Clinical Trial Result Information
Title of Study:
Randomized, double-blind, placebo-controlled, dose-finding study to evaluate the effects of a partial alpha1A/1L-adrenoceptor agonist, RO 115-1240 in women with stress incontinence or mixed urinary incontinence.
Fast Facts:
| Protocol number: | NN16378 |
| Sponsor: | Hoffmann-La Roche Inc |
| Company division: | Pharmaceutical |
| Product name: | Alpha 1A/1L agonist |
| Phase of development: | II |
| Therapeutic area, approved indication: | Urinary Incontinence, Stress |
| Date of report: | 1/1/2006 |
Clinical study summary:
This was a randomized, double-blind, parallel group study to evaluate the efficacy and safety of 12 weeks’ treatment with alpha 1A/1L agonist in women with urinary incontinence.
Study center(s) :
65 centers in Australia, Brazil, Canada, Israel, South Africa, Spain and the United States.
Objectives:
To assess the efficacy and safety of 4 dose levels of alpha 1A/1L agonist compared with placebo in reducing the number of stress incontinence episodes in women with stress urinary incontinence (SUI) or mixed urinary incontinence with a preponderance of stress urinary incontinence symptoms.
Methodology:
After a screening period and a 1-week placebo run-in period, eligible patients were randomly assigned to study treatment (placebo or 0.5, 1, 1.5 or 2.25mg alpha 1A/1L agonist). Patients recorded urinary incontinence episodes during the screening and placebo run-in periods and for 1 week prior to the visits at weeks 4, 8 and 12 of the double-blind period. Safety assessments (BP, HR, clinical laboratory testing) were conducted at baseline, at intervals up to week 12, and at follow-up approximately 2 weeks after the end of treatment. ECGs were done at baseline, at intervals up to week 12 and at follow up.
Number of patients (planned/analyzed):
647 patients were randomized.
Diagnosis and main criteria for inclusion:
Women 18 to 70 years of age with SUI or mixed urinary incontinence with a preponderance of SUI symptoms.
Test product, dose and mode of administration or test procedure:
Oral doses of alpha 1A/1L agonist 0.5, 1, 1.5, or 2.25 mg twice daily (bid), at breakfast and lunch, with at least 5 hours between doses.
Duration of treatment:
12 weeks of treatment.
Reference therapy, dose and mode of administration or reference procedure:
Oral doses of placebo bid, same regimen and duration as for the trial drug.
Criteria for evaluation (efficacy, safety):
Efficacy: Number of SUI episodes per week (actual and percentage change from baseline) during double-blind treatment, percentage change from baseline in urinary incontinence episodes per week during double-blind treatment.
Safety: Adverse events, blood pressure (BP), heart rate (HR), clinical laboratory tests, ECGs.
Statistical methods:
Inferential statistical analyses were planned in the protocol for efficacy variables.
Summary (efficacy, safety, other results):
Efficacy: The percentage decreases from baseline during week 12 in the weekly number of SUI episodes and in the weekly number of all urinary incontinence episodes were similar for the 5 treatment groups.
Safety: The most frequent adverse events during the 12-week double-blind treatment period were scalp tingling, headache and goose bumps. Scalp tingling was more frequent in the alpha 1A/1L agonist groups (6% in the 0.5 mg group, 18% to 23% in the other alpha 1A/1L agonist groups) than in the placebo group (2%). Headache appeared to be more frequent in the alpha 1A/1L agonist groups (8% to 11%) than in the placebo group (5%), but the incidence was not dose related. Goose bumps were frequent in the 2.25 mg group (13% of patients), less frequent in the 1 mg and 1.5 mg groups (4% and 5% respectively), infrequent in the placebo group (<1%), and not reported in the 0.5 mg group. Chills were more frequent in the 1.5 mg and 2.25 mg groups (8%) than in the other 3 groups (0% to <1%). The prevalence of scalp tingling, goose bumps and chills did not decrease over time.
One patient, a 22-year-old woman in the 1 mg group, died during the treatment period at day 55, due to cardiac arrhythmia. The investigator considered the relationship of the death to study treatment to be remote. In each of the 5 treatment groups, 1 to 3 patients had serious adverse events. Apart from the previously mentioned death, 1 other serious adverse event, sinus bradycardia in a patient in the placebo group, was considered related to study treatment by the investigator, while still blinded to study treatment.
Higher percentages of patients withdrew from treatment because of adverse events in the 1.5 mg and 2.25 mg groups (7% and 9%, respectively) than in the other 3 groups (3% to 5%). Withdrawals due to headache and pruritus in the 2.25 mg group and due to hypertension in the 1.5 mg group contributed to the higher rates of withdrawal in those 2 groups. The mean changes from baseline in supine systolic BP varied among the treatment groups over the course of the study, with no apparent dose relationship. In results obtained at 1.5 to 3 hours postdose during the week 2 visit, the percentage of patients with elevations in supine systolic BP was higher in the 2.25 mg group (5%) than in the other groups (0% to 2%).
The mean changes from baseline in supine HR tended to be slightly lower in the alpha 1A/1L agonist groups than in the placebo group.
The mean changes in laboratory values from baseline over time were generally small and similar across the 5 treatment groups. No evidence of dose-related or time-related effects on laboratory values was seen. The percentages of patients with markedly abnormal laboratory test values were not related to the dose of alpha 1A/1L agonist for any of the laboratory parameters.
The mean changes in ECG parameters showed no obvious dose relationship. The percentages of patients with PR intervals of 200 msec or longer and of patients with clinically significant ECG abnormalities varied among treatment groups with no particular pattern.
Conclusions:
Alpha 1A/1L agonist was generally well tolerated. The drug had little or no effect on vital signs, clinical laboratory results, or ECGs. None of the 4 dose levels of alpha 1A/1L agonist reduced the number of SUI episodes or the number of urinary incontinence episodes more than the placebo treatment did. However, the presence of 3 drug-related adverse events (goose bumps, chills and scalp tingling) indicates that there was a pharmacologic effect.
