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

NCT00115349 | Terminated Phase 2 Results DMC

• 6 other identifiers: 181U01HL065260U01HL065244U01HL065239U01HL065238U01HL065232
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 6

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.

Conditions

Cardiovascular Diseases; Heart Diseases; Beta-Thalassemia

Outcome Measures

Primary Outcomes (1)

• Change in Left Ventricular Ejection Fraction (LVEF).

  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.

  Baseline to one year

Secondary Outcomes (6)

• Evaluate Whether L1/DFO Combination Therapy is Superior to DFO Monotherapy in Lowering Myocardial Iron Burden Estimated by Myocardial T2*.

  one year

• Change in Left Ventricular (LV) Volume From Screening to One Year.

  one year

• Change in ECHO LV Volume, Ejection Fraction, Shortening Fraction, and VCFc/Wall Stress Z-score From Baseline to One Year.

  one year

• Change in Holter Monitor Scores From Baseline to One Year.

  one year

• Initiation of or Increase in Cardiac Medications

  continuous

Study Arms (2)

L1/DFO

EXPERIMENTAL

Deferoxamine (DFO) and deferiprone (L1) combination therapy

Drug: Deferoxamine; Drug: Deferiprone (L1)

DFO

ACTIVE COMPARATOR

Deferoxamine (DFO) monotherapy

Drug: Deferoxamine

Interventions

Deferoxamine DRUG

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.

Also known as: DFO

DFO; L1/DFO

Deferiprone (L1) DRUG

The dose of L1, 75mg/kg in three divided oral doses, is the maximum dose at which toxicity has been tested in prospective trials

Also known as: L1

L1/DFO

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Carelon Research: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (6)

Children's Hospital of Los Angeles

Los Angeles, California, 90027, United States

Location

Children's Hospital

Oakland, California, 94609, United States

Location

Children's Memorial Hospital

Chicago, Illinois, 60614-3394, United States

Location

Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Weill Medical College of Cornell University

New York, New York, 10021, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104-4399, United States

Location

Related Publications (1)

• Padhani ZA, Gangwani MK, Sadaf A, Hasan B, Colan S, Alvi N, Das JK. Calcium channel blockers for preventing cardiomyopathy due to iron overload in people with transfusion-dependent beta thalassaemia. Cochrane Database Syst Rev. 2023 Nov 17;11(11):CD011626. doi: 10.1002/14651858.CD011626.pub3.

  PMID: 37975597 DERIVED

MeSH Terms

Conditions

Cardiovascular Diseases; Heart Diseases; beta-Thalassemia

Interventions

Deferoxamine; Deferiprone; Long Interspersed Nucleotide Elements

Condition Hierarchy (Ancestors)

Thalassemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Hydroxamic Acids; Hydroxylamines; Amines; Organic Chemicals; Hydroxy Acids; Carboxylic Acids; Pyridones; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Retroelements; Interspersed Repetitive Sequences; Repetitive Sequences, Nucleic Acid; Base Sequence; Molecular Structure; Biochemical Phenomena; Chemical Phenomena; Genetic Structures; Genetic Phenomena; Genome Components; Genome

Limitations and 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.

Results Point of Contact

• Title: John Porter, MD, Principal Investigator
• Organization: UCL Cancer Institute

j.porter@ucl.ac.uk

+011 (44) 207 679 6224

Study Officials

• John Porter, MD

  University College, London

  PRINCIPAL INVESTIGATOR

• 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 CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 21, 2005
• First Posted: June 22, 2005
• Study Start: June 1, 2005
• Primary Completion: July 1, 2008
• Study Completion: April 1, 2009
• Last Updated: March 1, 2018
• Results First Posted: January 14, 2014

Record last verified: 2014-01

Locations

US (6)