A review and additional post-hoc analyses of the incidence and impact of constipation observed in darifenacin clinical trials

Figures & data

Table 1 Details of included studies

Reference and NCT numbera	Study design		Active treatments	Incidence of constipationb (%)					Discontinuations due to constipationb (%)
				DAR total	7.5 mg/day	15 mg/day	PBO	TOL 4 mg/day	DAR total	7.5 mg/day	15 mg/day	PBO	TOL 4 mg/day
Fixed-dose Phase III trials included in the pooled analysis
Foote and Elhilali^Citation39	12-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group in patients aged ≥18 years		DAR 15 mg/day or 30 mg/day, TOL 4 mg/day	n/a	n/a	28/112 (24.1%)	7/115 (6.1%)	28/223 (12.6%)		0	3/112 (2.7%)	0	4/232 (1.8%)
Hill et al^Citation40	12-week, multicenter, double-blind, randomized, placebo-controlled, dose-response in patients aged ≥18 years		DAR 7.5 mg/day, 15 mg/day, 30 mg/day	n/a	17/108 (15.7%)	27/107 (25.2%)	5/109 (4.6%)	n/a	1/324 (0.3%)	0	0	0	n/a
Haab et al^Citation41	12-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group study in patients aged ≥18 years		DAR 3.75 mg/day, 7.5 mg/day, 15 mg/day	n/a	33/229 (14.4%)	16/115 (13.9%)	12/164 (7.3%)	n/a	n/a	2/229 (0.9%)	1/115 (0.9%)	1/164 (0.6%)	n/a
Reference	Study no	Study design	Active treatments	Incidence of constipationb (%)					Discontinuations due to constipationb (%)
				DAR total	7.5 mg/d	15 mg/d	PBO	TOL 4 mg/d	DAR total	7.5 mg/d	15 mg/d	PBO	TOL 4 mg/d
Phase IIIb studies
Haab et al^Citation42 170755	1	2-year, open-label, multicenter, extension study to the Phase II trials	DAR 7.5 mg/day or 15 mg/day	150/716 (20.9%)	n/a	n/a	n/a	n/a	17/716 (2.4%)	n/a	n/a	n/a	n/a
Steers et al^Citation14	2	12-week, Phase IIb flexible-dosing, multicenter, double-blind, randomized, placebo-controlled parallel-group study in patients aged ≥18 years	DAR 7.5 mg/day with optional uptitration to 15 mg/day	56/268 (20.9%)	n/a	n/a	10/127 (7.9%)	n/a	6/268 (2.2%)	n/a	n/a	1/127 (0.8%)	n/a
Zinner et al^Citation45 171145	3	12-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study to assess effects on warning time	DAR 15 mg/day	n/a	n/a	38/214 (17.8%)	11/225 (4.9%)	n/a	n/a	n/a	5/214 (2.3%)	0/225 (0.0%)	n/a
Phase IV studies
Zinner et al^Citation43 366002	4	12-week, open-label, single-arm, multicenter switch study in patients with OAB dissatisfied with previous treatment with oxybutynin or TOL	DAR 7.5 mg/day with optional uptitration to 15 mg/day	70/497 (14.1%)	n/a	n/a	n/a	n/a	4/497 (0.8%)	n/a	n/a	n/a	n/a
Chancellor et al^Citation44 127270	5	12-week, randomized, open-label, parallel-group, multicenter study in OAB patients	DAR 7.5 mg/day with optional uptitration to 15 mg/day, alone or in combination with a behavioral modification plan	73/395 (18.5%)	n/a	n/a	n/a	n/a	8/395 (2.0%)	n/a	n/a	n/a	n/a
Chapple et al^Citation46 171184	6	12-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study in patients ≥65 years of age with OAB	DAR 7.5 mg/day with optional uptitration to 15 mg/day	43/266 (16.2%)	n/a	n/a	11/133 (8.3%)	n/a	2/266 (0.8%)	n/a	n/a	1/133 (0.8%)c	n/a

Notes:

a NCT numbers provided where applicable (studies without a number were completed prior to the registration mandate), all numbers are prefixed 00;

b these data reflect the two licensed darifenacin doses (7.5 mg/day and 15 mg/day);

c safety population.

Abbreviations: DAR, darifenacin; OAB, overactive bladder; n/a, not applicable; PBO, placebo; TOL, tolterodine.

Figure 1 Incidences of constipation (all-causality), new-onset use of constipation remedies and discontinuations resulting from constipation during 12 weeks’ treatment with darifenacin 7.5 mg/day or 15 mg/day, tolterodine 4 mg/day or placebo in patients with overactive bladder.

Note: ^†Laxatives, stool softeners or fiber supplements.

Table 2 Incidence of all-causality constipation in fixed-dose Phase III studies in OAB patients

Constipation severity	Darifenacin 7.5 mg/day N = 337	Darifenacin 15 mg/d N = 334	Tolterodine 4 mg/d N = 223	Placebo N = 388
Mild, N (%)	29 (8.6)	39 (11.7)	15 (6.7)	15 (3.9)
Moderate, N (%)	19 (5.6)	23 (6.9)	9 (4.0)	7 (1.8)
Severe, N (%)	2 (0.6)	9 (2.7)	4 (1.8)	2 (0.5)
Total	50 (14.8)	71 (21.3)	28 (12.6)	24 (6.2)

Abbreviation: OAB, overactive bladder.

Figure 2 Proportion of new cases of all-causality constipation reported at different time points during treatment with darifenacin 7.5 mg/day or 15 mg/day, tolterodine 4 mg/day or placebo.

Table 3 Concomitant laxative use in fixed-dose Phase III studies in OAB patients

	Darifenacin 7.5 mg/day	Darifenacin 15 mg/day	Tolterodine 4 mg/day	Placebo
All patients
N	337	334	223	388
Using laxatives at baseline (%)	9 (2.7)	13 (3.9)	8 (3.6)	15 (3.9)
Using laxatives during trial (%)	20 (5.9)	32 (9.6)	23 (10.3)	24 (6.2)
Patients with constipation
N (%)	50 (14.8)	71 (21.3)	28 (12.6)	24 (6.2)
Using laxatives at baseline (%)	2 (4.0)	4 (5.6)	1 (3.6)	0 (0)
Using laxatives during trial (%)	11 (22.0)	22 (31.0)	16 (57.1)	6 (25.0)
Patients with no constipation
N (%)	287 (85.2)	263 (78.7)	195 (87.4)	364 (93.8)
Using laxatives at baseline (%)	7 (2.4)	9 (3.4)	7 (3.6)	15 (4.1)
Using laxatives during trial (%)	9 (3.1)	10 (3.8)	7 (3.6)	18 (4.9)

Abbreviation: OAB, overactive bladder.

Figure 3 Patient perception of quality of treatment in fixed-dose Phase III studies in overactive bladder patients. (A) Patient satisfaction with drug; (B) Patient preference for study drug over previous therapy; (C) patient willingness to re-use study drug.

Table 4 Bowel habit questionnaires

(A) Used in the long-term extension study (all questions refer to the 2 weeks preceding the visit)

On how many days did you open your bowels?

On days you opened your bowels how many times did you go to the toilet?

How many days were your bowel movements hard and/or lumpy?

How many days did you have to strain to open bowels?

How many days did you feel your bowels were not fully emptied after a visit to the lavatory?

How many days did you feel your bowel habits affected your life?

If your bowel habits affected your life, overall how much was this effect?

(B) Phase IV study in patients ≥65 years of age

Q1: Did you have to strain to move your bowels?

No

Yes

Q2: If yes, how much straining did you have to do? (if no, skip question)

Acceptable straining

Too much straining

Q3: What was the usual consistency of your bowel movements? (choose one)

Separate hard lumps, like nuts (hard to pass)

Sausage shaped but lumpy

Like a sausage but with cracks on its surface

Like a sausage or snake, smooth and soft

Soft blobs with clear cut edges (passed easily)

Fluffy pieces with ragged edge, a mushy stool

Watery, no solid pieces

Q4: How often do you have bowel movements?

Less often

Unchanged

More often

Q5: Do you still: (check one)

Move your bowels every day

Move your bowels every other day

Move your bowels 2 or less times per week

Other

Q6: Have you had to strain to move your bowels?

No

Yes

Q7: If yes, how much straining have you had to do? (if no, skip question)

Acceptable straining

Too much straining

Q8: What has been the usual consistency of your bowel movements? (choose one)

Separate hard lumps, like nuts (hard to pass)

Sausage shaped but lumpy

Like a sausage but with cracks on its surface

Like a sausage or snake, smooth and soft

Soft blobs with clear cut edges (passed easily)

Fluffy pieces with ragged edge, a mushy stool

Watery, no solid pieces

Q9: Has the change in your bowel habits affected or interfered with your life in general? (check one)

Yes, in a bad way

Not at all

Yes, in a good way

Q10: How much has the change in your bowel habits affected or interfered with your life in general? (check one)

Very little

Moderately

Quite a lot

Very much

Figure 4 (A) Summary of bowel habit questionnaire responses in patients in a long-term 2-year study; (B) Summary of bowel habit questionnaire responses in patients aged ≥65 years; results relate to the last 2 weeks of treatment.

Note: “Feeder study” refers to last visit or last observation carried forward from the feeder study.
Abbreviations: BL, baseline; BM, bowel movements; EOS, end of study.

FooteJElhilaliMDarifenacin Study GroupBritish Geriatrics SocietyA multicenter, randomized, double-blind study of darifenacin versus tolterodine in the treatment of overactive bladder (OAB)Communications to the Autumn Meeting of the British Geriatrics Society: Programme of AbstractsPoster presented at the British Geriatrics Society Annual MeetingHarrogate, UKOctober 6–8, 2004 Poster 56. Available from: http://www.bgs.org.uk/PDF%20Downloads/Abstracts%20Autumn2004.pdfAccessed January 20, 2012.

 Google Scholar

HillSKhullarVWyndaeleJJLheritierKDarifenacin Study GroupDose response with darifenacin, a novel once-daily M3 selective receptor antagonist for the treatment of overactive bladder: results of a fixed dose studyInt Urogynecol J Pelvic Floor Dysfunct200617323924715999217

 PubMed Web of Science ®Google Scholar

HaabFStewartLDwyerPDarifenacin, an M3 selective receptor antagonist, is an effective and well-tolerated once-daily treatment for overactive bladderEur Urol200445442042915041104

 PubMed Web of Science ®Google Scholar

HaabFCorcosJSiamiPLong-term treatment with darifenacin for overactive bladder: results of a 2-year, open-label extension studyBJU Int20069851025103216879437

 PubMed Web of Science ®Google Scholar

SteersWCorcosJFooteJKralidisGAn investigation of dose titration with darifenacin, an M3-selective receptor antagonistBJU Int200595458058615705084

 PubMed Web of Science ®Google Scholar

ZinnerNSussetJGittelmanMArguinzonizMRekedaLHaabFEfficacy, tolerability and safety of darifenacin, an M3 selective receptor antagonist: an investigation of warning time in patients with OABInt J Clin Pract200660111912616409440

 PubMed Web of Science ®Google Scholar

ZinnerNKobashiKCEbingerUDarifenacin treatment for overactive bladder in patients who expressed dissatisfaction with prior extended-release antimuscarinic therapyInt J Clin Pract200862111664167418811599

 PubMed Web of Science ®Google Scholar

ChancellorMBKianifardFBeamerEA comparison of the efficacy of darifenacin alone vs darifenacin plus a Behavioural Modification Programme upon the symptoms of overactive bladderInt J Clin Pract200862460661318324952

 PubMed Web of Science ®Google Scholar

ChappleCDuBeauCEbingerURekedaLViegasADarifenacin treatment of patients ≥65 years with overactive bladder: results of a randomized, controlled, 12-week trialCurr Med Res Opin200723102347235817706004

 PubMed Web of Science ®Google Scholar