Biomedical Engineering Reference
In-Depth Information
allogeneic HSCs (with donor T cells removed to prevent graft versus host disease)
without previous myeloablation in patients with refractory to all available Crohn's
medications or with a relapse after autologous HSCs. The primary goals are
survival and duration of remission in 5 years follow-up. The other phase I/II trial
(NCT00278577, published) has been commented before. The only really ongoing
phase II (NCT00271947) is comparative and randomized (non-myeloablative
autologous HSCs vs standard therapy) and applied to severe refractory Crohn's
patients (CDAI 225-400); the follow-up is 1 year. In the phase III trial
(NCT00297193), with a follow-up period of 1 year, autologous HSCs are first
mobilized, then myeloablation is done and HSCs are supplied at 4 or 59 weeks to
determine whether the effects are due to mobilization agents or to HSCs.
Regarding BM-MSCs, all trials employ allogeneic cells. One phase II
(NCT00294112) was commented before (see published ones) and the other
(NCT01090817) is a single group safety and efficacy study during 6 weeks for
refractory (included biological) Crohn's with surgical treatment not recommended
or refused by the patient. The three phase III trials are being conducted by Custer et al.
from Osiris Therapeutics Inc with Prochymal
TM
; the first two (NCT00482092 and
NCT00543374) are double-blinded, placebo controlled and multicenter efficacy
trials. The first one seeks to assess relapses, clinical and quality of life improvements
or reduction in draining fistulas number in the short term (28 days) in patients with
moderate to severe Crohn (CDAI 250-450) refractory to at least one steroid and at
least one immunosuppressant and at least one biologic drug. Cells (600 or 1200
million) were applied intravenously. The second is applied to subjects with at least
100 points reduction in CDAI at 28 day; it studies response duration (follow-up
6 months) and contemplates reinfusion and the ability to re-induce benefits. Both
were stopped in March 2009 because an interim analysis showed an excessive
response in placebo group, but not any safety concern, as reported by Osiris in a press
release and as it was commented in Nature Biotechnology [
87
]. In another press
release (May 2010), Osiris announced that enrollment had resumed according to the
prespecified design [
88
]. Following those events the company registered the last trial
(NCT01233960) to provide retreatment and study deeply efficacy and security for
patients from the first trial receiving the treatment recently. Three infusions of 200
million cells are contemplated and the follow-up is 180 days.
There is one Phase II trial with the first placental-derived stem cell (PDSCs) product
(PDA001). The main benefits observed in the preclinical studies are: powerful immu-
nosuppressive properties, safety and unlimited source. It is a multicenter, comparative
(with placebo) and randomized safety and efficacy study for patients with CDAI
220-450 and refractory to an agent (not all as other trials) during a 6 weeks follow-up.
12.8.1.3 Critical Analysis
Most of the published studies show some improvement in clinical scores and
provide safety data. There are some methodological concerns such as the small
number of patients in each study (maybe explained because they are phase I or II
