Study design:
A patient and outcome assessor blinded, multiple- arm, randomized, placebo controlled
clinical trial Setting: All India Institute of Medical sciences New Delhi
Selection of patients:
Consecutive patients diagnosed with Oral Submucous Fibrosis based on WHO clinical
criteria (Warnakulsurya et al 2007, 2021) and classified as Moderate Oral Submucous
Fibrosis based on functional staging of More et al 2011 (Functional staging M2 and M3:
maximal interincisal distance 15-35 mm) will be prospectively recruited after ethical
clearance and informed written consent.
Clinicopathologic characteristics:
The clinical demographics, Tobacco and Areca nut habit history ( Type, quantity,
frequency, duration), association with other habits like smoking/ smokeless tobacco with/
without slaked lime, alcohol and addictive drugs will be recorded. The clinical
characteristics and staging/grading of OSMF would be recorded as per prepared proforma
and protocol. The clinical grading of moderate OSMF will be done according to WHO
clinical criteria and More et al 2011 classification. Biopsy of any suspicious oral
lesions if found will be done to rule out malignancy and referred to the cancer center
for further management and excluded from study. Enrolment of subjects fulfilling the
inclusion and none of the exclusion criteria will be done after information and written
informed consent before any further investigation. Routine blood investigations to rule
out common systemic conditions ( CBC, Blood glucose, LFT, KFT) Participants will be
randomized into three arms (1:1:1) Group A: Photobiomodulation therapy (parameters
defined below) given intraorally on bilateral buccal mucosa and extraorally (sham) with
conventional non-invasive management.
Group B: Photobiomodulation therapy (parameters defined below) given intraorally
(bilateral buccal mucosa) and extraorally (bilateral masseter muscle) with conventional
non-invasive management.
Group C: Sham (Use of laser handpiece with only red guide light and without using the
foot pedal which activates the laser)Photobiomodulation therapy(Placebo) (Intraoral and
Extraoral) with conventional non-invasive management.
Randomization:
Block randomization with varying block size will be done using computer generated random
numbers using the Nquery software.
Allocation concealment:
Participants will be randomized using sequentially numbered, opaque sealed envelopes
(SNOSE). 315 white envelopes will be prepared with aluminum foil sheet and carbon sheet
in each. Assigned treatment protocol will be mentioned clearly on a paper and put in each
envelope. For each treatment protocol 105 envelopes will be prepared and sealed. Each
envelope will have an identifier of trial on its front. Envelopes will be opened
sequentially by an operator blinded to the study protocol after which patients will be
allotted a study arm as per the treatment mentioned in the envelope. Before opening the
envelope we will write the patient's study identifier number, date and operator's
signature in front of the envelope, which will be transferred on white paper through
carbon paper. Used envelopes will be stored separately until the completion of trial.
Blinding:
The subjects will be blinded to the group assignment as they will receive PBM ( Active or
Sham as per group assignment ) both intraorally and extraorally The outcome assessor will
be blinded to the group assignment of the subjects as they will be identified by unique
randomization code only
Conventional non-invasive management (Usual care):
All subjects in the three groups will receive the same standard conventional non-
invasive management advised for moderate OSMF as per current scientific evidence.
Brief behavioral Tobacco, areca nut and alcohol habit cessation counseling as per WHO 5As
and 5Rs technique at baseline and each follow up.
Oral prophylaxis Removal of oral irritational factors like sharp teeth, appliances or
prosthesis, impacted buccoverted third molars, parafunctional habits Oral hygiene
maintenance instructions Oral physiotherapy(Mouth opening and cheek ballooning exercises)
Control of systemic conditions (Anemia, Diabetes, hypertension, thyroid disorders) by
specialist referral Removal of all predisposing factors for oral candida infection
Advocacy for safe sexual practices Nutrition and diet counseling( seasonal and regional
food rich in nutrients, vitamins, antioxidants avoidance of spicy /sour/ hot foods and
drinks) Regular surveillance for malignant transformation
Photobiomodulation Therapy (PBM therapy):
PBM will be given with 940nm long infrared wavelength diode laser with following
specifications Biolase Epic X Diode LASER (USFDA and CE approved) LASER Classification-
IV Medium- InGaAsP Semi-Conductor Diode Wavelength- 940+10nm Maximum Output Power= 10W
Pulse repetition rate= upto 20kHz Pulse duration Rate= 0.01ms- 20ms Power modes-
Continuous/ Pulsed Protocol for PhotoBioModulation( PBM) therapy Protocol for PBM therapy
has been made as per guidelines of the consensus statement ( Zelcha et al 2016) regarding
the applications, protocols, safety, dosimetric considerations of PBM in management of
side effects of chemoradiation therapy in Head and neck cancers like mucositis and
fibrosis.
Protective laser wavelength specific eyewear will be used for patient, operator. The
device will be used according to the manufacturer's instructions and calibration before
each therapy in the trial. The surgical handpiece (diameter 0.6cm) will be used without
the fibre optic tips in defocused mode and head sanitized before therapy.
Peak Power : 0.3Watts Power density: 1 Watt/cm2 Fluence: 4J/cm2 per cycle Spot size :
0.28cm2 Distance : 2mm from surface Mode: Continuous, Non- contact mode, circular motion,
overlapping, in clockwise concentric manner with laser handpiece perpendicular to surface
Duration of cycle : 20 seconds with interval of 30 seconds alternating with other side
Cycles per sitting: Three for each side Four Sittings: Day 0,3, 7, and 15 Intraoral:
Bilateral buccal mucosa will be divided arbitrarily into three zones superior, middle and
inferior for equal distribution of laser energy during each cycle Extraoral :Bilateral
masseter muscle will be divided into three zones superior, middle and inferior for equal
distribution of laser energy during each cycle Therapeutic monitoring: Site of
application of LASER will be evaluated continuously for any discomfort, signs of
inflammation like redness of skin/ mucosa during therapy and during follow up. The
following options will be considered during therapy Move the Handpiece relative to the
affected anatomy. Defocus the energy by moving the Handpiece further away from the skin.
Decrease the power setting.(considering the Fitzpatrick Skin type scale) Stop/ Defer the
treatment. Patient will be interviewed to know any adverse effects they might be feeling
after initiation of treatment with Laser.
Training of operators:
All the operators giving intraoral and extraoral PBM therapy will be trained in the
protocol as per study before subject recruitment.
Withdrawal criteria: If any patient withdraws consent after treatment is initiated or
develops any of the conditions mentioned in exclusion criteria, the patient will be
withdrawn from the study.
Protocol Deviation : When/If subjects develop changes suspicious of malignancy (erosion,
ulceration, induration, exophytic growth) during follow up after Usual care/PBM, they
will undergo incisional biopsy to rule out malignant changes and managed as per
institutional protocol for oral malignant lesions by referral to cancer center at IRCH.
Statistical Analysis: Data will be entered in an electronic data form and managed using
Research Electronic Data Capture (REDcap) software. Comparison of baseline continuous
variables will be compared between the two groups( A and C, B and C) using Unpaired
T-test and categorical variables will be compared using Chi Squared Test or Fisher's
Exact Test. The primary outcome measure- Interincisal Distance at maximum mouth opening
will be compared between the two groups using Unpaired T-test and analyzed using
Intention to Treat and Per Protocol Analysis. Secondary continuous outcome variables will
be compared between the two groups using Unpaired T-test or Wilcoxon Rank Test as
appropriate. Secondary categorical outcome variables will be compared between the two
groups for two proportions/Z-test. Comparison between primary and secondary outcome
variables between groups A and B will also be done using the same scheme although the
sample size is not estimated for the same. Results will be presented as Difference in
Means/Proportions with 95% confidence interval and p<0.05 will be considered
statistically significant.