The impact of biological interventions for ulcerative colitis on health-related quality of life

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

The primary objective is to systematically assess the impact of biologic therapy on the QoL of ulcerative colitis patients.

Background

Ulcerative colitis (UC) is an idiopathic chronic intestinal inflammation of the colon characterized by periods of abdominal pain and bloody diarrhea. UC has a major impact on patients' quality of life (QoL). QoL and general life satisfaction are significantly lower in patients with UC compared to that of the general population (Petrak 2001; Janke 2004; Bernklev 2005; Janke 2005; Irvine 2008). Variables that influence the QoL of patients with UC include disease course (extent, severity, and relapse pattern), medical therapy (efficacy, adverse events and adherence issues), and demographic, psychosocial and socioeconomic characteristics (Irvine 2008). Disease activity is the most important predictor of QoL (Janke 2005; Irvine 2008). Patients with UC experience difficulty with regular daily activities of living resulting in workplace and school absenteeism (Boonen 2002; Marri 2005; Bernklev 2006; Reinisch 2007). Randomized controlled trials evaluating medical interventions for UC have traditionally used clinical disease activity indices which focus on subjective symptoms to define primary outcomes such as clinical remission or improvement. This focus on symptomatology results in a failure to assess QoL, work productivity and other important indicators of successful treatment such as mucosal healing. Mucosal healing is associated with a reduced likelihood of future relapses, need for surgery and hospitalizations (Ha 2010).

The introduction of effective but very expensive treatments (e.g. biologics) for ulcerative colitis forces physicians and society to make decisions regarding the allocation of scarce resources (Feagan 1999). Such decisions are often based on pharmacoeconomic analyses that evaluate the incremental cost required to achieve clinically meaningful outcomes including disease symptoms and complications, surgery, hospitalization and health-related QoL (Feagan 1999). An assessment of the QoL of patients receiving a biological intervention also allows for a cost-utility analysis which can guide clinical decision-making and health care policy (Feagan 1999; Irvine 2008).

Health-related QoL includes four main components: physical function, social and emotional well-being, ability to work and freedom from disease symptoms (Feagan 1999). Two psychometric questionnaires, the IBD questionnaire (Guyatt 1989; Irvine 1994; Irvine 1996) and the general short form-36 health survey (Ware 1992) have been commonly used to assess QoL in patients with inflammatory bowel disease including ulcerative colitis. The IBD questionnaire (IBDQ) is comprised of 32 questions covering bowel function (e.g. loose stool, abdominal pain), systemic function (e.g. fatigue, altered sleep pattern), social function (e.g. work attendance, need to cancel social events) and emotional function (e.g. anger, irritability, depression). Each question is scored using a seven-point Likert scale with one indicating severe issues and seven indicating no issues (Feagan 1999). The short form-36 health survey (SF-36) assesses physical functioning, role limitations due to physical or emotional problems, bodily pain, general health, vitality, social functioning, mental health and change in health status over the previous year (Feagan 2007). The European QoL index (EQ-5D) is comprised of five questions relating to the subjects level of impairment in; mobility, self-care, usual activities, pain or discomfort, and anxiety or depression (Konig 2002). Each instrument has been extensively validated in patients with IBD.

The impact of biologics on QoL in UC has not been studied comprehensively, although a 2009 review of studies that assessed QoL after biological therapies in patients with Crohn's or UC found that in only one out of eight studies did the biological intervention not significantly improve QoL as compared to the placebo or control group (Vogelaar 2009). Seven of the eight studies were in Crohn's patients and thus, the intent of this review is to assess the health-related QoL with biologics therapy specifically in patients with active or quiescent ulcerative colitis.

Objectives

The primary objective is to systematically assess the impact of biologic therapy on the QoL of ulcerative colitis patients.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials comparing biologics (e.g. infliximab, adalimumab, certolizumab pegol, golimumab, vedolizumab, natalizumab, interferon alpha and rituximab) with placebo will be considered for inclusion.

Types of participants

Adult patients with ulcerative colitis (active or quiescent) defined by a combination of clinical, radiographic, endoscopic and histological criteria will be included.

Types of interventions

Studies that review the use of biologics for active or quiescent ulcerative colitis will be considered for inclusion. Studies that do not measure QoL as an outcome will not be included.

Types of outcome measures

Primary outcomes

The primary outcome will be the proportion of patients achieving improvement in QoL as defined by the studies (e.g. validated QoL instruments such as IBDQ, SF-36 or EQ-5D) and expressed as a percentage of patients randomized (intention to treat analysis).

Secondary outcomes

Changes in mean quality of life scores (e.g. IBDQ, EQ-5D and SF-36) will be assessed as a secondary outcome. Some other secondary outcomes that may be important include workplace productivity and participation and will be assessed if enough data exists to complete such an analysis.

Search methods for identification of studies

Electronic searches

Electronic searches will include:

1. MEDLINE (1946 - present);

2. EMBASE (1974 - present);

3. Cochrane Register of Controlled Trials (CENTRAL); and

4. Digestive Disease Week (DDW) abstracts of randomized controlled and controlled clinical trials (1981 to 2012).

The databases will be searched for randomized controlled and controlled clinical trials using the search strategies described in Appendix 1. There will be no language or date restrictions.

Searching other resources

The reference lists of studies and review articles identified by the literature search will be hand searched to identify other potential studies.

Data collection and analysis

Selection of studies

All studies identified by the literature search will be independently assessed for eligibility by two authors (MM and KAB) based on the inclusion criteria described above. Disagreements will be resolved by consensus. Studies published in abstract form only will be included if enough data are provided to assess outcome. Abstract authors will be contacted by the reviewer for missing data and/or information.

Data extraction and management

Data extraction forms will be developed and used to extract information on the results of included studies. Two authors will independently extract data. Disagreements will be resolved by consensus. The following data will be retrieved from the eligible studies:

1. General information: title, journal, year, published/unpublished;

2. Study information: design, methods of randomization, concealment of allocation and binding, power calculation, a priori and post hoc analyses;

3. Intervention and control: type and dose of a medication, placebo or active comparator;

4. Eligibility: inclusion/exclusion criteria, total number screened and randomized;

5. Baseline characteristics (in each group) age, sex, race, disease severity (and how evaluated) concurrent medications used;

6. Follow-up: length of follow-up, assessment of compliance of treatment, withdrawals and loss to follow-up; and

7. Outcomes: primary and secondary outcomes, QoL outcomes, adverse events.

Assessment of risk of bias in included studies

All studies will be independently reviewed by each author to assess methodological quality using the Cochrane risk of bias tool (Higgins 2011). Factors to be assessed will include:
1) sequence generation (i.e. was the allocation sequence adequately generated?);
2) allocation sequence concealment (i.e. was allocation adequately concealed?);
3) blinding (i.e. was knowledge of the allocated intervention adequately prevented during the study?);
4) incomplete outcome data (i.e. were incomplete outcome data adequately addressed?);
5) selective outcome reporting (i.e. are reports of the study free of suggestion of selective outcome reporting?); and
6) other potential sources of bias (i.e. was the study apparently free of other problems that could put it at a high risk of bias?).

A judgement of 'Yes' indicates low risk of bias, 'No' indicates high risk of bias, and 'Unclear' indicates unclear or unknown risk of bias.

We will use the GRADE criteria to evaluate the overall quality of evidence for the primary outcomes and selected secondary outcomes (Guyatt 2008; Schünemann 2011). Randomized trials start as high quality evidence, but may be downgraded due to: (1) risk of bias, (2) indirectness of evidence, (3) unexplained heterogeneity, (4) sparse data, and (5) publication bias. The overall quality of evidence for each outcome will be determined after considering each of these elements, and categorized as high quality (i.e. further research is very unlikely to change our confidence in the estimate of effect); moderate quality (i.e. further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate); low quality (i.e. further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate); or very low quality (i.e. we are very uncertain about the estimate).

Measures of treatment effect

Data will be analyzed using Review Manager (RevMan 5.2). The relative risk (RR) with 95% confidence intervals (95% CI) will be calculated for each dichotomous outcome. The number needed to treat (NNT) and risk difference (RD) will be calculated where appropriate. For continuous variables, the mean difference (MD) or standardized mean difference (SMD) with 95% CI will be calculated. In cross-over studies, only data from the first arm will be included. All data will be analyzed on an intention-to-treat basis. The presence of heterogeneity among studies will be assessed using the Chi2 test (a P value of 0.10 will be regarded as statistically significant). The l2 statistic will be used to estimate the degree of heterogeneity. This measure describes the percentage of total variation across studies that results from heterogeneity rather than chance. A value of 25% is considered to indicate low heterogeneity, 50% moderate heterogeneity and 75% high heterogeneity (Higgins 2003). Data will be pooled for analysis if interventions, patient populations, and outcome measures are similar enough to justify pooling (determined by consensus). Data will not be pooled for meta-analysis if a high degree of heterogeneity is detected (i.e. l2 > 75%). A fixed-effect model will be used to pool data in the absence of heterogeneity. A random-effects model will be used if significant heterogeneity is detected. The pooled RR and 95% CI will be calculated for dichotomous outcomes. For continuous outcomes the pooled MD or SMD and 95% CI will be calculated as appropriate.

Subgroup analysis and investigation of heterogeneity

Subgroup analyses will be performed by type of biological intervention (e.g. monoclonial antibodies, leukocyte trafficking inhibitors and other). When significant heterogeneity is detected, we will explore potential causes for heterogeneity including differences in patient populations, outcomes and interventions.

Sensitivity analysis

Planned sensitivity analyses include the exclusion of poor quality studies and studies published in abstract form.

Acknowledgements

Funding for the IBD/FBD Review Group (September 1, 2010 - August 31, 2015) has been provided by the Canadian Institutes of Health Research (CIHR) Knowledge Translation Branch (CON - 105529) and the CIHR Institutes of Nutrition, Metabolism and Diabetes (INMD); and Infection and Immunity (III) and the Ontario Ministry of Health and Long Term Care (HLTC3968FL-2010-2235).

Miss Ila Stewart has provided support for the IBD/FBD Review Group through the Olive Stewart Fund.

Appendices

Appendix 1. Search strategies

Pubmed (1946 – Present)

Search Query

#5 Search (#1 AND #2 AND #3 AND #4)

#4 Search (HRQoL OR HRQL OR “quality of life” OR SF-36 OR “short form-36” OR SF-36V2 OR IBDQ OR OR “inflammatory bowel disease questionnaire” OR EQ-5D OR WPAI* OR “work productivity” OR “activity impairment” OR questionnaire OR questionnaire* OR “activities of daily living” OR ADL OR questionnaire [MH])

#3 Search ((colitis AND ulcerat*) OR proctosigmoiditis OR rectocolitis OR rectosigmoiditis OR (ulcerative AND rectocolitis) OR (ulcerative AND proctocolitis) OR (haemorrhagic AND ulcerative) OR (hemorrhagic AND ulcerative) OR (haemorrhagic AND proctocolitis) OR (hemorrhagic AND proctocolitis) OR proctitis)

#2 Search ("anti tnf" OR anti-tnf OR anti-TNF* OR "anti TNF*" OR anti-tum* OR antitum* OR "anti IL*" OR anti-IL* OR etanercept OR infliximab OR "mab CA2" OR ustekinumab OR "CNTO 1275" OR certolizumab* OR CDP870 OR natalizumab OR anti-alpha* OR "anti alpha*" OR onercept OR r-hTBP-1 OR vedolizumab OR MLN0002 OR basiliximab "CHI 621" OR certolizumab OR "rhuMAb*" OR visilizumab OR "HuM291" OR daclizumab OR "DAC HYP" OR briakinumab OR ABT-874 OR adalimumab OR D2E7 OR anti-CD* OR "anti CD*" OR anti-integr* OR antiintegr* OR "anti madcam" OR anti-madcam OR CDP571 OR PF00547 OR PF-00547 OR IFN* OR interferon* OR RDP58 OR antibodies, monoclonal [MH])

#1 Search (singl* OR doubl* OR tripl* OR trebl* OR blind* OR mask* OR placebo* OR single-blind* OR double-blind* OR triple-blind* OR random* OR controlled)

EMBASE (1974 – Present)

# Searches

1 random$.tw.

2 factorial$.tw.

3 (crossover$ or cross over$ or cross-over$).tw.

4 placebo$.tw.

5 single blind.mp.

6 double blind.mp.

7 triple blind.mp.

8 (singl$ adj blind$).tw.

9 (double$ adj blind$).tw.

10 (tripl$ adj blind$).tw.

11 assign$.tw.

12 allocat$.tw.

13 crossover procedure/

14 double blind procedure/

15 single blind procedure/

16 triple blind procedure/

17 randomized controlled trial/

18 or/1-17

19 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human

or humans).ti.)

20 18 not 19

21 exp monoclonal antibody/

22 anti-tum*.mp. or exp anti tumor necrosis factor/

23 exp tumor necrosis factor antibody/ or exp tumor necrosis factor alpha antibody/ or

anti-TNF*.mp.

24 exp interleukin 2 receptor antibody/ or anti-IL*.mp.

25 etanercept.mp. or exp etanercept/

26 infliximab.mp. or exp infliximab/

27 ustekinumab.mp. or exp ustekinumab/

28 exp certolizumab pegol/ or certolizumab*.mp.

29 natalizumab.mp. or exp natalizumab/

30 anti-alpha.mp.

31 onercept.mp. or exp onercept/

32 vedolizumab.mp. or exp vedolizumab/

33 basiliximab.mp. or exp basiliximab/

34 visilizumab.mp. or exp visilizumab/

35 daclizumab.mp. or exp daclizumab/

36 briakinumab.mp. or exp briakinumab/

37 adalimumab.mp. or exp adalimumab/

38 anti-CD*.mp.

39 exp mucosal addressin cell adhesion molecule 1/ or anti-madcam.mp.

40 IFN.mp. or exp interferon/

41 interferon*.mp. [mp=title, abstract, subject headings, heading word, drug trade name,

original title, device manufacturer, drug manufacturer, device trade name, keyword] 42 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or

36 or 37 or 38 or 39 or 40 or 41

43 20 and 42

44 exp ulcerative colitis/ or exp colitis/

45 (rectocolitis or proctitis or proctocolitis or rectocolitis or rectosigmoiditis or

proctosigmoiditis).mp. [mp=title, abstract, subject headings, heading word, drug trade

name, original title, device manufacturer, drug manufacturer, device trade name,

keyword]

46 44 or 45

47 43 and 46

48 exp "quality of life"/

49 quality of life.mp. [mp=title, abstract, subject headings, heading word, drug trade name,

original title, device manufacturer, drug manufacturer, device trade name, keyword]

50 (HRQL or HRQoL).mp. [mp=title, abstract, subject headings, heading word, drug trade

name, original title, device manufacturer, drug manufacturer, device trade name,

keyword]

51 SF-36.mp. or exp Short Form 36/

52 short form 36.mp.

53 inflammatory bowel disease questionnaire.mp.

54 IBDQ.mp.

55 EQ-5D.mp.

56 exp productivity/ or WPAI*.mp.

57 activity impairment.mp. or exp absenteeism/

58 exp questionnaire/ or questionnair*.mp.

59 activities of daily living.mp. or exp daily life activity/

60 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59

61 47 and 60

Medline (In-process and other non-indexed citations) (1946 – present)

# Searches

1 random$.tw.

2 factorial$.tw.

3 (crossover$ or cross over$ or cross-over$).tw.

4 placebo$.tw.

5 single blind.mp.

6 double blind.mp.

7 triple blind.mp.

8 (singl$ adj blind$).tw.

9 (double$ adj blind$).tw.

10 (tripl$ adj blind$).tw.

11 assign$.tw.

12 allocat$.tw.

13 crossover procedure/

14 double blind procedure/

15 single blind procedure/

16 triple blind procedure/

17 randomized controlled trial/

18 or/1-17

19 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or

humans).ti.)

20 18 not 19

21 anti-tum*.mp. or exp anti tumor necrosis factor/

22 exp tumor necrosis factor antibody/ or exp tumor necrosis factor alpha antibody/ or anti-

TNF*.mp.

23 exp interleukin 2 receptor antibody/ or anti-IL*.mp.

24 etanercept.mp. or exp etanercept/

25 infliximab.mp. or exp infliximab/

26 ustekinumab.mp. or exp ustekinumab/

27 exp certolizumab pegol/ or certolizumab*.mp.

28 natalizumab.mp. or exp natalizumab/

29 anti-alpha.mp.

30 onercept.mp. or exp onercept/

31 vedolizumab.mp. or exp vedolizumab/

32 basiliximab.mp. or exp basiliximab/

33 visilizumab.mp. or exp visilizumab/

34 daclizumab.mp. or exp daclizumab/

35 briakinumab.mp. or exp briakinumab/

36 adalimumab.mp. or exp adalimumab/

37 exp mucosal addressin cell adhesion molecule 1/ or anti-madcam.mp.

38 IFN.mp. or exp interferon/

39 interferon*.mp. [mp=title, abstract, original title, name of substance word, subject heading

word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]

40 exp Antibodies, Monoclonal/ or monoclonal antibod*.mp.

41 21 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37

or 38 or 39 or 40

42 20 and 41

43 ulcerative colitis.mp. or exp Colitis, Ulcerative/

44 (rectocolitis or proctitis or proctocolitis or rectocolitis or rectosigmoiditis or

proctosigmoiditis).mp. [mp=title, abstract, original title, name of substance word, subject

heading word, keyword heading word, protocol supplementary concept, rare disease

supplementary concept, unique identifier]

45 43 or 44

46 42 and 45

47 quality of life.mp. or exp "Quality of Life"/

48 (HRQL or HRQoL).mp. [mp=title, abstract, original title, name of substance word, subject

heading word, keyword heading word, protocol supplementary concept, rare disease

supplementary concept, unique identifier]

49 short form 36.mp.

50 SF-36.mp.

51 inflammatory bowel disease questionnaire.mp.

52 IBDQ.mp.

53 EQ-5D.mp.

54 exp Absenteeism/ or WPAI*.mp.

55 exp Efficiency/ or activity impairment.mp.

56 questionnair*.mp.

57 questionnaire.mp. or Questionnaires/

58 activities of daily living.mp. or exp "Activities of Daily Living"/

59 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58

60 46 and 59

Cochrane Central Library

ID Search

#1 ulcerative colitis or rectocolitis or proctitis or proctocolitis or rectocolitis or rectosigmoiditis or proctosigmoiditis

#2 "anti tnf" or anti-tnf or anti-TNF* or "anti TNF*" or anti-tum* or antitum* or "anti IL*" or anti-IL* or etanercept or infliximab or "mab CA2" or ustekinumab or "CNTO 1275" or certolizumab* or CDP870 or natalizumab or anti-alpha* or "anti alpha*" or onercept or r-hTBP-1 or vedolizumab or MLN0002 or basiliximab "CHI 621" or certolizumab or

"rhuMAb*" or visilizumab or "HuM291" or daclizumab or "DAC HYP" or briakinumab

or ABT-874 or adalimumab or D2E7 or anti-CD* or "anti CD*" or anti-integr* or

antiintegr* or "anti madcam" or anti-madcam or CDP571 or PF00547 or PF-00547 or

IFN* or interferon* or RDP58

#3 HRQoL or HRQL or "quality of life" or SF-36 or "short form-36" or SF-36V2 or IBDQ

or “inflammatory bowel disease questionnaire" or EQ-5D or WPAI* or "work productivity" or "activity impairment" or questionnaire or questionnaire* or "activities

of daily living" or ADL

#4 #1 and #2 and #3

DDW Abstracts – (1981 – Present)

The termsulcerative colitis or rectocolitis or proctitis or proctocolitis or rectocolitis or rectosigmoiditis or proctosigmoiditis” will be cross-referenced with “HRQoL or HRQL or "quality of life" or SF-36 or "short form-36" or SF-36V2 or IBDQ or “inflammatory bowel disease questionnaire" or EQ-5D or WPAI* or "work productivity" or "activity impairment" or questionnaire or questionnaire* or "activities of daily living" or ADL” and the abstracts reviewed to determine their relevance to this review.

What's new

DateEventDescription
29 May 2013New citation required and minor changesNew authors added to protocol

Declarations of interest

None known.

Ancillary