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Abstract

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

Summary

Background

Adalimumab is effective in inducing remission in patients with active Crohn’s disease who had secondary failure to infliximab therapy.

Aim

To evaluate the efficacy and safety of adalimumab maintenance therapy in Crohn’s disease patients who previously responded to infliximab and then lost response or became intolerant.

Methods

Twenty-four patients with Crohn’s disease were enrolled in a 52-week open-label trial. The patients received a loading dose of adalimumab 80-mg at week 0, and then 40 mg every other week starting at week 2. The primary efficacy measure was clinical remission defined as Crohn’s Disease Activity Index score < 150 at week 52.

Results

Five patients lost response to adalimumab. None of the patients experienced intolerance to adalimumab. Clinical remission rates were higher at weeks 4 (16/24, 67%) and 52 (14/24, 58%) compared with baseline (8/24, 35%) (= 0.043 at week 52). This was accompanied by a decrease in mean C-reactive protein concentration from 31.8 mg/mL at baseline to 9.7 mg/mL at week 52, and 3/4 (75%) patients achieved steroid-free remission. No serious toxicities occurred in the study.

Conclusions

Adalimumab is well tolerated and appears to be effective in maintaining clinical remission in patients with Crohn’s disease and lost response or intolerance to infliximab.


Introduction

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

Tumour necrosis factor (TNF) is a cytokine playing a key role in the pathogenesis of Crohn’s disease (CD).1 Infliximab, a chimeric monoclonal antibody to TNF, is effective in inducing and maintaining response and remission in patients with moderate to severe CD.2, 3 However, infliximab is immunogenic and repeated administration can result in the development of antibodies to infliximab that lead to infusion reactions, loss of efficacy and delayed hypersensitivity reactions.4–6

Two anti-TNF agents which might be less immunogenic,7 namely adalimumab and certolizumab (a PEGylated humanized Fab′ fragment to TNF), have proven efficacy in the treatment of CD refractory to standard medical therapy with corticosteroids or immunomodulatory agents.8–13 Adalimumab is a recombinant human IgG1 human monoclonal antibody that binds with high affinity and specificity to human soluble TNF but not to lymphotoxin. In three placebo-controlled trials, adalimumab was effective for both induction and maintenance of clinical response and remission8–10 in moderate to severe CD.

Recently, two uncontrolled trials14, 15 and a 4-week randomized placebo-controlled trial named Gauging Adalimumab Efficacy in Infliximab Non-responders (GAIN)16 have demonstrated that adalimumab therapy was also effective in inducing remission in patients with active CD who had previously responded to infliximab and then lost response or became intolerant. Preliminary data from a retrospective study suggested that adalimumab may be an effective maintenance therapy for patients with CD who have experienced an attenuated response to infliximab.17 However, the long-term efficacy of adalimumab beyond 6 months in these patients is unknown.

We conducted a 52-week open-label trial to assess the long-term efficacy and safety of subcutaneous administration of adalimumab in CD patients who had an attenuated response to infliximab or had become intolerant to infliximab therapy.

Methods

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

Selection of patients

Eligible patients were males or females who were at least 18 years of age. Patients with CD who had previously responded to infliximab and then lost response or became intolerant were prospectively included. Loss of response to infliximab was defined as the presence of symptoms or evidence of disease activity as judged by their treating physician despite an increase of infliximab dosing to 10 mg/kg and a decrease in interval to 4 weeks between infliximab infusions. Inability to tolerate infliximab was defined when acute or delayed hypersensitivity reactions (as defined by the investigator) led to discontinuation of infliximab therapy. Information regarding the number of previous infliximab infusions was not collected. The diagnosis of CD was made at least 3 months earlier using radiological, endoscopical or histological evidence.

Patients were ineligible if they had a serious infection, history of previously untreated tuberculosis or concurrent tuberculosis, previous history of demyelinating disease or malignancy (other than basal cell carcinoma of the skin), a short bowel syndrome, bowel resection within 4 weeks of starting the study medication, symptomatic obstructive strictures, colostomy or ileostomy, history of drug or alcohol abuse or poorly controlled medical conditions. Pregnant and lactating women were also excluded. All patients had a negative tuberculin purified protein derivative skin test prior to starting adalimumab.

All patients gave consent and this study was approved by the University Hospital of Nancy Institutional Review Board.

Concomitant medications

Concurrent therapies, including stable doses of 5-aminosalicylates, corticosteroids, azathioprine, mercaptopurine, methotrexate and antibiotics, were permitted. All these agents were continued at a stable dose through week 4. After week 4, 5-aminosalicylates, corticosteroids and antibiotics could be discontinued at the investigator’s discretion, while treatment with azathioprine, mercaptopurine and methotrexate was continued at a stable dose throughout the study. There was no predefined steroid tapering regimen that was used in patients treated with adalimumab.

Study design

This open-label study was performed at one single centre in France (University Hospital of Nancy). Pharmacist prepared 1.0-mL vials containing 40 mg/0.8 mL adalimumab. Injections of adalimumab were administered by medical staff at an on-site facility, and patients were monitored for 2 h following administration for adverse reactions. At the baseline visit (week 0), all patients who were eligible received a loading dose of 80-mg adalimumab subcutaneously followed by a 40-mg dose at week 2. Patients were then treated with 40-mg adalimumab every other week through week 52. After week 4, the dose could be escalated to 40 mg weekly in patients who did not achieve clinical remission, complete fistula closure and complete steroid withdrawal.

Efficacy and safety evaluations

Patients were assessed at weeks 0, 4, 12, 26 and 52. At each visit, the Crohn’s Disease Activity Index (CDAI) score was calculated. Patients were also assessed for the presence of open and actively draining perianal fistulas. At each visit, blood samples were taken for measurement of plasma concentrations of C-reactive protein (CRP), as well as for haematological, biochemical and liver function assessments.

Outcomes and statistical analyses

The primary outcome measure was the maintenance of clinical remission (CDAI score < 150) at week 52. Secondary outcome measures included clinical remission (CDAI score < 150) rate at each visit, changes in mean CDAI score and CRP concentration at each visit, loss of response or intolerance to adalimumab, steroid sparing at week 52 among the patients treated with corticosteroids (including budesonide) at baseline, complete fistula closure (defined as closure of all fistulas that were draining at baseline) at any visit and safety. Information regarding the Inflammatory Bowel Disease Questionnaire and antichimeric antibody to infliximab was not collected.

The intention to treat (ITT) population included all patients who received at least one dose of study treatment. All patients were included in the safety analysis. The percentages of patients who were in clinical remission at weeks 0 and 52 were compared using the chi-squared test.

Results

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

Characteristics of the patients

Between March 2005 and September 2005, 24 adult patients were screened and were treated with adalimumab. Thus, the ITT population consists of 24 patients. The baseline characteristics of the patients are shown in Table 1. Eighteen of the 24 patients (75%) experienced a loss of response to infliximab that led to discontinuation of such treatment; the remaining six patients became intolerant to infliximab therapy as defined by the investigator. The indication for administration of adalimumab was luminal disease in all patients included in this study. Table 2 summarizes the disposition of the patients. Eighteen of the 24 patients (75%) completed the 52-week study. Six of the 24 patients had a dose escalation between weeks 4 and 52 from 40 mg every other week to 40-mg adalimumab weekly due to incomplete response as judged by their physician. Five patients withdrew before the end of the study due to loss of response (of these, four patients discontinued adalimumab after a 6-month treatment period), and one patient discontinued study drug due to pregnancy. All patients were able to tolerate adalimumab, including six who previously experienced acute or delayed hypersensitivity reactions with infliximab.

Table 1.   Baseline characteristics of the 24 patients
Variablen (%)Mean (s.d.)
  1. * Patients may have Crohn’s disease involving more than one location.

  2. † No open enterocutaneous fistulae in the baseline population.

Male5 (20.8) 
Age at entry, years 35 (10)
Duration of Crohn’s disease, years 11 (7)
Location of Crohn’s disease*
 Ileum14 (58.3) 
 Colon21 (87.5) 
Open and draining perianal fistulae†3 (12.5) 
Previous intestinal resection8 (33.3) 
Current smoker13 (54.1) 
Crohn’s Disease Activity Index score 193.7 (67)
C-reactive protein concentration (mg/L) 31.8 (40)
Concomitant medications
 Corticosteroids (include budesonide)4 (16.6) 
 Azathioprine or mercaptopurine16 (66.6) 
 Methotrexate1 (4.1) 
 5-Aminosalicylates3 (12.5) 
Indication of adalimumab
 Loss of response to infliximab18 (75) 
 Intolerance to infliximab6 (25) 
Table 2.   Disposition of patients enrolled in the study
Variablen (%)
  1. * Pregnancy.

Completed the study18/24 (75)
Lost to follow-up0 (0)
Dose escalated throughout study6/24 (25)
Patients with ongoing adalimumab therapy at week 5218/24 (75)
Reasons for discontinuation of adalimumab therapy
 Loss of response5/6 (83.3)
 Intolerance0/6 (0)
 Other*1/6 (16.7)

Efficacy

At study entry (week 0), eight of 24 patients were in clinical remission (CDAI < 150). When considering the 24 patients who received at least one adalimumab infusion (ITT population), the clinical remission rates at weeks 4 and 12 (secondary pilot efficacy endpoints) were 16 of 24 (67%) and 14 of 24 (58%), respectively. The percentages of patients in clinical remission at weeks 26 and 52 (primary pilot efficacy endpoint) were also greater (67% and 58%, respectively) to that observed at week 0 (Table 3); difference reached statistical significance at week 52 (= 0.043 vs. baseline).

Table 3.   Clinical efficacy (ITT population)
Variablen (%)
  1. CDAI, Crohn’s Disease Activity Index; ITT, intention to treat.

Clinical remission (CDAI score < 150)
 Week 08/24 (33)
 Week 416/24 (67)
 Week 1214/24 (58)
 Week 2616/24 (67)
 Week 5214/24 (58)
Steroid sparing (successful discontinuation after week 4)3/4 (75)
Complete fistula closure at any visit (closure of all fistulas that were draining at baseline)2/3 (66.7)

Five of six (83.3%) patients with prior intolerance to infliximab were still in clinical remission at week 52, while nine of 18 (50%) patients with prior loss of response to infliximab had quiescent CD defined as CDAI < 150 at week 52.

The percentage of subjects receiving concomitant azathioprine or mercaptopurine was similar at baseline (16 of 24, 62.5%) and in patients in clinical remission at week 52 (nine of 14, 64.3%). The mean CDAI scores and CRP concentrations at each study visit are shown in Figures 1 and 2. The mean CRP value fell rapidly within the first month from 31.8 mg/L on study entry to 14.3 mg/L at week 4. At the end of the study (week 52), the mean CRP concentration (9.7 mg/L) was still lower than the mean CRP value at baseline (Figure 2). The changes in mean CDAI scores paralleled those in CRP concentrations. The mean CDAI scores at weeks 4, 12, 26 and 52 were 105, 115, 74.5 and 71, respectively (Figure 1).

image

Figure 1.  Mean Crohn’s Disease Activity Index score at each study visit.

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image

Figure 2.  Mean C-reactive protein concentration at each study visit.

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The percentage of patients who were able to taper and discontinue steroids (prednisone or budesonide) after week 4 was three of four (75%). The percentage of patients who had complete fistula closure at any visit was two of three (67%). Fistula closure occurred within the first month of adalimumab treatment period for the two patients. All three patients with open fistula tracts at baseline previously experienced loss of response to infliximab for both luminal and perianal disease (Table 3).

Safety

Adverse events occurred in 54.2% (13/24) of patients, but none of these events led to patient withdrawal (Table 4). The most frequently reported adverse events were injection site reactions [4/24 (16.7%)] and headache [3/24 (12.5%)]. None of the patients experienced serious adverse events (Table 4). There were no clinically significant changes in laboratory values (haematological, biochemical and liver function tests) during the study.

Table 4.   Adverse events in the 24 patients
Variablen (%)
Patients with any adverse event13 (54.2)
Patients with serious adverse events0
Patients with adverse events leading to withdrawal0
Deaths0
Adverse events
 Injection site reaction4 (16.7)
 Headache3 (12.5)
 Upper respiratory tract infection2 (8.3)
 Dermatitis2 (8.3)
 Pharyngitis1 (4.2)
 Otitis1 (4.2)
 Abdominal pain1 (4.2)
 Pyrexia1 (4.2)
 Palpitations1 (4.2)
 Tooth abscess1 (4.2)

Discussion

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

The development of an attenuated response or intolerance over time is a significant problem in CD patients treated with infliximab therapy. We found a rapid response to adalimumab therapy with first dose, as 16/24 (67%) of the patients were in clinical remission at week 4 compared with 8/24 (35%) at week 0. These findings are in agreement with the results of the GAIN study, a large phase III, double-bind, placebo-controlled trial, showing that approximately one of five patients (regardless of the placebo arm) treated with adalimumab benefit from the introduction of this anti-TNF agent.16 It should be noted that in our study, approximately one-third of the patients were in clinical remission defined as CDAI < 150 at week 0 because all patients who lost response or became intolerant were screened and treated with adalimumab, regardless of CDAI score. Only signs of disease activity (as judged by the treating physician) had to be present at screening. Nevertheless, the mean CRP concentration, which was 31.8 ± 40 mg/L at week 0 in this study, was higher to that reported (16.3 ± 24.5 mg/L) in a previous trial with similar design in which patients included had a baseline score ≥ 220,14 suggesting that most patients included in our study probably had active CD at time of screening.

More interestingly, 58% of the patients were still in clinical remission at the end of the study (primary pilot efficacy endpoint) compared with 35% of the patients at study entry. As all patients who were in clinical remission at study entry maintained remission at 1-year follow-up, we cannot conclude that these patients benefited from switching from infliximab to adalimumab. Thus, adalimumab may be effective in maintaining clinical remission in (at least) 20% of the patients who had secondary failure to infliximab therapy. The percentage of patients with prior intolerance to infliximab who were still in clinical remission at week 52 (83.3%) was higher to that in patients with prior response to infliximab who had quiescent CD defined as CDAI < 150 at week 52 (50%). These results indicate that switching from infliximab to adalimumab may be more efficacious for patients who became intolerant to infliximab than for those with prior loss of response to infliximab.

The percentage of subjects receiving concomitant azathioprine or mercaptopurine was similar at week 0 and in patients in clinical remission at week 52. Thus, the concomitant immunosuppressive therapy does not seem to influence the clinical efficacy of adalimumab in this population.

Clinical efficacy of adalimumab was accompanied by a decrease in plasma CRP concentrations at week 4, with an effect that persists at 1-year follow-up, reinforcing the potential benefit of adalimumab use in patients with CD who have secondary failure to infliximab therapy. Consistent with the results of the Crohn's trial of the fully Human antibody Adalimumab for Remission Maintenance (CHARM) trial,10 adalimumab also appears to be effective in treating fistulizing disease and obtaining steroid-free remission.

However, data regarding the efficacy of adalimumab in terms of clinical remission, steroid sparing and complete fistula closure should be interpreted with caution due to small sample size and the lack of placebo controls.

In the study by Papadakis et al.,17 patients were treated with adalimumab over a 6-month period. A longer duration of follow-up is likely required to assess the long-term efficacy of switching from infliximab to another anti-TNF agent in patients with loss of response or intolerance to this drug. Indeed, among the five patients who lost response to adalimumab therapy in our study, 4/5 (80%) had an attenuated response after a 6-month treatment period. These findings also highlight the need for a third-line treatment. As no other biologic agents as anti-TNF are currently available for the treatment of CD, patients who developed an attenuated response to both infliximab and adalimumab might benefit from switching to certolizumab. Additional investigations are required to address this issue.

Finally, none of the patients experienced intolerance to adalimumab that led to discontinuation of the drug, including six who previously experienced acute or delayed hypersensitivity reactions with infliximab. The safety profile was consistent with previous experience with this drug. Like in the GAIN trial,16 injection site reactions were the most common adverse events. None of the adverse events led to patient withdrawal. Moreover, no patients developed serious infections, malignancies, demyelinating disorders, drug-induced lupus, or died, but the power to detect these rare events was limited. Immunogenicity, i.e. occurrence of anti-adalimumab antibodies, was not evaluated in this study.

In conclusion, adalimumab therapy is well tolerated and appears to be effective in maintaining clinical remission in patients with luminal CD who had lost responsiveness or developed intolerance to infliximab. These preliminary data need to be confirmed in randomized, double-blind, placebo-controlled trials.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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    Direct Link: