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Trial registered on ANZCTR


Registration number
ACTRN12613000418774
Ethics application status
Approved
Date submitted
7/04/2013
Date registered
15/04/2013
Date last updated
3/09/2019
Date data sharing statement initially provided
3/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Effects of Galvus (Vildagliptin) on Markers of Inflammation in Diabetic Foot Ulcer: A prospective, randomized, double-blind, placebo-controlled pilot study
Scientific title
Effects of Galvus (Vildagliptin) on interleukin-6 in Diabetic Foot Ulcer
Secondary ID [1] 282265 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
GIED
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 Diabetes
Diabetic Foot Ulcer
288792 0
Anti-inflammatory effects of Vildagliptin 288793 0
Diabetic foot ulcer healing properties of Vildagliptin 288794 0
Condition category
Condition code
Metabolic and Endocrine 289151 289151 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: (Intervention group) will be on oral Metformin 500 mg to 3000 mg per oral in single or divided dosages (2 or 3 times a day) plus Vildagliptin 50 mg to 100 mg per day also to be administered orally for 12 weeks. The dosages of both medications will be determined based on blood glucose levels with the aim of achieving average fasting blood glucose of <7 mmol/l and post-prandial blood glucose of 10 mmol/l or below. Improved adherence will be enhanced by weekly clinic visit and drug tablet return as well as monitoring blood glucose control and progress of the diabetic foot ulcer.
Intervention code [1] 286891 0
Treatment: Drugs
Comparator / control treatment
Arm 2: (Comparator group) will be on given Metformin as described above plus Placebo comprising of lactose 50 mg to 100 mg per day to be taken orally for 12 weeks. The placebo will be identical in appearance to Vildagliptin without the active ingredient.
Control group
Placebo

Outcomes
Primary outcome [1] 289261 0
Significant (20%) reduction of serum levels of IL-6.

IL-6 will be quantified using the Multiplex FlowCytomix system (Bendermedsystems). Antibody-coated beads will be incubated with either patient serum, followed by a biotin-conjugated secondary antibody and finally streptavidin-PE. The sample will be run on BD caliber. Analysis will be performed using software provided by the manufacturer.
Timepoint [1] 289261 0
The IL-6 will be determined and compared at onset (week 1) and 12 weeks.
Secondary outcome [1] 302120 0
a) Partial or complete closure of foot ulcer.

Weekly measurement of the ulcer at the start (week 1) and week 12.
Timepoint [1] 302120 0
Week 1 compared with week 12.
Secondary outcome [2] 302261 0
b) Worsening of the foot ulcer beyond Wagner grade 2.

Weekly assessment of the ulcer throughout period of the study.
Timepoint [2] 302261 0
Week 1 compared with week 12.
Secondary outcome [3] 302262 0
c) Requirement for limb or toe amputation.

Clinical assessment requiring the amputation throughout the 12-week period of the study.
Timepoint [3] 302262 0
Week 1 compared with week 12.
Secondary outcome [4] 302263 0
d) Reduced levels of serum hsCRP, TNF-alpha, IL-1beta, platelet reactivity and significantly raised levels of adiponectin and tissue TGF- beta-1.

These will be quantified using the Multiplex FlowCytomix system (Bendermedsystems). Antibody-coated beads will be incubated with either patient serum, followed by a biotin-conjugated secondary antibody and finally streptavidin-PE. The sample will be run on BD caliber. Analysis will be performed using software provided by the manufacturer.
Timepoint [4] 302263 0
Week 1 compared with week 12.

Eligibility
Key inclusion criteria
1) Subjects >= 18 years of age diagnosed with diabetes (type 1 or 2) on diet only or any diabetic medication regime.
2) Existing diabetes index foot ulcer grade A1 or higher according to the University of Texas Wound Classification System of Diabetic Foot Ulcers on the day of study inclusion. A foot ulcer is defined as any full thickness skin defect existing for at least 14 days. In patients with multiple diabetic foot ulcers the index foot ulcer is defined as the foot ulcer with the largest wound area at the time of inclusion.
3) A suboptimal HBA1c >=7.0% documented somewhere in the patient source documents within 12 weeks prior to study inclusion or on the day of study inclusion.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Exclusion criteria will comply with local label
2. Clinical infection at the studied ulcer site (bacterial and fungal)
3. Planned surgical intervention for the DFU
4. Hypersensitivity to either of the study drug components
5. History of lactic acidosis
6. Type 1 diabetes
7. Current HbA1c <7 or >9%
8. Current Insulin treatment.
9. Active treatment with GLP-1 or other DPP4i medication
10. Use of thiazolidinediones, statins, anti-inflammatory or anti-platelet agents
11. Clinically significant lower-extremity ischemia (as defined by an ankle/brachial index of <0.65)
12. Significant medical conditions that would impair wound healing will also be excluded from the study. These conditions include hepatic, respiratory or cardiac failures, aplastic anemia, scleroderma and malignancy, treatment with immunosuppressive agents or steroids, myocardial infarcts, stroke, major surgery within 6 months of the study, usage of tobacco
13. Severe non-proliferative or proliferative diabetic retinopathy.
14. Active Charcot's foot as determined by clinical and radiographic examination
15. Ulcer of a non-diabetic pathophysiology (e.g., rheumatoid, radiation-related, and vasculitis-related ulcers, calciphylaxis or dystrophic calcinosis cutis)
16. Active malignancy other than basal cell carcinoma as well as subjects with cancerous or pre-cancerous lesions in the ulcer area
17. Renal dysfunction: eGFR <60 ml/min
18. Chronic inflammation (inflammatory bowel disease, inflammatory or rheumatoid arthritis)
19. Pregnancy, lactation or child-bearing potential
20. Recent venous thromboembolism
21. Inability to comply with study protocol

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
All subjects who fit the selection criteria will be invited to participate, and if willing will be provided with information on the study and participant consent will be obtained and then randomized. Patients in each stratum will be assigned numbers using a central stratified randomization scheme.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomization list will be prepared by an independent statistician by the method of computer-generated random numbers for each treatment. Randomization will be carried out following a 2-week period of stabilization on Metformin mono-therapy as described above. Patients will be randomized to treatment with Vildagliptin + Metformin therapy or Metformin + Placebo therapy. This study will be blinded to both patients and treating personnel. All laboratory tests, the major study endpoints, will be performed by professionals blinded to treatment allocation. An interim analysis will be performed after the recruiting 50% of proposed study participants.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The objective of this trial is to study the effects of Vildagliptin therapy on inflammatory markers in subjects with diabetic foot ulcer. We plan to prospectively enrol 50 patients with proven diabetic foot ulcer and randomize them in a 1:1, ratio to vildagliptin + metformin or placebo + metformin. We expect to show an improvement (defined as >20% serum IL-6 reduction between the baseline and 3-month assessment) that comprise the primary end point in at least 50% of the patients randomized to Vildagliptin and Metformin therapy and in <10% of the patients randomized to Metformin and Placebo therapy. Furthermore, the proposed sample size was calculated to demonstrate a significant improvement in the intervention group compared to the control group with at least 80% power and a two-sided 5% type 1 error. These requirements will be met with a sample size of 44 patients and a 1:1 randomization design to allow for an approximate dropout rate of 10%, 50 patients will be recruited: this will result in approximately 25 patients in the Vildagliptin + Metformin -intervention group and in the Placebo + Metformin -control group.

The data from the study will be pooled and summarized with respect to demographic and baseline characteristics and efficacy and safety observations. Exploratory analyses will be performed using descriptive statistics. Data will be presented for the complete intent-to-treat population (all patients having taken at least one dose of study medication) as well as the per-protocol population (all patients who completed the study without major protocol deviations).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 842 0
The Townsville Hospital - Douglas
Recruitment postcode(s) [1] 6662 0
4814 - Douglas

Funding & Sponsors
Funding source category [1] 287035 0
Commercial sector/Industry
Name [1] 287035 0
Novartis Pharmaceuticals
Address [1] 287035 0
Novartis Pharmaceuticals Australia Pty Limited
54 Waterloo Road
North Ryde NSW 2113
Country [1] 287035 0
Australia
Primary sponsor type
Individual
Name
Assoc. Professor Usman H. Malabu; FRCPI, FRACP.
Address
School of Medicine and Dentistry
James Cook University & Townsville Hospital
100 Angus Smith Drive
Douglas, Townsville
QLD 4814.
Country
Australia
Secondary sponsor category [1] 285813 0
None
Name [1] 285813 0
Address [1] 285813 0
Country [1] 285813 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289069 0
Townsville Hospital Human Research and Ethics Committee
Ethics committee address [1] 289069 0
100 Angus Smith Drive
Douglas
Townsville
QLD 4814
Ethics committee country [1] 289069 0
Australia
Date submitted for ethics approval [1] 289069 0
15/04/2013
Approval date [1] 289069 0
30/07/2013
Ethics approval number [1] 289069 0

Summary
Brief summary
Diabetic patients are at a particularly high risk for poor wound healing in general and foot ulcer in particular. The lifetime risk for developing chronic foot ulcer has been estimated to reach about 15-20% (1). Despite considerable advances in diabetic care, foot ulcers continue to be responsible for a high number of lower limb amputations that are associated with decrease in quality of life and increased risk of mortality (2). The major risk factors for diabetic foot ulcer (DFU) are polyneuropathy and peripheral vascular disease. Diabetes induces complex vascular changes, promoting accelerated atherosclerosis and
hypercoagulability complicating foot ulcer which can be assessed indirectly by a number of inflammatory markers.

Animal studies have suggested numerous beneficial anti-inflammatory effects of dipeptidyl peptidase-4 inhibitors (DPP4i), well beyond the effects on blood glucose alone (3). Interestingly, investigation on anti-inflammatory property of DPP4i-vildagliptin in human setting is scanty (4). Treatment with a DPP4i may offer an attractive blood glucose reduction with synergistic mechanism of action while exerting additional wound healing properties. Reduction of inflammatory marker levels is of great clinical importance and may correlate with improvement of diabetic wound healing. Therefore, in the present study we plan to focus on possible anti inflammatory properties of DPP4i in subjects with DFU.

Primary objective: To demonstrate that Vildagliptin therapy is associated with clinically significant reduction in biological markers of inflammation compared to placebo in patients with DFU. Our Primary aim is demonstration of a significant (= 20%) reduction in the serum levels of interleukin 6 (IL-6).

Secondary objectives: Partial or complete closure of foot ulcer or improvement in other biological markers of inflammation including: hs-CRP, platelet reactivity testing, TNF-alpha, interleukin 1 beta (IL-1 beta), adiponectin and tissue TGF- beta-1 levels.

References
1. Lavery LA, et al. Diabetes Care. 2006:1288.
2. Singh N, et al. JAMA 2005: 293:217.
3. Shah Z, et al. Circulation. 2011: 124:2338.
4. Rizzo MR, et al. Diabetes Care. 2012: 35:2076.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 39062 0
A/Prof Usman H. Malabu
Address 39062 0
Department of Endocrinology and Diabetes
Townsville Hospital
100 Angus Smith Drive
Douglas
Townsville
QLD 4814
Country 39062 0
Australia
Phone 39062 0
+61-7-4433 1111
Fax 39062 0
+61-7-4433 2239
Email 39062 0
usman.malabu@jcu.edu.au
Contact person for public queries
Name 39063 0
A/Prof Usman H. Malabu
Address 39063 0
Department of Endocrinology and Diabetes
Townsville Hospital
100 Angus Smith Drive
Douglas
Townsville
QLD 4814
Country 39063 0
Australia
Phone 39063 0
+61-7-4433 1111
Fax 39063 0
+61-7-4433 2239
Email 39063 0
usman.malabu@jcu.edu.au
Contact person for scientific queries
Name 39064 0
A/Prof Usman H. Malabu
Address 39064 0
Department of Endocrinology and Diabetes
Townsville Hospital
100 Angus Smith Drive
Douglas
Townsville
QLD 4814
Country 39064 0
Australia
Phone 39064 0
+61-7-4433 1111
Fax 39064 0
+61-7-4433 2239
Email 39064 0
usman.malabu@jcu.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Deidentified, individual participant data underlying published results only

When will data be available (start and end dates)?
Beginning 3 months and ending 5 years following main results publication

Available to whom?
researchers who provide a methodologically sound proposal
Available for what types of analyses?

for IPD meta-analyses, etc.
How or where can data be obtained?
usman.malabu@jcu.edu.au
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Ethical approval
How or where can supporting documents be obtained?
Type [1] 4248 0
Study protocol
Citation [1] 4248 0
Link [1] 4248 0
Email [1] 4248 0
usman.malabu@jcu.edu.au
Other [1] 4248 0
Attachment [1] 4248 0
Type [2] 4249 0
Ethical approval
Citation [2] 4249 0
Link [2] 4249 0
Email [2] 4249 0
usman.malabu@jcu.edu.au
Other [2] 4249 0
Attachment [2] 4249 0
Type [3] 4250 0
Statistical analysis plan
Citation [3] 4250 0
Link [3] 4250 0
Email [3] 4250 0
usman.malabu@jcu.edu.au
Other [3] 4250 0
Attachment [3] 4250 0
Summary results
No Results