Clinical Trial Result Information

Title of Study:
Open-label Extension for treatment of incontinent patients who have completed an Ro115-1240 study.

Fast Facts:

Protocol number:	NN16586
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 an open-label extension study, which was terminated prematurely because of a decision to discontinue development of alpha _1A/1L agonist.

Study center(s) :
57 centers in Australia, Brazil, Canada, Israel, South Africa, Spain and United States.

Objectives:
To provide alpha _1A/1L agonist for a longer period of time to patients who derived benefit from the treatment and to ensure its safe use. To obtain safety information concerning extended use.

Methodology:
Beginning at the baseline visit, all patients took 1.5 mg alpha _1A/1L agonist bid. Safety assessments were to be conducted at intervals up to week 52, and then quarterly.

Number of patients (planned/analyzed):
386 patients enrolled.

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; completion of study NN16378 or NN16691 without a tolerability concern or a clinically significant safety concern.

Test product, dose and mode of administration or test procedure:
Oral doses of _1A/1L agonist 1.5 mg twice daily (bid), at breakfast and lunch, with at least 5 hours between doses.

Duration of treatment:
Until study termination or withdrawal.

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

Criteria for evaluation (efficacy, 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):
A majority of the patients, 61% (234), were treated for more than 90 days, and 49% (187) were treated for more than 180 days. The most frequent adverse event was scalp tingling, which was reported by 18% of the patients. The percentage of patients reporting scalp tingling in this extension study tended to be lower for patients who had been in the higher alpha 1A/1L agonist dose groups of their previous study. The incidence of other frequent adverse events (goose bumps, headache, sinusitis, chills, upper respiratory tract infection and nasopharyngitis, each reported in at least 5% of patients overall) was not related to the previous dose level of alpha _1A/1L agonist.
In general, adverse events tended to be reported most frequently during the first 90 days of treatment. This was true for adverse events known to be associated with alpha _1A/1L agonist: scalp tingling, goose bumps and chills. There was no evidence of a delayed increase in the frequency of any of the adverse events, although data for the later follow-up periods are limited to small numbers of patients.
Seven patients had serious adverse events. One serious adverse event, severe chest pain, was considered remotely related to study treatment.
Overall, 11% of the patients withdrew from treatment because of adverse events. Scalp tingling led to withdrawal in 7 patients, and chills led to withdrawal in 4 patients. Other adverse events each led to withdrawal in less than 1% of patients.
The mean changes from baseline in supine systolic BP were generally small increases. Mean supine HR was slightly lower at week 1 than at screening or baseline and was generally stable thereafter.
The mean changes in laboratory values from baseline were small and not indicative of a trend over time. The most frequent marked laboratory abnormality was 4+ hematuria.
The mean changes in PR and QTc intervals were generally small and variable over time. The percentage of patients with PR intervals ≥200 msec remained fairly constant, ranging from 1.6% to 2.6% during the first year of treatment.

Conclusions:
Alpha _1A/1L agonist was generally well tolerated during long-term treatment (more than 90 days in the majority of patients). The drug had little or no effect on vital signs, clinical laboratory results, or ECGs.