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Keywords:

  • certolizumab pegol;
  • Crohn's disease;
  • anti-TNF-α;
  • perianal fistulizing disease

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Background:

Certolizumab pegol (Cimzia, CZP) was approved for the treatment of Crohn's disease (CD) patients in 2007 in Switzerland as the first country worldwide. This prospective phase IV study aimed to evaluate the efficacy and safety of CZP over 26 weeks in a multicenter cohort of practice-based patients.

Methods:

Evaluation questionnaires at baseline, week 6, and week 26 were completed by gastroenterologists in hospitals and private practices. Adverse events were evaluated according to World Health Organization (WHO) guidelines.

Results:

Sixty patients (38F/22M) were included; 53% had complicated disease (stricturing or penetrating), 45% had undergone prior CD-related surgery. All patients had prior exposure to systemic steroids, 96% to immunomodulators, 73% to infliximab, and 43% to adalimumab. A significant decrease of the Harvey–Bradshaw Index (HBI) was observed under CZP therapy (12.2 ± 4.9 at week 0 versus 6.3 ± 4.7 at week 6 and 6.7 ± 5.3 at week 26, both P < 0.001). Response and remission rates were 70% and 40% (week 6) and 67% and 36%, respectively (week 26). The complete perianal fistula closure rate was 36% at week 6 and 55% at week 26. The frequency of adverse drug reactions attributed to CZP was 5%. CZP was continued in 88% of patients beyond week 6 and in 67% beyond week 26.

Conclusions:

In a population of CD patients with predominantly complicated disease behavior, CZP proved to be effective in induction and maintenance of response and remission. This series provides the first evidence of CZP's effectiveness in perianal fistulizing CD in clinical practice. (Inflamm Bowel Dis 2011;)

The pathogenic hallmark of Crohn's disease (CD) is an intestinal and systemic chronic inflammation that is thought to result from an aberrant mucosal immune response to the microbiota of the gastrointestinal tract in genetically susceptible individuals.1, 2 The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) has a key role in mediating inflammation in CD and is closely associated with disease activity.3–7

Several biological agents targeting TNF-α have demonstrated clinical efficacy in CD patients in large randomized trials.8–17 At present, there are three anti-TNF-α agents available in Switzerland and the USA for treatment of moderate to severe CD. After the registration of infliximab (IFX, Remicade, Centocor, Malvern, PA) and adalimumab (ADA, Humira, Abbott Laboratories, Abbott Park, IL), Switzerland was the first country worldwide to approve certolizumab pegol (CZP, Cimzia, UCB, Belgium) for the treatment of active CD in patients with insufficient response to conventional therapy, on September 7 2007. CZP is a subcutaneously administered humanized pegylated Fab' of a monoclonal antibody against TNF-α. The clinical efficacy and the safety of CZP for the treatment of moderate to severe CD were demonstrated in the PRECiSE 1 and 2 studies.16, 17 Furthermore, the PRECiSE 3 study, which was recently published, demonstrated that CZP was also an effective long-term maintenance therapy for patients who had responded to CZP induction therapy.18

CD patients seen in daily practice may differ from the selected patients included in phase II and III randomized controlled clinical trials. Furthermore, only limited data on the efficacy and safety of CZP following use in daily clinical practice are available. This situation motivated us to perform a nationwide prospective survey (First Approved Certolizumab Therapeutic Experience in Switzerland survey: the FACTS survey) to evaluate the efficacy and safety of CZP in the treatment of patients presenting predominantly moderate to severe CD in clinical practice. We recently published our findings of the FACTS I survey, evaluating CZP efficacy and safety as induction therapy in unselected CD patients.19 Besides a favorable safety profile and clinical efficacy regarding disease activity, we also observed a short-term beneficial outcome on perianal fistulizing CD. We present here the 26-week data on 60 unselected consecutive CD patients, with special focus on efficacy towards disease activity, perianal fistulas, and safety.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Study Design

A prospective, questionnaire-based survey of patients treated with CZP was sent to all Swiss gastroenterologists since the time of the drug approval in Switzerland in September 2007. CD patients with moderate-to-severe luminal disease or with active perianal disease regardless of disease activity were included. The study design including patient numbers at different assessment timepoints is further depicted in Figure 1. Data were collected at baseline (week 0), just before the initiation of CZP therapy, at week 6, thus following CZP induction (400 mg subcutaneously [sc] at weeks 0, 2, and 4), and at week 26. These timepoints were selected to match those of the PRECiSE studies. The survey was conducted as a nested project of the Swiss Inflammatory Bowel Disease Cohort Study and was approved by the Ethics Committee of Lausanne University Medical Center.20

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Figure 1. Study design according to the PRECiSE trials. The red arrows indicate when CZP was applied and the stars indicate when a clinical assessment was performed. The survival curve illustrates the dropouts at the different timepoints (60 patients at week 0 and 46 patients at week 26).

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Questionnaires

A baseline data questionnaire and two follow-up questionnaires (weeks 6 and 26) were sent to gastroenterologists active in hospitals or in private practices in Switzerland through the office of IBDnet (http://www.ibdnet.ch), an association of Swiss scientists focusing on inflammatory bowel disease (IBD). The data collection period lasted from April 3 2008 to October 30 2009. Two of the authors (S.R.V. and A.M.S.) validated the data in case of incomplete or inconclusive information. Queries were sent to the participating physicians until all issues were clarified.

The baseline questionnaire (week 0) assessed the following items: coded patient identification and date of birth, CD location and phenotype, age at diagnosis, disease duration, smoking history, prior IBD drug history, disease activity (elements of the Harvey–Bradshaw Index, HBI), and current perianal fistula status (number of draining and nondraining perianal fistulas). Draining fistulas were defined as those with pus oozing under no or mild pressure. The follow-up questionnaire (weeks 6 and 26) assessed the following items: number, dosage, and date of CZP injections, current clinical (HBI) and perianal fistula status, adverse reactions under therapy including the physician's assessment of potential relation to CZP, the physician's decision to continue or not CZP therapy, as well as the reason for treatment interruption if applicable.

Evaluation of Disease Activity and Efficacy

CD activity was measured, in agreement with existing data on CZP, by the HBI, known to correlate closely with the Crohn's Disease Activity Index (CDAI).21, 22 In 2006, Best23 evaluated the two scores by regression modeling and found that a 1 point increase in HBI corresponds to a 27-point increase in the CDAI. According to the ECCO (European Crohn's and Colitis Organization) guidelines for the definition of CD activity,24 we applied the following definitions: an HBI from 0 to 4 points indicates clinical remission (corresponding to a mean CDAI from 26 ± 26 to 134 ± 39); an HBI from 5 to 7 points indicates mild disease (CDAI: 161 ± 42 to 216 ± 49); an HBI from 8 to 15 indicates moderate disease (CDAI: 243 ± 52 to 432 ± 75); an HBI ≥16 indicates severe disease (CDAI ≥459 ± 78). We defined clinical remission as an HBI ≤4 points and clinical response as an HBI decrease of ≥3 points versus baseline. Corticosteroid-free clinical remission was defined according to the SONIC trial as clinical remission in patients who had not received budesonide at a daily dose of more than 6 mg or systemic corticosteroids for at least 3 weeks.25

Drug Safety Issues

The questionnaires assessed frequency and type of adverse reactions and recorded the following items: injection site reaction, allergic reaction outside injection site, headache, gastrointestinal complaints (not CD-related), bleeding, infection, perianal/perineal abscess and other adverse effects. The items were classified according to their probability of being CZP-related into “unclassifiable,” “conditional,” “unlikely,” “possible,” “probable,” and “certain,” according to the WHO definitions of causality assessment.26, 27

Inclusion and Exclusion Criteria

All CD patients treated with CZP since its approval in Switzerland in September 2007 were eligible, provided that their diagnosis of CD was established on the basis of standard clinical, endoscopic, and histologic criteria at least 6 months prior to inclusion.28 Patients were excluded if induction and maintenance treatment with CZP was not performed according to the label that recommends induction treatment with 400 mg sc at weeks 0, 2, and 4 and then 400 mg sc every 4 weeks. Patients who received one additional CZP injection in the maintenance period between weeks 6 and 26 were kept in the study.

Patient Characteristics

A total of 60 patients (38 women, 22 men, mean age 38.5 ± 13 years, range 20–70 years) were prospectively enrolled in the study. Table 1 gives an overview of the patient characteristics. Disease phenotypes were characterized according to the Montreal Classification.28, 29 The observed involved segments were ileum (L1) in 20%, ileum and upper gastrointestinal tract (GIT) (L1+L4) in 2%, colon (L2) in 23%, ileocolon (L3) in 48%, and ileocolon and upper GIT (L3+L4) in 7%. Twenty-two patients (37%) were smokers. Fifty-three percent of the patients presented complicated phenotypes (B2+B3, and perianal disease) and the majority (75%) had long-standing disease (duration >5 years). In total, 27 CD patients (45%) had undergone CD-related surgery, including ileal resections (2%), ileocecal resections (18%), colonic resections (5%), ileocecal and colonic resections (5%), and temporary ileostomy (5%). None of the patients had an ileostomy at the time of inclusion. Eleven of 14 patients with perianal disease (18% of the overall population) had undergone previous incisions and/or drainages of perianal abscesses and/or fistulas. One patient in remission was included due to perianal fistulizing disease and one because of intolerance to infliximab.

Table 1. Baseline Characteristics of Patients According to the Montreal Classification
ItemFrequency
  1. GIT = gastrointestinal tract.

Number of patients60
Females/males38/22
Age (yrs, mean ± SD)38.5±13, range 20-70
Age at diagnosis
 A1 below 16 yrs9 (15%)
 A2 between 17 and 40yrs39 (65%)
 A3 above 40 yrs12 (20%)
Disease location
 L1 Ileum12 (20%)
 L1+L4 Ileum+upper GIT1 (2%)
 L2 Colon14 (23%)
 L3 Ileocolonic29 (48%)
 L3+L4 Ileocolonic+upper GIT4 (7%)
Behavior
 B1 non-stricturing, non-penetrating28 (47%)
 B1p B1 + perianal disease8 (13%)
 B2 stricturing9 (15%)
 B2p stricturing + perianal disease2 (3%)
 B3 penetrating9 (15%)
 B3p penetrating + perianal disease4 (7%)
Disease duration (yrs)
 <1 year0
 1-2 years3 (5%)
 2-5 years12 (20%)
 >5 years45 (75%)
Active smokers22 (37%)
Surgical history
 CD related surgery27 (45%)
 Ileal resection1 (2%)
 Ileocecal resection11 (18%)
 Colonic resection3 (5%)
 Ileocecal and colonic resection3 (5%)
 Temporary ileostomy3 (5%)
 Perianal fistula drainage11 (18%)

Statistical Analysis

Data were analyzed using Stata software (v. 9, College Station, TX). Results of numerical data are presented as mean or median ± SD and range. Binary and categorical data were compared by means of chi-squared tests for contingency tables. The mean HBI values at weeks 0, 6, and 26 were formally compared using one-way analysis of variance (ANOVA). Pairwise comparisons of means were then performed using the Bonferroni method after statistically significant ANOVA. A P-value <0.05 was considered statistically significant. For graphical evaluation, boxplots were calculated. Response and remission rates were calculated according to the “intention-to-treat” (ITT) principle.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Prior CD-related Drug History

Data on the current and past IBD medication(s) were thoroughly collected. An overview of the medication history is presented in Table 2. All patients had received previous therapy with systemic steroids, of whom 72% had no or insufficient response, or secondary loss of response. There were four patients under systemic steroids at the time CZP was started (all of them in a tapering down scheme, prednisolone doses at CZP start were 15, 10, and 2 times 5 mg, corresponding to a mean dose of 8.7 ± 4.8 mg). All these patients were at least 3 weeks off steroids at week 6 evaluation. All except two patients had been previously treated with azathioprine or 6-mercaptopurine, 50% of whom with no or insufficient response, or secondary loss of response. Azathioprine/6-mercaptopurine use was associated with side effects in 33% of patients. Forty percent of patients had been treated with methotrexate before initiation of CZP therapy. Furthermore, 44 patients (73%) had been previously treated with infliximab. Of those, 64% reported no or insufficient response, or secondary loss of response. Treatment with infliximab was associated with side effects in 36% of patients. Twenty-six patients (43%) had also been treated with adalimumab prior to CZP, 77% of whom with no, insufficient, or secondary loss of response.

Table 2. Prior Drug History in the 60 CD Patients Under CZP Treatment
DrugEver treatedNo/Insufficient responseLoss of responseSide effectsOngoing
  1. Percentages in the “ever treated” group refer to n = 60, in the other groups to the number of treated CD patients. 5-ASA = 5-aminosalicylates; 6-MP = 6-mercaptopurine.

5-ASA36 (60%)31 (86%)2 (6%)2 (6%)1 (2%)
Budesonide35 (58%)27 (77%)2 (6%)1 (3%)5 (14%)
Systemic steroids60 (100%)37 (62%)6 (10%)13 (21%)4 (7%)
Azathioprine/6-MP58 (97%)25 (43%)5 (9%)19 (33%)9 (15%)
Methotrexate24 (40%)12 (50%)2 (8%)10 (42%)0
Infliximab44 (73%)8 (18%)20 (46%)16 (36%)0
Adalimumab26 (43%)11 (42%)9 (35%)6 (23%)0

CD-related Drug History During the Observation Period

This section clarifies what kind of concomitant medication was applied during the observation period.

Azathioprine or 6-mercaptopurine was prescribed in nine (15%) patients and continued throughout the entire observation period in unchanged dosage (2–2.5 mg/kg body weight).

Antibiotics were prescribed in 13 patients (22%), with the major indication being symptomatic treatment of perianal fistulizing disease besides treatment of symptomatic developing infections. One patient was prescribed isoniazide (INH) for 9 months because of latent tuberculosis and entered the survey at month 2 of the INH treatment. The remaining 12 patients were treated with short-term antibiotics (mean duration 3.7 ± 2.7 weeks, range 1–8 weeks). Five patients (8%) were treated with ciprofloxacine, 5 (8%) with metronidazole, and 3 (5%) with amoxicillin/clavulanic acid.

In total, eight patients were prescribed systemic steroids between weeks 6 and 26. Indication in all cases was a flare-up of CD and the mean prednisone dose given was 43 ± 8.5 mg (range 30–55 mg), mean duration of the steroid treatment was 6 ± 1.6 weeks (range 4–8 weeks). All patients were off systemic steroids for at least 3 weeks at week 26 evaluation.

An additional CZP to restore response was applied in 15/60 (25%) of the patients. All the additional doses were provided between weeks 10 and 26. The dropout rate until week 26 did not differ between the two groups (3/15, 20%, versus 11/45, 24%, P = 0.724).

CZP Efficacy as Induction and Maintenance Therapy

The impact of CZP therapy was first analyzed by comparing HBI scores at different timepoints. Sixty patients were included at weeks 0 and 6 compared to 46 patients at week 26 (14 dropouts). The mean HBI values at week 0 (12.2 ± 4.9, range 2–26) were significantly higher compared to week 6 (6.3 ± 4.7, range 0–20) and week 26 (6.7 ± 5.3, range 0–25) (P < 0.001 for both week 0 versus week 6 and week 26, P = 0.699 week 6 versus week 26). These findings are further depicted by means of comparative boxplots in Figure 2.

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Figure 2. The boxplots demonstrate the significant decrease of the HBI from week 0 to week 6 (n = 60), the mean HBI at week 26 (n = 46) does not differ from week 6. The horizontal line in the middle of the box is the median, the box represents the lower and upper quartile, whereas the whiskers indicate the 95% confidence interval of the values. The values outside the whiskers represent individual outliers.

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We further compared the HBI kinetics of the 46 patients who underwent 26 weeks of CZP treatment to those of the 14 CD patients who discontinued before week 26 in order to test the hypothesis that these patients had a less pronounced HBI decrease in the induction period. Similar to the analysis of the entire cohort, the mean HBI of the 46 patients reaching week 26 under CZP was significantly lower at week 6 (5.6 ± 4.4, range 0–20) and week 26 (6.7 ± 5.3, range 0–25) compared to week 0 (12.3 ± 5.2, range 2–26). In the dropout group (n = 14) in contrast, the mean HBI was 11.7 ± 4 (range 5–20) at week 0 and 8.8 ± 5.2 (range 0–19) at week 6 (P = 0.133). Mean HBI values between the dropout and maintenance group were not different at week 0 (P = 0.709) but CD patients in the dropout group had significantly higher mean HBI values at week 6 (P = 0.035) as compared to the maintenance group (under CZP until week 26). These data appear to demonstrate that a poor decrease in HBI during the CZP induction period is associated with early termination of CZP therapy.

Impact of CZP on Disease Activity

In a second step, the impact of CZP induction and maintenance therapy was analyzed by categories of disease activity: clinical remission (HBI 0–4), mild disease (HBI 5–7), moderate disease (HBI 8–15), and severe disease (HBI ≥16) and clinical response and remission rates were calculated.

An overview of the patients in the different disease categories in the time course is presented in Figure 3. The figure shows that a significant percentage of patients were brought into clinical remission at weeks 6 and 26 under CZP therapy and furthermore that the percentage of patients with moderate disease was significantly reduced at weeks 6 and 26. The percentage of patients with severe disease was also significantly reduced at both weeks 6 and 26.

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Figure 3. Impact of CZP therapy on disease activity. Patients number analyzed at weeks 0 and 6 = 60 and 46 at week 26 (14 dropouts). Definitions of disease activity according to HBI: remission 0–4; mild disease 5–7; moderate disease 8–15; severe disease ≥16. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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Response and remission rates were further analyzed by ITT, which considers all dropouts and loss of follow-up as treatment failures. Corresponding response and remission rates are shown in Table 3 (first ITT population for weeks 6 and 26 response and remission rates = all included patients, n = 60; second ITT population = week 6 responders only, n = 42, following the analysis strategy in the PRECiSE 2 study).17 These data show that CZP induced a response in 70% of patients and that treatment response was maintained at week 26 in 67% of the week 6 responders (remission rates of 40% at week 6 and 36% at week 26).

Table 3. Response and Remission Rates at Baseline, Week 6, and Week 26
TimepointWeek 0 (n = 60)Week 6 (n = 60)Week 26P-value Week 0 vs. 6, Week 0 vs. 26, Week 6 vs. 26
  1. Stratified according to two different ITT populations, the first one including all patients (n = 60) whereas the second ITT population is represented by week 6 responders only (n = 42) according to the PRECISE 2 analysis. According to ITT definition, all the 14 patient dropouts between week 6 and week 26 are considered as treatment failure. NA = not available, ITT = intention-to-treat principle.

ITT analysis (ITT population for week 6 and week 26 rates = 60 patients)
Response rateNA42/60 (70%)31/60 (52%)P = 0.040
Remission rate2/60 (3%)24/60 (40%)16/60 (27%)P < 0.001, P < 0.001, P = 0.121
ITT analysis (ITT population for week 26 = week 6 responders only, n = 42 patients)
Response rateNA42/60 (70%)28/42 (67%)P = 0.721
Remission rate2/60 (3%)24/60 (40%)15/42 (36%)P < 0.001, P < 0.001, P = 0.661

Response and Remission Rates Under CZP in Patients with Primary or Secondary Failure to Prior Anti-TNF Therapy

We analyzed the response and remission rates in the patient groups with either loss of response or primary nonresponse or insufficient response to prior infliximab or adalimumab therapy. In the group with prior infliximab treatment, 20/44 (46%) of patients had a loss of response. In this cohort, none of them were in remission at week zero, a response at week 6 was observed in 75% (15/20) and a remission in 30% (6/20), whereas a response was documented at week 26 in 67% (10/15) and a remission in 27% (4/15). There were eight patients (18%) with primary nonresponse or insufficient response to infliximab treatment, none of these patients were in remission at week 0. At week 6 a response was measured in 33% (2/6) and a remission in 0%, whereas in week 26 a response was documented in 100% (3/3) and a remission in 0% (0/3).

There were nine patients (35%) with loss of response to prior adalimumab therapy, of which none was in remission at week zero. At week 6 a response of 67% (6/9) and a remission rate of 56% (5/9) was found, whereas in week 26 the response was 71% (5/7) and the remission rate 43% (3/7). Eleven patients (42%) experienced no or insufficient response to prior adalimumab therapy; none of them were in remission at week zero. Forty-five percent (5/11) had a response at week 6 (remission rate 0%) and 75% (6/8) at week 26 (remission rate 25%, 2/8).

Impact of CZP Therapy on Perianal Disease

Fourteen patients (23%) were identified with penetrating perianal disease. All suffered from complex fistulas and had a perianal disease duration >3 months. We assessed the following items under treatment with CZP: number of patients with perianal fistulizing disease, number of patients with draining perianal fistulas, number of draining fistulas per cohort (n = 60), number of nondraining fistulas per cohort, 50% fistula closure rate, and 100% fistula closure rate. The 50% fistula closure rate was defined as a decrease of ≥50% in number of draining perianal fistulas under treatment with CZP. Accordingly, the 100% fistula closure rate was defined as a complete absence of draining fistulas. The endpoint “draining or nondraining fistula” was based on the examiner's clinical evaluation. A perianal fistula was considered closed when it no longer drained pus despite gentle finger compression.31 Three patients (3/14, 21%) with perianal fistulizing CD discontinued CZP therapy between week 6 and week 26. An overview of the fistula findings during CZP treatment is provided in Table 4. The number of patients with active perianal fistulas was significantly reduced during the 26-week treatment period (23% versus 9%, P = 0.047). The number of patients with draining perianal fistulas was also significantly reduced during CZP treatment (20% at baseline versus 7% week 26, P = 0.048), as well as the total number of draining perianal fistulas (45% at baseline versus 17% at week 6 and 15% at week 26, P = 0.001 for both). The 100% fistula closure rate at week 6 was 36% compared to 55% at week 26, whereas the 50% fistula closure rate was 71% at week 6 compared to 64% at week 26.

Table 4. Impact of CZP Therapy on Perianal Fistulizing CD
TimepointWeek 0 (n = 60)Week 6 (n = 60)Week 26 (n = 46)P-value Week 0 vs. 6, Week 0 vs. 26, Week 6 vs. 26
Patients with perianal fistulas14/60 (23%)11/60 (18%)4/46 (9%)P = 0.05, P = 0.047, P = 0.158
Patients with draining fistulas12/60 (20%)7/60 (12%)3/46 (7%)P = 0.211, P = 0.048, P = 0.369
Number of draining fistulas27/60 (45%)10/60 (17%)7/46 (15%)P = 0.001, P = 0.001, P = 0.84
Number of nondraining fistulas12/60 (20%)10/60 (17%)1/46 (2%)P = 0.637, P = 0.006, P = 0.015
100% fistula response rateNA5/14 (36%)6/11 (55%)NA
50% fistula response rateNA10/14 (71%)7/11 (64%)NA

Safety of CZP Induction and Maintenance Therapy

All safety events that occurred during the study period and their relationship to the study drug are reported in Table 5. Only the WHO causality categories “possible,” “probable,” and “certain” are included in the table. According to the WHO guidelines, patients in the category “certain” had to undergo a positive rechallenge.

Table 5. Adverse Reactions Classified According to WHO Guidelines
EventsNo adverse reactionAdverse reactions: causality
PossibleProbableCertain
  1. Reported in the table is the number of patients undergoing distinct events. GI = gastrointestinal.

Injection site reaction56 (93%)121
Allergic reaction other than injection site53 (88%)430
Headache56 (93%)211
GI complaints (not CD)57 (95%)120
Bleeding57 (95%)300
Infection56 (93%)211
Perineal/-anal abscess57 (95%)300
Death60 (100%)000
Tuberculosis60 (100%)000
Dysplasia/cancer60 (100%)000
Lymphoma60 (100%)000

We have already reported on the adverse events in the induction period (week 0 to week 6) in the FACTS I analysis.19 Of interest, most adverse events were recorded in the first 6 weeks of the treatment. In the treatment period from week 7 to week 26 no additional case of injection site reaction was recorded. Other adverse reactions included one patient with probable allergic reaction other than an injection site reaction and one patient with a possibly CZP-related headache. There were in total three possibly CZP-related bleeding episodes, all occurred during the induction period: one patient experienced microhematuria, one gingival bleeding during teeth brushing, and one had a CD-related rectal hemorrhage. All of these bleeding events were mild and self-limiting. In total, four infections were recorded, two female patients with urinary tract infection (one in induction and one in maintenance period), one patient with Clostridiumdifficile colitis (induction period), and one with skin infection other than injection site. The additional CZP dose in 15 patients was not associated with a higher number of adverse events compared to the group not receiving this additional dose (injection site reaction 0/15 versus 4/45 (P = 0.232), allergic reaction other than injection site 1/15 versus 6/45 (P = 0.486), headache 0/15 versus 4/45 (P = 0.232), GI complaints (not CD) 0/15 versus 3/45 (P = 0.305), bleeding 0/15 versus 3/45 (P = 0.305), infection 2/15 versus 2/45 (P = 0.232), perianal abscess 2/15 versus 1/45 (P = 0.232).

In summary, CZP was well tolerated and showed a favorable benefit:risk profile over the 26-week treatment period. No patient died under CZP therapy, no cases of clinically overt tuberculosis were detected, and no dysplasia/cancer or lymphoma reported. No cases of clinically relevant bleeding were observed. Furthermore, the rate of injection site reactions was low (2%).

Hospitalizations and CD-related Operations

Only one patient was hospitalized for undergoing a segmental resection of a stenosed terminal ileum during the 26-week observation period (hospital stay for 6 days). One additional patient underwent a mariscectomy in an outpatient setting. In summary, 98% of the reported 60 patients were managed as outpatients and only 3% underwent a CD-related operation during the observation period.

Medical Decisions at Week 6 and Week 26 Regarding CZP Continuation

At week 6, CZP was continued beyond week 6 in 53 out of the 60 patients initially treated (88%). Reasons for CZP discontinuation in seven patients at week 6 were: insufficient response in four cases, intolerance/side effects in two cases (including the case of C.difficile colitis), and patient wish in one case. In three additional patients CZP was stopped at week 8 and in four patients at week 12. In all these last seven patients the reason for discontinuation was insufficient response to therapy. As depicted in Table 3, 42/60 (70%) responded to therapy at week 6 and CZP was continued in 53 patients beyond week 6. The 11 patients classified as “nonresponders” who were on continued CZP therapy beyond week 6 presented a partial response, not meeting the definition of an HBI decrease ≥3 points versus baseline. A reinduction (one additional 400 mg CZP dose between two regular doses at 4-week interval) was applied in four of the seven patients discontinuing CZP therapy between weeks 6 and 26.

After week 26, CZP therapy was stopped in six additional patients (total number of dropouts since baseline = 20 patients, 33%) due to insufficient/loss of clinical response in all of them. Two of them additionally demonstrated intolerance/side effects attributed to CZP. In summary, CZP was continued in 88% of CD patients after week 6 and in 67% after week 26.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Our phase IV multicenter survey demonstrates that CZP is effective in inducing and maintaining response (70% at week 6 and 67% at week 26) and remission (40% at week 6 and 36% at week 26) over 26 weeks in a population of CD patients with predominantly moderate to severe disease, complicated disease behavior, and a high failure rate to previous anti-TNF-α agents. Furthermore, CZP proved also effective in treating perianal fistulizing disease and had a favorable safety profile.

The long-term efficacy of CZP to maintain response and remission have been established in the PRECiSE 2 study17 and in its open-label extension study PRECiSE 3.33 In PRECiSE 2, a phase III, 26-week, open-label induction, double-blind maintenance trial, 64% of patients had a response (CDAI decrease ≥100) at week 6 after induction treatment. Among the responders further randomized to the maintenance phase (CZP 400 mg every 4 weeks) the response and remission rates were 63% and 48% at week 26. In the open-label PRECiSE 333 study, patients allocated to CZP therapy 400 mg every 4 weeks had a clinical response rate of 77.8% and a remission rate of 59.1%, as defined by an HBI decrease of ≥3 points and a final score of ≤4 points. Our response rate at week 6 (70%) compares with the PRECiSE 2 data and our response rate at week 26 (67%) is similar to the PRECiSE 2 and PRECiSE 3 data. However, we observed a lower remission rate at week 26 (36%) as compared to PRECiSE 2 (48%).

This discrepancy may be explained by differences in patient populations. The response and remission rates in our dataset were achieved despite the inclusion of a high proportion of patients with complicated disease phenotype (56%), a high frequency of CD-related surgery (52%), and a considerable proportion of patients with multiple primary or secondary failures to prior CD therapies. In particular, we included a considerable proportion of patients with failure to previous anti-TNF-α therapy (73% with previous infliximab and 43% with previous adalimumab failure). By comparison, only 24% of CD patients had previous exposure to an anti-TNF-α medication in the PRECiSE 2 trial. A subgroup analysis from PRECiSE 2 revealed that the efficacy of CZP in patients with previous infliximab-treatment was lower compared to infliximab-naive patients (44% in infliximab-exposed patients versus 69% in infliximab-naive patients had maintained clinical response at week 26).17 Other factors previously correlated with low treatment response were comparable in both cohorts (active smokers 37% in FACTS II versus 30% in PRECiSE 2, CD-related bowel resection 35% in FACTS II versus 30% in PRECiSE 2).34, 35 In summary, despite the presence of predictors of negative treatment outcome in a high percentage of our patients, CZP proved efficient in inducing and maintaining a meaningful clinical improvement in a high proportion of CD patients with moderate to severe disease.

Based on the results of FACTS I that had shown for the first time an effectiveness of CZP on perianal fistulizing disease,19 we were particularly interested in the impact of CZP induction and maintenance therapy on perianal fistulizing disease. Keeping the limited number of patients with perianal fistulas in mind, CZP treatment over 26 weeks proved effective in significantly reducing the number of patients suffering from perianal fistulas, the number of patients suffering from draining perianal fistulas, as well as the total number of draining perianal fistulas. Furthermore, CZP treatment was associated with a complete fistula closure rate of 55% at week 26. The literature on CZP efficacy on perianal fistulizing disease is scarce. Besides the fistula data of induction treatment from the FACTS I survey and one case report on the closure of an enterocutaneous fistula,19, 36 Schreiber et al37 published an abstract on CZP efficacy in perianal fistulizing disease (fistula post-hoc analysis of PRECiSE 2). In that analysis, 28 patients with perianal fistulizing disease were randomized to CPZ and 30 patients to placebo. The 50% fistula closure rate at week 26 in the CZP-treated patients was 73% versus 38% in the placebo group and the 100% fistula closure rate was 67% versus 31%. Although the patient number is limited in our survey, our data support the findings reported by Schreiber et al and suggest that CZP represents a valuable option for treatment of perianal fistulizing CD. These findings should stimulate the initiation of a randomized trial to assess the impact of CZP in a larger patient cohort with perianal fistulizing disease.

We further assessed the safety profile of CZP induction and 26-week maintenance treatment in our multicenter cohort according to the WHO guidelines. Our safety data demonstrated that CZP was well tolerated and showed a favorable benefit:risk profile. Notably, no deaths, clinically overt tuberculosis, cancer, or lymphoma were reported. Furthermore, the rate of injection reactions and infections remained low over 26 weeks. Our data are in accordance with the findings from the randomized trials.16, 17 Recently, a pooled analysis of six studies evaluating safety aspects of CZP in 1313 patients was presented.38 There was no relationship between the duration of CZP exposure and the incidence of all treatment-emergent adverse events (i.e., malignancies, including lymphoma, cardiac failure, hepatic failure, tuberculosis, and death). Of interest, infections increased with duration of exposure in both CZP-treated and placebo-treated patients and the rates of local and systemic reactions were lower in the CZP patients than in the placebo comparators. More long-term data of phase IV studies are needed to increase our knowledge on the impact of anti-TNF-α agents on infections and neoplasias.39

Our survey has method-inherent strengths and also limitations. The first limitation lies in the limited number of patients. However, our goal was not to conduct a randomized clinical trial, but to collect “real-life” experience with CZP at the time of its launch, through a survey that would allow us to evaluate the benefits and risks of this drug in an environment where it would be the third anti-TNF agent available for CD therapy. Second, our data represent a voluntary survey and, as such, cases may have escaped collection. In contrast, however, through this survey design we were able to collect experience not only from tertiary centers but also from colleagues in private practice that used the drug for the first time in a context less stringent than the one of randomized trials. In this regard, our results are interesting as they suggest that CZP can be used successfully and safely in general gastroenterology practices.

In conclusion, CZP proved effective in inducing and maintaining clinical response and remission in CD patients with moderate to severe disease characterized by complicated disease behavior and high percentage of failure to previous anti-TNF-α medications and immunosuppressants. Furthermore, this series provides the first evidence of effectiveness of maintenance CZP therapy in perianal fistulizing CD in clinical practice. CZP was well tolerated with a low frequency of adverse drug reactions. Further phase IV data on larger patient cohorts on CZP maintenance therapy are needed to further define the position of CZP in treatment of luminal and perianal fistulizing CD.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES