Phase II Randomized Trial:Arginine Butyrate Plus Standard Local Therapy in Patients With Refractory Sickle Cell Ulcers

• Sponsor: Susan P. Perrine (Other)
• Overall Status: Completed
• CT.gov ID: NCT00004412
• Collaborator: Boston Medical Center (Other), University of Illinois at Chicago (Other), Icahn School of Medicine at Mount Sinai (Other), University of Tennessee Health Science Center (Other), Schneider Children's Medical Center, Israel (Other)
• Enrollment: 23
• Locations: 4
• Arms: 3
• Duration (Months): 89
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

OBJECTIVES: I. Compare the efficacy of local care alone vs local care plus arginine butyrate in terms of healing rate in patients with refractory sickle cell ulcers.

1. Determine the effect of arginine butyrate therapy on tissue factors related to promotion or inhibition of wound healing in these patients.

2. Determine whether the regimen used in this study is appropriate for testing in pivotal trials.

Condition or Disease	Intervention/Treatment	Phase
Skin Ulcers; Sickle Cell Anemia	Drug: Arginine Butyrate; Other: Standard local care dressing	Phase 2

Detailed Description

PROTOCOL OUTLINE: This is a randomized, multicenter study. Patients are randomized to one of two treatment arms. Arm I: Patients receive arginine butyrate IV over 6-9 hours at night 5 days a week for 12 weeks, plus concurrent standard local therapy consisting of cleaning, saline irrigation, and dressing changes as prescribed by each patient's physician. Patients who experience progressive healing receive arginine butyrate 3-4 times a week. Arginine butyrate treatment may be discontinued and reinstated following a single 2 week medical complication.

Arm II: Patients receive standard local therapy alone for 12 weeks. Patients randomized to arm II may cross over to receive arginine butyrate if no or less than 25% healing is observed after 12 weeks.

Patients whose ulcers have closed by at least 15% per cycle may receive 2 additional 8-week cycles of arginine butyrate therapy and are followed for 2 months after healing is completed.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Arginine Butyrate for Treatment of Refractory Leg Ulcers in Sickle Cell Disease or Beta Thalassemia
• Study Start Date: Sep 1, 1997
• Actual Primary Completion Date: Dec 1, 2002
• Actual Study Completion Date: Feb 1, 2005

Arms and Interventions

Arm	Intervention/Treatment
Other: Standard local care dressing Each subject provided his/her own dressing e.g,standard local care includes cleaning, saline irrigation, dressing changes only for 8 weeks twice a week.	Other: Standard local care dressing; To heal leg ulcers.
Experimental: Arginine Butyrate Arginine Butyrate IV plus Standard local care dressing for a total of 12 weeks. Low dose 500 mg/kg or, increased dose 750 mg/kg. First week AB given 5 days in a row, over 6 to 12hours.	Drug: Arginine Butyrate; To determine if Arginine Butyrate accelerates healing of refractory leg ulcers over Standard Local Care alone.; Other: Standard local care dressing; To heal leg ulcers.
Other: Crossover Patients are randomly assigned (following a table of random numbers prepared by a blinded statistician) between two arms of the study. Arm I is Standard local care dressing only, and Arm II is standard local care plus Arginine Butyrate (AB), the Investigational New Drug. Ulcers observed & traced weekly. Ulcer area calculated by computerized planimetry. After 12 weeks of therapy, if the ulcer size decreased by at least 25%, the AB may be continued for another 8 weeks (twice), or until the ulcer closes, plus an additional 2 weeks. The patients randomized to the Control Arm (standard local care) were given the option of crossing over to Arm II If, ulcers did not close after 8 weeks of standard local care.	Drug: Arginine Butyrate; To determine if Arginine Butyrate accelerates healing of refractory leg ulcers over Standard Local Care alone.; Other: Standard local care dressing; To heal leg ulcers.

Outcome Measures

Primary Outcome Measures

1. Healing Defined as a Decrease in Ulcer Area by at Least 25% of the Initial Area [participants were followed for an average of 3 months]

   Treatment Arm: The AB is given as an IV infusion at 500 mg/kg over 6-9 hrs. 5 days per week for 12 weeks. After 12 weeks of therapy, if he ulcer has decreased by 25% , the AB may be continued for additional 8 weeks (twice) or, until ulcer closes plus 2 weeks, additionally. Ulcers photographed, traced, and ulcer areas calculated by computerized planimetry.

Secondary Outcome Measures

1. % Ulcers Which Completely Healed in Each Group, After 3 Months [two additional courses of 8 week cycles]

   Control Arm: given option to crossover to Treatment Arm if, ulcers have not closed after 12 weeks standard local care alone.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

PROTOCOL CRITERIA

INCLUSION:

--Disease Characteristics-- Significant sickle cell syndrome including Hemoglobin SS (HbSS), Hemoglobin S-beta thalassemia, and hemoglobin variants. Lower extremity or ankle ulcer (or ulcers) present for at least 6 months without healing --Patient Characteristics-- Age: 16-60 yrs Performance status: Not specified Hematopoietic: Not specified Hepatic: No hepatic compromise Transaminases no greater than 250 IU Renal: No renal compromise Creatinine no greater than 1.2 mg/mL (adults) Creatinine no greater than 0.9 mg/mL (teenagers) Other: Not pregnant Fertile patients must use effective contraception No poorly controlled seizure disorders No other secondary conditions that might inhibit immune function

• Prior/Concurrent Therapy Other: Must be treated with antibiotics prior to entry for complicating cellulitis or secondary infections

EXCLUSION :

--Prior/Concurrent Therapy-- Biologic therapy: chronic transfusion therapy Chemotherapy: prior or concurrent cancer chemotherapy concurrent butyrate derivatives Endocrine therapy: concurrent corticosteroid therapy Radiotherapy: Not specified Surgery: Not specified --Patient Characteristics-- Hepatic: hepatic compromise Transaminases greater than 250 IU Renal: renal compromise Creatinine greater than 1.2 mg/mL (adults) Creatinine greater than 0.9 mg/mL (teenagers) Other: pregnant; Fertile patients with no effective contraception Poorly controlled seizure disorders other secondary conditions that might inhibit immune function

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Illinois College of Medicine	Chicago	Illinois	United States	60612
2	Boston University School of Medicine	Boston	Massachusetts	United States	02118
3	Mount Sinai School of Medicine	New York	New York	United States	10029
4	University of Tennessee, Memphis Cancer Center	Memphis	Tennessee	United States	38103

Sponsors and Collaborators

• Susan P. Perrine
• Boston Medical Center
• University of Illinois at Chicago
• Icahn School of Medicine at Mount Sinai
• University of Tennessee Health Science Center
• Schneider Children's Medical Center, Israel

Investigators

• Study Chair: Douglas V. Faller, Boston University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Susan P. Perrine, Susan P. Perrine MD, Professor, Boston University School of Medicine, Boston University
• ClinicalTrials.gov Identifier: NCT00004412
• Other Study ID Numbers: 199/13302; BUSM-FDR001376; IND 36,957
• First Posted: Oct 19, 1999
• Last Update Posted: Mar 31, 2015
• Last Verified: Mar 1, 2015

• Keywords provided by Susan P. Perrine, Susan P. Perrine MD, Professor, Boston University School of Medicine, Boston University: dermatologic disorders; genetic diseases and dysmorphic syndromes; hematologic disorders; rare disease; sickle cell anemia; skin ulcers; thalassemia major
• Additional relevant MeSH terms: Anemia, Sickle Cell; Skin Ulcer; Ulcer; Arginine butyrate

Study Results

Participant Flow

Recruitment Details	Study began 1998, contacted physicians at several medical centers with patients under their care for SCD with refractory leg ulcers. Electronic materials describing the study and its sponsor were transmitted to medical centers.

Arm/Group Title	Standard Local Care Dressing	Arginine Butyrate	Crossover
Arm/Group Description	Standard local care includng cleaning, saline irrigation, dressing changes only for 8 weeks twice a week.	Arginine Butyrate IV plus Standard local care dressing for a total of 12 weeks. Low dose 250 mg/kg or, increased dose 750 mg/kg. First week AB given 5 days in a row, over 8 to 12hours.	Patients are randomly assigned (following a table of random numbers prepared by a blinded statistician) between two arms of the study. Arm I is Allevyn Hydrophilic PU dressing (standard local care) only, and Arm II is standard local care plus Arginine Butyrate (AB), the Investigational New Drug. Ulcers observed & traced weekly. Ulcer area calculated by computerized planimetry. After 12 weeks of therapy, if the ulcer size decreased by at least 25%, the AB may be continued for another 8 weeks (twice), or until the ulcer closes, plus an additional 2 weeks. The patients randomized to the Control Arm ( standard local care) were given the option of crossing over to Arm II If, ulcers did not close after 8 weeks of standard local care.
Period Title: Randomized Period
STARTED	11	12	0
COMPLETED	8	12	0
NOT COMPLETED	3	0	0
Period Title: Randomized Period
STARTED	8	12	3
COMPLETED	8	12	3
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Standard Local Care Dressing	Arginine Butyrate	Crossover	Total
Arm/Group Description	Standard local care dressing including cleaning, saline irrigation, dressing changes only for 8 weeks twice a week.	Arginine Butyrate IV plus Standard local care dressing for a total of 12 weeks. Low dose 250 mg/kg or, increased dose 750 mg/kg. First week AB given 5 days in a row, over 8 to 12hours.	Patients are randomly assigned (following a table of random numbers prepared by a blinded statistician) between two arms of the study. Arm I is Standard local care dressing only, and Arm II is standard local care plus Arginine Butyrate (AB), the Investigational New Drug. Ulcers observed & traced weekly. Ulcer area calculated by computerized planimetry. After 12 weeks of therapy, if the ulcer size decreased by at least 25%, the AB may be continued for another 8 weeks (twice), or until the ulcer closes, plus an additional 2 weeks. The patients randomized to the Control Arm ( standard local care) were given the option of crossing over to Arm II If, ulcers did not close after 8 weeks of standard local care.	Total of all reporting groups
Overall Participants	8	12	3	23
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	8 100%	12 100%	3 100%	23 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31 (12.57478)	33 (9.14985)	31 (2.3094)	32 (1.1547)
Sex: Female, Male (Count of Participants)
Female	5 62.5%	5 41.7%	1 33.3%	11 47.8%
Male	3 37.5%	7 58.3%	2 66.7%	12 52.2%
Region of Enrollment (participants) [Number]
United States	8 100%	12 100%	2 66.7%	22 95.7%
Israel	0 0%	0 0%	1 33.3%	1 4.3%

Outcome Measures

1. Primary Outcome

Title	Healing Defined as a Decrease in Ulcer Area by at Least 25% of the Initial Area
Description	Treatment Arm: The AB is given as an IV infusion at 500 mg/kg over 6-9 hrs. 5 days per week for 12 weeks. After 12 weeks of therapy, if he ulcer has decreased by 25% , the AB may be continued for additional 8 weeks (twice) or, until ulcer closes plus 2 weeks, additionally. Ulcers photographed, traced, and ulcer areas calculated by computerized planimetry.
Time Frame	participants were followed for an average of 3 months

Outcome Measure Data

Analysis Population Description

Per protocol

Arm/Group Title	Standard Local Care Dressing	Arginine Butyrate
Arm/Group Description	Standard local care includng cleaning, saline irrigation, dressing changes only for 8 weeks twice a week.	Arginine Butyrate IV plus Standard local care dressing for a total of 12 weeks. Low dose 250 mg/kg or, increased dose 750 mg/kg. First week AB given 5 days in a row, over 8 to 12hours.
Measure Participants	11	12
Measure number of ulcers	25	37
Number [percentage of healed ulcers]	24	78

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Standard Local Care Dressing, Arginine Butyrate
	Comments	Percentage of ulcers undergoing partial and complete healing compared at 12 weeks. Mean Ulcer areas were calculated utilizing computerized planimetry, ulcer area tracings, and photography for baseline and 12 weeks and compared between the two study Arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.5
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	% Ulcers Which Completely Healed in Each Group, After 3 Months
Description	Control Arm: given option to crossover to Treatment Arm if, ulcers have not closed after 12 weeks standard local care alone.
Time Frame	two additional courses of 8 week cycles

Outcome Measure Data

Analysis Population Description

Per Protocol

Arm/Group Title	Standard Local Care Dressing	Arginine Butyrate
Arm/Group Description	Standard local care includng cleaning, saline irrigation, dressing changes only for 8 weeks twice a week.	Arginine Butyrate IV plus Standard local care dressing for a total of 12 weeks. Low dose 250 mg/kg or, increased dose 750 mg/kg. First week AB given 5 days in a row, over 8 to 12hours.
Measure Participants	8	15
Measure Number of ulcers	25	48
Number [percentage of completely healed ulcers]	8	31

Adverse Events

Arm/Group Title	Standard Local Care Dressing		Arginine Butyrate
Arm/Group Description	Standard local care including cleaning, saline irrigation, dressing changes only for 8 weeks twice a week.		Arginine Butyrate IV plus Standard local care dressing for a total of 12 weeks. Low dose 250 mg/kg or, increased dose 750 mg/kg. First week AB given 5 days in a row, over 8 to 12hours.
All Cause Mortality
	Standard Local Care Dressing		Arginine Butyrate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Standard Local Care Dressing		Arginine Butyrate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/11 (45.5%)		9/15 (60%)
Blood and lymphatic system disorders
Vaso-occlusive crisis (VOC))	4/11 (36.4%)	13	7/15 (46.7%)	9
Cardiac disorders
Pleural effusion and Pericardial Effusion	0/11 (0%)	0	1/15 (6.7%)	1
Chest Pain , SOB	1/11 (9.1%)	1	0/15 (0%)	0
Eye disorders
Head & Eye Pain	1/11 (9.1%)	1	0/15 (0%)	0
Gastrointestinal disorders
Bloody Diarrhea	1/11 (9.1%)	1	0/15 (0%)	0
Infections and infestations
Septic arthritis	0/11 (0%)	0	1/15 (6.7%)	1
Ulcer Infection	0/11 (0%)	0	1/15 (6.7%)	1
Pre-existing Osteomyelitis of Left Foot	0/11 (0%)	0	1/15 (6.7%)	1
Musculoskeletal and connective tissue disorders
Chronic Limb Pain	0/11 (0%)	0	1/15 (6.7%)	1
Skin and subcutaneous tissue disorders
Possible Celluitis	0/11 (0%)	0	1/15 (6.7%)	1
Vascular disorders
Thrombosis	0/11 (0%)	0	2/15 (13.3%)	2
Clotted Portacath	0/11 (0%)	0	1/15 (6.7%)	1
Hypotension	1/11 (9.1%)	1	0/15 (0%)	0
Other (Not Including Serious) Adverse Events
	Standard Local Care Dressing		Arginine Butyrate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/11 (9.1%)		0/15 (0%)
Gastrointestinal disorders
Nausea	1/11 (9.1%)	1	0/15 (0%)	0
Decreased Appetite	1/11 (9.1%)	1	0/15 (0%)	0
General disorders
Headache	1/11 (9.1%)	1	0/15 (0%)	0

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.