Aliment Pharmacol Ther 2003; 18: 191-198. (cid:9)
`
`doi: 10.1046/j.1365-2036.2003.01648.x
`
`Studies of compliance with delayed-release mesalazine therapy
`in patients with inflammatory bowel disease
`
`M. J. SHALE & S. A. RILEY
`Department of Gastroenterology, Northern General Hospital, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK
`
`Accepted for publication 1 May 2003
`
`SUMMARY
`
`Background: Non-compliance with maintenance mesal-
`azine therapy may be a risk factor for relapse in
`inflammatory bowel disease, but the prevalence and
`determinants of non-compliance are unknown.
`Aim: To study the prevalence and determinants of non-
`compliance in patients with inflammatory bowel dis-
`ease.
`Methods: Out-patients receiving delayed-release mesala-
`zine were studied. Compliance was determined by direct
`enquiry and by analysis of urine samples for 5-amino-
`salicylic acid/N-acetyl-5-aminosalicylic acid. Potential
`determinants of compliance were assessed.
`Results: Ninety-eight patients were studied. Forty-two
`patients (43%) reported taking < 80% of their pre-
`scribed dose. Logistic regression revealed the indepen-
`dent predictors of non-compliance to be three-times
`daily dosing [odds ratio (OR), 3.1; 95% confidence
`
`interval (CI), 1.8-8.4] and full-time employment (OR,
`2.7; 95% CI, 1.1-6.9). Urine from 12 patients (12%)
`contained no detectable 5-aminosalicylic acid/N-acetyl-
`5-aminosalicylic acid, and 18 patients (18%) had levels
`below those expected. Depression was the only inde-
`pendent predictor of complete non-compliance (OR,
`10.5; 95% CI, 1.8-79.0), and three-times daily dosing
`was the only independent predictor of partial non-
`compliance (OR, 3.7; 95% CI, 1.8-8.9). Self-reporting
`correctly identified 66% of patients judged to be non-
`compliant on urinary drug measurement.
`Conclusions: Non-compliance with maintenance mesal-
`azine therapy is common in patients with inflammatory
`bowel disease. Three-times daily dosing and full-time
`employment are predictors of partial non-compliance,
`whilst depression is associated with complete non-
`compliance. Self-reporting detects most non-compliant
`patients.
`
`INTRODUCTION
`
`Delayed-release mesalazine has a well-established role in
`the management of patients with inflammatory bowel
`disease.' It is of some benefit in active disease, but is of
`particular value when taken regularly, as it reduces the
`relapse rates in patients with ulcerative colitis'-1 and
`possibly also in those with Crohn's disease.5' 6 Further-
`more, recent studies have suggested that mesalazine-
`based drugs may reduce the increased risk of colorectal
`
`Correspondence to: Dr S. A. Riley, Department of Gastroenterology,
`Northern General Hospital, Herries Road. Sheffield S7 SALT. UK.
`E-mail: stuart.riley@sth.nhs.uk
`
`cancer in some patients with inflammatory bowel
`disease.7-9 For these reasons, most patients are encour-
`aged to take life-long maintenance treatment.
`Unfortunately, non-compliance with maintenance
`medication in patients with inflammatory bowel disease
`is common1°-12 and, although the data are limited, one
`recent study has suggested that such patients are at
`increased risk of relapse.13 The reasons for non-
`compliance are often complex. A variety of patient-,
`disease-, treatment- and doctor-related factors have
`been implicated in a variety of disease states.14-2° but
`there has been no systematic study in patients with
`inflammatory bowel disease.
`
`© 2003 Blackwell Publishing Ltd
`
`191
`
`SALIXN00012263
`
`Dr. Falk Ex. 2020
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 1
`
`

`
`192 M. . SHALE & S. A. RILEY
`
`Furthermore, compliance itself is difficult to study.
`Patient self-reporting, physician estimation, pill counts,
`the use of pharmacy records and even electronic
`monitoring of pill dispensing have been employed, but
`may not truly reflect drug intake.20-24 The determin-
`ation of a drug or its metabolite in biological fluids is a
`more objective measure of consumption,20. 21. 25 but
`this has not been studied previously as a measure of
`compliance with delayed-release mesalazine in patients
`with inflammatory bowel disease.
`The aims of the present study were to investigate the use
`of urinary drug excretion as an objective measure of
`compliance, and to study the prevalence and determi-
`nants of compliance with maintenance mesalazine in a
`cohort of patients with inflammatory bowel disease using
`both patient self-reporting and urinary drug testing.
`
`METHODS
`
`Urinary drug excretion in healthy volunteers
`
`In order to establish the range of urinary drug excretion
`in spot samples during various mesalazine dosage
`regimens and withdrawal from those regimens,
`10 healthy volunteers were recruited. Subjects were
`selected by their willingness to be strictly compliant.
`Each was asked to take three commonly used regimens
`of delayed-release mesalazine (Asacol, SmithKline Bee-
`cham, Uxbridge, UK): 400 mg twice daily, 800 mg twice
`daily and 800 mg three times daily. Each regimen was
`taken for seven consecutive days with a minimum 7-day
`drug-free interval. Doses were taken at 09.00, 14.00
`and 21.00 h as dictated by the regimen. The need for
`strict compliance was stressed and a tablet count was
`performed to corroborate adherence to each regimen.
`Urine samples were collected on days 7-10. On days 7,
`8 and 9, spot samples of urine were collected at hourly
`intervals during the normal working day (09.00, 10.00,
`11.00. 12.00, 14.00, 15.00, 16.00 and 17.00 h). On
`day 10, a single spot urine sample was collected at
`09.00 h. Urine samples were frozen at - 20 °C prior to
`analysis.
`
`Patient compliance study
`
`Patients were recruited from the out-patient clinics at
`the Northern General and Royal Hallamshire Hospitals
`in Sheffield, UK. Patients with ulcerative colitis, Crohn's
`disease or indeterminate colitis were eligible for the
`
`study if they were receiving maintenance therapy with
`delayed-release mesalazine (Asacol). Patients in whom
`the dose of mesalazine had been changed in the last
`4 weeks and those using other mesalazine-containing
`formulations or drugs known to alter gastrointestinal
`tract pH were excluded. Patients were unaware of the
`study prior to clinic attendance. All patients provided
`written informed consent and the protocol was
`approved by the local research ethics committees.
`Patients underwent a structured interview detailing
`the disease characteristics and medication use. Each was
`asked to gauge his or her own compliance (0-100%).
`Patients then completed a number of validated ques-
`tionnaires assessing: (i) disease activity (Simple Clinical
`Colitis Activity Index for ulcerative colitis26 or the
`Harvey-Bradshaw Index for Crohn's disease27); (ii) qual-
`ity of life (Short Inflammatory Bowel Disease Question-
`naire28); (iii) the doctor-patient relationship (Stanford
`Trust in Physician Scale29); and (iv) psychiatric mor-
`bidity (Hospital Anxiety and Depression Scale3°).
`Finally, patients were asked to provide a spot sample of
`urine. The time was noted and the sample was frozen at
`- 20 °C prior to analysis.
`
`Analytical method
`
`Urinary 5-aminosalicylic acid (5-ASA) and N-acetyl-5-
`ASA were measured by high-performance liquid chro-
`matography, using a previously described method.31
`Calibration curves were linear over the range 0.1-
`1000 µg/mL, and the limit of detection for both 5-ASA
`and N-acetyl-5-ASA was < 0.1 µg/mL. Correlation
`coefficients exceeded 0.99 (5-ASA, r2 = 0.994;
`N-acetyl-5-ASA, r2 = 0.999). The intra- and inter-
`assay coefficients of variation were < 8%.
`In order to correct for variations in urinary concen-
`tration between the samples, the total 5-ASA concen-
`tration (5-ASA + N-acetyl-5-ASA) was expressed as a
`ratio to the urinary creatinine concentration. Urinary
`creatinine was measured using the Jaffe reaction32
`(ABX Diagnostics, Montpellier, France), developed for a
`CobasBio Autoanalyser (Roche Diagnostics, Welwyn,
`UK). The intra- and inter-assay coefficients of variation
`were < 3% and < 7%, respectively.
`
`Statistical analysis
`
`All results are expressed as the median and range values
`unless otherwise stated. Between-group comparisons
`
`© 2003 Blackwell Publishing Ltd. Aliment Pharmacol Ther 18, 191-198
`
`SAUXN00012264
`
`Dr. Falk Ex. 2020
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 2
`
`

`
`COMPLIANCE WITH MAINTENANCE THERAPY IN IBD 193
`
`were made using the Mann-Whitney U-test, and the
`Friedman two-way analysis of variance was used to
`compare differences across the three dosage groups in
`the healthy volunteer study. Correlations were sought
`using the Spearman rank correlation coefficient, and
`categorical data were analysed using Pearson's chi-
`squared method. Logistic regression analysis was used
`to determine the independence of the variables.
`
`RESULTS
`
`Urinary drug excretion in healthy volunteers
`
`Ten healthy volunteers (five males, five females; age,
`22-46 years) completed the study. All remained well.
`Four volunteers admitted to missing a single dose and
`each repeated that phase of the study. All other
`volunteers reported full compliance and this was
`corroborated by pill counts.
`The results of the total urinary 5-ASA to creatinine
`ratios on day 7 of each dosing period are shown in
`Figure 1. As expected, the total urinary 5-ASA to
`creatinine ratios increased with increasing oral dose
`[400 mg b.d., 1.3 (0.08-16.3); 800 mg b.d., 3.3
`(1.1-15.2); 800 mg t.d.s., 4.8 (1.5-9.8); r2 = 0.02;
`P < 0.01]. At each dose, a modest intra-subject
`variation throughout the day was apparent [coefficients
`of variation: 400 mg b.d., 60% (26-99%); 800 mg b.d.,
`40% (13-82%); 800 mg t.d.s., 27% (9-46%)], although
`
`1
`
`16
`
`14
`
`.2
`
`12
`
`4
`
`this was not statistically significant at any time point.
`The inter-subject variation was more marked, but fell as
`the oral dose increased [coefficients of variation:
`400 mg b.d., 106% (92-119%); 800 mg b.d., 66%
`(48-78%); 800 mg t.d.s., 52% (41-59%)].
`Although direct interpretation of the oral dose was not
`possible due to inter-subject variation, it was clear that.
`at oral doses of 800 mg b.d. and above, no subject
`provided a sample with a total 5-ASA to creatinine ratio
`of less than unity (Figure 2).
`On stopping the drug, the total urinary 5-ASA to
`creatinine ratios fell, but this did not achieve statistical
`significance, at any dose, until the samples collected at
`least 36 h after the drug had been stopped were
`analysed. All samples collected on day 10 (60 h after
`the last dose) had undetectable levels of 5-ASA and
`N-acetyl-5-ASA (Figure 3).
`
`Patient compliance study
`
`Ninety-eight patients were studied. Fifty-one were male
`and the age ranged from 17 to 85 years. Sixty-two
`patients had ulcerative colitis, 26 had Crohn's disease
`and 10 had indeterminate colitis. Patients had been
`
`10
`
`5
`
`3
`
`5
`
`000
`00
`
`09 00 (cid:9)
`
`10.00 (cid:9)
`
`11.00 (cid:9)
`
`12.00 (cid:9)
`Sample collection time(n)
`
`14.00 (cid:9)
`
`15.00 (cid:9)
`
`16 00 (cid:9)
`
`17.00
`
`Figure 1. Urinary total 5-aminosalicylic acid (5-ASA and
`N-acetyl-5-ASA) to creatinine ratios on day 7 of each study period
`in healthy volunteers (median and range): 0 400 mg b.d.; •,
`800 mg b.d.: A, 800 mg t.d.s.
`
`© 2003 Blackwell Publishing Ltd. Aliment PharmacnI Titer 18, 191-198
`
`08.00
`
`16.00 (cid:9)
`
`24.00
`
`Dose of mesalazine (mg/day)
`
`Figure 2. Logarithmic plot of urinary total 5-aminosalicylic acid
`(5-ASA) to creatinine ratios in healthy volunteers. Each point
`represents one of the eight samples collected on day 7 of each
`study period. Note that no volunteer taking 1600 mg or more of
`delayed-release mesalazine had a log urinary total 5-ASA to
`creatinine ratio of less than unity.
`
`SALIXN00012265
`
`Dr. Falk Ex. 2020
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 3
`
`(cid:9)
`

`
`194 M. I. SHALE & S. A. RILEY
`
`Mesalastine stopped (last dose 2100 hours)
`
`8 88 8
`8 `1.:=
`&I 7
`
`8 888
`8
`days
`Semple collection lime (t)
`
`8 888
`5 :=1:
`(1.19
`
`Figure 3. Urinary total 5-aminosalicylic acid (5-ASA and
`N-acetyl-5-ASA) to creatinine ratios after stopping mesalazine in
`healthy volunteers (median and range): 0, 400 mg b.d.;
`U, 800 mg b.d.; D, 800 mg t.d.s. *P < 0.001 compared with
`day 7 values.
`
`Table 1. Patient and disease characteristics
`
`Age (years)
`Sex (male : female)
`Married (%)
`Education beyond age of 16 years (%)
`Full-time employment (%)
`Membership of patient group
`(NACC or IBD Club) (%)
`
`Disease type (%)
`Ulcerative colitis
`Crohn's disease
`Indeterminate colitis
`
`Disease extent (%)
`Pancolitis
`Left-sided/distal
`Proctitis
`Terminal ileal Crohn's
`Disease duration (years)
`Disease activity (% in remission*)
`
`49 (17-85)
`51 : 47
`63
`32
`48
`27
`
`63
`27
`10
`
`34
`38
`21
`7
`8.6 (0.2-53)
`95
`
`Frequency of relapse in previous 2 years (%)
`Less than 1/year
`Once per year
`More than 1/year
`
`53
`26
`21
`
`1131). inflammatory bowel disease; NACC, National Association for
`Colitis and Crohn's disease.
`'4 Defined as a Simple Clinical Colitis Activity Index of < 6 for ulcera-
`tive colitis/indeterminate colitis26 or a Harvey-Bradshaw Index of < 8
`for Crohn's disease.27
`
`Table 2. Treatment details and rating scale results
`
`Dose of mesalazine (g/day)
`Prescribed regimen (%)
`Three times daily
`Twice daily
`Once daily
`Duration of niesalazine therapy (years)
`
`Concomitant medications (%)
`0
`1
`2
`> 3
`
`2.4 (0.4-3.6)
`
`64
`34
`2
`4.3 (0.2-14)
`
`50
`25
`6
`19
`
`Patient perceptions of effectiveness of mesalazine (%)
`Totally effective
`28
`Effective
`48
`Not sure
`18
`Not effective
`6
`SIBDQ*
`5.2 (2.3-7.0)
`Trust In Physician Scale
`85 (60-100)
`
`Hospital Anxiety and Depression Scale
`Anxiety sub-scale score
`Score > 8 on anxiety sub-scale (%)
`Depression sub-scale score
`Score > 8 on depression sub-scale (%)
`
`6 (0-17)
`34
`3 (0-13)
`16
`
`* Short Inflammatory Bowel Disease Questionnaire. Scores out of 7.
`Higher scores indicate better quality of life.28
`t Trust in Physician Scale. Scores out of 100. Higher scores indicate
`greater trust.29
`Hospital Anxiety and Depression Scale. Scores of 8 and above in
`either sub-scale indicate depression or aruciety.3°
`
`taking delayed-release mesalazine (Asacol) at 2.4 g/day
`(0.4-3.6 g/day) for 4.3 years (0.2-13 years). The full
`clinical and demographic details are shown in Table 1,
`and details of mesalazine therapy and rating scale
`results are shown in Table 2.
`Patients were invited to estimate their level of compli-
`ance in the range 0-100%, and the results are shown in
`Figure 4. Fifty-one patients (52%) reported full compli-
`ance with their prescribed regimen of maintenance
`5-ASA therapy, whilst 42 patients (43%) reported
`regular non-compliance (defined as taking < 80% of
`the prescribed medication).
`Patients reporting regular non-compliance were
`younger than compliant patients (P < 0.05), more
`likely to have been educated beyond the age of 16 years
`(P < 0.001), more likely to be in full-time employment
`(P < 0.05), more likely to be prescribed a three-times-a-
`day regimen (P < 0.05), more likely to be taking no
`other medications (P < 0.01) and more likely to
`perceive their medication as ineffective (P < 0.05).
`
`© 2003 Blackwell Publishing Ltd. Aliment Pharmacol Ther 18, 191-198
`
`SALIXN00012266
`
`Dr. Falk Ex. 2020
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 4
`
`

`
`COMPLIANCE WITH MAINTENANCE THERAPY IN IBD 195
`
`Compliant and non-compliant patients were, however,
`similar with respect to disease duration, activity and
`extent, the use of concomitant inflammatory bowel
`disease medications, family history of inflammatory
`bowel disease, membership of a patient organization
`(National Association for Colitis and Crohn's disease or
`Inflammatory Bowel Disease Club), quality of life (Short
`Inflammatory Bowel Disease Questionnaire) scores and
`rates of psychiatric morbidity (Hospital Anxiety and
`Depression Scale). Knowledge of the medication and
`experience of side-effects were also similar in both
`groups, as were the Trust in Physician Scale scores and
`the time since last out-patient visit. Logistic regression
`analysis, however, revealed that the only independent
`predictors of self-reported non-compliance were three-
`times daily dosing regimens [odds ratio (OR), 3.1; 95%
`confidence interval (CI), 1.8-8.4] and full-time employ-
`ment (OR, 2.7; 95% CI, 1.1-6.9). Of the 63 patients
`who were prescribed mesalazine three times daily, 57%
`admitted non-compliance and, of the 47 patients in full-
`time employment, 62% admitted non-compliance.
`All patients provided a spot sample of urine at the time
`of clinic attendance. The results of urinary drug
`measurement are shown in Figure 5. Twelve samples
`(12%) contained no detectable 5-ASA or N-acetyl-
`5-ASA. Patients providing these samples were more
`likely to have Crohn's disease (P < 0.01), to have
`poorer quality of life scores (Short Inflammatory Bowel
`Disease Questionnaire) (P < 0.01) and to have anxiety
`and/or depression as assessed by the Hospital Anxiety
`and Depression Scale (a score of more than eight on
`either sub-scale: anxiety, P < 0.01; depression,
`P < 0.001). Logistic regression analysis, however,
`showed that depression was the only independent
`predictor of failure to take any medication (OR, 10.5;
`95% CI, 1.8-79.0). Of the 16 patients scoring more
`than eight on the depression sub-scale of the Hospital
`Anxiety and Depression Scale, 42% had undetectable
`urinary drug levels.
`In addition to the 12 patients who had undetectable
`urinary drug levels, 18 patients (18%) had urinary total
`5-ASA to creatinine ratios lower than expected from the
`healthy volunteer data (ratio of 1 in patients pre-
`scribed (cid:9)
`1.6 g/day). Such patients were younger
`(P < 0.01) than those providing samples with expected
`levels, more likely to be in full-time employment
`(P < 0.05) and more likely to be prescribed three-
`times-daily regimens (P < 0.01). However, three-times-
`daily dosing was the only independent predictor of such
`
`© 2003 Blackwell Publishing Ltd. Aliment Pharmacol 7'her 18, 191-198
`
`4
`
`100% 90',
`
`MIMS
`80% 70% 60% 50% 30% 0%
`Self-rated compliance
`
`Figure 4. Self-reported levels of compliance in patients prescribed
`delayed-release mesalazine (n = 98).
`
`Dose of mesalazine (mg/day)
`
`Figure 5. Logarithmic plot of urinary total 5-aminosalicylic acid
`(5-ASA) to creatinine ratios in patients. Each point represents one
`patient sample (n = 98).
`
`partial non-compliance (OR, 3.7; 95% CI, 1.8-8.9).
`Urinary drug levels appeared to be unrelated to disease
`activity.
`Seven of the 12 patients (58%) providing samples
`containing no detectable 5-ASA or N-acetyl-5-ASA
`admitted to some degree of non-compliance, but only
`two (16%) admitted to complete non-compliance.
`Thirteen of the 18 patients (72%) providing urine
`samples suggesting partial non-compliance admitted to
`less than 80% compliance.
`
`SAUXN00012267
`
`Dr. Falk Ex. 2020
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 5
`
`

`
`196 M. . SHALE & S. A. RILEY
`
`DISCUSSION
`
`Non-compliance is recognized as a key determinant of
`treatment failure in a variety of clinical settings.25. 33-36
`The causes of non-compliance, however, are often
`unclear, and a number of factors may contribute.14-19
`Compliance data in patients with inflammatory bowel
`disease are limited.
`In the present study, on direct enquiry, 48% of patients
`admitted to regularly missing doses of medication, and
`43% estimated their regular compliance to be less than
`80% of the prescribed amount, with 2% admitting to
`taking no medication at all. Three-times-daily dosing
`and full-time employment were identified as independ-
`ent risk factors for non-compliance. Urinary drug
`analysis, on the other hand, revealed no detectable
`drug or metabolite in 12% of patients, and an additional
`18% had urinary levels suggesting partial non-compli-
`ance. Complete failure to take medication was associ-
`ated with depression. and partial compliance with
`three-times-daily dosing. Direct patient enquiry identi-
`fied most of the patients who were judged to be partially
`non-compliant on the basis of urinary drug testing
`(13 of 18), but only two of 12 who were completely
`non-compliant, although five of these admitted to
`partial non-compliance.
`The prevalence of non-compliance in this study is
`similar to that reported in other chronic disease
`states19. 21. 23. 33. 34. 37 and in the few previous
`studies of compliance in patients with ulcerative
`colitis.1°-12 Van Hees and Van Tongeren, who also
`measured drug levels, reported partial compliance with
`maintenance sulfasalazine therapy in 41% of patients,
`and total non-compliance in 12%.1° Kane et al., study-
`ing pharmacy records, found that 60% of patients with
`quiescent ulcerative colitis collected less than 80% of
`prescribed medication. In this study, male sex and more
`than four concomitant medications appeared to in-
`crease the risk of poor compliance, whereas recent
`endoscopy and being married were associated with good
`compliance." In a more recent study, Nigro et al., using
`patient self-reporting, found that 7% of patients admit-
`ted complete non-compliance and 10.5% reported
`partial non-compliance. Psychiatric morbidity and dis-
`ease severity were risk factors for poor compliance,
`whereas a longer duration of disease was associated
`with better compliance.12
`In the present study. three-times-daily dosing was the
`most significant risk factor for partial non-compliance.
`
`This association is perhaps not surprising as, in other
`disease states, compliance is similar when medications
`are prescribed once or twice daily, but falls when
`treatments are given in three or more daily doses.18-2°
`The current recommendation for sulfasalazine dosing.
`in both active and quiescent disease, however, is still
`four times daily, although many use the drug twice
`daily. Dosing recommendations with the newer amino-
`salicylates vary somewhat. All recommend divided daily
`dosing for both active and quiescent disease, some
`specifying three-times-daily dosing in active disease, and
`some, but not all, specifying twice-daily dosing for
`maintenance of disease remission.38
`Pharmacokinetic studies show that peak serum 5-ASA
`and N-acetyl-5-ASA levels are similar following once-
`daily or divided daily dosing with delayed-release
`mesalazine,39 suggesting that dose-related toxicity is
`likely to be similar with the two regimens. Furthermore,
`rectal mucosal levels of 5-ASA and N-acetyl-5-ASA, the
`probable determinant of therapeutic success, are similar
`following once-daily or divided daily dosing, suggesting
`that the clinical efficacy should also be equivalent.39
`Once- or twice-daily dosing therefore seems to be both
`feasible and desirable.
`The association of partial non-compliance with full-
`time employment was somewhat surprising, partic-
`ularly given its apparent independence from the effect of
`three-times-daily regimens, suggesting that the incon-
`venience of taking medication at work was not the
`explanation. Whether this relates to differences in
`reporting, the influence of a busier lifestyle or other
`factors is unclear.
`The association of complete non-compliance with
`depression is to be expected, and confirms the observa-
`tions of Nigro et al., who found that psychiatric
`disorders, including depression and anxiety, were
`present in five of six completely non-compliant patients
`and in six of nine partially compliant patients with
`inflammatory bowel disease.12 Depression is not uncom-
`mon in patients with inflammatory bowel disease,4°' 41
`and may go unrecognized. The identification of depres-
`sion is clearly important as appropriate treatment may
`not only improve psychiatric morbidity, but may
`improve compliance. In the present study, the patient-
`rated Hospital Anxiety and Depression Scale proved to
`be a convenient and useful tool for the detection of often
`unrecognized depression.
`Whilst the impact of complete non-compliance on the
`disease process is clear,42 the influence of partial non-
`
`© 2003 Blackwell Publishing Ltd. Aliment Pharmacol Ther 18, 191-198
`
`SALIXN00012268
`
`Dr. Falk Ex. 2020
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 6
`
`

`
`COMPLIANCE WITH MAINTENANCE THERAPY IN IBD 197
`
`compliance is less certain. An increased risk of relapse
`seems likely,13 although the efficacy of intermittent
`dosing regimens in clinical trials suggests that the
`impact may vary between patients, and may relate to
`patterns of non-compliance 43' " The effect of partial
`compliance on cancer risk is similarly unknown. The
`imprecise definition of compliance used in studies
`examining the effect of mesalazine on cancer risk (the
`absence of documentation of non-compliance in the
`medical notes) suggests that even partial compliance
`with maintenance mesalazine therapy may be protect-
`ive.7-9 Further studies in this area are clearly desirable.
`It is important to acknowledge that our study is likely
`to have underestimated the prevalence of non-compli-
`ance. Firstly, we studied compliance at the time of clinic
`attendance and, although patients were unaware of the
`study prior to arrival, compliance is known to improve
`around the time of clinic attendance.45 Secondly, we
`studied only clinic attenders, and it seems likely that
`non-attenders are more likely to be non-compliant.
`Thirdly, we studied urinary drug levels in healthy
`volunteers in an attempt to give a more objective
`measure of compliance. Although this is clearly of value
`when drug levels are undetectable, the interpretation of
`low drug levels is difficult given the marked variability in
`drug excretion at a given dose. We deliberately chose a
`low cut-off point to define non-compliance, but appre-
`ciate that this will probably have led to an underesti-
`mation of the frequency of partial non-compliance.
`In conclusion, the results of this study show that
`non-compliance with maintenance mesalazine therapy
`is widespread in patients with inflammatory bowel
`disease. Direct enquiry revealed partial non-compliance
`in 48% and urine testing revealed complete non-
`compliance in 12%. Three-times-daily dosing and
`full-time employment emerged as independent risk
`factors for partial non-compliance and depression as
`an independent risk factor for complete non-compli-
`ance. Direct enquiry detects most patients who are
`non-compliant, but few patients with undetectable
`urinary drug levels admit to complete non-compliance.
`These factors should be considered when choosing a
`maintenance drug regimen and when monitoring
`compliance.
`
`ACKNOWLEDGEMENTS
`
`We wish to express our gratitude to our colleagues in
`the Sheffield Teaching Hospitals NHS Trust who allowed
`
`© 2003 Blackwell Publishing Ltd. Aliment Pharmacol 7'her 18,191-198
`
`us to study their patients, and to Swann Morton for
`financial support.
`
`REFERENCES
`
`1 Riley SA. What dose of 5-aminosalicylic acid (mesalazine) in
`ulcerative colitis? Gut 1997: 42: 761-3.
`2 Misiewicz JJ, Lennard-Jones JE, Connell AM, et al. Controlled
`trial of sulphasalazine in maintenance therapy for ulcerative
`colitis. Lancet 1965; i: 185-8.
`3 Riley SA, Mani V, Goodman MJ, et al. Comparison of delayed-
`release 5-aminosalicylic acid (mesalazine) and sulphasalazine
`as maintenance treatment for patients with ulcerative colitis.
`Gastroenterology 1988; 94: 1383-9.
`4 The Mesalamine Study Group. An oral preparation of mesal-
`amine as long-term maintenance therapy for ulcerative colitis.
`A randomised, placebo controlled trial. Ann Intern Med 1996;
`124: 204-21.
`5 Prantera C, Pallone F, Brunetti G, et al. Oral 5-aminosalicylic
`acid (Asacol) in the maintenance treatment of Crohn's
`disease. Gastroenterology 1992; 103: 363-8.
`6 Caprilli R, Andreoli A, Capurso L, et al. Oral mesalazine
`(5-aminosalicylic acid: Asacol) for the prevention of post-
`operative recurrence in Crohn's disease. Aliment Pharmacol
`Ther 1994; 8: 35-43.
`7 Moody GA, Jayanthi V, Probert CS, et al. Long-term therapy
`with sulphasalazine protects against colorectal cancer in
`ulcerative colitis: a retrospective study of colorectal cancer
`risk and compliance with treatment in Leicestershire. Eur J
`Gastroenterol 11epatol 1996; 8: 1179-83.
`8 Pinczowski D, Ekbom A, Baron J, et al. Risk factors for colo-
`rectal cancer in patients with ulcerative colitis: a case control
`study. Gastroenterology 1994; 107: 117-20.
`9 Eaden J, Abrams K, Ekbom A, et al. Colorectal cancer pre-
`vention in ulcerative colitis: a case—control study. Aliment
`Pharmacol Ther 2000; 14: 145-53.
`10 Van Hees PA, Van Tongeren JH. Compliance to therapy in
`patients on a maintenance dose of sulphasalazine. J Clin
`Gastroenterol 1982; 4: 333-6.
`11 Kane SV, Cohen RD, Aitkens JE, et al. Prevalence of non-
`adherence with maintenance mesalamine in quiescent
`ulcerative colitis. Am J Gastroenterol 2001; 96: 2929-33.
`12 Nigro G, Angelini G, Grosso SB, et al. Psychiatric predictors of
`noncompliance in inflammatory bowel disease: psychiatry
`and compliance. J Clin Gastroenterol 2001; 32: 66-8.
`13 Kane SV, Hanauer SB. Medication adherence is asso-
`ciated with improved outcomes in patients with quiescent
`ulcerative colitis (UC) [Abstract]. Gastroenterology 2000;
`118: 4900.
`14 Haynes RB. Determinants of compliance: the disease and
`mechanics of treatment. In: Haynes RB, Taylor DT, Sackett
`DL, eds. Compliance in Health Care. Baltimore, MD: Johns
`Hopkins University Press, 1979.
`15 Cienchanowski PS, Katon WJ, Russo JE. Depression and dia-
`betes: impact of depressive symptoms on adherence, function
`and costs. Arch Intern Med 2000; 160: 3278-85.
`
`SALIXN00012269
`
`Dr. Falk Ex. 2020
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 7
`
`

`
`198 M. I. SHALE & S. A. RILEY
`
`16 Eraker SA, Kirscht JP, Becker MH. Understanding and
`improving patient compliance. Ann Intern Med 1984; 100:
`258-68.
`17 Peck CL, King NJ. Compliance and the doctor-patient
`relationship. Drugs 1985; 30: 78-84.
`18 Eisen SA, Miller DK, Woodward RS, et al. The effect of pre-
`scribed dose frequency on patient medication compliance.
`Arch Intern Med 1990; 150: 1881-4.
`19 Greenberg RN. Overview of patient compliance with medica-
`tion dosing: a literature review. Clin Ther 1984; 6: 590-9.
`20 Puller T, Birtwell AJ, Wiles PG, et al. Use of a pharmacological
`indicator to compare compliance with tablets prescribed to be
`taken once, twice, or three times daily. Clin Pharmacol Ther
`1989: 44: 540-5.
`21 Fletcher SW, Pappius EM, Harper SJ. Measurement of medi-
`cation compliance in a clinical setting: comparison of three
`methods in patients prescribed digoxin. Arch Intern Med
`1979; 139: 635-8.
`22 Choo PW, Rand CS, Inui TS, et al. Validation of patient
`reports, automated pharmacy records, and pill counts with
`electronic monitoring of adherence to antihypertensive ther-
`apy. Med Care 1999; 37: 846-57.
`23 Stephenson BJ, Rowe BH, Haynes RB, et al. Is this patient
`taking the treatment as prescribed? J Am Med Assoc 1993;
`269: 2779-81.
`24 Gilbert JR, Evans CE, Haynes RB, et al. Predicting compliance
`with a regimen of digoxin therapy in family practice. Can Med
`Assoc J 1980; 123: 119-22.
`25 Pullar T, Peaker S, Martin MFR, et al. The use of a pharma-
`cological indicator to investigate compliance in patients with
`a poor response to anti-rheumatic therapy. Br J Rheumatol
`1988; 27: 381-4.
`26 Walmsley RS, Ayres RC, Pounder RE, et al. A simple clinical
`colitis activity index. Gut 1998: 43: 29-32.
`27 Harvey RF, Bradshaw JM. A simple index of Crohn's disease
`activity. Lancet 1980; i: 514.
`28 Irvine EJ, Zhou Q, Thompson AK, et al. The Short Inflamma-
`tory Bowel Disease Questionnaire: a quality of life instrument
`for community physicians managing inflammatory bowel
`disease. Am J Gastroenterol 1996; 91: 1571-8.
`29 Thom DH, Ribisl KM, Stewart AL, et al. Further validation and
`reliability testing of the Trust in Physician Scale. Med Care
`1999; 37: 510-7.
`30 Zigmond AS, Snaith RP. The hospital anxiety and depression
`scale. Acta Psychiatr Scand 1983; 67: 361-70.
`31 Hussain FN, Ajjan RA, Moustafa M, et al. Simple method for
`the determination of 5-aminosalicylic and N-acetyl-5-amino-
`
`salicylic acid in rectal tissue biopsies. J Chromatogr B 1998;
`716: 257-66.
`32 Husdan H, Rappoport A. Estimation of creatinine by the Jaffe
`reaction: a comparison of three methods. Clin Chem 1968;
`14: 222-38.
`33 Paterson DL, Swindells S, Mohr J, et al. Adherence to protease
`inhibitor therapy and outcomes in patients with HIV infection.
`Ann Intern Med 2000; 133: 21-30.
`34 Graham DY, Lew GM, Malaty HM, et al. Factors influencing
`the eradication of Helicobacter pylori with triple therapy.
`Gastroenterology 1992; 102: 493-6.
`35 Hilbrands LB. Hoitsma AJ, Ke