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

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ClinicalTrials.gov Identifier: NCT00115349
Recruitment Status : Terminated (due to low enrollment)
First Posted : June 22, 2005
Results First Posted : January 14, 2014
Last Update Posted : March 1, 2018
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
HealthCore-NERI

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Conditions Cardiovascular Diseases
Heart Diseases
Beta-Thalassemia
Interventions Drug: Deferoxamine
Drug: Deferiprone (L1)
Enrollment 20
Recruitment Details First patient enrolled in August, 2005 and study closed due to low enrollment in June, 2008. 8 participating sites.
Pre-assignment Details 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
Hide 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 [1] 9 [1]
Completed 0 [2] 0 [2]
Not Completed 11 9
Reason Not Completed
Study closed due to low enrollment.             11             9
[1]
Target was 43 subjects in this arm.
[2]
Study closed due to low enrollment.
Arm/Group Title Deferoxamine (DFO) and Deferiprone (L1) Combination Therapy Deferoxamine (DFO) + Monotherapy Total
Hide 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 Number of Baseline Participants 11 9 20
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 11 participants 9 participants 20 participants
<=18 years
0
   0.0%
1
  11.1%
1
   5.0%
Between 18 and 65 years
11
 100.0%
8
  88.9%
19
  95.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 11 participants 9 participants 20 participants
26.5  (5.1) 25.8  (7.6) 26.15  (6.18)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 11 participants 9 participants 20 participants
Female
3
  27.3%
5
  55.6%
8
  40.0%
Male
8
  72.7%
4
  44.4%
12
  60.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 11 participants 9 participants 20 participants
Canada 3 3 6
United States 6 4 10
Lebanon 2 2 4
1.Primary Outcome
Title Change in Left Ventricular Ejection Fraction (LVEF).
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Deferoxamine (DFO) and Deferiprone (L1) Combination Therapy Deferoxamine (DFO) + Monotherapy
Hide 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.

Overall Number of Participants Analyzed 11 9
Least Squares Mean (Standard Error)
Unit of Measure: Percent of the blood in left ventricle
7.2  (1.9) 6.3  (3.3)
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.89
Comments [Not Specified]
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*.
Hide Description [Not Specified]
Time Frame one year
Outcome Measure Data Not Reported
3.Secondary Outcome
Title Change in Left Ventricular (LV) Volume From Screening to One Year.
Hide Description [Not Specified]
Time Frame one year
Outcome Measure Data Not Reported
4.Secondary Outcome
Title Change in ECHO LV Volume, Ejection Fraction, Shortening Fraction, and VCFc/Wall Stress Z-score From Baseline to One Year.
Hide Description [Not Specified]
Time Frame one year
Outcome Measure Data Not Reported
5.Secondary Outcome
Title Change in Holter Monitor Scores From Baseline to One Year.
Hide Description [Not Specified]
Time Frame one year
Outcome Measure Data Not Reported
6.Secondary Outcome
Title Initiation of or Increase in Cardiac Medications
Hide Description [Not Specified]
Time Frame continuous
Outcome Measure Data Not Reported
7.Secondary Outcome
Title Adverse Events
Hide Description [Not Specified]
Time Frame continous
Outcome Measure Data Not Reported
Time Frame 1 year
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Deferoxamine (DFO) and Deferiprone (L1) Combination Therapy Deferoxamine (DFO) + Monotherapy
Hide 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 (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
Deferoxamine (DFO) and Deferiprone (L1) Combination Therapy Deferoxamine (DFO) + Monotherapy
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   6/11 (54.55%)      3/9 (33.33%)    
Blood and lymphatic system disorders     
Clot * 1 [1]  1/11 (9.09%)  1 0/9 (0.00%)  0
Splenectomy * 1 [2]  0/11 (0.00%)  0 1/9 (11.11%)  1
Cardiac disorders     
Congestive heart failure * 1 [3]  1/11 (9.09%)  1 2/9 (22.22%)  2
Palpitation * 1 [4]  0/11 (0.00%)  0 1/9 (11.11%)  2
Arrhythmia * 1 [5]  2/11 (18.18%)  2 0/9 (0.00%)  0
Eye disorders     
Retinal toxicity- drug induced * 1 [6]  1/11 (9.09%)  1 0/9 (0.00%)  0
General disorders     
Watery diarrhea & hypotension * 1 [7]  1/11 (9.09%)  1 0/9 (0.00%)  0
Hepatobiliary disorders     
Abnormal LFTs  1 [8]  1/11 (9.09%)  1 0/9 (0.00%)  0
Abdominal Pain * 1 [9]  1/11 (9.09%)  1 0/9 (0.00%)  0
Infections and infestations     
Cellulitis * 1 [10]  0/11 (0.00%)  0 0/9 (0.00%)  0
Meningitis (unkown viral vs. bacterial) * 1 [11]  1/11 (9.09%)  1 0/9 (0.00%)  0
high grade fever and chills * 1 [12]  1/11 (9.09%)  1 0/9 (0.00%)  0
Pneumonia * 1 [13]  0/11 (0.00%)  0 1/9 (11.11%)  1
Central venous line infection * 1 [14]  1/11 (9.09%)  2 0/9 (0.00%)  0
Metabolism and nutrition disorders     
Syncope * 1 [15]  1/11 (9.09%)  1 0/9 (0.00%)  0
Hyperkalemia * 1 [16]  1/11 (9.09%)  1 0/9 (0.00%)  0
Renal and urinary disorders     
Renal Disease * 1 [17]  1/11 (9.09%)  1 0/9 (0.00%)  0
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, CTCAE (3.0)
[1]
Pt had arm swelling and ultrasound revealed clot in left PICC line. Pt treated with vancomycin.
[2]
Subject scheduled her for splenectomy. Had no complications.
[3]
Subject complaint of congestion and bloating. ECHO EF%= 20%, a decrease from 45%. Admitted for higher dose deferoxamine, & management. Deferoxamine was increased to 75 mg/kg/day, 7 days per week over 24 hours. Lasix 40 mg IV x 1 was administered.
[4]
Subject complained of palpitations. ECG showed Atrial fibrillation. converting to normal sinus rhythm before started on any medication.
[5]
Subject admitted with CHF. Noted tachycardia to 140s. He was in atrial flutter, then atrial fibrillation. Was not hypotensive w/ no evidence of ventricular arrhythmia. Rx and converted to NSR. This event was possibly related to study drug.
[6]
Distance vision was blurry and was seen by ophthalmology. ERG analysis shows deficits in both scotopic and photopic responses. These were not present on previous ERG. He c/o blurry vision and could not be corrected with glasses.
[7]
5 day history of watery diarrhea. Dx w/ dehydration and syncopal event.
[8]
Nausea & abdominal discomfort occurring while taking deferiprone/placebo. Also reported "muscular type" aches & pains in the upper chest and arms. Severe elevation in liver enzymes was identified.
[9]
Subject c/o stomach discomfort. 05/21 ANC was 1.4 and L1/Placebo was stopped. CBC was done and the ANC was 1.9. Treatment was restarted. An MRI (R2/T2*) was performed to assess liver iron. Summary stopped L1/Placebo, stopped DFO-S, MRI performed.
[10]
Fever of 102 and cellulitis at the insertion site of his central venous catheter. Redness and pus drained from around this insertion site. The subject received nafcillin and Ceftriaxone IV. Desferal infusion continued during this time.
[11]
Subject developed a fever 39.2C PO. Creatinine elevated to 2.2. Study drug held. CT without contrast done, "no obvious signs of meningitis or abcess." Treated w/ doses of Vancomycin and Cefotaxime.
[12]
Subject complained of high grade fever and chills associated with dysuria. Subject presented to the ER and prelim results showed urinary tract infection but was admitted for monitoring due to low blood pressure.
[13]
Subject had been feeling fatigued with episodes of CP. Rx w/ Lasix and aldactone. Subject feeling worse with nausea and vomiting.CT scan showed left lower lobe pneumonia. Started on 10 day course of Levaquin. Discharged in good condition.
[14]
Subject was admitted with cellulitis at the insertion site of his central venous catheter. The subject received vancomycin I.V. & developed Redman's syndrome. The vancomycin was stopped and was given Nafcillin IV.
[15]
Admitted with episode of syncope. His vision became dark and he felt dizzy. He was unable to support himself and fell to the ground hitting the side of his face. He reports that he was conscious throughout.
[16]
Serum potassium =7.5 meq/L and received calcium carbonate infusion, and normal saline bolus. Glucose rose to 635 mg/dL. History of insulin dependent diabetes. Received Lasix & NS bolus were given. Potassium level returned to normal.
[17]
A routine chemistry showed elevated BUN 30mg/dl and creatinine 1.5mg/dl.
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Deferoxamine (DFO) and Deferiprone (L1) Combination Therapy Deferoxamine (DFO) + Monotherapy
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   8/11 (72.73%)      6/9 (66.67%)    
Blood and lymphatic system disorders     
Abnormal LFTs  1  1/11 (9.09%)  1 0/9 (0.00%)  0
Neutropenia * 1  1/11 (9.09%)  2 1/9 (11.11%)  2
Cardiac disorders     
Palpitations with dizziness * 1  1/11 (9.09%)  1 0/9 (0.00%)  0
Heart palpatations  1  0/11 (0.00%)  0 1/9 (11.11%)  1
Gastrointestinal disorders     
Dry mouth * 1  1/11 (9.09%)  1 0/9 (0.00%)  0
Nausea * 1  3/11 (27.27%)  4 0/9 (0.00%)  0
stomach discomfort * 1  0/11 (0.00%)  0 1/9 (11.11%)  1
Abdominal pain * 1  0/11 (0.00%)  0 1/9 (11.11%)  1
Abdominal Bloating * 1  0/11 (0.00%)  0 1/9 (11.11%)  1
General disorders     
Dizziness * 1  2/11 (18.18%)  2 0/9 (0.00%)  0
Fever * 1  2/11 (18.18%)  2 1/9 (11.11%)  1
Low Grade Fever and Sore Throay * 1  1/11 (9.09%)  1 0/9 (0.00%)  0
Nausea and Vomiting * 1  2/11 (18.18%)  2 1/9 (11.11%)  1
Infections and infestations     
Strep Throat * 1  1/11 (9.09%)  1 0/9 (0.00%)  0
Injury, poisoning and procedural complications     
Phlebotic pain at blood infusion * 1  1/11 (9.09%)  1 0/9 (0.00%)  0
Allergic transfusion reactions hives  1  1/11 (9.09%)  1 1/9 (11.11%)  1
tooth ache * 1  1/11 (9.09%)  1 0/9 (0.00%)  0
Ankle pain * 1  0/11 (0.00%)  0 1/9 (11.11%)  1
Musculoskeletal and connective tissue disorders     
Bilerateral Hip Pain  1  1/11 (9.09%)  1 0/9 (0.00%)  0
Myalgia  1  1/11 (9.09%)  1 0/9 (0.00%)  0
Sternocleidomastoid muscle spasm * 1  1/11 (9.09%)  1 0/9 (0.00%)  0
Vomiting * 1  1/11 (9.09%)  1 1/9 (11.11%)  1
Nervous system disorders     
Otitis media * 1  2/11 (18.18%)  2 0/9 (0.00%)  0
Pregnancy, puerperium and perinatal conditions     
Fanconi  1  1/11 (9.09%)  1 0/9 (0.00%)  0
Psychiatric disorders     
Anxiety attack * 1  0/11 (0.00%)  0 1/9 (11.11%)  2
Renal and urinary disorders     
Urinary Tract Infection  1  0/11 (0.00%)  0 1/9 (11.11%)  1
Respiratory, thoracic and mediastinal disorders     
Chest Ache * 1  1/11 (9.09%)  1 0/9 (0.00%)  0
sore throat * 1  1/11 (9.09%)  1 2/9 (22.22%)  2
Upper Respiratory Infection * 1  2/11 (18.18%)  4 0/9 (0.00%)  0
sore throat and cough * 1  1/11 (9.09%)  1 0/9 (0.00%)  0
stomach flu * 1  1/11 (9.09%)  1 0/9 (0.00%)  0
Shortness of Breath/fatigue * 1  0/11 (0.00%)  0 1/9 (11.11%)  1
Cough * 1  0/11 (0.00%)  0 1/9 (11.11%)  1
Skin and subcutaneous tissue disorders     
Epistaxis * 1  1/11 (9.09%)  1 0/9 (0.00%)  0
Social circumstances     
Common Cold * 1  1/11 (9.09%)  2 0/9 (0.00%)  0
Kicked in chest * 1  1/11 (9.09%)  1 0/9 (0.00%)  0
Vascular disorders     
Vertigo  1  2/11 (18.18%)  2 0/9 (0.00%)  0
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, CTCAE (3.0)
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.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: John Porter, MD, Principal Investigator
Organization: UCL Cancer Institute
Phone: +011 (44) 207 679 6224
EMail: j.porter@ucl.ac.uk
Layout table for additonal information
Responsible Party: HealthCore-NERI
ClinicalTrials.gov Identifier: NCT00115349    
Other Study ID Numbers: 181
U01HL065260 ( U.S. NIH Grant/Contract )
U01HL065244 ( U.S. NIH Grant/Contract )
U01HL065239 ( U.S. NIH Grant/Contract )
U01HL065238 ( U.S. NIH Grant/Contract )
U01HL065232 ( U.S. NIH Grant/Contract )
First Submitted: June 21, 2005
First Posted: June 22, 2005
Results First Submitted: May 16, 2013
Results First Posted: January 14, 2014
Last Update Posted: March 1, 2018