details of the patient population , along with inclusion and exclusion criteria , have been previously described . in brief , patients 18 years of age with active up or ups extending 5 cm , but no further than 40 cm , from the anal verge were eligible for enrollment in the studies ( clinicaltrials.gov : nct01008410 and nct01008423 ) . patients
had a baseline modified mayo disease activity index ( mmdai ) score 5 but 10 , with subscale ratings 2 for rectal bleeding and endoscopic appearance .
the mmdai score is the sum of 4 subscale scores : stool frequency , rectal bleeding , endoscopic appearance , and physician 's global assessment . since publication of the original mmdai ,
the endoscopic appearance subscale was modified to classify patients with any degree of friability with a subscale score of 2 .
exclusion criteria included the use of systemic , oral , topical , or rectal corticosteroids or laxatives or enemas ( other than mesalamine ) during the preceding 14 days .
concomitant use of a stable oral 5-asa regimen was permitted at doses up to 4.8 g / d .
rectal 5-asa use was discontinued during the run - in phase of the study ( i.e. , 47 days before randomization ) and was not permitted during the studies .
all authors had full access to the study data and reviewed and approved the final manuscript .
details of the study design have been previously described . in brief , 2 identically designed , phase 3 , randomized , double - blind , placebo - controlled , multicenter studies were conducted in the united states and russia ( bucf3001 [ clinicaltrials.gov identifier nct01008410 ] and bucf3002 [ clinicaltrials.gov identifier nct01008423 ] ) .
each study was comprised of a 2-week screening phase , a run - in / stabilization phase of 4 to 7 days , a 6-week treatment phase , and a 2-week follow - up phase ( fig .
, patients received single - blind placebo rectal foam twice daily , to familiarize themselves with study drug administration . in the treatment phase of each study , patients were randomized 1:1 to receive budesonide rectal foam 2 mg/25 ml twice daily for 2 weeks , then once daily for 4 weeks , or matching placebo . a colonoscopy was required for patients with newly diagnosed uc or without a confirmed diagnosis of uc within 12 months of the screening visit .
colonoscopy , if necessary , was performed no greater than 10 days and no less than 4 days before randomization . for patients not meeting the requirement for colonoscopy ,
, twice daily ; eos , end of study ; eot , end of trial ; q.d .
subgroup analyses for the primary , key secondary , and safety endpoints were performed for patients with baseline oral 5-asa use ( i.e. , at the time the first study dose [ budesonide foam or placebo ] was received ) during the studies .
the primary efficacy endpoint was the percentage of patients achieving remission ( defined as mmdai endoscopy subscale score 1 , mmdai rectal bleeding subscale score 0 , and improvement or no change from baseline in mmdai stool frequency subscale score ) at week 6 .
scores ranged from 0 to 3 for each mmdai subscale ( endoscopy subscale score : 0 = normal or inactive disease , 1 = mild disease , 2 = moderate disease , 3 = severe disease ; rectal bleeding subscale score : 0 = no blood seen , 1 = streaks of blood with stool less than half the time , 2 = obvious blood with stool most of the time , 3 = blood alone passed ; stool frequency subscale score : 0 = normal number of stools per d for each individual patient , 1 = 1 to 2 stools more than normal , 2 = 3 to 4 stools more than normal , 3 = 5 stools more than normal ; physician 's global assessment subscale score : 0 = normal , 1 = mild disease , 2 = moderate disease , 3 = severe disease ) . endoscopic disease extent and activity were determined by local investigators .
key secondary efficacy endpoints included the percentage of patients achieving an mmdai rectal bleeding subscale score of 0 and the percentage of patients achieving an mmdai endoscopy subscale score 1 at week 6 .
safety endpoints included monitoring of adverse events ( aes ) , laboratory parameters ( including morning cortisol concentrations and adrenocorticotropic hormone challenge tests ) , and vital signs .
the safety population included all patients in the intent - to - treat population who received 1 dose of study drug .
details of the patient population , along with inclusion and exclusion criteria , have been previously described . in brief , patients 18 years of age with active up or ups extending 5 cm , but no further than 40 cm , from the anal verge were eligible for enrollment in the studies ( clinicaltrials.gov : nct01008410 and nct01008423 ) . patients
had a baseline modified mayo disease activity index ( mmdai ) score 5 but 10 , with subscale ratings 2 for rectal bleeding and endoscopic appearance .
the mmdai score is the sum of 4 subscale scores : stool frequency , rectal bleeding , endoscopic appearance , and physician 's global assessment . since publication of the original mmdai ,
the endoscopic appearance subscale was modified to classify patients with any degree of friability with a subscale score of 2 .
exclusion criteria included the use of systemic , oral , topical , or rectal corticosteroids or laxatives or enemas ( other than mesalamine ) during the preceding 14 days .
concomitant use of a stable oral 5-asa regimen was permitted at doses up to 4.8 g / d .
rectal 5-asa use was discontinued during the run - in phase of the study ( i.e. , 47 days before randomization ) and was not permitted during the studies .
all authors had full access to the study data and reviewed and approved the final manuscript .
details of the study design have been previously described . in brief , 2 identically designed , phase 3 , randomized , double - blind , placebo - controlled , multicenter studies were conducted in the united states and russia ( bucf3001 [ clinicaltrials.gov identifier nct01008410 ] and bucf3002 [ clinicaltrials.gov identifier nct01008423 ] ) .
each study was comprised of a 2-week screening phase , a run - in / stabilization phase of 4 to 7 days , a 6-week treatment phase , and a 2-week follow - up phase ( fig .
, patients received single - blind placebo rectal foam twice daily , to familiarize themselves with study drug administration . in the treatment phase of each study , patients were randomized 1:1 to receive budesonide rectal foam 2 mg/25 ml twice daily for 2 weeks , then once daily for 4 weeks , or matching placebo . a colonoscopy was required for patients with newly diagnosed uc or without a confirmed diagnosis of uc within 12 months of the screening visit .
colonoscopy , if necessary , was performed no greater than 10 days and no less than 4 days before randomization . for patients not meeting the requirement for colonoscopy
, a sigmoidoscopy was scheduled 4 to 7 days before randomization . study design . b.i.d .
, twice daily ; eos , end of study ; eot , end of trial ; q.d .
subgroup analyses for the primary , key secondary , and safety endpoints were performed for patients with baseline oral 5-asa use ( i.e. , at the time the first study dose [ budesonide foam or placebo ] was received ) during the studies .
the primary efficacy endpoint was the percentage of patients achieving remission ( defined as mmdai endoscopy subscale score 1 , mmdai rectal bleeding subscale score 0 , and improvement or no change from baseline in mmdai stool frequency subscale score ) at week 6 .
scores ranged from 0 to 3 for each mmdai subscale ( endoscopy subscale score : 0 = normal or inactive disease , 1 = mild disease , 2 = moderate disease , 3 = severe disease ; rectal bleeding subscale score : 0 = no blood seen , 1 = streaks of blood with stool less than half the time , 2 = obvious blood with stool most of the time , 3 = blood alone passed ; stool frequency subscale score : 0 = normal number of stools per d for each individual patient , 1 = 1 to 2 stools more than normal , 2 = 3 to 4 stools more than normal , 3 = 5 stools more than normal ; physician 's global assessment subscale score : 0 = normal , 1 = mild disease , 2 = moderate disease , 3 = severe disease ) .
key secondary efficacy endpoints included the percentage of patients achieving an mmdai rectal bleeding subscale score of 0 and the percentage of patients achieving an mmdai endoscopy subscale score 1 at week 6 .
safety endpoints included monitoring of adverse events ( aes ) , laboratory parameters ( including morning cortisol concentrations and adrenocorticotropic hormone challenge tests ) , and vital signs .
the safety population included all patients in the intent - to - treat population who received 1 dose of study drug .
of the patients receiving budesonide foam ( n = 267 ) and placebo ( n = 279 ) in the pooled intent - to - treat population , 147 ( 55.1% ) and 154 ( 55.2% ) patients , respectively , reported baseline 5-asa use during the double - blind treatment phase of the studies .
there were no significant differences in demographic and baseline characteristics across groups , regardless of baseline 5-asa use ( table 1 ) .
demographic and baseline characteristics ( intent - to - treat population ) significant treatment effects favored budesonide foam versus placebo for the percentage of patients achieving remission ( primary endpoint ) , as well as patients with an mmdai rectal bleeding subscale score of 0 at week 6 ( key secondary endpoint ) , regardless of whether patients reported baseline 5-asa use ( fig .
2 ) . treatment with budesonide foam induced remission in a significantly greater percentage of patients with or without baseline oral 5-asa use compared with placebo at week 6 ( 5-asa , 42.2% versus 31.8% , respectively ; p = 0.03 : no 5-asa , 40.0% versus 14.4% ; p < 0.0001 )
. a significantly greater percentage of patients receiving budesonide foam achieved an mmdai rectal bleeding subscale score of 0 , regardless of baseline oral 5-asa use at week 6 ( 5-asa , 50.3% versus 35.7% ; p = 0.003 : no 5-asa , 45.8% versus 19.2% ; p < 0.0001 ) .
a significant treatment effect for achieving an mmdai endoscopy subscale score of 0 or 1 was observed in patients receiving budesonide foam versus placebo without baseline use of oral 5-asas ( 55.8% versus 31.2% ; p = 0.0004 ) ; however , while treatment with budesonide foam was favored compared with placebo , the treatment difference for the subgroup of patients with baseline oral 5-asa use did not reach statistical significance ( 55.8% versus 46.8% ; p = 0.08 ) .
furthermore , although the rates of response for the 2 subgroups of patients ( baseline 5-asa use versus no 5-asa use ) were comparable across the primary and key secondary efficacy endpoints , the treatment effect favoring budesonide foam was relatively greater in the subgroup of patients without baseline 5-asa use .
patients with baseline oral 5-asa use had greater response rates with placebo compared with patients without baseline oral 5-asa use .
the safety profile of budesonide foam was comparable between patients with and without baseline oral 5-asa use during the studies ( table 2 ) .
the most common aes ( 2% in the budesonide foam group ) occurred with comparable frequency in patients with and without baseline 5-asa use : blood cortisol decreased ( 20% versus 14% , respectively ) , adrenal insufficiency ( 3% versus 4% ) , headache ( 3% versus 2% ) , and nausea ( 1% versus 3% ) .
of the patients receiving budesonide foam ( n = 267 ) and placebo ( n = 279 ) in the pooled intent - to - treat population , 147 ( 55.1% ) and 154 ( 55.2% ) patients , respectively , reported baseline 5-asa use during the double - blind treatment phase of the studies .
there were no significant differences in demographic and baseline characteristics across groups , regardless of baseline 5-asa use ( table 1 ) .
significant treatment effects favored budesonide foam versus placebo for the percentage of patients achieving remission ( primary endpoint ) , as well as patients with an mmdai rectal bleeding subscale score of 0 at week 6 ( key secondary endpoint ) , regardless of whether patients reported baseline 5-asa use ( fig .
2 ) . treatment with budesonide foam induced remission in a significantly greater percentage of patients with or without baseline oral 5-asa use compared with placebo at week 6 ( 5-asa , 42.2% versus 31.8% , respectively ; p = 0.03 : no 5-asa , 40.0% versus 14.4% ; p < 0.0001 ) .
a significantly greater percentage of patients receiving budesonide foam achieved an mmdai rectal bleeding subscale score of 0 , regardless of baseline oral 5-asa use at week 6 ( 5-asa , 50.3% versus 35.7% ; p = 0.003 : no 5-asa , 45.8% versus 19.2% ; p < 0.0001 ) .
a significant treatment effect for achieving an mmdai endoscopy subscale score of 0 or 1 was observed in patients receiving budesonide foam versus placebo without baseline use of oral 5-asas ( 55.8% versus 31.2% ; p = 0.0004 ) ; however , while treatment with budesonide foam was favored compared with placebo , the treatment difference for the subgroup of patients with baseline oral 5-asa use did not reach statistical significance ( 55.8% versus 46.8% ; p = 0.08 ) .
furthermore , although the rates of response for the 2 subgroups of patients ( baseline 5-asa use versus no 5-asa use ) were comparable across the primary and key secondary efficacy endpoints , the treatment effect favoring budesonide foam was relatively greater in the subgroup of patients without baseline 5-asa use .
patients with baseline oral 5-asa use had greater response rates with placebo compared with patients without baseline oral 5-asa use .
the safety profile of budesonide foam was comparable between patients with and without baseline oral 5-asa use during the studies ( table 2 ) .
the most common aes ( 2% in the budesonide foam group ) occurred with comparable frequency in patients with and without baseline 5-asa use : blood cortisol decreased ( 20% versus 14% , respectively ) , adrenal insufficiency ( 3% versus 4% ) , headache ( 3% versus 2% ) , and nausea ( 1% versus 3% ) .
the overall results of the 2 identically designed , randomized , placebo - controlled studies demonstrated that a significantly greater percentage of patients with active , mild to moderate up or ups receiving budesonide foam achieved remission at week 6 ( primary efficacy endpoint ) compared with placebo ( 41.2% versus 24.0% , respectively ; p < 0.0001 ) .
furthermore , a significantly greater percentage of patients receiving budesonide foam achieved secondary outcome measures of rectal bleeding resolution ( 48.3% versus 28.3% ; p < 0.0001 ) and endoscopic improvement ( 55.8% versus 39.8% ; p = 0.0002 ) . the results of this analysis suggest that budesonide foam was efficacious and safe for induction of remission of mild to moderate up or ups in patients receiving oral 5-asa at baseline and those who were not .
furthermore , baseline oral 5-asa use had no apparent effect on the safety profile of budesonide foam .
baseline oral 5-asa use has been reported in a number of clinical studies of rectal therapies for the induction of remission of mild to moderate distal forms of uc ; however , these studies did not perform further efficacy or safety analyses in patients with baseline use of oral 5-asas . in a double - blind , double - dummy , randomized , comparative study of budesonide foam and budesonide enema in patients with active up or ups , response or lack of response to oral 5-asa therapy
had no significant effect on the percentage of patients in clinical remission with either treatment after 4 weeks .
furthermore , results of a randomized , double - blind , placebo - controlled study of patients with extensive mild to moderate uc demonstrated that concomitant treatment with oral and rectal 5-asas improved efficacy compared with oral 5-asas alone after 4 and 8 weeks .
these studies suggest that baseline oral 5-asa use does not aberrantly affect the efficacy of rectal therapies in patients with up or ups .
rectal 5-asas are currently the first - line treatment for patients with active , mild to moderate up or ups .
pooled analysis demonstrated that treatment with rectal 5-asas was associated with significant symptomatic improvement , endoscopic improvement , and histologic improvement , as well as symptomatic remission , endoscopic remission , and histologic remission , compared with placebo in patients with distal forms of uc .
however , the second - generation corticosteroid budesonide foam has demonstrated efficacy and safety in patients with mild to moderate up and ups , thus providing patients who fail treatment with rectal 5-asas a safe and efficacious therapeutic option .
furthermore , patients with up or ups preferred foam to enema ( 83.6% versus 6.2% , respectively ) in a head - to - head comparison study of these budesonide formulations .
the findings of this study further support the use of budesonide foam in patients with active mild to moderate up or ups , regardless of baseline oral 5-asa use
. limitations of this study include the fact that further analyses stratified by the various formulations of 5-asa and by the range of 5-asa doses were not conducted because of sample size limitations . although the combination of oral and rectal 5-asa therapies had greater efficacy than oral or rectal 5-asa monotherapy for the treatment of mild to moderate up or ups , it is possible that some patients in this study had recently discontinued rectal 5-asa monotherapy . whereas the findings of this analysis favored treatment with budesonide foam , regardless of whether patients were using 5-asas , additional prospective studies are warranted to further examine the potential benefit of oral 5-asas or other oral agents ( e.g. , budesonide multi - matrix ) in combination with budesonide foam in patients with mild to moderate up or ups . in conclusion ,
budesonide foam was efficacious and well tolerated for the induction of remission in patients with active , mild to moderate up and ups receiving oral 5-asas at baseline , as well as in those who were not .
 background : rectal budesonide foam is a second - generation corticosteroid efficacious for active mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis . 
 this subgroup analysis examined the impact of baseline oral 5-aminosalicylic acid ( 5-asa ) on the efficacy and safety of budesonide foam in patients with mild to moderate ulcerative proctitis or ulcerative proctosigmoiditis.methods:patients received budesonide foam 2 mg/25 ml twice daily for 2 weeks , then once daily for 4 weeks , or placebo , with or without continued stable dosing of baseline oral 5-asas , for remission induction at week 6 ( primary endpoint ) in 2 identically designed , randomized , double - blind , phase 3 studies.results:of the 267 and 279 patients randomized to treatment with budesonide foam or placebo ( pooled population ) , 55.1% and 55.2% , respectively , reported baseline 5-asa use . a significantly greater percentage of patients achieved remission with budesonide foam versus placebo , either with ( 42.2% versus 31.8% , respectively ; p = 0.03 ) or without ( 40.0% versus 14.4% ; p < 0.0001 ) baseline 5-asa use at week 6 
 . a significantly greater percentage of patients achieved a modified mayo disease activity index rectal bleeding subscale score of 0 at week 6 , regardless of baseline 5-asa use ( 5-asa , 50.3% versus 35.7% ; p = 0.003 : no 5-asa , 45.8% versus 19.2% ; p < 0.0001 ) . 
 the frequency of adverse events was comparable between groups , regardless of baseline 5-asa use.conclusions:budesonide foam was efficacious and safe for induction of remission of mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis in patients receiving oral 5-asa at baseline and those who were not ( clinicaltrials.gov : nct01008410 and nct01008423 ) . 
MATERIALS AND METHODS
Patients
Study Design
Assessments
Statistical Analyses
RESULTS
Patient Disposition and Demographics
Efficacy
Safety
DISCUSSION