Sickle Cell Disease
Conditions
Keywords
Deferasirox, ICL670A, Iron chelators, Sickle Cell Disease, Transfusional Hemosiderosis
Brief summary
The safety, tolerability, effects on liver iron concentration and pharmacokinetics of ICL670 is studied in sickle cell disease patients with transfusional hemosiderosis.
Detailed description
The treatment period started once the patient completed the core study and signed informed consent. It is continued for up to 4 years. Safety parameters were assessed every 4 weeks. Eye and Ear examinations were performed on a yearly basis. To further investigate the extent of iron overload, serum ferritin, iron, and transferrin were monitored every four weeks. The Program Safety Board monitored the safety of ICL670 during the study to evaluate and categorize any serious case reported in association with ICL670.
Interventions
DRUGICL670
Daily doses of ICL670 were taken orally 30 minutes before breakfast. The doses range from 5-40 mg/kg and were determined based on the patient's trend in serum ferritin over time during the core study (0109) and on the frequency of blood transfusions the patient received. The treatment duration was up to 4 years.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients were included who met the following criteria: * Completion of the core \[Study 0109\] * Serum ferritin greater than or equal to 500 µg/L * Ability to comply with all study-related procedures, medications, and evaluations * Sexually active post-menarche 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 and assent by the patient and or their parents or legal guardian. Additional inclusion criteria for pediatric patients The definition of the term 'pediatric' for enrollment and study conduct was in accordance with local law. Parents or the legal guardians were fully informed by the investigator as to the requirements of the study. The pediatric patients themselves were informed according to their capabilities in a language and terms that they were able to understand. Written informed consent was obtained from their legal guardian on the patient's behalf in accordance with national legislation. If capable, all patients had to also personally sign their written informed consent.
Exclusion criteria
Patients who met the following criteria were to be excluded: * History of non-compliance to medical regimens and patients who are considered potentially unreliable and/or not cooperative * Serum creatinine above the age-appropriate upper limit of normal within one week prior to entry * Patients with ALT ≥ 500 U/L within one week prior to entry * Evidence of chelation-related cataracts or hearing loss within 4 weeks prior to baseline * Pregnancy (as indicated by serum β-HCG pregnancy test for all female patients with the potential to become pregnant) and patients who are breastfeeding * Patients treated with systemic investigational drug within 4 weeks prior to or with topical investigational drug within 7 days prior to the baseline visit Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events After Start of ICL670 | 0 - 60 months | Safety as assessed by the number of participants with adverse event or death after the start of ICL670. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum Ferritin From Start of ICL670 to End of Study | 0 - 60 months | The main efficacy variable was change in serum ferritin in response to therapy with ICL670. Due to variability of serum ferritin, end of study was considered as the mean of at most the last 3 available observations after the start of ICL670. |
Countries
Canada, France, Italy, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ICL670 Participants treated with ICL670 during the Core Study 0109(NCT00067080) and during the extension phase. ICL670 was administered orally once a day based on the participant's body weight. | 132 |
| Crossover Participants treated with Deferoxamine (DFO) during the Core Study 0109 (NCT00067080) and treated with ICL670 during the extension phase. ICL670 was administered orally once a day based on the participant's body weight. | 53 |
| Total | 185 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal Lab Values | 3 | 1 |
| Overall Study | Abnormal Test Procedure Results | 2 | 0 |
| Overall Study | Administrative problems | 6 | 4 |
| Overall Study | Adverse Event | 12 | 2 |
| Overall Study | Condition no longer requires drug | 5 | 4 |
| Overall Study | Death | 1 | 2 |
| Overall Study | Lost to Follow-up | 11 | 6 |
| Overall Study | Protocol Violation | 2 | 1 |
| Overall Study | Stopped end of core | 7 | 0 |
| Overall Study | Stopped end of extension 1# | 3 | 1 |
| Overall Study | Unsatisfactory therapeutic effect | 4 | 2 |
| Overall Study | Withdrew consent | 33 | 11 |
Baseline characteristics
| Characteristic | ICL670 | Crossover | Total |
|---|---|---|---|
| Age, Customized 12 - <16 years | 32 participants | 11 participants | 43 participants |
| Age, Customized <12 years | 33 participants | 14 participants | 47 participants |
| Age, Customized 16 - <65 years | 67 participants | 28 participants | 95 participants |
| Region of Enrollment Canada | 0 participants | 1 participants | 1 participants |
| Region of Enrollment France | 10 participants | 2 participants | 12 participants |
| Region of Enrollment Italy | 7 participants | 3 participants | 10 participants |
| Region of Enrollment United Kingdom | 5 participants | 1 participants | 6 participants |
| Region of Enrollment United States | 110 participants | 46 participants | 156 participants |
| Sex: Female, Male Female | 80 Participants | 31 Participants | 111 Participants |
| Sex: Female, Male Male | 52 Participants | 22 Participants | 74 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 129 / 132 | 47 / 53 |
| serious Total, serious adverse events | 97 / 132 | 34 / 53 |
Outcome results
Primary
Number of Participants With Adverse Events After Start of ICL670
Safety as assessed by the number of participants with adverse event or death after the start of ICL670.
Time frame: 0 - 60 months
Population: The primary analysis was on Safety Analysis Set which comprised all participants who received at least one dose of ICL670 during the core/extension phase of the study. All participants previously treated with ICL670/DFO for 52weeks in the core study.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| ICL670 | Number of Participants With Adverse Events After Start of ICL670 | Adverse Events | 131 participants | 10.66 |
| ICL670 | Number of Participants With Adverse Events After Start of ICL670 | Deaths | 1 participants | — |
| Crossover | Number of Participants With Adverse Events After Start of ICL670 | Adverse Events | 49 participants | 11.32 |
| Crossover | Number of Participants With Adverse Events After Start of ICL670 | Deaths | 2 participants | — |
Secondary
Change in Serum Ferritin From Start of ICL670 to End of Study
The main efficacy variable was change in serum ferritin in response to therapy with ICL670. Due to variability of serum ferritin, end of study was considered as the mean of at most the last 3 available observations after the start of ICL670.
Time frame: 0 - 60 months
Population: The primary analysis was on Full Analysis Set which comprised all participants who received at least one dose of ICL670 during the core or the extension phase of the study. All participants previously treated with ICL670 or DFO for 52 weeks in the core study were eligible for enrollment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ICL670 | Change in Serum Ferritin From Start of ICL670 to End of Study | -245.5 µg/L |
| Crossover | Change in Serum Ferritin From Start of ICL670 to End of Study | -134.3 µg/L |