Hemolytic Anemia, Iron Overload, Sickle Cell Disease
Conditions
Keywords
Sickle Cell Disease, Iron Overload from Repeated Blood Transfusions, Iron Overload, Blood Transfusions
Brief summary
This study will examine the long-term safety and efficacy of Deferasirox in patients with sickle cell disease and iron overload from repeated blood transfusions.
Interventions
Deferasirox was provided in 125 mg, 250 mg, and 500 mg dispersible tablets and was administered orally at an initial dose of 20 mg/kg/day.
Deferoxamine was supplied in vials of 500 mg and 2000 mg administered subcutaneously for a weekly dose of 175 mg/kg.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age greater than or equal to 2 years * Male or female patients with sickle cell disease (SS, SC, SD, Sβo or Sβ+ thalassemia) * Iron overload from repeated blood transfusion, as defined by one of the following: 1. For patients \> 16 years old receiving simple transfusions: lifetime history of receipt of at least 120 ml/kg or 30 adult units of packed red blood cells, OR 2. For patients ≤ 16 years old receiving simple transfusions: lifetime history of receipt of at least 120 ml/kg of packed red blood cells, OR 3. For all patients receiving exchange transfusions in the absence of a previous attempt to achieve negative iron balance: lifetime performance of at least 20 procedures, OR 4. For all patients: liver iron content ≥ 7 mg Fe/g dry weight as measured by biopsy, Magnetic Resonance Imaging (MRI), or magnetic susceptibility performed within 3 months prior to entry into screening * For entry into the screening period: serum ferritin of ≥ 1000 µg/mL on at least two occasions during the prior year obtained in the absence of concomitant infection. * Body weight \> 10 kg * No known allergy or contraindication to the administration of deferoxamine * Ability to comply with all study-related procedures, medications, and evaluations * Sexually active pre-menopausal female patients must use double-barrier contraception, oral contraceptive plus barrier contraceptive, or must have undergone clinically documented total hysterectomy and/or oophorectomy, tubal ligation or be postmenopausal defined by amenorrhea for at least 12 months. * Written informed consent by the patient or for pediatric patient's consent of the patient's legal guardian. The definition of the term 'pediatric' for enrollment and study conduct will be in accordance with the local legislation.
Exclusion criteria
* Serum creatinine above the upper limit of normal * Significant proteinuria * History of nephrotic syndrome * Alanine aminotransferase (ALT) ≥ 250 U/L at screening * Clinical evidence of active hepatitis B or hepatitis C * History of HIV * Fever or other signs/symptoms of infection within 10 days prior to the screening visit * Uncontrolled systemic hypertension * History of Myocardial Infarction, Congestive Heart Failure or unstable cardiac disease not controlled by standard medical therapy * Clinically relevant cataract or a previous history of clinically relevant ocular toxicity related to iron chelation * Presence of a surgical or medical condition that might significantly alter the absorption, distribution, metabolism or excretion of any study drug * History of drug or alcohol abuse within the 12 months prior to enrollment * Pregnant or breast feeding patients * Patients treated with systemic investigational drug within 4 weeks prior or with topical investigational drug 7 days prior to the screening visit * Randomization in a previous clinical trial involving ICL670 Other protocol-related inclusion /
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | 24 Weeks | The number of participants with Adverse Events (AEs) overall and according to Medical Dictionary for Regulatory Activities (MedDRA) preferred term greater than or equal to 5% participants in any group by treatment in the first 24 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Serum Ferritin From Baseline to Week 24 | Baseline, 24 Weeks | Absolute change from baseline serum ferritin after 24 weeks of treatment with Deferasirox (ICL670) and absolute change from baseline serum ferritin after 24 weeks of treatment with Deferoxamine. Means were adjusted for the amount of transfused blood. |
| Absolute Change in Serum Ferritin After Start of Treatment With Deferasirox (ICL670) to Week 24 and to Week 52 | Start of Deferasirox (ICL670) treatment, 24 Weeks, 52 Weeks | Absolute change in serum ferritin after start of treatment with Deferasirox (ICL670) to week 24 and the absolute change in serum ferritin after start of treatment with Deferasirox (ICL670) to week 52 for the Deferasirox treatment group and the Deferoxamine then Deferasirox treatment group. Means were adjusted for the amount of transfused blood. |
| Absolute Change in Serum Ferritin After Start of Treatment With Deferasirox (ICL670) to Week 104 | Start of Deferasirox (ICL670) treatment, 104 Weeks | Absolute change in serum ferritin after start of treatment with Deferasirox (ICL670) to week 104 for the Deferasirox treatment group. Means were adjusted for the amount of transfused blood. |
Countries
Canada, United States
Participant flow
Pre-assignment details
212 participants were enrolled in the study; however, 9 participants from Site 512 were excluded due to severe Good Clinical Practice (GCP) violations. 203 participants are included in the Full Analysis Set 1.
Participants by arm
| Arm | Count |
|---|---|
| Deferasirox (ICL670) Deferasirox (ICL670) 20 mg/kg orally once daily for 104 weeks. | 135 |
| Deferoxamine (DFO) Then ICL670 Deferoxamine (DFO) subcutaneously for a weekly dose of 175 mg/kg for 24 weeks then crossed over to receive Deferasirox (ICL670) orally 20 mg/kg for a total of 104 weeks on therapy. | 68 |
| Total | 203 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal Laboratory Value | 4 | 2 |
| Overall Study | Administrative problems | 6 | 5 |
| Overall Study | Adverse Event | 2 | 4 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Did not receive study drug | 0 | 12 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Lost to Follow-up | 9 | 1 |
| Overall Study | Patient no longer requires study drug | 1 | 0 |
| Overall Study | Protocol Violation | 5 | 0 |
| Overall Study | Withdrawal by Subject | 10 | 4 |
Baseline characteristics
| Characteristic | Deferasirox (ICL670) | Total | Deferoxamine (DFO) Then ICL670 |
|---|---|---|---|
| Age Continuous | 16.4 years STANDARD_DEVIATION 10.31 | 16.3 years STANDARD_DEVIATION 10.23 | 16.2 years STANDARD_DEVIATION 10.15 |
| Age, Customized 12- <16 Years | 35 participants | 53 participants | 18 participants |
| Age, Customized 16- < 50 Years | 50 participants | 74 participants | 24 participants |
| Age, Customized 2- < 6 Years | 6 participants | 10 participants | 4 participants |
| Age, Customized 50- <65 Years | 2 participants | 3 participants | 1 participants |
| Age, Customized 6- <12 Years | 42 participants | 63 participants | 21 participants |
| Age, Customized = 65 Years | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Black | 130 Participants | 195 Participants | 65 Participants |
| Race/Ethnicity, Customized Caucasian | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Oriental | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Female | 56 Participants | 89 Participants | 33 Participants |
| Sex: Female, Male Male | 79 Participants | 114 Participants | 35 Participants |
| Weight Group 15- <35 kg | 39 Participants | 62 Participants | 23 Participants |
| Weight Group <15 kg | 0 Participants | 0 Participants | 0 Participants |
| Weight Group 35- < 55 kg | 43 Participants | 61 Participants | 18 Participants |
| Weight Group 55- <75 kg | 42 Participants | 64 Participants | 22 Participants |
| Weight Group =75 kg | 10 Participants | 13 Participants | 3 Participants |
| Weight Group Missing | 1 Participants | 3 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 91 / 135 | 39 / 56 | 118 / 135 | 44 / 53 |
| serious Total, serious adverse events | 40 / 135 | 20 / 56 | 78 / 135 | 22 / 53 |
Outcome results
Primary
The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment
The number of participants with Adverse Events (AEs) overall and according to Medical Dictionary for Regulatory Activities (MedDRA) preferred term greater than or equal to 5% participants in any group by treatment in the first 24 weeks.
Time frame: 24 Weeks
Population: Safety-1 set: All participants, except participants enrolled in Center 512, who received at least one dose of study medication during the first 24 weeks.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Abdominal pain | 16 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Sickle cell anaemia with crisis | 30 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Diarrhoea | 30 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Vomiting | 21 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Pyrexia | 19 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Nausea | 20 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Headache | 30 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Upper respiratory tract infection | 10 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Rash | 14 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Cough | 10 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Constipation | 11 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Pain in Extremity | 10 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Back Pain | 8 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Chest Pain | 7 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Oropharyngeal pain | 7 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Pruritus | 7 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Abdominal pain upper | 8 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Nasal congestion | 6 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Urinary tract infection | 9 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Arthralgia | 7 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Nasopharyngitis | 4 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Insomnia | 3 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Dizziness | 2 participants |
| Deferasirox (ICL670) | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Injection site pain | 0 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Nasopharyngitis | 3 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Headache | 17 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Back Pain | 4 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Sickle cell anaemia with crisis | 8 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Urinary tract infection | 0 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Diarrhoea | 5 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Chest Pain | 5 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Vomiting | 9 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Dizziness | 3 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Pyrexia | 9 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Oropharyngeal pain | 5 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Nausea | 4 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Arthralgia | 1 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Abdominal pain | 6 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Pruritus | 5 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Upper respiratory tract infection | 9 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Insomnia | 3 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Rash | 3 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Abdominal pain upper | 3 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Cough | 7 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Injection site pain | 3 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Constipation | 2 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Nasal congestion | 4 participants |
| Deferoxamine (DFO) Then ICL670 | The Number of Participants With Adverse Events (AEs) in the First 24 Weeks of Treatment | Pain in Extremity | 3 participants |
Secondary
Absolute Change in Serum Ferritin After Start of Treatment With Deferasirox (ICL670) to Week 104
Absolute change in serum ferritin after start of treatment with Deferasirox (ICL670) to week 104 for the Deferasirox treatment group. Means were adjusted for the amount of transfused blood.
Time frame: Start of Deferasirox (ICL670) treatment, 104 Weeks
Population: Per Protocol- 2 set defined as all participants who received study drug and had assessment of serum ferritin at Start of ICL670 treatment and at 104 weeks.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Deferasirox (ICL670) | Absolute Change in Serum Ferritin After Start of Treatment With Deferasirox (ICL670) to Week 104 | -682.6 mg/mL |
Secondary
Absolute Change in Serum Ferritin After Start of Treatment With Deferasirox (ICL670) to Week 24 and to Week 52
Absolute change in serum ferritin after start of treatment with Deferasirox (ICL670) to week 24 and the absolute change in serum ferritin after start of treatment with Deferasirox (ICL670) to week 52 for the Deferasirox treatment group and the Deferoxamine then Deferasirox treatment group. Means were adjusted for the amount of transfused blood.
Time frame: Start of Deferasirox (ICL670) treatment, 24 Weeks, 52 Weeks
Population: Per Protocol- 2 set defined as all participants who received study drug and had an assessment of serum ferritin at Start of ICL670 treatment and at 24 weeks or 52 weeks.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Deferasirox (ICL670) | Absolute Change in Serum Ferritin After Start of Treatment With Deferasirox (ICL670) to Week 24 and to Week 52 | 24 weeks from ICL670 treatment start (n=111,47) | -146.7 mg/mL |
| Deferasirox (ICL670) | Absolute Change in Serum Ferritin After Start of Treatment With Deferasirox (ICL670) to Week 24 and to Week 52 | 52 weeks from ICL670 treatment start (n=113,40) | -487.3 mg/mL |
| Deferoxamine (DFO) Then ICL670 | Absolute Change in Serum Ferritin After Start of Treatment With Deferasirox (ICL670) to Week 24 and to Week 52 | 24 weeks from ICL670 treatment start (n=111,47) | -204.7 mg/mL |
| Deferoxamine (DFO) Then ICL670 | Absolute Change in Serum Ferritin After Start of Treatment With Deferasirox (ICL670) to Week 24 and to Week 52 | 52 weeks from ICL670 treatment start (n=113,40) | -545.7 mg/mL |
Secondary
Absolute Change in Serum Ferritin From Baseline to Week 24
Absolute change from baseline serum ferritin after 24 weeks of treatment with Deferasirox (ICL670) and absolute change from baseline serum ferritin after 24 weeks of treatment with Deferoxamine. Means were adjusted for the amount of transfused blood.
Time frame: Baseline, 24 Weeks
Population: Per protocol- 1 defined as all participants who had study drug and had an assessment of serum ferritin at Baseline and at Week 24.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Deferasirox (ICL670) | Absolute Change in Serum Ferritin From Baseline to Week 24 | -173.2 mg/mL |
| Deferoxamine (DFO) Then ICL670 | Absolute Change in Serum Ferritin From Baseline to Week 24 | -868.7 mg/mL |