This is a parallel group, single centre, examiner-blind, non-inferiority randomised
controlled trial (RCT) to compare the effect of the interventions below in the healing
of periodontal intrabony defects in 66 periodontitis (CP) patients:
- a novel non-surgical treatment protocol (modified MINST)
- a surgical protocol (M-MIST)
Inclusion Criteria
The following criteria will be considered for inclusion in the study:
i) Age 25-70, ii) Diagnosis of ‘Periodontitis’ stage III or IV (grades A to C), iii)
Presence of ≥1 ‘intrabony defect’ (PPD, >5 mm with intrabony defect depth ≥3mm at
screening radiograph), iv) Signed informed consent.
Exclusion Criteria
i) Smoking (current or in past 5 years), ii) Medical history including diabetes or hepatic
or renal disease, or other serious medical conditions or transmittable diseases, ii)
History of conditions requiring prophylactic antibiotic coverage prior to invasive
dental procedures, iii) Anti-inflammatory or anticoagulant therapy during the month
preceding the baseline exam, iv) Systemic antibiotic therapy during the 3 months preceding
the baseline exam, v) History of alcohol or drug abuse, vi) Self-reported pregnancy
or lactation, vii) Other severe acute or chronic medical or psychiatric condition
or laboratory abnormality that according to the investigator may increase the risk
associated with trial participation, viii) Periodontal treatment to the study site
within the last 12 months.
Study Design / Plan – Study Visits
All patients will be recruited from the Restorative and Periodontal new patient clinics
at Barts & The London Dental Hospital, where potentially suitable new periodontitis
patients will be informed about the study. Then a member of the research team will
approach potentially-interested patients, will provide more information about the
study procedures together with the benefits and risks of participation and will give
suitable patients the Patient Information Sheet, which they will be advised to read
carefully. Potential participants will be informed that they will be allowed to withdraw
their participation at any stage of the study. The patients will then be contacted
within 1 week to enquire about their willingness to take part in the study and to
give them the opportunity to ask any questions about the study. Upon agreeing to partake,
they will be offered a baseline appointment. A written informed consent (including
clinical procedures and collection of study samples) will be obtained before enrolment.
Informed consent will follow the Barts and The London and QMUL standard operating
procedures and will be conducted by staff trained in taking consent.
Study visits
Each subject will attend between 8 and 13 study visits over a period approximately
16 months (attached Table 1 with study visit schedule and procedures). All the visits will take place in the clinics of Barts & The London Dental Hospital. The schedule of assessment is also presented in Figure 1 (‘Study plan and visits’)
and in Figure 2 in the form of CONSORT diagram.
Study procedures
Medical history
A complete medical history will be obtained at the screening visit, including demographic
background information and dental status information. This will be reviewed and updated
throughout the duration of the study. All concomitant medications, procedures and
adjunctive product use will be monitored and recorded throughout the study. Tobacco
use history will be recorded at baseline based on self-report. Body Mass Index will
be calculated after measuring participants’ height and weight.
Clinical periodontal assessment
The following periodontal measurements will be taken by the calibrated examiner (author
VK) at six sites/tooth using a manual University of North Carolina (UNC-15) periodontal
probe (Hu-Friedy, Chicago, IL): dichotomous full mouth plaque scores (FMPS) [19], full mouth probing pocket depth
(PPD), recession of the gingival margin from the cemento-enamel junction (CEJ), dichotomous
6-point bleeding on probing (FMBS) [19], tooth mobility [20] and furcation involvement
with a Nabers probe (Hu-Friedy, Chicago, IL) [21]. Clinical attachment level (CAL)
will be calculated as PPD+ recession. The Early Healing Index [22] will be measured
for controls 1 week after surgery. Dentine/root sensitivity (DS/RS) will be assessed
on the tested intrabony tooth and on the 2 neighboring teeth, following isolation
using cotton wool rolls, by using an evaporative/thermal stimuli from a one second
blast of air from a dental unit syringe at 40–65 psi (19°-23°C) directed perpendicular
to the tooth surface at a distance of 0.5-1cm to the exposed root surface (Evaporative
Examination) [23]. Following the air blast, the subject will be given a Visual Analogue
Scale (VAS) form to complete each assessment. The VAS is scored from 0= no pain to
10=extreme pain and the subject can indicate the degree of discomfort by indicating
either a numerical value from 0-10 or by marking vertically across the VAS scale.
Repeatability
Following initial training, for a repeatability exercise the examiner and back-up
examiner will perform repeated examinations on 10 subjects for PPD and recession with
at least 15 minutes separation. Upon completion of all measurements, intra-examiner
repeatability for PPD measurements will be assessed. In order to test inter-examiner
repeatability, at least 10 subjects will be probed twice (once by each examiner).
The reproducibility of the examiner will be tested using the Bland–Altman approach
[24] and by calculating Lin’s concordance correlation coefficient [25]. A co-efficient
of repeatability less than ± 2mm in 95% of the cases is considered acceptable. If
this target is not achieved, further examiner assessment and training will be carried
out before a new reproducibility exercise.
Clinical photographs
Clinical photographs and videos of procedures carried out, will be taken in some of
the study visits for better documentation of cases and will be anonymized and stored
in the study database.
Radiographic analyses
Standardised radiographs of selected study sites will be taken at baseline and at
the 9-month and 15-month follow-up visits using the parallel technique with a customised
holder and an occlusal platform, which will allow a cold-cure acrylic resin occlusal
registration to be made (bite index), facilitating relocation of the holder and preserving
the projection geometry in subsequent radiographs. Aluminium stepwedges will be used
as a densitometric reference, in an attempt to minimize errors due to variation in
exposure time and/or film processing which may result in false positive analysis [26].
The linear radiographic measurement analysis will be carried out by a single calibrated
examiner using semi-automated radiographic software with specific landmarks, as described
by Nibali et al. [27]. In brief, horizontal and vertical bone loss of the intrabony
defects will be measured after identifying the following landmarks in periapical radiographs:
cemento-enamel junction (CEJ) on the tooth with the intrabony defect, most coronal
part of the alveolar bone and most apical part of the alveolar bone crest, where the
periodontal ligament space was judged to retain its normal width. The radiographs
will be analysed by the same trained and calibrated examiner in a masked, random order
with the use of a computer software measurement tool (Emago®, Oral Diagnostic Systems,
Amsterdam, Netherlands).
Test procedure (MINST)
Based on our previous study [17], a modified MINST protocol for this study consists
of the following:
Local anaesthesia by infiltration without adrenaline in the study site (not intrasulcular)
Thorough debridement of the root surface up to the bottom of the periodontal pocket
under local anesthesia
Attempt to minimize the trauma to the soft tissues and especially to the papilla,
using a sub-papillary access for debridement (trying not to touch the most coronal
part of the interdental papilla)
Use of exclusively piezo-electric devices with specific thin and delicate tips
Deliberately avoid to ‘smooth’ the root surface or to perform gingival curettage
Use of 3-4x magnification loupes
Attempt to stimulate the formation of a stable blood clot, by natural filling of the
intrabony defect with blood following debridement (no use of any subgingival rinses)
This modified protocol differs slightly from the published protocol [17] in the use
of a sub-papillary access, exclusively piezo-electric devices (no curettes), the specific
use of anesthesia without adrenaline and not intrasulcular, and the first subgingival
probing at 6 months post-treatment (rather than 3 months). These slight refinements
from the earlier studies [17] aim to further reduce tissue trauma and to stimulate
a stable blood clot, for optimal healing. This modified MINST protocol will be applied
to the intrabony sites and all other affected sites in test patients. The same treatment
protocol is currently being tested in a separate single-arm prospective multicenter
study (clinicaltrials.gov reference NCT03741374).
Control procedure (M-MIST)
This will be performed as described in the literature [28,14]:
Scaling and root planing using conventional ultrasonic tips and curettes under local
anaesthesia
Periodontal re-evaluation and charting 3 months later
In case of residual PPD>5mm, surgical access, with the following protocol:
Ideally, the experimental sites will be accessed with the M-MIST technique (elevation
of only buccal flap with simplified or modified papilla preservation incisions, no
papilla elevation) and carefully debrided.
When a defect wraps around the lingual aspect of a tooth and the M-MIST is not applicable,
elevation of the inter-dental soft tissues becomes necessary and a MIST becomes the
preferred approach. This consists of elevation of small buccal and lingual flaps (with
modified papilla preservation incision in case of interproximal space width of at
least 2 mm or otherwise simplified papilla preservation [29]
When the position of the residual buccal/lingual bony wall(s) is very deep and difficult
or impossible to reach with the above-described minimal incision of the defect-associated
inter-dental space, the flap(s) will be further extended mesially or distally involving
one extra inter-dental space to obtain a larger flap reflection [29].
Should the FMPS not reach the threshold below 25% before surgery, additional OH instructions
will be given before proceeding with surgical intervention. If after 3 additional
OH sessions, the FMPS is still not below 25%, the patient will be exited from the
study as not considered suitable for surgery [30]. Measurements will be taken during
surgery to characterize the defect anatomy (number of walls, depth, and width). No
regenerative material/devices will be applied. Flaps will be sutured with modified
internal mattress sutures (and single interrupted sutures if necessary).
Need for further treatment during and following study completion
Treatment to sites other than the selected ‘intrabony site’ throughout the study will
consist of subgingival debridement (as allocated by randomization in test and control
patients) and supportive therapy as per protocol. The need for other surgical interventions
will be reviewed following the 15-months follow-up. Should deterioration be detected
during the study in any sites, where urgent need for surgery or antibiotics is needed,
this will be carried out in additional visits during the study and will be documented
in the case-report forms. Following the 15-month follow-up, the possible need for
further treatment will be assessed based on residual PPDs > 5mm [31, 4].
Gingival crevicular fluid (GCF) sampling
An ‘intrabony site’ (IS) and a ‘comparison site’ will be chosen for sampling for each
patient among buccal sites. The ‘intrabony’ site is selected according to the inclusion
definitions above. In case of multiple IS per patient, the site with deepest PPD will
be chosen. The ‘comparison’ site will be a site with PPD<4mm and not bleeding on probing
at the screening visit. Samples of GCF will be collected from the selected IS and
CS (for both test and control subjects) at baseline, at the 3-months visit and at
9 and 15 months follow-ups, prior to periodontal probing to avoid contamination by
blood. In the 20 randomly selected subjects taking part in the ‘GTI sub-study’, additional
GCF sampling will be conducted at day 1- and day 5- visits following initial treatment
(for both test and control subjects). Saliva will be removed from the supra-gingival
area using saliva ejector and cotton rolls, being careful not to touch the gingival
margin area; supra-gingival plaque, if present, will be removed using a curette to
prevent saliva and/or plaque contamination. GCF will be collected for 30 seconds using
methylcellulose strips carefully placed gently at the entrance of the sulcus until
slight resistance is felt. GCF volume will be routinely estimated by Periotron (OraFlow
Inc., New York, U.S.A.). GCF will be immediately extracted in acidic buffer to better
preserve inflammatory mediators of periodontal disease from breakdown and/or oxidative
processes, which occur on major extent on the paper strips during the storage [32].
GCF samples will be then immediately placed into small conic vials and stored at -80°C
until time of analysis. Samples will then be processed at the Blizard Institute, Barts
and the London School of Medicine & Dentistry, where immunoassay of inflammatory molecules
(including for example levels of cytokines) and growth factors (including for example
BMP-2; bone morphogenetic protein-2) in the GCF will be performed. COCR and the Blizzard’s
local standard operating procedures, working practices and risk assessments will be
followed to ensure the integrity and viability of all samples to be anonymised, labelled,
stored and transferred.
Subgingival plaque sampling
Following GCF collection, ‘intrabony site’ and ‘comparison site’ will have samples
of subgingival plaque collected (for both test and control subjects) from the palatal-lingual
aspect. Plaque samples will be collected from the selected IS and CS (for both test
and control subjects) at baseline, at the 3-months visit and at 9- and 15-months follow-ups.
In the 20 randomly selected subjects taking part in the ‘GTI sub-study’, additional
plaque sampling will be conducted at day 1- and day 5- visits following initial treatment
(for both test and control subjects). Ahead of the sampling procedure, the supra-gingival
plaque will be carefully removed, the site isolated with cotton rolls and gently dried.
A sterile curette will then be inserted to the bottom of the pocket and removed after
a single stroke and the content will be placed in a test tube containing reduced transport
fluid until time of analysis. Plaque samples will be analysed using next generation
marker DNA sequencing to characterise the subgingival microbiota in order to identify
and determine the levels of key periodontal bacterial pathogens and microbial community-wide
changes in sites treated with both test and control protocols.
GTI (Geometric/Thermal Imaging) sub-study
A random sample of 20 subjects (10 in each arm) will be randomly selected to take
part in the Geometric/Thermal Imaging (GTI) sub-study. The GT image capturing is based
on the principle of optical triangulation, it is non-contact and non-invasive to patient
and it aims to clarify differences in the wound healing pattern and association to
clinical and patient-centered outcomes between the two groups. These subjects will
undergo all study visits in the same way as other subjects but will attend the additional
imaging analysis at some study visits, as well as at some additional visits as outlined
below. The image capture, analysis and measurements will be performed in the selected
participants at baseline, day-1 and day-5 after non-surgical treatment, 3-month and
9-month follow-ups and, in the surgical group, additional measurements will be performed
at 1-week and 1-month after surgery.
Patient-reported outcomes (PROMS)
A substantial body of evidence suggests that presence of periodontitis has a considerable
effect on the quality of life of affected individuals [33]. This effect will be assessed
by measuring patient-reported outcome measures (PROMs). Patient-reported outcomes
will be collected using validated patient questionnaires (OIDP, EQ-5D, global ratings
for periodontal health and QoL) [34, 35, 36] at baseline, 3-, 9- and 15-months follow-ups.
In addition, subjects allocated to the control group (MIST) will provide PROMS at
the 1-week review appointment after the surgical procedure. Furthermore, the subjects
allocated to the GTI subgroup will provide PROMS at the 1- and 5-days post-treatment
visits.
Statistical analysis plan
Primary Objectives and Outcomes: To investigate whether MINST is not inferior to M-MIST
in terms of intrabony defect depth healing in patients with periodontitis after 15
months follow-up, measured as:
Primary outcome: Radiographic intrabony defect depth change
oPPD and CAL change (in mm)
o
Inflammatory markers and growth factors in gingival crevicular fluid (GCF)
o
Bacterial detection associated with presence of intrabony defects
o
Gingival inflammation and healing (as measured by geometric/thermal camera imaging
in a subset of 10 test and 10 control patients)
o
Patient-reported outcomes
The sample size calculation was based on the assumption that the proposed modified
MINST protocol is an acceptable alternative to the M-MIST protocol (non-inferiority),
with the advantage of reduced costs and morbidity. A non-inferiority margin of 1 mm
is considered to be the largest difference that is acceptable between MINST and M-MIST
(a lower threshold than the expected difference in bone gain between regenerative
surgeries and open flap debridement in intrabony defects) [12] for MINST to be adopted
in clinical practices because of the associated advantages of MINST. Single flap approaches
such as M-MIST have previously been reported to lead to radiographic bone gains from
1.8 mm ± 1.2 [37], 2 mm [38] to 3.5 ± 1.0 mm [14] in small trials. MINST has been
reported to lead to 2.4 ± 2.1 mm radiographic bone gain in a retrospective study [17].
Therefore, we assume that the two protocols lead to the same bone gain for the sample
size calculation. Accounting for a 10% drop-out rate and using a pooled standard deviation
of 1.27, recruiting n=66 participants will be sufficient to confer 90% power to reject
the inferiority null hypothesis. Should the true mean bone gain difference between
MINST and M-MIST be 0.19 mm in favour of M-MINST the study would retain statistical
power of 80%. The primary outcome analysis will compare the intrabony defect depth
between treatment groups at 15 months using a general linear model (ANCOVA) with treatment
as a factor and the corresponding baseline value as a covariate and adjusting for
pre-specified prognostic baseline factors (age, FMPS, BMI, defect angle, tooth mobility).
For the primary efficacy endpoint, non-inferiority of M-MIST to MINST could be claimed
if the lower limit of the 95% confidence interval (for the difference in mean change
of radiographic intrabony defect depth change) was greater than −1.0mm. The primary
outcome analysis will be the per-protocol analysis and the intention-to-treat analysis
considered as sensitivity analysis. For other non-inferiority endpoints the per-protocol
analysis will also be considered the main analysis. Superiority endpoint will be analysed
on an intention-to-treat basis. Subject-based and site-based analyses will be conducted.
PROMs analysis will be based on linear or logistic regression (for continuous/categorical
variables) comparing PROMs scores or categories of scores at follow-up (3-, 9- and
15-months post-intervention) between the two groups, accounting for the respective
scores at baseline. We will also look at the minimally important difference for PROMs
where applicable, such as in the case of the OIDP, and whether any difference between
the two groups is clinically meaningful.
Data management
All data will be entered in a dedicated secure database application with secure web
connection (REDCap). A customised REDCap project will be set up for this study and will be used to cover
all data capture for the study. Different levels of access will be set up for the
different end users/study team delegates. Data will be proofed for entry errors before
being locked and exported for analysis.
Randomisation and allocation concealment
Following the baseline visit, all participants enrolled into the study will be randomly
assigned to one of the two treatment groups and whether or not to be included into
the GTI sub-study; that is, individual level randomisation to MINST, M-MIST, MINST
+ GTI or M-MIST + GTI will be performed using a 2:2:1:1 allocation ratio. Random permuted
block randomisation with block sizes 6 and 12 will be employed. The centralised online
randomisation service ‘Sealed Envelope’ with web front-end will be used ensuring allocation
concealment. No minimization or stratification is planned.
Blinding
Due to the nature of the intervention only blinding of all outcome examiners is possible.
Both participants and clinicians administering treatment will be unblinded. Members
of the trial steering committee and other study team members will remain blinded to
treatment allocation until the randomisation code is broken (after last follow-up
data is recorded and the database locked).
Potential Risks or Burdens for Research Participants and How to Minimise Them
No risks or burdens are expected from the basic periodontal examination and treatment.
Minor pain or discomfort may follow the sub gingival debridement and can be easily
controlled by using 0.2% chlorhexidine gluconate solution rinse and, if needed, paracetamol
2x 500 mg up to 4 times a day for the first two days. The surgical interventions are
also standard routine procedures and will be carefully planned and performed under
local anaesthesia. The following post-operative regime will be followed in the first
and second weeks following the completion of the treatment in order to minimise the
patient's discomfort and risk of complications: post-operative pain will be controlled
with paracetamol if required, all patients will be instructed to discontinue locally
tooth brushing at the surgical site to minimise trauma and to rinse with 0.2% chlorhexidine
digluconate 2 times/day for the first 2 weeks.
Adverse Events (AEs) which may be related to Periodontal Surgery, Geometric-Thermal
Images and other dental or non-dental (including samples’ collection) procedures may
be recorded on the AE log based on the study medical team assessments. AEs which are
assessed by the study medical team as deviating; i.e. in severity, intensity and frequency;
from potentially expected AEs will be recorded on the AE log. Potentially expected
AEs are commonly-reported adverse events following non-surgical and surgical periodontal
therapy such as gingival bleeding, bruising and swelling in the first 2-3 days post-therapy
and increase in tooth sensitivity in the first 1-2 weeks post-therapy.
Any serious adverse event (SAE) occurring to a research participant will be reported
to the sponsor within 24 hours of learning of the event and to the REC within 15 days
if in the opinion of the Chief Investigator the event was related to the study research
procedures and unexpected.
Risk considerations for this study include the following:
1) Safety of patients’ sensitive data: we will mitigate this by following the current
information governance regulations. All patients’ data held will be coded and anonymised,
encrypted and physically stored in a protected (locked or in a cloud) data point.
2) Safety of dental and other procedures: all dental or other procedures (including
radiographs and sample collection) proposed in this study fall within the scope of
mainstream periodontal treatment. Furthermore, all clinical treatment will be performed
by an appropriately trained clinician. In case of unfavourable adverse event or reaction,
the study medical team will assess its severity, relatedness and potential consequences
to the study patients and will make an informed decision as per the patient suitability
to remain or be exited from the study. Should the patient be exited from the study
he/she will be offered appropriate periodontal or dental treatment and any other support
as needed.
3) Risk of not being able to complete the study due to lack of patient recruitment:
careful analysis of patient flow and current experience from other studies has estimated
that 66 suitable patients could be screened and enrolled in 6-7 months. If not, study
recruitment period will be extended or other contingencies will be sought after including
opening more sites if needed.
Reporting of any suspected expected or unexpected serious adverse events will be communicated
to the study sponsor following standard research governance protocols as well as to
the REC committee approving this study. The study monitoring will be performed by
the Clinical Research Facility manager and/or the study coordinator in pre-determined
intervals as per monitoring and management plan. Annual & safety reports to REC committee
will be submitted annually whilst notifying the REC of any corrective actions or mitigations
and contingencies planned or implemented as necessary.
Data handling and record keeping
Barts Health NHS Trust will collect information from patients in order to contact
them when needed and to make sure that relevant information about the study is recorded
for their care. Barts Health NHS Trust will keep identifiable information about patients
in this study for 20 years after the study has finished. Information related to participants
will be kept confidential and managed in accordance with the General Data Protection
Regulation (GDPR) (EU) 2016/679 Data Protection Act, NHS Caldecott Principles, The
Research Governance Framework for Health and Social Care, and the conditions of Research
Ethics Committee Approval.
Monitoring and auditing
Internal regular monitoring visits will take place to ensure that all trial’s related
activities are conducted according to the trial protocol and the data were recorded,
analysed and accurately reported according to the protocol, sponsor's standard operating
procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).
Internal audits may be conducted by a sponsor’s- QMUL- or funder- Bart’s Charity for
this study- representative if deemed necessary. The QMUL Centre for Oral Clinical
Research (COCR) will internally monitor and manage the study on behalf of the sponsor
(QMUL). The trial management and monitoring plan (including the frequency of monitoring
visits), the level of Source Data Verification (SDV) and percentage of consent monitoring
or the level of proportional review for data transfer from source docs to Case Report
Forms (CRFs) will be set up at the beginning of the trial by COCR delegated personnel.
Any arrangement for monitoring and auditing the conduct of the study will be critically
examined to ensure it complies with the relevant parties’ allocation of responsibilities
as set out in the Research Governance Framework.
Trial committees
Focus groups including study investigators, nurses, patients and members of the public
were organised in the planning stages of the study and then to review study documents
including patient information sheet and consent form. A study specific Trial Management
Group (TMG) will take place ideally every month including the study CI as well as
the relevant co-investigators and other team members. TMGs are aimed at discussing
the routine management of this research project and any clinical or other type of
deviations from the study protocol, sponsor's SOPs, GCP and the applicable regulatory
requirement(s). A Trial Steering Committee (TSC) including the trial statistician,
the study CI, the imaging scientist, co-investigators or collaborators, the study
data management and coordinating team, a member of the public and a patient representative
will convene ideally every 6 months. Study focus groups including 1 or 2 study investigators,
study coordinator or nurse and a panel of 4-5 individuals selected from hospital patients
and public will be held annually starting from the set-up phase, in order to advice
on study design and delivery.
Dissemination
Results of this study are likely to be disseminated through scientific dental journals
with open access policies and International periodontal conferences. Public access
to the full protocol, participant-level dataset, and statistical code will be provided
upon reasonable request. We also plan to disseminate our research findings in a language
that needs to be easily understood by a lay person attending the local public engagement
meetings, through leaflet distribution and our webpages and with the use of patient
forums. Dissemination of project outcomes will also take place across the larger Bart’s
Health communities and stakeholders, setting up future research pathways, support
and collaborative agreements.