Tegaserod for the treatment of irritable bowel syndrome and chronic constipation

Beti W Evans; Wendy K Clark; David J Moore; Peter J Whorwell

doi:10.1002/14651858.CD003960.pub3

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Analysis 1.1

Comparison 1 Tegaserod 12mg vs placebo, Outcome 1 SGA of Relief at endpoint.

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Analysis 1.2

Comparison 1 Tegaserod 12mg vs placebo, Outcome 2 Abdominal pain and discomfort at endpoint.

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Analysis 1.3

Comparison 1 Tegaserod 12mg vs placebo, Outcome 3 SGA of relief at endpoint (fully published studies only).

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Analysis 1.4

Comparison 1 Tegaserod 12mg vs placebo, Outcome 4 Bowel habit.

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Analysis 1.5

Comparison 1 Tegaserod 12mg vs placebo, Outcome 5 Diarrhoea.

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Analysis 1.6

Comparison 1 Tegaserod 12mg vs placebo, Outcome 6 Headache.

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Analysis 1.7

Comparison 1 Tegaserod 12mg vs placebo, Outcome 7 Abdominal pain.

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Analysis 1.8

Comparison 1 Tegaserod 12mg vs placebo, Outcome 8 Nausea.

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Analysis 1.9

Comparison 1 Tegaserod 12mg vs placebo, Outcome 9 Complete spontaneous bowel movement responders at week 12.

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Analysis 1.10

Comparison 1 Tegaserod 12mg vs placebo, Outcome 10 Weekly frequency of bowel movements.

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Analysis 1.11

Comparison 1 Tegaserod 12mg vs placebo, Outcome 11 SGA of relief weeks 1‐4 of DB treatment.

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Analysis 2.1

Comparison 2 Tegaserod 4mg vs placebo, Outcome 1 SGA of Relief at endpoint.

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Analysis 2.2

Comparison 2 Tegaserod 4mg vs placebo, Outcome 2 Abdominal pain and discomfort at endpoint.

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Analysis 2.3

Comparison 2 Tegaserod 4mg vs placebo, Outcome 3 Bowel habit.

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Analysis 2.4

Comparison 2 Tegaserod 4mg vs placebo, Outcome 4 Weekly frequency of bowel movements.

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Analysis 2.5

Comparison 2 Tegaserod 4mg vs placebo, Outcome 5 Diarrhoea.

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Analysis 3.1

Comparison 3 Tegaserod 12mg vs 4mg, Outcome 1 SGA of Relief at endpoint.

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Analysis 3.2

Comparison 3 Tegaserod 12mg vs 4mg, Outcome 2 Abdominal pain and discomfort at endpoint.

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Analysis 3.3

Comparison 3 Tegaserod 12mg vs 4mg, Outcome 3 Bowel habit.

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Analysis 3.4

Comparison 3 Tegaserod 12mg vs 4mg, Outcome 4 Weekly frequency of bowel movements.

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Analysis 4.1

Comparison 4 Tegaserod 4mg & 12mg vs placebo, Outcome 1 SGA of Relief at endpoint.

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Analysis 4.2

Comparison 4 Tegaserod 4mg & 12mg vs placebo, Outcome 2 Abdominal pain and discomfort at endpoint.

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Analysis 4.3

Comparison 4 Tegaserod 4mg & 12mg vs placebo, Outcome 3 Bowel habit.

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Table 1. SGA of Relief responder rates

Study	Tegaserod 12 mg	Tegaserod 4 mg	Placebo	Comments
B307	42.2%	38.3%	37.0%	Applies to last 4 weeks of DB treatment. In the 12 mg group, patients started on 4 mg for one month, which could be increased to 12 mg according to response (65% of patients took 12 mg after the first month). The responder rate is adjusted for missing SGAs, laxative use, and duration of treatment. P = 0.142 for 12 mg vs placebo, P = 0.837 for 4 mg vs placebo
Kellow 2003	46.8%	No 4 mg group	28.3%	Applies to weeks 1 to 4 of DB treatment. P < 0.0001 for 12 mg vs placebo
Lefkowitz 1999b	45.7%	38.9%	33.3%	Applies to last 4 weeks of DB treatment. The responder rate is adjusted for missing SGAs, laxative use, and duration of treatment. P = 0.004 for 12 mg vs placebo, P = 0.157 for 4 mg vs placebo
Muller‐Lissner 2001	38.4%	38.8%	30.2%	Applies to last 4 weeks of DB treatment. The responder rate is adjusted for missing SGAs, laxative use, and duration of treatment. P = 0.033 for 12 mg vs placebo, P = 0.018 for 4 mg vs placebo
Novick 2002	43.5%	No 4 mg group	38.8%	Applies to last 4 weeks of DB treatment. The responder rate is adjusted for missing SGAs, laxative use, and duration of treatment. P < 0.033 for 12 mg vs placebo
Hamling 1998	No numerical data	No numerical data	No numerical data	Responder rates reported in abstract but not for ITT population, or for each tegaserod dosage group
Lefkowitz 1999a	No numerical data	No numerical data	No numerical data
Nyhlin 2004	30.5%	No 4 mg group	20.8%	Applies to weeks 1 to 4 of DB treatment. P = 0.006 for 12 mg vs placebo
Nyhlin 2004	31%	No 4 mg group	20.4%	Applies to weeks 1 to 12 of DB treatment. P = 0.0027 for 12 mg vs placebo
Tack 2005	33.7%	No 4 mg group	24.2%	Applies to weeks 1 to 4 of DB treatment. Difference in response rate 9.3%, 95% CI 5.3 to 13.3), P < 0.0001

Table 1. SGA of Relief responder rates

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Table 2. Abdominal pain and discomfort responder rates

Study	Tegaserod 12 mg	Tegaserod 4 mg	Placebo	Comments
B307	27.6%	25.5%	30.6%	In the 12 mg group, patients started on 4 mg for one month, which could be increased to 12 mg according to response (65% of patients took 12 mg after the first month). P = 0.411 for 12 mg vs placebo, P = 0.141 for 4 mg vs placebo
Hamling 1998	No numerical data	No numerical data	No numerical data	Responder rates reported in abstract but not for ITT population, or for each tegaserod dosage group
Lefkowitz 1999a	No numerical data	No numerical data	No numerical data
Lefkowitz 1999b	25.1%	23.4%	18.7%	P = 0.075 for 12 mg vs placebo, P = 0.185 for 4 mg vs placebo
Muller‐Lissner 2001	29.9%	29.8%	22.6%	P = 0.044 for 12 mg vs placebo, P = 0.055 for 4 mg vs placebo
Novick 2002	No responder rate	No 4mg group	No responder rate	Mean score differences reported on 7‐point scale (endpoint minus baseline); ‐1.01 for 12 mg, ‐0.80 for placebo, P < 0.003

Table 2. Abdominal pain and discomfort responder rates

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Table 3. Abdominal pain

Study	Outcome	Teg 12 mg + laxative	Laxative	Comments
Khoshoo 2006	Mean pain score at 4 weeks	4.29 (SD 2.31)	6.15 (SD 2.38)	Scored on a scale of 0 to 10. P < 0.05 between groups
Khosoo 2006	% with good pain reduction (3 or more points on scale)	66.7%	18.5%	P < 0.05 between groups
Khosoo 2006	% with no pain reduction (2 points or less on pain scale)	23.8%	59.3%	P < 0.05 between groups
Khosoo 2006	% with increased pain (not defined)	9.5%	22.2%	P < 0.05 between groups

Table 3. Abdominal pain

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Table 4. Bowel habit responder rates

Study	Tegaserod 12 mg	Tegaserod 4 mg	Placebo	Comments
B307	24.0%	27.0%	25.0%	In the 12 mg group, patients started on 4 mg for one month, which could be increased to 12 mg according to response (65% took 12mg after the first month). P = 0.847 for 12 mg vs placebo, P = 0.661 for 4 mg vs placebo
Lefkowitz 1999b	24.7%	26.4%	20.2%	P = 0.218 for 12 mg vs placebo, P = 0.082 for 4 mg vs placebo
Muller‐Lissner 2001	26.2%	28.8%	22.6%	P = 0.337 for 12 mg vs placebo, P = 0.096 for 4 mg vs placebo
Novick 2002	No responder rate	No 4 mg group	No responder rate	Mean score difference (endpoint minus baseline) reported, on a 7‐point ordinal scale; ‐1.30 for 12 mg, ‐0.95 for placebo, P < 0.001

Table 4. Bowel habit responder rates

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Table 5. Satisfaction with bowel habit response rates

Novick 2002	Month 1	Month 2	Month 3
Tegaserod 12 mg	56.0%	58.7%	60.4%
Placebo	41.1%	50.1%	52.7%
P for tegaserod vs placebo	P < 0.001	P = 0.002	P = 0.007

Table 5. Satisfaction with bowel habit response rates

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Table 6. Outcomes of repeated tegaserod treatment (Tack 2005)

Outcome	Tegaserod 12mg	Placebo	Comments
Satisfactory relief of overall IBS symptoms (75% of the time)	44.9%	28.7%	(difference in response rate 16.6%, 95% CI 10.5 to 22.2), P < 0.0001
Satisfactory relief of abdominal pain and discomfort (75% of the time)	42.4%	27.1%	(difference in response rate 15.9%, 95% CI 10.3 to 21.5), P < 0.0001
Satisfactory relief of constipation (75% of the time)	45.1%	27.5%	P < 0.0001
Improvement in abdominal pain and discomfort	54.2%	41.8%	P < 0.0001 (1‐point or greater improvement on 7‐point scale)

Table 6. Outcomes of repeated tegaserod treatment (Tack 2005)

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Table 7. Responder rate for complete spontaneous bowel movements

Study	Week assessed	Tegaserod 4 mg	Tegaserod 12 mg	Placebo	Comments
Kamm 2005	4	35.6%	40.2%	26.7%	P < 0.0001 for 12 mg vs placebo, P = 0.059 for 4 mg vs placebo
Kamm 2005	12	no numerical data	43.2%	30.6%	P < 0.0001 for 12 mg vs placebo, P = 0.14 for 4 mg vs placebo
Johanson 2004	4	41.4%	43.2%	25.1%	P < 0.0001 for 12 mg vs placebo, P < 0.0001 for 4 mg vs placebo
Johanson 2004	12	40.3%	44.8%	26.9%	P < 0.0001 for 12 mg vs placebo, P < 0.0001 for 4 mg vs placebo

Table 7. Responder rate for complete spontaneous bowel movements

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Table 8. Time to first bowel movement (median)

Study	Tegaserod 4 mg	Tegaserod 12 mg	Placebo	Comments
Kamm 2005	174.3	98	286.3	Hours to CSBM. P < 0.007 for 4 mg and 12 mg vs placebo
Johanson 2004	117	73	229	Hours to CSBM. P < 0.01 for 4 mg and P < 0.001 for 12 mg vs placebo
Kamm 2005	21.3	18.4	37.2	Hours to SBM. P < 0.001 for 4 mg and 12 mg vs placebo
Johanson 2004	data shown in graph only	data shown in graph only	data shown in graph only

Table 8. Time to first bowel movement (median)

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Table 9. Diarrhoea (adverse effect)

Study	Tegaserod 12 mg	Tegaserod 4 mg	Placebo	Comments
Fidelholtz 2002	17.6%	48.6%	35.3%	Study included D‐IBS patients. P = NS between groups
Kellow 2003	10.0%	No 4 mg group	3.1%	Study included C‐IBS patients. P value not reported
Muller‐Lissner 2001	9.6%	7.1%	2.5%	Study included C‐IBS patients. P value not reported
Novick 2002	6.4%	No 4 mg group	2.9%	Study included C‐IBS patients. P value not reported
Nyhlin 2004	9.2%	No 4 mg group	1.3%	Study included C‐IBS patients. P value not reported
Kamm 2005	5.8%	3.9%	2.2%	Study included patients with chronic constipation. P = 0.1516 for 4 mg vs placebo, P = 0.0072 for 12 mg vs placebo
Johanson 2004	7.3%	4.5%	3.8%	Study included C‐IBS patients. P value not reported

Table 9. Diarrhoea (adverse effect)

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Table 10. Headache (adverse effect)

Study	Tegaserod 12 mg	Tegaserod 4 mg	Placebo	Comments
Fidelholtz 2002	20.6%	28.6%	23.5%	P = NS
Kellow 2003	12.0%	No 4 mg group	11.1%	P value not reported
Muller‐Lissner 2001	27.3%	30.6%	27.3%	P value not reported
Novick 2002	9.0%	No 4 mg group	5.7%	P value not reported
Nyhlin 2004	8.0%	No 4 mg group	4.7%	P value not reported
Kamm 2005	12.3%	11.1%	13.7%	P value not reported
Johanson 2004	9.8%	9.2%	12.8%	P value not reported

Table 10. Headache (adverse effect)

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Table 11. Abdominal pain (adverse effect)

Study	Tegaserod 12 mg	Tegaserod 4 mg	Placebo	Comments
Fidelholtz 2002	20.6%	31.4%	23.5%	P = NS
Kellow 2003	5.8%	No 4 mg group	3.1%	P value not reported
Muller‐Lissner 2001	16.7%	16.5%	17.1%	P value not reported
Novick 2002	6.4%	No 4 mg group	5.7%	P value not reported
Nyhlin 2004	4.9%	No 4 mg group	3.8%	P value not reported

Table 11. Abdominal pain (adverse effect)

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Table 12. Nausea (adverse effect)

Study	Tegaserod 12 mg	Tegaserod 4 mg	Placebo	Comments
Kellow 2003	4.2%	No 4 mg group	3.4%	P value not reported
Muller‐Lissner 2001	7.2%	7.4%	8.7%	P value not reported
Novick 2002	6.8%	No 4 mg group	4.7%	P value not reported
Nyhlin 2004	5.5%	No 4 mg group	5.1%	P value not reported

Table 12. Nausea (adverse effect)

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Comparison 1. Tegaserod 12mg vs placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SGA of Relief at endpoint Show forest plot	4	3194	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [1.09, 1.29]

2 Abdominal pain and discomfort at endpoint Show forest plot	3	1675	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.89, 1.51]

3 SGA of relief at endpoint (fully published studies only) Show forest plot	2	2101	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [1.04, 1.29]

4 Bowel habit Show forest plot	3	1675	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.93, 1.31]

5 Diarrhoea Show forest plot	6	5010	Risk Ratio (M‐H, Fixed, 95% CI)	2.80 [2.13, 3.68]

6 Headache Show forest plot	6	5010	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.92, 1.24]

7 Abdominal pain Show forest plot	5	4112	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.83, 1.28]

8 Nausea Show forest plot	5	4112	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.93, 1.57]

9 Complete spontaneous bowel movement responders at week 12 Show forest plot	2	1745	Risk Ratio (M‐H, Fixed, 95% CI)	1.54 [1.35, 1.75]

10 Weekly frequency of bowel movements Show forest plot	2	5154	Mean Difference (IV, Fixed, 95% CI)	0.69 [0.55, 0.83]

10.1 Complete spontaneous bowel movements (CSBM)	2	1718	Mean Difference (IV, Fixed, 95% CI)	0.60 [0.42, 0.78]
10.2 Spontaneous bowel movements (SBM)	2	1718	Mean Difference (IV, Fixed, 95% CI)	0.91 [0.59, 1.23]
10.3 Bowel movements	2	1718	Mean Difference (IV, Fixed, 95% CI)	0.75 [0.46, 1.05]
11 SGA of relief weeks 1‐4 of DB treatment Show forest plot	2	3180	Risk Ratio (M‐H, Fixed, 95% CI)	1.46 [1.28, 1.66]

Comparison 1. Tegaserod 12mg vs placebo

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Comparison 2. Tegaserod 4mg vs placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SGA of Relief at endpoint Show forest plot	3	1685	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [1.02, 1.31]

2 Abdominal pain and discomfort at endpoint Show forest plot	3	1685	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.82, 1.49]

3 Bowel habit Show forest plot	3	1685	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [1.02, 1.43]

4 Weekly frequency of bowel movements Show forest plot	2	5103	Mean Difference (IV, Fixed, 95% CI)	0.52 [0.38, 0.66]

4.1 Complete spontaneous bowel movements (CSBM)	2	1701	Mean Difference (IV, Fixed, 95% CI)	0.44 [0.26, 0.62]
4.2 Spontaneous bowel movements (SBM)	2	1701	Mean Difference (IV, Fixed, 95% CI)	0.73 [0.41, 1.05]
4.3 Bowel movements	2	1701	Mean Difference (IV, Fixed, 95% CI)	0.58 [0.28, 0.88]
5 Diarrhoea Show forest plot	3	2317	Risk Ratio (M‐H, Fixed, 95% CI)	1.70 [1.12, 2.59]

Comparison 2. Tegaserod 4mg vs placebo

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Comparison 3. Tegaserod 12mg vs 4mg

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SGA of Relief at endpoint Show forest plot	3	1682	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.97, 1.22]

2 Abdominal pain and discomfort at endpoint Show forest plot	3	1682	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.90, 1.23]

3 Bowel habit Show forest plot	3	1682	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.78, 1.07]

4 Weekly frequency of bowel movements Show forest plot	2	5175	Mean Difference (IV, Fixed, 95% CI)	0.17 [0.02, 0.32]

4.1 CSBM	2	1725	Mean Difference (IV, Fixed, 95% CI)	0.16 [‐0.04, 0.36]
4.2 SBM	2	1725	Mean Difference (IV, Fixed, 95% CI)	0.19 [‐0.14, 0.53]
4.3 Bowel movements	2	1725	Mean Difference (IV, Fixed, 95% CI)	0.19 [‐0.12, 0.50]

Comparison 3. Tegaserod 12mg vs 4mg

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Comparison 4. Tegaserod 4mg & 12mg vs placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SGA of Relief at endpoint Show forest plot	4	4040	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [1.08, 1.27]

2 Abdominal pain and discomfort at endpoint Show forest plot	3	2521	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.85, 1.51]

3 Bowel habit Show forest plot	3	2521	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [1.00, 1.34]

Comparison 4. Tegaserod 4mg & 12mg vs placebo

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