Table 2.

Effect of trial characteristics on magnitude of the placebo response

	No. of trials	No. of patients receiving placebo	Pooled placebo response rate (%)	95% C	${\mathit{I}}^2$ (%)	P value for ${\mathit{I}}^2$
All trialsa	46	5,992	28.75	23.83–33.67	93.6	<0 .001 ***
Year of publication
Before 2015	19	1,311	28.22	21.83–34.61	87.2	<0.001 ***
2015 or later	27	4,681	28.92	21.81–36.03	95.3	<0.001 ***
Trial location
Europe	11	1,050	34.56	23.90–45.22	93.1	<0.001 ***
Oceania	1	64	43.75	31.60–55.90	—	—
Asia	20	1842	29.55	22.51–36.58	90.3	<0.001 ***
South America	2	53	29.11	0.00–59.08	78.9	0.03 *
North America	11	2,561	21.11	11.10–31.12	92.6	<0.001 ***
International	1	422	21.33	17.42–25.24	—	—
No. of centers
Single center	7	249	32.34	20.87–43.82	83.4	<0.001 ***
Multicenter	29	5,165	24.85	19.33–30.36	92.1	<0.001 ***
Not stated	10	578	38.27	25.51–51.04	92.8	<0.001 ***
Diagnosis of participants
IBS-C	9	1754	22.76	16.97–28.56	77.1	<0.01 **
FC	21	2,360	32.91	24.20–41.61	94.7	<0.001 ***
FC and IBS-C	3	217	36.17	10.19–62.16	94.6	<0.001 ***
CC	13	1,661	23.35	16.58–30.12	92.1	<0.001 ***
Duration of therapy
1–4 wk	25	1,671	34.21	27.03–41.38	92.0	<0.001 ***
5–8 wk	7	873	31.75	18.39–45.11	93.4	<0.001 ***
9–12 wk	14	3,448	17.43	13.32–21.53	90.1	<0.001 ***
Study design
RCT	45	5,980	28.70	23.71–33.69	93.8	<0.001 ***
Crossover	1	12	33.33	6.66–60.01	—	—
Proportion of trial patients assigned to placebo
Approximately 50%	29	2,940	29.20	23.99–34.41	88.9	<0.001 ***
Significantly less than 50%	17	3,052	27.81	17.77–37.85	95.8	<0.001 ***
Dosing schedule
q.d.	26	3,908	30.31	23.00–37.62	94.1	<0.001 ***
b.i.d.	14	810	30.19	23.54–36.84	81.5	<0.001 ***
t.i.d.	1	20	50.00	28.09–71.91	—	—
Less than 1 time per da	2	581	19.86	2.26–37.47	84.5	<0.001 ***
Not stated	3	673	8.81	3.16–14.46	78.8	<0.001 ***
Active treatmentb
Secretagogues	13	3,321	16.49	12.33–20.65	90.2	<0.001 ***
Serotonergic enterokinetic agents	3	298	23.42	1.44–45.40	86.2	<0.001 ***
Laxatives	5	429	34.48	13.71–55.24	94.2	<0.001 ***
Dietary supplement	9	410	46.48	34.42–58.54	88.4	<0.001 ***
Alternative treatment	9	958	29.18	18.64–39.72	91.7	<0.001 ***
Others	7	576	28.17	24.34–32.01	0.0	0.43
Endpoint assessment
Subjective improvement	16	1,246	41.40	31.65–51.15	94.4	<0.001 ***
Composite improvement	9	1,545	20.35	16.77–23.93	62.1	<0.01 **
CSBM/CBM	17	3,027	18.31	13.38–23.23	88.6	<0.001 ***
PAC−SYM scores	1	41	43.90	28.71–59.09	—	—
Improvement in stool consistency	3	133	35.12	27.04–43.20	0.0	0.61

CC, chronic constipation; CI, confidence interval; CSBM/CBM, complete (spontaneous) bowel movement; FC, functional constipation; IBS-C, irritable bowel syndrome with predominant constipation; PAC−SYM, Patients Assessment on Constipation Symptoms; PEG, polyethylene glycol; RCT, randomized controlled trial; SNS, sacral nerve stimulation; SPS, sodium picosulfate.

^aTwo studies using electroacupuncture assigned the treatment as “5 sessions in each of the first 2 weeks, and 3 sessions in each of the remaining 6 weeks”.

^bActive treatment: secretagogues: linaclotide, plecanatide, lubiprostone, etc. Serotonergic enterokinetic agents: prucalopride, renzapride, cisapride, tegaserod, velusetrag, etc. Laxatives: PEG, bisacodyl, SPS, PMF-100, etc. Dietary supplement: fiber, probiotics, symbiotic, etc. Alternative treatment: herbal medicine, electrical stimulation such as SNS, etc. Others: CO2-releasing suppository, neurotrophin-3, mineral water, and other treatment that cannot be classified using above categories.