Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03938584 |
| Other study ID # |
HSR# 1-4276 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
October 12, 2017 |
| Est. completion date |
June 1, 2021 |
Study information
| Verified date |
January 2022 |
| Source |
Hennepin Healthcare Research Institute |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The goal of this study is to perform a randomized clinical trial to assess the effects of
vitamin C versus placebo on wound healing in mandibular fracture patients.
Description:
In a prospective, randomized clinical trial of de novo mandibular fracture patients requiring
intraoral surgical repair with plating, the investigators will:
1. Compare the effects of supplemental vitamin C to placebo on soft tissue wound healing,
measured by a) biomarkers of soft tissue repair (Procollagen I and III, Matrix
Metallo-Proteinases 1,2,3 & 9, C-reactive protein, neutrophil count, Interleukins 6 & 8,
TBARS and TEAC) and b) clinical outcomes (wound dehiscence and Wound Score).
Hypothesis1: Supplemental vitamin C will improve soft tissue healing post-mandibular
fracture, measured by improved procollagen I, other biomarker levels and clinical
outcomes, compared to placebo.
Rationale. The clinical literature describes impaired soft tissue wound healing in
mandibular fracture patients, including wound infection, wound dehiscence, and plate
exposure. Vitamin C is a necessary co-factor for the production of types I and III
collagen, as well as procollagen, the precursor to collagen, via the hydroxylation of
proline and lysine. In the setting of vitamin C deficiency, collagen production is
abnormal leading to defective vessel and connective tissue formation with degradation of
unstable collagen molecules.90-91,34, 63, 108,109
The investigators will collect a robust set of clinical outcomes including clinician
evaluation and Wound Healing Score to measure soft tissue healing. Biomarkers of soft
tissue wound healing will be used to measure biochemical healing pathways as well. As a
precursor to collagen, procollagen I and III are widely used biomarkers of collagen
production in wound healing research. The investigators will assess these levels at
baseline and at 3 to 5weeks post-operatively to evaluate the effect of vitamin C on
collagen production. In addition, the antioxidant effects of vitamin C are critical
during the ordered phases of wound healing, from the inflammatory phase (including the
initial hemostatic cascade) to the proliferative phase. Antioxidant depletion during
these phases results in imbalanced proteolytic enzyme cascades (including matrix
metalloproteinases or MMPs) with resulting tissue destruction as well as an
over-exuberant inflammatory milieu. Further, the antioxidant deficit resulting from
vitamin C deficiency results in diminished monocyte and neutrophil chemotaxis and
diminished bacteriocidal oxidative burst capabilities. Thus, the investigators will
additionally measure the effects of vitamin C supplementation on proteolytic enzyme
pathways (MMPs) and systemic markers of infection and inflammation (neutrophil count,
c-reactive protein level, interleukins (IL) 1 and 6). Finally, the investigators will
use indicators of oxidative stress at baseline and 6 weeks to measure the effects of
vitamin C supplementation on antioxidant capacity (TBARS and TEAC).
2. Compare the effects of supplemental vitamin C to placebo on bone repair, measured by a)
biomarkers of bone repair (alkaline phosphatase, TRACP 5b, osteocalcin, RANKL,
osteoprotegerin, and carboxy terminal collagen crosslinks) and b) clinical outcomes
(radiologic imaging and pain).
Hypothesis 2: Supplemental vitamin C will improve bone healing post-mandibular fracture,
measured by improved biomarkers of bone healing and more robust radiological bone
imaging, compared to placebo.
Rationale. A body of literature, from animal studies to randomized clinical trials,
supports the notion that vitamin C is necessary for bone health and healing. Multiple
animal studies demonstrate that vitamin C promotes bone formation / mineralization,
strengthens developing callous, and supports bone maintenance. Further, a number of
studies show that supplemental vitamin C prevents fracture in menopausal women and may
be protective against arthritis.10,11,12,69 Several well done randomized controlled
clinical trials have shown that supplemental vitamin C diminishes regional pain syndrome
after distal radius fractures and less robust data suggests this for foot and ankle
fractures. Well-done randomized controlled clinical trials are needed to develop Vitamin
C guidelines in traumatic facial fracture.
The investigators will collect a comprehensive set of biochemical, clinical, and
radiological outcome measures to evaluate bony healing after mandibular fracture. The
biomarker evaluation will include assessment of osteoblast and osteoclast number
(alkaline phosphatase and TRACP 5b respectively), osteoblast activity (osteocalcin),
osteoclast differentiation (receptor activator for nuclear factor, B ligand or RANKL and
osteoprotegerin or decoy receptor for RANKL) and osteoclast activity (carboxy terminal
collagen crosslinks). The investigators will measure clinical outcomes about 1 and 3 to
5 weeks postoperatively. Finally, each subject will undergo a non-contrast CT of the
mandible 3to 5 weeks post-operatively for radiological evaluation of bone healing. The
CT scan may or may not be standard of care.30,36,135
3. Determine the effects of supplemental vitamin C on soft tissue and bone healing by
smoking status in patients with traumatic mandibular fracture.
Hypothesis 3: Current smokers will have a higher prevalence of vitamin C deficiency than
nonsmokers at baseline, and vitamin C supplementation will improve soft tissue and bone
healing more in smokers than nonsmokers.
Rationale. Despite clinical evidence for smoking-related impairment in wound healing, much is
unknown about the pathophysiologic mechanisms underlying this effect.21. It is postulated
that after injury, smoking impedes the inflammatory phase of wound healing by diminishing
cellular chemotactic responsiveness, migratory function, and oxidative bacterial killing, and
by creating an imbalance in protease-protease inhibitor relationships. The proliferative
phase of wound healing is also potentially impaired by smoking, with diminished fibroblast
proliferation and migration resulting in decreased collagen production.124-30 Increases in
oxidative stress and hypoxia further diminish healing in smokers.62,74,76,102 Vitamin C is
postulated to be an important contributor to the diminished wound healing evidenced in
smokers. Both population and experimental studies have shown smokers are more likely to be
deficient in Vitamin C, with 25% of female smokers and 30% of male smokers having severe
deficiency. This deficiency is likely secondary to a systemic depletion by the many reactive
oxygen species in tobacco smoke as well as a diet lacking antioxidants. The investigators
will evaluate the effects of vitamin C on wound healing in current versus non smokers with
detailed assessment of tobacco use.
This project assembles a multidisciplinary team with expertise in wound healing,
maxillofacial surgery, medical effects of tobacco use, fracture repair, biomechanics of bone,
and conduct of clinical trials. The proposed work will define specific effects of
supplemental Vitamin C on soft tissue and bone healing, with additional attention to smoking
status in patients with mandibular fractures. For the many patients who are at high risk for
vitamin C deficiency and poor wound healing, this investigation will provide critical
knowledge of the role of oxidative stress and anti-oxidants in the mechanisms of impaired
healing. These data will provide pilot data to support randomized controlled trials of
interventions to improve post-operative wound healing in patients suffering from mandibular
and other traumatic fractures. Establishing the safety and efficacy of supplemental Vitamin C
in the peri-operative setting will improve wound healing outcomes for thousands of patients
undergoing traumatic fracture surgery and could be a transformative step in treatment
guidelines for any smoker undergoing surgery.
