To study the effect of apotransferrin administration in patients with β thalassemia intermedia on erythropoiesis as reflected by hemoglobin level or transfusion dependency. Secondary objectives are the effect of apotransferrin on the…
ID
Source
Brief title
Condition
- Red blood cell disorders
- Blood and lymphatic system disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy parameter is the haematological response defined as the
change from baseline of haemoglobin level, expressed as mmol/L and percentage,
in NTDβTI/TDβTI patients or change from baseline of the number of RBC units
transfused/week in TDβ1TI patients.
Secondary outcome
Secondary parameters include an increase of > 0.9 mmol/l (1.5 g/dl) in Hb in
NTDβTI and TDβTI (before transfusion) and a reduction of at least 50% of the
number of Red Blood Cell (RBC) units transfused/week from baseline in TDβTI.
The pharmacokinetics of transferrin in plasma and changes in iron metabolism as
reflected by serum iron, NTBI and LPI levels, hepcidin, ferritin, sTfR and iron
saturation will be studied. Oxidative stress will be assessed by plasma levels
of advanced glycation end products (AGEs) and the lipid peroxidation product
malondialdehyde (MDA). Moreover, the effect on markers of erythropoiesis like
reticulocyte count, erythropoietin levels, red blood cell indices, and spleen
size will be studied. All adverse events (number, type) will be analysed
regarding to causality, seriousness, outcome and expectedness.
Background summary
Beta thalassemia is an inherited disorder characterized by the defective
synthesis of β-globin chains. Patient with β thalassemia intermedia suffer from
anemia due to ineffective erythropoiesis, chronic hemolysis and extramedullary
erythropoiesis resulting in splenomegaly and iron overload. Treatment of
Bbbth1/th1 mice, a mice model of β-thalassemia intermedia, with human
apotransferrin markedly improved the disturbances in iron and red cell turnover
characteristic for thalassemia. Apotransferrin normalized labile plasma iron
concentrations, increased hepcidin expression, normalized red blood cell
survival and increased hemoglobin production, and concomitantly decreased
reticulocytosis, erythropoietin level and splenomegaly.
Study objective
To study the effect of apotransferrin administration in patients with β
thalassemia intermedia on erythropoiesis as reflected by hemoglobin level or
transfusion dependency. Secondary objectives are the effect of apotransferrin
on the pharmacokinetics of transferrin plasma levels, iron metabolism,
oxidative stress, and erythropoiesis. Moreover the safety of apotransferrin
transfusion will be studied.
Study design
A phase II prospective, open-label, non-controlled, single-centre trial
Intervention
Patients will receive an intravenous dose of 340 mg/kg human apotransferrin
every two weeks for 14 weeks (NTDβTI) or 16 weeks (TDβTI).
Study burden and risks
NTDβTI patients will receive an intravenous dose of human apotransferrin in the
hospital every two weeks for 16 weeks. The patients will be followed after the
last infusion until the transferrin levels are back to baseline (total study
period 16 weeks + 1-3 weeks expected follow-up). The study period of NTDβTI
patients will be prolonged by 4 weeks for two extra apotransferrin infusions.
So total study period will be 18 weeks + 1-3 weeks expected follow-up.
Several blood samples will be taken during the study. Prior each infusion and 2
weeks after the last infusion, blood samples are taken to determine clinical
chemistry variables (including transferrin levels, serum iron, ferritin, MDA,
AGEs) (1 x 5 ml) and haematology variables (1x 6 ml). Moreover, a sample (1x 3
ml) is taken to determine sTfR, NTBI, LPI, hepcidin-25 and erythroferrone). For
erythropoietin 5 ml blood is taken at the start and 2 weeks after last infusion
(*week 16*) (in NTDβTI patients only). Serum iron, transferrin, NTBI/LPI and
erythroferrone will be monitored every 2 weeks till transferrin levels are back
to baseline (starting *week 17* for NTDβTI patients and *week 19* for TDβTI
patients). After the third infusion (week 4) blood samples for pharmacokinetic
analysis of transferrin (3.5 ml) are drawn 5 minutes and 2 hours after stopping
the infusion, and subsequently on day 1, 4, 7, and 14. A pre-treatment serum
and EDTA-plasma sample (3 ml each) before the first apotransferrin infusion
will be stored at -70 ºC by Sanquin Diagnostic Services BV for possible future
testing of virus infection.
Vital signs are measured before each infusion and directly after the infusion
with apotransferrin. A MRI of the spleen (if present) is performed to determine
the size at the start and end of the study.
Patients may have direct benefit from treatment with human apotransferrin. No
safety concerns are expected since human apotransferrin is a normal constituent
of the human plasma. Moreover, previous clinical studies showed that
apotransferrin can be transfused in high doses without serious adverse drug
reactions.
Plesmanlaan 125
Amsterdam 1066 CX
NL
Plesmanlaan 125
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
1. Non-transfusion dependent β-thalassemia intermedia, defined as patients with
microcytic anaemia in combination with an elevated HbA2 (>2.5%) and a
haemoglobin of <6.2 mmol/L, or transfusion dependent β-thalassemia treated with
a regular transfusion schedule.
2. Age >=18 years.
3. Adequate renal and hepatic function tests as indicated by the following
laboratory values:
• Serum creatinine <=1.0 mg/dl (<= 88.7 µmol/L); if serum creatinine >1.0 mg/dl
(>88.7 µmol/L), then the glomerular filtration rate (GFR) must be >60
ml/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease
equation where the predicted GFR (ml/min/1.73 m2) = 186 x (Serum Creatinine in
mg/dl) -1.154 x (age in years) - 0.203 x (0.742 if patient is female) x (1.212
if patient is black)
NOTE: if serum creatinine is measured in µmol/L, recalculate it in mg/dl
according to the equation: 1 mg/dl = 88.7 µmol/L) and used above mentioned
formula.
• Aspartate aminotransferase (ASAT)/ alanine aminotransferase (ALAT) <=2.5 × ULN
• Alkaline phosphatase (AP) <= 2.5 × ULN
4. WHO performance 0, 1 or 2.
5. Signed informed consent.
Exclusion criteria
1. Known with allergic reactions against human plasma or plasma products.
2. Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled
diabetes, infection, hypertension, pulmonary disease).
3. Cardiac dysfunction as defined by: myocardial infarction within the last 6
months of study entry, unstable angina, or unstable cardiac arrhythmias.
4. Pregnant or lactating females.
5. Known with IgA deficiency with anti-IgA antibodies
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 | EUCTR2014-001936-12-NL |
| CCMO | NL68157.018.18 |