Clinical Trial Result Information
Title of Study:
Randomized, double-blind, placebo-controlled, study to evaluate the safety of a partial alpha1A/1L-adrenoceptor agonist, RO 115-1240, in women with stress urinary incontinence or mixed urinary incontinence.
Fast Facts:
| Protocol number: | NN16691 |
| 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: | 8/1/2005 |
Clinical study summary:
This was a randomized, double-blind, parallel group study to assess the safety of 2 weeks’ treatment with alpha 1A/1L agonist in women with urinary incontinence.
Study center(s) :
20 centers in the United States.
Objectives:
To assess the safety of 4 dose levels of alpha 1A/1L agonist compared with placebo, with an emphasis on blood pressure and heart rate, in women with stress urinary incontinence (SUI) or mixed urinary incontinence with a preponderance of SUI symptoms. To characterize the pharmacokinetics of alpha 1A/1L agonist in women with SUI or mixed urinary incontinence.
Methodology:
After a screening period and placebo lead-in period (each 1 week), patients were randomly assigned to study treatment (placebo or 0.5, 1, 1.5, or 2.25 mg alpha 1A/1L agonist).
BP and HR were measured at screening, at baseline, after 1 and 2 weeks of treatment and at a follow-up visit. Intensive BP and HR were measured with the patient standing and supine at intervals up to 4 hours after each of the 2 doses at baseline and at week 2 of treatment. Clinical laboratory testing was done at baseline, week 1, week 2, and follow-up. ECGs were done at baseline, week 1, and week 2.
Number of patients (planned/analyzed):
154 patients were randomized.
Diagnosis and main criteria for inclusion:
Females 18 to 70 years of age with either 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. On the day of the randomization visit and the day of the week 2 clinic visit, the first dose was taken at 8am with food, and the second dose was taken 4 hours later, without food.
Duration of treatment:
2 weeks
Reference therapy, dose and mode of administration or reference procedure:
Oral doses of placebo capsules bid, same regimen and duration as for the trial drug.
Criteria for evaluation (efficacy, safety):
Pharmacokinetic: Pharmacokinetic data were not analyzed.
Safety: Adverse events, blood pressure (BP), heart rate (HR), clinical laboratory tests, ECGs.
Statistical methods:
All safety data were summarized using descriptive statistics.
Summary (efficacy, safety, other results):
Safety: The numbers of patients reporting scalp tingling, chills and goose bumps increased with dose of active drug. No patients in the placebo group and approximately 20% of patients in the 2.25 mg group reported these adverse events. Except for severe ear pain in one patient in the 1 mg group, all adverse events were mild or moderate. One patient (in the 1.5 mg group) had a serious adverse event, breast cancer, diagnosed approximately 1 week after she completed the study. The cancer was judged by the investigator to be unrelated to study medication.
The mean change from baseline in supine systolic BP at the time of peak drug effect (ie mean of values from 1 to 2.5 hours after the first dose at week 2) was the largest in the 2.25 mg group (≈3 mm). No patient had supine systolic BP >160 mmHg. In each treatment group, 2 to 3 patients had supine systolic BP >140 mmHg.
The mean change from baseline in supine HR at the time of peak drug effect was greatest in the 2.25 mg group (≈3 bpm). No other dose-response relationship was evident. Several patients had supine HR <50 bpm, but none had HR <45 bpm.
Hematuria occurred in 1 patient each in the placebo and 1.5 mg groups and 3 patients in the 1 mg group, 4 in the 2.25 mg group, and 5 in the 0.5 mg group. Two patients in the 1.5 mg group had markedly low phosphate levels. One patient in the placebo group and one in the 2.25 mg group had proteinuria. Other marked laboratory abnormalities only occurred in 1 patient.
Summary statistics generally showed small, variable changes in laboratory results among the treatment groups at weeks 1 and 2 and at follow-up. Mean changes in platelet counts were small and positive in the placebo group and tended to be negative in the alpha 1A/1L agonist groups, particularly in the 1.5 and 2.25 mg groups (mean change, -4 to -20 x 109/L). In the ECG analysis, mean changes in ventricular rate at weeks 1 and 2 relative to screening were positive for the placebo group and, in most cases, negative for the alpha 1A/1L agonist groups. Mean changes in QRS intervals were small and positive in the 1.5 and 2.25 mg groups and negative in the other groups. Other mean changes in ECG intervals showed no patterns. Seven patients (1 to 2 per treatment group) had a prolonged PR interval (≥200 msec). For 1 of the patients, the prolongation occurred at screening only.
Conclusions:
The four dose levels of alpha 1A/1L agonist had little effect on vital signs, clinical laboratory results, or ECGs and were well tolerated.
