Derived cell ATMP implantation for the treatment of fecal incontinence: a multicentre, randomized, double-blind, placebo-controlled, parallel-group, dose-finding clinical study.

CASE STUDY TYPE

ATMP interventional clinical trial in Gastro-Enterology (phase II – EU)

BACKGROUND

Fecal incontinence (FI) is a common disease and can be a devastating social disability. It can lead to a loss of self-esteem, social isolation, and a diminished quality of life. FI affects people of all ages, but its prevalence is disproportionally higher in women, in the elderly, and in nursing home residents. Conservative treatments like modification of diet, biofeedback, loperamide hydrochloride, or estrogen replacement may show an insufficient long-term efficacy and surgical treatment offered to patients with severe FI shows not satisfactory long-term results and total continence can usually not be achieved.

Cell-based therapy with autologous myoblasts and fibroblasts injected into the sphincter is an innovative and promising new therapy for the treatment of IF. Once implanted this ATMP, is able to regenerate or enhance the biological function of the dysfunctional tissue. It has already shown positive results in stress urinary incontinence in a phase I trial. It is safe and well tolerated.

The aim of this clinical trial was to find the optimal cell count for functional regeneration of the external anal sphincter in female and male patients with FI.

METHODS

This was a phase IIb, multinational, multicentre, randomized, double-blind, dose-finding, placebo-controlled study with a parallel group design with 3 treatments:

Low cell count group
High cell count group
Placebo group (cell-free suspension)

OBJECTIVES

PRIMARY OBJECTIVES

Determine change in incontinence episode frequency (IEF) at day 180 from baseline.

SECONDARY OBJECTIVES

Evaluate change in the Wexner score

Assess the Visual Analogue Scale

Evaluate anorectal manometry data
Document patient-reported quality of life.

SCIENTIFIC and DATA VALORISATION

Trial results used for the ATMP marketing authorisation and further Phase II design

Key factors of success

ICTA’s capability to adapt to new regulatory procedure (project started in 2012)
ICTA’s responsiveness and ability to develop adapted IT tool
ICTA’s flexibility to manage additional statistical analyses

LESSONS LEARNED to speed up the start-up phase of the next study

Importance of close collaboration between ICTA and Sponsor especially in the context of a rescue study
Active involvement of the Sponsor during the study to maintain the centres’ commitment
Optimal project coordination: Timelines, logistics, sub-contractors management, reporting tools implementation, events management.

CHALLENGES

KEY CHALLENGES	ICTA’s SOLUTIONS	ICTA’s ACHIEVEMENTS
Rescue project and long delay before Sponsor decides to reactivate the project	Pro-active communication with the sponsor on bi-weekly basis during the handover Complete quality check of the TMF And key study documents to be consistent with trial objectives	Successful project including complete Clinical Study Report (CSR) used to obtain ATMP market approval in Europe
ATMP logistics and regulatory procedures 9 participating countries and 1 laboratory producing the autologous cells	Development of a specific IT tool for a smooth workflow of the ATMP from site to sponsor and sponsor to site.	3 inspections performed by the Regulatory Authorities in 3 different countries ➔ 0 critical finding
Sites recruitment due to ATMP regulatory procedure to respect Product and fecal sample management	Selection of back-up countries Assessment of each site facilities and level of staffing to facilitate patient recruitment	99.6% of the originally planned patients were recruited
Multiple statistical analyses requested after project re-start	Statistical analysis plan (SAP) check and completed by additional subgroups analyses Update of the statistical program	TFLs provided within timelines to Sponsor Enabling data valorization within the CSR writing and marketing authorisation dossier