Combination Therapy Compared With Single-Drug Therapy in Patients With Cardiac Diseases

• Sponsor: HealthCore-NERI (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00115349
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 20
• Locations: 6
• Arms: 2
• Duration (Months): 46
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether left ventricular function improves more rapidly with deferoxamine (DFO) and deferiprone (L1) combination therapy than with DFO monotherapy in patients with thalassemia and decreased ejection fractions. Secondary aims include evaluating changes in myocardial iron burden using T2* and estimating the relative incidence and severity of chelator-induced toxicity.

Condition or Disease	Intervention/Treatment	Phase
Cardiovascular Diseases; Heart Diseases; Beta-Thalassemia	Drug: Deferoxamine; Drug: Deferiprone (L1)	Phase 2

Detailed Description

DESIGN NARRATIVE:

Participants will be randomized to 1 year of treatment with L1/DFO combination therapy or DFO monotherapy. At baseline, 6 months, and 1 year on therapy, cardiac function will be assessed by MRI measurement of left ventricular ejection fraction (LVEF), T2*, Holter monitoring, and electrocardiography. Additional monitoring for safety includes weekly blood testing, monthly visits, and periodic eye and ear exams.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Thalassemia Clinical Research Network - Cardiac L1/DFO Trial
• Study Start Date: Jun 1, 2005
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Apr 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: L1/DFO Deferoxamine (DFO) and deferiprone (L1) combination therapy	Drug: Deferoxamine; Deferoxamine will be given daily for 12-24h/day 7 days a week either subcutaneous or intravenous at up to 50-60 mg/kg/day.; Other Names: DFO ; Drug: Deferiprone (L1); The dose of L1, 75mg/kg in three divided oral doses, is the maximum dose at which toxicity has been tested in prospective trials; Other Names: L1
Active Comparator: DFO Deferoxamine (DFO) monotherapy	Drug: Deferoxamine; Deferoxamine will be given daily for 12-24h/day 7 days a week either subcutaneous or intravenous at up to 50-60 mg/kg/day.; Other Names: DFO

Outcome Measures

Primary Outcome Measures

1. Change in Left Ventricular Ejection Fraction (LVEF). [Baseline to one year]

   The primary outcome variable is change in left ventricular ejection fraction (blood ejected from the heart into the body) as measured by MRI from baseline to one year. The unit of primary outcome (left ventricular ejection fraction) is the percent of the blood in left ventricle.

Secondary Outcome Measures

1. Evaluate Whether L1/DFO Combination Therapy is Superior to DFO Monotherapy in Lowering Myocardial Iron Burden Estimated by Myocardial T2*. [one year]

2. Change in Left Ventricular (LV) Volume From Screening to One Year. [one year]

3. Change in ECHO LV Volume, Ejection Fraction, Shortening Fraction, and VCFc/Wall Stress Z-score From Baseline to One Year. [one year]

4. Change in Holter Monitor Scores From Baseline to One Year. [one year]

5. Initiation of or Increase in Cardiac Medications [continuous]

6. Adverse Events [continous]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Transfusion-dependent beta-thalassemia (eight or more transfusion episodes in the previous year)

• Left ventricular ejection fraction by MRI less than or equal to 56% by balanced steady-state free precession (SSFP) or 63% by spoiled gradient recalled echo (SPGR)

• Currently on treatment with subcutaneous or intravenous DFO; participants must be willing and able to chelate 7 days per week 12 - 24 hours per day

• Serum ferritin greater than 1000 µg/L or ferritin between 500 µg/L and 1000 µg/L and cardiac T2* less than 20 ms

Exclusion Criteria:

• Pacemaker, severe claustrophobia, or other contraindications to MRI; severe congestive heart failure (New York Heart Association Classification IV); congenital or acquired valvular heart disease significant enough to require surgery or medications

• Currently receiving treatment for hepatitis; renal insufficiency defined by a clinically significant abnormal serum creatinine with a calculated creatinine clearance of less than 50 ml/min according to the Cockroft formula

• A neutrophil count less than 1.5 x 109/L on two or more occasions at least 4 weeks apart within the past year and not associated with an acute viral illness or a platelet count less than 80 x 109/L on two or more occasions at least 4 weeks apart within the past year

• Treatment with L1 or Exjade during the previous 2 weeks or previous adverse experience to L1 requiring suspension

• Infection with HIV

• Active participation in other investigational drug or device studies

• Unwilling to consider treatment with DFO at a dose of 50-60 mg/kg 12-24 hours per day 7 days per week

• Women who are pregnant or breast feeding

• Systemic infection or cardiovascular, hepatic, renal, pulmonary, or gastrointestinal disease that would prevent patients from undergoing any of the study-required treatments or procedures or requires treatment with any contraindicated medication(s)

• Presence of any other condition that, in the opinion of the investigator, would make the patient unsuitable for enrollment or could interfere with the patient's compliance with the protocol; may include but is not limited to alcohol or drug abuse

• For women of child-bearing potential, an inability or unwillingness to use a highly effective method of contraception (e.g., implants, injectables, combined oral contraceptives, or some intrauterine devices)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Los Angeles	Los Angeles	California	United States	90027
2	Children's Hospital	Oakland	California	United States	94609
3	Children's Memorial Hospital	Chicago	Illinois	United States	60614-3394
4	Children's Hospital	Boston	Massachusetts	United States	02115
5	Weill Medical College of Cornell University	New York	New York	United States	10021
6	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104-4399

Sponsors and Collaborators

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

Investigators

• Principal Investigator: John Porter, MD, University College, London
• Study Chair: Patricia J. Giardina, MD, Weill Medical College of Cornell University
• Study Chair: Ellis J. Neufeld, MD, Boston Children's Hospital
• Study Chair: Elliott P, Vichinsky, MD, Children's Hospital and Research Institute, Oakland
• Study Chair: Sonja McKinlay, Ph.D., New England Research Institutes, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: HealthCore-NERI
• ClinicalTrials.gov Identifier: NCT00115349
• Other Study ID Numbers: 181; U01HL065260; U01HL065244; U01HL065239; U01HL065238; U01HL065232
• First Posted: Jun 22, 2005
• Last Update Posted: Mar 1, 2018
• Last Verified: Jan 1, 2014

• Additional relevant MeSH terms: Cardiovascular Diseases; Heart Diseases; Thalassemia; beta-Thalassemia; Deferiprone; Deferoxamine

Study Results

Participant Flow

Recruitment Details	First patient enrolled in August, 2005 and study closed due to low enrollment in June, 2008. 8 participating sites.
Pre-assignment Detail	Patients were evaluated for eligibility based on the following criterial. If not eligible, they were not randomized to a treatment arm.

Arm/Group Title	Deferoxamine (DFO) and Deferiprone (L1) Combination Therapy	Deferoxamine (DFO) + Monotherapy
Arm/Group Description	DFO + L1 DFO Administered daily at 50-60 mg/kg for 12-24 hr/day 7 days a week either subcutaneous or intravenous. L1 Administered daily at 75 mg/kg in 3 divided doses taken orally and timed so that 2 of 3 doses will be simultaneous with DFO infusion.	DFO + Placebo DFO Administered daily at 50-60 mg/kg for 12-24 hr/day 7 days a week either subcutaneous or intravenous. Placebo Administered orally three times daily.
Period Title: Overall Study
STARTED	11	9
COMPLETED	0	0
NOT COMPLETED	11	9

Baseline Characteristics

Arm/Group Title	Deferoxamine (DFO) and Deferiprone (L1) Combination Therapy	Deferoxamine (DFO) + Monotherapy	Total
Arm/Group Description	DFO + L1 DFO Administered daily at 50-60 mg/kg for 12-24 hr/day 7 days a week either subcutaneous or intravenous. L1 Administered daily at 75 mg/kg in 3 divided doses taken orally and timed so that 2 of 3 doses will be simultaneous with DFO infusion.	DFO + Placebo DFO Administered daily at 50-60 mg/kg for 12-24 hr/day 7 days a week either subcutaneous or intravenous. Placebo Administered orally three times daily.	Total of all reporting groups
Overall Participants	11	9	20
Age (Count of Participants)
<=18 years	0 0%	1 11.1%	1 5%
Between 18 and 65 years	11 100%	8 88.9%	19 95%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	26.5 (5.1)	25.8 (7.6)	26.15 (6.18)
Sex: Female, Male (Count of Participants)
Female	3 27.3%	5 55.6%	8 40%
Male	8 72.7%	4 44.4%	12 60%
Region of Enrollment (participants) [Number]
Canada	3 27.3%	3 33.3%	6 30%
United States	6 54.5%	4 44.4%	10 50%
Lebanon	2 18.2%	2 22.2%	4 20%

Outcome Measures

1. Primary Outcome

Title	Change in Left Ventricular Ejection Fraction (LVEF).
Description	The primary outcome variable is change in left ventricular ejection fraction (blood ejected from the heart into the body) as measured by MRI from baseline to one year. The unit of primary outcome (left ventricular ejection fraction) is the percent of the blood in left ventricle.
Time Frame	Baseline to one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Deferoxamine (DFO) and Deferiprone (L1) Combination Therapy	Deferoxamine (DFO) + Monotherapy
Arm/Group Description	DFO + L1 DFO Administered daily at 50-60 mg/kg for 12-24 hr/day 7 days a week either subcutaneous or intravenous. L1 Administered daily at 75 mg/kg in 3 divided doses taken orally and timed so that 2 of 3 doses will be simultaneous with DFO infusion.	DFO + Placebo DFO Administered daily at 50-60 mg/kg for 12-24 hr/day 7 days a week either subcutaneous or intravenous. Placebo Administered orally three times daily.
Measure Participants	11	9
Least Squares Mean (Standard Error) [Percent of the blood in left ventricle]	7.2 (1.9)	6.3 (3.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Deferoxamine (DFO) and Deferiprone (L1) Combination Therapy, Deferoxamine (DFO) + Monotherapy
	Comments	The intended sample size of 86 patients (N=43 per arm) had 80% power to detect a 5% difference in LVEF between the two arms after 1 year of treatment, assuming a standard deviation of change in LVEF of 7.46%, and 20% loss to follow-up. The study was stopped early by NHLBI when analysis of the interim data confirmed a required sample size of 86 that was not achievable within the required time frame within the participating or planned centres.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.89
	Comments
	Method	Mixed Models Analysis
	Comments	Linear mixed models with treatment, time, and treatment x time interaction were used, allowing for random participant-specific intercepts and slopes.

2. Secondary Outcome

Title	Evaluate Whether L1/DFO Combination Therapy is Superior to DFO Monotherapy in Lowering Myocardial Iron Burden Estimated by Myocardial T2*.
Time Frame	one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Change in Left Ventricular (LV) Volume From Screening to One Year.
Time Frame	one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Change in ECHO LV Volume, Ejection Fraction, Shortening Fraction, and VCFc/Wall Stress Z-score From Baseline to One Year.
Time Frame	one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Change in Holter Monitor Scores From Baseline to One Year.
Time Frame	one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Initiation of or Increase in Cardiac Medications
Time Frame	continuous

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Adverse Events
Time Frame	continous

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	1 year
Arm/Group Title	Deferoxamine (DFO) and Deferiprone (L1) Combination Therapy		Deferoxamine (DFO) + Monotherapy
Arm/Group Description	DFO + L1 DFO Administered daily at 50-60 mg/kg for 12-24 hr/day 7 days a week either subcutaneous or intravenous. L1 Administered daily at 75 mg/kg in 3 divided doses taken orally and timed so that 2 of 3 doses will be simultaneous with DFO infusion.		DFO + Placebo DFO Administered daily at 50-60 mg/kg for 12-24 hr/day 7 days a week either subcutaneous or intravenous. Placebo Administered orally three times daily.
All Cause Mortality
	Deferoxamine (DFO) and Deferiprone (L1) Combination Therapy		Deferoxamine (DFO) + Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Deferoxamine (DFO) and Deferiprone (L1) Combination Therapy		Deferoxamine (DFO) + Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/11 (54.5%)		3/9 (33.3%)
Blood and lymphatic system disorders
Clot	1/11 (9.1%)	1	0/9 (0%)	0
Splenectomy	0/11 (0%)	0	1/9 (11.1%)	1
Cardiac disorders
Congestive heart failure	1/11 (9.1%)	1	2/9 (22.2%)	2
Palpitation	0/11 (0%)	0	1/9 (11.1%)	2
Arrhythmia	2/11 (18.2%)	2	0/9 (0%)	0
Eye disorders
Retinal toxicity- drug induced	1/11 (9.1%)	1	0/9 (0%)	0
General disorders
Watery diarrhea & hypotension	1/11 (9.1%)	1	0/9 (0%)	0
Hepatobiliary disorders
Abnormal LFTs	1/11 (9.1%)	1	0/9 (0%)	0
Abdominal Pain	1/11 (9.1%)	1	0/9 (0%)	0
Infections and infestations
Cellulitis	0/11 (0%)	0	0/9 (0%)	0
Meningitis (unkown viral vs. bacterial)	1/11 (9.1%)	1	0/9 (0%)	0
high grade fever and chills	1/11 (9.1%)	1	0/9 (0%)	0
Pneumonia	0/11 (0%)	0	1/9 (11.1%)	1
Central venous line infection	1/11 (9.1%)	2	0/9 (0%)	0
Metabolism and nutrition disorders
Syncope	1/11 (9.1%)	1	0/9 (0%)	0
Hyperkalemia	1/11 (9.1%)	1	0/9 (0%)	0
Renal and urinary disorders
Renal Disease	1/11 (9.1%)	1	0/9 (0%)	0
Other (Not Including Serious) Adverse Events
	Deferoxamine (DFO) and Deferiprone (L1) Combination Therapy		Deferoxamine (DFO) + Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/11 (72.7%)		6/9 (66.7%)
Blood and lymphatic system disorders
Abnormal LFTs	1/11 (9.1%)	1	0/9 (0%)	0
Neutropenia	1/11 (9.1%)	2	1/9 (11.1%)	2
Cardiac disorders
Palpitations with dizziness	1/11 (9.1%)	1	0/9 (0%)	0
Heart palpatations	0/11 (0%)	0	1/9 (11.1%)	1
Gastrointestinal disorders
Dry mouth	1/11 (9.1%)	1	0/9 (0%)	0
Nausea	3/11 (27.3%)	4	0/9 (0%)	0
stomach discomfort	0/11 (0%)	0	1/9 (11.1%)	1
Abdominal pain	0/11 (0%)	0	1/9 (11.1%)	1
Abdominal Bloating	0/11 (0%)	0	1/9 (11.1%)	1
General disorders
Dizziness	2/11 (18.2%)	2	0/9 (0%)	0
Fever	2/11 (18.2%)	2	1/9 (11.1%)	1
Low Grade Fever and Sore Throay	1/11 (9.1%)	1	0/9 (0%)	0
Nausea and Vomiting	2/11 (18.2%)	2	1/9 (11.1%)	1
Infections and infestations
Strep Throat	1/11 (9.1%)	1	0/9 (0%)	0
Injury, poisoning and procedural complications
Phlebotic pain at blood infusion	1/11 (9.1%)	1	0/9 (0%)	0
Allergic transfusion reactions hives	1/11 (9.1%)	1	1/9 (11.1%)	1
tooth ache	1/11 (9.1%)	1	0/9 (0%)	0
Ankle pain	0/11 (0%)	0	1/9 (11.1%)	1
Musculoskeletal and connective tissue disorders
Bilerateral Hip Pain	1/11 (9.1%)	1	0/9 (0%)	0
Myalgia	1/11 (9.1%)	1	0/9 (0%)	0
Sternocleidomastoid muscle spasm	1/11 (9.1%)	1	0/9 (0%)	0
Vomiting	1/11 (9.1%)	1	1/9 (11.1%)	1
Nervous system disorders
Otitis media	2/11 (18.2%)	2	0/9 (0%)	0
Pregnancy, puerperium and perinatal conditions
Fanconi	1/11 (9.1%)	1	0/9 (0%)	0
Psychiatric disorders
Anxiety attack	0/11 (0%)	0	1/9 (11.1%)	2
Renal and urinary disorders
Urinary Tract Infection	0/11 (0%)	0	1/9 (11.1%)	1
Respiratory, thoracic and mediastinal disorders
Chest Ache	1/11 (9.1%)	1	0/9 (0%)	0
sore throat	1/11 (9.1%)	1	2/9 (22.2%)	2
Upper Respiratory Infection	2/11 (18.2%)	4	0/9 (0%)	0
sore throat and cough	1/11 (9.1%)	1	0/9 (0%)	0
stomach flu	1/11 (9.1%)	1	0/9 (0%)	0
Shortness of Breath/fatigue	0/11 (0%)	0	1/9 (11.1%)	1
Cough	0/11 (0%)	0	1/9 (11.1%)	1
Skin and subcutaneous tissue disorders
Epistaxis	1/11 (9.1%)	1	0/9 (0%)	0
Social circumstances
Common Cold	1/11 (9.1%)	2	0/9 (0%)	0
Kicked in chest	1/11 (9.1%)	1	0/9 (0%)	0
Vascular disorders
Vertigo	2/11 (18.2%)	2	0/9 (0%)	0

Limitations/Caveats

The study was stopped early by NHLBI when analysis of the interim data confirmed a required sample size of 86 that was not achievable within the required time frame within the participating or planned centres.

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.