Erythrocytapheresis versus Phlebotomy as maintenance therapy in patients with hereditairy hemochromatosis; a randomised, single blinded, sequential, cross-over trial

Hereditary Hemochromatosis (HH) is a genetic disorder of iron metabolism,
resulting in excessive iron overload. Phlebotomy (P) is currently the standard
therapy which consists of removal of 500 ml whole blood weekly. The aim is to
reduce the serum ferritin levels to 50µg/L or lower and/or transferrin
saturation <= 50%. Current therapy with phlebotomy requires, depending on the
initial ferritin levels, between 20 to 100 procedures over a period of 6 to 24
months. Thereafter P procedures are reduced to 3 to 6 times as a lifelong
maintenance therapy.
More recently Therapeutic Erythrocytapheresis (TE) has become a new therapeutic
modality, which potentially offers a more efficient method to remove iron
overload with fewer procedures in a shorter treatment period and with less side
effects. The results from our pilot study showed a reduction in both total
number and duration of treatment of 69% by use of TE instead of P by newly
diagnosed HH patients Preliminary results from our ongoing randomised
controlled trial (NCT 00202436, MEC 04-150) presented during the AASLD single
topic conference in Atlanta USA, on September 9th, 2007, indicated that TE
seems to be an effective and safe method to remove iron overload in initial
treatment of patients with HH. TE showed already a substantial reduction in the
number of TE procedures necessary to bring the initial ferritine levels (at
inclusion) to half their values, when compared to treatment by P.
In proposed clinical trial we will study whether TE can keep the ferritin
levels in patients requiring maintenance therapy for HH < 50 µg/L, with
minimally half the number of treatment procedures when compared to current
standard therapy by P.

The primary objective of the study is to determine the gain in effectiveness of
TE compared with P when applied to remove excess iron during maintenance
therapy of HH patients.

A randomized, single blinded, sequential, cross-over, clinical trial among
patients currently receiving Phlebotomy as maintenance therapy for their iron
overload due to HH.

TE as a new therapeutic modality to reduce and/or prevent iron overload during
maintenance therapy. This method will be compared with P, which is the current
standard maintenance therapy. TE allows a more intense treatment since
erythrocytes can be selectively removed from circulation. With TE up to 1000 ml
erythrocytes per procedure can be removed, in comparison to 250 ml erythrocytes
(500 ml whole blood) per Phlebotomy procedure.
The advantages of the TE treatment are multiple,
a TE is more patient friendly
b TE is more effective, given the intensity of iron removal per treatment
procedure
c TE limits the number of required interventions per period of an entire
treatment .

Possible side effects of both procedures are related to the risk of
(hypo-volemic) collapse, which is slightly higher in the P, but lower in the
TE. In the latter however mild citrate reactions may occur during some of the
TE procedures. These episodes are basically self-limiting or can be remedied by
drinking a glass of milk.
Based on an ongoing clinical trial on the impact of TE as initial treatment of
newly diagnosed patients with HH, the observed risks of TE (compared with P)
seem lower.
We already observed a clear reduction in side effects in TE (1/81) versus P
(9/294).
In both study arms bi-monthly blood will be collected to measure ferritin
levels and Zinc Proto Porphyrine (ZPP) levels, the latter to safeguard against
removing to much iron resulting in sub-clinical iron deficiency.