Intravenous Allopurinol in Heart Failure

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00181155
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 18
• Location: 1
• Arms: 2
• Duration (Months): 73
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study tests the hypothesis that allopurinol, a xanthine oxidase inhibitor, improves heart metabolism in patients with heart failure.

Condition or Disease	Intervention/Treatment	Phase
Congestive Heart Failure	Drug: Allopurinol; Drug: Placebo	Phase 2

Detailed Description

Xanthine oxidase have been reported to improve mechano-energetic coupling in failing hearts. The investigators developed a means to directly measure creatine kinase flux, the major energy reserve of the heart, in the human heart exploiting new magnetic resonance technologies.

The investigators propose to study 10 healthy subjects and up to 25 with heart failure (dilated cardiomyopathy) before and after a single 300mg IV infusion of allopurinol.

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Effects of Xanthine Oxidase Inhibition on Mechano-Energetic Coupling in Heart Failure
• Study Start Date: Nov 1, 2004
• Actual Primary Completion Date: Dec 1, 2010
• Actual Study Completion Date: Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Allopurinol One time intravenous administration of Allopurinol 300 mg infused over approximately 20 minutes.	Drug: Allopurinol; intravenous infusion of allopurinol (300mg); Other Names: Aloprim
Placebo Comparator: Placebo One time intravenous administration of 50 ml dose of 5% dextrose infused over approximately 20 minutes.	Drug: Placebo; intravenous infusion of 50 ml dose of 5% dextrose; Other Names: 5% Dextrose

Outcome Measures

Primary Outcome Measures

1. Myocardial Creatine Kinase (CK) Flux Pre Intravenous Allopurinol Infusion [Onset of imaging acquisition.]

   Magnetic resonance spectroscopy (MRS) Measurement of Myocardial CK Flux Pre Intravenous Allopurinol Infusion

2. Myocardial CK Flux Post Intravenous Allopurinol Infusion. [acute (within 15 minutes of single infusion)]

   The mean rate of adenosine triphosphate (ATP) flux through the creatine kinase reaction in the heart.

Secondary Outcome Measures

1. Cardiac PCr/ATP Pre Intravenous Infusion [Onset of image acquisition.]

   The mean ratio of creatine phosphate (PCr) to ATP in the heart. This measure, as a ratio, is unitless.

2. Cardiac PCr/ATP Post Intravenous Infusion [acute (within 15 minutes of single infusion)]

   The mean ratio of creatine phosphate (PCr) to ATP in the heart. This measure, as a ratio, is unitless.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age > 18 years

• The patient is willing and able to provide informed consent

• Clinical diagnosis of chronic heart failure

• Ejection fraction (EF) < 40% by echocardiography, nuclear multigated acquisition (MUGA) or cath ventriculography

• No significant coronary disease at cardiac catheterization

• New York Heart Association (NYHA) Class I-IV symptoms

• Clinical stabilization for two weeks if following recent congestive heart failure (CHF) decompensation.

Exclusion Criteria:

• Metallic implant prohibiting magnetic resonance (MR) evaluation

• Inability to lie flat for MR study

• Administration of additional investigational drugs

• Calculated creatinine clearance < 50 mL/min

• Allergy to allopurinol

• Current gout flare

• Currently taking oral allopurinol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287

Sponsors and Collaborators

• Johns Hopkins University
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Robert G Weiss, MD, Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Robert G. Weiss, Professor of Medicine and Radiology, Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT00181155
• Other Study ID Numbers: IRB: 04-10-12-06; 5R01HL061912-14
• First Posted: Sep 16, 2005
• Last Update Posted: May 30, 2017
• Last Verified: Apr 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Robert G. Weiss, Professor of Medicine and Radiology, Johns Hopkins University: metabolism; congestive heart failure; allopurinol; Adenosine triphosphate (ATP)
• Additional relevant MeSH terms: Heart Failure; Allopurinol

Study Results

Participant Flow

Recruitment Details	Participants with Non-Ischemic Cardiomyopathy were recruited as approved by the Johns Hopkins Institutional Review Board for Human Investigation.
Pre-assignment Detail	The study drug allocation was randomized in a 4:1 fashion by the research pharmacy. Participants were randomized to Placebo only for the purposes of blinding; Adverse Events were collected for the Placebo arm.

Arm/Group Title	Allopurinol	Placebo
Arm/Group Description	Each participant underwent magnetic resonance spectroscopy before and following infusion of either allopurinol 300mg or placebo.	Each participant underwent magnetic resonance spectroscopy before and following infusion of either allopurinol 300mg or placebo.
Period Title: Overall Study
STARTED	15	3
COMPLETED	13	3
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	Intravenous Allopurinol
Arm/Group Description	We randomized patients with nonischemic cardiomyopathy in a double-blind fashion to allopurinol (300 mg intravenously) or placebo infusion, 4-to-1, the latter for purposes of blinding only. The myocardial concentrations of ATP and creatine phosphate (PCr) and the rate of adenosine triphosphate (ATP) synthesis through CK (CK flux) were determined by 31-Phosphorus (31P) magnetic resonance spectroscopy.
Overall Participants	13
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	13 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.8 (12.9)
Sex: Female, Male (Count of Participants)
Female	4 30.8%
Male	9 69.2%
Region of Enrollment (participants) [Number]
United States	13 100%

Outcome Measures

1. Primary Outcome

Title	Myocardial Creatine Kinase (CK) Flux Pre Intravenous Allopurinol Infusion
Description	Magnetic resonance spectroscopy (MRS) Measurement of Myocardial CK Flux Pre Intravenous Allopurinol Infusion
Time Frame	Onset of imaging acquisition.

Outcome Measure Data

Analysis Population Description

Data were analyzed for all participants who completed the MRS per protocol.

Arm/Group Title	Baseline
Arm/Group Description	Each participant underwent baseline MRS imaging prior to infusion of Aloprim 300 mg in 50 cc of 5% Dextrose.
Measure Participants	13
Mean (Standard Deviation) [umol/g/sec]	2.07 (1.27)

2. Secondary Outcome

Title	Cardiac PCr/ATP Pre Intravenous Infusion
Description	The mean ratio of creatine phosphate (PCr) to ATP in the heart. This measure, as a ratio, is unitless.
Time Frame	Onset of image acquisition.

Outcome Measure Data

Analysis Population Description

Data were analyzed for all participants who completed the MRS per protocol.

Arm/Group Title	Baseline
Arm/Group Description	Each participant underwent baseline MRS imaging prior to infusion of Aloprim 300 mg in 50 cc of 5% Dextrose.
Measure Participants	13
Mean (Standard Deviation) [ratio]	1.58 (0.41)

3. Primary Outcome

Title	Myocardial CK Flux Post Intravenous Allopurinol Infusion.
Description	The mean rate of adenosine triphosphate (ATP) flux through the creatine kinase reaction in the heart.
Time Frame	acute (within 15 minutes of single infusion)

Outcome Measure Data

Analysis Population Description

Data were analyzed for all participants who completed the MRS per protocol.

Arm/Group Title	Intravenous Allopurinol
Arm/Group Description	Infused Aloprim 300 mg in 50cc 5% dextrose. Post MRS data acquired on each subject.
Measure Participants	13
Mean (Standard Deviation) [umol/g/sec]	2.87 (1.82)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Baseline
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.007
	Comments	vs. baseline
	Method	Two-sided paired t tests
	Comments

4. Secondary Outcome

Title	Cardiac PCr/ATP Post Intravenous Infusion
Description	The mean ratio of creatine phosphate (PCr) to ATP in the heart. This measure, as a ratio, is unitless.
Time Frame	acute (within 15 minutes of single infusion)

Outcome Measure Data

Analysis Population Description

Data were analyzed for all participants who completed the MRS per protocol.

Arm/Group Title	Intravenous Allopurinol
Arm/Group Description	Infused Aloprim 300 mg in 50cc of 5% dextrose. Post infusion MRS data acquired on each subject.
Measure Participants	13
Mean (Standard Deviation) [ratio]	1.75 (0.59)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Baseline
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.02
	Comments	vs. baseline
	Method	Two-sided paired t tests
	Comments

Adverse Events

Arm/Group Title	Arm 1 - Intravenous Allopurinol		Arm 2 - Placebo
Arm/Group Description	Each participant received pre and post MRS images following infusion of 50 cc of Aloprim 300mg in 5% Dextrose.		Each participant received pre and post MRS images following infusion of 50 cc of 5% Dextrose (equivalent volume to active treatment arm).
All Cause Mortality
	Arm 1 - Intravenous Allopurinol		Arm 2 - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm 1 - Intravenous Allopurinol		Arm 2 - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/3 (0%)
Other (Not Including Serious) Adverse Events
	Arm 1 - Intravenous Allopurinol		Arm 2 - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/3 (0%)

Limitations/Caveats

The limitations of the current study include the small placebo group sample size and the etiologic heterogeneity of the nonischemic cardiomyopathy group.

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.