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

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ClinicalTrials.gov Identifier: NCT00004412
Recruitment Status : Completed
First Posted : October 19, 1999
Results First Posted : March 31, 2015
Last Update Posted : March 31, 2015
Sponsor:
Collaborators:
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
Information provided by (Responsible Party):
Susan P. Perrine, Boston University

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Skin Ulcers
Sickle Cell Anemia
Interventions Drug: Arginine Butyrate
Other: Standard local care dressing
Enrollment 23
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.
Pre-assignment Details  
Arm/Group Title Standard Local Care Dressing Arginine Butyrate Crossover
Hide 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
Reason Not Completed
Moved to Crossover Period             3             0             0
Period Title: Crossover Period
Started 8 [1] 12 [2] 3 [3]
Completed 8 [4] 12 [5] 3 [6]
Not Completed 0 0 0
[1]
Eight subjects were randomized to Standard of Care dressing Arm
[2]
Twelve patients were randomized to the Arginine Butyrate plus Standard local care dressing Arm
[3]
Three of Randomized Period's Arm I elected to move to Crossover Period's Crossover Arm.
[4]
Eight subjects in this arm completed study without crossing over.
[5]
Twelve subjects in this arm completed the study.
[6]
Three subjects, from Arm I, who crossed- over to Arm II completed the study.
Arm/Group Title Standard Local Care Dressing Arginine Butyrate Crossover Total
Hide 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 Number of Baseline Participants 8 12 3 23
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 8 participants 12 participants 3 participants 23 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
8
 100.0%
12
 100.0%
3
 100.0%
23
 100.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 8 participants 12 participants 3 participants 23 participants
31  (12.57478) 33  (9.14985) 31  (2.3094) 32  (1.1547)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 8 participants 12 participants 3 participants 23 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  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 8 participants 12 participants 3 participants 23 participants
United States 8 12 2 22
Israel 0 0 1 1
1.Primary Outcome
Title Healing Defined as a Decrease in Ulcer Area by at Least 25% of the Initial Area
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol
Arm/Group Title Standard Local Care Dressing Arginine Butyrate
Hide 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.
Overall Number of Participants Analyzed 11 12
Overall Number of Units Analyzed
Type of Units Analyzed: Number of ulcers
25 37
Measure Type: Number
Unit of Measure: percentage of healed ulcers
24 78
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.05
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.5
Estimation Comments [Not Specified]
2.Secondary Outcome
Title % Ulcers Which Completely Healed in Each Group, After 3 Months
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Per Protocol
Arm/Group Title Standard Local Care Dressing Arginine Butyrate
Hide 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.
Overall Number of Participants Analyzed 8 15
Overall Number of Units Analyzed
Type of Units Analyzed: Number of ulcers
25 48
Measure Type: Number
Unit of Measure: percentage of completely healed ulcers
8 31
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Standard Local Care Dressing Arginine Butyrate
Hide 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 (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
Standard Local Care Dressing Arginine Butyrate
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5/11 (45.45%)      9/15 (60.00%)    
Blood and lymphatic system disorders     
Vaso-occlusive crisis (VOC))   4/11 (36.36%)  13 7/15 (46.67%)  9
Cardiac disorders     
Pleural effusion and Pericardial Effusion   0/11 (0.00%)  0 1/15 (6.67%)  1
Chest Pain , SOB   1/11 (9.09%)  1 0/15 (0.00%)  0
Eye disorders     
Head & Eye Pain *  1/11 (9.09%)  1 0/15 (0.00%)  0
Gastrointestinal disorders     
Bloody Diarrhea   1/11 (9.09%)  1 0/15 (0.00%)  0
Infections and infestations     
Septic arthritis *  0/11 (0.00%)  0 1/15 (6.67%)  1
Ulcer Infection *  0/11 (0.00%)  0 1/15 (6.67%)  1
Pre-existing Osteomyelitis of Left Foot   0/11 (0.00%)  0 1/15 (6.67%)  1
Musculoskeletal and connective tissue disorders     
Chronic Limb Pain   0/11 (0.00%)  0 1/15 (6.67%)  1
Skin and subcutaneous tissue disorders     
Possible Celluitis *  0/11 (0.00%)  0 1/15 (6.67%)  1
Vascular disorders     
Thrombosis   0/11 (0.00%)  0 2/15 (13.33%)  2
Clotted Portacath   0/11 (0.00%)  0 1/15 (6.67%)  1
Hypotension   1/11 (9.09%)  1 0/15 (0.00%)  0
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
Standard Local Care Dressing Arginine Butyrate
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/11 (9.09%)      0/15 (0.00%)    
Gastrointestinal disorders     
Nausea   1/11 (9.09%)  1 0/15 (0.00%)  0
Decreased Appetite   1/11 (9.09%)  1 0/15 (0.00%)  0
General disorders     
Headache   1/11 (9.09%)  1 0/15 (0.00%)  0
Indicates events were collected by systematic assessment
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: Douglas V. Faller, Ph.D., M.D., Susan P. Perrine, M.D.
Organization: Boston University School of Medicine
Phone: (617) 638-5639
EMail: sperrine@bu.edu
Layout table for additonal information
Responsible Party: Susan P. Perrine, Boston University
ClinicalTrials.gov Identifier: NCT00004412    
Other Study ID Numbers: 199/13302
BUSM-FDR001376 ( Other Identifier: Food & Drug Administration )
IND 36,957 ( Other Identifier: Food & Drug Administration )
First Submitted: October 18, 1999
First Posted: October 19, 1999
Results First Submitted: July 22, 2013
Results First Posted: March 31, 2015
Last Update Posted: March 31, 2015