Study Design
Patients completing either of two phase 3 pivotal trials (study 191622-09521 or 191622-520;20 total n = 1,106) were eligible to be enrolled in an open-label extension study (study 191622-096)54 for up to 104 weeks following entry into this open-label extension study to evaluate the long-term safety and efficacy of onabotulinumtoxinA (Ona A). During the extension study, all patients fulfilling all treatment criteria (listed below) received active treatment with Ona A in doses of 100 units (if second treatment), or 150 units if they met the pre-defined criteria (listed below)). Post-treatment follow-up occurred at two, six, and 12 weeks; further follow-up occurred thereafter every 12 weeks until such time that further re-treatment was required or the patient exited the study.
For the patient to qualify for treatment, all of the following criteria had to be met: patient had to initiate the request for treatment; patient had to have experienced two or more urge-incontinence episodes, with no more than one urge incontinence–free day, as recorded in a three-day diary in the week prior to the qualification for the treatment 2 visit; a minimum of 12 weeks had to have elapsed since the previous treatment; patient had to have a post-void residual urine volume of < 200 mL; and the investigator had to have deemed treatment to be appropriate.
Patients received Ona A 150 units if they fulfilled the following criteria: it was at least their third treatment (i.e., treatment 1 and treatment 2 had already been received; the patient wanted an increase in study treatment and was willing to receive a higher dose; the patient’s post-void residual urine volume was < 200 mL; and the investigator deemed treatment to be appropriate.
Results
At the time of the interim data cut-off (July 29, 2011), 834 patients had enrolled and 814 were included in the Ona A–treated population (i.e., enrolled into the long-term study and had had at least one dose of Ona A in either of the two phase 3 pivotal trials [095 or 520] or the open-label extension study [096]); no patients had completed the open-label extension study. Most patients (89.6% [729 out of 814]) were still ongoing, while 10.4% (85 out of 814) had discontinued the study. During the study, a majority of Ona A–treated patients had received the 100-unit (76.5% [623 out of 814]) compared with the 150-unit (23.5% [191 out of 814]) Ona A dose (). The total duration of Ona A exposure was defined as the number of days from the administration of the first Ona A treatment until the day of study exit or interim data cut-off. The median duration of Ona A exposure across treatment cycles was 45.8 weeks (range: 0.1 to 91.9 weeks) for all Ona A doses, and 43.1 weeks (range: 0.1 to 88.4 weeks) for the 100-unit dose.
Patient Disposition — Ona A–Treated Population.
At baseline, Ona A–treated patients receiving the 100-unit dose during the extension trial had a mean (standard deviation [SD]) age of 60.4 (13.1) years, a mean (SD) overactive bladder (OAB) history of 6.5 (7.8) years, and were predominantly female (90.7%) and Caucasian (92.6%); 41.8% of patients were 65 years of age or older. At baseline, the 100 unit treatment subgroup experienced a mean (SD) of 5.4 (3.5) urinary incontinence, 4.9 (3.3) urinary urgency incontinence, 11.6 (3.4) micturition, 8.4 (4.0) urgency, and 2.1 (1.4) nocturia episodes per day. These baseline data generally tended to reflect the baseline data from the phase 3 pivotal trials, except for OAB history, which also appeared to differ between the two phase 3 trials.
The median time for an Ona A re-treatment request (i.e., time between treatment and request for subsequent treatment), regardless of Ona A dose, was 23.3 weeks for cycle 1, 24.0 weeks for cycle 2, and 16.6 weeks for cycle 3. Urinary-incontinence episodes, identified by the highest proportion of patients, comprised the most frequent OAB symptom driving requests for re-treatment. It is difficult to compare the consistency of the extension trial’s efficacy findings with those of the two phase 3 trials because of the lack of placebo comparator in the extension trial. In addition, the extension trial permitted repeated administration of Ona A treatment, which was not a design feature of the phase 3 trials. Despite these limitations, directionally speaking, the patients receiving the 100 unit dose of Ona A appeared to show consistent decreases from the baseline data from the two phase 3 pivotal trials in micturition, urinary incontinence, nocturia, and urgency episodes over the subsequent treatment cycles for which data are available. Similarly, improvements were noted in the Incontinence Quality of Life Questionnaire (I-QOL) instrument and the King’s Health Questionnaire (KHQ; i.e., role limitations and social limitations domains); however, the magnitude of improvement in I-QOL score appeared to decline over repeated cycles of treatment. The proportion of patients with ≥ 50% improvement in urinary-incontinence episodes also seemed to decline (67.9%, 64.5%, 55.0%, and 53.3%) over repeated cycles of treatment.
Number of Patients in Each Ona A Treatment Cycle (Ona A–Treated Population).
Adverse events are presented in . Since these adverse events reflect the effect of repeated Ona A treatments, it is potentially problematic to draw comparisons between the adverse event data from the extension trial and those from the phase 3 trials. Nonetheless, at the end of cycle 1, the proportion of patients experiencing any adverse events seemed comparable with that reported for Ona A–treated patients in study 191622-095,21 but higher than that reported for 191622-520.20 Serious adverse events in the extension trial seemed to occur slightly more often than in either of the two phase 3 trials, while withdrawals due to adverse events appeared to be less frequent in the extension trial than the phase 3 trials ().
The frequency of urinary tract infections (UTIs) seemed stable across four cycles of Ona A treatment in the extension trial and comparable to the frequency of UTI reported in study 191622-520,20 but higher than that reported for study 191622-095.21 Urinary retention appeared to occur at a lower frequency in the extension trial compared with the phase 3 trials, and at a similar frequency across four cycles of Ona A treatment ().
Number of Patients With Urinary Tract Infection and Urinary Retention.
Bladder and kidney ultrasound examinations were performed serially pre- and post-treatment and at study exit to detect the presence of kidney and bladder stones. There were no abnormal findings reported from bladder ultrasound. Renal cysts were said to be observed in the majority of cases, but the frequencies were not reported. Other findings by renal ultrasonography revealed the following in patients who received Ona A 100 units:
Cycle 1: six patients with kidney stones and one patient with pyelocaliectasis
Cycle 2: two patients with hydronephrosis, one patient with pyelocaliectasis, and one patient with renal cancer (judged unrelated to study treatment)
Cycle 3: one patient with hydronephrosis
Cycle 4: no abnormal findings reported.
