Factors Affecting Dissatisfaction to Treatments in Patients With Chronic Constipation and IBS With Constipation
Condition: Constipation; Irritable Bowel Syndrome
MeSH terms: Irritable Bowel Syndrome; Syndrome; Constipation
Study type: Observational

Summary: 
      Chronic constipation (CC) and Irritable Bowel Syndrome with Constipation (IBS-C) are two
      conditions difficult to manage because factors affecting dissatisfaction to treatments are
      misleading. This observational multicentric national study is aimed to assess which factors
      are related with a clinically significant improvement in patients with CC and IBS-C. Patients
      will be evaluated at baseline and after every one-month "standard of care" therapy with
      standardised questionnaires to assess bowel habit and satisfaction to treatments.
      Somatisation, quality of life, colonic transit time and resting anal pressure will be
      assessed at baseline.
    

Detailed description: 
      Introduction: Chronic constipation (CC) and Irritable Bowel Syndrome with Constipation
      (IBS-C) are two overlapping conditions in which the patients are dissatisfied of their bowel
      habit. In a non negligible proportion of patients, the dissatisfaction persists after a first
      line treatment with effective laxatives such as macrogol and bisacodyl. Prucalopride and
      linaclotide are two relatively new treatments that are used in these conditions. Prucalopride
      is a prokinetic drug licensed for patients with CC not responsive to standard laxative
      treatments. Linaclotide is a guanylate cyclase-C agonist that has been shown to improve both
      abdominal pain and bowel habits in patients with IBS-C. Despite these new treatments, a
      consistent number of patients remains dissatisfied suggesting that they complain of a
      "refractory" or "intractable" form of constipation.

      Both IBS-C and CC are diseases defined by patients symptoms, as well as the lack of response
      to treatments. The Patient Assessment of Constipation-Symptoms (PAC-SYM) is a validated
      self-report questionnaire able to assess over time both general constipation severity and
      cluster of symptoms specific of this condition and to indicate the patient perspective on the
      disorder. Some limitations on the performances of this questionnaire have however emerged and
      it has recently been demonstrated that a Modified version of the PAC-SYM (M:PAC-SYM) is a
      better tool to assess constipation severity in patients recruited in tertiary referral
      centres. A change > 0.24 in the M:PAC-SYM score has been shown to define whether the response
      to treatment is adequate or not, but how this variation persists in the long term has not yet
      been investigated.

      Several factors may influence the lack of response to treatments. Stool characteristics,
      psychological alterations (somatisation), delayed colonic transit and increased resting anal
      pressure may influence constipation severity, but the relative role of these factors is still
      unknown. On the other hand the bowel frequency, that is commonly believed to reflect
      constipation, does not seem to play a major role.

      Aims: The purpose of this study will be to perform a pooled analysis of multiple prospective
      treatment optimization N-of-1 trials in patients with IBS-C and CC aimed at: 1) define how
      many patients achieve a sustained improvement; 2) define which factors are associated with a
      sustained improvement; 3) evaluate the suitability of M:PAC-SYM for treatment optimization
      among patients with CC or IBS-C 4) assess in a longitudinal follow up the natural history of
      IBS-C and CC submitted to standardised treatments.

      Study design: All patients aged 18 - 80 years old with IBS-C and CC will be included in this
      observational multicentric national study. Patients with secondary causes of CC will be
      excluded. The diagnosis of CC and IBS-C will be defined according to Rome III criteria. All
      patients should undergo a thorough clinical examination including a rectal examination
      searching for both anatomical and functional defects. Dietary advices and supplementation
      with soluble fibres in those patients reporting insufficient dietary fibre intake will be
      given. Basic principles of defecation will be given to all patients and in particular to
      those with dyssynergic behaviour during straining.

      The following items will be recorded at enrolment: 1) demographic data; 2) clinical history
      including pregnancy and anorectal surgery; 3) causes of secondary constipation (TSH and
      calcium levels, ultrasonography and colonoscopy when necessary); 4) rectal examination (anal
      pressure at rest and puborectalis relaxation during simulated evacuation); 5) ongoing
      therapy; 6) "satisfaction" with the current therapy (recorded with two items: 1-7 point
      visual analogue scale (VAS) and -7 +7 VAS ; 7) M:PAC-SYM; 8) Somatisation (Short Form-12
      (SF-12) including the 12 questions of the Symptom Checklist-90 Revised (SCL-90-R)
      somatisation score); 9) quality of life (SF36, a validated questionnaire evaluating patients'
      perceptions of functional impairment into eight subscales that give rise to two composite
      scores assessing perceived physical and mental health); 10) colonic transit time (recorded
      according to Metcalf et al, off of laxatives and maintaining the usual diet. Patients will
      ingest 20 radio-opaque markers at 9 on each of three consecutive days and an abdominal X ray
      will be obtained at 9 of the fourth day. Colonic transit time will be calculated as the
      number of retained markers x 1.2; 11) anal resting pressure (the anal pressure (mmHg) will be
      recorded in resting conditions for ten minutes and it will be measured as the average of the
      last 30 seconds pressure recording on the channel with the highest pressure).

      Enrolled patients will be directed to a one-month therapy with macrogol (17-34 mg per day)
      and if needed with bisacodyl (5-10 mg per day) ± bowel enema. Optimization of frequency of
      laxatives and dose titration will be encouraged. During the month, patients will fill a daily
      diary asking for bowel habits (stool frequency and consistency), abdominal pain, straining,
      incomplete evacuation and urgency. After one-month therapy (T1) patients will be admitted to
      the outpatient service for a follow up visit and "satisfaction" with the current therapy
      (recorded with two items: 1-7 point visual analogue scale (VAS) and -7 +7 VAS ) and M:PAC-SYM
      will be recorded.

      Satisfied patients (satisfaction score>4) will be invited to continue the same therapy.
      Unsatisfied or partially satisfied patients (satisfaction score≤4) with a diagnosis of CC
      will be directed to one-month therapy with prucalopride 2 mg per day. Unsatisfied or
      partially satisfied patients (satisfaction score≤4) with a diagnosis of IBS-C will be
      directed to one-month therapy with linaclotide 290 mcg per day. When necessary, both patients
      with CC and IBS-C will be allowed to take bisacodyl (max 2 tablets a day, 5 mg each) and
      otilonium bromide (max 2 tablets a day, 40 mg each). As during the first month of therapy,
      patients will fill a daily diary asking for bowel habits (stool frequency and consistency
      according to 1-7 Bristol score ), abdominal pain (0-10) , straining, incomplete evacuation
      and urgency. After the one month therapy the patients will be evaluated as after the first
      follow-up visit (see T1). Patients will repeat for one month the previous treatment if
      satisfied or will be switched to the other treatment for one month, that will be repeated if
      satisfied.

      Statistical analysis A pooled analysis will be performed on all patients achieving a
      sustained improvement or failing to achieve this improvement after all the three treatment
      options. Clinical and demographic information, along with self-reported outcomes will be
      abstracted from clinical charts and daily diary. The analytic dataset will include the
      following variables: Socio-demographics (age, gender, education, employment status); Clinical
      history (comorbidities, abdominal and extra-abdominal surgery, concurrent medications,
      previous pregnancy, life-style, dietary habits and ongoing therapy); Results of rectal
      examination; Psychological Profile (SF-12); Quality of life (SF36); Colonic transit time;
      Anal resting pressure; "satisfaction" with the current therapy (recorded with two items: 1-7
      point visual analogue scale (VAS) and -7 +7 VAS ) and M:PAC-SYM; bowel habits (stool
      frequency and consistency), severity of abdominal pain, straining, incomplete evacuation and
      urgency/month.

      Data will be reported as absolute and relative frequencies or means and standard deviations
      for discrete or continuous variables respectively. Agreement between responder status defined
      by treatment satisfaction scores or by M-PAC-SYM changes will be assessed with K coefficient
      for all assessment time-point. The investigators will calculate the variance partition
      coefficient from a random-intercept hierarchical logistic model (level 1: each study
      time-period; level 2: patient) in order to evaluate the proportion of variance explained by
      treatment-related vs patient-related factors in the likelihood of treatment response (change
      in satisfaction>2). Such model would allow to account for the auto-correlation of each
      observation within patients. Treatment modality will be accommodated with time-varying
      covariates indicating active/inactive treatments at each study periods. If the variance
      partition coefficient suggest that a significant share of variance in the likelihood of
      treatment response is explained by patient-related factors, socio-demographic, clinical,
      psychological and physiological patient-related factors will be included in the model. In
      order to assess the role of constipation-related symptoms in driving patients global
      satisfaction with treatment, the investigators will specify two additional models. In the
      first additional model, the M:ABD and the M:STO subscale scores of the M:PAC-SYM
      questionnaire will be included in the model of treatment response likelihood as time-varying
      covariate. In the second specification all M:PAC-SYM items will be included simultaneously as
      time-varying covariates.

      Power calculations relative to key analysis planned for the study:

        1. Impact of somatization and quality of life on treatment response likelihood (change in
           satisfaction>2): A sample of 82 patients completing at least 4 assessments would achieve
           80% power of detecting a f=0,25 effect size difference in treatment response likelihood
           for patients diagnosed with somatization disorder, based on established SCL-90-R
           cut-off.

        2. Impact of constipation-related symptoms on treatment response likelihood
           (satisfaction>2): A sample of 38 patients completing at least 4 assessments would
           achieve 80% power of detecting a f=0,25 effect size difference in treatment response
           likelihood for patients reporting each constipation-related symptoms (absent-mild
           symptoms vs moderate-severe PAC-SYM items) after Bonferroni correction for multiple
           testing (corrected alpha= 0.0045455).

      According to these power calculations it is planned to reach the sample size of 90 patients
      achieving a sustained response or dissatisfied of the proposed treatments.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        outpatients reffering to a third level center