Elsevier

The Lancet

Volume 388, Issue 10051, 24–30 September 2016, Pages 1281-1290
The Lancet

Articles
Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial

https://doi.org/10.1016/S0140-6736(16)31203-XGet rights and content

Summary

Background

Complex perianal fistulas in Crohn's disease are challenging to treat. Allogeneic, expanded, adipose-derived stem cells (Cx601) are a promising new therapeutic approach. We aimed to assess the safety and efficacy of Cx601 for treatment-refractory complex perianal fistulas in patients with Crohn's disease.

Methods

We did this randomised, double-blind, parallel-group, placebo-controlled study at 49 hospitals in seven European countries and Israel from July 6, 2012, to July 27, 2015. Adult patients (≥18 years) with Crohn's disease and treatment-refractory, draining complex perianal fistulas were randomly assigned (1:1) using a pre-established randomisation list to a single intralesional injection of 120 million Cx601 cells or 24 mL saline solution (placebo), with stratification according to concomitant baseline treatment. Treatment was administered by an unmasked surgeon, with a masked gastroenterologist and radiologist assessing the therapeutic effect. The primary endpoint was combined remission at week 24 (ie, clinical assessment of closure of all treated external openings that were draining at baseline, and absence of collections >2 cm of the treated perianal fistulas confirmed by masked central MRI). Efficacy was assessed in the intention-to-treat (ITT) and modified ITT populations; safety was assessed in the safety population. This study is registered with ClinicalTrials.gov, number NCT01541579.

Findings

212 patients were randomly assigned: 107 to Cx601 and 105 to placebo. A significantly greater proportion of patients treated with Cx601 versus placebo achieved combined remission in the ITT (53 of 107 [50%] vs 36 of 105 [34%]; difference 15·2%, 97·5% CI 0·2–30·3; p=0·024) and modified ITT populations (53 of 103 [51%] vs 36 of 101 [36%]; 15·8%, 0·5–31·2; p=0·021). 18 (17%) of 103 patients in the Cx601 group versus 30 (29%) of 103 in the placebo group experienced treatment-related adverse events, the most common of which were anal abscess (six in the Cx601 group vs nine in the placebo group) and proctalgia (five vs nine).

Interpretation

Cx601 is an effective and safe treatment for complex perianal fistulas in patients with Crohn's disease who did not respond to conventional or biological treatments, or both.

Funding

TiGenix.

Introduction

Crohn's disease is a chronic inflammatory bowel disease characterised by transmural inflammation and fistula formation.1 The prevalence of Crohn's disease varies geographically, with the highest figures reported in the USA, Canada, and Europe, where prevalence rates above 300 per 100 000 people have been described.2

Perianal fistulas are a common complication of Crohn's disease and are estimated to affect up to 28% of patients in the first two decades after diagnosis,3, 4 particularly those with colonic disease and rectal involvement.5 They severely impair patients' quality of life and cause substantial morbidity.6 About 70–80% of perianal fistulas are complex,4, 7 and these are challenging to treat since they are particularly refractory to conventional medical treatment strategies (ie, antibiotics and immunomodulators) and anti-tumour necrosis factor (anti-TNF) treatments.8, 9, 10, 11, 12 Furthermore, 60–70% of patients relapse after stopping treatment,13, 14, 15, 16, 17 and only a few patients achieve long-term remission.18 So far, the only approved drug that has shown efficacy in a randomised clinical trial setting is the anti-TNF drug infliximab.8, 12 Failure of or intolerability to medical treatment can ultimately result in debilitating surgical approaches, such as diverting stoma or proctectomy.19 Therefore, there remains an unmet need for alternative treatments for perianal fistulising Crohn's disease.

Although the exact pathogenesis of perianal fistulas is largely unknown, they are thought to arise from an epithelial defect that might be caused by ongoing inflammation.6 Adipose-derived mesenchymal stem cells are a promising new approach for the treatment of such fistulas because of their anti-inflammatory and immunomodulatory potential.20, 21, 22 Initial proof of concept was achieved in an open-label phase 1/2a clinical study23 of allogeneic, expanded adipose-derived stem cells (Cx601) in 24 patients with Crohn's disease and complex perianal fistulas,23 with 56% of patients showing complete closure of the external opening and the absence of collections measured by MRI of the treated fistula 24 weeks after treatment. We therefore undertook a placebo-controlled study to assess the safety and efficacy of Cx601 added on to current medical treatment for treatment-refractory complex perianal fistulas in patients with Crohn's disease.

Research in context

Evidence before this study

We searched PubMed from Jan 1, 1980, to Dec 31, 2015, for publications on the treatment of complex perianal fistulas in patients with Crohn's disease using the following search terms: “perianal”, “fistul*”, “Crohn's disease”, and “treatment”. This search yielded 639 results, of which 52 were clinical studies. These studies showed that: (1) existing pharmacological treatments for complex perianal fistulas have low efficacy in inducing fistula healing (antibiotics 21–48%; thiopurines 20–40%; anti-tumour necrosis factor [TNF] treatment 23% complete responders [36% of 64% of patients who responded to induction treatment]); (2) the only approved drug that has shown efficacy in a randomised clinical trial is the anti-TNF drug infliximab; and (3) few treatment options exist for drug-treatment-refractory patients, and repeated surgical options are associated with substantial morbidity (eg, incontinence) and with a significant risk of permanent stoma. These findings emphasised the need for novel treatment options for treatment-refractory complex perianal fistulas in patients with Crohn's disease. Available data suggest that Crohn's-disease-associated fistulas originate from an epithelial defect that might be caused by ongoing inflammation. Since adipose-derived mesenchymal stem cells have anti-inflammatory and immunomodulatory potential, they seem to be suitable candidates to treat this disorder. Initial clinical results suggested they might have therapeutic potential in this setting.

Added value of this study

This study is, to our knowledge, the first randomised, placebo-controlled study of adipose-derived mesenchymal stem cells (Cx601) for the treatment of complex treatment-refractory perianal fistulas in patients with Crohn's disease. Our findings suggest that local treatment with Cx601 added on to established treatments for Crohn's disease might open new therapeutic options for refractory perianal disease. In this study, we assessed therapeutic effect using an innovative and distinctive primary endpoint combining both clinical assessment of fistula closure and MRI. 50% of patients treated with Cx601, compared with 34% of the placebo group, achieved combined remission 24 weeks after treatment, and the stem-cell treatment was well tolerated.

Implications of all the available evidence

Our findings suggest that Cx601 might offer patients with Crohn's disease who have treatment-refractory complex perianal fistulas a novel and minimally invasive closure alternative to avoid the need for systemic immunosuppression or surgery.

Section snippets

Study design and participants

We did this phase 3, randomised, double-blind, parallel-group, placebo-controlled study at 49 hospitals in seven European countries and Israel from July 6, 2012, to July 27, 2015. The study design is shown in the appendix (p 5). We enrolled adults aged 18 years or older who had non-active or mildly active luminal Crohn's disease for at least 6 months, defined by a Crohn's Disease Activity Index (CDAI) of 220 or less,24 and had complex perianal fistulas, defined as one or more of the following:

Results

289 patients were screened, 212 of whom were randomly assigned: 107 to Cx601 and 105 to placebo (figure 1). The baseline characteristics of the two groups in the ITT population were similar (table 1). Most patients had received at least one treatment for Crohn's disease in the past 6 months. 48 (45%) of 107 patients in the Cx601 group compared with 31 (30%) of 105 in the placebo group had more than one tract fistula. The baseline characteristics of patients in the mITT population were similar

Discussion

Our findings show that in a difficult-to-treat study population of patients who had Crohn's disease with complex perianal fistulas and had not responded to conventional or biological treatment, 50% of patients treated with an injection of Cx601 alone or added on to current medical treatment achieved combined remission at week 24 compared with 34% of those who received placebo. This result was consistent across all statistical populations, despite more patients in the Cx601 group than the

References (37)

  • G Hellers et al.

    Occurrence and outcome after primary treatment of anal fistulae in Crohn's disease

    Gut

    (1980)
  • M Scharl et al.

    Pathophysiology of fistula formation in Crohn's disease

    World J Gastrointest Pathophysiol

    (2014)
  • SJ Bell et al.

    The clinical course of fistulating Crohn's disease

    Aliment Pharmacol Ther

    (2003)
  • BE Sands et al.

    Infliximab maintenance therapy for fistulizing Crohn's disease

    N Engl J Med

    (2004)
  • KT Thia et al.

    Ciprofloxacin or metronidazole for the treatment of perianal fistulas in patients with Crohn's disease: a randomized, double-blind, placebo-controlled pilot study

    Inflamm Bowel Dis

    (2009)
  • DH Present et al.

    Treatment of Crohn's disease with 6-mercaptopurine. A long-term, randomized, double-blind study

    N Engl J Med

    (1980)
  • DC Pearson et al.

    Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis

    Ann Intern Med

    (1995)
  • DH Present et al.

    Infliximab for the treatment of fistulas in patients with Crohn's disease

    N Engl J Med

    (1999)
  • Cited by (0)

    Members listed at end of paper

    View full text