Validation of the Bowel Function Index to detect clinically meaningful changes in opioid-induced constipation

Figures & data

Figure 1. Overview of study design. (a) Study OXN2401: six study visits (V1–V6) were undertaken over the course of up to 10 weeks. (b) Study OXN3401. (c) Study OXN3001 (R = Randomization).

Figure 2. The Bowel Function Index (BFI) tool. The BFI is a 3-item questionnaire to measure constipation from the patient's perspective. It is intended to be used by healthcare professionals to question patients and should not be used for patient self-administration.

Table 1a. Overview of patient visits and questionnaire completion by participants in study OXN2401.

Study phase	Pre-randomization		Double-blind phase			Follow-up*
Study period	Screening	Run-in
Visit	V1	V2	V3	V4	V5	V6
Duration	≤14 days	≤21 days
Study day			1	8	28	42
BFI		x	x	x	x	x
BFM^†		x	x	x	x	x

*With oxycodone only; ^†Bowel function measures including stool frequency (bowel evacuations per day), stool consistency and laxative intake (number of days with laxative use).

Table 1b. Overview of patient visits and questionnaire completion by participants in study OXN3401.

Study phase	Pre-randomization		Double-blind
Study period	Screening opioid taper	Run-in
Visit	V1–V3	V3–V4	V5	V6	V7	V8
Duration	14 days	14 days
Study day			14	28	56	84
BFI		x	x	x	x	x
BFM*		x	x	x	x	x

*Bowel function measures including stool frequency (bowel evacuations per day), stool consistency, laxative intake (number of days of laxative intake prior to each bowel movement), stool completion and evaluation of the completeness of the bowel movement).

Table 1c. Overview of patient visits and questionnaire completion by participants in study OXN3001.

Study phase	Pre-randomization			Double-blind phase
Study period	Screening	Run-in*
Visit	V1	V2 – V3		V4	V5	V6	V7	V8
Duration	≤14 days	≤14 days
Study day			1	8	15	29	57	85
BFI	x	x	x	x	x	x	x	x
PAC-SYM	x	x	x	x	x	x	x	x
BFM^†			x	x	x	x

*Run-in phase with immediate release oxycodone (7–28 days); ^†Bowel function measures including stool frequency (number of complete spontaneous bowel movements, stool consistency, laxative intake (number of days of laxative intake prior to each bowel movement), stool completion and evaluation of the completeness of the bowel movement for the first 4 weeks.

Table 2. Demographic information / clinical parameters of patients included in the study.

Characteristic	Mean parameter
	Study OXN2401 n=202	Study OXN3401 n=460	Study OXN3001 n=323
Age years*	56.3 (13.1)	56.4 (11.0)	58.7 (12.0)
Gender
Female	127 (62.9%)	284 (61.7%)	195 (60.4%)
Male	75 (37.1%)	176 (38.3%)	128 (39.6%)
Stool consistency (Likert scale 1–4)**	2.5	3.0	2.0^§
Stool consistency^‡
Hard	NE	55 (10.2%)	25 (7.7%)
Solid	NE	153 (28.3%)	182 (56.3%)
Semi-solid	NE	299 (55.4%)	88 (27.2%)
Watery	NE	33 (6.1%)	17 (5.3%)
Laxative intake^†	6.0 (1.9)	13.5 (33.7)	NE

NE, not evaluated; ^‡(n[%]); ^†(mean no. of days [SD]); *mean [SD]; **Likert scale (median values according to patients’ diaries) with hard = 1, solid = 2, semi-solid = 3 and watery =4; ^§Stool consistency was originally measured by the Bristol Stool Form Scale. To match the stool consistency data collected in OXN2401 and OXN3401, the respective 7-point response scale was recoded to a 4-point scale. If the median value was located between two values, the worst case was selected for use in the analysis.

Table 3. Correlations between each BFI item and internal consistency across studies OXN2401 (n=202), OXN3401 (n=460) and OXN3001 (n=323).

BFI item	Ease of defecation	Feeling of incomplete bowel evacuation	Judgment regarding constipation	Total score	Cronbach's alpha
Ease of defecation
OXN2401	1.00	0.59*	0.86*	0.91*
OXN3401	1.00	0.75†	0.82†	0.96†
OXN3001	1.00	0.64*	0.79*	0.89*
Feeling of incomplete bowel evacuation
OXN2401		1.00	0.60*	0.84*
OXN3401		1.00	0.7†	0.87†
OXN3001		1.00	0.70*	0.87*
Judgment regarding constipation
OXN2401			1.00	0.91*
OXN3401			1.00	0.89^†
OXN3001			1.00	0.91*
Total score
OXN2401				1.00	0.87
OXN3401				1.00	0.91
OXN3001				1.00	0.88

*p < 0.001; ^†p < 0.0001.

Table 4a. Reproducibility of BFI items visit 5 to visit 6 for patients randomized to (a) placebo.

(a) Patients randomized to placebo.
	Mean BFI visit 5 (SD)	Mean BFI visit 6 (SD)	Difference	ICC	Pearson's correlation (r)
Ease of defecation
OXN2401 (n=43)	49.5 (24.2)	52.7 (27.5)	3.1	0.53	0.53*
OXN3401 (n=135)	19.4 (23.0)	20.9 (22.5)	1.48	0.80	0.80*
Feeling of incomplete bowel evacuation
OXN2401 (n=43)	37.0 (19.3)	41.7 (27.5)	4.8	0.72	0.72*
OXN3401 (n=135)	20.4 (22.9)	19.1 (22.6)	–1.26	0.77	0.77*
Judgment regarding constipation
OXN2401 (n=43)	49.9 (26.2)	53.5 (26.4)	3.6	0.63	0.63*
OXN3401 (n=135)	14.4 (22.7)	15.0 (24.4)	0.59	0.79	0.79*
Total score
OXN2401 (n=43)	45.6 (22.5)	50.0 (24.4)	4.4	0.64	0.65*
OXN3401 (n=135)	18.0 (21.2)	18.3 (21.3)	0.27	0.85	0.85*

*p<0.001.

Table 4b. Reproducibility of BFI items visit 5 to visit 6 for patients randomized to (b) those subjects who had no change in stool frequency between visit 5 and visit 6 in study OXN2401.

(b) Data for stable patients – study OXN2401 (n=12).
	Mean BFI visit 5 (SD)	Mean BFI visit 6 (SD)	Difference	ICC	Pearson's correlation (r)
Ease of defecation	48.3 (18.0)	50.8 (23.5)	2.5	0.29	0.28
Feeling of incomplete bowel evacuation	31.7 (22.1)	40.4 (21.6)	8.8*	0.82	0.88*
Judgment regarding constipation	49.2 (17.3)	50.4 (24.7)	1.3	0.14	0.14
Total score	43.1 (15.0)	47.2 (21.5)	4.2	0.49	0.51

*p<0.001.

Table 4c. Reproducibility of BFI items visit 5 to visit 6 for patients randomized to (c) those subjects who had no change in stool frequency between visit 5 and visit 6 in study OXN3401.

(c) Data for stable patients – study OXN3401 (n=120)
	Mean BFI visit 5 (SD)	Mean BFI visit 6 (SD)	Difference	ICC	Pearson's correlation (r)
Ease of defecation	20.7 (22.0)	20.0 (20.7)	–0.67	0.71	0.71*
Feeling of incomplete bowel evacuation	19.7 (22.6)	16.5 (19.2)	–3.17	0.65	0.66*
Judgment regarding constipation	15.1 (21.3)	13.8 (20.5)	–1.25	0.63	0.63*
Total score	18.5 (20.5)	16.8 (18.6)	–1.69	0.7	0.70*

*p=0.001.

Table 4d. Reproducibility of BFI items visit 5 to visit 6 for patients randomized to (d) entire subject group in study OXN3001 between visit 1 and visit 2.

(d) Data for patients in study OXN3001
	Mean BFI visit 1 (SD)	Mean BFI visit 2 (SD)	Difference	ICC	Pearson's correlation (r)
Ease of defecation	60.1 (24.3)	60.4 (22.7)	0.34	0.64	0.64*
Feeling of incomplete bowel evacuation	54.1 (27.4)	55.9 (27.0)	1.77	0.62	0.62*
Judgment regarding constipation	59.2 (25.5)	58.6 (24.9)	–0.55	0.63	0.62*
Total score	57.8 (22.5)	58.6 (24.9)	0.51	0.63	0.62*

*p=0.001.

Table 5. Determining known-groups validity of the BFI tool, constipation severity based on stool consistency (ANCOVA analysis).

	Mild	Moderate	Severe	Overall F-value
Ease of defecation
OXN2401	36.6 (28.1)	36.0 (22.3)	58.5 (24.6)	5.88*
OXN3401	21.1 (1.3)	28.1 (1.9)	38.6 (5.3)	50.5^†
OXN3001	33.7 (2.0)	48.3 (2.5)	62.3 (6.9)	15.6^†
Feeling of incomplete bowel evacuation
OXN2401	27.2 (26.9)	24.9 (22.0)	53.8 (26.3)	7.00*
OXN3401	20.1 (1.3)	23.5 (1.8)	34.1 (5.2)	39.5^†
OXN3001	34.7 (2.1)	45.6 (2.7)	62.7 (7.5)	20.0^†
Judgment regarding constipation
OXN2401	35.3 (30.1)	34.0 (22.4)	57.9 (27.1)	5.02*
OXN3401	15.3 (1.3)	22.8 (1.9)	28.5 (5.4)	49.9^†
OXN3001	30.8 (2.0)	44.5 (2.6)	61.4 (7.1)	22.1^†
Total score
OXN2401	33.0 (25.3)	31.6 (19.5)	56.8 (24.9)	7.40*
OXN3401	18.8 (1.2)	24.7 (1.7)	33.6 (4.8)	55.9^†
OXN3001	33.1 (1.9)	46.1 (2.4)	61.9 (6.5)	22.0^†

*p<0.01; ^†p<0.001.

Table 6. Spearman's rank order correlations of BFI items and clinical data of stool consistency, frequency and number of days the patients received laxatives in studies OXN2401, OXN3401 and OXN3001*.

	Stool frequency	Stool consistency	No. of days laxatives received	Patient rated assessment of global tolerability
Ease of defecation
OXN2401	–0.28	–0.23	0.42	0.23
OXN3401	–0.40	–0.18	0.43	NE
OXN3001	–0.27	–0.18	0.19	NE
Feeling of incomplete bowel evacuation
OXN2401	–0.23	–0.26	0.33	0.34
OXN3401	–0.26	–0.08	0.39	NE
OXN3001	–0.45	–0.07	0.16	NE
Judgment regarding constipation
OXN2401	–0.28	–0.20	0.44	0.29
OXN3401	–0.39	–0.17	0.44	NE
OXN3001	–0.28	–0.17	0.28	NE
Total score
OXN2401	–0.29	–0.24	0.45	0.31
OXN3401	–0.37	–0.15	0.43	NE
OXN3001	–0.36	–0.15	0.22	NE

NE, not evaluated; *Stool frequency for OXN3001 was calculated from complete spontaneous bowel movement (CSBM).

Figure 3a. Responsiveness of BFI in study OXN2401 (n =169). Responsiveness of individual BFI items and total BFI score by treatment group.

Figure 3b. Responsiveness of BFI in studies OXN3401 and OXN3001. Responsiveness of individual BFI items and total BFI score.