CAPABLe: Controlling Anal Incontinence by Performing Anal Exercises with Biofeedback or Loperamide
CAPABLe was a multicenter, placebo-controlled 2×2 factorial randomized trial in 300 women with bothersome fecal incontinence and normal stool consistency that compared loperamide with oral placebo and anorectal manometry-assisted biofeedback with an education pamphlet, with change in St Mark's (Vaizey) score at 24 weeks as the primary endpoint. Neither loperamide nor biofeedback differed significantly from its control, the combination did not differ significantly from either component, and constipation was more frequent in the loperamide groups.[1]
- Design and population
- Multicenter, placebo-controlled 2×2 factorial randomized superiority trial. 300 women at eight US centers with at least monthly bothersome fecal incontinence, normal stool consistency (Bristol types 1 and 7 excluded) and negative colon cancer screening.
- Arms
- Oral placebo plus education pamphlet versus placebo plus anorectal manometry-assisted biofeedback versus loperamide plus education pamphlet versus loperamide plus anorectal manometry-assisted biofeedback
- Report and follow-up
- 2019 · 24 weeks; PAC-SYM data at 12 or 24 weeks for 247/296 women (analyzed update)
| Endpoint | Results | Effect | Finding |
|---|---|---|---|
| Change in Patient Assessment of Constipation Symptoms global score from baseline to 24 weeks (0 to 4; negative is improvement) | −0.3 (−0.5 to −0.1) vs −0.3 (−0.4 to −0.2) vs −0.1 (−0.3 to 0.0) vs −0.3 (−0.4 to −0.2) | — | Not met |
Design
Eight academic centers in the Pelvic Floor Disorders Network enrolled women with uncontrolled loss of liquid or solid stool at least monthly over the preceding three months, bothersome enough that they wanted treatment, and a negative colon cancer screen. Women whose usual stool was Bristol type 1 (hard) or type 7 (watery) and women with prior abdominal or pelvic radiation were excluded. Of 377 women enrolled, 300 were randomized 0.5:1:1:1 (stratified by site) to oral placebo plus education (42), placebo plus biofeedback (84), loperamide plus education (88) or loperamide plus biofeedback (86); fewer women were assigned to the minimal-intervention group to limit its burden. Four women found ineligible after randomization were dropped from the efficacy analyses, leaving 296.[1]
Loperamide and placebo were over-encapsulated to match, so participants and study staff other than the research pharmacist were masked to medication. Investigators, interviewers and outcome evaluators were masked to biofeedback assignment. Every woman received the National Institute of Diabetes and Digestive and Kidney Diseases bowel-control pamphlet, edited to delete a reference to loperamide.[1]
The primary endpoint was the change in St Mark's (Vaizey) score from baseline to 24 weeks. Four comparisons were prespecified: loperamide versus placebo and biofeedback versus education (each at a two-sided alpha of 0.025), and the combination versus each single treatment (alpha 0.05). A sample of 245 gave 90% power to detect a 5-point marginal difference, the minimally important difference, assuming a standard deviation of 8.5; allowing for 85% follow-up, the target was 294. Secondary outcomes were exploratory and were not adjusted for multiple comparisons.[1]
Results
Mean age was 63.7 years and women reported a mean 1.6 leaks per day. Baseline St Mark's score averaged 14.1 to 14.2 across the marginal groups. At 24 weeks, 266 of 296 eligible women (90%) had outcome data, and every group improved.[1]
| Comparison | 24-week change in St Mark's score (95% CI) | Model-estimated difference (95% CI) | P |
|---|---|---|---|
| Loperamide (n=155) versus placebo (n=111) | −6.2 (−7.4 to −5.0) versus −4.7 (−6.2 to −3.1) | −1.5 (−3.4 to 0.4) | 0.12 |
| Biofeedback (n=149) versus education only (n=117) | −5.8 (−7.0 to −4.6) versus −5.1 (−6.6 to −3.6) | −0.7 (−2.6 to 1.2) | 0.47 |
| Loperamide plus biofeedback versus placebo plus biofeedback | Not reported in text | −1.9 (−4.1 to 0.3) | 0.09 |
| Loperamide plus biofeedback versus loperamide plus education | Not reported in text | −1.1 (−3.4 to 1.1) | 0.33 |
The lower confidence limits for loperamide (−3.4) and biofeedback (−2.6) are smaller in magnitude than the 5-point difference used for sample-size planning. Multiple imputation for missing outcomes gave consistent results.[1]
Among secondary outcomes, daily leaks fell by 1.2 with loperamide and 1.0 with placebo (difference −0.1, 95% CI −0.7 to 0.4; P = 0.61), and by 1.0 with biofeedback and 1.2 with education only (difference 0.2, 95% CI −0.4 to 0.8; P = 0.50). Exploratory proportions reporting improvement on the Patient Global Impression of Improvement were 127/146 (87.0%) with loperamide versus 84/105 (80.0%) with placebo (P = 0.10) and 126/142 (88.7%) with biofeedback versus 85/109 (78.0%) with education only (P = 0.046). A post hoc analysis found a 50% or greater reduction in daily leaks in 113/135 (83.7%) with biofeedback versus 61/106 (57.5%) with education only (P = 0.0009), and in 101/139 (72.7%) with loperamide versus 73/102 (71.6%) with placebo (P = 0.83).[1]
In per-protocol analyses, loperamide plus biofeedback improved the St Mark's score by 3.8 points more than placebo plus biofeedback (95% CI −6.9 to −0.7; P = 0.017) and by 3.5 points more than loperamide plus education (95% CI −6.4 to −0.6; P = 0.018); the report states that both differences were smaller than the minimally important difference.[1]
A planned secondary analysis measured constipation with the Patient Assessment of Constipation Symptoms (PAC-SYM) questionnaire in 247 women with data at 12 or 24 weeks. The global score (0 to 4) changed by −0.3 with placebo plus education, −0.3 with placebo plus biofeedback, −0.1 with loperamide plus education and −0.3 with loperamide plus biofeedback, without significant differences between groups, and all changes were below the proposed minimal important difference of 0.6. Women who responded on the St Mark's score improved more on PAC-SYM than non-responders (−0.39 versus −0.15).[2]
A second planned secondary analysis defined response three ways. At least a 5-point St Mark's improvement occurred in 137/266 women (52%), a 50% or greater reduction in diary episodes in 174/256 (68%), and both in 108/262 (41%). Higher baseline St Mark's score (adjusted odds ratio 1.20, 95% CI 1.11 to 1.28) and overweight versus normal or underweight BMI (adjusted odds ratio 2.15, 95% CI 1.07 to 4.34) were independently associated with a St Mark's response. Loperamide plus biofeedback was associated with a diary response compared with placebo plus education (adjusted odds ratio 4.04, 95% CI 1.36 to 11.98).[3]
Surgery and treatment delivery
Women assigned to biofeedback had a diagnostic anorectal manometry, strength training, and sensory or urge-resistance training with mcompass software (Medspira), followed by an individualized home exercise program based on their performance. They received six visits, and all interventionists completed standardized training. Study visits were at baseline, 2, 4, 6, 9, 12 and 24 weeks for the biofeedback groups.[1]
Loperamide or placebo began at 2 mg (one capsule) daily. Study coordinators raised the dose to at most four capsules daily, or lowered it to one capsule every other day, by balancing patient ratings of symptom control against ratings of bothersome side effects. Women with inadequate control and bothersome side effects were told to stop the drug and were followed if possible; those whose leakage worsened after stopping could restart. Adherence was limited at 24 weeks (33/85, 39%, in the loperamide plus biofeedback group).[1]
Adverse events
Any adverse event occurred in 26/42 (62%) with placebo plus education, 62/84 (74%) with placebo plus biofeedback, 62/88 (70%) with loperamide plus education and 72/86 (84%) with loperamide plus biofeedback (P = 0.04). Constipation was the most common event: 5/42 (12%), 19/84 (23%), 33/88 (38%) and 44/86 (51%) in those groups (P < 0.001). Grade 3 or higher events occurred in 4/42 (10%), 6/84 (7%), 13/88 (15%) and 8/86 (9%) (P = 0.43); constipation was the most common grade 3 or higher event, in 2/88 (2%) and 2/86 (2%) of the two loperamide groups.[1]
Serious adverse events occurred in 3/42 (7%), 5/84 (6%), 10/88 (11%) and 6/86 (7%) (P = 0.62). One serious event, a small bowel obstruction in the placebo plus biofeedback group, was considered possibly related to treatment; the adverse event table lists one fatal event, also in that group.[1]
Limitations
The placebo-plus-education group improved more than anticipated, and biofeedback was compared with an education pamphlet, not sham biofeedback. Outcome data were missing for some women (266/296 at 24 weeks), which precluded a strict intention-to-treat analysis, and adherence at 24 weeks was limited. Most of the significant findings arose from per-protocol or secondary analyses without multiplicity adjustment. The trial had limited power to detect differences between combination therapy and a single treatment. Interventionists who performed manometry were masked to medication but not to biofeedback assignment, so manometry findings are interpreted with caution. Only women were enrolled, and the loperamide dose-adjustment details were not reported.[1]
In conversation
Report history
| Published | Report | Cutoff | Headline results | Citation |
|---|---|---|---|---|
| 2019-07-15 | 24-week randomized report · primary | — | Model-estimated 24-week change in St Mark's (Vaizey) score, pooled loperamide groups (n=155) minus pooled placebo groups (n=111): Change −6.2 (95% CI −7.4 to −5.0) with loperamide versus −4.7 (−6.2 to −3.1) with placebo; a negative difference favors loperamide. Prespecified two-sided alpha 0.025.; difference -1.5; CI -3.4–0.4; P 0.12 Not met Model-estimated 24-week change in St Mark's (Vaizey) score, pooled biofeedback groups (n=149) minus pooled education-only groups (n=117): Change −5.8 (95% CI −7.0 to −4.6) with biofeedback versus −5.1 (−6.6 to −3.6) with education only; a negative difference favors biofeedback. Prespecified two-sided alpha 0.025.; difference -0.7; CI -2.6–1.2; P 0.47 Not met Model-estimated 24-week difference in St Mark's score change, loperamide plus biofeedback minus placebo plus biofeedback: Prespecified comparison of the combination with each component; alpha 0.05.; difference -1.9; CI -4.1–0.3; P 0.09 Not met Model-estimated 24-week difference in St Mark's score change, loperamide plus biofeedback minus loperamide plus education: Prespecified comparison of the combination with each component; alpha 0.05.; difference -1.1; CI -3.4–1.1; P 0.33 Not met Model-estimated 24-week change in total leaks per day, pooled loperamide (n=149) minus pooled placebo (n=107): Change −1.2 (95% CI −1.5 to −0.8) with loperamide versus −1.0 (−1.5 to −0.5) with placebo. Secondary outcomes were exploratory and unadjusted for multiple comparisons.; difference -0.1; CI -0.7–0.4; P 0.61 Model-estimated 24-week change in total leaks per day, pooled biofeedback (n=143) minus pooled education only (n=113): Change −1.0 (95% CI −1.3 to −0.6) with biofeedback versus −1.2 (−1.7 to −0.7) with education only.; difference 0.2; CI -0.4–0.8; P 0.50 Patient Global Impression of Improvement 'a little better' or better at 24 weeks, pooled loperamide versus pooled placebo: 127/146 (87.0%) with loperamide versus 84/105 (80.0%) with placebo.; P 0.0991 Patient Global Impression of Improvement 'a little better' or better at 24 weeks, pooled biofeedback versus pooled education only: 126/142 (88.7%) with biofeedback versus 85/109 (78.0%) with education only.; P 0.0463 At least 50% reduction in leaks per day at 24 weeks, pooled loperamide versus pooled placebo (post hoc): 101/139 (72.7%) with loperamide versus 73/102 (71.6%) with placebo. Post hoc, not part of the preplanned analysis.; P 0.8282 At least 50% reduction in leaks per day at 24 weeks, pooled biofeedback versus pooled education only (post hoc): 113/135 (83.7%) with biofeedback versus 61/106 (57.5%) with education only. Post hoc, not part of the preplanned analysis.; P 0.0009 Per-protocol 24-week difference in St Mark's score change, loperamide plus biofeedback minus placebo plus biofeedback: Per-protocol analysis; the report states the difference was smaller than the minimally important difference.; difference -3.8; CI -6.9–-0.7; P 0.017 Per-protocol 24-week difference in St Mark's score change, loperamide plus biofeedback minus loperamide plus education: Per-protocol analysis; the report states the difference was smaller than the minimally important difference.; difference -3.5; CI -6.4–-0.6; P 0.018 | Jelovsek JE, Markland AD, Whitehead WE, et al. Controlling faecal incontinence in women by performing anal exercises with biofeedback or loperamide: a randomised clinical trial. *Lancet Gastroenterol Hepatol.* 2019;4(9):698-710. doi:10.1016/S2468-1253(19)30193-1 DOI |
| 2019-11-23 | Constipation-symptom analysis · secondary | — | Change in Patient Assessment of Constipation Symptoms global score from baseline to 24 weeks (0 to 4; negative is improvement): −0.3 (−0.5 to −0.1) vs −0.3 (−0.4 to −0.2) vs −0.1 (−0.3 to 0.0) vs −0.3 (−0.4 to −0.2); — Not met Change in PAC-SYM global score at 24 weeks, responders (at least 5-point St Mark's improvement; n=124) versus non-responders (n=119): Responders −0.39 (95% CI −0.50 to −0.28) versus non-responders −0.15 (−0.26 to −0.03); baseline scores were similar.; difference 0.2; CI 0.1–0.4; P <0.01 | Andy UU, Jelovsek JE, Carper B, et al. Impact of treatment for fecal incontinence on constipation symptoms. *Am J Obstet Gynecol.* 2020;222(6):590.e1-590.e8. doi:10.1016/j.ajog.2019.11.1256 DOI |
| 2020-01-03 | Treatment-response predictors · secondary | — | Responders (at least 5-point St Mark's improvement) at 24 weeks: 137/266 (52%) responders. Higher baseline St Mark's score (adjusted OR 1.20, 95% CI 1.11 to 1.28) and overweight versus normal or underweight BMI (adjusted OR 2.15, 95% CI 1.07 to 4.34) were independently associated with response.; — Descriptive Responders (at least 50% reduction in bowel-diary FI episodes) at 24 weeks: 174/256 (68%) responders. Loperamide plus biofeedback versus placebo plus education: adjusted OR 4.04 (95% CI 1.36 to 11.98).; — Descriptive Responders meeting both the St Mark's minimal important difference and a 50% reduction in FI episodes: 108/262 (41%) responders.; — Descriptive | Richter HE, Jelovsek JE, Iyer P, et al. Characteristics associated with clinically important treatment responses in women undergoing nonsurgical therapy for fecal incontinence. *Am J Gastroenterol.* 2020;115(1):115-127. doi:10.14309/ajg.0000000000000482 DOI |
References
1. Jelovsek JE, Markland AD, Whitehead WE, et al. "Controlling Faecal Incontinence in Women by Performing Anal Exercises with Biofeedback or Loperamide: A Randomised Clinical Trial." Lancet Gastroenterol Hepatol. 2019;4(9):698-710. doi:10.1016/S2468-1253(19)30193-1
2. Andy UU, Jelovsek JE, Carper B, et al. "Impact of Treatment for Fecal Incontinence on Constipation Symptoms." Am J Obstet Gynecol. 2020;222(6):590.e1-590.e8. doi:10.1016/j.ajog.2019.11.1256
3. Richter HE, Jelovsek JE, Iyer P, et al. "Characteristics Associated with Clinically Important Treatment Responses in Women Undergoing Nonsurgical Therapy for Fecal Incontinence." Am J Gastroenterol. 2020;115(1):115-127. doi:10.14309/ajg.0000000000000482