Efficacy of the Combination of Isosorbide Dinitrate Spray and Chitosan in Diabetic Foot Ulcers

• Sponsor: University of Guadalajara (Other)
• Overall Status: Completed
• CT.gov ID: NCT02789033
• Collaborator: (none)
• Enrollment: 68
• Arms: 3
• Duration (Months): 2

Study Details

Study Description

Brief Summary

The prevalence of diabetic foot ulceration in the diabetic population is 4-10%; the condition is more frequent in elder patients. It is estimated that about 5% of all patients with diabetes present a history of foot ulceration, while the lifetime risk of diabetic patients developing this complication is 15%. The majority (60-80%) of foot ulcers will heal, while 10-15% of them will remain active, and 5-24% of them will finally lead to limb amputation within a period of 6-18 months after the first evaluation , 2 out of 3 patients with a limb amputation could also be involved in a new amputation in the next year; higher or in the other leg , Eighty-five percent of lower-limb amputations in patients with diabetes are preceded by foot ulceration. The management of chronic diabetic foot ulcers (DFU) suggests multi-disciplinary approaches including control of diabetes, orthotic shoe wear, off-loading device, wound care and surgery in selected cases. However, treatment of DFU remains challenging because of unsatisfactory results from surgical and non-surgical treatments. Many adjunctive therapies are designed to improve the care of DFU including negative pressure wound therapy , ultrasound, recombinant human platelet-derived growth factor-BB (rPDGF-BB) Hyperbaric oxygen and acellular matrix product among others.

Condition or Disease	Intervention/Treatment	Phase
Diabetic Foot Ulcers	Drug: Chitosan; Drug: Isosorbide dinitrate; Drug: Placebo	Phase 3

Detailed Description

A randomized, placebo controlled, double-blind Clinical trial was designed. 60 Patients with diabetic foot ulcers in grade I and II of the classification of Wagner, with leg arm index> 0.8 and without specific treatment for foot ulcers referred to the experimental and clinical Therapeutic Institute will be included. All patients give written informed consent; previously the protocol was approved for the bioethics committee of the CUCS, of the Guadalajara University, registration number 030-2010. Patients with another type of topical medication will be excluded. Isosorbide dinitrate spray (2.5 mg).

Preparation of chitosan Hydrogels: The composition of gel formulation will be given prior training. ISDN and chitosan gel will be applied handled under aseptic conditions to the wound, and covered with sterile bandages. The patients will be evaluated every 2 weeks (macroscopic study and measurement of the ulcerated area) until 6 views. A second biopsy will be done one week before the finalization of the treatment of 15 weeks. The biopsies will be embedded on paraformaldehyde (4%) and paraffin. Sections of 5 µm were analyzed by a pathologist to determine hypertrophic and hyperplasic capillaries, inflammation and cellular matrix using Hematoxylin & eosin and Masson's trichrome stains. An immunohistochemical stain was also realized to evaluate several molecular markers such as α-SMA (abcam, Cambridge, MA), Desmin (abcam, Cambridge, MA), VEGF (abcam, Cambridge, MA) and Von Willebrand Factor (Chemicon, CA). (figure 1) Statistical analysis: It will be done using SPSS program for Windows Version 10.0, the results of quantitative variables were expressed in average and standard deviation. The differences between baseline and subsequent pharmacologic intervention measurements will be investigated with the Wilcoxon test. The Mann Whitney U test will be used to compare groups. Frequencies by categories as well as percentages will be quantified for qualitative variables. Comparisons between groups were performed with Chi2. For all comparisons p < 0.05 will be considered as significant.

Study Design

• Study Type: Interventional
• Actual Enrollment: 68 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Efficacy of the Combination of Isosorbide Dinitrate Spray and Chitosan in Diabetic Foot Ulcers
• Study Start Date: Jun 1, 2015
• Actual Primary Completion Date: Aug 1, 2015
• Actual Study Completion Date: Aug 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Chitosan Chitosan chemically is a high-molecular-weight linear polycationic heteropolysaccharide comprising copolymers of 1,4-linked D-glucosamine and N-acetyl-D-glucosamine	Drug: Chitosan; Chitosan chemically is a high-molecular-weight linear polycationic heteropolysaccharide comprising copolymers of 1,4-linked D-glucosamine and N-acetyl-D-glucosamine; Other Names: polymers ; Drug: Isosorbide dinitrate; Isosorbide dinitrate (ISDN), is an organic nitrate, is a vasodilator with effects on both arteries and veins. The chemical name of ISDN is 1,4:3,6-dianhydro-D-glucitol 2,5-dinitrate; Other Names: organic nitrate
Active Comparator: Isosorbide dinitrate spray Isosorbide dinitrate spray (2.5 mg) is an organic nitrate, is a vasodilator with effects on both arteries and veins. The chemical name of ISDN is 1,4:3,6-dianhydro-D-glucitol 2,5-dinitrate.	Drug: Chitosan; Chitosan chemically is a high-molecular-weight linear polycationic heteropolysaccharide comprising copolymers of 1,4-linked D-glucosamine and N-acetyl-D-glucosamine; Other Names: polymers ; Drug: Isosorbide dinitrate; Isosorbide dinitrate (ISDN), is an organic nitrate, is a vasodilator with effects on both arteries and veins. The chemical name of ISDN is 1,4:3,6-dianhydro-D-glucitol 2,5-dinitrate; Other Names: organic nitrate
Placebo Comparator: Placebo Placebo in the same pharmacological presentation	Drug: Placebo; placebo; Other Names: Magnessium Calcuim

Outcome Measures

Primary Outcome Measures

1. Biopsies [75 days]

   Histological changes in ulcers

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Patients with diabetic foot ulcers in grade I and II of the classification of Wagner

• with leg arm index> 0.8 and

• without specific treatment for foot ulcers referred to the experimental and clinical

Exclusion Criteria:

• Patients with another type of topical medication

• patients with diabetic foot ulcers in grade III and

• with leg arm index <0.8

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• University of Guadalajara

Investigators

• Principal Investigator: Leonel Garcia, PhD, University of Guadalajara

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• The outcome of management of diabetic foot ulceration (DFU) is poor and insufficient. DFU therapy includes the standard management as debridement of the wound, revascularization procedures,off-loading of the ulcer and antibacterial actions,

Publications

• Alexiadou K, Doupis J. Management of diabetic foot ulcers. Diabetes Ther. 2012 Nov;3(1):4. doi: 10.1007/s13300-012-0004-9. Epub 2012 Apr 20.
• Andrews KL, Irvine JC, Tare M, Apostolopoulos J, Favaloro JL, Triggle CR, Kemp-Harper BK. A role for nitroxyl (HNO) as an endothelium-derived relaxing and hyperpolarizing factor in resistance arteries. Br J Pharmacol. 2009 Jun;157(4):540-50. doi: 10.1111/j.1476-5381.2009.00150.x. Epub 2009 Mar 26.
• Chabbert-Buffet N, LeDevehat C, Khodabandhelou T, Allaire E, Gaitz JP, Tribout L, Abdoucheli-Baudot N, Vayssairat M. Evidence for associated cutaneous microangiopathy in diabetic patients with neuropathic foot ulceration. Diabetes Care. 2003 Mar;26(3):960-1.
• Girach A, Manner D, Porta M. Diabetic microvascular complications: can patients at risk be identified? A review. Int J Clin Pract. 2006 Nov;60(11):1471-83. Review.
• Raafat D, von Bargen K, Haas A, Sahl HG. Insights into the mode of action of chitosan as an antibacterial compound. Appl Environ Microbiol. 2008 Jun;74(12):3764-73. doi: 10.1128/AEM.00453-08. Epub 2008 May 2. Erratum in: Appl Environ Microbiol. 2008 Dec;74(23):7455.
• Reiber GE, Lipsky BA, Gibbons GW. The burden of diabetic foot ulcers. Am J Surg. 1998 Aug;176(2A Suppl):5S-10S. Review.
• Richards AM, Floyd DC, Terenghi G, McGrouther DA. Cellular changes in denervated tissue during wound healing in a rat model. Br J Dermatol. 1999 Jun;140(6):1093-9.
• Schäffer MR, Tantry U, Efron PA, Ahrendt GM, Thornton FJ, Barbul A. Diabetes-impaired healing and reduced wound nitric oxide synthesis: a possible pathophysiologic correlation. Surgery. 1997 May;121(5):513-9.
• Sezer AD, Cevher E, Hatipoğlu F, Oğurtan Z, Baş AL, Akbuğa J. Preparation of fucoidan-chitosan hydrogel and its application as burn healing accelerator on rabbits. Biol Pharm Bull. 2008 Dec;31(12):2326-33.
• Tiaka EK, Papanas N, Manolakis AC, Maltezos E. The role of hyperbaric oxygen in the treatment of diabetic foot ulcers. Angiology. 2012 May;63(4):302-14. doi: 10.1177/0003319711416804. Epub 2011 Aug 25. Review.
• Xie X, McGregor M, Dendukuri N. The clinical effectiveness of negative pressure wound therapy: a systematic review. J Wound Care. 2010 Nov;19(11):490-5. Review. Erratum in: J Wound Care. 2011 Feb;20(2):89.

• Responsible Party: Leonel Garcia Benavides, Professor researcher, University of Guadalajara
• ClinicalTrials.gov Identifier: NCT02789033
• Other Study ID Numbers: 030-2010
• First Posted: Jun 2, 2016
• Last Update Posted: Jan 12, 2021
• Last Verified: Dec 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Leonel Garcia Benavides, Professor researcher, University of Guadalajara: diabetic foot ulcers; chitosan; isosorbide dinitrate spray
• Additional relevant MeSH terms: Diabetic Foot; Foot Ulcer; Ulcer; Isosorbide; Isosorbide Dinitrate; Isosorbide-5-mononitrate; Chitosan

Study Results

Participant Flow

Pre-assignment Detail	ADDITIONAL PARTICIPANTS WERE INCLUDED ANTICIPATING PARTICIPANTS WHO DO NOT COMPLETE THE CLINICAL TRIAL

Arm/Group Title	Active Comparator: Chitosan	Active Comparator: Isosorbide Dinitrate Spray	Combination: IDS and Chitosan	Placebo Comparator: Placebo
Arm/Group Description	Chitosan chemically is a high-molecular-weight linear polycationic heteropolysaccharide comprising copolymers of 1,4-linked D-glucosamine and N-acetyl-D-glucosamine And Placebo in the same pharmacological presentation that Isosorbide dinitrate spray	Isosorbide dinitrate spray (2.5 mg) is an organic nitrate, is a vasodilator with effects on both arteries and veins. The chemical name of ISDN is 1,4:3,6-dianhydro-D-glucitol 2,5-dinitrate. And Placebo in the same pharmacological presentation that Chitosan	Isosorbide dinitrate spray (2.5 mg) is an organic nitrate, is a vasodilator with effects on both arteries and veins. The chemical name of ISDN is 1,4:3,6-dianhydro-D-glucitol 2,5-dinitrate. And Chitosan chemically is a high-molecular-weight linear polycationic heteropolysaccharide comprising copolymers of 1,4-linked D-glucosamine and N-acetyl-D-glucosamine	Placebo in the same pharmacological presentation that both, IDS and Chitosan.
Period Title: Overall Study
STARTED	17	17	17	17
COMPLETED	15	15	16	15
NOT COMPLETED	2	2	1	2

Baseline Characteristics

Arm/Group Title	Active Comparator: Chitosan	Active Comparator: Isosorbide Dinitrate Spray	Combination: IDS and Chitosan	Placebo Comparator: Placebo	Total
Arm/Group Description	Chitosan chemically is a high-molecular-weight linear polycationic heteropolysaccharide comprising copolymers of 1,4-linked D-glucosamine and N-acetyl-D-glucosamine And Placebo in the same pharmacological presentation that Isosorbide dinitrate spray	Isosorbide dinitrate spray (2.5 mg) is an organic nitrate, is a vasodilator with effects on both arteries and veins. The chemical name of ISDN is 1,4:3,6-dianhydro-D-glucitol 2,5-dinitrate. And Placebo in the same pharmacological presentation that Chitosan	Isosorbide dinitrate spray (2.5 mg) is an organic nitrate, is a vasodilator with effects on both arteries and veins. The chemical name of ISDN is 1,4:3,6-dianhydro-D-glucitol 2,5-dinitrate. And Chitosan chemically is a high-molecular-weight linear polycationic heteropolysaccharide comprising copolymers of 1,4-linked D-glucosamine and N-acetyl-D-glucosamine	Placebo in the same pharmacological presentation that both, IDS and Chitosan.	Total of all reporting groups
Overall Participants	17	17	17	17	68
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	17 100%	17 100%	17 100%	17 100%	68 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	8 47.1%	8 47.1%	8 47.1%	8 47.1%	32 47.1%
Male	9 52.9%	9 52.9%	9 52.9%	9 52.9%	36 52.9%
Diameter of the ulcer (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	10.5 (5.8)	12.1 (7.0)	11.4 (8.2)	15.8 (9.3)	12.3 (7.5)

Outcome Measures

1. Primary Outcome

Title	Biopsies
Description	Histological changes in ulcers
Time Frame	75 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Comparator: Chitosan	Active Comparator: Isosorbide Dinitrate Spray	Combination: IDS and Chitosan	Placebo Comparator: Placebo
Arm/Group Description	Chitosan chemically is a high-molecular-weight linear polycationic heteropolysaccharide comprising copolymers of 1,4-linked D-glucosamine and N-acetyl-D-glucosamine And Placebo in the same pharmacological presentation that Isosorbide dinitrate spray	Isosorbide dinitrate spray (2.5 mg) is an organic nitrate, is a vasodilator with effects on both arteries and veins. The chemical name of ISDN is 1,4:3,6-dianhydro-D-glucitol 2,5-dinitrate. And Placebo in the same pharmacological presentation that Chitosan	Isosorbide dinitrate spray (2.5 mg) is an organic nitrate, is a vasodilator with effects on both arteries and veins. The chemical name of ISDN is 1,4:3,6-dianhydro-D-glucitol 2,5-dinitrate. And Chitosan chemically is a high-molecular-weight linear polycationic heteropolysaccharide comprising copolymers of 1,4-linked D-glucosamine and N-acetyl-D-glucosamine	Placebo in the same pharmacological presentation that both, IDS and Chitosan.
Measure Participants	15	15	16	15
α-smooth muscle actin	2.46 (0.6)	2.64 (0.6)	2.56 (0.6)	2.07 (0.6)
Von Willebrand Factor	2.38 (0.65)	2.28 (0.82)	2.31 (0.8)	2.15 (0.5)
vascular endothelial growth factor-A	2.23 (0.8)	2.6 (0.6)	2.43 (0.6)	2.07 (0.7)
desmin	2.3 (0.8)	2.5 (0.6)	2.6 (0.6)	2.3 (0.6)

Adverse Events

Time Frame	3 months
Adverse Event Reporting Description	Chitosan and isosorbide dinitrate are widely used substances, in addition they were used in regular doses for a short period of time, locally.
Arm/Group Title	Active Comparator: Chitosan		Active Comparator: Isosorbide Dinitrate Spray		Combination: IDS and Chitosan		Placebo Comparator: Placebo
Arm/Group Description	Chitosan chemically is a high-molecular-weight linear polycationic heteropolysaccharide comprising copolymers of 1,4-linked D-glucosamine and N-acetyl-D-glucosamine And Placebo in the same pharmacological presentation that Isosorbide dinitrate spray		Isosorbide dinitrate spray (2.5 mg) is an organic nitrate, is a vasodilator with effects on both arteries and veins. The chemical name of ISDN is 1,4:3,6-dianhydro-D-glucitol 2,5-dinitrate. And Placebo in the same pharmacological presentation that Chitosan		Isosorbide dinitrate spray (2.5 mg) is an organic nitrate, is a vasodilator with effects on both arteries and veins. The chemical name of ISDN is 1,4:3,6-dianhydro-D-glucitol 2,5-dinitrate. And Chitosan chemically is a high-molecular-weight linear polycationic heteropolysaccharide comprising copolymers of 1,4-linked D-glucosamine and N-acetyl-D-glucosamine		Placebo in the same pharmacological presentation that both, IDS and Chitosan.
All Cause Mortality
	Active Comparator: Chitosan		Active Comparator: Isosorbide Dinitrate Spray		Combination: IDS and Chitosan		Placebo Comparator: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/17 (0%)		0/17 (0%)		0/17 (0%)
Serious Adverse Events
	Active Comparator: Chitosan		Active Comparator: Isosorbide Dinitrate Spray		Combination: IDS and Chitosan		Placebo Comparator: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/17 (0%)		0/17 (0%)		0/17 (0%)
Other (Not Including Serious) Adverse Events
	Active Comparator: Chitosan		Active Comparator: Isosorbide Dinitrate Spray		Combination: IDS and Chitosan		Placebo Comparator: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/17 (0%)		0/17 (0%)		0/17 (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.