Iron Balance Study of Deferasirox, Deferoxamine and the Combination of Both
| Status: | Completed |
|---|---|
| Conditions: | Hematology |
| Therapuetic Areas: | Hematology |
| Healthy: | No |
| Age Range: | 18 - 50 |
| Updated: | 4/2/2016 |
| Start Date: | August 2008 |
| End Date: | December 2009 |
| Contact: | Robert W Grady, Ph.D. |
| Email: | rwgrady@med.cornell.edu |
| Phone: | 212-746-3422 |
An Iron Balance Study Comparing Deferasirox, Deferoxamine and the Combination of Both Drugs
Subjects with thalassemia major require regular transfusion therapy to sustain life. The
iron present in the transfused blood remains in the body where it can cause a variety of
organ dysfunctions. Lifelong iron chelation therapy is needed to maintain iron balance but
its effectiveness varies greatly. Like that of deferoxamine (Desferal, DFO) the mainstay of
chelation therapy for 30 years, the effectiveness of deferasirox (Exjade, ICL670), the newly
approved, orally effective iron chelating drug, is not satisfactory in all subjects. Even
with good compliance, the iron excretion induced by a given drug exhibits wide
subject-to-subject variability. There is often persistent iron overload of extra hepatic
tissues such as the heart and pancreas leading to cardiac disease and diabetes. Combining
the drugs may be a better approach in those subjects at increased risk. The iron balance
studies proposed will permit an assessment of the potential of such a combination to place
subjects in net negative iron balance and the relative effectiveness of the combination in
relation to that of the individual drugs, an additive effect being expected. With such
information, physicians will be able to design individualized chelation regimens that
maximize effectiveness while minimizing side effects by adjusting the ratio and/or the
dosing schedule of the two drugs.
iron present in the transfused blood remains in the body where it can cause a variety of
organ dysfunctions. Lifelong iron chelation therapy is needed to maintain iron balance but
its effectiveness varies greatly. Like that of deferoxamine (Desferal, DFO) the mainstay of
chelation therapy for 30 years, the effectiveness of deferasirox (Exjade, ICL670), the newly
approved, orally effective iron chelating drug, is not satisfactory in all subjects. Even
with good compliance, the iron excretion induced by a given drug exhibits wide
subject-to-subject variability. There is often persistent iron overload of extra hepatic
tissues such as the heart and pancreas leading to cardiac disease and diabetes. Combining
the drugs may be a better approach in those subjects at increased risk. The iron balance
studies proposed will permit an assessment of the potential of such a combination to place
subjects in net negative iron balance and the relative effectiveness of the combination in
relation to that of the individual drugs, an additive effect being expected. With such
information, physicians will be able to design individualized chelation regimens that
maximize effectiveness while minimizing side effects by adjusting the ratio and/or the
dosing schedule of the two drugs.
The study involves a 34-day hospital stay during which we will conduct metabolic iron
balance studies wherein deferasirox and deferoxamine are evaluated separately and in
combination, each subject serving as his/her own control. In the studies currently proposed,
deferasirox (20, 30 or 40 mg/kg, administered p.o. 30 minutes before breakfast) and
deferoxamine (30, 40, 50 or 60 mg/kg infused subcutaneously over 8 hours at night) will be
evaluated both alone and in combination, the drugs being given sequentially as above or
simultaneously wherein deferasirox is administered 30 minutes after beginning the infusion
of deferoxamine. In the first phase of the studies, the combination of drugs will be given
sequentially, deferasirox 30 minutes prior to breakfast at a dose of 30 mg/kg and
deferoxamine during the night at 40 mg/kg.
On days 5 - 10, the subjects will receive their first chelation regimen, deferoxamine
infused subcutaneously over 8 hours during the night. They will receive a daily multivitamin
preparation containing 60 -100 mg of vitamin C, 1 mg of folic acid and 400 I.U. of vitamin
E. On days 15 - 20, the subjects will be given deferasirox 30 minutes prior to breakfast.
Finally, on days 25 - 30, the subjects will receive both deferoxamine and deferasirox, the
combination of drugs being given either sequentially (deferasirox in the morning and
deferoxamine at night) or simultaneously (infusion of deferoxamine beginning 30 minutes
prior to taking deferasirox). Non-drug days allow for clearance of stool iron induced by the
previous treatment. A period of 4 days was chosen because this includes the normal
gastrointestinal transit time of most individuals. A stool marker (brilliant blue) will be
administered before the first and after the last dose of each drug to help in quantifying
fecal iron excretion.
Upon admission and discharge, each subject will be given a complete physical examination and
various clinical and laboratory parameters will be measured. These include a routine blood
profile (complete blood count with differential, and platelet count), a serum chemistry
profile (fasting blood sugar, total protein, albumin, AST, ALT, BUN, creatinine, bilirubin
(total), bilirubin (direct), alkaline phosphatase, uric acid, calcium, phosphorus,
magnesium, zinc, copper, sodium, potassium, chloride and carbon dioxide) and a urinalysis
(protein, beta-2 microglobulin, glucose, ketones, hemoglobin, pH, specific gravity and
bacteria; if abnormal, a microscopic examination for RBC, WBC, casts, crystals and cells).
Additional blood tests to be done at admission include serum ferritin, serum iron, iron
binding capacity, % saturation, vitamin C, a serum pregnancy test, hepatitis C antibody and
HIV-PCR with viral load. At the beginning and end of the study, an ophthalmology workup
including a slit lamp and retinal examination, an audiogram, and an electrocardiogram will
also be performed. In addition to those studies conducted upon admission and discharge,
serial blood tests and urinalyses will be done on days 6, 10, 14, 16, 20, 24, 26 and 30 to
ensure adequate monitoring of organ function.
Each subject will be placed on a fixed low-iron diet consisting of four rotating meal plans
designed by our nutritionists in consultation with the subjects themselves. Twenty-four hour
specimens of urine and stool will be collected daily and their iron content determined by
atomic absorption. Net excretion will be determined taking into account the iron content of
all uneaten food. The excretion of copper and zinc will also be monitored to insure that
these physiologically important metals are not depleted. Each subject will be given a unit
of blood on days 1, 11, 21 and 34. This will ensure that the level of erythropoiesis is
approximately the same before each drug regimen.
In order to reduce the stress and boredom of the 34-day hospitalization, it is anticipated
that the subjects will be studied in pairs so that they will always have someone in a
similar situation to interact with. They will have free access to television, the internet
and local phone service while in the clinical research unit. The subjects must eat breakfast
and dinner in the research unit and sleep there. Otherwise, they may go out on pass during
the day and after dinner in the evenings for shopping, entertainment, etc. We will pack
their lunch if they choose to go out for the day as they will not be allowed to consume any
food or drink other than what is provided in their agreed upon diet. Visitors will be
allowed during normal hospital visiting hours.
balance studies wherein deferasirox and deferoxamine are evaluated separately and in
combination, each subject serving as his/her own control. In the studies currently proposed,
deferasirox (20, 30 or 40 mg/kg, administered p.o. 30 minutes before breakfast) and
deferoxamine (30, 40, 50 or 60 mg/kg infused subcutaneously over 8 hours at night) will be
evaluated both alone and in combination, the drugs being given sequentially as above or
simultaneously wherein deferasirox is administered 30 minutes after beginning the infusion
of deferoxamine. In the first phase of the studies, the combination of drugs will be given
sequentially, deferasirox 30 minutes prior to breakfast at a dose of 30 mg/kg and
deferoxamine during the night at 40 mg/kg.
On days 5 - 10, the subjects will receive their first chelation regimen, deferoxamine
infused subcutaneously over 8 hours during the night. They will receive a daily multivitamin
preparation containing 60 -100 mg of vitamin C, 1 mg of folic acid and 400 I.U. of vitamin
E. On days 15 - 20, the subjects will be given deferasirox 30 minutes prior to breakfast.
Finally, on days 25 - 30, the subjects will receive both deferoxamine and deferasirox, the
combination of drugs being given either sequentially (deferasirox in the morning and
deferoxamine at night) or simultaneously (infusion of deferoxamine beginning 30 minutes
prior to taking deferasirox). Non-drug days allow for clearance of stool iron induced by the
previous treatment. A period of 4 days was chosen because this includes the normal
gastrointestinal transit time of most individuals. A stool marker (brilliant blue) will be
administered before the first and after the last dose of each drug to help in quantifying
fecal iron excretion.
Upon admission and discharge, each subject will be given a complete physical examination and
various clinical and laboratory parameters will be measured. These include a routine blood
profile (complete blood count with differential, and platelet count), a serum chemistry
profile (fasting blood sugar, total protein, albumin, AST, ALT, BUN, creatinine, bilirubin
(total), bilirubin (direct), alkaline phosphatase, uric acid, calcium, phosphorus,
magnesium, zinc, copper, sodium, potassium, chloride and carbon dioxide) and a urinalysis
(protein, beta-2 microglobulin, glucose, ketones, hemoglobin, pH, specific gravity and
bacteria; if abnormal, a microscopic examination for RBC, WBC, casts, crystals and cells).
Additional blood tests to be done at admission include serum ferritin, serum iron, iron
binding capacity, % saturation, vitamin C, a serum pregnancy test, hepatitis C antibody and
HIV-PCR with viral load. At the beginning and end of the study, an ophthalmology workup
including a slit lamp and retinal examination, an audiogram, and an electrocardiogram will
also be performed. In addition to those studies conducted upon admission and discharge,
serial blood tests and urinalyses will be done on days 6, 10, 14, 16, 20, 24, 26 and 30 to
ensure adequate monitoring of organ function.
Each subject will be placed on a fixed low-iron diet consisting of four rotating meal plans
designed by our nutritionists in consultation with the subjects themselves. Twenty-four hour
specimens of urine and stool will be collected daily and their iron content determined by
atomic absorption. Net excretion will be determined taking into account the iron content of
all uneaten food. The excretion of copper and zinc will also be monitored to insure that
these physiologically important metals are not depleted. Each subject will be given a unit
of blood on days 1, 11, 21 and 34. This will ensure that the level of erythropoiesis is
approximately the same before each drug regimen.
In order to reduce the stress and boredom of the 34-day hospitalization, it is anticipated
that the subjects will be studied in pairs so that they will always have someone in a
similar situation to interact with. They will have free access to television, the internet
and local phone service while in the clinical research unit. The subjects must eat breakfast
and dinner in the research unit and sleep there. Otherwise, they may go out on pass during
the day and after dinner in the evenings for shopping, entertainment, etc. We will pack
their lunch if they choose to go out for the day as they will not be allowed to consume any
food or drink other than what is provided in their agreed upon diet. Visitors will be
allowed during normal hospital visiting hours.
Inclusion Criteria:
- Subjects with transfusional iron overload secondary to thalassemia major, aged 18 or
older, may participate after giving written informed consent. Subjects must have no
clinically significant finding in their medical history, on physical examination or
as a result of laboratory assessments other than those consistent with thalassemia
major and its complications, such as compensated cirrhosis, endocrine insufficiency
and diabetes.
- Subjects must have a serum ferritin greater than 1000 ng/mL, a platelet count greater
than 100,000/mm3, and a serum creatinine within the normal range.
- Subjects must be willing and able to discontinue their usual regimen of DFO,
deferiprone (L1, Ferriprox) or Exjade for the duration of the study.
- A woman of childbearing potential must have a negative serum pregnancy test at
screening. She must use a medically acceptable form of birth control during the study
and for 1 month afterward. Acceptable birth control measures include: abstinence,
oral contraceptives, hormonal contraceptive implants, barrier contraceptives (condom,
diaphragm with spermicide), IUD, and/or a vasectomized partner. Male subjects must
also use barrier contraceptives during the study and for 1 month thereafter.
- The subjects must also have a level of understanding and willingness to cooperate
with the confinement and procedures described in the consent form and scheduled by
the study site. In addition, he/she must be able to provide voluntary written
informed consent.
- Subjects must weigh at least 40 kg.
Exclusion Criteria:
- Subjects can not have a history of clinically significant gastrointestinal, renal,
hepatic, endocrine, oncologic, infectious, pulmonary or cardiovascular disease, other
than conditions associated with thalassemia and iron overload, such as compensated
cirrhosis, endocrine insufficiency and diabetes, or a history of tuberculosis,
epilepsy, psychosis, glaucoma or any other condition, which in the opinion of the
investigators, would jeopardize the safety of the subject or impact the validity of
the study results.
- Subjects can not be HIV positive or have active HCV.
- A history of serious immunologic hypersensitivity to any medication, such as
anaphylaxis or angioedema.
- Participation in a previous investigational drug study within the 30 days preceding
screening. A chelation regimen including deferiprone or Exjade within 30 days of
screening would not exclude subjects coming from regions where these drugs are an
approved medication.
- Women who are pregnant, or breast-feeding.
- Current alcohol or drug abuse.
- An inability to adhere to the designated procedures and restrictions of this
protocol.
- Subjects with abnormal or irregular bowel function (defined as more than 3 bowel
movements/day or less than 1 bowel movement every other day).
- Subjects receiving warfarin, digoxin, or anti-arrhythmic or anti-seizure medications.
- Subjects with a known allergy to Exjade or DFO that prevents chronic administration.
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