Evaluating the Safety and Effectiveness of Decitabine in People With Thalassemia Intermedia

• Sponsor: HealthCore-NERI (Other)
• Overall Status: Completed
• CT.gov ID: NCT00661726
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 6
• Locations: 3
• Arm: 1
• Duration (Months): 32
• Patients Per Site: 2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Thalassemia	Drug: Decitabine (USAN, INN)	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase IIA Study of Subcutaneous 5-aza-2'- Deoxycytidine (Decitabine) in Patients With Thalassemia Intermedia
• Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: May 1, 2010
• Actual Study Completion Date: Sep 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Participants will receive injected decitabine for 12 weeks.	Drug: Decitabine (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.; Other Names: 5-aza-2'-deoxycytidine (NCS 127716) DAC 5-Aza-CdR Deoxyazacytidine 1-(2'deoxy-D-ribofuranosy1)-5-azacytosine Dezocitidine Dacogen

Outcome Measures

Primary Outcome Measures

1. Number of Evaluable Patients With an Increase From Baseline in Hemoglobin (Hb) of ≥1.5 g/dL [up to 12 weeks]

2. Change in Total Hemoglobin (Hb) From Baseline to Peak (the Follow-up Time Point With the Highest Value) [up to 12 weeks]

Secondary Outcome Measures

1. Change in Absolute Fetal Hemoglobin (HbF) From Baseline to Peak (the Follow-up Time Point With the Highest Value) [up to 12 weeks]

2. Change in Indirect Bilirubin From Baseline to Nadir (the Follow-up Time Point With the Lowest Value) [up to 12 weeks]

3. Change in Serum Lactate Dehydrogenase (LDH) From Baseline to Nadir (the Follow-up Time Point With the Lowest Value) [up to 12 weeks]

4. Change in Absolute Reticulocyte Count From Baseline to Nadir (the Follow-up Time Point With the Lowest Value) [up to 12 weeks]

5. Change in Erythropoietin Levels From Baseline to Nadir (the Follow-up Time Point With the Lowest Value) [up to 12 weeks]

6. Change in Platelet Count From Baseline to Peak (the Follow-up Time Point With the Highest Value) [up to 12 weeks]

7. Change in Neutrophil Counts From Baseline to Nadir (the Follow-up Time Point With the Lowest Value) [up to 12 weeks]

8. 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.

9. 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]

10. Change in Percentage of Annexin-positive Cells From Baseline to Nadir (the Follow-up Time Point With the Lowest Value) [up to 12 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital and Research Center at Oakland	Oakland	California	United States	94609
2	Children's Hospital Philadelphia	Philadelphia	Pennsylvania	United States	19104
3	University Health Network	Toronto		Canada	M5G 2C4

Sponsors and Collaborators

• HealthCore-NERI
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Study Chair: Nancy Olivieri, MD, University Health Network/Toronto General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: HealthCore-NERI
• ClinicalTrials.gov Identifier: NCT00661726
• Other Study ID Numbers: 569; U01HL065238; 68,995
• First Posted: Apr 18, 2008
• Last Update Posted: Apr 25, 2014
• Last Verified: Feb 1, 2014

• Keywords provided by HealthCore-NERI: Thalassemia Intermedia
• Additional relevant MeSH terms: Thalassemia; beta-Thalassemia; Decitabine; Azacitidine

Study Results

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 Detail	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).

Arm/Group Title	Phase IIA Open Label, Single-arm, Multi-center Pilot Study
Arm/Group Description	Participants will receive injected decitabine for 12 weeks.
Period Title: Overall Study
STARTED	6
COMPLETED	5
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Phase IIA Open Label, Single-arm, Multi-center Pilot Study
Arm/Group Description	Participants will receive injected decitabine for 12 weeks.
Overall Participants	6
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	6 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.2 (11.8)
Sex: Female, Male (Count of Participants)
Female	1 16.7%
Male	5 83.3%
Region of Enrollment (participants) [Number]
United States	3 50%
Canada	3 50%
Patients that had been splenectomized (participants) [Number]
Yes	5 83.3%
No	1 16.7%
Received transfusion in preceding year but > 120 days before protocol therapy (participants) [Number]
Yes	4 66.7%
No	2 33.3%
Baseline Hemoglobin (g/dl) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [g/dl]	7.9 (1.8)
Documented Concomitant Mutation at the alpha-globin locus (participants) [Number]
Yes	1 16.7%
No	5 83.3%

Outcome Measures

1. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.

Arm/Group Title	Decitabine
Arm/Group Description	Decitabine 0.2 mg/kg was administered subcutaneously daily on the same 2 consecutive days each week for 12 weeks.
Measure Participants	5
Mean (Standard Error) [g/dL]	0.65 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Decitabine
	Comments	Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Regression, Linear
	Comments

2. Primary Outcome

Title	Number of Evaluable Patients With an Increase From Baseline in Hemoglobin (Hb) of ≥1.5 g/dL
Time Frame	up to 12 weeks

Outcome Measure Data

Analysis Population Description

One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.

Arm/Group Title	Decitabine
Arm/Group Description	Decitabine 0.2 mg/kg was administered subcutaneously daily on the same 2 consecutive days each week for 12 weeks.
Measure Participants	5
Number [participants]	2 33.3%

3. Secondary Outcome

Title	Change in Indirect Bilirubin From Baseline to Nadir (the Follow-up Time Point With the Lowest Value)
Time Frame	up to 12 weeks

Outcome Measure Data

Analysis Population Description

One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.

Arm/Group Title	Decitabine
Arm/Group Description	Decitabine 0.2 mg/kg was administered subcutaneously daily on the same 2 consecutive days each week for 12 weeks.
Measure Participants	5
Mean (Standard Error) [µmol/L]	-17.36 (6.95)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Decitabine
	Comments	Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.045
	Comments
	Method	Regression, Linear
	Comments

4. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.

Arm/Group Title	Decitabine
Arm/Group Description	Decitabine 0.2 mg/kg was administered subcutaneously daily on the same 2 consecutive days each week for 12 weeks.
Measure Participants	5
Mean (Standard Error) [U/L]	-116.60 (40.81)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Decitabine
	Comments	Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.083
	Comments
	Method	Regression, Linear
	Comments

5. Secondary Outcome

Title	Change in Absolute Reticulocyte Count From Baseline to Nadir (the Follow-up Time Point With the Lowest Value)
Time Frame	up to 12 weeks

Outcome Measure Data

Analysis Population Description

One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.

Arm/Group Title	Decitabine
Arm/Group Description	Decitabine 0.2 mg/kg was administered subcutaneously daily on the same 2 consecutive days each week for 12 weeks.
Measure Participants	5
Mean (Standard Error) [X (10^9)/L]	-34.00 (12.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Decitabine
	Comments	Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.039
	Comments
	Method	Regression, Linear
	Comments

6. Secondary Outcome

Title	Change in Erythropoietin Levels From Baseline to Nadir (the Follow-up Time Point With the Lowest Value)
Time Frame	up to 12 weeks

Outcome Measure Data

Analysis Population Description

One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.

Arm/Group Title	Decitabine
Arm/Group Description	Decitabine 0.2 mg/kg was administered subcutaneously daily on the same 2 consecutive days each week for 12 weeks.
Measure Participants	5
Mean (Standard Error) [mIU/mL]	-43.78 (21.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Decitabine
	Comments	Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.18
	Comments
	Method	Regression, Linear
	Comments

7. Secondary Outcome

Title	Change in Platelet Count From Baseline to Peak (the Follow-up Time Point With the Highest Value)
Time Frame	up to 12 weeks

Outcome Measure Data

Analysis Population Description

One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.

Arm/Group Title	Decitabine
Arm/Group Description	Decitabine 0.2 mg/kg was administered subcutaneously daily on the same 2 consecutive days each week for 12 weeks.
Measure Participants	5
Mean (Standard Error) [X (10^9)/L]	355.0 (102.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Decitabine
	Comments	Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Regression, Linear
	Comments

8. Secondary Outcome

Title	Change in Neutrophil Counts From Baseline to Nadir (the Follow-up Time Point With the Lowest Value)
Time Frame	up to 12 weeks

Outcome Measure Data

Analysis Population Description

One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.

Arm/Group Title	Decitabine
Arm/Group Description	Decitabine 0.2 mg/kg was administered subcutaneously daily on the same 2 consecutive days each week for 12 weeks.
Measure Participants	5
Mean (Standard Error) [X (10^9)/L]	-3.15 (1.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Decitabine
	Comments	Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.069
	Comments
	Method	Regression, Linear
	Comments

9. Secondary Outcome

Title	Change in Red Blood Cell (RBC) Deformability From Baseline to Peak (the Follow-up Time Point With the Highest Value)
Description	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

Outcome Measure Data

Analysis Population Description

One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.

Arm/Group Title	Decitabine
Arm/Group Description	Decitabine 0.2 mg/kg was administered subcutaneously daily on the same 2 consecutive days each week for 12 weeks.
Measure Participants	5
Baseline	0.43 (0.03)
Change From Baseline	0.09 (0.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Decitabine
	Comments	Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.18
	Comments
	Method	Regression, Linear
	Comments

10. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.

Arm/Group Title	Decitabine
Arm/Group Description	Decitabine 0.2 mg/kg was administered subcutaneously daily on the same 2 consecutive days each week for 12 weeks.
Measure Participants	5
Mean (Standard Error) [% of RBC Hb Concentration]	7.06 (1.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Decitabine
	Comments	Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments
	Method	Regression, Linear
	Comments

11. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.

Arm/Group Title	Decitabine
Arm/Group Description	Decitabine 0.2 mg/kg was administered subcutaneously daily on the same 2 consecutive days each week for 12 weeks.
Measure Participants	5
Mean (Standard Error) [% of Annexin-Positive Cells]	-1.26 (0.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Decitabine
	Comments	Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments
	Method	Regression, Linear
	Comments

12. Primary Outcome

Title	Change in Total Hemoglobin (Hb) From Baseline to Peak (the Follow-up Time Point With the Highest Value)
Time Frame	up to 12 weeks

Outcome Measure Data

Analysis Population Description

One of 6 enrolled patients withdrew from study after week 2 and was not used for analysis.

Arm/Group Title	Decitabine
Arm/Group Description	Decitabine 0.2 mg/kg was administered subcutaneously daily on the same 2 consecutive days each week for 12 weeks.
Measure Participants	5
Mean (Standard Error) [g/dL]	1.16 (0.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Decitabine
	Comments	Linear regression after adjusting for time duration was used to test the mean difference between baseline and follow-up values.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Regression, Linear
	Comments

Adverse Events

Arm/Group Title	Decitabine
Arm/Group Description	Decitabine 0.2 mg/kg was administered subcutaneously daily on the same 2 consecutive days each week for 12 weeks.
All Cause Mortality
	Decitabine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Decitabine
	Affected / at Risk (%)	# Events
Total	3/5 (60%)
Blood and lymphatic system disorders
High Platelets Count	3/5 (60%)	3
Other (Not Including Serious) Adverse Events
	Decitabine
	Affected / at Risk (%)	# Events
Total	4/5 (80%)
Cardiac disorders
Palpitation	1/5 (20%)	1
General disorders
Radiating Pain in Right Shoulder	1/5 (20%)	1
Pain - joint	1/5 (20%)	1
Musculoskeletal and connective tissue disorders
Fracture	1/5 (20%)	1
Vascular disorders
Ocular/ visual- other: Conjunctival Infection	1/5 (20%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.