Thalassemia
Conditions
Keywords
Thalassemia Intermedia
Brief summary
Thalassemia intermedia (TI) is an inherited blood disorder that can cause anemia due to low levels of hemoglobin. Decitabine is a medication that may be effective at increasing hemoglobin levels. This study will evaluate the safety and effectiveness of decitabine at increasing hemoglobin levels in people with TI.
Detailed description
Thalassemias are inherited blood disorders that are characterized by low levels of hemoglobin and healthy red blood cells, which can lead to anemia. There are many different types of thalassemias, and TI is one type. People with TI often have moderate to severe anemia and may have a shortened life span, organ damage, and a lower quality of life as a result of the disease. Decitabine is a medication used to treat people with diseases that affect bone marrow and blood cells. The medication may be an effective treatment for people with TI because it may have the ability to interact with a person's DNA and increase hemoglobin levels. Previous studies in people with anemia have shown that decitabine has increased hemoglobin levels in some participants. The purpose of this study is to evaluate the safety and effectiveness of decitabine at increasing hemoglobin levels in people with TI. This study will enroll people with TI. Following an 8-week screening period, participants will attend a baseline study visit, which will include a blood collection, pregnancy test, physical exam, and echocardiogram heart imaging procedure. Decitabine will be injected under the skin in the abdomen, thigh, or upper arm. Participants will be observed for a minimum of 30 minutes after the injection to assess pain or adverse reactions. Participants will then receive low doses of decitabine twice a week, on consecutive days, for 12 weeks. They will be closely monitored and dosages will be adjusted or stopped as needed. Every 2 weeks, participants will undergo a blood collection for safety testing. Every 4 weeks, participants will attend a study visit for a pregnancy test, physical exam, blood collection, and review of medication effects. Additionally, at the Week 12 visit, a repeat echocardiogram will occur. During Weeks 12 to 24, participants will not receive decitabine injections but will attend monthly study visits for repeat testing. Study researchers will contact participants by phone every 3 months during Year 1 and then every 6 months for the duration of the study to collect long-term survival and medical information.
Interventions
DRUGDecitabine (USAN, INN)
Participants will receive 0.2 mg/kg of decitabine subcutaneously twice a week for 12 weeks. The dose will be reduced for toxicities as needed. The maximum dose of decitabine to be given will be 0.2 mg/kg.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Carelon Research
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Beta-thalassemia and beta thalassemia-hemoglobin E (HbE), as confirmed by DNA testing * Transfusion independent for at least 120 days before study entry * Red blood cell folate levels above the lower limit of normal
Exclusion criteria
* Absolute neutrophil count (ANC) less than 2000/mm3 in the 8 weeks before study entry or a history of chronic neutropenia, defined as an ANC less than 2000/mm3 * Platelet count less than 100,000/mm3 or greater than 1,000,000/mm3 in the 8 weeks before study entry * Family history of an inherited disease resulting in low ANC or bone marrow failure * Serum creatinine level greater than 2 mg/dL in the 8 weeks before study entry * Evidence of liver disease, as defined by one or more of the following conditions: 1. Alanine aminotransferase (ALT) level greater than 3 times the upper limit of normal in the 8 weeks before study entry 2. Serum albumin level less than 3 g/dL in the 8 weeks before study entry 3. Evidence of cirrhosis on liver biopsy obtained in the 6 months before study entry * Approaching death; has concurrent liver, kidney, cardiac, or metabolic disease; or has any disease of such severity that death within 7 to 10 days of study entry is likely * Pregnant, planning to become pregnant, or breastfeeding * Sexually active female of childbearing potential who is unwilling to use at least two acceptable methods of contraception, as determined by the investigator * Sexually active male whose partner is of child-bearing potential and who is unwilling to use at least two acceptable methods of contraception, as determined by the investigator, during and for 2 months after decitabine treatment * Diagnosed with cancer (except non-melanoma skin cancer) in the 5 years before study entry. In particular, suspicion or evidence of myelodysplastic syndrome (MDS) on clinically indicated bone marrow aspirate or a family history of MDS or concurrent leukemia * HIV infection * Not expected to be able to complete 24 weeks of study follow-up * Currently being treated with any experimental or fetal hemoglobin modulating agent * Current participation in any other studies of investigational drugs or devices * Unable to comply with study medication regimen * Any condition, which in the opinion of the investigator, would place the individual at undue risk if treated with twice-weekly low-dose decitabine for 12 weeks
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Evaluable Patients With an Increase From Baseline in Hemoglobin (Hb) of ≥1.5 g/dL | up to 12 weeks |
| Change in Total Hemoglobin (Hb) From Baseline to Peak (the Follow-up Time Point With the Highest Value) | up to 12 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum Lactate Dehydrogenase (LDH) From Baseline to Nadir (the Follow-up Time Point With the Lowest Value) | up to 12 weeks | — |
| Change in Absolute Reticulocyte Count From Baseline to Nadir (the Follow-up Time Point With the Lowest Value) | up to 12 weeks | — |
| Change in Erythropoietin Levels From Baseline to Nadir (the Follow-up Time Point With the Lowest Value) | up to 12 weeks | — |
| Change in Platelet Count From Baseline to Peak (the Follow-up Time Point With the Highest Value) | up to 12 weeks | — |
| Change in Absolute Fetal Hemoglobin (HbF) From Baseline to Peak (the Follow-up Time Point With the Highest Value) | up to 12 weeks | — |
| Change in Red Blood Cell (RBC) Deformability From Baseline to Peak (the Follow-up Time Point With the Highest Value) | up to 12 weeks | Deformability was assessed by ektacytometry. Normal RBC have maximal deformability, measurable by osmotic ektacytometry, at isotonicity (290 mosmol). A decrease on the Deformability Index (measured in arbitrary units) corresponds to an impairment in the cell membrane's ability to alter its shape under stress. |
| Change in Percentage of Red Blood Cell (RBC) Hb Concentration From Baseline to Peak (the Follow-up Time Point With the Highest Value) | up to 12 weeks | — |
| Change in Percentage of Annexin-positive Cells From Baseline to Nadir (the Follow-up Time Point With the Lowest Value) | up to 12 weeks | — |
| Change in Neutrophil Counts From Baseline to Nadir (the Follow-up Time Point With the Lowest Value) | up to 12 weeks | — |
| Change in Indirect Bilirubin From Baseline to Nadir (the Follow-up Time Point With the Lowest Value) | up to 12 weeks | — |
Countries
Canada, United States
Participant flow
Recruitment details
Recruitment began in early 2007 at one site, Toronto General Hospital. When recruitment became too challenging, the study was moved to the Thalassemia Clinical Research Network and opened at 2 more sites in 2008. These included Children's Hospital in Philadelphia and Children's Hospital in Oakland. Recruitment closed in May, 2010 with 6 subjects.
Pre-assignment details
To be eligible, patients had to be \>=18 years of age and have beta thalassemia intermedia or beta thalassemia-HbE intermedia, no transfusions for 120 days, no hydroxyurea for 120 days, have RBC folate levels above the lower limit of normal, and steady-state anemia (post pt #2, the protocol was amended to define anemia hemoglobin level of \<10g/dl).
Participants by arm
| Arm | Count |
|---|---|
| Phase IIA Open Label, Single-arm, Multi-center Pilot Study Participants will receive injected decitabine for 12 weeks. | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Phase IIA Open Label, Single-arm, Multi-center Pilot Study |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Age, Continuous | 39.2 years STANDARD_DEVIATION 11.8 |
| Baseline Hemoglobin | 7.9 g/dl STANDARD_DEVIATION 1.8 |
| Documented Concomitant Mutation at the alpha-globin locus No | 5 participants |
| Documented Concomitant Mutation at the alpha-globin locus Yes | 1 participants |
| Patients that had been splenectomized No | 1 participants |
| Patients that had been splenectomized Yes | 5 participants |
| Received transfusion in preceding year but > 120 days before protocol therapy No | 2 participants |
| Received transfusion in preceding year but > 120 days before protocol therapy Yes | 4 participants |
| Region of Enrollment Canada | 3 participants |
| Region of Enrollment United States | 3 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 4 / 5 |
| serious Total, serious adverse events | 3 / 5 |
Outcome results
Primary
Change in Total Hemoglobin (Hb) From Baseline to Peak (the Follow-up Time Point With the Highest Value)
Time frame: up to 12 weeks
Population: One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Decitabine | Change in Total Hemoglobin (Hb) From Baseline to Peak (the Follow-up Time Point With the Highest Value) | 1.16 g/dL | Standard Error 0.2 |
Comparison: Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.p-value: <0.01Regression, Linear
Primary
Number of Evaluable Patients With an Increase From Baseline in Hemoglobin (Hb) of ≥1.5 g/dL
Time frame: up to 12 weeks
Population: One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Decitabine | Number of Evaluable Patients With an Increase From Baseline in Hemoglobin (Hb) of ≥1.5 g/dL | 2 participants |
Secondary
Change in Absolute Fetal Hemoglobin (HbF) From Baseline to Peak (the Follow-up Time Point With the Highest Value)
Time frame: up to 12 weeks
Population: One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Decitabine | Change in Absolute Fetal Hemoglobin (HbF) From Baseline to Peak (the Follow-up Time Point With the Highest Value) | 0.65 g/dL | Standard Error 0.06 |
Comparison: Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.p-value: <0.01Regression, Linear
Secondary
Change in Absolute Reticulocyte Count From Baseline to Nadir (the Follow-up Time Point With the Lowest Value)
Time frame: up to 12 weeks
Population: One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Decitabine | Change in Absolute Reticulocyte Count From Baseline to Nadir (the Follow-up Time Point With the Lowest Value) | -34.00 X (10^9)/L | Standard Error 12.5 |
Comparison: Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.p-value: 0.039Regression, Linear
Secondary
Change in Erythropoietin Levels From Baseline to Nadir (the Follow-up Time Point With the Lowest Value)
Time frame: up to 12 weeks
Population: One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Decitabine | Change in Erythropoietin Levels From Baseline to Nadir (the Follow-up Time Point With the Lowest Value) | -43.78 mIU/mL | Standard Error 21.6 |
Comparison: Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.p-value: 0.18Regression, Linear
Secondary
Change in Indirect Bilirubin From Baseline to Nadir (the Follow-up Time Point With the Lowest Value)
Time frame: up to 12 weeks
Population: One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Decitabine | Change in Indirect Bilirubin From Baseline to Nadir (the Follow-up Time Point With the Lowest Value) | -17.36 µmol/L | Standard Error 6.95 |
Comparison: Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.p-value: 0.045Regression, Linear
Secondary
Change in Neutrophil Counts From Baseline to Nadir (the Follow-up Time Point With the Lowest Value)
Time frame: up to 12 weeks
Population: One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Decitabine | Change in Neutrophil Counts From Baseline to Nadir (the Follow-up Time Point With the Lowest Value) | -3.15 X (10^9)/L | Standard Error 1.03 |
Comparison: Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.p-value: 0.069Regression, Linear
Secondary
Change in Percentage of Annexin-positive Cells From Baseline to Nadir (the Follow-up Time Point With the Lowest Value)
Time frame: up to 12 weeks
Population: One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Decitabine | Change in Percentage of Annexin-positive Cells From Baseline to Nadir (the Follow-up Time Point With the Lowest Value) | -1.26 % of Annexin-Positive Cells | Standard Error 0.55 |
Comparison: Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.p-value: 0.11Regression, Linear
Secondary
Change in Percentage of Red Blood Cell (RBC) Hb Concentration From Baseline to Peak (the Follow-up Time Point With the Highest Value)
Time frame: up to 12 weeks
Population: One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Decitabine | Change in Percentage of Red Blood Cell (RBC) Hb Concentration From Baseline to Peak (the Follow-up Time Point With the Highest Value) | 7.06 % of RBC Hb Concentration | Standard Error 1.56 |
Comparison: Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.p-value: 0.022Regression, Linear
Secondary
Change in Platelet Count From Baseline to Peak (the Follow-up Time Point With the Highest Value)
Time frame: up to 12 weeks
Population: One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Decitabine | Change in Platelet Count From Baseline to Peak (the Follow-up Time Point With the Highest Value) | 355.0 X (10^9)/L | Standard Error 102 |
Comparison: Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.p-value: <0.01Regression, Linear
Secondary
Change in Red Blood Cell (RBC) Deformability From Baseline to Peak (the Follow-up Time Point With the Highest Value)
Deformability was assessed by ektacytometry. Normal RBC have maximal deformability, measurable by osmotic ektacytometry, at isotonicity (290 mosmol). A decrease on the Deformability Index (measured in arbitrary units) corresponds to an impairment in the cell membrane's ability to alter its shape under stress.
Time frame: up to 12 weeks
Population: One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Decitabine | Change in Red Blood Cell (RBC) Deformability From Baseline to Peak (the Follow-up Time Point With the Highest Value) | Change From Baseline | 0.09 Arbitrary Units | Standard Error 0.05 |
| Decitabine | Change in Red Blood Cell (RBC) Deformability From Baseline to Peak (the Follow-up Time Point With the Highest Value) | Baseline | 0.43 Arbitrary Units | Standard Error 0.03 |
Comparison: Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.p-value: 0.18Regression, Linear
Secondary
Change in Serum Lactate Dehydrogenase (LDH) From Baseline to Nadir (the Follow-up Time Point With the Lowest Value)
Time frame: up to 12 weeks
Population: One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Decitabine | Change in Serum Lactate Dehydrogenase (LDH) From Baseline to Nadir (the Follow-up Time Point With the Lowest Value) | -116.60 U/L | Standard Error 40.81 |
Comparison: Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.p-value: 0.083Regression, Linear