Ondansetron for the Treatment of IBS With Diarrhea
Ondansetron for the Treatment of IBS With Diarrhea
This was a two-centre, randomised, double-blind, placebo-controlled crossover study of ondansetron 4 mg/tablet versus placebo. Patients were given one to two tablets three times a day with dose titration for the first 3 weeks of each period and a 2–3-week washout period (figure 1). The trial was registered on clinicaltrials.gov (identifier NCT00745004), approved by Nottingham Research Ethics Committee 2 (REC reference number 08/H0408/134) and by the Medicines and Healthcare Regulatory authority (MHRA, London, UK), and conducted according to Good Clinical Practice guidelines. Funding was provided by the National Institute for Health Research through a Research for Patient Benefit grant and salary support for Dr Garsed from the Nottingham Digestive Diseases Biomedical Research Unit. There were no changes to protocol from that initially registered with clinicaltrials.gov.
(Enlarge Image)
Figure 1.
Study design. This shows the two 5-week treatment periods during which subjects were randomised to either ondansetron or placebo. Week 1 was for baseline assessment, Each 5-week treatment period allowed dose adjustment until weeks 4 and 5 when no further dose adjustment or rescue medication was allowed. Symptoms on weeks 4 and 5 provided the clinical endpoints. Symptoms were assessed throughout the study and during the washout period to ensure symptoms had returned to baseline before starting the next treatment. Frequent visits and telephone contact ensured protocol compliance.
Sequence allocation randomisation was carried out by Nottingham Clinical Trials Support Unit (CTSU) with random permuted blocks of randomly varying size and stratified by centre. The supervising staff obtained a randomisation reference number by a remote, internet-based randomisation system. All participants stayed blinded until the study, data collection and assessments were complete. CTSU Data Manager and the Queen Medical Centre (QMC) Trials pharmacy had access to the treatment allocations. The code was never broken.
From previous studies the estimated mean (SD) stool consistency in healthy controls was 3.6 (1.1) and recent unpublished data suggest a within-person correlation of 0.5. To detect a difference of 0.4 which was considered clinically signficant with 90% power and 1% type I error we needed 113 subjects. To acount for dropouts we randomised 120.
Patients with IBS-D were recruited from IBS clinics at the Queen's Medical Centre Nottingham and Wythenshawe Hospital, Manchester and via the Trent Primary Care Research Network from 1 January 2009 to May 2011 using the Rome III diagnostic criteria. To exclude other causes of diarrhoea we required a normal colonoscopy and colonic biopsies, normal full blood count, serum calcium and albumen, C-reactive protein and negative serological tests for celiac disease. All patients consuming more than the equivalent of 240 ml of milk/day were tested for lactose intolerance. Most had either a therapeutic trial of colestyramine or a test of bile salt absorption using the 7-day retention of selenium-labelled homocholic acid taurine to exclude bile salt malabsorption. Patients gave written informed consent. Inclusion criteria were age 18–75 years; meeting Rome III criteria; no evidence of inflammatory bowel disease/microscopic colitis and able to give informed consent. Women of child-bearing potential tested negatively on pregnancy test and had to agree to adequate contraception during the study. Patients on selective serotonin reuptake inhibitors or tricyclic antidepressants were included, provided they had been on medication for at least 3 months and the dose remained unaltered throughout the study. Exclusion criteria were pregnancy or breast feeding, unwilling to stop anti-diarrhoeal medication (loperamide or codeine phosphate), prior abdominal surgery other than appendectomy and cholecystectomy, being in another trial or being in the opinion of the investigator unsuitable.
We also studied 21 healthy controls to provide normal values for the transit studies. They completed the same questionnaires and underwent the same transit measurement protocol. None met Rome III IBS criteria. They comprised 16 women and 5 men, with median age (IQR) of 45 (23–56) years. Bowel frequency was median (IQR) of 1.0 (1.0–1.4) bowel movements per day.
Each participant received 5 weeks of oral placebo treatment and 5 weeks of ondansetron 4 mg tablets using dose titration for the first 3 weeks of each period with a 2–3-week washout period in between each treatment period (figure 1). The hospital pharmacy provided the 5-week drug supply at the beginning of each period. The investigational medicinal product was either a 4 mg ondansetron tablet (Pliva, Zagreb, Croatia) or placebo, both identically over-encapsulated in a gelatine capsule by Bilcare (Crickhowell, Powys, UK). The placebo formulation matched that of the ondansetron in appearance and composition, except for the active drug.
The patients were instructed to start with one capsule once a day, increasing daily to a maximum of two capsules three times a day, depending on the response. If stool consistency increased to stool form 1 or 2, or if bowel frequency dropped below one per day the dose was reduced to a minimum of one capsule taken every 2 days. Patients were required to stay on a stable dose for the last 2 weeks of each period. Loperamide, 2 mg twice daily, was allowed as rescue medication in the event of uncontrolled diarrhoea, but needed to be discontinued for the final 2 weeks of each period. Patients attended for a total of seven visits as follows (figure 1): screening visit 1 was followed by a 1-week period when stool and symptom diaries were completed (week 1). At visit 2, after checking patients met Rome III criteria and had completed the stool diaries, they were enrolled and instructed to start treatment at one capsule daily increasing or decreasing the dose by one capsule per day every 2 days to a maximum of two capsules three times daily. They were told to increase the dose if the stool form was 6 or 7 and decrease if it was 2 or 1. After 1 week patients were telephoned to confirm the dose was optimum. They were also called a few days before visit 3 to confirm the appointment and before visit 4 to remind them to take the transit markers for 3 days before the visit. Visit 3 was after 3 weeks of treatment and visit 4 was the final visit of the first treatment period when stool diaries were collected and colonic transit assessed by a plain X-ray. There was then a 2-week washout which was extended if necessary to ensure bowel habit had returned to baseline. Return to baseline was confirmed by asking patients whether their bowel dysfunction was back to pre-study levels and this was objectively corroborated by examination of the visit 5 diaries. In those participants in whom pre-study levels had not been reached by 2 weeks, initiation of the second treatment phase was delayed until pre-study levels were confirmed.
The second treatment period was identical to the first. Compliance was monitored by asking the patient at each study visit and by a final pill count of all returned medicines.
Personal baseline data were collected at visit 1: age, gender, depression and anxiety scores from the Hospital and Depression Scale, score from the Patient Health Questionnaire 15, perceived stress score from the Perceived Stress Scale Questionnaire. IBS-related quality of life from the IBS Quality of Life Questionnaire and IBS severity score from the IBSS Severity Score Questionnaire were collected at visit 1 and at the end of each treatment period (visits 4 and 7). We used our previously described daily stool diary throughout the study to provide information on stool form (Bristol Stool Form score, from 1 (very hard) to 7 (water)) and pain perception, urgency of defecation and bloating, the last three scored as none, mild, moderate or severe (0–3). Frequency of defaecation and number of days when pain, urgency or bloating was present were recorded.
The baseline values are averages from the screening week.
The primary endpoint (stool form) and secondary endpoints (pain perception, urgency of defaecation, bloating, frequency of defaecation per day, number of days per week with pain, urgency or bloating, and IBS SS) are averages over the last 2 weeks of each treatment period. Information provided for less than 10 days (out of 14) was recorded as missing.
At the end of each period patients were asked: 'over the last 2 weeks did you obtain adequate relief of your IBS symptoms?', and at the end of the study: 'which treatment if any did you prefer?', and 'which treatment, if any would you prefer to continue with now the trial has finished?' Percentage reporting adequate relief of IBS symtpoms (yes/no), proportion of patients preferring particular treatment (yes/no) and proportion wanting to continue with particular treatment (yes/no) were recorded as secondary endpoints.
Bloods were collected for genetic analysis for the serotonin transporter promoter polymorphism (see online supplementary appendix).
We used the US Food and Drug Administration (FDA) definition of 'a Stool Consistency Responder' as a 'patient who experiences a 50 percent or greater reduction in the number of days per week with at least one stool that has a consistency of Type 6 or 7 compared with baseline' and a 'pain responder' as a patient who experienced a fall of 30% in pain compared to baseline.
The FDA recommends that for IBS a dual endpoint should be used to define a 'responder' who should be both a Stool Consistency responder and a 'pain responder'.
We used the Metcalf's radio-opaque marker technique. Subjects took 20 silicon markers impregnated with 13.5% barium (Altimex, Nottingham, UK) at 09:00 each morning for three consecutive days. The number identified on plain abdominal X-ray taken on the morning of day 4 was multiplied by 1.2 to give whole gut transit time (WGTT) in hours. Regional transit was assessed from the number of pellets assigned to the ascending colon, transverse, descending and rectosigmoid as described by Metcalf and colleagues.
Methods
Trial Design
This was a two-centre, randomised, double-blind, placebo-controlled crossover study of ondansetron 4 mg/tablet versus placebo. Patients were given one to two tablets three times a day with dose titration for the first 3 weeks of each period and a 2–3-week washout period (figure 1). The trial was registered on clinicaltrials.gov (identifier NCT00745004), approved by Nottingham Research Ethics Committee 2 (REC reference number 08/H0408/134) and by the Medicines and Healthcare Regulatory authority (MHRA, London, UK), and conducted according to Good Clinical Practice guidelines. Funding was provided by the National Institute for Health Research through a Research for Patient Benefit grant and salary support for Dr Garsed from the Nottingham Digestive Diseases Biomedical Research Unit. There were no changes to protocol from that initially registered with clinicaltrials.gov.
(Enlarge Image)
Figure 1.
Study design. This shows the two 5-week treatment periods during which subjects were randomised to either ondansetron or placebo. Week 1 was for baseline assessment, Each 5-week treatment period allowed dose adjustment until weeks 4 and 5 when no further dose adjustment or rescue medication was allowed. Symptoms on weeks 4 and 5 provided the clinical endpoints. Symptoms were assessed throughout the study and during the washout period to ensure symptoms had returned to baseline before starting the next treatment. Frequent visits and telephone contact ensured protocol compliance.
Randomisation
Sequence allocation randomisation was carried out by Nottingham Clinical Trials Support Unit (CTSU) with random permuted blocks of randomly varying size and stratified by centre. The supervising staff obtained a randomisation reference number by a remote, internet-based randomisation system. All participants stayed blinded until the study, data collection and assessments were complete. CTSU Data Manager and the Queen Medical Centre (QMC) Trials pharmacy had access to the treatment allocations. The code was never broken.
Sample Size Calculation
From previous studies the estimated mean (SD) stool consistency in healthy controls was 3.6 (1.1) and recent unpublished data suggest a within-person correlation of 0.5. To detect a difference of 0.4 which was considered clinically signficant with 90% power and 1% type I error we needed 113 subjects. To acount for dropouts we randomised 120.
Participants
Patients with IBS-D were recruited from IBS clinics at the Queen's Medical Centre Nottingham and Wythenshawe Hospital, Manchester and via the Trent Primary Care Research Network from 1 January 2009 to May 2011 using the Rome III diagnostic criteria. To exclude other causes of diarrhoea we required a normal colonoscopy and colonic biopsies, normal full blood count, serum calcium and albumen, C-reactive protein and negative serological tests for celiac disease. All patients consuming more than the equivalent of 240 ml of milk/day were tested for lactose intolerance. Most had either a therapeutic trial of colestyramine or a test of bile salt absorption using the 7-day retention of selenium-labelled homocholic acid taurine to exclude bile salt malabsorption. Patients gave written informed consent. Inclusion criteria were age 18–75 years; meeting Rome III criteria; no evidence of inflammatory bowel disease/microscopic colitis and able to give informed consent. Women of child-bearing potential tested negatively on pregnancy test and had to agree to adequate contraception during the study. Patients on selective serotonin reuptake inhibitors or tricyclic antidepressants were included, provided they had been on medication for at least 3 months and the dose remained unaltered throughout the study. Exclusion criteria were pregnancy or breast feeding, unwilling to stop anti-diarrhoeal medication (loperamide or codeine phosphate), prior abdominal surgery other than appendectomy and cholecystectomy, being in another trial or being in the opinion of the investigator unsuitable.
Healthy Controls for Transit Studies
We also studied 21 healthy controls to provide normal values for the transit studies. They completed the same questionnaires and underwent the same transit measurement protocol. None met Rome III IBS criteria. They comprised 16 women and 5 men, with median age (IQR) of 45 (23–56) years. Bowel frequency was median (IQR) of 1.0 (1.0–1.4) bowel movements per day.
Intervention
Each participant received 5 weeks of oral placebo treatment and 5 weeks of ondansetron 4 mg tablets using dose titration for the first 3 weeks of each period with a 2–3-week washout period in between each treatment period (figure 1). The hospital pharmacy provided the 5-week drug supply at the beginning of each period. The investigational medicinal product was either a 4 mg ondansetron tablet (Pliva, Zagreb, Croatia) or placebo, both identically over-encapsulated in a gelatine capsule by Bilcare (Crickhowell, Powys, UK). The placebo formulation matched that of the ondansetron in appearance and composition, except for the active drug.
The patients were instructed to start with one capsule once a day, increasing daily to a maximum of two capsules three times a day, depending on the response. If stool consistency increased to stool form 1 or 2, or if bowel frequency dropped below one per day the dose was reduced to a minimum of one capsule taken every 2 days. Patients were required to stay on a stable dose for the last 2 weeks of each period. Loperamide, 2 mg twice daily, was allowed as rescue medication in the event of uncontrolled diarrhoea, but needed to be discontinued for the final 2 weeks of each period. Patients attended for a total of seven visits as follows (figure 1): screening visit 1 was followed by a 1-week period when stool and symptom diaries were completed (week 1). At visit 2, after checking patients met Rome III criteria and had completed the stool diaries, they were enrolled and instructed to start treatment at one capsule daily increasing or decreasing the dose by one capsule per day every 2 days to a maximum of two capsules three times daily. They were told to increase the dose if the stool form was 6 or 7 and decrease if it was 2 or 1. After 1 week patients were telephoned to confirm the dose was optimum. They were also called a few days before visit 3 to confirm the appointment and before visit 4 to remind them to take the transit markers for 3 days before the visit. Visit 3 was after 3 weeks of treatment and visit 4 was the final visit of the first treatment period when stool diaries were collected and colonic transit assessed by a plain X-ray. There was then a 2-week washout which was extended if necessary to ensure bowel habit had returned to baseline. Return to baseline was confirmed by asking patients whether their bowel dysfunction was back to pre-study levels and this was objectively corroborated by examination of the visit 5 diaries. In those participants in whom pre-study levels had not been reached by 2 weeks, initiation of the second treatment phase was delayed until pre-study levels were confirmed.
The second treatment period was identical to the first. Compliance was monitored by asking the patient at each study visit and by a final pill count of all returned medicines.
Data Collection
Personal baseline data were collected at visit 1: age, gender, depression and anxiety scores from the Hospital and Depression Scale, score from the Patient Health Questionnaire 15, perceived stress score from the Perceived Stress Scale Questionnaire. IBS-related quality of life from the IBS Quality of Life Questionnaire and IBS severity score from the IBSS Severity Score Questionnaire were collected at visit 1 and at the end of each treatment period (visits 4 and 7). We used our previously described daily stool diary throughout the study to provide information on stool form (Bristol Stool Form score, from 1 (very hard) to 7 (water)) and pain perception, urgency of defecation and bloating, the last three scored as none, mild, moderate or severe (0–3). Frequency of defaecation and number of days when pain, urgency or bloating was present were recorded.
The baseline values are averages from the screening week.
Endpoints
The primary endpoint (stool form) and secondary endpoints (pain perception, urgency of defaecation, bloating, frequency of defaecation per day, number of days per week with pain, urgency or bloating, and IBS SS) are averages over the last 2 weeks of each treatment period. Information provided for less than 10 days (out of 14) was recorded as missing.
At the end of each period patients were asked: 'over the last 2 weeks did you obtain adequate relief of your IBS symptoms?', and at the end of the study: 'which treatment if any did you prefer?', and 'which treatment, if any would you prefer to continue with now the trial has finished?' Percentage reporting adequate relief of IBS symtpoms (yes/no), proportion of patients preferring particular treatment (yes/no) and proportion wanting to continue with particular treatment (yes/no) were recorded as secondary endpoints.
Bloods were collected for genetic analysis for the serotonin transporter promoter polymorphism (see online supplementary appendix).
Responder Definition
We used the US Food and Drug Administration (FDA) definition of 'a Stool Consistency Responder' as a 'patient who experiences a 50 percent or greater reduction in the number of days per week with at least one stool that has a consistency of Type 6 or 7 compared with baseline' and a 'pain responder' as a patient who experienced a fall of 30% in pain compared to baseline.
The FDA recommends that for IBS a dual endpoint should be used to define a 'responder' who should be both a Stool Consistency responder and a 'pain responder'.
Whole Gut Transit Measurement
We used the Metcalf's radio-opaque marker technique. Subjects took 20 silicon markers impregnated with 13.5% barium (Altimex, Nottingham, UK) at 09:00 each morning for three consecutive days. The number identified on plain abdominal X-ray taken on the morning of day 4 was multiplied by 1.2 to give whole gut transit time (WGTT) in hours. Regional transit was assessed from the number of pellets assigned to the ascending colon, transverse, descending and rectosigmoid as described by Metcalf and colleagues.
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