Gut 1997; 41: 209-214
`
`209
`
`Oral budesonideis as effective as oral
`prednisolone in active Crohn’s disease
`
`M Campieri, A Ferguson, W Doe, T Persson, L-G Nilsson, and the Global Budesonide
`Study Group
`
`Abstract
`Background—tThe use of corticosteroids
`in active Crohn’s disease often becomes
`limited by side effects. Budesonide is a
`potent corticosteroid with low systemic
`bioavailability due to an extensive first
`pass liver metabolism.
`Aims—To comparetheefficacy and safety
`of two dosage regimens of budesonide and
`prednisolone
`in patients with active
`Crohn’s disease affecting the ileum and/or
`the ascending colon.
`Patients and methods—One hundred and
`
`seventy eight patients were randomised to
`receive budesonide controlled ileal release
`
`(CIR) capsules 9 mg once daily or 4.5 mg
`twice daily, or prednisolone tablets 40 mg
`once daily. The treatment period was 12
`weeks. The primary efficacy variable was
`clinical remission, defined as a Crohn’s
`Disease Activity Index (CDAI) of 150 or
`less.
`
`Results—After eight weeks of treatment,
`remission occurred in 60% of patients
`receiving budesonide once daily or pred-
`nisolone and in 42% of those receiving
`budesonide twice daily (p=0.062). The
`presence of glucocorticoid associated side
`effects was similar in all groups; however,
`moon face was more commonin the pred-
`nisolone group (p=0.0005). The highest
`frequency of impaired adrenal function, as
`measured by a short ACTHtest, was found
`in the prednisolone group (p=0.0023).
`Conclusions—Budesonide CIR, adminis-
`tered at 9 mg once daily or 4.5 mg twice
`daily, is comparable to prednisolone in
`inducing remission in active Crohn’s
`disease. The single dose administration is
`as promptly effective as prednisolone and
`represents a simpler and safer therapeutic
`approach, with a considerable reduction
`in side effects.
`(Gut 1997; 41: 209-214)
`
`function; CDAI; glucocorticoid;
`Keywords: adrenal
`glucocorticoid associated side effects
`
`Crohn’s disease is a chronic inflammatorydis-
`order of unknownaetiology. Although any por-
`tion of the digestive tract from mouth to anus
`may be involved, the most commonly affected
`parts are the distal ileum and the ascending
`colon.’ To date, glucocorticoids
`(GCS)—
`prednisone or prednisolone—have been the
`mosteffective drugs in inducing clinical remis-
`sion in these patients with Crohn’s disease’;
`
`therapeutic efficacy is
`unfortunately their
`counterbalanced by unwanted side effects
`attributable to their absorption and pharmaco-
`logical (systemic) action or to their suppression
`of endogenousadrenalfunction.’ Moreover,in
`clinical practice it has often been difficult to
`wean patients off systemically active GCS
`withouttriggering a relapse of the disease. New
`GCS have been developed which possess
`potent topical anti-inflammatory activity and
`with a systemic activity less than conventional
`GCS.’ The unique therapeutic ratio of the new
`analogues is due to a high potency combined
`with their extensive and rapid first pass liver
`metabolism, where the metabolites have mini-
`mal or no GCS activity.
`Budesonide is the most extensively studied
`compound of this new group of GCS. When
`administered by inhalation, budesonide has
`been foundto beeffective and safe in the treat-
`mentof both asthmaandrhinitis.” Given as an
`enema,it has also been foundto be as effective
`as conventional GCS enemasin the treatment
`of distal ulcerative colitis but has the clear
`
`advantage of producingsignificantly less adre-
`nal suppression than conventional GCS.*°
`Budesonide has also been developed in a
`gastric resistant formulation (Entocort® cap-
`sules, Astra Draco, Lund, Sweden) containing
`pellets with slow release properties; this prepa-
`ration allows the drug to be delivered mainly to
`the ileum and ascending colon.” The proper-
`ties of this formulation, together with the high
`GCS potency and extensive first pass liver
`metabolism of budesonide, offer
`improved
`therapy for Crohn’s disease by reducing the
`risk of steroid associated side effects. In previ-
`ous studies,'’'*? budesonide controlled intesti-
`nal release (CIR) capsules 9 mg daily were
`effective in inducing remission in patients with
`active Crohn’s disease affecting the ileum and
`the ascending colon. In a placebo controlled
`dose finding study,” budesonide CIR 4.5 mg
`twice daily was foundto bethe lowesteffective
`dose, while in a study designed to compare
`budesonide 9 mg once daily and prednisolone
`40 mg,” both agents were equally effective in
`inducing remission.
`However, prednisolone reduced the mean
`Crohn’s Disease Activity Index (CDAI) scores
`significantly more, whereas budesonide 9 mg
`once daily gave rise to significantly fewer
`glucocorticoid associated side effects and less
`suppression of endogenous cortisol produc-
`tion. It was felt important to study further the
`clinical efficacy of budesonide and the impact
`on the adrenal glands in comparison with
`
`MSN Exhibit 1008 - Page 1 of 6
`MSNv. Bausch - IPR2023-00016
`
`Medical and
`Gastroenterological
`Clinic, University of
`Bologna,Italy
`M Campieri
`
`Departmentof
`Medicine, University
`of Edinburgh,
`Edinburgh
`A Ferguson
`
`Division of Molecular
`Medicine, John Curtin
`School of Medical
`Research, Canberra,
`Australia
`W Doe
`
`Astra Draco AB, Lund,
`Sweden
`T Persson
`L-G Nilsson
`
`Correspondenceto:
`Professor M Campieri,
`Medical and
`Gastroenterological Clinic,
`University of Bologna,
`Policlinico S Orsola, Via
`Massarenti, 9, I-40138
`Bologna,Italy.
`
`Accepted for publication
`23 January 1997
`
`

`

`210
`
`Campieri, Ferguson, Doe, Persson, Nilsson
`
`prednisolone, and whether there were any
`differences if budesonide was given once or
`twice daily.
`
`drugs duringtheir actual treatmentperiod orif
`they interrupted the study drugs for more than
`five consecutive days.
`
`Methods
`SELECTION OF PATIENTS
`
`Twentysix investigational centres in the United
`Kingdom,Ireland, Italy, Australia, New Zea-
`land, Germany, Sweden, Belgium, and The
`Netherlandsparticipated in the study.
`Eligible patients were older than 18 years of
`age, with a confirmed diagnosis of active
`Crohn’s disease, as defined by a score of 200 or
`higher on the CDAI.” The extent of disease
`had to be defined within 24 months before
`randomisation; entry was restricted to patients
`with disease involving the ileum and/or the
`ascending colon but not extending beyond the
`hepatic flexure. Patients who had undergone
`ileostomy or more extensive resection of the
`ileum (>100 cm), and those with severe disease
`requiring imminentsurgery, were not enrolled
`in the study. They werenoteligible if they had
`complications
`including abscesses, perfora-
`tions, or active fistulas. Patients with concomi-
`tant active peptic ulcer orclinically important
`hepatic, renal, cardiovascular, or psychiatric
`conditions were also excluded. Immunosup-
`pressive drugs were allowed until three months
`before the study, 5-aminosalicylates and met-
`ronidazole until the day before the study, and
`corticosteroids allowed until one week before
`the study. The trial was performed in accord-
`ance with the Declaration of Helsinki and was
`approved by the Ethics Committeesatall cen-
`tres; all patients gave written or oral informed
`consent.
`
`STUDY DESIGN
`
`Thetrial was a randomised double blind, dou-
`ble dummy study. A baseline CDAI was
`obtained during a run-in period of three to
`seven days. The patients were subsequently
`randomised to treatment with either budeso-
`nide CIR capsules 9 mg oncedaily or 4.5 mg
`twice daily or prednisolone 40 mg oncedaily.
`Budesonide CIR was tapered to 6 mg after
`eight weeks and to 3 mg after a further two
`weeks. Prednisolone wastapered to 30 mgafter
`two weeks and then continuously throughout
`the study, reaching 5 mg after nine weeks. The
`5 mg dose was then continued for three weeks
`so that the total treatmentperiod was 12 weeks.
`Follow up visits were carried out after two,
`four, eight, and 12 weeks of treatment.
`
`STUDY DRUGS
`
`The controlled ileal release gelatine capsules
`containing 3 or 1.5 mg budesonide used in the
`study (Entocort® capsules) and placebo cap-
`sules were manufactured by Astra Draco AB
`(Lund, Sweden). The prednisolone tablets, 5
`and 10 mg, and placebotablets were obtained
`from As Hydro Pharma (Elverum, Norway).
`The drugs were provided in identical blister
`packages. Compliance was checked by the
`study personnel by counting unopened bDlis-
`ters. Patients were considered non-compliantif
`they consumed less then 75% of the study
`
`CLINICAL ASSESSMENT
`
`At entry, patients’ demographic characteristics,
`relevant current and past diagnoses, current
`medication, and history of previous bowel sur-
`gery were recorded. Thedistal part of the colon
`was assessed by sigmoidoscopy to exclude
`inflammationin the rectum. Disease extent was
`confirmed by endoscopy or radiology assess-
`mentif not done within the 24 monthsprior to
`thefirst visit.
`CDAI was the main clinical assessment for
`determination of drug efficacy and it was
`calculated at the randomisation visit andatall
`subsequentvisits. Remission was defined as a
`CDAI of 150 or
`less. The patients were
`provided with diary cards for all weeks of the
`study. On these, they recorded (each evening)
`the number of stools, general well being,
`abdominal
`pain,
`and
`intake
`of
`study
`medication. Adverse events were also recorded
`at each visit, as
`responses to a standard
`question (“Have you had any health problems
`or symptomsnot usually associated with your
`bowel disorder since the last visit?”). Scores
`from the seven days preceding theclinic visit
`were used for the CDAI calculation.
`The following analyses were done at each
`visit and used as measures of inflammation:
`erythrocyte sedimentation rate (ESR), platelet
`particle concentration, serum C-reactive pro-
`tein (CRP) (before treatment and after four
`and 12 weeks), and serum orosomucoid.
`Safety assessments consisted of the record-
`ing of any symptoms,clinical and haematologi-
`cal measurements, and an examination by the
`investigator for corticosteroid associated side
`effects. Blood samples for plasma cortisol
`analysis were drawn between
`7.30
`and
`9.30 am, always at
`the same time on each
`occasion.
`
`SHORT ACTH TEST
`
`to the short ACTH test
`The responses
`(Synacthen®, Ciba-Geigy), at randomisation
`and after eight weeks of treatment, were
`analysed with regard to plasma cortisol con-
`centrations before and 30 minutes after the
`ACTHinjection; the magnitudeofthe increase
`was determined. Plasmacortisol concentration
`was analysed both at the centre and at Astra
`Draco AB. The analyses carried out at each
`centre were used only for safety purposes,
`whereastheresults from analyses done at Astra
`Draco AB, using an HPLC method,” are
`reported here. The adrenal
`function was
`considered normalif the 0-minute plasma cor-
`tisol
`level was 2150 nmol/l and either the
`plasma cortisol increase was 2200 nmol/l or
`the 30-minute plasma cortisol concentration
`was 2400 nmol/l.
`
`STATISTICAL ANALYSIS
`
`From the National Cooperative Crohn’s Dis-
`ease Study (NCCDS)andotherreports it was
`estimated that
`the remission rates after 10
`weeks would reach 70% in the prednisolone
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`

`Budesonide versus prednisolone in Crohn’s disease
`
`211
`
`
`
`
`
`Budesonide
`once daily
`MM Budesonide
`twice daily
`Prednisolone
`
`I
`I
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2
`
`8
`4
`Weeksof treatment
`
`12
`
`—~ 100 —
`&
`L
`< 80
`|
`3
`|= 60b
`o
`L
`£& 40-
`g
`L
`Cc
`L& 20;
`L
`o
`
`0
`
`55
`
`group.’*'°'” No orlittle difference in efficacy
`between the two budesonide regimens was
`assumed, while there might possibly be a
`difference between either of the budesonide
`regimens and prednisolone. The primary aim
`of this study was to assess the remission rates
`after two, eight, and 12 weeks of treatment.
`With 50 patients per group there was an 80%
`probability of detecting a significant difference
`if the budesonide remission rate was 40%. A
`95% confidence interval for the difference in
`remission rates between any two groups would
`have an uncertainty of +19%. In order to com-
`pensate for non-evaluable patients, it was esti-
`mated that 180 randomised patients would be
`required. The analyses were based on data for
`all patients treated andthelast available value
`after the baseline value. No correlations for
`multiple comparisons have been made.
`
`Results
`PATIENT ENROLMENT
`
`Figure 1: Mean (SE) proportion ofpatients in remission
`after two, four, eight, and 12 weeks of treatment with
`budesonide or prednisolone.
`
`Analyses with respect to prognostic factors
`Analyses of remission rates by two-way analysis
`of variance were also performed with respect to
`the following prognostic factors:
`e disease activity at inclusion (CDAI 2300/
`CDAI <300)
`© previous bowelresection (yes/no)
`sex
`
`A total of 178 patients were randomised and
`177 were treated; 58 patients received budeso-
`nide 9 mg once daily, 61 budesonide 4.5 mg
`twice daily, and 58 received prednisolone. The
`© previous steroid treatment during the past
`demography anddiseasehistory for all patients
`year (yes/no).
`treated, recruited at 26 centres, are presented
`After eight weeks of treatment patients
`in table 1. The groups were well matched. Out
`admitted to the study with a CDAI <300
`of the 177 patients treated in the study, 36 pre-
`showed an overall remission rate significantly
`maturely discontinuedtheir treatment.
`higher than patients who entered with a CDAI
`The major reason (15%) for treatment with-
`drawal was disease deterioration or no im-
`>300. Of the patients admitted with a CDAI
`<300, remission was achieved in 31/44 in the
`provement(therapeutic failure). The frequen-
`budesonide once daily group, in 21/40 in the
`cies of therapeutic failure observed were
`budesonide twice daily group, and in 22/44 in
`comparable in the three groups—that is, 16%
`the prednisolone group. In the group with a
`in the budesonideoncedaily group,16% in the
`CDAI 2300, remission was achieved in 4/13,
`budesonidetwice daily group, and 12% in the
`3/18, and 7/13 in the budesonide oncedaily,
`prednisolone group. A y’
`test showed no
`budesonide twice daily, and prednisolone
`significant differences between the treatment
`groups, respectively. Disease activity was a
`groups (p=0.78).
`
`
`prognostic factor=which significantly
`CLINICAL EFFICACY
`(p=0.0007)
`influenced the remission rates;
`Remission rates
`however, the difference between treatments did
`Statistical evaluation of all patients treated
`not depend on the disease activity. Further-
`showed that after two weeks of treatment the
`more,the absolute decrease in mean CDAI was
`highest remission rate of 48% was observed in
`largest
`in the budesonide once daily group,
`the budesonide once daily group, compared
`irrespective of severity at entry.
`There was a statistically significant interac-
`with 37% in the prednisolone group, and 27%
`tion between treatment and the presence or
`in the budesonide twice daily group (fig 1).
`These differences in remission rates were not
`absence of previous resection (p=0.030); al-
`though the remission rate was higher among
`significant (p=0.052). After eight weeks treat-
`non-resected patients in both the budesonide
`ment, equal remission rates of 60% were found
`once daily group and the prednisolone group,
`in the budesonide oncedaily and prednisolone
`the rate was higher amongresected patients in
`groups, compared with 42% in the budesonide
`the budesonide twice daily group. Remission
`twice daily group (fig 1). The differences
`rates for male or femalepatients, or for patients
`betweenthe three groups werenotstatistically
`whohadordid not have previoussteroid treat-
`significant (p=0.062).
`
`TABLE 1 Demographic characteristics and disease history
`
`Budesonide once daily (n=58)
`
`Budesonide twice daily (n=61)
`
`Prednisolone (n=58)
`
`Mean
`
`Range
`
`Mean
`
`Range
`
`Sex ratio (M/F)
`Age (years)
`Weight (kg)
`CDAI
`Disease duration (years)
`Current exacerbation (months)
`Previous resection (Y/N)
`Time since resection (years)
`
`36
`63
`277
`8.3
`4.0
`
`5.8
`
`21/37
`17-71
`41-118
`121-476
`0-30
`0-46
`28/30
`0-22
`
`38
`63
`274
`7.9
`7.6
`
`5.3
`
`28/33
`20-71
`35-94
`107-465
`0-37
`0-98
`27/34
`0-23
`
`Mean
`
`23/35
`36
`61
`279
`6.7
`5.5
`
`4.6
`
`Range
`
`19-70
`39-93
`202-458
`0-27
`0-65
`34/24
`0-13
`
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`

`212
`
`300 —
`a
`|
`
`0
`
`0
`
`
`
`
`—-— Budesonide
`
`once daily
`— Budesonide
`
`twice daily
`o..|
`NL Prednisolone
`
`5 200 |—
`.
`-
`
`
`a ee E
`t
`
`
`So ------- Sleeesaes
`c
`mi
`oO
`S 100 /-
`
`|
`2
`
`8
`4
`Weeksof treatment
`
`|
`12
`
`Figure 2: Mean (SE) CDAIscore at randomisation and
`after two, four, eight, and 12 weeks of treatment with
`budesonide or prednisolone.
`
`ment, were notsignificantly different (p=0.80,
`p=0.15).
`
`CDAIchange
`The meaninitial CDAI score was 277 for the
`budesonide once daily group, 274 for the
`budesonide twice daily group, and 279 for the
`prednisolone group. The most pronounced
`decrease in CDAI scorein all three groups was
`observed duringthefirst two treatment weeks.
`As reflected by remission rates, the mean
`CDAIscores decreased more in the budeso-
`nide oncedaily group and prednisolone group
`than in the budesonide twice daily group. The
`difference between the groupsin reduction of
`CDAIscore wasstatistically significant after
`two weeks (p=0.050) but not after eight weeks
`(p=0.093) (fig 2).
`
`SAFETY RESULTS
`Adverse events
`(any unfavourable events—
`Adverse events
`such as clinical signs, symptoms, changes in
`laboratory data—temporarily associated with
`administration of the study drug) were regis-
`tered in 78% of patients in the budesonide
`once daily group, 90% in the budesonide twice
`daily group, and 90% in the prednisolone
`group. Most adverse events were related to the
`gastrointestinal system, probably reflecting the
`underlying disease. A slightly higher frequency
`of dyspepsia was observed in the budesonide
`once daily group, while nausea and epigastric
`pain were more frequent in the budesonide
`twice daily group. The highest frequency of
`patients with Cushingoid features was ob-
`served in the prednisolone group. Four patients
`in the budesonide once daily group reported
`rashes compared with none in the other
`groups;
`the frequency of depression and
`insomnia,palpitations, and flushing was higher
`in the prednisolone group. The number of
`patients with urinary tract
`infections was
`higher in the budesonide twice daily group
`whereas increased frequency of micturition was
`reported only by prednisolonetreated patients.
`Eighteen adverse events in 17 patients, of
`which 10 discontinued study treatment, re-
`sulted in hospitalisation and wereclassified as
`serious. The majority of admissions were for
`disease deterioration or
`complications of
`Crohn’s disease. A relationship between these
`serious adverse events and the study drug was
`judged, bythe investigator, to be unlikely.
`
`Campieri, Ferguson, Doe, Persson, Nilsson
`
`There was a significant difference between
`the three groups with respect to change in
`weight: after eight weeks, mean body weight
`increased by 1.0 kg in the budesonide once
`daily group and by 2.1 kg in the prednisolone
`group, but notat all in the budesonide twice
`daily group (p<0.0001).
`
`Haematology, clinical chemistry, and
`inflammatory indicators
`Most of the laboratory values found outside
`normal reference ranges were considered by
`the investigators to be related to the underlying
`Crohn’s disease. There were nostatistically
`significant differences between the
`three
`groups with respect to changes in the inflam-
`matory indicators (ESR, serum CRP, serum
`orosomucoid).
`Comparison of the mean changes in haema-
`tological and clinical chemistry variables from
`baseline
`showed
`a
`significant
`difference
`(p=0.029) at 12 weeks between the groups
`with respect to leucocyte count. After 12 weeks
`the mean leucocyte countin the prednisolone
`groupsignificantly increased by 0.9 x 10°/1; it
`decreased by 0.5 x 10°/1 in the budesonide
`once daily group, and veryslightly increased by
`0.1 x 10°/ in the budesonidetwice daily group.
`Noother haematologicalandclinical chemistry
`variables differed significantly between the
`groups.
`
`Basal plasmacortisol
`The meanplasmacortisol values at randomisa-
`tion were similar
`in the groups—that
`is,
`382 nmol/l in the budesonide once daily group,
`374 nmol/l
`in the budesonide twice daily
`group, and 375 nmol/l
`in the prednisolone
`group. There was a decreasein all three groups
`duringthe treatmentperiod (fig 3). After eight
`weeks of treatment the mean plasmacortisol
`value had decreased by 258 nmol/l in the pred-
`nisolone group, by 194 nmol/l in the budeso-
`nide oncedaily group, and by 132 nmol/] in the
`budesonide twice daily group. The difference
`between the groups wasstatistically significant
`(p=0.0035). There was no significant differ-
`ence between the two budesonide groups
`(p=0.096). Mean plasmacortisol values after
`two, eight, and 12 weeks were always lower in
`the prednisolone group.
`The proportionof patients with values below
`the lower plasma cortisol normal reference
`limit—150 nmol/l—wassignificantly higher in
`—-— Budesonide
`once daily
`—— Budesonide
`twice daily
`
`fe Prednisolone
`7
`
`_
`-
`~ re
`
`
`
`
`
`
`
`
`
`
`= 500
`=
`= 4007
`&
`WN
`‘Oo 300
`2
`c
`8 200;-
`Oo
`E 100
`8
`=
`
`0
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`0
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`\
`
`\
`
`Eo
`_ a
`\ ee ee
`—
`co
`F
`2
`
`|
`
`8
`Weeksof treatment
`
`12
`
`Figure 3: Mean (SE) morning plasmacortisol at
`randomisation and after two, four, eight, and 12 weeks of
`treatment with budesonide or prednisolone.
`
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`

`Budesonide versus prednisolone in Crohn’s disease
`
`213
`
`TABLE 2. Adrenalfunction (short ACTHtest) before and after treatment
`
`Treatment
`
`At randomisation
`(%)
`
`After 8 weeks
`(%)
`
`Budesonide oncedaily
`
`Budesonide twice daily
`Prednisolone
`
`86
`
`90
`95
`
`42
`
`50
`16
`
`Comparisons
`after 8 weeks
`
`p = 0.55*
`p = 0.013+
`p = 0.0015¢
`
`*Versus budesonide twice daily; tversus prednisolone; tversus prednisolone.
`
`the prednisolone group compared with both
`budesonide groups. After eight weeks, 76% of
`prednisolone treated patients had plasma
`cortisol values below 150 nmol/l] compared
`with 41% in the budesonide once daily group
`(p=0.0004) and 36% in the budesonide twice
`daily group (p<0.0001).
`Analysis of adrenal function (short ACTH
`test) revealedstatistically significant differences
`betweenthe groupsat eight weeks (p=0.0023)
`(table 2). After eight weeks, the proportion of
`patients with normal adrenal function was
`reduced in all three groups. The maximum
`reduction was
`found in the prednisolone
`group, the difference versus both budesonide
`once daily (p=0.013) and budesonide twice
`daily (p=0.0015) being significant. There was
`no significant difference between the two
`budesonide groupsin this respect.
`
`Glucocorticoid associated side effects
`The proportion of patients with glucocorticoid
`associated side effects was notsignificantly dif-
`ferent between the three groups: 50% in the
`budesonide once daily group, 44% in the
`budesonidetwice daily group, and 59% in the
`prednisolone group. However, the number of
`patients with moon faces found in the pred-
`nisolone group was approximately three times
`higher
`than in
`the budesonide
`groups
`(p=0.0005). The difference between the
`groups with respect to other GCS associated
`side effects was also significant (p=0.0098).
`Table 3 presents a summaryofside effects.
`
`Discussion
`Althoughcorticosteroid therapy represents the
`keystone approach for treating patients with
`active Crohn’s disease, its therapeutic value is
`counterbalanced by a numberof side effects
`related to systemic activity and to suppression
`of endogenous adrenal function with associ-
`ated long term problemsand,rarely, idiosyn-
`
`TABLE 3
`
`Glucocorticoid associated side effects
`
`Budesonide once daily
`
`Budesonide twice daily
`
`Prednisolone
`
`Before
`study
`
`During
`study
`
`Before
`study
`
`During
`study
`
`Before
`study
`
`During
`study
`
`[Reale
`
`8
`12
`5
`7
`5
`=
`_
`4
`
`2.
`6
`=
`4
`1
`=
`1
`=
`
`7
`1l
`2
`10
`3
`-
`_
`9
`
`2)
`=
`=
`2.
`2
`=
`_
`1
`
`22
`ll
`3
`7
`3
`2
`_
`16
`
`Sign
`
`Moonface
`Acne
`Swollen ankles
`Bruiseseasily
`Hirsutism
`Buffalo hump
`Skin striae
`Others*
`
`Some patients experienced more than one glucocorticocoid associated side effect.
`*Symptomsconsidered by the investigator to be signs of possible adverse effects were: weight
`increase, sweating, dyspepsia, nausea,stiff joints, headache, depression, insomnia, weakness, irri-
`tated facial skin, mood swings, limb discomfort, hot flushes, sleep disorder, impaired healing,
`localised papules, mentally stimulated, crampsin calves, agitation,irritability, emotional lability,
`generalised oedema,palpitations, localised erythema, facial oedema, and epigastric pain.
`
`cratic or allergic reactions. The possibility of
`using a second generation of corticosteroids
`with comparable efficacy but with fewer side
`effects offers the prospect of a safer therapy.
`Budesonide was shown to be active when
`given in rectal enemasto patients with ulcera-
`tive colitis. An early study showed that it was
`better than placebo, and othertrials have dem-
`onstrated that
`it was comparable to pred-
`nisolone in its efficacy but with significantly
`less action on the pituitary adrenalaxis.* 7° The
`CIR formulation was devised to treat patients
`with active Crohn’s disease localised to the
`ileum or the ascending colon”andthevalue of
`this formulation has been tested in two
`trials..7'* A placebo controlled dose finding
`study” suggested that 9 mg daily (4.5 mg twice
`daily)
`is
`the minimal effective dosage of
`budesonide. In the second study,’* budesonide
`9 mg once daily was as effective as pred-
`nisolone 40 mg once daily in inducing remis-
`sion; at eight weeks, 52% of patients in the
`budesonide group were in remission compared
`with 65% in the prednisolone group (p=0.12).
`The purpose of
`the present
`study was,
`therefore, to compare the two different dose
`regimens of budesonide CIR therapy—asingle
`morning doseversus a twice daily dosage—and
`these two approaches were again compared
`with the standard prednisolone regimen of
`40 mg daily, with special reference to efficacy
`and effects on adrenal axis function. After two
`weeks of treatment, nosignificant differences in
`clinical response were observed between the
`prednisolone
`and budesonide once daily
`groups but fewer remissions were observed in
`the budesonide twice daily group. After eight
`weeks, equal remission rates were obtained in
`the prednisolone and budesonide once daily
`groups and a somewhat lower remission rate
`with budesonidetwice daily.
`The CDAI scores for patients on pred-
`nisolone or budesonide once daily decreased in
`a similar fashion, with a less rapid decline in the
`budesonide twice daily group. As one of the
`first aims in treating patients with inflamma-
`tory bowel disease is the prompt disappearance
`of symptoms,
`this goal was most clearly
`achieved with budesonide once daily and pred-
`nisolone within the first
`two weeks. These
`results confirm that budesonide 9 mg daily,
`given as a single morning dose,is as effective as
`40 mg prednisolone,
`as
`indicated in the
`previous study.”* As we found that budesonide
`was associated with much less impairment of
`adrenal axis function, this treatment may well
`represent the first choice for the management
`of patients with active Crohn’s disease.
`Patients with CDAI >300 showedgenerally a
`weaker response to treatment compared with
`those with CDAI <300. In the former group, a
`higher
`remission rate was obtained with
`prednisolone compared with the two budeso-
`nide treatments (54%, 31%, and 17% respec-
`tively). This trend is notstatistically significant
`(p=0.07) but it might indicate that corticoster-
`oids with systemic effects have a specific role in
`the treatment of the most severe cases of
`Crohn’s disease. However, even in this sub-
`group, budesonide would be an important
`MSNExhibit 1008 - Page 5 of 6
`MSNv. Bausch - IPR2023-00016
`
`

`

`214
`
`alternative for patients in whom systemically
`active steroids should be avoided, such as dia-
`betics.
`In the previous comparative study of budeso-
`nide 9 mg daily versus prednisolone 40 mg
`daily, CDAI remission rates at two, four, and
`eight weeks always favoured prednisolone, and
`were significant at four weeks (67% wv 40%,
`p<0.001).’* However, in the present study, the
`highest remission rate occurred with budeso-
`nide once daily after two weeks; at eight weeks,
`budesonide once daily did as well as pred-
`nisolone. It is difficult to explain the difference
`betweenour findings and thoseof the previous
`study. There was no substantial difference in
`severity of the study groups as judged by CDAI
`scores, and in both studies a single morning
`dose of budesonide was used. With regard to
`the different rates of remission observed in the
`budesonide once daily and the budesonide
`twice daily groups, it seems that a pulsed dos-
`age
`regimen produces
`a more powerful
`effect.’* ° As a once daily approach is the most
`practical and acceptable way to administer a
`drug to patients and may achieve better
`compliance, the single morning administration
`can be recommended. Evidence of adrenal axis
`suppression was significantly greater in the
`prednisolone treated patients than in budeso-
`nide treated patients. Prednisolone treated
`patients also showed significant increases in
`peripheral leucocyte counts and othereffects
`associated with the systemic action of cortico-
`steroids. The conclusions of our multicentre
`trial are:
`e Budesonide CIR, administered as a single
`daily dosage of 9 mg daily or 4.5 mg twice
`daily, is comparable to prednisolone for the
`induction of remission in patients with active
`Crohn’s disease.
`e The
`single morning administration of
`budesonide CIR is as promptly effective as
`prednisolone and represents a simpler and
`safer therapeutic approach, with a reduction
`in sideeffects.”
`e Budesonide CIR offers a useful advance in
`the treatmentof active Crohn’s disease while
`we await a new breakthrough in the therapy
`of this challenging disease.”
`
`Appendix
`Members of the Global Budesonide Study
`Group are: H Malchow, Medizinische Klinik
`II, Leverkusen, Germany; C Prantera, Depart-
`ment of Gastroenterology, Ospedale “Nuovo
`Regina Margherita”, Rome, Italy; V Mani,
`Leigh Infirmary, Leigh, UK; C O’Morain,
`Meath Hospital, Dublin, Ireland; W Selby,
`Royal Prince Alfred Medical Centre, New-
`town, Australia; F Pallone, II Clinica Medica-
`Policlinico, Rome, Italy; M Mazzetti di Pi-
`etralata, S Eugenio Hospital, Rome, Italy; R
`Sjédahl, University Hospital, Linképing, Swe-
`den; T Florin, Mater Adult Hospital, Australia;
`P Smith, Llandough Hospital, South Glamor-
`gan, UK; P Bianchi,
`Instituto di Clinica
`Medica I, Milan, Italy; R L6fberg, Huddinge
`
`Campieri, Ferguson, Doe, Persson, Nilsson
`
`Hospital, Sweden; P Rutgeerts, University of
`Leuven, Belgium; R Smallwood, Repatriation
`General Hospital, Heidelberg, Australia; C B
`H W Lamers, University Hospital, Leiden, The
`Netherlands; C Tasman-Jones, Auckland Uni-
`versity School of Medicine, Auckland, New
`Zealand; JO Hunter, Addenbrooke's Hospital,
`Cambridge, UK; H Hodgson, Hammersmith
`Hospital, London, UK; A Danielsson, Univer-
`sity Hospital, Umea, Sweden; F I Lee, Victoria
`Hospital, Blackpool, UK; G Piacitelli, Hospital
`S Giovanni, Rome,Italy; A Ellis, Broadgreen
`Hospital, Liverpool, UK; D G Weir, St James’
`Hospital, Dublin, Ireland.
`
`This study was supported by a grant from Astra Draco AB,
`Sweden.
`
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