Within RETHRIM, clinical work is the central part of the project. The three main objectives are all closely linked to the clinical trial. In short the objective can be characterised as Treat, Design and Recommend as outlined below:

Objective 1, Treat patients to establish therapy effectiveness

Acute Graft-versus-Host-Disease with organ involvement (visceral GvHD) is associated with significant mortality rates up to 75% (Ferrara et al., 2009). The consortium partners have been involved in a number of phase I/II trials that indicated that the use of third-party Mesenchymal Stromal Cells (MSC) might be an effective therapy for visceral GvHD. However, no definitive proof of effectiveness through double-blind placebo controlled multicentre studies has been obtained. The current phase III clinical trial is aimed at setting a new standard for the treatment of visceral GvHD. MSC regenerative therapy will be employed to determine its potential to improve the rates of remission and overall survival and to improve quality of life.

• To conduct and analyse outcome of a prospective, randomized, double-blind, placebo- controlled, multi-centre phase III trial to study the safety, efficacy and repeatability of the use of Mesenchymal Stromal Cells (MSC) to repair damaged organs in patients suffering from visceral Graft-versus-Host-Disease (GvHD) (WP3)
• To evaluate the quality of life of patients treated with MSC in comparison with controls up to two years after MSC regenerative therapy (WP5).

Objective 2, Design potency signatures for MSC and biomarker assays to predict therapy outcome.

The project is bedside-to-bench oriented. Patient samples obtained from the clinical trial and the MSC products produced to treat patients will be extensively studied to provide insight into the mechanisms of response to MSC therapy. Ideally this will provide insight for diagnostic and therapeutic development of MSC potency assays and biomarker assays to predict response to therapy.

• To assess product heterogeneity and establish an immune-potency profile of MSC derived from different donors (WP2).
• To develop a score by means of clinical and laboratory parameters that allows for identification of patients that will respond to MSC regenerative therapy (WP4).
• To deliver a business plan to interest SMEs or industry to set a production plant for the production of MSC that can be distributed to European centres using MSC for regenerative therapies and to market biomarker and potency assays (WP8).

Objective 3, Provide recommendations to initiate changes in clinical practice and to allow the implementation of better regulatory requirements for regenerative therapies.

Alongside the clinical trial data from quality of life, health technology assessment and ethical studies will be collected. Output from these studies will allow the consortium to formulate a set of measures to convince health authorities, regulatory bodies and insurance companies on the usefulness of MSC therapy and provide suggestions and recommendations for changes in clinical practise, legislation and regulation of MSC regenerative therapy.

• To perform a cost-effectiveness study investigating the potential to use MSC as standard treatment leading to changes in clinical practice (WP6).
• To set ethical criteria that justify withholding potential beneficial treatments from patients enrolled in a randomized placebo controlled trial (WP7).
• To make an inventory of and report on the hurdles encountered in setting up a multi-centre European study using Advanced Therapy Medicinal Products and where necessary provide suggestions for improving legislation and regulation surrounding regenerative medicine (WP8).
• To assess the effect of sex differences in product characteristics and on clinical outcome. (WP 2, 3) and to identify possible gender differences in QoL perception (WP 5).