To evaluate the efficacy, safety and feasibility of combined immune modulation with rituximab, ITI and MSCs in terms of eradication of FVIII inhibitory activity in hemophilia A patients.
ID
Source
Brief title
Condition
- Coagulopathies and bleeding diatheses (excl thrombocytopenic)
- Immune disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary objective is to evaluate the efficacy, safety and feasibility of
combined immune modulation with rituximab, ITI and MSCs in terms of eradication
of FVIII inhibitory activity in hemophilia A patients.
Secondary outcome
Secondary endpoints are to evaluate the immune changes during the TRIUMPH
protocol in terms of T-cell and B-cell proliferation and modulation, time to
Complete Response and Partial Response, time to Relapse and adverse events
Background summary
The hallmark of treatment of patients with hemophilia A is regular infusion
with clotting factor concentrates. Currently, one of the biggest challenges in
hemophilia A treatment in developed countries is the treatment after formation
of allo-antibodies (inhibitors) against administered Factor VIII (FVIII), which
happens in about 25% of the patients. These patients are treated with Immune
Tolerance Induction (ITI) with a success rate of 70-85%. About 15-30% of
patients is refractory to ITI and in another 15% relapses occur after initial
inhibitor eradication. For these patients, no standard protocol is available
for inhibitor eradication. In selected cases, rituximab is used in combination
with ITI, but the long-term efficacy of this approach is only 10-15%. New
treatment options are urgently needed for refractory inhibitor patients. We
will evaluate the efficacy, feasibility and safety of the treatment of
hemophilia A patients with refractory inhibitors using triple therapy with ITI,
rituximab and Mesenchymal Stromal Cells (MSCs). We will characterize how this
triple treatment affects the immune system and its response to administration
of recombinant FVIII (rFVIII).
Study objective
To evaluate the efficacy, safety and feasibility of combined immune modulation
with rituximab, ITI and MSCs in terms of eradication of FVIII inhibitory
activity in hemophilia A patients.
Study design
Open-label, prospective, single centre, non-randomized prospective phase I/II
study.
Intervention
Patients will be treated with rituximab, MSCs and rFVIII.
Study burden and risks
Burden consists of repetitive infusions of rituximab, MSCs and rFVIII,
additional blood draws. Reported side effects of rituximab include infusion
related reactions, infections and allergic reactions. For rFVIII this includes
allergic reactions. Documented side effects of MSCs infusion has been limited
to infusion reactions. So far no severe side effects have been reported
concerning treatment with MSCs. Theoretical risks are infusion reaction,
toxicity of DMSO, microbiological contamination of MSCs product leading to
severe infections, ectopic tissue formation, tumorigenicity and
graft-versus-host disease when allogeneic MSCs are used.
However, considering the life -threatening bleedings which can occur in these
patients, we expect an overall benefit in terms of improved hemostasis.
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
Inclusion criteria
Adult patients with mild, moderate or severe hemophilia A with a current anti-FVIII inhibitor that have failed previous regular ITI, independent of titre height.
Exclusion criteria
- Patients with active, severe or uncontrolled infection
- HIV positivity and/or CD4 < 400 mm3/ml
- Significant hepatic dysfunction (total bilirubin * 30 µmol/l or transaminases * 2.5x upper normal limit)
- Significant renal dysfunction requiring hemodialysis
- Intolerance of exogenous protein administration
- Currently participating in interventional hemophilia studies
- Known uncontrolled toxicity for DMSO
- Any psychological, familial, sociological and/or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
- Life expectancy <3 years
- History of active cancer during the past 5 years, except basal carcinoma of the skin
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-000661-43-NL |
| CCMO | NL54758.000.15 |