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Sa1263 A Prospective Multicenter Trial Evaluating the Benefit of Initial Seton Placement Prior to Starting Anti-TNF Therapy for the Treatment of Crohn's Perianal Fistulas
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PRO2 change of 8. RESULTS At Week 12, a significantly greater proportion of subjects who received Mongersen at daily doses of 40 mg and 160 mg attained CDAI and PRO2-based clinical remission and response compared to patients who received placebo. No significant difference was observed with the 10 mg/day dose (Table 1). Pearson correlation coefficients showed a high degree of concordance ( r=0.73-0.90, P<0.0001) between CDAI and PRO2 change from baseline for all Mongersen treatment groups at each time point (Table 2). Rates of adverse events (AEs) and serious AEs were similar across groups. Mongersen was generally safe and well tolerated. CONCLUSIONS Two weeks of induction therapy with orally administered, topically active Mongersen for patients with active CD was well tolerated and resulted in significant improvements in both CDAI and PRO2-defined clinical remission and response through 12 weeks. Changes in the PRO2 score correlated well with changes in CDAI scores. PRO2 may be a valuable instrument in assessing response to therapy in patients with active CD. Reference: Khanna R, Zou G, D'Haens G, et al. A retrospective analysis: the development of patient reported outcome measures for the assessment of Crohn's disease activity. Aliment Pharmacol Ther. 2014; doi:10.1111/apt.13001. Table 1: Proportion of Subjects in Clinical Remission, as Defined by CDAI Score <150 or a PRO2 Score <8 at Weeks 2, 4, and 12 (ITT Population)
AGA Abstracts
Vedolizumab for the Treatment of Fistulizing Crohn's Disease: An Exploratory Analysis of Data From GEMINI 2 Brian G. Feagan, David A. Schwartz, Silvio Danese, David T. Rubin, Brihad Abhyankar, Michael D. Smyth, Jing Xu, Karen Lasch Background Fistulizing disease occurs in up to 40% of patients with Crohn's disease (CD) . Symptoms, including anal pain, purulent discharge, and incontinence, are associated with high morbidity and impaired quality of life. Vedolizumab (VDZ) is a monoclonal antibody to alpha4beta7 integrin with demonstrated efficacy and safety in the treatment of patients with CD. The present exploratory analysis evaluated the efficacy of VDZ in the subpopulation of patients with fistulizing CD from a phase 3, randomized, placebo (PBO)-controlled trial (GEMINI 2).1 Methods In the GEMINI 2 study, patients who received 2 doses of VDZ during the induction phase and achieved a clinical response at week 6 received treatment with PBO or VDZ 300 mg every 8 weeks (Q8W) or every 4 weeks (Q4W) for an additional 46 weeks (maintenance intent-to-treat [ITT] population). Fistula closure, a prespecified exploratory endpoint, was assessed at each visit (2-6 week intervals) until week 52. The percentage of patients achieving fistula closure and mean time to fistula closure were calculated. Results Among the maintenance ITT population (N=461), 57 patients (12%) had 1 or more draining fistulae at study entry, with 74% of fistulae located perianally. Of these patients, 44-49% had failed prior anti-tumor necrosis factor therapy and 39-54% had prior surgery for CD. By week 14, 28% of patients treated with VDZ/VDZ (Q8W + Q4W combined) had achieved fistula closure versus 11% of those receiving VDZ/PBO (Table). This treatment difference was maintained up to week 52. Kaplan-Meier probabilities of fistula closure with VDZ treatment were 29.2% and 33.4% at 6 and 12 months, respectively; notably, the number of patients at risk was small (Figure). Conclusion In the GEMINI 2 maintenance ITT population, a greater percentage of patients with draining fistulae at study entry achieved fistula closure when they continued treatment with VDZ compared with those who were re-randomized to PBO. This effect was maintained through to week 52.These preliminary findings support the role of VDZ in the treatment of fistulizing disease and warrant further investigation in dedicated prospective studies in this population. Reference 1. Sandborn WJ, et al. N Engl J Med. 2013;369(8):711-721; NCT00783692. The clinical study was funded by Millennium Pharmaceuticals, Inc. (d/b/a Takeda Pharmaceuticals International Co.). Medical writing assistance was provided by inVentiv Medical Communications and supported by Takeda Pharmaceuticals International, Inc.
*P<0.001; **P<0.01; ***P<0.05 Table 2: Correlation Coefficient Between Change in PRO2 and Change in CDAI by Treatment and Time Point
Sa1263 A Prospective Multicenter Trial Evaluating the Benefit of Initial Seton Placement Prior to Starting Anti-TNF Therapy for the Treatment of Crohn's Perianal Fistulas David A. Schwartz, Raymond Cross, Miguel Regueiro, Leyla J. Ghazi, Jason M. Swoger, Dawn B. Beaulieu, Sara N. Horst, Mark Flasar, Seema Patil, Alan Herline, Tim Geiger, Roberta Muldoon, Molly M. Cone, James C. Slaughter, Paul E. Wise Sa1262 Background: Perianal fistulas are a debilitating and frequent manifestation of Crohn's disease (CD). Anti-tumor necrosis factor alpha agents (TNF) and/or seton drainage are effective options for treating these patients. The need for seton placement prior to initiation of an anti- TNF is controversial. A multi-center prospective randomized study was designed to assess the fistula healing rates in patients with CD who had seton placement prior to starting TNF therapy compared to those who started anti-TNF treatment without seton placement. Methods: Patients (pts) with both simple and complex perianal fistulas were randomized in a 1:1 fashion to either combination medical and surgical treatment (anti-TNF and seton placement=COMBO) or medical (anti-TNF) therapy alone (MED). Pts with abscesses > 2 cm were excluded. Pts randomized to the COMBO treatment arm had seton placement prior to initiating therapy with certolizumab pegol (CZP). Pts randomized to the MED therapy arm were not evaluated by a colorectal surgeon. All pts received azathioprine, 6-mercaptopurine or methotrexate at therapeutic doses (unless intolerant or contraindicated), and either metronidazole or ciprofloxacin. Pts received CZP 400 mg at weeks (wks) 0, 2, and 4 and then 400 mg every 4 wks. Pts were not allowed to change the dose of CZP during the study. Pts in the COMBO arm had setons removed at wk 20 unless they had significant persistent fistula drainage. They were reassessed at each visit and seton(s) removed once drainage improved. The primary endpoint was the rate of durable fistula healing at wk 52 as assessed by the Fistula Drainage Assessment method. The study was stopped early secondary to an interim analysis suggesting no significant difference between the 2 groups. Results: 21 pts enrolled (15 females) with a median duration of CD was approximately 3 years. Baseline demographics were similar between groups, including number and type of baseline fistulas (84% complex, 40% with > 1 fistula at baseline). The median baseline Perianal Disease
Patient-Reported Outcomes With GED-0301 (Mongersen), an Oral Smad7 Antisense Oligonucleotide, in Active Crohn's Disease: Correlation of PRO2 With CDAI Score Brian G. Feagan, Reena Khanna, Markus F. Neurath, Antonio Di Sabatino, Sandro Ardizzone, Francesco Pallone, Xiaojiang Zhan, Keith Usiskin, Giovanni Monteleone INTRODUCTION Mongersen is an oral locally active Smad7 antisense oligonucleotide that targets ileal and colonic Smad7, and has been evaluated for the treatment of Crohn's disease (CD). Although the Crohn's Disease Activity Index (CDAI) has traditionally been used as the primary outcome measure in clinical trials, there is growing regulatory interest in patientreported outcomes (PROs). PRO2, a composite outcome of stool frequency and abdominal pain, has been shown to correlate with CDAI outcomes (Khanna et al, 2014). AIMS & METHODS The safety and efficacy of Mongersen induction therapy was evaluated in a double-blind, placebo-controlled trial, in which 166 patients with active, steroid-dependent or steroid-resistant CD (CDAI score of 220-400) were randomized to placebo or 10, 40, or 160 mg of daily Mongersen for 2 weeks and followed up for an additional 10 weeks. For the current analysis, we report assessments of CDAI and PRO response and remission at Week 12, as well as correlation between PRO2 and CDAI outcomes. Scores for PRO2 were created by using 5 times the 7-day average of abdominal pain (scale of 0 to 3) plus 2 times the 7-day average of the number of liquid or very soft stools for the 7 days prior to the visit. Clinical trial data analysis suggests a CDAI score of 150 for remission correlated with a PRO2 of 8, and a change in CDAI of 100 points for clinical response correlates with a
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Table 1: PP analysis revealed significant improvements from baseline, in favour of GWP42003, for PGAS (where a treatment difference of -1 would equate to improving by one category; i.e. transitioning from moderate to mild disease) and IBDQ (where increased scores reflected improvement in a combination of patients' bowel symptoms, systematic symptoms, emotional status and social functioning).
AGA Abstracts
Activity Index (PDAI) was 7. A dropout rate of 24% (5 pts) was mainly due to increase in symptoms. Overall fistula healing rates at wk 52 was 52%, and an analysis utilizing the "last-observation-carried-forward" showed no significant difference between the two groups at wk 52 in either complete cessation of drainage (MED 55% vs. COMBO 50% [p=0.83], Figure) or PDAI (MED 3 vs. COMBO 3.5 [p=0.86]). Time to cessation of drainage was also similar in both groups. Conclusion: There was no significant benefit to seton placement prior to starting anti-TNF therapy in terms of perianal fistula healing in CD. While setons should be used when clinically indicated, their routine use with an anti-TNF to facilitate fistula healing if large abscesses are absent was not supported by this study.
Fistula Healing Over Time
Figure 1: Change from baseline comparisons of Mayo total score and 9-point partial Mayo score (no endoscopy subscore) reveals treatment differences that significantly favour GWP42003.
Sa1264
Sa1265
A Randomised, Double-Blind, Placebo-Controlled, Parallel Group, MultiCentred Pilot Study to Assess the Symptomatic Treatment of Ulcerative Colitis With Cannabidiol Peter M. Irving, Tariq Iqbal, Chuka Nwokolo, Sreedhar Subramanian, Stuart L. Bloom, Neeraj Prasad, Ailsa Hart, Charles Murray, James O. Lindsay, Adam Taylor, Rachel Barron, Stephen Wright
Adalimumab Serum Concentration As a Predictor for Clinical Efficacy in Ulcerative Colitis Nael M. Mostafa, Anne M. Robinson, Shringi Sharma, William Sandborn, Subrata Ghosh, Stephen B. Hanauer, Jean-Frederic Colombel, Roopal Thakkar, Walid M. Awni OBJECTIVE: The relationship between adalimumab trough concentration and efficacy (clinical remission and response) in patients with ulcerative colitis has been previously characterized [1]. The purpose of this analysis was to explore whether an adalimumab concentration threshold is predictive of adalimumab efficacy in ulcerative colitis. METHODS: Data from 242 patients with moderate to severe ulcerative colitis enrolled in the adalimumab treatment arm in ULTRA2 were included in the analysis. Patients received 160/80 mg adalimumab at Week 0/2 and 40 mg eow thereafter. Adalimumab trough concentration at Week 8 was used to predict clinical remission and response per Full Mayo scores at Week 8, 32 or 52. In case of dropouts or missing Week 8 concentrations, values were imputed using lastobservation-carried-forward method. For Week 8, 32 and 52, efficacy, non-responder imputation was implemented such that subjects were considered not in remission/response if they were discontinued or moved to open-label prior to the time point of efficacy assessment or if they had a missing Mayo score at the time point of efficacy assessment. Receiver operating characteristic (ROC) curves were constructed and area-under the ROC curves (AUC) were calculated using R Ver 3.0.3. Determination of predictive adalimumab trough concentration thresholds was based on the choice of corresponding specificity and sensitivity pair determined from the ROC curves. RESULTS: Mean (range) adalimumab trough concentrations at Week 8 were 8.7 (0-22.8 µg/mL). ROC curves showed AUC values ranging from 0.64 to 0.67 for remission and 0.55 to 0.63 for response at Week 8, 32 and 52. No concentration threshold exhibited a combination of specificity and sensitivity that was highly predictive of remission or response at Week 8, 32 or 52. The highest value for AUC (0.67) was associated with Week 52 remission, for which the algorithm-determined threshold showed a specificity and sensitivity of 0.52and 0.78, respectively. CONCLUSION: ROC analyses were conducted and did not identify an adalimumab trough concentration threshold that predicts clinical remission or response at Week 8, 32 or 52 in ulcerative colitis. REFERENCES: [1] Mostafa, N. M., Eckert, D., Pradhan, R. S., Mensing, S., Robinson, A., Sandborn W.J., et al. (2013). Exposure-Efficacy Relationship (ER) for Adalimumab During Induction Phase of Treatment of Adult Patients With Moderate to Severe Ulcerative Colitis. Gastroenterology, 144(5), S-225.
Cannabidiol (CBD), the main non-psychoactive constituent of cannabis, exhibits anti-inflammatory properties that could be exploited for the symptomatic relief of IBD. This proof-ofconcept, double blind, randomised, placebo controlled trial assessed the efficacy, safety and tolerability of CBD botanical drug substance (BDS) in patients with mild to moderate UC. Patients with left-sided or extensive UC aged ‡18 years, with a Mayo score 4-10 (endoscopy score of ‡1) and on a stable dose of 5-ASA (or previously used 5-ASA), were randomised 1:1 to receive either CBD BDS (GWP42003) (29 patients) or placebo (31 patients). The IMP was presented as hard gelatin capsules containing 50 mg GWP42003 (purified from a proprietary Cannabis sativa L. chemotype containing predominantly CBD and 4% D9tetrahydrocannabinol [THC]); or excipients alone for the placebo. Patients titrated to their maximal tolerated dose over two-weeks, aiming to achieve 500 mg daily (250 mg b.d.) and maintained this dose for 10 weeks. The primary endpoint was the number of patients in remission (Mayo total score £2; no sub-score >1) at week 10. Statistical tests were twosided at the 10% significance level. GW42003 patients found the IMP more difficult to tolerate than placebo patients, averaging one-third fewer capsules during the maintenance period, and having a higher number of compliance-related major protocol deviations (12 vs 4); principally insufficient exposure ( £28 days). With only 59% protocol-compliance in the GWP42003 group, the more relevant per-protocol (PP) analysis set was used to assess many efficacy measures. Remission was observed in both groups at the end of treatment; whilst proportionally in favour of GWP42003 in the Intention to Treat (ITT) (28% vs 26%) and PP (41% vs 30%) analysis sets, the difference was not significant (p=0.753 and p= 0.703, respectively). PP analysis of the change in Mayo total score from baseline significantly favoured GWP42003 (p=0.068); whereas both ITT and PP analysis of partial Mayo score revealed significant treatment differences favouring GWP42003 (p=0.087 and p=0.038, respectively); Figure 1. PP analysis of PGAS and IBDQ significantly favoured GWP42003 (p=0.069 and p=0.065, respectively); Table 1. Subjects Global Impression of Change was significantly in favour of GWP42003 for the ITT (odds ratio= 2.76; p=0.033) and PP (odds ratio=6.32; p=0.003) analysis sets. All 60 patients were included in the safety analysis; the majority of AEs were mild to moderate in severity and many in the GWP42003 group were likely attributed to the THC. A higher proportion of GI-related AEs, indicative of a worsening in underlying UC, was seen in placebo patients. Whilst this exploratory trial did not reach its primary endpoint, several signals suggest that GWP42003 may be beneficial for the symptomatic treatment of UC; larger trials are warranted.
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PRO2 change of 8. RESULTS At Week 12, a significantly greater proportion of subjects who received Mongersen at daily doses of 40 mg and 160 mg attained CDAI and PRO2-based clinical remission and response compared to patients who received placebo. No significant difference was observed with the 10 mg/day dose (Table 1). Pearson correlation coefficients showed a high degree of concordance ( r=0.73-0.90, P<0.0001) between CDAI and PRO2 change from baseline for all Mongersen treatment groups at each time point (Table 2). Rates of adverse events (AEs) and serious AEs were similar across groups. Mongersen was generally safe and well tolerated. CONCLUSIONS Two weeks of induction therapy with orally administered, topically active Mongersen for patients with active CD was well tolerated and resulted in significant improvements in both CDAI and PRO2-defined clinical remission and response through 12 weeks. Changes in the PRO2 score correlated well with changes in CDAI scores. PRO2 may be a valuable instrument in assessing response to therapy in patients with active CD. Reference: Khanna R, Zou G, D'Haens G, et al. A retrospective analysis: the development of patient reported outcome measures for the assessment of Crohn's disease activity. Aliment Pharmacol Ther. 2014; doi:10.1111/apt.13001. Table 1: Proportion of Subjects in Clinical Remission, as Defined by CDAI Score <150 or a PRO2 Score <8 at Weeks 2, 4, and 12 (ITT Population)
AGA Abstracts
Vedolizumab for the Treatment of Fistulizing Crohn's Disease: An Exploratory Analysis of Data From GEMINI 2 Brian G. Feagan, David A. Schwartz, Silvio Danese, David T. Rubin, Brihad Abhyankar, Michael D. Smyth, Jing Xu, Karen Lasch Background Fistulizing disease occurs in up to 40% of patients with Crohn's disease (CD) . Symptoms, including anal pain, purulent discharge, and incontinence, are associated with high morbidity and impaired quality of life. Vedolizumab (VDZ) is a monoclonal antibody to alpha4beta7 integrin with demonstrated efficacy and safety in the treatment of patients with CD. The present exploratory analysis evaluated the efficacy of VDZ in the subpopulation of patients with fistulizing CD from a phase 3, randomized, placebo (PBO)-controlled trial (GEMINI 2).1 Methods In the GEMINI 2 study, patients who received 2 doses of VDZ during the induction phase and achieved a clinical response at week 6 received treatment with PBO or VDZ 300 mg every 8 weeks (Q8W) or every 4 weeks (Q4W) for an additional 46 weeks (maintenance intent-to-treat [ITT] population). Fistula closure, a prespecified exploratory endpoint, was assessed at each visit (2-6 week intervals) until week 52. The percentage of patients achieving fistula closure and mean time to fistula closure were calculated. Results Among the maintenance ITT population (N=461), 57 patients (12%) had 1 or more draining fistulae at study entry, with 74% of fistulae located perianally. Of these patients, 44-49% had failed prior anti-tumor necrosis factor therapy and 39-54% had prior surgery for CD. By week 14, 28% of patients treated with VDZ/VDZ (Q8W + Q4W combined) had achieved fistula closure versus 11% of those receiving VDZ/PBO (Table). This treatment difference was maintained up to week 52. Kaplan-Meier probabilities of fistula closure with VDZ treatment were 29.2% and 33.4% at 6 and 12 months, respectively; notably, the number of patients at risk was small (Figure). Conclusion In the GEMINI 2 maintenance ITT population, a greater percentage of patients with draining fistulae at study entry achieved fistula closure when they continued treatment with VDZ compared with those who were re-randomized to PBO. This effect was maintained through to week 52.These preliminary findings support the role of VDZ in the treatment of fistulizing disease and warrant further investigation in dedicated prospective studies in this population. Reference 1. Sandborn WJ, et al. N Engl J Med. 2013;369(8):711-721; NCT00783692. The clinical study was funded by Millennium Pharmaceuticals, Inc. (d/b/a Takeda Pharmaceuticals International Co.). Medical writing assistance was provided by inVentiv Medical Communications and supported by Takeda Pharmaceuticals International, Inc.
*P<0.001; **P<0.01; ***P<0.05 Table 2: Correlation Coefficient Between Change in PRO2 and Change in CDAI by Treatment and Time Point
Sa1263 A Prospective Multicenter Trial Evaluating the Benefit of Initial Seton Placement Prior to Starting Anti-TNF Therapy for the Treatment of Crohn's Perianal Fistulas David A. Schwartz, Raymond Cross, Miguel Regueiro, Leyla J. Ghazi, Jason M. Swoger, Dawn B. Beaulieu, Sara N. Horst, Mark Flasar, Seema Patil, Alan Herline, Tim Geiger, Roberta Muldoon, Molly M. Cone, James C. Slaughter, Paul E. Wise Sa1262 Background: Perianal fistulas are a debilitating and frequent manifestation of Crohn's disease (CD). Anti-tumor necrosis factor alpha agents (TNF) and/or seton drainage are effective options for treating these patients. The need for seton placement prior to initiation of an anti- TNF is controversial. A multi-center prospective randomized study was designed to assess the fistula healing rates in patients with CD who had seton placement prior to starting TNF therapy compared to those who started anti-TNF treatment without seton placement. Methods: Patients (pts) with both simple and complex perianal fistulas were randomized in a 1:1 fashion to either combination medical and surgical treatment (anti-TNF and seton placement=COMBO) or medical (anti-TNF) therapy alone (MED). Pts with abscesses > 2 cm were excluded. Pts randomized to the COMBO treatment arm had seton placement prior to initiating therapy with certolizumab pegol (CZP). Pts randomized to the MED therapy arm were not evaluated by a colorectal surgeon. All pts received azathioprine, 6-mercaptopurine or methotrexate at therapeutic doses (unless intolerant or contraindicated), and either metronidazole or ciprofloxacin. Pts received CZP 400 mg at weeks (wks) 0, 2, and 4 and then 400 mg every 4 wks. Pts were not allowed to change the dose of CZP during the study. Pts in the COMBO arm had setons removed at wk 20 unless they had significant persistent fistula drainage. They were reassessed at each visit and seton(s) removed once drainage improved. The primary endpoint was the rate of durable fistula healing at wk 52 as assessed by the Fistula Drainage Assessment method. The study was stopped early secondary to an interim analysis suggesting no significant difference between the 2 groups. Results: 21 pts enrolled (15 females) with a median duration of CD was approximately 3 years. Baseline demographics were similar between groups, including number and type of baseline fistulas (84% complex, 40% with > 1 fistula at baseline). The median baseline Perianal Disease
Patient-Reported Outcomes With GED-0301 (Mongersen), an Oral Smad7 Antisense Oligonucleotide, in Active Crohn's Disease: Correlation of PRO2 With CDAI Score Brian G. Feagan, Reena Khanna, Markus F. Neurath, Antonio Di Sabatino, Sandro Ardizzone, Francesco Pallone, Xiaojiang Zhan, Keith Usiskin, Giovanni Monteleone INTRODUCTION Mongersen is an oral locally active Smad7 antisense oligonucleotide that targets ileal and colonic Smad7, and has been evaluated for the treatment of Crohn's disease (CD). Although the Crohn's Disease Activity Index (CDAI) has traditionally been used as the primary outcome measure in clinical trials, there is growing regulatory interest in patientreported outcomes (PROs). PRO2, a composite outcome of stool frequency and abdominal pain, has been shown to correlate with CDAI outcomes (Khanna et al, 2014). AIMS & METHODS The safety and efficacy of Mongersen induction therapy was evaluated in a double-blind, placebo-controlled trial, in which 166 patients with active, steroid-dependent or steroid-resistant CD (CDAI score of 220-400) were randomized to placebo or 10, 40, or 160 mg of daily Mongersen for 2 weeks and followed up for an additional 10 weeks. For the current analysis, we report assessments of CDAI and PRO response and remission at Week 12, as well as correlation between PRO2 and CDAI outcomes. Scores for PRO2 were created by using 5 times the 7-day average of abdominal pain (scale of 0 to 3) plus 2 times the 7-day average of the number of liquid or very soft stools for the 7 days prior to the visit. Clinical trial data analysis suggests a CDAI score of 150 for remission correlated with a PRO2 of 8, and a change in CDAI of 100 points for clinical response correlates with a
AGA Abstracts
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Table 1: PP analysis revealed significant improvements from baseline, in favour of GWP42003, for PGAS (where a treatment difference of -1 would equate to improving by one category; i.e. transitioning from moderate to mild disease) and IBDQ (where increased scores reflected improvement in a combination of patients' bowel symptoms, systematic symptoms, emotional status and social functioning).
AGA Abstracts
Activity Index (PDAI) was 7. A dropout rate of 24% (5 pts) was mainly due to increase in symptoms. Overall fistula healing rates at wk 52 was 52%, and an analysis utilizing the "last-observation-carried-forward" showed no significant difference between the two groups at wk 52 in either complete cessation of drainage (MED 55% vs. COMBO 50% [p=0.83], Figure) or PDAI (MED 3 vs. COMBO 3.5 [p=0.86]). Time to cessation of drainage was also similar in both groups. Conclusion: There was no significant benefit to seton placement prior to starting anti-TNF therapy in terms of perianal fistula healing in CD. While setons should be used when clinically indicated, their routine use with an anti-TNF to facilitate fistula healing if large abscesses are absent was not supported by this study.
Fistula Healing Over Time
Figure 1: Change from baseline comparisons of Mayo total score and 9-point partial Mayo score (no endoscopy subscore) reveals treatment differences that significantly favour GWP42003.
Sa1264
Sa1265
A Randomised, Double-Blind, Placebo-Controlled, Parallel Group, MultiCentred Pilot Study to Assess the Symptomatic Treatment of Ulcerative Colitis With Cannabidiol Peter M. Irving, Tariq Iqbal, Chuka Nwokolo, Sreedhar Subramanian, Stuart L. Bloom, Neeraj Prasad, Ailsa Hart, Charles Murray, James O. Lindsay, Adam Taylor, Rachel Barron, Stephen Wright
Adalimumab Serum Concentration As a Predictor for Clinical Efficacy in Ulcerative Colitis Nael M. Mostafa, Anne M. Robinson, Shringi Sharma, William Sandborn, Subrata Ghosh, Stephen B. Hanauer, Jean-Frederic Colombel, Roopal Thakkar, Walid M. Awni OBJECTIVE: The relationship between adalimumab trough concentration and efficacy (clinical remission and response) in patients with ulcerative colitis has been previously characterized [1]. The purpose of this analysis was to explore whether an adalimumab concentration threshold is predictive of adalimumab efficacy in ulcerative colitis. METHODS: Data from 242 patients with moderate to severe ulcerative colitis enrolled in the adalimumab treatment arm in ULTRA2 were included in the analysis. Patients received 160/80 mg adalimumab at Week 0/2 and 40 mg eow thereafter. Adalimumab trough concentration at Week 8 was used to predict clinical remission and response per Full Mayo scores at Week 8, 32 or 52. In case of dropouts or missing Week 8 concentrations, values were imputed using lastobservation-carried-forward method. For Week 8, 32 and 52, efficacy, non-responder imputation was implemented such that subjects were considered not in remission/response if they were discontinued or moved to open-label prior to the time point of efficacy assessment or if they had a missing Mayo score at the time point of efficacy assessment. Receiver operating characteristic (ROC) curves were constructed and area-under the ROC curves (AUC) were calculated using R Ver 3.0.3. Determination of predictive adalimumab trough concentration thresholds was based on the choice of corresponding specificity and sensitivity pair determined from the ROC curves. RESULTS: Mean (range) adalimumab trough concentrations at Week 8 were 8.7 (0-22.8 µg/mL). ROC curves showed AUC values ranging from 0.64 to 0.67 for remission and 0.55 to 0.63 for response at Week 8, 32 and 52. No concentration threshold exhibited a combination of specificity and sensitivity that was highly predictive of remission or response at Week 8, 32 or 52. The highest value for AUC (0.67) was associated with Week 52 remission, for which the algorithm-determined threshold showed a specificity and sensitivity of 0.52and 0.78, respectively. CONCLUSION: ROC analyses were conducted and did not identify an adalimumab trough concentration threshold that predicts clinical remission or response at Week 8, 32 or 52 in ulcerative colitis. REFERENCES: [1] Mostafa, N. M., Eckert, D., Pradhan, R. S., Mensing, S., Robinson, A., Sandborn W.J., et al. (2013). Exposure-Efficacy Relationship (ER) for Adalimumab During Induction Phase of Treatment of Adult Patients With Moderate to Severe Ulcerative Colitis. Gastroenterology, 144(5), S-225.
Cannabidiol (CBD), the main non-psychoactive constituent of cannabis, exhibits anti-inflammatory properties that could be exploited for the symptomatic relief of IBD. This proof-ofconcept, double blind, randomised, placebo controlled trial assessed the efficacy, safety and tolerability of CBD botanical drug substance (BDS) in patients with mild to moderate UC. Patients with left-sided or extensive UC aged ‡18 years, with a Mayo score 4-10 (endoscopy score of ‡1) and on a stable dose of 5-ASA (or previously used 5-ASA), were randomised 1:1 to receive either CBD BDS (GWP42003) (29 patients) or placebo (31 patients). The IMP was presented as hard gelatin capsules containing 50 mg GWP42003 (purified from a proprietary Cannabis sativa L. chemotype containing predominantly CBD and 4% D9tetrahydrocannabinol [THC]); or excipients alone for the placebo. Patients titrated to their maximal tolerated dose over two-weeks, aiming to achieve 500 mg daily (250 mg b.d.) and maintained this dose for 10 weeks. The primary endpoint was the number of patients in remission (Mayo total score £2; no sub-score >1) at week 10. Statistical tests were twosided at the 10% significance level. GW42003 patients found the IMP more difficult to tolerate than placebo patients, averaging one-third fewer capsules during the maintenance period, and having a higher number of compliance-related major protocol deviations (12 vs 4); principally insufficient exposure ( £28 days). With only 59% protocol-compliance in the GWP42003 group, the more relevant per-protocol (PP) analysis set was used to assess many efficacy measures. Remission was observed in both groups at the end of treatment; whilst proportionally in favour of GWP42003 in the Intention to Treat (ITT) (28% vs 26%) and PP (41% vs 30%) analysis sets, the difference was not significant (p=0.753 and p= 0.703, respectively). PP analysis of the change in Mayo total score from baseline significantly favoured GWP42003 (p=0.068); whereas both ITT and PP analysis of partial Mayo score revealed significant treatment differences favouring GWP42003 (p=0.087 and p=0.038, respectively); Figure 1. PP analysis of PGAS and IBDQ significantly favoured GWP42003 (p=0.069 and p=0.065, respectively); Table 1. Subjects Global Impression of Change was significantly in favour of GWP42003 for the ITT (odds ratio= 2.76; p=0.033) and PP (odds ratio=6.32; p=0.003) analysis sets. All 60 patients were included in the safety analysis; the majority of AEs were mild to moderate in severity and many in the GWP42003 group were likely attributed to the THC. A higher proportion of GI-related AEs, indicative of a worsening in underlying UC, was seen in placebo patients. Whilst this exploratory trial did not reach its primary endpoint, several signals suggest that GWP42003 may be beneficial for the symptomatic treatment of UC; larger trials are warranted.
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AGA Abstracts