Diabetes Mellitus, Type 2NCT04475861
Metabolomics and Wound Healing in Diabetes
A study testing L-arginine supplements and nutritional supports in people with Diabetes Mellitus, Type 2 and Infection, run by Chang Gung Memorial Hospital at 1 site in Taiwan.
Trial summary
The dysfunction of wound healing in diabetes involves multiple healing processes by diminished inflammatory responses and delayed deposition of matrix components, wound remodeling, and closure. Furthermore, hyperglycemia increases the infection susceptibility of wounds. Read more about this study
- Who is it for?
- Ages 40 to 80 years
- Conditions the study is for
- Diabetes Mellitus, Type 2, Infection
- What is being tested?
- L-arginine supplements and nutritional supports
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteTaiwan
- Study dates
- 31 Oct 2018to 18 Jun 2025
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- are men or non-pregnant women, aged ≥ 40 years or ≤ 80 years
- have a history of foot ulcers for more than 1 month
- have a serum albumin level ≤ 4.0 or an ABI level ≤ 1
Who cannot join
- Have active malignancy
- Have acute gastrointestinal surgery
- are receiving dialysis
- have heart failure (NYHA Fc ≥ 3), liver cirrhosis (Child class > B), or myocardial infarction in the past 3 months,
- have wounds complicated with persistent osteomyelitis or Charcot deformity
- are receiving hydroxyurea or steroid treatment
- have alcohol abuse, any mental or physiological condition that may interfere with dietary intake, and those who are unable to follow orders or cooperate.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Metabolomics and Wound Healing in Diabetes-Mechanisms and Clinical Value of Arginine Supplement in Patients With Diabetic Foot Ulcers
The dysfunction of wound healing in diabetes involves multiple healing processes by diminished inflammatory responses and delayed deposition of matrix components, wound remodeling, and closure. Furthermore, hyperglycemia increases the infection susceptibility of wounds. In Taiwan, we have data demonstrating the nutrition status associated the outcome of diabetic foot ulcer (DFU) acute treatment and value of serum arginine level (in preliminary metabolomics study) to predict one-year healing of DFUs. The arginine has the beneficial effects on wound healing by the action of its metabolites, including vasodilatation, bactericide, growth factors recruitment and collage formation. Nevertheless, its supplement and mechanism in patients with diabetes is still remains unproven. This study aims at (1) defining the effects of arginine supplement, on top of the traditional treatment and risk reduction, on healing outcomes of patients with DFUs, (2) studying the modes of action of arginine supplements in diabetes, and (3) verifying the metabolomics factors and their association with wound healing prospects in patients with DFUs. A total of 120 patients with chronic diabetic foot ulcer will be enrolled and survey in 3 years. Along with standard of care, patients will receive, in a randomized fashion, either arginine (treatment group) or whey protein (control group) 5 g per day supplement for 4 weeks. The wound status will be collected with features in wound size, tissue perfusion, and infection status before and after treatment. Nutritional surveys, nitrogen balance as well as various molecular studies such as metabolomics analysis and neutrophil-to-lymphocyte ratio will be performed to study the association between the molecules of nutrients and the healing
Read the detailed description
The dysfunction of wound healing in diabetes involves multiple healing processes by diminished inflammatory responses and delayed deposition of matrix components, wound remodeling, and closure. Furthermore, hyperglycemia increases the infection susceptibility of wounds. The wounds noted at distal limb of body, the diabetic foot ulcers, have more significant impacts clinically and socioeconomically compare to those injuries from surgery or pressure sores.
- Urge for Novel treatments in patients with diabetic foot ulcers: 1.1. Facts: Diabetic foot ulcer (DFU) is a major complication of diabetes that can lead to limb loss and premature death. According to a report from the International Diabetes Federation in 2017, DFU is also the most common cause of hospitalization for patients with diabetes. In Taiwan, 1% of patients with diabetes are admitted to hospital for the treatment of DFU annually. However, considering that the lower-extremity amputation (LEA) rate is around 30%,the treatment outcomes are obviously unsatisfactory. 1.2. Standard treatment for DFU 1.2.1 In 2016, we formed a Taiwan national working group on diabetic foot under the authorization of Diabetes Association of the Republic of China and subsequently published a Diabetic foot guideline in Taiwan in 2017 (ISBN 978-986-82436-8-2). In addition, I also participated in the writing of a clinical foot care guideline released 2017 by International Diabetes Federation . 1.2.2 These two most updated guidelines detail the diagnosis, management and prevention for patients with DFUs with specifically focused on (1) infection, (2) peripheral artery diseases, (3) wound care and surgical intervention, and (4) off-loading and risks reduction. Suggestions for the appropriate medications for patients with various clinical characteristics were also provided. Nevertheless, in addition to treating acute infections and limb ischemia, the optimum healing of a foot ulcer requires treating the complex biological and molecular events of cell migration and proliferation, and of extracellular matrix deposition, remodeling, and tissue microcirculation. This is why the prognosis for patients with DFU is still unsatisfactory, worldwide. Novel treatments are therefore needed to provide better tissue healing in patients with diabetes. Unfortunately, recent results of well-designed novel treatments for patients with DFU have been disappointing.
- The role of nutrition in wound healing The relationship between nutrition and wound healing, whether after injury or surgical intervention, has been recognized for centuries and adequate carbohydrate, fat and protein intake is known to be necessary for healing to take place. Wound failure, as reflected by wound infections and/or delayed healing, significantly contributes to the financial burden imposed on health care systems worldwide. 2.1. Molecular pathogenesis of diabetic wound healing In healthy individuals, the wound healing requires maintenance of multiple signals (cytokines and chemokines) released by keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets. During wound-induced hypoxia, VEGF released by macrophages, fibroblasts, and epithelial cells induces nitric oxide synthase (NOS) resulting in an increase in nitric oxide (NO) levels. 2.2. Role of nutrition in wound healing in patients with diabetes Studies have shown that changes in energy, carbohydrate, protein, fat, vitamin, and mineral metabolism affect the healing process12. Loss of protein due to protein-calorie malnutrition, the most common form of malnutrition, leads to decreased wound tensile strength, decreased T-cell function, decreased phagocytic activity, and decreased complement and antibody levels,ultimately diminishing the body's ability to defend the wound against infection. Furthermore, wounding increases metabolic rates, catecholamine levels, loss of total body water, and cellular protein turnover, resulting in an overall state of catabolism. Patients with diabetes have a significantly impaired ability to heal wounds, and therefore, exhibit increased complication rates compared with their euglycemic counterparts. The mechanisms at work are multifactorial and need to be further verified.Recent evidence has shown that patients with diabetes exhibit a diminished early inflammatory response and inhibition of fibroblast and endothelial cell activities. Subsequently, when inflammatory cells eventually arrive at the site of injury, they initiate a prolonged inflammatory phase that results in delayed deposition of matrix components, wound remodeling, and closure. Furthermore, hyperglycemia interferes with the cellular transport of ascorbic acid into fibroblasts and leukocytes and decreases leukocyte chemotaxis. In addition, patients with diabetes are more susceptible to infection2 because of decreased host resistance and phagocytosis ability.
- Preliminary data highlights the role of L-arginine in wound healing in patients with DFU In our diabetic foot center, we have consistently observed that a lower serum albumin level is an independent risk factor for lower-extremity amputation (LEA) . Furthermore, we identified an association between nutritional status and treatment outcomes in patients with limb-threatening DFU. Using the Mini Nutritional Assessment (MNA) and Geriatric Nutritional Risk Index (GNRI) tools, we confirmed a high prevalence of nutritional problems among these patients. We further identified that the nutritional status of the patients was an independent predictor for acute treatment outcomes.
More recently, we analyzed the effect of metabolomic molecules and clinical and wound characteristics on the 1-year outcomes of wound healing in patients with limb-threatening foot ulcer.
- Conditions
- Diabetes Mellitus, Type 2, Infection
- Being tested
- L-arginine supplements and nutritional supports
- Medical subject headings
- Diabetes Mellitus, Type 2, Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-arginine supplements and nutritional supportsDietary supplement
The enrolled subjects will then be randomized into two groups. The subjects will receive either L-arginine (the study group) or another amino acid supplement (the control group), with 60 patients in each group. All the food intake of the subjects during the 4 weeks of the study will be recorded and supervised by responsible dietitians.
| Study group | Role | What they receive |
|---|---|---|
| L-arginine supplements | Experimental | The enrolled subjects will then be randomized into two groups. Study Group: will take a supplementation pill containing 5 g L-arginine (0.5g/ pill, GNC, USA) All the food intake of the subjects during the 4 weeks of the study will be recorded and supervised by responsible dietitians. Receives: Dietary Supplement: L-arginine supplements and nutritional supports |
| nutritional supports | No intervention | The enrolled subjects will then be randomized into two groups. Control group: will take a supplementation pill containing 5 g whey protein (5g/ pack, Santosa,Taiwan). All the food intake of the subjects during the 4 weeks of the study will be recorded and supervised by responsible dietitians. |
What is being measured
The primary outcome is the main question the study is designed to answer.
PEDIS
Wound assessment was recorded using the PEDIS system
Measured: up to 1 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Jul 2020
- Study start31 Oct 2018 (estimated)
- Primary completion1 Dec 2018 (estimated)
- Study completion18 Jun 2025 (estimated)
Why it stopped: no participants enrolled
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Diabetes Mellitus, Type 2Studies of the same condition, open and under way.
- More trials run by Chang Gung Memorial HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Health services research
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Chang Gung Memorial Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Ministry of Science and Technology, Taiwan
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04475861
- Sponsor's protocol ID
- 201702332A3
- Status last verified
- Jun 2018
- First submitted
- 18 Sep 2018
- Last updated
- 17 Jul 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 17 Jul 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Metabolomics and Wound Healing in Diabetes-Mechanisms and Clinical Value of Arginine Supplement in Patients With Diabetic Foot Ulcers
- ClinicalTrials.gov ID
- NCT04475861
- Acronym / sponsor ID
- 201702332A3
- Conditions
- Diabetes Mellitus, Type 2, Infection
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: no participants enrolled
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Chang Gung Memorial HospitalUniversity, hospital or other
- Collaborators
- Ministry of Science and Technology, Taiwan
- Study start
- 31 Oct 2018 (estimated)
- Primary completion
- 1 Dec 2018 (estimated)
- Study completion
- 18 Jun 2025 (estimated)
- First posted
- 17 Jul 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The dysfunction of wound healing in diabetes involves multiple healing processes by diminished inflammatory responses and delayed deposition of matrix components, wound remodeling, and closure. Furthermore, hyperglycemia increases the infection susceptibility of wounds. In Taiwan, we have data demonstrating the nutrition status associated the outcome of diabetic foot ulcer (DFU) acute treatment and value of serum arginine level (in preliminary metabolomics study) to predict one-year healing of DFUs. The arginine has the beneficial effects on wound healing by the action of its metabolites, including vasodilatation, bactericide, growth factors recruitment and collage formation. Nevertheless, its supplement and mechanism in patients with diabetes is still remains unproven. This study aims at (1) defining the effects of arginine supplement, on top of the traditional treatment and risk reduction, on healing outcomes of patients with DFUs, (2) studying the modes of action of arginine supplements in diabetes, and (3) verifying the metabolomics factors and their association with wound healing prospects in patients with DFUs. A total of 120 patients with chronic diabetic foot ulcer will be enrolled and survey in 3 years. Along with standard of care, patients will receive, in a randomized fashion, either arginine (treatment group) or whey protein (control group) 5 g per day supplement for 4 weeks. The wound status will be collected with features in wound size, tissue perfusion, and infection status before and after treatment. Nutritional surveys, nitrogen balance as well as various molecular studies such as metabolomics analysis and neutrophil-to-lymphocyte ratio will be performed to study the association between the molecules of nutrients and the healing
Detailed description
The dysfunction of wound healing in diabetes involves multiple healing processes by diminished inflammatory responses and delayed deposition of matrix components, wound remodeling, and closure. Furthermore, hyperglycemia increases the infection susceptibility of wounds. The wounds noted at distal limb of body, the diabetic foot ulcers, have more significant impacts clinically and socioeconomically compare to those injuries from surgery or pressure sores.
- Urge for Novel treatments in patients with diabetic foot ulcers: 1.1. Facts: Diabetic foot ulcer (DFU) is a major complication of diabetes that can lead to limb loss and premature death. According to a report from the International Diabetes Federation in 2017, DFU is also the most common cause of hospitalization for patients with diabetes. In Taiwan, 1% of patients with diabetes are admitted to hospital for the treatment of DFU annually. However, considering that the lower-extremity amputation (LEA) rate is around 30%,the treatment outcomes are obviously unsatisfactory. 1.2. Standard treatment for DFU 1.2.1 In 2016, we formed a Taiwan national working group on diabetic foot under the authorization of Diabetes Association of the Republic of China and subsequently published a Diabetic foot guideline in Taiwan in 2017 (ISBN 978-986-82436-8-2). In addition, I also participated in the writing of a clinical foot care guideline released 2017 by International Diabetes Federation . 1.2.2 These two most updated guidelines detail the diagnosis, management and prevention for patients with DFUs with specifically focused on (1) infection, (2) peripheral artery diseases, (3) wound care and surgical intervention, and (4) off-loading and risks reduction. Suggestions for the appropriate medications for patients with various clinical characteristics were also provided. Nevertheless, in addition to treating acute infections and limb ischemia, the optimum healing of a foot ulcer requires treating the complex biological and molecular events of cell migration and proliferation, and of extracellular matrix deposition, remodeling, and tissue microcirculation. This is why the prognosis for patients with DFU is still unsatisfactory, worldwide. Novel treatments are therefore needed to provide better tissue healing in patients with diabetes. Unfortunately, recent results of well-designed novel treatments for patients with DFU have been disappointing.
- The role of nutrition in wound healing The relationship between nutrition and wound healing, whether after injury or surgical intervention, has been recognized for centuries and adequate carbohydrate, fat and protein intake is known to be necessary for healing to take place. Wound failure, as reflected by wound infections and/or delayed healing, significantly contributes to the financial burden imposed on health care systems worldwide. 2.1. Molecular pathogenesis of diabetic wound healing In healthy individuals, the wound healing requires maintenance of multiple signals (cytokines and chemokines) released by keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets. During wound-induced hypoxia, VEGF released by macrophages, fibroblasts, and epithelial cells induces nitric oxide synthase (NOS) resulting in an increase in nitric oxide (NO) levels. 2.2. Role of nutrition in wound healing in patients with diabetes Studies have shown that changes in energy, carbohydrate, protein, fat, vitamin, and mineral metabolism affect the healing process12. Loss of protein due to protein-calorie malnutrition, the most common form of malnutrition, leads to decreased wound tensile strength, decreased T-cell function, decreased phagocytic activity, and decreased complement and antibody levels,ultimately diminishing the body's ability to defend the wound against infection. Furthermore, wounding increases metabolic rates, catecholamine levels, loss of total body water, and cellular protein turnover, resulting in an overall state of catabolism. Patients with diabetes have a significantly impaired ability to heal wounds, and therefore, exhibit increased complication rates compared with their euglycemic counterparts. The mechanisms at work are multifactorial and need to be further verified.Recent evidence has shown that patients with diabetes exhibit a diminished early inflammatory response and inhibition of fibroblast and endothelial cell activities. Subsequently, when inflammatory cells eventually arrive at the site of injury, they initiate a prolonged inflammatory phase that results in delayed deposition of matrix components, wound remodeling, and closure. Furthermore, hyperglycemia interferes with the cellular transport of ascorbic acid into fibroblasts and leukocytes and decreases leukocyte chemotaxis. In addition, patients with diabetes are more susceptible to infection2 because of decreased host resistance and phagocytosis ability.
- Preliminary data highlights the role of L-arginine in wound healing in patients with DFU In our diabetic foot center, we have consistently observed that a lower serum albumin level is an independent risk factor for lower-extremity amputation (LEA) . Furthermore, we identified an association between nutritional status and treatment outcomes in patients with limb-threatening DFU. Using the Mini Nutritional Assessment (MNA) and Geriatric Nutritional Risk Index (GNRI) tools, we confirmed a high prevalence of nutritional problems among these patients. We further identified that the nutritional status of the patients was an independent predictor for acute treatment outcomes.
More recently, we analyzed the effect of metabolomic molecules and clinical and wound characteristics on the 1-year outcomes of wound healing in patients with limb-threatening foot ulcer.
Study design
- Primary purpose
- Health services research
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| L-arginine supplements | Experimental | Dietary Supplement: L-arginine supplements and nutritional supportsThe enrolled subjects will then be randomized into two groups. Study Group: will take a supplementation pill containing 5 g L-arginine (0.5g/ pill, GNC, USA) All the food intake of the subjects during the 4 weeks of the study will be recorded and supervised by responsible dietitians. |
| nutritional supports | No intervention | –The enrolled subjects will then be randomized into two groups. Control group: will take a supplementation pill containing 5 g whey protein (5g/ pack, Santosa,Taiwan). All the food intake of the subjects during the 4 weeks of the study will be recorded and supervised by responsible dietitians. |
Who may qualify
- Ages
- 40 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- are men or non-pregnant women, aged ≥ 40 years or ≤ 80 years
- have a history of foot ulcers for more than 1 month
- have a serum albumin level ≤ 4.0 or an ABI level ≤ 1
Key exclusion criteria (7 listed)
- Have active malignancy
- Have acute gastrointestinal surgery
- are receiving dialysis
- have heart failure (NYHA Fc ≥ 3), liver cirrhosis (Child class > B), or myocardial infarction in the past 3 months,
- have wounds complicated with persistent osteomyelitis or Charcot deformity
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| L-arginine supplements and nutritional supportsThe enrolled subjects will then be randomized into two groups. The subjects will receive either L-arginine (the study group) or another amino acid supplement (the control group), with 60 patients in each group. All the food intake of the subjects during the 4 weeks of the study will be recorded and supervised by responsible dietitians. | Dietary supplement | L-arginine supplements |
Primary outcome
PEDIS
Time frame: up to 1 months
Wound assessment was recorded using the PEDIS system
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Jul 2020.
- Individual participant dataSharing planned: Undecided
Related trials for Diabetes Mellitus, Type 2
Not yet recruitingPhase 3
Efficacy and Safety of Once-Weekly SHR-3167 Compared With Once-Daily Insulin Glargine in Adults With Insulin-Naive Type 2 Diabetes
Type 2 Diabetes
Active, not recruiting
Digital Reinforcement of Motivational Interviewing Micro-Skills Among Primary Care Healthcare Professionals
Hypertension (Without Type 2 Diabetes Mellitus)
Recruiting
Investigating Vascular Properties of HEMI and SPG Signals in Individuals With or at Risk for Chronic Kidney Disease
Chronic Kidney Disease, Hypertension (HTN)
Not yet recruitingPhase 3
A Study to Evaluate the Effectiveness and Safety of the Drug AZD6234 for Managing Weight in Adults Who Are Obese or Overweight. These Participants May or May Not Also Have Type 2 Diabetes
Obesity, Overweight
Not yet recruiting
Impact of Endoscopic Sleeve Gastroplasty (ESG) in Obese Adults With Type 2 Diabetes (T2D)
Type 2 Diabetes Mellitus (T2D), Obesity (BMI>30)
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing L-arginine supplements and nutritional supports in people with Diabetes Mellitus, Type 2 and Infection, run by Chang Gung Memorial Hospital at 1 site in Taiwan.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 17 Jul 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Taiwan. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
PEDIS (time frame: up to 1 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jul 2020.