Clinical Trial Result Information

Protocol number
ML17259

Title of Study
Open study to evaluate the efficacy and safety of milnacipran in outpatients experiencing major depression and non-responders to SSRI therapy.

Sponsor
F. Hoffmann-La Roche Ltd

Company division
Pharmaceutical

Product name
Ixel

Generic name
milnacipran

Therapeutic area
Major Depression Disorder (MDD)

Clinical study summary
This was an open label study of the efficacy and safety of Ixel (milnacipran) in patients with major depression who had failed to respond to SSRI treatment.

Study center(s)
5 centers in Brazil. 

Phase of development
IV

Objectives
Primary: To evaluate the efficacy of milnacipran in outpatients experiencing serious major depression and failing to respond to SSRI therapy. (Efficacy was defined as a reduction of ≥50% in HAMD score at the end of treatment).
Secondary: To evaluate the activity of milnacipran in anhedonia and anxiety. To evaluate the safety profile, including effects on sexual function. To evaluate signs and symptoms and change in symptom severity emerging from treatment discontinuation. To evaluate the impact of milnacipran therapy on patients' quality of life. The study was also designed to evaluate the efficacy and safety of milnacipran therapy in an elderly pilot group (over 60 years old).

Methodology
Eligible patients who had failed to respond to SSRI therapy for 6 weeks, with a 1-2 week washout, were treated with milnacipran, 25mg bid in the first week followed by 50mg from week 2 onwards. Increases in doses up to 200mg/day could be made at the investigator's discretion after 4 weeks treatment.

Number of patients (planned/analyzed)
82 enrolled. 80 evaluable for efficacy and safety.

Diagnosis and main criteria for inclusion
Male and female patients, 18-60 years of age, with moderate or severe major depression; HAMD score ≥18 after 6+ weeks SSRI treatment; DSM-IV criteria for major depression.

Test product, dose and mode of administration or test procedure
Ixel (milnacipran) 50-100mg bid po.

Duration of treatment
12 weeks.

Reference therapy, dose and mode of administration or reference procedure
N/A

Criteria for evaluation (efficacy, safety)
Efficacy: Depression scores (HAM-D, CGI, Fawcett-Clark pleasure scale).
Safety: AEs, weight, sexual dysfunction questionnaire, WHO QoL questionnaire.

Statistical methods
The proportion of non-responders to SSRI and responders to milnacipran after 8 weeks of treatment was expected to be 50%. A total of 70 patients would be necessary to demonstrate a 50% response to treatment, with a 90% confidence interval [38%;62%]. Considering a 10% drop-out rate, it was calculated that ≥78 patients should be included in the study.
Analyses of ITT and PP populations were performed. Since there were no relevant differences between ITT and PP populations only ITT population results are summarized.
Changes in HAM-D and WHO-QoL BRIEF global score and dimensions scores compared to baseline were analyzed by linear models for repeated measures, including visit as a fixed effect and center as a covariable.
Response to treatment by visit was analyzed with a logistic model for repeated measures, including Center as a covariable and visit as fixed effect.
Linear models for repeated measures with multinominial response distribution were employed to analyse the CGI seriousness and Fawcett-Clark items by visit.
LOCF was used in all analyses.

Summary (efficacy, safety, other results)
Efficacy: The mean HAMD-17 score of the sample was 27 (7.2). The response rate for milnacipran was 61.3% achieving the primary efficacy objective. At baseline, 70.9% of the patients were markedly or severely ill, and none was evaluated as normal asymptomatic, borderline or mildly ill, according to CGI. At treatment end, 48.1% of patients were evaluated as normal asymptomatic or borderline, and 20.2% were mildly ill. The improvement was also evident using broader outcome measures such as the generic Quality of Life instrument WHOQOL-brief. The four instrument domains (Physical, Psychological, Social Relationships and Enviroment) all demonstrated statistical and clinical differences. In addition, the Fawcett-Clark sexual dysfunction questionnaire results demonstrated that sexual function improved significantly during treatment.

Safety: The most frequent adverse events were disorders of the nervous system (21.8%), psychiatric disorders (21.2%) and gastrointestinal disorders (21.0%). Most adverse events resolved with no sequala (81.5%) and were of moderate intensity (61.7%). A total of 25% of the adverse events were related to study drug. Two patients discontinued treatment due to serious adverse events (life-threatening acute pulmonary edema, and moderate hypertension).

Conclusions
These results suggest that milnacipran is an effective alternative for patients with severe unipolar depression resistant to treatment with SSRIs. Efficacy was demonstrated not only in terms of response, but also by Quality of Life measurements. Milnacipran was generally well tolerated.

Date of report
12/1/2005

Click here for the protocol registry listing of this trial.