Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04323462 |
| Other study ID # |
100/20 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
October 1, 2021 |
| Est. completion date |
December 2022 |
Study information
| Verified date |
October 2021 |
| Source |
Postgraduate Institute of Medical Education and Research |
| Contact |
Ashu Rastogi, MD, DM |
| Phone |
919781001046 |
| Email |
ashuendo[@]gmail.com |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
With the available molecular and cellular evidence of impaired wound healing due to
hyperglycemia, investigators postulate hypothesis asking whether intensive glycemic control
could improve diabetic foot ulcer healing rates. A study showed improvement in phagocytic
activity of macrophages after 5 days of intensive glycemic improvement in 21 patients of
diabetes. Another retrospective cohort study studied the effect on HbA1c as predictor of
healing rate in DFU. Latter found significant association of HbA1c with wound area healing
rate. However a recent systematic review failed to find any randomized control trial
comparing the effect of intensive versus conventional glycemic control for treating DFU.
Hence, investigators want to explore the hypothesis by conducting a randomized control trial
with the primary aim of wound healing in patients of diabetic foot ulcer in response to
intensive glycemic control in comparison to conventional glycemic management.
Description:
BURDEN OF DIABETIC FOOT According to International Diabetic Federation, there will be over
642 million people with diabetes in the world by 2040.Diabetic Foot Ulcer (DFU) is one of the
most serious, most costly and at times life threatening complication of diabetes. The
lifetime incidence of foot ulcer occurrence in diabetes is up to 25%. Both prevalence and
incidence of DFU is higher in developing countries due to multitude of factors like poverty,
poor sanitation & hygiene, barefoot walking, lack of education, poor healthcare access.
DFU related morbidity and hospitalization has shown a meteoric rise. One study showed that
20% of admissions in patients of diabetes were due to DFU. 56%of ulcers become infected and 1
in 5 of these will requiresome level of amputation.In addition, it has been projected that
15% of diabetic foot ulcers result in lowerextremity amputations and 85% of diabetic
patientswho undergo lower extremity amputations had an ulcerprior to amputation.The 5-year
relative mortality afterdiabetic foot ulcer is 48%, second only to lung cancer.
Multiple risk factors have been attributed to the development of DFU including male gender,
duration of diabetes >10 years, older age, diminished vision, peripheral vascular disease,
high BMI, sensory neuropathy, retinopathy, nephropathy, HbA1c, foot deformity, high plantar
pressures, poor foot care habits, barefoot walking etc. From DCCT there exists robust
evidence that strict glycemic control can decrease all diabetic related complications. There
are other studies demonstrating improvements in neuropathy and peripheral vascular disease as
a result of strict glycemic control. However, there is no specific evidence/intervention for
DFU prevention.
IMPAIRED WOUND HEALING IN DIABETES Wound healing is impaired in diabetes at multiple stages.
The defects are observed at both cellular and molecular levels. Extrinsic factors like
mechanical stress, trauma and ischemia negatively influence the healing process.
Hyperglycemia itself has been shown to have deleterious effect on wound healing through
formation of advanced glycation end products (AGEs) & reactive oxygen species (ROS) which
induce the production of inflammatory molecules (TNF-α, IL-1) and interfere with collagen
synthesis. There is interference in collagen synthesis due to increased expression of matrix
metalloproteinases.
CHALLENGES WITH RESEARCH IN THIS AREA With the clinical benchmarks set by major trials like
UKPDS, it is often difficult for clinicians to ethically conduct any study investigating the
effects of intensive versus conventional glycemic control. Even on demonstrating the clinical
benefit involving intensive glycemic control, it is a difficult task to recruit as well as
follow up subjects. Many diabetic patients are frail and have multiple co-morbidities that
render them incapable of following such interventions. Intensive glycemic control makes these
individuals prone to the detrimental effects of hypoglycemia. In a trial investigating the
effect of hyperglycemia and intensive glycemic control on DFU healing, the authors faced many
challenges in recruiting and allocating the patients. This trial was completed without any
results.
There is marked variation in the definition of intensive glycemic control between guidelines
and trials.Most of the current glycemic targets for diabetes are based onseveral pioneering
trials that investigated the effects of intensiveglycemic control compared to conventional
treatments. Importantly, the beneficial effects on microvascular complicationsfrom using
intensive glycemic control took more than five yearsto emerge, and the benefits were less
pronounced for people withadvanced type 2 diabetes compared to those with new-onset type2
diabetes. Nevertheless, diabetic foot ulcer specific outcomes were not studied or neglected
in these trials. Hence, the onus is on new investigators to study the outcomes in DFU through
the prism of intensive glycemic control.
In many trials investigating intensive versus conventional glycemic control,lower limb
amputation was an outcome measure. This outcome was not reported in relation to presentation
with, development of, or healing of foot ulceration. Amputation was due to the ease of
measurement and definitive nature of such a practical end-point. However, there are
inconsistencies in the true estimation of amputation as an outcome. The UKPDS defined
amputation as a major limbcomplication requiring lower limb amputation of a digit or anylimb
for any reason and included digital amputations which areusually classified as minor
amputations. A Cochrane review concluded that intensive glucose control reduced the risk of
amputation by 36% in type 2 diabetes (RR 0.64, 95% CI: 0.43 to 0.95; 6960 participants
ineight trials). However, this information was based on amputations defined in several ways
(including both minor and major amputations). Although this data provides evidence to endorse
the efficacy of intensive glycemic control in preventing amputations, its exact correlation
to foot ulcer healing remains unanswered.It is a known fact that foot ulceration often
precedes amputation, therefore, ulcer specific measures like time to ulcer healing, percent
reduction in ulcer area, need to be measured as an outcome. From a patient and HRQoL point of
view, foot ulcer healing can be seen as a beneficial outcome over a damaging endpoint like
amputation.
In a meta-analysis of the six control arms ofwound-healing trials in patients with a
neuropathic ulcer, 24% of the ulcers were healed at 12 weeks and only 31%at 20 weeks. But
these data were likely influenced by selection bias, as the elderly patient with multiple
co-morbidities is usually excluded from such trials, follow-up was short and treatment was
suboptimal and non- EVIDENCE OFNEED FOR INTENSIVE GLYCEMIC CONTROL IN DFU Various studies
highlighting the importance of hyperglycemia and glycemic control in diabetic foot ulcer
healing are described below.
In a multi-center study, poor glycemic (blood glucose) control was evident in nearly half of
the participants who had foot ulcers, with 49% having an HbA1c (glycemic measure) level above
8.4%.
In a retrospective cohort study of 183 diabetic patients conducted at the John Hopkins Wound
Center, it was seen that HbA1c was an important clinical predictor of the rate of wound
healing. The mean HbA1c was 8.0%. For each 1%-point increase in HbA1c level,the daily wound
healing ratedecreased by 0.028 cm² per day (95% CI: 0.003 to 0.054). This was irrespective of
presence of neuropathy (n=109), smoking status (n=121) and peripheral arterial disease
(n=53). The study didn't throw any light on anti-diabetic treatment received by patients.
In another retrospective study of 63 diabetic patients conducted at a Midwestern outpatient
wound care clinic in USA for 3 years, it was seen that the HbA1c values closest to ulcer
closure ranged from 5.3 to12.3 (mean, 7.68 [SD, 1.81]). It was also found that patients with
higher HbA1c levels did experience wound healing, but in a significantlylonger period than
those with lower HbA1c. Approximately 80% of this sample (n = 50)had peripheral vascular
disease, and more than 60% (n = 39) hadrenal disease. Here also the investigators didn't
mention the anti-diabetic treatment being received by patients.
An Indian prospective study (over 2 years) has explored the concept of HbA1c as a predictor
of healing rate in diabetic ulcers. 100 diabetic patients were equally divided into 2 groups
with mean HbA1c levels of 6.50 ± 0.441 in Group A and Group B with the mean value of 10.40 ±
1.550. Subsequently, standard treatment protocols were followed, and mean reduction in ulcer
area, length, and width were measured; a statistically significant difference was found in
the mean area change per day between the two groups with P<0.0001. However, the study did not
explore the effect of intensive glycemic treatment in the uncontrolled diabetic subgroup.
Investigators in Barcelona, Spain addressed the issue of impairment in phagocytic activity in
relation to glycemic control and, whether or not this impairment could be reversible after
improving blood glucose levels. In their case control study, 21 type 2 DM and 21 healthy
volunteers were prospectively recruited. Baseline HbA1c was 8.78 ± 2.01 in T2DM patients
whereas it was 5.79 ± 0.45 in healthy volunteers. Baseline FBG was 9.49 ± 3.15 in T2DM
patients whereas it was 5.73 ± 0.83 in healthy volunteers. By use of flow cytometry they were
able to deduce that Type 2 diabetic patients showed a lower percentage of activated
macrophages in comparison with non-diabetic subjects (54.00618.93 vs 68.53612.77%; p =
0.006). Also,significant negative correlations between phagocytic activity and fastingglucose
(r = 20.619, p = 0.004) and HbA1c (r = 20.506, p = 0.019) were detected. In their
intervention study 12 previous T2DM patients were admitted and treated intensively (9-point
blood glucose profile) for 5 days. In these patients who underwent metabolic optimization, a
significant increase in phagocytic activitywas observed (p = 0.029). The investigators
postulated that the reversibility of phagocytosis dysfunction after a short period of
glycemic control may have been attributable not only to the normalization of the diabetic
milieu but also to the effect of exogenous insulin.
Another prospective study conducted in Oregon, USA investigated whether different diabetic
treatment regimens affect diabetic foot ulcer healing. In this study 85 patients were
followed up for a period of 2 years. Insulin treatment was apart of diabetes management in 52
(61.2%) cases. Insulin therapy significantly increased thewound healing rate (30.3% [20/66
ulcers] vs. 9.8% [4/41 ulcers]) (p=0.013). In multivariaterandom-effect logistic regression
model, adjusting for age, gender, smoking status, type of diabetes, hypertension, chronic
kidney disease, peripheral arterial disease, oral hypoglycemic use, wound infection, involved
side, presence of Charcot's deformity, gangrene, osteomyelitis on x-ray, and serum hemoglobin
A1C levels, insulin treatment was associated with a higher chance of complete healing
(beta±SE: 15.2±6.1, P=0.013).
In a Cochrane systematic review aimed to assess the effects of intensive glycemic control
compared to conventional control on the treatment of foot ulcers in people with type 1 and
type 2 diabetes. The authors searched for evidence in both published and unpublished
material. They were unable to find any clinical trials which had successfully investigated
the impact of intensive versus conventional glycemic control on foot ulcer outcomes.
Investigators want to fill this lacuna by conducting a randomized control trial with the
primary aim of wound healing in participants of diabetic foot ulcer on intensive glycemic
control versus conventional treatment.
