Several changes to dose, risk-benefit assessment and other statistical analyses were made to align the current protocol with the updated opinion of the Paediatric Committee (PDCO) of the EMA (published as: opinion of the PDCO on the acceptance of a modification of an agreed PIP (EMEA-000573-PIP01-09-M01). Other changes were: increase in number of sites, inclusion criterion 3 was updated to reflect differences in national legislation with regard to informed consent (IC) for adolescents in clinical studies, inclusion criterion 4 was updated to provide more clarity on who should be subject to birth control, the discontinuation criterion relating to the QT interval was updated to reflect the use of QT interval corrected for heart rate by Bazett formula (QTcB), acute urinary retention (AUR) was defined as “urinary retention for which an intervention is required or has taken place” to provide clarification to investigators, it was added that no important identified risks for solifenacin had been captured in a pediatric population to date, a requirement for leucocyturia, defined as white blood cell (WBC) count > 100/mcL as a prior step to urine culture was added, Tri- and tetracyclic antidepressants were added to the list of restricted medication, the recording of the urgency grade in adolescents according to the PPIUS was reduced from 7 days per diary period to 2 days, the requirement of a sitting position of the patient for these assessments and the use of the same arm for every blood pressure measurement was specified to further standardize the measurement, instructions were changed to repeat the PVR volume assessment only once when the initial PVR volume was > 20 mL, specifications (comparison to age-appropriate norms) were added to aid data interpretation and ensure consistency in the assessment and evaluation of vital signs, laboratory results and height and weight, the SAE reporting instruction was slightly rephrased to provide better guidance to investigators.

After finalization and first regulatory submissions of Substantial Amendment 1 dated 20 Apr 2012 (Protocol version 2.0), inconsistencies were identified in the changes made to the respective paragraphs across the protocol (e.g., changes made only in the synopsis part of the protocol, but not in the body text of the protocol). These were corrected in Protocol version 2.1, including Substantial Amendment 1 dated 20 Apr 2012.

Germany country-specific amendment: A local substantial Amendment 1 dated 7 Sep 2012 was issued. This amendment corresponds to the global substantial Amendment 2 dated 30 Oct 2012. In addition, the pharmacokinetic samples scheduled to be taken in Study 905-CL-076 were instead to be taken in this unblinded extension Study 905-CL-077. No patients were enrolled at the study sites in Germany.

The Netherlands country-specific amendment: A local substantial Amendment 1 dated 24 Sep 2012 was issued. This amendment corresponds to the global substantial Amendment 2 dated 30 Oct 2012. No patients were enrolled at the study sites in the Netherlands before this amendment was implemented.

UK country-specific amendment: A local substantial Amendment 1 dated 17 Oct 2012 was issued. This amendment corresponds to the global substantial Amendment 2 dated 30 Oct 2012. No patients were enrolled at the study sites in the UK before this amendment was implemented.

This global amendment was prepared and submitted after approval of the country specific amendments. The sections “Study Design”,“Dose Rationale”, “Discontinuation Criteria for Individual Subjects”, “Dose/Dose Regimen and Administration Period”, and “Increase or Reduction in Dose of the Study Drugs” were updated to reflect the inclusion of the possibility to down titrate to “no treatment” (i.e., interruption of treatment) for a period of 3 weeks and the subsequent possibility to discontinue the study in case no symptoms of OAB occur in this period. This amendment was developed to limit unnecessary exposure to solifenacin in patients who did no longer require treatment with OAB medication. The objective was to identify patients who did not require treatment with OAB medication.

Several changes were made to align current protocol with the updated opinion of the PDCO of the EMA regarding solifenacin (published as: opinion of the Paediatric Committee on the acceptance of a modification of an agreed PIP [EMEA-000573-PIP01-09-M04]). Other changes were: the number of patients was changed from at least 120 patients (at least 60 children and 60 adolescents) to at least 120 patients (at least 100 children and at least 20 adolescents) evaluable for the primary endpoint, an additional inclusion criterion was added “Subject agrees not to participate in another interventional study while on treatment”, as well as the main analyses of safety and efficacy, which were performed separately in both children and adolescent cohorts, further statistical methods were described that used the data from the patients in this study together with data from adults in the solifenacin phase 3 program, to interpolate between children and adults, and provide estimates of treatment effects in adolescents based on an extensive data set, in assessing the PVR volume, the instruction that the bladder was to be emptied when it was initially filled > 50% of the bladder capacity for age was changed such that the bladder should only be emptied when it was initially filled with preferably > 50% of the bladder capacity for age, the calculation of the baseline QTcB mean was revised to use the average of the QTcB means of the ECG triplicates from the 2 prerandomization visits (i.e., visits 2 and 3) of Study 905-CL-076 instead of using the QTcB mean from visit 3 ECG triplicates only, the definition of SAE was reworded for clarification and the events of interest that may require expedited reporting and/or safety evaluation were defined and categorized.