- Email: [email protected]
929c A randomized, placebo controlled trial of fecal microbiota therapy in active ulcerative colitis.
929d Eluxadoline for the Treatment of Diarrhea-Predominant Irritable Bowel Syndrome: Results of 2 Randomized, Double-blind, Placebo-Controlled Phase 3 Clinical Trials of Efficacy and Safety Anthony Lembo, Scott Dove, David Andrae, J. Michael Davenport, Gail McIntyre, June Almenoff, Paul S. Covington
929b Larazotide Acetate, a First In-Class, Novel Tight Junction Regulator, Meets Primary Endpoint and Significantly Reduces Signs and Symptoms of Celiac Disease in Patients on a Gluten-Free Diet: Results of a Multicenter, Randomized, Placebo Controlled Trial Chao Wang, Henrik Rasmussen, Wendy Perrow, Ciaran P. Kelly, Daniel Le7ffler, Peter Green, Richard N. Fedorak, Anthony J. DiMarino, Premysl Bercik, Joseph A. Murray, Natalie M. Bachir
Background & Aims: Eluxadoline is a locally active, mixed mu opioid receptor (μOR) agonist and delta opioid receptor (δOR) antagonist being developed to treat the abdominal pain and diarrhea of diarrhea-predominant irritable bowel syndrome (IBS-d). We evaluated the efficacy and safety of eluxadoline in two Phase 3 clinical trials in patients with IBS-d. Methods: Two double-blind, placebo-controlled, Phase 3 clinical trials (IBS3001 and IBS3002) randomized patients meeting Rome III criteria for IBS-d to twice-daily treatment with eluxadoline (75 or 100 mg) or placebo (PBO). Both clinical trials evaluated efficacy through 26 weeks of double-blind treatment. Thereafter, IBS3001 included an additional 26 weeks of double-blind treatment for long-term safety evaluations while IBS3002 included a 4-week placebo withdrawal period. In both clinical trials, the primary endpoint was composite response (based on simultaneous daily improvement in abdominal pain and stool consistency) evaluated over Weeks 1-12 (FDA responder endpoint) and Weeks 1-26 (EMA responder endpoint). Additional efficacy measures included assessments of abdominal and bowel symptoms and global endpoints (e.g., adequate relief, IBS-d global symptoms, and quality of life). Results: A total of 2428 patients with IBS-d were enrolled across the two clinical trials (66% females; mean age of 45 years). In both clinical trials, significantly (P<0.005) more patients receiving 100 mg eluxadoline were FDA and EMA composite responders than patients receiving PBO (see Table below). Comparable results for both endpoints were seen for the 75 mg eluxadoline group though the difference over PBO was not significant for the EMA response in IBS3001. Patients receiving eluxadoline were also significantly more likely than PBO patients to have adequate relief of IBS symptoms. Responder rates for individual components of the FDA and EMA responder endpoints for both eluxadoline groups were significantly higher than PBO for the stool consistency component, and numerically higher for the pain component. Patients receiving eluxadoline at both doses also had greater improvements in numbers of daily bowel movements and urgent episodes, daily IBS-d global symptom scores, and IBS-Quality of Life scores (P<.05). The most commonly reported adverse events in the two clinical trials were constipation (7.4% and 8.3% for eluxadoline 75 mg and 100 mg; 2.4% for PBO) and nausea (7.8% and 7.3% for eluxadoline 75 mg and 100 mg; 4.8% for PBO). Conclusions: Results from two Phase 3 clinical trials demonstrated that eluxadoline was an effective treatment for IBS-d based on the FDA and EMA composite endpoints. Results were highly durable over the 26week treatment periods and were associated with improvements in other global symptom measures.
Background: Celiac disease (CeD) is a genetic autoimmune condition affecting 1% of the western population. Triggered by the ingestion of gluten, CeD is managed by a Gluten-Free diet (GFD), however recurrent symptoms due to inadvertent exposure and non-adherence to GFD are common and found in up to 71.8% of individuals with CeD. Symptoms can significantly impact quality of life and the disease is associated with an increased risk of gastrointestinal (GI) cancers and T-cell lymphoma. Tight junctions (TJ) control paracellular permeability, increased in CeD, caused in part, by an inflammatory immune response subsequent to paracellular transport of gluten peptides into the intestinal lamina propria through epithelial TJs. Larazotide acetate is a first-in-class oral peptide that prevents TJ opening and reduces gluten uptake, inhibiting gluten and cytokine-induced intestinal permeability and inflammation in vivo. The aim of the study was to investigate the efficacy of Larazotide acetate to improve signs and symptoms in individuals with CeD while on a GFD. Methods: In this outpatient, randomized, parallel, double-blind, placebo-controlled, multicenter study, conducted in 74 sites in North America, 342 CeD patients on a GFD for ≥12 months were randomized to receive placebo or Larazotide acetate 0.5, 1, or 2 mg three times daily (TID). The 20-week study had a 4-week placebo run-in, 12-week treatment phase, and 4-week placebo run-out. The primary outcome was the average on-treatment score in the Celiac Disease Gastrointestinal Symptom Rating Scale (CeD GSRS) domains of Diarrhea, Indigestion, and Abdominal pain. Results: The primary endpoint of symptom reduction was met at the 0.5 mg dose of Larazotide acetate compared with placebo in both Modified Intention To Treat (MITT) (ANCOVA p=0.022, MMRM p=0.005) and Per Protocol (PP) analysis (ANCOVA p=0.007, MMRM p=0.001) (Figure 1). The 0.5 mg dose showed favorable outcomes for CeD Patient Reported Outcome (CeD PRO) GI domain, decrease in CeD PRO Symptomatic days (MITT ANCOVA 0.017) (Figure 2), an increase in SymptomFree days (MITT ANCOVA p=0.034) and a decrease in Non-GI symptoms (MITT ANCOVA p=0.010). No increases in anti-tTG (IgA and IgG) titers were observed at any dose of Larazotide acetate. Safety of Larazotide acetate was comparable to placebo. Conclusion: Larazotide acetate 0.5 mg reduced GI and non-GI symptoms, while reducing the number of Symptomatic days. The safety and tolerability profile of Larazotide acetate was comparable to placebo. This study represents the first large therapeutic trial in CeD to meet its primary endpoint of reducing signs and symptoms and is the first successful trial of a novel class of agents targeting TJ regulation. Larazotide acetate 0.5 mg has the potential to be the first pharmacologic CeD treatment and warrants further investigation in Phase III clinical trials.
929e PEARL-II: Randomized Phase 3 Trial of Interferon-Free, 12-Week Regimen of ABT-450/r/ABT-267, ABT-333 With or Without Ribavirin in Hepatitis C Virus Genotype 1b-Infected, Treatment-Experienced Patients Pietro Andreone, Massimo Colombo, Jeffrey V. Enejosa, Iftihar Koksal, Peter Ferenci, Andreas Maieron, Beat Müllhaupt, Yves Horsmans, Ola Weiland, Henk W. Reesink, Lino Rodrigues Jr, Yiran B. Hu, Thomas Podsadecki
929c A randomized, placebo controlled trial of fecal microbiota therapy in active ulcerative colitis. Paul Moayyedi, Michael Surette, Melanie Wolfe, Rita Taraschi, Peter Kim, Josie Libertucci, David Armstrong, John K. Marshall, Walter Reinisch, Christine H. Lee
Background: Interferon (IFN)-free treatment regimens of direct-acting antivirals (DAA) are capable of achieving sustained virologic response (SVR) in HCV genotype (GT) 1b-infected patients, reducing interferon-related toxicities. Phase 2 studies suggest high SVR rates can still be attained without inclusion of ribavirin (RBV) in treatment regimens while further decreasing safety concerns. Whether RBV is required for high SVR rates in a 3 DAA IFNfree regimen was evaluated in non-cirrhotic HCV GT1b-infected patients who failed treatment with pegIFN/RBV. Methods: PEARL-II is a phase 3 open-label study in HCV GT1b-infected patients who were randomized 1:1 to receive ABT-450 (protease inhibitor identified by AbbVie and Enanta, 150 mg dosed with 100 mg ritonavir [r] QD), coformulated with ABT267 (NS5A inhibitor, 25 mg QD) (ABT-450/r/ABT-267), and ABT-333 (non-nucleoside polymerase inhibitor, 250 mg BID) (3D regimen) with RBV (Arm A) or without RBV (Arm B) for 12 weeks. Twelve weeks post-treatment, SVR rates for each treatment arm were compared to a historical telaprevir plus pegIFN/RBV threshold. Adverse events (AEs) were recorded for all patients receiving at least 1 dose of study drug. Results: Of 187 treatmentexperienced, randomized GT1b-infected patients, 186 were dosed with study drug and included in safety analyses; 179 patients received ABT-450/r/ABT-267 coformulated drug and were included in ITT efficacy analyses. In the ITT population, 35.2% were nullresponders, 28.5% partial responders, and 36.3% relapsers to previous pegIFN/RBV treatment. Mean age (54.2 vs. 54.2 years), sex (49.5% vs. 60.0% male), and IL28B genotype CC (11.0 % vs. 7.4%) were comparable between Arms A and B, respectively. After 12 weeks of treatment, intent-to-treat SVR12 rates were 96.6% for Arm A and 100% for Arm B (Table). Similarly high SVR12 rates were observed in null-responders, partial responders, and relapsers. No patients experienced virologic failure; 2 patients in Arm A discontinued drug due to AEs. Adverse events were generally mild and the most frequent AEs were fatigue (31.9% vs. 15.8%, P = .015), headache (24.2% vs. 23.2%, P > .05), and nausea (20.9% vs 6.3%, P = .005) in Arms A and B, respectively. The proportions of patients with hemoglobin below the lower limit of normal at the end of treatment and bilirubin > 3X upper limit of normal were higher in patients receiving RBV; only 1.1% (2/186) of patients experienced hemoglobin < 10 g/dL, both in Arm A. Conclusions: A 12-week regimen of ABT 450/r/ ABT-267 and ABT-333 with or without RBV achieved high rates of SVR12 (96.6% 3D + RBV, 100% 3D) and was generally well tolerated, as evidenced by the low rate of treatment discontinuation and serious adverse events. The 3D regimen without RBV was associated with lower rates of laboratory abnormalities including bilirubin elevation and hemoglobin decrease.
Introduction Fecal microbiota therapy (FMT) has been successful in treating Clostridium difficile(CDI) colitis. Small case series have given conflicting results regarding the efficacy of FMT in active ulcerative colitis (UC). We report the first randomized placebo-controlled trial of the efficacy of FMT in UC. Methods Ambulatory patients with active UC (Mayo score ≥4 with an endoscopic Mayo score ≥ 1 with no upper limit on Mayo score) who tested negative for C. difficile toxin gene by PCR were eligible. Participants were allowed to be on any other UC medications provided these were stable (taken at the same dose for at least 12 weeks (therapy continued in the trial), steroids for 4 weeks) and had not taken antibiotics within 30 days. Patients, clinicians and investigators assessing participants were blinded to the treatment allocated. Randomization was by a computer-generated list held by personnel in a clinical trials unit to maintain concealment of allocation. Eligible participants had a flexible sigmoidoscopy at baseline and were randomized to receive FMT given by a 50ml retention enema from an anonymous donor or placebo (50ml water enema) once per week for 6 weeks. The primary outcome was remission of UC defined as Mayo score ≤ 2 with an endoscopic Mayo score = 0 at week 7. Secondary outcomes included change in Mayo score, IBDQ and EQ5D. Patients gave stool at baseline and each week before the FMT to assess the fecal microbiome via amplification of the V3 rRNA region and MiSeq Illumina sequencing. Results We have randomized 63 subjects and 53 (FMT = 27, placebo = 26) have completed the trial with the other 10 patients still undergoing 6 weeks of treatment. Baseline characteristics were similar between the two groups with 45% having pancolitis, 42% on steroids, 19% on immunomodulators and 9% on biologics. There was no difference in the primary outcome or any of the secondary outcomes between the two groups (table). Sixteen patients in the active arm felt subjectively that FMT was improving their symptoms even though they were not in remission at week 7. These patients were continued on open FMT once per week for a further 6-12 weeks. Overall 9/27 (33%; 95% CI = 15-51%) were in remission if therapy was extended. There were no major adverse events in this study attributable to FMT. Data on the microbiome in a nested case control of successful and failed FMT will be outlined in a separate abstract. Conclusion This is the first randomized placebo controlled trial of FMT in UC and shows there was no statistically significant effect of FMT in active UC. However there is a possibility that FMT may be effective when administered longer than 6 weeks. Future studies should evaluate FMT over longer time periods, possibly with more intensive therapy but this approach should only be offered to UC patients in the context of a clinical study.
S-159
AGA Abstracts
AGA Abstracts
significant improvements in other symptoms of DG, in addition to the prokinetic actions and effects on vomiting.
929b Larazotide Acetate, a First In-Class, Novel Tight Junction Regulator, Meets Primary Endpoint and Significantly Reduces Signs and Symptoms of Celiac Disease in Patients on a Gluten-Free Diet: Results of a Multicenter, Randomized, Placebo Controlled Trial Chao Wang, Henrik Rasmussen, Wendy Perrow, Ciaran P. Kelly, Daniel Le7ffler, Peter Green, Richard N. Fedorak, Anthony J. DiMarino, Premysl Bercik, Joseph A. Murray, Natalie M. Bachir
Background & Aims: Eluxadoline is a locally active, mixed mu opioid receptor (μOR) agonist and delta opioid receptor (δOR) antagonist being developed to treat the abdominal pain and diarrhea of diarrhea-predominant irritable bowel syndrome (IBS-d). We evaluated the efficacy and safety of eluxadoline in two Phase 3 clinical trials in patients with IBS-d. Methods: Two double-blind, placebo-controlled, Phase 3 clinical trials (IBS3001 and IBS3002) randomized patients meeting Rome III criteria for IBS-d to twice-daily treatment with eluxadoline (75 or 100 mg) or placebo (PBO). Both clinical trials evaluated efficacy through 26 weeks of double-blind treatment. Thereafter, IBS3001 included an additional 26 weeks of double-blind treatment for long-term safety evaluations while IBS3002 included a 4-week placebo withdrawal period. In both clinical trials, the primary endpoint was composite response (based on simultaneous daily improvement in abdominal pain and stool consistency) evaluated over Weeks 1-12 (FDA responder endpoint) and Weeks 1-26 (EMA responder endpoint). Additional efficacy measures included assessments of abdominal and bowel symptoms and global endpoints (e.g., adequate relief, IBS-d global symptoms, and quality of life). Results: A total of 2428 patients with IBS-d were enrolled across the two clinical trials (66% females; mean age of 45 years). In both clinical trials, significantly (P<0.005) more patients receiving 100 mg eluxadoline were FDA and EMA composite responders than patients receiving PBO (see Table below). Comparable results for both endpoints were seen for the 75 mg eluxadoline group though the difference over PBO was not significant for the EMA response in IBS3001. Patients receiving eluxadoline were also significantly more likely than PBO patients to have adequate relief of IBS symptoms. Responder rates for individual components of the FDA and EMA responder endpoints for both eluxadoline groups were significantly higher than PBO for the stool consistency component, and numerically higher for the pain component. Patients receiving eluxadoline at both doses also had greater improvements in numbers of daily bowel movements and urgent episodes, daily IBS-d global symptom scores, and IBS-Quality of Life scores (P<.05). The most commonly reported adverse events in the two clinical trials were constipation (7.4% and 8.3% for eluxadoline 75 mg and 100 mg; 2.4% for PBO) and nausea (7.8% and 7.3% for eluxadoline 75 mg and 100 mg; 4.8% for PBO). Conclusions: Results from two Phase 3 clinical trials demonstrated that eluxadoline was an effective treatment for IBS-d based on the FDA and EMA composite endpoints. Results were highly durable over the 26week treatment periods and were associated with improvements in other global symptom measures.
Background: Celiac disease (CeD) is a genetic autoimmune condition affecting 1% of the western population. Triggered by the ingestion of gluten, CeD is managed by a Gluten-Free diet (GFD), however recurrent symptoms due to inadvertent exposure and non-adherence to GFD are common and found in up to 71.8% of individuals with CeD. Symptoms can significantly impact quality of life and the disease is associated with an increased risk of gastrointestinal (GI) cancers and T-cell lymphoma. Tight junctions (TJ) control paracellular permeability, increased in CeD, caused in part, by an inflammatory immune response subsequent to paracellular transport of gluten peptides into the intestinal lamina propria through epithelial TJs. Larazotide acetate is a first-in-class oral peptide that prevents TJ opening and reduces gluten uptake, inhibiting gluten and cytokine-induced intestinal permeability and inflammation in vivo. The aim of the study was to investigate the efficacy of Larazotide acetate to improve signs and symptoms in individuals with CeD while on a GFD. Methods: In this outpatient, randomized, parallel, double-blind, placebo-controlled, multicenter study, conducted in 74 sites in North America, 342 CeD patients on a GFD for ≥12 months were randomized to receive placebo or Larazotide acetate 0.5, 1, or 2 mg three times daily (TID). The 20-week study had a 4-week placebo run-in, 12-week treatment phase, and 4-week placebo run-out. The primary outcome was the average on-treatment score in the Celiac Disease Gastrointestinal Symptom Rating Scale (CeD GSRS) domains of Diarrhea, Indigestion, and Abdominal pain. Results: The primary endpoint of symptom reduction was met at the 0.5 mg dose of Larazotide acetate compared with placebo in both Modified Intention To Treat (MITT) (ANCOVA p=0.022, MMRM p=0.005) and Per Protocol (PP) analysis (ANCOVA p=0.007, MMRM p=0.001) (Figure 1). The 0.5 mg dose showed favorable outcomes for CeD Patient Reported Outcome (CeD PRO) GI domain, decrease in CeD PRO Symptomatic days (MITT ANCOVA 0.017) (Figure 2), an increase in SymptomFree days (MITT ANCOVA p=0.034) and a decrease in Non-GI symptoms (MITT ANCOVA p=0.010). No increases in anti-tTG (IgA and IgG) titers were observed at any dose of Larazotide acetate. Safety of Larazotide acetate was comparable to placebo. Conclusion: Larazotide acetate 0.5 mg reduced GI and non-GI symptoms, while reducing the number of Symptomatic days. The safety and tolerability profile of Larazotide acetate was comparable to placebo. This study represents the first large therapeutic trial in CeD to meet its primary endpoint of reducing signs and symptoms and is the first successful trial of a novel class of agents targeting TJ regulation. Larazotide acetate 0.5 mg has the potential to be the first pharmacologic CeD treatment and warrants further investigation in Phase III clinical trials.
929e PEARL-II: Randomized Phase 3 Trial of Interferon-Free, 12-Week Regimen of ABT-450/r/ABT-267, ABT-333 With or Without Ribavirin in Hepatitis C Virus Genotype 1b-Infected, Treatment-Experienced Patients Pietro Andreone, Massimo Colombo, Jeffrey V. Enejosa, Iftihar Koksal, Peter Ferenci, Andreas Maieron, Beat Müllhaupt, Yves Horsmans, Ola Weiland, Henk W. Reesink, Lino Rodrigues Jr, Yiran B. Hu, Thomas Podsadecki
929c A randomized, placebo controlled trial of fecal microbiota therapy in active ulcerative colitis. Paul Moayyedi, Michael Surette, Melanie Wolfe, Rita Taraschi, Peter Kim, Josie Libertucci, David Armstrong, John K. Marshall, Walter Reinisch, Christine H. Lee
Background: Interferon (IFN)-free treatment regimens of direct-acting antivirals (DAA) are capable of achieving sustained virologic response (SVR) in HCV genotype (GT) 1b-infected patients, reducing interferon-related toxicities. Phase 2 studies suggest high SVR rates can still be attained without inclusion of ribavirin (RBV) in treatment regimens while further decreasing safety concerns. Whether RBV is required for high SVR rates in a 3 DAA IFNfree regimen was evaluated in non-cirrhotic HCV GT1b-infected patients who failed treatment with pegIFN/RBV. Methods: PEARL-II is a phase 3 open-label study in HCV GT1b-infected patients who were randomized 1:1 to receive ABT-450 (protease inhibitor identified by AbbVie and Enanta, 150 mg dosed with 100 mg ritonavir [r] QD), coformulated with ABT267 (NS5A inhibitor, 25 mg QD) (ABT-450/r/ABT-267), and ABT-333 (non-nucleoside polymerase inhibitor, 250 mg BID) (3D regimen) with RBV (Arm A) or without RBV (Arm B) for 12 weeks. Twelve weeks post-treatment, SVR rates for each treatment arm were compared to a historical telaprevir plus pegIFN/RBV threshold. Adverse events (AEs) were recorded for all patients receiving at least 1 dose of study drug. Results: Of 187 treatmentexperienced, randomized GT1b-infected patients, 186 were dosed with study drug and included in safety analyses; 179 patients received ABT-450/r/ABT-267 coformulated drug and were included in ITT efficacy analyses. In the ITT population, 35.2% were nullresponders, 28.5% partial responders, and 36.3% relapsers to previous pegIFN/RBV treatment. Mean age (54.2 vs. 54.2 years), sex (49.5% vs. 60.0% male), and IL28B genotype CC (11.0 % vs. 7.4%) were comparable between Arms A and B, respectively. After 12 weeks of treatment, intent-to-treat SVR12 rates were 96.6% for Arm A and 100% for Arm B (Table). Similarly high SVR12 rates were observed in null-responders, partial responders, and relapsers. No patients experienced virologic failure; 2 patients in Arm A discontinued drug due to AEs. Adverse events were generally mild and the most frequent AEs were fatigue (31.9% vs. 15.8%, P = .015), headache (24.2% vs. 23.2%, P > .05), and nausea (20.9% vs 6.3%, P = .005) in Arms A and B, respectively. The proportions of patients with hemoglobin below the lower limit of normal at the end of treatment and bilirubin > 3X upper limit of normal were higher in patients receiving RBV; only 1.1% (2/186) of patients experienced hemoglobin < 10 g/dL, both in Arm A. Conclusions: A 12-week regimen of ABT 450/r/ ABT-267 and ABT-333 with or without RBV achieved high rates of SVR12 (96.6% 3D + RBV, 100% 3D) and was generally well tolerated, as evidenced by the low rate of treatment discontinuation and serious adverse events. The 3D regimen without RBV was associated with lower rates of laboratory abnormalities including bilirubin elevation and hemoglobin decrease.
Introduction Fecal microbiota therapy (FMT) has been successful in treating Clostridium difficile(CDI) colitis. Small case series have given conflicting results regarding the efficacy of FMT in active ulcerative colitis (UC). We report the first randomized placebo-controlled trial of the efficacy of FMT in UC. Methods Ambulatory patients with active UC (Mayo score ≥4 with an endoscopic Mayo score ≥ 1 with no upper limit on Mayo score) who tested negative for C. difficile toxin gene by PCR were eligible. Participants were allowed to be on any other UC medications provided these were stable (taken at the same dose for at least 12 weeks (therapy continued in the trial), steroids for 4 weeks) and had not taken antibiotics within 30 days. Patients, clinicians and investigators assessing participants were blinded to the treatment allocated. Randomization was by a computer-generated list held by personnel in a clinical trials unit to maintain concealment of allocation. Eligible participants had a flexible sigmoidoscopy at baseline and were randomized to receive FMT given by a 50ml retention enema from an anonymous donor or placebo (50ml water enema) once per week for 6 weeks. The primary outcome was remission of UC defined as Mayo score ≤ 2 with an endoscopic Mayo score = 0 at week 7. Secondary outcomes included change in Mayo score, IBDQ and EQ5D. Patients gave stool at baseline and each week before the FMT to assess the fecal microbiome via amplification of the V3 rRNA region and MiSeq Illumina sequencing. Results We have randomized 63 subjects and 53 (FMT = 27, placebo = 26) have completed the trial with the other 10 patients still undergoing 6 weeks of treatment. Baseline characteristics were similar between the two groups with 45% having pancolitis, 42% on steroids, 19% on immunomodulators and 9% on biologics. There was no difference in the primary outcome or any of the secondary outcomes between the two groups (table). Sixteen patients in the active arm felt subjectively that FMT was improving their symptoms even though they were not in remission at week 7. These patients were continued on open FMT once per week for a further 6-12 weeks. Overall 9/27 (33%; 95% CI = 15-51%) were in remission if therapy was extended. There were no major adverse events in this study attributable to FMT. Data on the microbiome in a nested case control of successful and failed FMT will be outlined in a separate abstract. Conclusion This is the first randomized placebo controlled trial of FMT in UC and shows there was no statistically significant effect of FMT in active UC. However there is a possibility that FMT may be effective when administered longer than 6 weeks. Future studies should evaluate FMT over longer time periods, possibly with more intensive therapy but this approach should only be offered to UC patients in the context of a clinical study.
S-159
AGA Abstracts
AGA Abstracts
significant improvements in other symptoms of DG, in addition to the prokinetic actions and effects on vomiting.