Clinical trial NCT02173951: An Algorithm to Start Iron Chelation in Minimally Transfused Young Beta-thalassemia Major Patients
Official title: A Decisional Algorithm to Start Iron Chelation in Minimally Transfused Young Beta-thalassemia Major Patients Naive to Iron Chelation Therapy. A Comparative Randomized Prospective Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Beta Thalassemia Major
Keywords: young minimally transfused beta thalassemia major
labile plasma iron (LPI)
Transferrin saturation (TSAT)
Deferiprone
Transfusional iron loading rate
Transfusion units
Lead sponsor: Ain Shams University
Sponsor class: OTHER
First posted: 2014-06-25
Enrollment: 64
Sex: ALL
Minimum age (years): 6
Maximum age (years): 36
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: A prospective randomized study on Safety, Tolerability and Efficacy of oral Low dose DFP (50 mg/kg/day) in minimally transfused B-TM after 5 transfusions when SF reaches 500 ng/m and with either appearance of LPI \> 0.2 or TSAT reaches 50% compared with non treatment arm.

So the aim of this study:

1. To determine the time as well as amount of transfused iron ( calculated in mg iron/kg ) which lead to Serum ferritin reaches 500 ng /ml and LPI appearance \>0.2 as well as TSAT reaches 50 % .
2. Tolerability and safety of early low dose DFP 50mg/kg and effectiveness to postpone or prevent SF from reaching 1000 ng/ml or LPI \>0.6 or TSAT \>70% in comparison to patients not starting chelation therapy
3. Determine adverse events whether drug or non drug related

Detailed description: This is a 1 year randomized prospective study that will include 64 patients with β-thalassemia major 6-36 months, those already engaged in transfusion program and received 5-7 transfusions recruited from the thalassemia clinic children hospital Ain Shams University. Consents will be taken from patient or legal guardian after explaining to them the nature of the study.

Inclusion criteria

1. Young beta thalassemia major patients (diagnosed by HPLC, CBC) who started transfusion therapy who received 5-7transfusions or less, aged more than 6 months.
2. Pre-transfusional Hb should be \>9 g/dL.
3. Serum ferritin should be ≤ 500ng/ml, transferrin saturation ≤ 50%.

Exclusion criteria:

1. Beta thalassemia intermedia patients, patients with other transfusion dependent anemias (myelodysplasia, other chronic hemolytic anemias , pure red cell aplasia , aplastic anemia )
2. Patients with levels of ALT \>5 the upper limit of normal (ULN), serum creatinine \> ULN on 2 measurements.
3. Patients with history of agranulocytosis \[absolute neutrophil count (ANC) \<0.5×109/L\].
4. Non complaint patients acknowledged by reviewing the patient's records.

Enrollment period: expected to be 6 months period with a mean follow up period 12 months.

Randomization: the patients enrolled as they entered the study and randomised alternatively either to arm 1 or 2 using a closed envelope system that devised by the statistician

Sample size: It was calculated to be 32 patients in each study group to detect significant difference at 0.05 with study power 95%

Arms, Groups and Cohorts:

Sixty-four thalassemia major patients naive to chelation therapy will be randomized into 2 groups: 1st group: with DFP 50 mg/kg for 12 months or 2nd group: no treatment arm

Active Comparator arm : iron chelation Included 32 thalassemia major patients with low serum ferritin (≥500) . They will receive low dose DFP on 50 mg/kg/d.

Placebo Comparator arm: blood transfusion only Included 32 thalassemia patients with low serum ferritin (≥500). They receive blood transfusion with no chelation. Primary end point is elevation of SF to around 1000 ng/ml or more or Tsat \> 90 % and or LPI \> 0.6 Both groups will be followed up with intervals of 3 months both clinically and laboratory with a mean time of 12 months.

Patients reaching serum ferritin ≥1000 will be subjected to dose escalation of DFP to 75 mg/kg/d.in Active Comparator arm and start of DFP 75MG/KG/D in Placebo Comparator arm.

Study procedures:

1. Medical records of thalassemia patients will be reviewed \& data will be gathered including:

   * Age at onset.
   * Transfusion history:

     * Amount in each transfusion: grams of administered RBCs
     * Frequency.
     * Calculation of the transfusion index in ml packed red cell per body weight in Kg per year.
     * Transfusional iron loading rate: This will be calculated from the blood volume transfused between baseline and the end of the study. The average iron content per transfusion unit, derived from the measured hematocrit. The transfusional iron loading rate will be then expressed in mg of the transfused iron per kg body weight per day.
   * History of viral hepatitis (hepatitis B and C virus).
2. Laboratory investigations:

   1. Pre-transfusion Complete blood picture (Both manual and electronic ANC ).
   2. Liver and kidney functions.
   3. LPI, Serum Ferritin, serum iron and transferring saturation measurement :

Serum ferritin, transferring saturation (TSAT) and LPI will be checked prior to transfusion at base line, 3, 6, 9, and 12 month interval.

Positive predictive value of LPI will be estimated in relation to TSAT, SF, frequency of blood transfusion, transfusion index, and transfusional iron loading rate at which patients will start oral chelation therapy.

Compliance to ICT: Compliance to chelation therapy was assessed by reviewing patient self-report of dose-taking and the appropriate number of doses taken during each day was checked by prescription refills and measure amount of the drug in the retained bottles; a cutoff point below 70% was considered as poor compliance to the regimen.

Eligibility criteria: Inclusion Criteria:

1. Young beta thalassemia major patients (diagnosed by HPLC, CBC) who started transfusion therapy who received 5-7transfusions or less, aged more than 6 months.
2. Pre-transfusional Hb should be \>9 g/dL.
3. Serum ferritin should be ≤ 500ng/ml, transferrin saturation ≤ 50%.

Exclusion Criteria:

* 1. Beta thalassemia intermedia patients, patients with other transfusion dependent anemias (myelodysplasia, other chronic hemolytic anemias , pure red cell aplasia , aplastic anemia ) 2. Patients with levels of ALT \>5 the upper limit of normal (ULN), serum creatinine \> ULN on 2 measurements.

  3. Patients with history of agranulocytosis \[absolute neutrophil count (ANC) \<0.5×109/L\].

  4. Non complaint patients acknowledged by reviewing the patient's records.

Primary outcomes:
measure: determine the time and number of transfusion units as well as amount of infused iron that will lead to appearance of LPI >0.2 or TSAT>50 % , serum ferritin ≥ 500 ng/ml in the studied thalassemic patients which warrant start of iron chelation
timeFrame: 12 months
Secondary outcomes:
measure: Evaluation of safety of early use of iron chelation Therapy (ICT) in terms of drug related AEs or SAEs
timeFrame: 12 months
Other outcomes:
Locations:
city: Cairo
country: Egypt
facility: Pediatric Hematology clinic, Ain Shams University
Study officials:
affiliation: Ain Shams University
name: Mohsen S Elalfy, professour
role: PRINCIPAL_INVESTIGATOR
References:
citation: Elalfy MS, Adly A, Awad H, Tarif Salam M, Berdoukas V, Tricta F. Safety and efficacy of early start of iron chelation therapy with deferiprone in young children newly diagnosed with transfusion-dependent thalassemia: A randomized controlled trial. Am J Hematol. 2018 Feb;93(2):262-268. doi: 10.1002/ajh.24966. Epub 2017 Nov 27.