Placebo response and remission rates in randomised trials of induction and maintenance therapy for Crohn’s disease

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

The objective of this review is to determine the factors that influence placebo response and remission rates in induction and maintenance trials of CD in which patients with active or quiescent disease were enrolled using the CDAI or Harvey‐Bradshaw Index (HBI).

Background

Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract with an incidence of 6 to 8 per 100,000 population in the United States (Loftus 2007), and a prevalence of 130 to 200 per 100,000 population (Kappelman 2007). There is no cure for CD and sufferers experience periodic relapses of disease activity. In addition, most patients will develop a complication at some point in their disease course. Conventional medical approaches for CD include treatment with corticosteroids, immunosuppressants, tumour necrosis factor‐alpha antagonists or other biologic agents.

In randomised controlled trials (RCTs) patients assigned to placebo often respond to treatment. Understanding factors that contribute to placebo response rates is important for estimating sample sizes in clinical trials and identifying a difference between active therapy and placebo, should one exist. Evidence from multiple therapeutic areas suggests that there are specific study design factors that may influence placebo response (Enck 2013; see Table 1).

Table 1.

Summary of design features in non‐IBD trials associated with increased or decreased placebo response rates

	Traditional design features	Novel design features	Other quality measures
Increase in placebo response	Follow up >12 months Cross‐over design Increasing number of arms Comparative effectiveness trials Higher randomisation ratio of active drug		Use of patient reported outcomes (PROs) Improving medication adherence
Decrease in placebo response	Using treatment naive patients	Induction phases to identify drug non‐responders Adaptive group allocation Stepped wedge trial (esp in intervals between steps)	Using biomarkers instead of PROs Enrolling patients with more severe disease Controlling for centre effects

Table constructed from information presented in Enck 2013.

In clinical trials of CD there has been considerable variance in placebo response and remission rates. A meta‐analysis published by Su et al. included 21 trials published up to 2001 in which patients with active CD received pharmacotherapy or placebo (Su 2004). Factors such as number and duration of follow‐up visits and Crohn's Disease Activity Score (CDAI) score at baseline were found to influence placebo response and remission rates (Su 2004; see Table 2).

Table 2.

Several factors associated with placebo response and remission rates in trials of CD

Increase in placebo response and remission rate	Longer duration of follow up More follow up visits
Decrease in placebo response and remission rate	Injectable medication Concurrent steroid/immunosuppressant use Mean/median CDAI > 250 at entry Minimum CDAI > 200 at entry Prior surgery More recent trial performance

Table constructed from information presented in Su 2004.

Why is it important to do this review

Since Su 2004 conducted their meta‐analysis, objective markers of disease activity such as inflammation assessed by endoscopy or C‐reactive protein have been increasingly used to enrol patients in RCTs rather than subjective measures such as symptom‐based diaries or disease activity indices. This review will examine whether the tool used to measure disease activity influences placebo response and remission rates.

While study duration and number of follow‐up visits were positively associated with placebo remission rates in the Su 2004 meta‐analysis, they did not examine whether there is a relationship between trial phase and placebo response. RCTs of CD can be generally classified as induction, maintenance or integrated (incorporating both induction and maintenance stages) studies. In this review we will explore whether placebo response is influenced by study type.

The establishment of a specific set of trial design elements capable of consistently yielding accurate placebo response and remission rates in controlled trials of CD will aid in the interpretation of existing data and make it possible to conduct more efficient and cost‐effective RCTs in the future.

Objectives

The objective of this review is to determine the factors that influence placebo response and remission rates in induction and maintenance trials of CD in which patients with active or quiescent disease were enrolled using the CDAI or Harvey‐Bradshaw Index (HBI).

Methods

Criteria for considering studies for this review

Types of studies

RCTs with an induction or maintenance phase or both comparing an active drug to placebo were considered for inclusion. Patients must have received placebo for a minimum of two weeks during the induction trial or phase and a minimum of four months during the maintenance trial or phase. Studies that did not use the CDAI or HBI for enrolment and assessment will be excluded. Trials that enrolled hospitalised patients will not be eligible for inclusion. Abstract publications will only be included if sufficient information is provided or if authors can be contacted for further information.

Types of participants

Adult patients (aged > 18 years) with active or quiescent CD defined by the CDAI or HBI will be considered for inclusion.

Types of interventions

Trials that compared corticosteroids, 5‐aminosalicylates (5‐ASAs), immunosuppressants, tumor necrosis factor‐alpha antagonists, or other biologic agents to placebo will be considered for inclusion.

Types of outcome measures

Primary outcomes

The primary outcome measure will be the proportion of patients in the placebo group achieving or maintaining clinical response or remission as defined by the included studies and expressed as a percentage of the total number of patients randomised (i.e. intention‐to‐treat analysis).

Secondary outcomes

The secondary outcomes will include the proportion of patients with steroid free remission, post‐operative recurrence, endoscopic remission, endoscopic response or histological response.

Search methods for identification of studies

Electronic searches

We will search the following databases for relevant studies:

1. MEDLINE (Ovid, 1946 to present);

2. EMBASE (Ovid, 1984 to present);

3. The Cochrare Central Register of Controlled Trials; and

4. The Cochrane IBD Group Specialized Register.

The search strategies are listed in Appendix 1.

Searching other resources

We will search the reference lists of potentially relevant trials and papers to identify additional studies. Abstracts from Digestive Disease Week and United European Gastroenterolgy Week will be hand searched to identify studies reported in abstract form only.

Data collection and analysis

Selection of studies

Two authors (CP and VJ) will independently screen titles and abstracts of reports identified by the literature search to determine eligibility based on the inclusion criteria described above (i.e. type of study, participants and interventions). Any disagreement among authors will be resolved through discussion until consensus is reached.

Data extraction and management

A standardised data extraction form will be used to collect data from the included studies. The form is based on the Cochrane checklist of items to consider for data extraction (Higgins 2011a) Sixteen authors will be paired into eight teams of two (TC and NA; TA and TA; PD and MA; MS and DM; AK and EM; MM and MA; SB and MG; OK and SR). Each team will be assigned a set of included studies from which they will independently extract data. Any disagreement among authors will be resolved through discussion until consensus is reached. If the team is unable to reach consensus, a third author (VJ or JKM) will be consulted to resolve the disagreement.

Data from five key areas will be recorded from each included study as follows:

A. Trial design (publication year, number of treatment arms, trial phase, type of design, location, number of centres, number of patients randomised, blinding, number of screening visits, number of follow‐up visits, frequency of follow‐up visits, duration of follow‐up visits, disease severity score used, minimum CDAI/HBI inclusion score at entry, endoscopy sub‐score for inclusion, bleeding sub‐score for inclusion, definition of response, time point to measure response, definition of remission, time point to measure remission, whether endoscopy was performed at entry, whether active disease was confirmed by central reading, whether active disease was confirmed by histology at entry).

B. Participants (age, gender, disease severity at enrolment, C‐reactive protein at entry, fecal calprotectin at entry, disease duration prior to enrolment, proportion with prior surgery for CD, proportion taking concurrent corticosteroids, proportion taking concurrent 5‐ASA drugs, proportion taking concurrent immunosuppressive drugs, proportion taking concurrent biological agents, proportion taking antibiotics, proportion with ileal disease, proportion with colonic disease, proportion with perianal disease, proportion with ileo‐colonic disease).

C. Intervetions (drug name, route of administration, active comparator, dose of active comparator, frequency of placebo administrations, number of placebo administrations, ration of active treatment versus placebo, frequency of active drug administrations); and

D. Outcomes (number of participants in placebo arm, intention‐to‐treat analysis, proportion of drop‐outs post‐randomisation, number of patients in remission, proportion of patients in remission, number of patients with response, proportion of patients with response, proportion of patients in steroid‐free remission, proportion of patients with mucosal healing, proportion with histological improvement).

Assessment of risk of bias in included studies

The Cochrane risk of bias tool will be used to assess the methodological quality of the included studies (Higgins 2011b). Sixteen reviewers will be divided into eight teams of two (TC and NA; TA and TA; PD and MA; MS and DM; AK and EM; MM and MA; SB and MG; OK and SR). Each team will assigned a set of studies for which they will assess the risk of bias. Within team disagreements will be resolved through discussion until consensus is reached. If a consensus is not reached a third author (VJ or JKM) will be consulted to resolve the disagreement. Factors to be assessed include:

1. Sequence generation (Selection bias);

2. Allocation concealment (selection bias);

3. Blinding of participants and personnel (performance bias);

4. Blinding of outcome assessment (detection bias);

5. Completeness of outcome data (attrition bias);

6. Selective reporting (reporting bias); and

7. Other sources of bias.

These categories will be rated as 'low risk', 'high risk' or 'unclear risk' for each included study. Study authors will be contacted when there is insufficient data to determine risk of bias.

Measures of treatment effect

Proportions and corresponding 95% confidence intervals (95% CI) will be calculated for dichotomous outcomes. For continuous outcomes we will calculate the mean difference (MD) and corresponding 95% CI. The potential effects of study level variables on the proportions will be quantified using odds ratios (OR).

Unit of analysis issues

Data will only be extracted from the first phase of the study if any cross‐over trials are included (i.e. before the cross‐over occurred). Where response or remission are defined at multiple time points the primary outcome as defined in the study will be extracted. If the primary outcome is not defined the results from the final assessment time point will be recorded.

Dealing with missing data

Primary study authors will be contacted to supply missing data or explain data loss. Data will be analysed according to the intention‐to‐treat principle. Data that remains missing will considered to be negative (i.e. treatment failure).

Assessment of heterogeneity

Potential heterogeneity will be investigated by visually inspecting forest plots and by calculating the Chi² statistic (P value of 0.10 will be regarded as statistically significant) and I² statistic (Higgins 2002). If significant heterogeneity is detected (i.e. I² ≥ 50%) sensitivity analysis will be used to examine possible explanations.

Assessment of reporting biases

Funnel plots will be used to assess potential publication bias (Egger 1997). The trim and fill method will be used to correct funnel plots if necessary (Duval 2000).

Data synthesis

A binomial model for proportions will be used to calculate the pooled proportions and corresponding 95% CI of placebo response and remission rates (Stijnen 2010). Induction and maintenance phases will be pooled separately. The effects of study‐level characteristics will be assessed by conducting random‐effects meta‐regression as appropriate (Thompson 2002). Where possible we will assess the following study‐level characteristics: trial design features (i.e. setting, design, country of origin, duration of follow‐up, number of study visits, time of outcome assessment, and publication date), inclusion criteria (including stringent versus less stringent criteria, disease severity, the presence of markers of active disease at enrolment, disease distribution, drug class, concomitant medications, and disease duration), and the assessment of response and remission (including stringent versus less stringent criteria and mucosal healing). P‐values of less than 0.05 will be considered statistically significant. Analyses will be carried out using SAS 9.3 (SAS Institute, Cary, NC) and Stata 12.1 (STATA Corp).

Subgroup analysis and investigation of heterogeneity

If there are sufficient data subgroup analyses will be performed to examine the effects of:

1. Higher versus lower baseline inclusion scores (i.e. moderate to severe disease vs. mild to moderate disease);

2. Trials published after 2000 versus those published before 2000;

3. Class of drug; and

4. Use of endoscopic or histological criteria to define remission.

Sensitivity analysis

If there are sufficient data sensitivity analyses will be conducted to determine the impact of excluding studies with lower methodological quality (i.e. those trials rates as having high or unclear risk of bias, trials with < 50 participants and trials published in abstract form).

Appendices

Appendix 1. Search strategies for MEDLINE, EMBASE and CENTRAL databases

1. MEDLINE (1950 ‐ current)

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 Crohn disease/ or crohn*.mp. 20. 18 and 19

2. EMBASE (1980 ‐ current)

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 Crohn disease/ or crohn*.mp. 20. 18 and 19

3. Cochrane Library (CENTRAL)

Crohn

4. SR‐IBD

Crohn (ti/ab)

What's new

Date	Event	Description
16 January 2017	Amended	This protocol is being withdrawn. The author team does not have the time and resources to complete the review.

Sources of support

Internal sources

• None, Other.

External sources

• No sources of support supplied

Declarations of interest

Vipul Jairath has received payment for consultancy from Takeda, Abbvie, Sandoz, and Ferring; travel/accommodations/meeting expenses from Vifor and Takeda; scientific advisory board fees from AbbVie and Sandoz; and payments for lectures/speakers bureaux from Janssen and Takeda;

Guangyong Zou has no known conflicts of interest to declare;

Claire Parker has no known conflicts of interest to declare;

John MacDonald has no known conflicts of interest to declare;

Mahmoud Mosli has no known conflicts of interest to declare;

Turki AlAmeel has no known conflicts of interest to declare;

Mohammad AlBeshir has no known conflicts of interest to declare;

Majid AlMadi has no known conflicts of interest to declare;

Talal Al‐Taweel has received travel/accommodation/meeting expenses from Janssen, AbbVie and Novartis, and consultancy and lecture fees from AbbVie;

Nathan Atkinson has received ravel/accommodations/meeting expenses from AbbVie;

Sujata Biswas has no known conflicts of interest to declare;

Thomas Chapman has received ravel/accommodations/meeting expenses from Warner Chilcott;

Parambir Dulai is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (Grant 5T32DK007202);

Mark Glaire has no known conflicts of interest to declare;

Daniel Hoekman has no known conflicts of interest to declare;

Omar Kherad has no known conflicts of interest to declare;

Andreas Koutsoupas has no known conflicts of interest to declare;

Elizabeth Minas has no known conflicts of interest to declare;

Sophie Restellini has no known conflicts of interest to declare;

Mark Samaan has received advisory board fees from Hospira, and payments for lectures from Hospira, Takeda and MSD;

Reena Khanna has received payment for consultancy from AbbVie, Jansen, Takeda, Pfizer, and Shire;

Barrett Levesque has received payment for consultancy from Takeda, AbbVie and Nestle Health Sciences; and payment for lectures including service on speakers bureaus from Mitsubishi Tanabe Pharma.

Geert D’Haens has received consulting fees from Abbvie, Ablynx, Amakem, AM Pharma, Biogen, Bristol Meiers Squibb, Boerhinger Ingelheim, Celgene, Celltrion, Covidien, Ferring, Engene, Galapagos, Gilead, Glaxo Smith Kline, Hospira, Immunic, Johnson and Johnson, Lycera, Medimetrics, Millenium/Takeda, Mitsubishi Pharma, Merck Sharp Dome, Mundipharma, Novonordisk, Pfizer, Prometheus laboratories/Nestle, Protagonist, Receptos, Robarts Clinical Trials, Salix, Sandoz, Setpoint, Shire, Tillotts, Topivert, Versant and Vifor; research grants from Abbvie, Ferring, Johnson and Johnson, Merck Sharp Dome, Mundipharma, Pfizer, Millenium/Takeda, Tillotts; payments for lectures/speakers bureaux from Abbvie, Ferring, Johnson and Johnson, Merck Sharp Dome, Mundipharma, Pfizer, Shire, Millenium/Takeda, Tillotts, Biogen; and has stock/stock options with Engene;

Simon Travis has received payment for consultancy from AbbVie, Astra Zeneca, Amgen, Biogen, Celgene, Falk, Ferring, GSK, Janssen, Lilly (Institution), Merck (to the Institution), Novartis, Novo Nordisk (both self and Institution), NPS Pharmaceuticals, Pfizer, Proximagen, Takeda, Topivert, Vertex (to the Institution), VHSquared, Warner‐Chilcott; grants/grants pending from IOIBD; Norman Collison Foundation; Warner Chilcott; payment for lectures including service on speakers bureaus from AbbVie, Ferring, Takeda; and royalties from Wiley Blackwell, Elsevier and Oxford Univeristy Press;

William Sandborn has received consulting fees from Abbott, ActoGeniX NV, AGI Therapeutics Inc, Alba Therapeutics Corp, Albireo, Alfa Wasserman, Amgen, AM‐Pharma BV, Anaphore, Astellas, Athersys Inc, Atlantic Healthcare Ltd, Aptalis, BioBalance Corp, Boehringer‐Ingelheim, Bristol‐Myers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle Pharmaceuticals, EnGene Inc, Eli Lilly, Enteromedics, Exagen Diagnostics Inc, Ferring Pharmaceuticals, Flexio Therapeutics Inc, Funxional Therapeutics Ltd, Genzyme Corp, Gilead Sciences, Given Imaging, GSK, Human Genome Sciences, Ironwood Pharmaceuticals, KaloBios Pharmaceuticals, Lexicon Pharmaceuticals, Lycera Corp, Meda Pharmaceuticals, Merck Research Laboratories, Merck Serono, Millenium Pharmaceuticals, Nisshin Kyorin Pharmaceuticals, Novo Nordisk, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics Inc, PDL Biopharma, Pfizer, Procter and Gamble, Prometheus Laboratories, ProtAb Ltd, Purgenesis Technologies Inc, Relypsa Inc, Roche, Salient Pharmaceuticals, Salix Pharmaceuticals, Santarus, Schering Plough, Shire Pharmaceuticals, Sigmoid Pharma Ltd, Sirtris Pharmaceuticals, SLA Pharma UK Ltd, Targacept, Teva Pharmaceuticals, Therakos, Tillotts Pharma AG, TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics Ltd, Warner Chilcott UK Ltd and Wyeth; research grants from Abbott, Bristol‐Myers Squibb, Genentech, GSK, Janssen, Milennium Pharmaceuticals, Novartis, Pfizer, Procter and Gamble, Shire Pharmaceuticals and UCB Pharma; payments for lectures/speakers bureaux from Abbott, Bristol‐Myers Squibb and Janssen; and holds stock/stock options in Enteromedics; and

Brian Feagan has received grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma AG, Abbott Labs, Novartis Pharmaceuticals, Centocor Inc., Elan/Biogen, UCB Pharma, Bristol‐Myers Squibb, Genentech, ActoGenix, Wyeth Pharmaceuticals Inc.; Consulting fees from Millennium Pharmaceuticals, Merck, Centocor Inc., Elan/Biogen, Janssen‐Ortho, Teva Pharmaceuticals, Bristol‐Myers Squibb, Celgene, UCB Pharma, Abbott Labs, Astra Zeneca, Serono, Genentech, Tillotts Pharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging Inc., Salix Pharmaceuticals, Novonordisk, GSK, Actogenix, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, GiCare Pharma Inc. Sigmoid Pharma; Speakers Bureau for UCB, Abbott, J&J/Janssen.

Notes

The author team has decided that they do not have the time and resources to complete this review.

Withdrawn from publication for reasons stated in the review