Subjects randomized to the placebo treatment are unlikely to benefit from the study. However, OAB is not a life-threatening disease and it is not expected that a 12 to 15 week exposure to placebo treatment will have a negative impact on disease…
ID
Source
Brief title
Condition
- Bladder and bladder neck disorders (excl calculi)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change from baseline in mean volume voided per micturition after 12 weeks of
treatment
Secondary outcome
Key secondary efficacy variables:
* Change from baseline in mean number of micturitions/24 h
* Change from baseline in mean number of incontinence episodes/24 h
Other secondary efficacy variables:
* Change from baseline in mean volume voided per micturition at secondary time
points(i.e., after 2, 4 and 8 weeks of treatment)
* Change from baseline in mean number of urgency incontinence episodes/24 h
* Change from baseline in mean number of urgency episodes (grade 3 and/or 4)/24
h (PPIUS scale)
* Change from baseline in mean level of urgency
* Change from baseline in Patient Perception of Bladder Condition (PPBC)
* Change from baseline in symptom bother and health related quality of life
scores asassessed by the Overactive Bladder Questionnaire (OAB-q)
* Change from baseline in scores as assessed by European Quality of Life
questionnaire in 5 Dimensions (EQ-5D) questionnaire
* Change from baseline in scores as assessed by the Work Productivity and
Activity Impairment: Specific Health Problem (WPAI:SHP) questionnaire
* Change from baseline in the subject's assessment of Treatment Satisfaction
(TS-VAS)
* Change from baseline in mean number of incontinence pads used/24 h
* Change from baseline in mean number of nocturia episodes/24 h
Safety and Tolerability Variables
* Incidence and severity of all AEs
* Vital signs: sitting systolic and diastolic blood pressure (BP) and pulse
rate (PR)
* Physical examination
* Laboratory tests: hematology, biochemistry, urinalysis
* ECG parameters
* PVR volume
Background summary
Background of the study (p31)
The present study is designed to evaluate combination therapy with the beta-3
adrenoceptor (AR) agonist mirabegron (YM178) and the muscarinic receptor
antagonist, solifenacinsuccinate (YM905) in the treatment of overactive bladder
(OAB). Solifenacin succinate is indicated for the relief of symptoms of urinary
frequency, urinary incontinence or urgency associated with overactive bladder
in adults. Solifenacin succinate was first approved in The Netherlands in 2003
and subsequently approved throughout Europe via the mutual recognition
procedure during 2004 and 2005. It was approved in the USA in 2004 and Japan in
2006. Mirabegron*s proposed indication is for the relief of symptoms of urinary
frequency, urgency incontinence or urgency associated with OAB in adults.
Mirabegron hasrecently been submitted for regulatory approval in Japan and
applications for submission in Europe and the USA are currently under
preparation.
Study objective
Subjects randomized to the placebo treatment are unlikely to benefit from the
study. However, OAB is not a life-threatening disease and it is not expected
that a 12 to 15 week exposure to placebo treatment will have a negative impact
on disease progress. Subjects have a less than 6% chance of being randomized to
placebo. Subjects in the other arms of the study, either receiving monotherapy
or combination therapy, are likely to benefit from at least a partial relief of
symptoms during the study. Solifenacin succinate and mirabegron monotherapies
have documented efficacy in the treatment of OAB symptoms in patients.
Muscarinic antagonists and beta-3 adrenergic agonists modulate bladder function
through distinct molecular pathways and have demonstrated an additive effect in
pre-clinical studies. Thus concomitant use of solifenacin succinate and
mirabegron offers the possibility of enhancing efficacy in the treatment of
OAB. The potential of combination therapy to offer
enhanced efficacy will be evaluated in the study.
Study design
This is a multinational, multicenter, double-blind, randomized, factorial,
parallel-group, active and placebo-controlled Phase 2A/B study.
It is planned to recruit subjects from approximately 125 sites in approximately
19 countries in Europe, and potentially outside of Europe.
Approximately 1658 enrolled, 1326 randomized, and 1190 evaluable subjects will
be included in the main study. Subjects will be asked to participate in a PK
substudy, which will involve additional PK profiling at one visit. It is
planned for 120 subjects (10 subjects per treatment arm) to participate in this
substudy.
Intervention
The study consists of 9 visits: visit 1 (screening), visit 2 (placebo run-in),
visit 3 (randomization), visit 4, 5, 6, 7 & 8 (double-blind treatment), visit 9
(follow-up ).
Screening Phase (Visit 1 [a & b])
Initially, subjects will provide signed informed consent and current medication
will be reviewed. Subjects who are taking medications intended to treat OAB or
prohibited medications will be asked to stop these medications and return to
the clinic to undergo screening assessments after a 2-week (wash-out) period.
Subjects who are not taking medications intended to treat OAB or prohibited
medications may undergo the Screening assessments at the same visit. These will
include eligibility screening, safety laboratory evaluation, physical
examination, pregnancy test (female subjects), post void residual (PVR) volume,
vital signs, ECG and urinalysis to exclude UTI. Upon passing screening (Visit
1b), subjects will complete a daily diary (including 5 consecutive days prior
to the Visit 2/Placebo Run-in for vital signs and 3 consecutive days prior to
the Visit 2/Placebo Run-in for micturition and incontinence) to check
willingness and ability to complete diaries.
Placebo Run-in Phase (Visit 2)
Upon passing Visit 2/Placebo Run-in, subjects will be enrolled into a 2-week,
single-blind, placebo run-in period. Subjects will be asked to take study
medication (placebo, once daily) and complete a daily diary (including 5
consecutive days prior to the next visit for vital signs and 3 consecutive days
prior to the next visit for micturition and incontinence) to establish baseline
data.
Treatment Phase (Visits 3-8)
Following the completion of the Screening and placebo run-in phases, it is
planned to randomize approximately 1326 eligible subjects to 12 treatment arms
with either 156 or 78 subjects per arm. Each of the following 5 treatment arms
of primary interest will consist of approximately 156 randomized subjects:
* Solifenacin succinate 2.5 mg + mirabegron 25 mg
* Solifenacin succinate 2.5 mg + mirabegron 50 mg
* Solifenacin succinate 5 mg + mirabegron 25 mg
* Solifenacin succinate 5 mg + mirabegron 50 mg
* Solifenacin succinate 5 mg
Each of the following 7 treatment arms of secondary interest will consist of
approximately 78 randomized subjects:
* Solifenacin succinate 10 mg + mirabegron 25 mg
* Solifenacin succinate 10 mg + mirabegron 50 mg
* Solifenacin succinate 2.5 mg
* Solifenacin succinate 10 mg
* Mirabegron 25 mg
* Mirabegron 50 mg
* Placebo
Two randomization schemes will be used. For subjects who will participate in
the main study only, randomization will be stratified by gender, age category
(< 65 years and * 65 year) and geographic region (Western Europe, Eastern
Europe, Southern Europe, and other [if other is applicable]). Subjects who
agree to participate in the PK substudy will be stratified by gender and age (<
65 years and * 65 years).
The duration of the treatment phase is 12 weeks (including scheduled visits at
Weeks 0, 1, 2, 4, 8 and 12). Safety, efficacy and PK assessments will be
performed at each visit according to the Schedule of Assessments. During the PK
substudy at Visit 5/Week 2, additional blood samples will be taken from
consenting subjects.
Follow-up Phase (Visit 9)
Following the completion (or the early termination) of the treatment phase,
subjects will enter the 2-week follow-up phase. Subjects will not take any OAB
treatment during the follow-up phase. Safety assessments will be performed at
this visit.
Study burden and risks
All of the identified and potential safety risks of monotherapy or combination
use of mirabegron and solifenacin succinate are monitorable and will be
measured during the study. Adverse events will be reviewed on a regular basis
by a Data Safety Monitoring Board (DSMB) who will advise the Sponsor on
appropriate steps to protect study participants including the early termination
of one or more treatment arms. None of the identified or potential risks are
considered capable of inducing irreversible or long-term harm in study
participants.
Subjects randomized to the placebo treatment are unlikely to benefit from the
study. However, OAB is not a life-threatening disease and it is not expected
that a 12 to 15 week exposure to placebo treatment will have a negative impact
on disease progress. Subjects have a less than 6% chance of being randomized to
placebo. Subjects in the other arms of the study, either receiving monotherapy
or combination therapy, are likely to benefit from at least a partial relief of
symptoms during the study. Solifenacin succinate and mirabegron monotherapies
have documented efficacy in the treatment of OAB symptoms in patients.
Muscarinic antagonists and beta-3 adrenergic agonists modulate bladder function
through distinct molecular pathways and have demonstrated an additive effect in
pre-clinical studies. Thus concomitant use of solifenacin succinate and
mirabegron offers the possibility of enhancing efficacy in the treatment of
OAB. The potential of combination therapy to offer
enhanced efficacy will be evaluated in the study.
The Sponsor considers that the favorable benefit-risk of the various treatment
arms to subjects with OAB participating in Study 178-CL-100 warrants further
investigation to examine the potential benefits of combination therapy.
Elisabethhof 19
2353 EW Leiderdorp
NL
Elisabethhof 19
2353 EW Leiderdorp
NL
Listed location countries
Age
Inclusion criteria
* Inclusion Criteria at Visit 1/Screening:
1. Subject is male or female and at least 18 years of age;
2. Subject has a Body Mass Index (BMI) of between 18 and 35 kg/m2 and a total body weight between 50 and 95 kg;
3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written
informed consent and privacy language as per national regulations has been obtained
from the subject prior to any study-related procedures (including discontinuation of
prohibited medication, if applicable);
4. Subject is willing and able to complete the micturition diary and questionnaires correctly
and is willing and able to measure his/her vital signs at home at stipulated time points,
using the device provided by the study personnel, and to adequately record the readings;
5. Subject has symptoms of OAB (urinary frequency, urgency and/or urgency
incontinence) for at least 3 months.;* Inclusion Criteria at Visit 2/Placebo Run-In
6. Subject must still fulfill all inclusion criteria and none of the exclusion criteria for Visit 1;
7. Subject is willing and able to complete the micturition diary correctly and is willing and able to measure his/her vital signs at home at stipulated time points, using the device provided by the study personnel, and to adequately record the readings.;* Inclusion Criteria at Visit 3/Baseline
8. Subject continues to meet all inclusion criteria and none of the exclusion criteria for Visit 1;
9. Subject has experienced frequency of micturition on average * 8 times per 24-hour period during the 3-day micturition diary period (incontinence episode should not be counted as a micturition);
10. Subject must experience at least 1 episode of urgency (grade 3 or 4) per 24-hour period
(with or without urgency incontinence) during the 3-day micturition diary period.
Exclusion criteria
* Exclusion Criteria at Visit 1/Screening
1. Subject is breastfeeding, pregnant or intends to become pregnant during the study. The pregnancy test (*-HCG in serum) at Screening must be negative in women of childbearing potential;
2. Female subjects of childbearing potential and not using a highly effective method of birth control during the study and for 30 days after final study drug administration.Male subjects (unless surgically sterile) with female spouses/partners who are of childbearing potential, and not using a barrier method of contraception during the study and for 30 days after final study drug administration. In addition, female spouses/partners of male subjects and who are of childbearing potential should also use a highly effective method of birth control during the study and for 30 days after final study drug administration. Highly effective methods of birth control are defined as those, alone or in combination, that result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly.
3. In the opinion of the Investigator, the subject has clinically significant bladder outflow
obstruction at risk of urinary retention;
4. Subject has significant PVR volume (> 150 mL);
5. Subject has significant stress incontinence or mixed stress/urgency incontinence where
stress is the predominant factor as determined by the Investigator (for female subjects
confirmed by the cough provocation test [Appendix 4]);
6. Subject has a neurological cause for detrusor overactivity;
7. Subject has an indwelling catheter or practices intermittent self-catheterization;
8. Subject has diabetic neuropathy;
9. Subject has chronic inflammation such as interstitial cystitis, bladder stones, previous
pelvic radiation therapy or previous or current malignant disease of the pelvic organs;
10. Subject has had previous lower urinary tract or pelvic floor surgery (except cystoscopy);
11. Subject has had intravesical treatment in the past 12 months with e.g., botulinum toxin,
resiniferatoxin, capsaicin;
12. Subject has uncontrolled narrow angle glaucoma, urinary or gastric retention, severe ulcerative colitis or Crohn*s Disease, toxic megacolon, myasthenia gravis or any other
condition which makes the use of anticholinergics contraindicated;
13. Subject has clinically significant cardiovascular or cerebrovascular diseases within
6 months prior to Screening, such as myocardial infarction, uncontrolled angina, significant ventricular arrhythmias, heart failure and stroke;
14. Subject is receiving current non-drug treatment including electro-stimulation therapy (with the exception of a bladder training program or pelvic floor exercises which started more than 30 days prior to Screening);
15. Subject is using medications intended to treat OAB or prohibited medications. Subject is
excluded if using restricted medications under conditions different to those specified in the 'Concomitant Medication' section;
16. Subject has known or suspected hypersensitivity to solifenacin succinate, mirabegron or
any of their excipients;
17. Subject has any significant neurological disease or defect affecting bladder function
(e.g., neurogenic bladder, systemic or central neurological disease such as MS and
Parkinson*s disease);
18. Subject has severe hypertension which is defined as a sitting average systolic blood
pressure * 180 mmHg and/or an average diastolic blood pressure * 110 mmHg;
19. Subject has any clinically significant condition which in the opinion of the Investigator
makes the subject unsuitable for the study;
20. Subject who participated in any clinical study or who has been treated with any
investigational drug or device within 30 days (90 days in the UK) or the period stipulated
by local regulations, whichever is longer, prior to Screening;
21. Subject works a night shift and is not able to avoid night shift work during the duration
of the study.
22. Subject is an employee of the Astellas Group, third parties associated with the study or
the clinical study site team;;* Exclusion Criteria at Visit 2/Placebo Run-In
23. Subject has evidence of a UTI (urine culture containing > 100,000 cfu/mL). The subject
can be enrolled into the study after successful treatment of the UTI (confirmed by a
laboratory result of negative urine culture). However, the subject must be re-screened if
the initial screening visit (Visit 1b) was > 28 days;
24. Subject has a QT interval > 450 ms or is at risk of QT prolongation (e.g., family history
of long QT syndrome, hypokalaemia) or is on drug treatment known to be associated
with QT prolongation;
25. Subject has clinically significant abnormalities on the 12-lead ECG;
26. Subject has serum creatinine > 150 *mol/L, AST and/or ALT > 2x upper limit of normal
(ULN), *-GT > 3x ULN, or total bilirubin > 2x ULN, as assessed in Screening samples;;* Exclusion Criteria at Visit 3/Baseline
27. Subject had an average total daily urine volume > 3000 mL as recorded in the
micturition diary period;
28. Subject has severe hypertension which is defined as a sitting average systolic blood
pressure * 180 mmHg and/or an average diastolic blood pressure * 110 mmHg.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-020601-32-NL |
| CCMO | NL36487.018.11 |