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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Background  The use of placebo in randomized clinical trials (PC-RCTs) is often required to evaluate drug efficacy in maintenance of Crohn’s disease (CD).

Aim  To determine pooled estimates of placebo rates of maintaining clinical remission and endoscopic recurrence following surgery for CD and identify factors that influenced placebo outcomes.

Methods  We performed a systematic review and meta-analysis of PC-RCTs evaluating post-operative maintenance therapies for CD identified from MEDLINE from 1966 to 2005.

Results  Twelve studies met our inclusion criteria. The pooled placebo rate of maintaining clinical remission was 56% (95% CI 47–64%; range 34–89%) during a median follow-up of 52 weeks (range 12–156 weeks), but significant heterogeneity existed among the studies (< 0.001). Prior steroid therapy was the only factor found to be associated with maintaining remission (= 0.04). The pooled placebo endoscopic recurrence rate was 58% (95% CI 51–65%; range 36–80%) during a median follow-up of 52 weeks (range 12–156 weeks), with significant heterogeneity noted (= 0.0003). Prior surgery, concomitant small bowel and colonic disease, fistulizing phenotype, or prior immunomodulator therapy influenced endoscopic recurrence (< 0.05).

Conclusion  Placebo rates in PC-RCTs evaluating post-operative clinical and endoscopic recurrence demonstrate significant variability, which is influenced by specific study characteristics.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Crohn’s disease (CD) is a chronic, relapsing and remitting, inflammatory condition, which may affect any part of the gastrointestinal tract from the mouth to the anus. In a majority of patients with CD, surgical therapy is required, at some point in their lifetime, to treat disease complications such as fistulas, strictures, perforations and abscesses. Unlike ulcerative colitis, surgery is not curative for patients with CD. Rather, recurrence is common, with endoscopic recurrence rates in excess of 70% within the first year after surgery.1 Currently, there is no standard regimen recommended to prevent relapse of CD after surgery.

Placebo-controlled randomized clinical trials (PC-RCTs) provide the strongest evidence for the efficacy of a drug in maintaining remission in CD. However, a number of studies have shown conflicting results regarding the efficacy of certain drugs in the post-operative prevention of CD recurrence. These disparate results may be a consequence of features within the study design (such as the outcome of interest, sample size and study duration). As defining clinical relapse is somewhat subjective, despite the use of endoscopic evaluation and disease activity scales, understanding the outcomes associated with placebo therapy is extremely important for designing future studies.2 In addition, a response pattern noted within this subpopulation can provide insight into factors, which may be potentially associated with maintaining clinical remission or having endoscopic recurrence while not on ‘active’ medical therapy.

A prior systematic review and meta-analysis was conducted, which determined the placebo response and remission rates in PC-RCTs of active CD and identified statistically significant heterogeneity among the trials. The duration of the study, number of study visits and baseline disease activity measured by a standardized disease activity index were associated with the placebo remission and response rates.1 The same investigators also determined the placebo remission and response rates from a systematic review and meta-analysis of PC-RCTs of active ulcerative colitis, again identifying duration of the study as an important factor.2 The aims of this study were to determine the pooled estimates among placebo-treated patients of maintaining clinical remission and endoscopic recurrence from prior PC-RCTs for post-operative maintenance therapy as well to determine factors that influence these rates.

Materials and Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Study identification and inclusion

Placebo-controlled randomized clinical trials for post-operative maintenance therapy of CD were identified from the MEDLINE electronic database from January 1966 to September 2005. We used the following medical subject headings in our search strategy: ‘Crohn’s disease’, ‘Crohns disease’, ‘Crohn’s’, ‘ileitis’, ‘inflammatory bowel disease’ and ‘placebo’, ‘clinical trial’ and ‘therapy’, ‘maintenance’, ‘maintenance therapy’, ‘recurrence’ excluding ‘ulcerative colitis’. The studies were limited to ‘humans and English language’ while excluding ‘comment or editorial or letter or review’. Analysis was performed on studies that fulfilled the following inclusion criteria:1 the study was placebo-controlled,2 all study patients had surgically induced remission,3 the study reported methodology on defining recurrence and/or maintenance of remission, and4 the study reported data on the proportion of patients maintaining remission and/or having clinical or endoscopic recurrence in placebo-treated patients. We excluded from the analyses, studies that included subjects with medically induced remission in the sample population when the recurrence rates for only those with surgically induced remission were not reported separately. Similarly, we excluded studies that included patients with active CD post-operatively in their sample population and clinical remission rates for the inactive CD patients were not reported separately from the entire sample population. We did not exclude studies based on activity of CD prior to or at the time of surgery as long as all patients in the sample were free of residual active CD and considered in remission at the start of the randomized trial.

Data abstraction

Data abstraction was performed independently by two reviewers (M.P. and C.S.). The study outcomes for the placebo and treatment groups, study features and the definitions of remission and clinical and/or endoscopic recurrence were abstracted from the studies. Specific study features which were abstracted included publication year, location(s), sample size of placebo and active treatment groups, active treatment modalities and route of administration, duration of follow-up, duration of treatment, mean age of patients, smoking status, prior surgery, prior medical therapy, concomitant medical therapy, disease distribution and disease phenotype. Clinical outcomes were reported in terms of remission rates. Thus, for those studies which reported clinical recurrence rates, clinical remission rates were extrapolated from the data provided. Outcomes were dichotomized into clinical remission or no clinical remission and endoscopic recurrence or no endoscopic recurrence based on the definition for recurrence used in each individual study (Table 1). The frequency of agreement by the reviewers was >95%. Discrepancies were resolved through discussion. Several variables including prior medical therapy, entry and exit C-reactive protein (CRP) and surgical recurrence rates could not be fully evaluated because of limited amount of data in the published studies.

Table 1.   Characteristics of placebo-controlled randomized clinical trials containing clinical remission/recurrence data on post-operative maintenance therapy
AuthorPublication yearActive therapy Placebo size (n)Study follow-up duration (week)Placebo remission rate % (95% CI)Endoscopic recurrence rate % (95% CI)Clinical recurrence definitionEndoscopic definition
Rutgeerts et al.52005Ornidazole405263 (46–77)80 (64–91)CDAI ≥ 250, reoperation, or Crohn’s disease (CD) requiring additional txRutgeerts ≥2
Hanauer et al.62004Mesalazine (mesalamine) /mercaptopurine4010423 (11–38)65 (48–79)Clinical grading scale = 1Rutgeerts ≥2
Prantera et al.72002Lactobacillus GG225291 (71–99)36 (17–59)CDAI > 150 OR CD signs requiring additional rx.Rutgeerts ≥2
Colombel et al.82001Interleukin-1221650 (28–72)Rutgeerts >0
Lochs et al.92000Mesalazine1668867 (59–74)50 (42–58)CDAI > 250, CDAI > 200 + increase >60 pt over 2 weeks, surgery, new fistula, or septic complicationRutgeerts ≥2
Ewe et al.101999Budesonide405253 (36–68)70 (53–83)CDAI > 150Rutgeerts ≥2 (if refused endo, CDAI ≥ 60 pt or CDAI > 200 w/ signs or symptoms)
Hellers et al.111999Budesonide665258 (45–70)CDAI ≥200Rutgeerts ≥2
Florent et al.121996Mesalazine611234 (23–48)62 (49–74)CDAI>200Rutgeerts ≥1
McLeod et al.131995Mesalazine7615655 (43–67)CD signs requiring additional tx, radiological, endoscopic recurrence
Rutgeerts et al.141995Metronidazole3015650 (31–69)74 (55–88)Symptoms interpreted as active CDRutgeerts ≥1
Brignola et al.151995Mesalazine435267 (51–81)50 (35–65)CDAI > 150 + increase ≥100 ptsRutgeerts ≥3
Ewe et al.161989Sulfasalazine1215252 (43–61)Radiological, endoscopic, or surgery 

Statistical analyses

Pooled estimates of the placebo remission and recurrence rates and the stratum-specific rates for the different categories of study design were calculated using fixed effects logistic regression analysis, after applying sample weights according to placebo sample size, as implemented using stata’s (STATA Corp., College Station, TX, USA) xlogit command. Heterogeneity among studies was assessed with the Pearson chi-squared test. In addition, the medians and ranges were reported with the placebo clinical remission and endoscopic recurrence rates to complement the interpretation of the pooled estimates. The effect of study design on the placebo rates was estimated using univariate logistic regression models. For those factors which appeared to be significantly associated with the placebo rates in the univariate analyses based on a P-value of 0.10, stratified analyses were performed to determine if any of these factors contributed to the heterogeneity observed in the primary analysis. Analyses were also performed limited to studies using the same definition of outcomes. The correlation between clinical remission and endoscopic recurrence rates was assessed with Pearson correlation coefficient.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Description of the studies

Our search strategy identified 189 potentially relevant articles. Reviewing their titles and abstracts allowed us to exclude 128 articles that were not clinical trials of CD for the maintenance of remission. Of the 61 articles selected for full manuscript review, 12 fulfilled the inclusion criteria.5–16 Characteristics of the 12 studies which were included in the analyses are shown in Table 1. Eight studies5–7, 9, 10, 12, 14, 15 reported results in terms of both endoscopic recurrence rates and clinical remission or recurrence rates, two studies13, 16 reported only clinical remission or recurrence rates and two studies8, 11 reported only endoscopic recurrence rates (Figure 1). Reasons for exclusion included medically induced remission, inclusion of both inactive and active disease, steroid-dependent disease and lack of clinical data.

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Figure 1.  Schema for MEDLINE search and study inclusion.

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All studies were double-blinded and used a similar definition of ‘placebo’, which they described as an identically appearing formulation administered in the same frequency as the active study drug. All studies used intention-to-treat analysis, although in one of the studies,16 dropouts were considered not to have relapsed which led to estimations of placebo clinical remission rates different from our extrapolated estimate. However, we repeated our analyses using the alternative estimates of the placebo clinical remission rate. These analyses gave results similar to those reported here (data not shown).

Definition of outcomes

For the 10 studies5–7, 9, 10, 12–16 which reported clinical remission rates, six5, 7, 9, 10, 12, 15 used Crohn's Disease Activity Index (CDAI) in the definition of remission or recurrence (Table 2). Other definitions used for recurrence included using the value of >1 on a clinical grading scale or using symptoms as a marker of recurrence. For all the studies which reported endoscopic recurrence rates, the endoscopic scoring scale of Rutgeerts et al. was utilized.17 A majority of these studies (= 6) used a Rutgeerts score of ≥2 as a definition for recurrence, but these studies also demonstrated significant heterogeneity.5–7, 9–11 Three studies used a Rutgeerts score of ≥1,8, 12, 14 and one study used a Rutgeerts score of ≥3.15 While any level of endoscopic recurrence is considered to be recurrent disease, an endoscopic score of ≥3 has been shown to correlate best with earlier clinical recurrence.1

Table 2.   Pooled clinical remission rates by CDAI and test of heterogeneity
Definition of recurrenceNo. of studies% pooled remission rate (95% CI)P-value (test of heterogeneity) Range (%) Median (%)
All1056 (47–64)<0.00123–8954
Based on CDAI661 (50–71)<0.00134–8965
CDAI > 150 with or without a minimum point increase359 (44–72)<0.00153–8967
Using CDAI > 250 plus a minimum point increase163 (46–77)

Placebo clinical remission rate

The pooled estimate of the placebo rates of maintaining clinical remission after surgery was 56% (95% CI 47–64%) during a median follow-up time of 52 weeks (mean of 77.6 weeks, range 12–156 weeks, mode 52 weeks; Figure 2). Statistically significant heterogeneity was noted among the studies (< 0.00). This rate was similar when analysis was limited to the six studies which used CDAI as a definition of recurrence (61%, 95% CI 50–71%, test of heterogeneity, < 0.00). The duration of remission for patients prior to maintenance study enrolment in all the studies was <4 months. The only two study factors associated with greater clinical remission in the placebo group included greater use of prior steroids in the study population and higher remission rate in the treatment arm (Table 3). Study features which did not reach statistical significance but which may be suggestive of predicting clinical remission rates based on a P-value of <0.10 included visit frequency following surgery duration of disease prior to surgery and concurrent steroid treatment prior to surgery (Table 3).

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Figure 2.  Placebo rates of clinical remission in post-operative maintenance randomized clinical trials.

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Table 3.   Predictors of clinical remission rates and endoscopic recurrence rates in placebo treated patients
PredictorClinical remission OR (95% CI)Endoscopic recurrence OR (95% CI)
  1. McLeod et al.13 was the only North American study, while Hanauer et al.6 had both North American and European location.

  2. Hanauer et al.6 had both North American and European location, but the remaining studies for endoscopic recurrence were European.

  3. No studies for clinical remission had injectable administration.

  4. Only one study (Colombel et al.8) had an injectable administration.

  5. No studies for clinical remission had biological therapy.

  6. Only one study (Colombel et al.8) had biological therapy.

  7. NA, not applicable.

  8. P-value < 0.05.

  9. ** P-value < 0.10.

Publication year (per 1 year increase)1.01 (0.95–1.08)1.02 (0.93–1.12)
Geographic location (North America vs. Europe)0.88 (0.61–1.27)12
Number of centres involved in trial (per one centre increase)1.02 (0.99–1.04) 0.98 (0.96–0.99)*
Sample size ratio >1 (Y vs. N)0.21 (0.15–0.29)*1.08 (0.65–1.79)
Frequency of administration (≥3/day vs. <3/day)0.69 (0.32–1.51)0.93 (0.50–1.75)
Method of administration (injection vs. not)30.71 (0.53–0.96)4
Class of active treatment arm – steroid (Y vs. N)0.87 (0.60–1.27)1.24 (0.77–2.00)
Class of active treatment arm – immunomodulator (Y vs. N)1.29 (0.69–2.40)0.64 (0.44–0.95)*
Class of active treatment arm – biologics (Y vs. N)50.71 (0.53–0.96)6*
Follow-up duration (>52 weeks vs. ≤52 weeks)0.96 (0.45–2.07)0.71 (0.47–1.06)**
Visit frequency: number of follow-up visits/follow-up duration (months)0.43 (0.18–1.01)**0.93 (0.69–1.25)
Mean age of placebo patients (per 5 year increase)1.26 (0.83–1.91)0.70 (0.30–1.63)
Mean duration of disease for placebo patients (per 1 year increase)0.81 (0.64–1.02)**0.94 (0.75–1.16)
% of placebo patients with only small bowel involvement (per 10% increase)1.08 (0.95–1.23)0.79 (0.73–0.86)*
% of placebo patients with only colonic involvement (per 10% increase)1.19 (0.83–1.70)0.85 (0.66–1.08)
% of placebo patients with small bowel and colonic involvement (per 10% increase)0.92 (0.81–1.04)1.12 (1.03–1.23)*
% of placebo patients with fistulizing phenotype (per 10% increase)0.90 (0.62–1.31)1.59 (1.37–1.84)*
% of placebo patients with obstructive phenotype (per 10% increase)0.95 (0.85–1.07)0.88 (0.72–1.06)
% of placebo patients with inflammatory phenotype (per 10% increase)0.95 (0.83–1.08)0.64 (0.24–1.66)
% of placebo patients who were current smokers (per 10% increase)1.14 (0.45–2.87)1.23 (0.82–1.85)
% of placebo patients with prior surgery for Crohn’s disease (per 10% increase)0.85 (0.69–1.05)1.14 (1.04–1.26)*
% of placebo patients with prior steroid therapy (per 10% increase)1.41 (1.02–1.95)*0.84 (0.69–1.02)**
% of placebo patients with prior immunomodulator therapy (per 10% increase)1.32 (0.72–2.42)1.82 (1.27–2.62)*
Concurrent steroid treatment (Y vs. N)1.71 (0.95–3.07)**0.74 (0.43–1.25)
Remission rate in active treatment groups (per 10% increase)1.49 (1.20–1.85)*0.99 (0.78–1.25)
CDAI used in definition of recurrence (Y vs. N)1.67 (0.93–3.00)**0.58 (0.37–0.93)*
CDAI cutoff of 150 used in definition of recurrence (≤150 vs. >150)1.40 (0.57–3.42)0.90 (0.46–1.77)
Positive vs. negative study in terms of endoscopic recurrence rate0.70 (0.32–1.56)1.14 (0.58–2.27)
Endoscopic recurrence definition (Rutgeerts score ≥ 1 vs. ≥2)NA1.27 (0.77–2.08)
Endoscopic recurrence definition (Rutgeerts score ≥ 1 vs. ≥2 or ≥3)NA1.31 (0.83–2.08)

To examine whether associations of specific study features with the placebo remission rate may account for the heterogeneity among the studies, we next calculated pooled estimates of the placebo remission rate within each stratum of those study characteristics that were found to be significant predictors of placebo remission rate using a P-value of 0.10 to define significance. After stratifying across various categories of study design, heterogeneity remained statistically significant in most strata; thus, no one factor could account for the heterogeneity amongst the studies (Table 4).

Table 4.   Stratum-specific placebo remission rates according to study characteristics
Study characteristicnPlacebo clinical remission rate % (95% CI)Test for heterogeneity P-value
Overall1056 (47–64)<0.001
Studies with sample size ratio > 1 (Yes)123 (–)
Studies with sample size ratio >1 (No)958 (50–65)<0.001
Studies with visit frequency (no. fup visits/fup duration) <0.5558 (45–69)<0.001
Studies with visit Frequency (no. fup visits/fup duration) ≥0.5242 (30–54)0.07
Studies with mean duration of disease ≤6.75 yrs361 (54–68)0.37
Studies with mean duration of disease >6.75 years456 (37–73)<0.001
Studies with % placebo patients with or prior steroid therapy <50%246 (28–64)0.01
Studies with % placebo patients with or prior steroid therapy ≥50%264 (58–70)0.08
Studies allowing concurrent steroid treatment362 (54–69)0.08
Studies NOT allowing concurrent steroid treatment549 (37–61)<0.001
Studies with remission rate in active treatment group <70%544 (35–54)0.01
Studies with remission rate in active treatment group ≥70%565 (60–71)0.04
Studies using CDAI in definition of recurrence661 (50–71)<0.001
Studies NOT using CDAI in definition of recurrence448 (39–57)0.00
Studies with placebo endoscopic recurrence rate <70%557 (41–72)<0.001
Studies with placebo endoscopic recurrence rate ≥70%355 (49–62)0.52

Placebo endoscopic recurrence rate

The pooled estimate of the placebo endoscopic recurrence rate was 58% (95% CI 51–65%) during a median endoscopic follow-up time of 52 weeks (mean of 48.4 weeks, range 12–104 weeks, mode 52 weeks; Figure 3); however, there was statistically significant heterogeneity among the studies (= 0.003). This rate was similar when studies were limited to the six studies, which used a Rutgeerts score of ≥2 (57%, 95% CI 48–66%) as their definition of recurrence and the three studies, which used a Rutgeerts score of ≥1 (63%, 95% CI 55–71%) (Table 5) as their definition of recurrence. Factors which influenced endoscopic recurrence rates were identified using univariate logistic regression analyses (Table 3). Placebo-treated patients with only small bowel involvement were less likely to have endoscopic recurrence, whereas those patients who had both small and large bowel involvement of CD were more likely to have higher endoscopic recurrence rates. Studies which had an active immunomodulator treatment arm and studies that used CDAI in the definition of recurrence had a lower likelihood of endoscopic recurrence in the placebo-treated group. An increasing number of study centres (reported as ‘per one-centre increase’) involved in the trial were associated with lower placebo endoscopic recurrence rates. Subject factors that were found to influence placebo endoscopic recurrence rates were the percentage of patients who had therapy with an immunomodulator prior to surgery, patients who had prior surgery and patients with fistulizing phenotype of disease. Prior steroid therapy demonstrated lower endoscopic recurrence rates in placebo treated patients, although this was not statistically significant (Table 3).

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Figure 3.  Placebo rates of endoscopic recurrence in post-operative maintenance randomized clinical trials.

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Table 5.   Pooled endoscopic recurrence rates by rutgeerts score (1)
Definition of endoscopic recurrenceNo. of studies% pooled recurrence rate (95% CI)P-value (test of heterogeneity) Range (%) Median (%)
All1058 (51–65)0.0035–7961
Rutgeerts score ≥ 1363 (55–71)0.1952–7563
Rutgeerts score ≥ 2 657 (48–66)0.0035–7961
Rutgeerts score ≥ 3 150 (35–65)

Stratified analyses were performed on study characteristics which were found to be predictive of placebo endoscopic recurrence rates using a P-value of 0.10 to define statistical significance. There was no longer statistical heterogeneity when stratified by anatomic distribution of disease or fistulizing phenotype (Table 6). Among the eight studies which reported clinical remission or recurrence rates and endoscopic recurrence rates, there appeared to be a moderately negative correlation based on a Pearson correlation coefficient of −0.58 (Figure 4). There was no significant difference in the median or mean duration of follow-up between the studies which evaluated clinical remission (median 52 weeks, range 12–156 weeks, mean 77.6 weeks) compared with duration of follow-up for endoscopic recurrence (median 52 weeks, range 12–104 weeks, mean 48.9 weeks; = 0.13).

Table 6.   Stratum-specific placebo endoscopic recurrence rates according to study characteristics
Study characteristicsnEndoscopic recurrence rate % (95% CI)Test for heterogeneity P-value
Overall1058 (51–65)0.00
Number of centres involved in trial ≤5568 (57–77)0.01
Number of centres involved in trial >5553 (49–58)0.48
Studies with method of administration = injection152 (–)
Studies with method of administration = NOT injection958 (51–66)0.00
Studies with class of active treatment arm = immunomodulator352 (47–57)0.22
Studies with class of active treatment arm = NOT immunomodulator763 (55–70)0.01
Studies with class of active treatment arm = biologics152 (–)
Studies with class of active treatment arm = NOT biologics958 (51–66)0.00
Studies with endoscopic follow-up duration ≤52 weeks861 (54–68)0.00
Studies with endoscopic follow-up duration >52 weeks253 (46–59)0.09
Studies with % of placebo patients with or only small bowel involvement <40%275 (67–81)0.30
Studies with % of placebo patients with or only small bowel involvement ≥40%452 (46–57)0.17
Studies with % of placebo patients with or small bowel and colonic involvement <60%452 (46–57)0.17
Studies with % of placebo patients with or small bowel and colonic involvement ≥60%568 (59–75)0.15
Studies with % of placebo patients with or fistulizing phenotype <40%359 (49–68)0.06
Studies with % of placebo patients with or fistulizing phenotype ≥40%375 (69–79)0.59
Studies with % placebo patients with or prior surgery for Crohn’s disease (CD) <30%557 (46–68)0.01
Studies with % placebo patients with or prior surgery for CD ≥30%367 (61–73)0.47
Studies with % placebo patients with or prior steroid therapy <50%365 (55–73)0.06
Studies with % placebo patients with or prior steroid therapy ≥50%254 (45–62)0.01
Studies with % placebo patients with or prior immunomodulator therapy <20%253 (47–60)0.10
Studies with % placebo patients with or prior immunomodulator therapy ≥20%179 (–)
Studies using CDAI in definition of recurrence657 (48–65)0.00
Studies NOT using CDAI in definition of recurrence269 (62–75)0.41
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Figure 4.  Placebo clinical remission rates vs. placebo endoscopic recurrence rates. There was moderately negative correlation in the placebo group (r = −0.58).

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Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The use of placebo in randomized clinical trials is necessary in most diseases to establish drug efficacy. The use of placebo allows blinding of patients and investigators, which helps to prevent bias in determining endpoints. This is particularly important in inflammatory bowel disease (IBD) studies, which often utilize symptoms reported by the patients and assessments made by the investigators, to determine response and remission to medical therapy. In addition, the natural course of CD is marked by variable periods of relapse and remission. Therefore, understanding the outcomes of placebo-treated subjects is important in designing future clinical trials.

Maintenance of clinical remission

In this study, we identified significant heterogeneity among the studies in terms of rates of clinical remission. Interestingly, few features of the studies were associated with placebo remission rates. Prior steroid therapy was associated with an increased clinical remission rate. Otherwise, no features were statistically significant and stratified analyses provided limited insight into observed heterogeneity. The remission rates in the active treatment arm were found to be positively associated with remission rates in the placebo arm. This finding is not surprising because, in a single RCT, similar subject factors are enforced across both arms, making the sample relatively homogeneous.

The clinical outcomes were independent of duration of follow-up, a study feature previously shown to influence placebo remission rates in active CD.2 For practical reasons, most studies of post-operative therapy follow patients for 1 year to assess clinical outcomes. Given that most patients who undergo surgery will ultimately have a clinical relapse if followed long enough, the lack of an association of follow-up duration with remission rates in our analysis probably reflects the lack of variability in follow-up duration among the studies rather than a true biological effect. We performed additional analysis for study duration in terms of placebo remission or endoscopic recurrence rates on the basis of 4-week increases in duration of follow-up. Similarly, we did not find a significant association with placebo rates associated with increasing duration of follow-up (OR 1.0, 95% CI 0.9–1.02 for placebo remission rates, OR 0.98, 95% CI 0.95–1.01%).

Visit frequency, which was also found to be a significantly associated with placebo response rates in RCTs involving active CD, was found to be inversely related to maintaining clinical remission in the placebo arm, but this difference did not achieve statistical significance (OR 0.43, 95% CI 0.18–1.01). This may be because of detection bias as more visits or opportunities for probing by investigators may result in an increased likelihood for the patient to report symptoms and prompt intervention to evaluate for recurrence, such as through endoscopy or radiography.

Endoscopic recurrence

The evaluation of endoscopic recurrence is a frequently employed outcome measurement in clinical trials as it has been shown to provide prognosis for disease course and thus may aid in directing further therapy at an earlier time period. Endoscopic recurrence has been observed in up to 60% of patients who underwent ileocolonic resection at 6 months.1 The severity of the endoscopic lesions seen post-operatively in the absence of symptoms has been shown to be predictive of clinical recurrence.1 In our study, the endoscopic outcome was significantly associated with disease distribution and phenotype, which also explained some of the between-study heterogeneity. Interestingly, these subject characteristics did not significantly impact the clinical remission rates in the placebo treated group. As the median follow-up duration was the same for both outcomes, it is likely that clinical recurrence was delayed compared to endoscopic recurrence and with longer follow-up, the same associations may have been seen for clinical remission. Alternatively, the lack of significance seen in the clinical remission rates with respect to disease distribution and phenotype may also be as a result of misclassification bias given the less objective nature of measuring clinical outcomes. Finally, the associations observed in our analyses of clinical outcomes or endoscopic outcomes could have resulted from type-2 or type-1 statistical errors, respectively.

Lower placebo endoscopic recurrence rates were more likely to be associated with higher percentages of patients with only small bowel involvement. Inversely, it was found that placebo-treated patients with both small and large bowel involvement were more likely to have higher endoscopic recurrence rates. This is expected as patients with more extensive disease, in particular, concomitant small bowel and colonic disease, are more likely to relapse post-operatively than those patients who had isolated small bowel or colonic disease.18, 19 Fistulizing type of CD was also found to be associated with higher placebo endoscopic recurrence rates. This is consistent with previous observational studies, which have reported earlier recurrence and need for subsequent surgery in patients with perforating disease as opposed to nonperforating disease.20, 21

We also found in our study, higher rates of endoscopic recurrence in those placebo-treated patients who had been on prior immunomodulator therapy and/or had prior surgery. Withdrawal of immunomodulator therapy, primarily azathioprine, even after prolonged remission of CD has been shown to increase the risk of relapse of CD.22 While prior surgery may be indicative of preoperative disease severity and thus could contribute to higher endoscopic recurrence rates, the finding in our study of higher endoscopic rates with prior surgery is actually contrary to what has been shown in prospective and retrospective observational studies evaluating the natural course of CD post-operatively.1, 19

While our data suggest important insights for interpreting the results of prior studies, they may also contribute to the design of future clinical trials in post-operative maintenance of CD. While no single factor appeared to account for higher placebo clinical remission rates, there appeared to be several patient characteristics, which were associated with higher placebo endoscopic recurrence rates as mentioned previously. Therefore, modifying inclusion criteria on the basis of these characteristics may identify possible ‘high-risk’ groups which could potentially reduce the required sample size by establishing a larger treatment effect.

Theoretically, over a sufficiently long follow-up time, one should observe an increase in the cumulative relapse rate with increasing follow-up time. Surprisingly, our study did not identify a significant association between the duration of follow-up and placebo clinical remission or recurrence rates for the durations of follow-up which were used in the included studies (4 months – 3 years). Although not designed specifically to address this question, these data suggest that there is no substantial increase in the placebo recurrence rate with increasing duration within this time frame. As such, it may be more efficient in future studies to increase the number of patients with 1–2 years of follow-up rather than attempting to study fewer patients with longer follow-up, which would potentially lead to a higher attrition rate.

While there was no single predictor found to be associated with recurrence in all of the clinical trials, several of the individual studies found at least one of the significant predictors from our study to be a notable patient characteristic when evaluating clinical or endoscopic recurrence rates. These predictors included prior medical therapy, prior surgery for CD, disease distribution, disease duration and disease type.5, 6, 9, 15 The study by Lochs et al. contributed substantially to the pooled estimate of the placebo remission rate (Figure 2) and identified that duration of disease and steroid intake prior to surgery influenced their recurrence rates.9

Certain studies can be considered outliers in terms of the remission and recurrence rates. Possible hypotheses may be posed for the outliers of remission rates found among the clinical trials. For instance, the study by Hanauer et al., reported a placebo clinical remission rate of 23% at 2 years. The investigators postulated that their use of a clinical grading scale rather than CDAI for defining recurrence may have contributed to this.6 When directly comparing the high rate of placebo clinical remission (91% at 1 year) in the trial by Prantera et al.,7 with the low clinical remission rate (34% at 4 months) in the trial from Florent et al.,12 we can see that the baseline characteristics of the study groups differed with respect to disease distribution/location and percentage of subjects with previous operations for CD, which were identified as characteristics significantly influential on rate of placebo recurrence from this meta-analysis.

There are several limitations to this study. First, based on the study design, the collection and analyses of group-level data may not accurately reflect the responses of individual subjects and thus cautious application of results to individual patients must be applied. However, the results achieved are still potentially useful in the interpretation of study results in PC-RCTs in IBD, particularly with reference to factors that may differ between the study groups. Furthermore, it is important to note those characteristics, particularly disease distribution and phenotype, which may influence the outcome and should thus be accounted for in the study design or analyses.

Publication bias is a potential limitation of most meta-analyses. Studies which demonstrate a significant benefit in the active treatment arm may be more likely than negative studies to be published. This would be more likely to occur with small studies than with large studies given the large amount of time and money typically devoted to such studies. Conceivably, exclusion of a number of small, unpublished studies could influence our overall study results if those small studies consistently had higher or lower rates of recurrence in the placebo arm than the published studies. If lower recurrence rates in the placebo arm resulted in a lower likelihood of a statistical significance within small unpublished studies, our estimate of the placebo clinical remission rate may be slightly too low.

In conclusion, the placebo outcomes in PC-RCTs for postsurgical maintenance therapy in CD were highly variable. While there is no single design feature that explains the heterogeneity demonstrated in the estimate of clinical remission rates, endoscopic outcomes were associated with disease distribution and phenotype, and accounting for these factors removed the heterogeneity demonstrated within our study results. Knowledge of these factors can be helpful when comparing results of different studies and when planning new studies of post-operative therapy.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Declaration of personal and funding interests: Dr Lichtenstein has received research funding or honorarium from Salix, Prometheus, Shire, Proctor and Gamble. Dr Su served as a speaker, a consultant, and/or advisory board member for Abbott, Centocor, Shire, and Proctor and Gamble. Dr Su is an employee of Wyeth Pharmaceuticals and has equity interest in the company.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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