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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  Ulcerative colitis (UC) pathophysiology is characterized by an imbalance between pro- and anti-inflammatory cytokines. Interferon (IFN)-β-1a has potent immunoregulatory properties, including stimulation of host defence mechanisms and thus represents a potential treatment.

Aim  To extend pilot data and identify a suitable dose of IFN-β-1a to achieve endoscopically confirmed remission (ECR) in patients with moderately active UC and to evaluate safety.

Methods  In this multicentre, double-blind, placebo-controlled trial, adults with moderately active UC were randomized to IFN-β-1a 44 or 66 μg, or placebo, subcutaneously three times weekly for 8 weeks, with a 4-week follow-up.

Results  Endoscopically-confirmed remission was observed in 23.4% [95% confidence interval (CI): 13.8–35.7] of placebo patients, 29.2% (95% CI: 18.6–41.8) of the IFN-β-1a 44 μg group and 20.0% (95% CI: 11.1–31.8) of the 66 μg group (P = 0.45). Improvements with IFN-β-1a 44 μg were greater than with placebo for most secondary efficacy outcomes, although significance was not achieved. Placebo response rates were higher than expected from previous trials. Adverse events were similar to the known safety profile of IFN treatment.

Conclusions  Interferon-β-1a was generally well tolerated at the doses tested, but a significant therapeutic benefit in patients with UC was not observed.


Introduction

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

Ulcerative colitis (UC) is a chronic, relapsing and potentially fatal inflammatory disease of the colorectal mucosa with a prevalence of 0.04–0.5%.1 The aetiology and pathogenesis of UC are not fully understood, but UC is thought to be the result of an inappropriate immune response to gut luminal contents in genetically susceptible individuals.2, 3

The mainstays of treatment are local or systemic anti-inflammatory drugs such as 5-aminosalicylic acid (5-ASA) derivatives. Severe disease may be treated with corticosteroids, immunosuppressive agents or anti-tumour necrosis factor (anti-TNF) therapies.4 Proctocolectomy is required where medical treatment has failed or is associated with unacceptable side-effects.

Over the last decade, there has been considerable progress in defining key inflammatory pathways in the gut of patients with UC and identifying new potential therapeutic targets. In particular, administration or manipulation of immunomodulatory cytokines has been proposed as alternative therapeutic strategies to modulate or inhibit pro-inflammatory cytokine production in UC. The delicate balance between pro-inflammatory and immunoregulatory cytokines is disrupted in patients with UC, resulting in excessive activity of pro-inflammatory mediators and inflammatory tissue damage. Tissue and plasma concentrations of pro-inflammatory cytokines such as interferon (IFN)-γ, interleukin (IL)-1-β, IL-6, IL-8, IL-16 and TNF-α are elevated in UC5–12 and correlate with disease activity.12 These cytokines are obvious targets to investigate the benefits of specific blockade in therapeutic studies.

One approach that has been investigated is to utilize the antagonistic effect of IFN-β on both IFN-γ and TNF-α. Recombinant IFN-β has been shown to inhibit production of IFN-γ in multiple sclerosis (MS).13, 14 Further, IFN-β antagonizes early molecular events of the IFN-γ-signalling pathway, particularly the STAT1-controlled genes,15, 16 which may explain the significant inhibitory effect of IFN-β on IFN-γ-induced major histocompatibility complex class II expression observed in various cell types.17, 18 Moreover, peripheral mononuclear cells from patients with relapsing–remitting MS who were treated with IFN-β-1b showed a decreased CD3-mediated TNF-α secretion compared with pre-treatment values.19 IFN-β also enhances production of the anti-inflammatory cytokine, IL-1020 and enhances T-suppressor cell and natural killer cell activity.21–23 In addition to specific immune effects, IFN-γ induces expression of host defence factors, including NOD-like receptors.24

Although clinical experience with type I IFNs and, in particular, with IFN-β is limited in patients with UC, IFN-β is of special interest from an immunopathological point of view because of its effects on multiple pathways implicated in the pathogenesis of UC. A pilot phase Ib, proof-of-concept, dose-escalation trial (n = 18) by Nikolaus et al. indicated that treatment with IFN-β-1a does not exacerbate disease in patients with UC and can induce clinical remission in some patients with moderately active UC.25 Endoscopically confirmed remission (ECR) occurred during the treatment phase in 30% of patients treated with escalating doses of IFN-β-1a [22–88 μg administered subcutaneously (sc) three times weekly (tiw)] vs. 13% of patients given placebo. At the follow-up visit 4 weeks after the end of treatment, 30% of IFN-β-1a patients and 25% of placebo patients were in remission. In an open-label pilot study (n = 25) conducted by Musch et al., 88% of steroid-refractory patients with UC went into remission after receiving induction treatment with IFN-β-1b (0.5 MIU intravenously or 1.0 MIU sc once daily).26 These findings highlighted the need to evaluate IFN-β-1a in a larger, systematic study in UC and indicated an appropriate IFN dose range to test and time period needed to elicit a response in patients with UC.

This study (protocol: 22648) was designed to extend the pilot study of Nikolaus et al. and aimed to identify a suitable dose of IFN-β-1a to achieve ECR in patients with moderately active UC, and also to examine the safety profile of this dose.

Materials and methods

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

Study design

This was a phase II, multicentre (43 centres in 17 countries), double-blind, parallel-group, placebo-controlled trial (NCT00303381). It was conducted between December 2001 and January 2003 in accordance with the Declaration of Helsinki and Good Clinical Practice, as well as any applicable local regulations.

Patients were randomized to one of three trial arms: IFN-β-1a 44 μg, IFN-β-1a 66 μg, or matching placebo (same excipients but no IFN-β-1a). All study drugs were given sc tiw for 8 weeks and there was a 4-week follow-up period. Patients were randomized using stochastic minimization so that the existing balance of allocated treatments influenced allocation of patients to treatment: the minimization method considered overall balance, centre, region and current use of maintenance therapy (5-ASA) as minimization factors. The 44 μg dose of IFN-β-1a was selected for investigation as it was readily available and approached the estimated minimum effective dose (49.5 μg tiw) from the proof-of-concept study by Nikolaus et al.25 The 66 μg dose was chosen to investigate potentially increased efficacy of a higher dose, while avoiding safety concerns that have been associated with doses of 88 μg or higher. The duration of treatment (8 weeks) was felt to be the maximally accepted duration for an induction therapy, but was also selected based on the design of published studies and on the results of the proof-of-concept study25 in which remission was first observed after 28–56 days of treatment.

Following central randomization, each patient was assigned a treatment kit number corresponding to a blinded treatment kit containing sufficient medication for the 8 weeks of treatment. The solutions of study drug were physically indistinguishable from one another, prepared and administered using the same technique for all patients and the labelling and packaging were designed so as to preserve the blinded nature of the study.

Patients

Patients aged over 18 years who were diagnosed with moderately active UC, based on clinical, radiological and endoscopic or histological findings were eligible for the study. Moderately active disease was defined by proctosigmoidoscopic findings that indicated the presence of active disease, with colonic inflammation extending >20 cm from the anal verge and a moderate flare in disease activity during the 14 days before starting study treatment [defined as a Ulcerative Colitis Scoring System (UCSS)27 score between 6 and 10, with a Physician’s Global Assessment (PGA) <3 and a proctosigmoidoscopy score of 2 or 3] and at least one previous flare-up of UC. Patients had to have an adequate bone marrow reserve: white blood cell count >3.5 × 109/L, neutrophils >1.5 × 109/L, thrombocytes >100 × 109/L, haemoglobin >8.5 g/dL. Corticosteroids were not allowed during the study, with the exceptions of inhaled steroids or topical dermatological steroids. Patients were excluded if they had received immunosuppressants, IFNs or other biological agents in the 3 months before study entry, any investigational drug or procedure in the 4 weeks before study entry or >3 doses of rectally administered 5-ASA derivatives, >2 doses of systemically or rectally administered corticosteroids, nonsteroidal anti-inflammatory drugs or antibiotics in the 2 weeks before study entry. Female patients had to be neither pregnant nor breastfeeding and had to lack child-bearing potential or be taking adequate contraceptive measures. It was planned that the study would recruit 168 patients in 43 study centres.

Assessment criteria

The primary objective was to identify the best dose of IFN-β-1a for the induction of ECR and examine the safety profile of this dose. ECR was defined as UCSS scores for stool frequency, rectal bleeding and PGA equal to zero and a score of 0–1 for proctosigmoidoscopy findings. The UCSS assesses disease severity based on two symptom subscales (stool frequency and rectal bleeding),27 proctosigmoidoscopy findings and a PGA of the patient. Secondary objectives were: to investigate the safety and tolerability of IFN-β-1a in this population; to establish the dose needed to enable clinical response and a change in disease severity (measured by the UCSS); to estimate disease-related quality of life on the Inflammatory Bowel Disease Questionnaire (IBDQ); and assess changes in biological markers of inflammation [C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)]. A total IBDQ score of 170 points equates to IBDQ remission28 and an increase of ≥15 points in IBDQ score constitutes a meaningful clinical improvement.29–32 Clinical response was defined as a ≥3-point decrease in the sum of the UCSS symptoms score and PGA score. Treatment failure was defined as an increase in dose of maintenance therapy or introduction of a new medication for the management of UC during the study or worsening of the UCSS by a minimum of 3 points from baseline with a PGA score of >2 and a total symptoms score that increased by ≥1 point.

Safety was assessed in terms of the incidence and severity of adverse events, changes in routine haematology, blood chemistry, urinalysis and thyroid function tests, changes in vital signs and physical examination findings, occurrence of antibodies to IFN-β and concomitant medications used during the study. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria. An independent Safety Review Board reviewed any safety concerns arising during the trial.

Tests for antibodies to IFN-β were performed at a central laboratory. Samples were tested first for the presence of binding antibodies (BAbs) and those found to be positive were tested for neutralizing activity. Patients were considered to have neutralizing antibodies (NAbs) to IFN-β if they had a NAb titre ≥20 neutralizing units (NU)/mL, defined as follows: NU/mL = [observed neutralizing titre × (IFN-β concentration in Loomis units (LU)/mL)]/10, where 1 LU/mL was the reciprocal of the dilution of IFN that protected 50% of WISH cells from viral cytopathic effect.33

During the treatment period, patients were evaluated every 2 weeks. UCSS was assessed at each visit, using symptom diary cards completed daily by the patients. Safety was monitored through physical examination, measurement of vital signs, routine haematology, blood chemistry and urinalysis. Adverse events and concomitant therapies were followed throughout the study, recorded by patients on the diary cards. Patients underwent a follow-up visit 4 weeks after completion of treatment, during which physical examination, routine laboratory assessments, determination of antibody status and evaluation of the UCSS were performed.

Statistical analysis

The estimated sample size for a two-sample comparison of proportions between placebo and the best active dose was 56 patients per treatment arm, giving a total of 168 patients in the study. The calculations were based upon a two-sample continuity-corrected test of equal proportions, unadjusted for multiple comparisons, as this was a phase II study. This assumes a power of 80% and is based on expected ECR rates of 10% for placebo27 and 30% for the best active dose, with a one-sided significance level of 0.05.25 All efficacy endpoints were analysed using the intention-to-treat (ITT) population. The safety population also included all randomized patients who received at least one injection of study medication, but in safety analyses, patients were analysed as treated.

A two-sided Cochran–Mantel–Haenszel test, stratified by use of maintenance therapy and geographical region, was used to compare the treatments for the primary efficacy endpoint, which was the proportion of patients with ECR at any time during the study (including during the 4-week follow-up period, but before withdrawal or treatment failure). All statistical tests were performed at a two-sided significance level of 0.05.

Continuous endpoints were summarized using descriptive statistics, and 95% confidence intervals (CIs) were calculated where appropriate. Analysis of variance (anova) was used to test for differences between treatments for continuous outcomes, adjusted for geographical region and use of maintenance therapy. If model assumptions were not met, log-transformation or anova on ranked data was used. For categorical endpoints, Mantel–Haenszel chi-squared tests were used to detect any differences between treatments. For binary endpoints (response and remission), frequencies of patients achieving the endpoint were tabulated. Odds ratios (ORs) adjusted for region and maintenance therapy are presented for the two IFN-β-1a treatment groups compared with placebo. Kaplan–Meier methodology was used to illustrate time to response for the 20th percentile (for remission) and for the 40th percentile (for clinical response) with CIs. The log-rank test was used to investigate differences between treatments and results were stratified by geographical region and use of maintenance therapy; if assumptions were not met, the Wilcoxon test or log-rank test for trend was used. Because of observed differences in study conduct and response rates between regions (specifically, between Russian and Croatian centres and others), a number of baseline characteristics and outcomes were assessed by region as exploratory (post hoc) analyses.

Results

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

A total of 194 patients were enrolled and randomized (Figure 1). The ITT population consisted of 64 patients in the placebo group, 65 patients in the IFN-β-1a 44 μg group and 65 patients in the IFN-β-1a 66 μg group. The safety population consisted of 63 patients in the placebo group, 65 patients in the IFN-β-1a 44 μg group and 66 patients in the IFN-β-1a 66 μg group. Baseline characteristics were well balanced (except for the male/female ratio in the IFN-β-1a 44 μg group; Table 1).

image

Figure 1.  Patient disposition. † Defined as: an increased maintenance therapy dose or introduction of a new medication for disease management during the study, or worsening of the Ulcerative Colitis Scoring System by a minimum of 3 points from baseline with a Physician’s Global Assessment score of >2 and a total symptoms score that increased by ≥1 point. ECR, endoscopically confirmed remission; IFN, interferon; sc, subcutaneous; tiw, three times weekly.

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Table 1.   Patient demographics and disease characteristics
CharacteristicTreatment group
IFN-β-1a 44 μg sc tiw (n = 65)IFN-β-1a 66 μg sc tiw (n = 65)Placebo (n = 64)
  1. 5-ASA, 5-aminosalicylic acid; IFN, interferon; sc, subcutaneous; s.d., standard deviation; tiw, three times weekly.

Age [years; mean (s.d.)]39.9 (14.0)40.7 (13.3)41.1 (12.6)
Gender (male:female)37:2830:3531:33
Duration of disease [years; mean (s.d.)]7.2 (6.5)4.9 (5.1)5.6 (5.5)
Time since last disease flare [months; mean (s.d.)]6.8 (8.5)5.8 (6.9)9.6 (15.6)
Length of colonic involvement [cm; mean (s.d.)]53.5 (28.0)50.2 (27.5)52.4 (24.2)
Baseline Ulcerative Colitis Scoring System [mean (s.d.)]7.7 (1.2)7.8 (1.2)7.9 (1.1)
Smoking status (%)
 Never smoked66.267.775.0
 Currently smoking10.8 6.2 7.8
 Past smoker23.126.217.2
5-ASA use (%)75.470.875.0

Compared with patients in other regions, patients in Croatia tended to have more active disease: greater colonic involvement (median distance from the anal verge: 65.0 cm vs. 42.5 cm for non-Croatian centres); shorter time since their last disease flare (median 2.1 months vs. 4.1 months for non-Croatian centres); and were more likely to be smokers or ex-smokers (52% vs. 27% in non-Croatian centres). Other baseline characteristics were generally comparable between Croatian and non-Croatian centres. In the Croatian centre, there were no missed doses among patients randomized to IFN-β-1a and no premature withdrawals.

At enrolment, 73.7% of the patients were receiving chronic therapy. Overall, 38 patients discontinued the trial. Four patients in the IFN-β-1a 44 μg group and six in the IFN-β-1a 66 μg group discontinued the study due to adverse events (Figure 1).

Efficacy

For the primary endpoint, there was no statistically significant difference (P = 0.45) in the proportions of patients with ECR between the active treatment groups and the placebo group. ECR was observed in 23.4% (95% CI: 13.8–35.7) of the placebo group, 29.2% (95% CI: 18.6–41.8; OR: 1.42) of the IFN-β-1a 44 μg group and 20.0% (95% CI: 11.1–31.8; OR: 0.87) of the IFN-β-1a 66 μg group. Remission rates in the placebo group (23.4%) were considerably higher than expected for such a strictly defined endpoint (clinical and endoscopic remission; <10% in the study by Schroeder et al.27 The high placebo group remission rates were seen across all regions except Croatia, where ECR in the placebo group (n = 9) was 11.1% (95% CI: 0.3–48.2). Furthermore, ECR was achieved by more patients in the groups receiving active treatment in Croatia than in other geographical regions: 62.5% (95% CI: 24.5–91.5) for IFN-β-1a 44 μg and 50.0% (95% CI: 15.7–84.3) for IFN-β-1a 66 μg (Table 2).

Table 2.   Endoscopically confirmed remission rates for Croatia, Russia and Western Europe
Country/regionNumber of patients achieving ECR (%)
IFN-β-1a 44 μg sc tiwIFN-β-1a 66 μg sc tiwPlacebo
  1. ECR, endoscopically confirmed remission; IFN, interferon; sc, subcutaneous; tiw, three times weekly.

Croatia5/8 (62.5)4/8 (50.0)1/9 (11.1)
Russia6/14 (42.9)4/13 (30.8)3/14 (21.4)
Western Europe3/16 (18.8)2/18 (11.1)5/16 (31.3)

Clinical remission (UCSS and PGA scores of 0) was achieved by 28.1% (95% CI: 17.6–40.8) of patients in the placebo group, 35.4% (95% CI: 23.9–48.2; OR: 1.41) in the IFN-β-1a 44 μg group and 27.7% (95% CI: 17.3–40.2; OR: 1.03) in the IFN-β-1a 66 μg group (P = 0.51). The 20th percentile time to clinical remission was the same in all groups (57 days; Figure 2).

image

Figure 2.  Time to clinical remission in the three treatment arms – interferon (IFN)-β-1a, 44 or 66 μg subcutaneously (sc) three times weekly (tiw), or placebo.

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A clinical response (≥3-point decrease in UCSS and PGA scores) was achieved in 64.6% (95% CI: 51.8–76.1; OR: 1.11) of the IFN-β-1a 44 μg group, 61.5% (95% CI: 48.6–73.3; OR: 1.07) of the IFN-β-1a 66 μg group and 60.9% (95% CI: 47.9–72.9) of the placebo group (P = 0.89). The mean time to clinical response was shorter for patients treated with IFN-β-1a 44 μg (32 days; 95% CI: 24.6–39.4), compared with either the placebo (43 days; 95% CI: 32.1–53.9) or IFN-β-1a 66 μg (43 days; 95% CI: 33.8–52.2).

Treatment failure occurred in 26.6% of placebo patients, 21.5% of IFN-β-1a 44 μg patients and 18.5% of IFN-β-1a 66 μg patients. All treatment failures in the two active treatment groups occurred after treatment had been stopped in the 4-week follow-up period. In the placebo group, treatment failure occurred in three patients while receiving treatment.

Small changes in biological markers of inflammation were noted. Small decreases (median change ≤3 mm/h) in ESR were noted in all treatment groups, indicating a lessening of inflammation. CRP levels at follow-up were similar to those at baseline.

Quality of life

Quality of life scores on the IBDQ improved meaningfully (≥15-point improvement) in 40.6% of patients in the placebo group compared with 47.7% in the IFN-β-1a 44 μg group and 44.6% in the IFN-β-1a 66 μg group. Figure 3 shows the evolution of median IBDQ total scores over time; there was a trend towards greater improvement in the IFN-β-1a treatment group (particularly the 44 μg group) than in the placebo group, and the improvement was maintained only in the active treatment groups (particularly the 66 μg group) during the 4-week follow-up period.

image

Figure 3.  Changes in Inflammatory Bowel Disease Questionnaire score over the course of the study. FUP, follow-up period; IFN, interferon; sc, subcutaneous; tiw, three times weekly.

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Safety

Both doses of IFN-β were generally well tolerated in patients with UC. Adverse events occurred in 69.8% of the placebo group, 83.1% of the IFN-β-1a 44 μg group and 89.4% of the IFN-β-1a 66 μg group. The most common adverse events (occurring in >10% of patients) were constitutional symptoms known to be associated with IFNs (such as headache, influenza-like symptoms and fever) and application-site disorders (Table 3). All such adverse events were mild or moderate in intensity. Other adverse events occurring in <10% of patients and known to be associated with IFNs were musculoskeletal disorders (arthralgia or myalgia), liver and biliary system disorders (which were only found in the active treatment groups), laboratory abnormalities (elevated transaminases, anaemia and cytopenias), thyroid disorders and psychiatric disorders.

Table 3.   Most frequent adverse events, by treatment group, occurring in >10% of patients in the safety population
Adverse event (preferred term)Number of patients (%)
Placebo (n = 63)IFN-β-1a 44 μg sc tiw (n = 65)IFN-β-1a 66 μg sc tiw (n = 66)Total (n = 194)
  1. IFN, interferon; sc, subcutaneous; tiw, three times weekly.

Headache17 (27.0)24 (36.9)29 (43.9)70 (36.1)
Influenza-like symptoms10 (15.9)21 (32.3)25 (37.9)56 (28.9)
Fever8 (12.7)22 (33.8)22 (33.3)52 (26.8)
Injection-site reaction4 (6.3)8 (12.3)11 (16.7)23 (11.9)
Injection-site inflammation0 (0)6 (9.2)14 (21.2)22 (11.3)
Injection-site pain4 (6.3)8 (12.3)5 (7.6)17 (8.8)

There were no deaths and most of the events overall were mild (73.7% of patients) or moderate (50%) in severity. Only one patient (0.5%) had a life-threatening event (a gastrointestinal haemorrhage, which was not considered to be treatment-related). The percentage of patients with severe adverse events was 3.2% in the placebo group, compared with 12.3% in the IFN-β-1a 44 μg group and 6.1% in the IFN-β-1a 66 μg group. Of the five serious adverse events (one event in the placebo group and two in each IFN-β-1a group), three were considered ‘possibly’ or ‘probably’ related to study treatment: severe hypokalaemia in one patient in the 66 μg group, moderate thrombocytopenia in one patient in the 44 μg group and a severe peri-anal abscess in one placebo patient.

Ten patients withdrew from the study because of adverse events: four in the IFN-β-1a 44 μg group and six in the IFN-β-1a 66 μg group. Five patients (two in the IFN-β-1a 44 μg group and three in the IFN-β-1a 66 μg group) withdrew because of constitutional symptoms such as influenza-like symptoms, headache and malaise. One patient in the IFN-β-1a 66 μg group discontinued because of worsening of UC, and one patient in the IFN-β-1a 44 μg group withdrew because of severe thrombocytopenia, anaemia and macrohaematuria concurrent with an exacerbation of UC. These were considered ‘possibly’ or ‘probably’ related to study treatment. The remaining patients withdrew for reasons that were not considered related to study treatment.

The proportion of adverse events that were considered to be ‘probably’ or ‘possibly’ related to treatment was similar in the placebo and IFN-β-1a 44 μg groups (68% and 69.3% respectively). In the IFN-β-1a 66 μg group, 80.8% of adverse events were considered at least ‘possibly’ related to study treatment. Only 3.5% (2.8%, 4.1% and 3.5% in the placebo, 44 and 66 μg groups respectively) of adverse events that were considered at least ‘possibly’ related to treatment were classified as severe, and none was classified as life-threatening.

At the follow-up visit, a small proportion (10%) of patients were BAb positive, but no patient was NAb positive.

Discussion

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

This study aimed to find a suitable dose of IFN-β-1a (in terms of efficacy and safety) to treat patients with moderately active UC. The safety data demonstrated that treatment was generally well tolerated, with adverse events and laboratory abnormalities consistent with the known effects of IFN-β-1a, but a significant benefit of IFN-β-1a was not seen.

This trial did not achieve its primary endpoint: there was no statistically significant difference in the proportion of patients with ECR between the IFN-β-1a and placebo treatment groups. The possible trend towards improved ECR in patients treated with IFN-β-1a compared with placebo probably reflects the positive results seen in Croatian and Russian patients. The higher dose (66 μg) did not offer any substantial advantages over the 44 μg dose or placebo, for efficacy. The difference in ECR rates between active treatment and placebo was not as high as anticipated, most likely because placebo remission rates were approximately twice as high as predicted. The estimate that 10% of placebo patients would achieve ECR is in line with other trials in UC that used ECR as an endpoint (including a meta-analysis of 44 studies).34–36 Results for most secondary endpoints showed a similar pattern. Nonetheless, treatment-failure data suggest that IFN-β-1a may have a minor therapeutic effect: all treatment failures in the active-treatment groups occurred after discontinuation of IFN-β-1a, whereas three failures in the placebo group occurred during treatment. There was no evidence of improved efficacy with the higher 66 μg dose of IFN-β-1a, and for several outcomes, placebo patients fared better than those receiving the higher 66 μg dose of IFN-β-1a.

Interestingly, in this study, patients in Croatia did not conform to the general pattern of response to treatment seen in other geographical areas. ECR rates were greater in Croatia than in the other regions and Croatia was the only country to have an ECR rate in the placebo group that was similar to that seen in previous studies.34–36 Adherence to treatment tended to be better in the Croatian centres and these patients tended to have more active disease than those in other centres. However, the small numbers of patients in this post hoc regional sub-analysis result in large CIs and, therefore, any interpretation of such differences should be treated with caution.

Several categories of adverse events were given particular attention in this study because they are known or suspected to be associated with IFN therapy: influenza-like symptoms, injection-site reactions, hepatic abnormalities (particularly elevated transaminases), cytopenias, thyroid disorders and depression. As expected, such adverse events were reported more frequently in the IFN-β-1a groups than in the placebo group, with a tendency towards a higher frequency and severity in the higher-dose group.

The adverse event profile was similar to that observed in other trials with IFN-β-1a, such as the proof-of-concept trial in UC and large pivotal phase III trials in MS.25, 37–39 For MS, clinical trials and postmarketing data indicate that influenza-like symptoms occur in up to 75% of patients, while injection-site reactions occur in around 83% of patients receiving IFN-β-1a sc tiw.40 Liver enzyme elevations occur in up to 67% of patients during the first 2 years of treatment with IFN-β-1a sc tiw, but by the end of 2 years, the prevalence is similar to that seen in placebo-treated patients (11% vs. 6% respectively).40

In summary, these data do not demonstrate a clinically relevant benefit of IFN-β-1a in patients with moderately active UC. While these results are interesting from an immunological perspective, they do not support the further clinical development of IFN-β-1a in UC.

Both doses of IFN-β-1a (44 and 66 μg) were generally well tolerated over an 8-week period in patients with moderately active UC. Adverse events were consistent with the known safety profile of IFN-β-1a in patients with MS. Clinical outcomes, including the proportion of patients achieving ECR, were not statistically significantly superior in the IFN-β-1a treatment groups over placebo, although there was a trend in favour of IFN-β-1a, 44 μg sc tiw. Remission rates in the placebo group were higher than expected for this study design. The efficacy of IFN-β-1a at the doses studied here was not superior to placebo.

Acknowledgements

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

We acknowledge the valuable contribution of the following study Investigators. Belgium: P. Rutgeerts; Croatia: M. Duvnjak, M. Katicic, Z. Krznaric, S. Mise, D. Stimac; Germany: B. Bokemeyer, Y. Dörffel, K. Jessen, D. Ludwig, A. Raedler, J. Schölmerich; Israel: E. Goldin, Z. Halpern; The Netherlands: A. A. M. Geraedts; Norway: M.-B. Bengtson; Russia: A. Y. Baranovsky, E. A. Belousova, V. V. Grinevitch, T. L. Mikhailova, O. N. Minushkin, V. A. Rogozina, V. I. Simonenkov, A. P. Ternavsky, M. Y. Yourkov; Merck Serono International S.A.: J. Moehrle, T. Keilani, A. Rowley, Y. Grumser, A. Dubois, C. Filmer, C. Barra, A. Ferreira, S. Buffet, C. Haas; Singapore: C. J. Ooi; Spain: J. García-Paredes; Sweden: O. Suhr; Switzerland: G. Kullak-Ublick; Thailand: S. Manatsathit; UK: S. J. Middleton; US: S. Goldberg, R. Kaplan, W. Priebe; Yugoslavia: J. Jovic, T. Milosavljevic, R. Tomasevic. Declaration of personal interests: C. Pena-Rossi is an employee of Merck Serono International S.A. (an affiliate of Merck KGaA, Darmstadt, Germany). S. Schreiber has served as a paid consultant for Abbott Laboratories, Bayer, Berlex/Schering, Boehringer-Ingelheim, Bristol-Myers Squibb, Centocor, Elan Pharmaceuticals, Otsuka, Schering Pharmaceuticals, Schering-Plough and its subsidiary Essex Pharmaceuticals, Serono International S.A. (an affiliate of Merck KGaA, Darmstadt, Germany), Solvay, Teva and UCB Celltech, and has served as an unpaid consultant for ChemoCentryx. He has also given lectures or spoken at symposia sponsored by Abbott Laboratories, AstraZeneca, Falk, Ferring, Genizon, Schering Pharmaceuticals, Schering-Plough and its subsidiary Essex Pharmaceuticals, and UCB Celltech, and has received major institutional research grants from AstraZeneca, Berlex-Schering AG and UCB Celltech. S. Schreiber is also a stockholder of CONARIS Research Institute AG. Golubovic G. and A. Mertz-Nielsen have no competing interests to disclose. J. Panés has served as an advisory board member and speaker for Abbott Laboratories, Novartis, Schering-Plough Laboratories and UCB Pharmaceuticals. D. Rachmilewitz and M. J. Shieh have no competing interests to disclose. V. I. Simanenkov has received a research grant from the Soros Foundation and holds a patent for the management of chronic gastritis. D. Stanton has no competing interests to disclose. H. Graffner is an employee of Merck Serono International S.A. (an affiliate of Merck KGaA, Darmstadt, Germany). Declaration of funding interests: This study was funded in full by Merck Serono International S.A. (an affiliate of Merck KGaA, Darmstadt, Germany). The writing and preparation of this paper was funded by Merck Serono International S.A. (an affiliate of Merck KGaA, Darmstadt, Germany). Writing support was provided by Ann Le Good, funded by Merck Serono International S.A. (an affiliate of Merck KGaA, Darmstadt, Germany).

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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