Beta Thalassemia Major Anemia, Iron Overload
Conditions
Keywords
thalassemia, iron overload, chelation, deferiprone, Ferriprox
Brief summary
This study is looking at the effects of giving early treatment of deferiprone to young children with beta thalassemia who have started receiving regular blood transfusions but have not yet reached the criteria for starting on iron chelation therapy. Half the patients in the study will receive deferiprone, and the other half will receive placebo, for up to 12 months.
Detailed description
This study will give deferiprone to infants and young children with thalassemia who have started receiving regular blood transfusions but whose iron load is not yet at the level where chelation treatment would normally begin. The purpose is to see if doing this will postpone the build-up of iron without causing serious side effects. Half the children in the study will be given deferiprone at a dose that is lower than what is normally prescribed, and the other half will be given placebo. All patients will receive the assigned product three times a day for up to 12 months. Tests for signs of iron overload will be done monthly, and a patient whose iron load reaches the level where chelation therapy would normally begin will be immediately taken out of the study and started on standard chelation therapy.
Interventions
Liquid formulation of deferiprone, with a concentration of 80 mg/mL
DRUGPlacebo
Liquid solution that matches deferiprone oral solution in appearance and taste
Sponsors
Chiesi Canada Corp
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The placebo solution will have the same appearance and flavor as deferiprone oral solution, and will be administered at a volume matching that required for the dose of active product.
Eligibility
Sex/Gender
ALL
Age
6 Months to 9 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female aged ≥ 6 months to \< 10 years 2. Confirmed diagnosis of beta-thalassemia, as determined by high performance liquid chromatography (HPLC) or DNA testing 3. Started on a red blood cell (RBC) transfusion regimen, with a minimum of 2 transfusions already completed 4. Screening level of serum ferritin (SF) greater than \>200 μg/L but not more than 600 μg/L. Since SF level may be impacted by the presence of infection, it must additionally be verified that the child has had no signs of infection in the previous 7 days, including the day of screening, and that the level of C-reactive protein (CRP) is no greater than 20% higher than the normal range for the patient's age. If there are signs of infection and/or the CRP level is above this threshold, the SF level must be checked again a minimum of one week later.
Exclusion criteria
1. Prior use of iron chelation 2. Diagnosis of hepatitis B or C, or HIV infection 3. Evidence of abnormal liver or kidney function at screening: serum alanine transaminase (ALT) level \> 5 times upper limit of normal or creatinine levels \>2 times upper limit of normal 4. Disorders associated with neutropenia (absolute neutrophil count \< 1.5 x 10\^9/L) prior to the initiation of study medication 5. A serious, unstable illness, as judged by the investigator, during the previous 3 months before screening/baseline visit including but not limited to hepatic, renal, gastro-enterologic, respiratory, cardiovascular, endocrinologic, neurologic or immunologic disease. 6. Presence of any medical condition which in the opinion of the investigator would cause participation in the study to be unwise.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Patients in Each Treatment Group Who Still Have a Serum Ferritin Level < 1000 Micrograms Per Liter (μg/L) at Month 12 | 12 months | Current treatment guidelines are that standard iron chelation therapy should begin after a serum ferritin level of 1000 μg/L has been reached; thus, patients who were at this level at two consecutive visits were removed from the study so that they could start on this therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Serum Ferritin Still Below the Threshold at Different Time Points | 4, 8, and 12 months | The outcome measure was the percentage of patients in each group still below the serum ferritin threshold at Months 4, 8, and 12. Without adequate chelation therapy, most patients receiving red blood cell transfusions are likely to exceed this level within a few months. However, a safety feature of the study design was that patients who reached the serum ferritin threshold were withdrawn (i.e., so that they could begin standard chelation therapy). |
Countries
Egypt, Indonesia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Deferiprone Subjects in this group will receive deferiprone oral solution at a dosage up to 75 milligrams per kilogram of body weight (mg/kg) per day, divided into 3 equal doses
Deferiprone oral solution: Liquid formulation of deferiprone, with a concentration of 80 mg/mL | 32 |
| Placebo Subjects in this group will receive placebo solution at a volume equal to what they would receive if they were in the active arm, divided into 3 equal doses
Placebo: Liquid solution that matches deferiprone oral solution in appearance and taste | 32 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Deferiprone |
|---|---|---|---|
| Age, Continuous | 2.63 Years STANDARD_DEVIATION 1.7 | 2.83 Years STANDARD_DEVIATION 2.08 | 3.03 Years STANDARD_DEVIATION 2.42 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants | 63 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 9 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 29 Participants | 55 Participants | 26 Participants |
| Region of Enrollment Egypt | 29 Participants | 55 Participants | 26 Participants |
| Region of Enrollment Indonesia | 3 Participants | 9 Participants | 6 Participants |
| Serum ferritin (µg/L) | 451.69 micrograms per liter STANDARD_DEVIATION 196.43 | 482.76 micrograms per liter STANDARD_DEVIATION 217.68 | 513.84 micrograms per liter STANDARD_DEVIATION 236.06 |
| Sex: Female, Male Female | 11 Participants | 23 Participants | 12 Participants |
| Sex: Female, Male Male | 21 Participants | 41 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 32 |
| other Total, other adverse events | 29 / 32 | 29 / 32 |
| serious Total, serious adverse events | 5 / 32 | 2 / 32 |
Outcome results
Primary
The Percentage of Patients in Each Treatment Group Who Still Have a Serum Ferritin Level < 1000 Micrograms Per Liter (μg/L) at Month 12
Current treatment guidelines are that standard iron chelation therapy should begin after a serum ferritin level of 1000 μg/L has been reached; thus, patients who were at this level at two consecutive visits were removed from the study so that they could start on this therapy.
Time frame: 12 months
Population: Intent-to-Treat (ITT) population. For patients who withdrew early, imputed data were used to estimate the serum ferritin values that would likely have been seen at Month 12 had they continued.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Deferiprone | The Percentage of Patients in Each Treatment Group Who Still Have a Serum Ferritin Level < 1000 Micrograms Per Liter (μg/L) at Month 12 | 21 Participants |
| Placebo | The Percentage of Patients in Each Treatment Group Who Still Have a Serum Ferritin Level < 1000 Micrograms Per Liter (μg/L) at Month 12 | 12 Participants |
Comparison: Patients who reached the serum ferritin threshold at any time point prior to Month 12 were withdrawn from the study as per protocol, so that they could begin on standard chelation therapy. For these individuals, imputed data were used to estimate the values that would likely have been seen at Month 12 had they remained in the study.p-value: 0.0446Fisher Exact
Secondary
Percentage of Patients With Serum Ferritin Still Below the Threshold at Different Time Points
The outcome measure was the percentage of patients in each group still below the serum ferritin threshold at Months 4, 8, and 12. Without adequate chelation therapy, most patients receiving red blood cell transfusions are likely to exceed this level within a few months. However, a safety feature of the study design was that patients who reached the serum ferritin threshold were withdrawn (i.e., so that they could begin standard chelation therapy).
Time frame: 4, 8, and 12 months
Population: ITT population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Deferiprone | Percentage of Patients With Serum Ferritin Still Below the Threshold at Different Time Points | Number of patients still below threshold at Month 4 | 29 Participants |
| Deferiprone | Percentage of Patients With Serum Ferritin Still Below the Threshold at Different Time Points | Number of patients still below threshold at Month 8 | 22 Participants |
| Deferiprone | Percentage of Patients With Serum Ferritin Still Below the Threshold at Different Time Points | Number of patients still below threshold at Month 12 | 21 Participants |
| Placebo | Percentage of Patients With Serum Ferritin Still Below the Threshold at Different Time Points | Number of patients still below threshold at Month 4 | 28 Participants |
| Placebo | Percentage of Patients With Serum Ferritin Still Below the Threshold at Different Time Points | Number of patients still below threshold at Month 8 | 20 Participants |
| Placebo | Percentage of Patients With Serum Ferritin Still Below the Threshold at Different Time Points | Number of patients still below threshold at Month 12 | 12 Participants |
p-value: 0.0446Fisher Exact