report, or clinically judged to be at serious suicidal or homicidal risk.
6. No change is permitted in the status of psychotherapy for the duration of the study. Ongoing psychotherapy of stable intensity is allowed.
7. Urine drug screen at screening (Visit 0) positive for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, or phencyclidine. At randomization drug screen positive subjects for any of these substances or THC are excluded from participation in the double blind phase.
8. Any clinically significant, serious, or unstable hematologic, autoimmune, endocrine, cardiovascular, renal, hepatic, gastrointestinal, or neurological disorder, including, but not limited to:
• Any seizure disorder;
• Uncorrected hypothyroidism or hyperthyroidism. Patients must be on stable thyroid replacement therapy for hypothyroidism for at least 2 weeks prior to screening (Visit 0);
• History of life threatening neoplasm treated within the last 5 years, other than carcinoma in situ of the cervix or basal cell carcinoma of the skin.
9. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels >2 times the upper limit of normal.
10. Platelet count <125,000/mm3.
11. Serum sodium >150 or <130 mEq/L.
12. Creatinine clearance (CLcr) ≤60 mL/min (estimated from serum creatinine obtained at Visit 0, body weight, age, and gender using the Cockcroft and Gault equation, Safety Assessments Laboratory). Subjects who have an estimated CLcr ≤60 mL/min by this screening method may have their CLcr measured, at the investigator’s discretion, with a 24 hour urine collection performed at the central laboratory. If this 24 hour urine CLcr is >60 mL/min, the subject is not excluded. For SI units see Section 7.5.
13. Clinically significant abnormal electrocardiogram (ECG), including but not limited to the following abnormalities:
• Rhythm Conduction: Premature ventricular contractions >10/min; ventricular tachycardia; ventricular flutter; ventricular fibrillation; second degree AV block (Mobitz Type 1); second degree AV block (Mobitz Type 2); complete heart block; Wolff Parkinson White Syndrome; or left bundle branch block complete;
• Myocardial infarction: Recent or acute (<3 months prior to screening/Visit 0);
• QRS, ST T: ST T changes or abnormal Q (≥30 ms) compatible with ischemia; QTc prolongation (>500 msec); or QRS prolongation (>140 msec).
14. Pregnancy or lactation.
15. Prior exposure to pregabalin.
16. Participation in an experimental drug study within the last 30 days.
17. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the investigator, would make the subject inappropriate for entry into this trial.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The change in the HAM A total score from Baseline (start of double blind phase, Visit 8, Week 0) to termination of the double blind phase (Visit 15, Week 8 or at earlier termination if withdrawn from the study during the double blind phase) will be analyzed using a linear mixed model for repeated measures using the method of restricted maximum likelihood estimation.
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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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| 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 | 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) | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| 8 week prospective open label with background treatment |
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| 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
| Information not present in EudraCT |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 | Yes |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| 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 | 0 |
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