Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03069079 |
| Other study ID # |
COCR0004 |
| Secondary ID |
01137415/LO/1090 |
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
December 2016 |
| Est. completion date |
December 2019 |
Study information
| Verified date |
December 2016 |
| Source |
Queen Mary University of London |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Title: Investigation of neutrophil defects associated with periodontal disease and tooth loss
in children. A clinical study.
Objectives: The primary objective of this study is:
- To investigate presence of periodontal disease and response to periodontal treatment in
children affected by neutrophil defects
The secondary objectives of this study are:
- To investigate presence of other dental diseases in children affected by neutrophil
defects
- To assess oral microbiological and inflammatory parameters in children affected by
neutrophil defects
Primary outcomes: The primary outcomes are (a) presence of periodontal disease as assessed by
clinical factors: probing pocket depth, attachment level, bleeding on probing and
radiographic bone loss) (b) microbiological and host response factors: detected in
periodontal pockets and gingival crevicular fluid and (c) response to treatment
Study sample: Children affected by neutrophil defects and meeting outlined inclusion and
exclusion criteria
Number of participants: 50 children
Study design: This is a longitudinal treatment study. All participants will attend for 4-7
visits during the study as outlined below:
- Screening visit (visit 1): consent procedure, dental examination, saliva and plaque
sampling
- Baseline visit (visit 2):, detailed periodontal examination, dental radiographs,
sampling of gingival crevicular fluid and, if appropriate scaling, polishing and oral
hygiene instructions
- Non-surgical periodontal treatment (visit 3A to 3D, max 4 sessions): oral hygiene
instructions and supra- and sub-gingival debridement (under local anaesthesia if
necessary)
- Follow-up Visit (visit 4, 4th to 7th visit) (six months following treatment): detailed
dental examination, oral hygiene instructions, sampling of saliva, subgingival plaque
and gingival crevicular fluid, tooth scaling and polishing.
Description:
1. BACKGROUND Primary immunodeficiency diseases (PIDs) are a group of rare inherited
disorders that are estimated to affect approximately 1 in 2,000 children. In PIDs there
is an intrinsic defect in the human immune system, such as a failure to produce enough
antibodies to fight infection, or a failure in the cellular defences against infection .
These conditions usually manifest themselves early in life and are often
life-threatening. Rarer, severe forms of PIDs present in childhood with serious
infections and are often associated with additional autoimmune and inflammatory
complications. Periodontal diseases are inflammatory diseases of the gingivae (gums) due
to an imbalance in the host response to subgingival bacteria and are associated with
destruction of the supporting tissues of the teeth and early loss of the dentition and
masticatory function. While periodontitis and its non-destructive partner condition,
gingivitis (reversible plaque-induced gingival inflammation), are very common, the
prevalence of periodontitis in the primary dentition and in the second decade of life
appears very low, ranging from 0.1% to 1%. This prevalence increases dramatically in
children affected by PIDs, to the point that periodontitis is considered a common
feature of syndromic genetic conditions due to single gene defects affecting the host
response, such as leukocyte adhesion deficiency (LAD), severe congenital neutropenia,
cyclic neutropenia and Chediak-Higashi syndrome. Children with defects in neutrophil
activity seem particularly susceptible to develop severe periodontitis, due to the
important defensive role of neutrophils against periodontopathogenic bacteria. In such
cases, both primary and permanent dentitions are affected, with a devastating effect on
mastication, aesthetics and quality of life, also owing to the lack of reliable
restorative solutions. Furthermore, oral diseases (in particular periodontitis) may also
provide an additional systemic inflammatory burden for these subjects. This could occur
since periodontal bacteria have been shown to enter the systemic circulation from
inflamed gum tissues even during normal tooth brushing, have been found in atheromatous
plaques and in the amniotic fluid of pregnant women.
The treatment of periodontitis involves a non-specific reduction of the bacterial load
below the gingival margin, achieved by oral hygiene instructions and non-surgical
periodontal therapy (NSPT). More advanced cases need antibiotics, surgical treatment or
extractions. In children with PID the response to this treatment is highly variable and
the presence of periodontitis often leads to early tooth loss, adding to the poor
quality of life of sufferers. Incorporation of periodontal screening has been advocated
for early diagnosis and treatment of periodontal diseases in all children and especially
for children with neutrophil defects, in order to prevent disease progression and tooth
loss. However, most published papers on periodontitis in children with
immunodeficiencies are case reports or familial observations or reviews. Therefore,
there's a lack of well-designed studies investigating both the prevalence of
periodontitis and oral diseases in general in children with neutrophil defects and their
response to treatment. In particular, it is not clear which factors determine the onset
of periodontitis in a subset of children with PID. Such factors may range from the
composition of the subgingival microbiota, the immunological reaction against these
bacteria, to the inflammatory response in the periodontium. A better understanding of
the causative factors may help in early diagnosis and treatment, reducing the burden on
affected children.
2. AIMS AND OBJECTIVES
The hypotheses behind this study are that:
i) Specific microbiological and host response parameters dictate severity of periodontal
diseases and associated risk of early tooth loss in children suffering from neutrophil
defects ii) Periodontal treatment in children with neutrophil defects and periodontitis
can lead to an improvement in their oral health (reduction in periodontal pockets and
bleeding scores), which would reduce their risk of tooth loss and potentially improve
their future quality of life.
Therefore, the aims of this study are to offer specialist periodontal assessment and
treatment to children with neutrophil defects, to determine the impact of neutrophil
defects upon gingival health and to assess their response to periodontal therapy. This
will facilitate the development of novel therapeutic management pathways specific for
these conditions, and will determine whether there is a need for specific care protocols
with a consequent improvement in tooth retention, quality of life and systemic health.
- The primary objective of this study is:
- To investigate presence of periodontal disease and response to periodontal
treatment in children affected by neutrophil defects
- The secondary objectives of this study are:
- To investigate presence of other dental diseases in children affected by
neutrophil defects
- To assess oral microbiological and host response parameters in children
affected by neutrophil defects.
3. STUDY DESIGN 3.1 Overall study plan This is an exploratory longitudinal study. Fifty
children affected by neutrophil defects potentially affecting the periodontium will be
identified from subjects attending the Immunology and Haematology clinics at Great
Ormond Street Hospital (GOSH), following a medical examination. All children will
undergo a dental examination by a qualified dentist currently completing specialist
training in periodontology. Children will also provide samples of gingival crevicular
fluid (GCF) and subgingival plaque. Following the baseline, non-surgical periodontal
therapy will be provided as necessary and participants will be followed-up and
re-examined up to 6 months after treatment.
4. STUDY POPULATION 4.1 Participant Selection Fifty children affected by neutrophil defects
and under care at Great Ormond Street Hospital (GOSH) and meeting the inclusion criteria
will participate in the study. Most children attend GOSH regularly (at least 6-monthly)
for review/treatment planning appointments (seen by Dr Ancliff or Dr Worth). The
parents/guardians of potentially suitable children will be initially contacted by letter
prior to their attendance at GOSH. Every invitation will be followed up by a telephone
call to discuss any issues and enquiry about willingness to participate. When possible,
upon parents' agreement about study participation, patients could be enrolled and
undergo the screening visit on the same day as their routine GOSH visit (this would save
on extra travel for patients living outside London). Alternatively, they will be offered
another appointment. All the study visits will take place at GOSH. QMULwill only serves
as the sponsor and coordinating centre for this study. .
5. STUDY VISITS Study visits include baseline, non-surgical periodontal therapy and
follow-ups. All visits will be carried out at Great Ormond Street Hospital.
5.1 Visit 1 (Screening) o Informed consent
o Collection of data on clinical and laboratory diagnosis, time of diagnosis, previous
and current systemic treatment and on any previous dental treatment
o Basic Periodontal Examination (BPE) and assessment of caries (DMFT) and mucosal
diseases
o Saliva and plaque sample
- Clinical photographs
- Treatment plan All children found to have BPE scores of 1 (gingival bleeding), 2
(presence of calculus), 3 or 4 (presence of gingival pockets) will be offered the
possibility to enter the treatment phase of the study (from visit 2 onwards), which
will be provided at GOSH. Children found not to be affected by periodontal diseases
will be offered the possibility to be seen at GOSH for visit 2 only, if they wish
so.
5.2 Visit 2 (Baseline and first treatment session- ± 28 days) o Recording of any adverse
events (AE or concomitant medication)
- Full periodontal examination including collection of periodontal measurements (and
dental radiographs if appropriate)
- Gingival crevicular fluid (GCF) sample
- Session of tooth scaling, oral hygiene and polishing
All children found to require further treatment will need to attend an additional 1 to 4
treatment sessions at GOSH as detailed below:
5.3 Visit 3A to 3D (treatment, within 2 months of visit 1, from 1 to 4 visits) Update
medical history, check adverse events, non-surgical periodontal therapy (maximum 4
sessions): oral hygiene instructions and supra- and sub-gingival debridement.
5.4 Visit 4 (last follow-up, 6 months after last treatment visit ± 21 days) Update
medical history, check adverse events, dental examination and collection of periodontal
measurements, perform oral hygiene instructions, sampling of saliva, subgingival plaque
and gingival crevicular fluid, tooth scaling and polishing (if needed).
5.5 Medical and dental history A complete medical and dental history will be obtained
during screening and confirmed during the baseline visit. Information on previous
medical tests and status of current treatment will be obtained by the treating GOSH
physician. The histories will include demographic background information, ethnicity,
systemic and dental status information.
5.6 Concomitant medications All concomitant medications will be recorded throughout the
study.
5.7 Periodontal examination At the screening visit, a Basic Periodontal Examination
(BPE) will be performed, consisting of gentle probing between teeth and gums on index
teeth (UR6, UR1, UL6, LL6, LL1 and LR6 or URd,URc,ULd,LLD,LLc,LRd) to identify presence
of gum disease. A number between 0 (health) and 4 (gingival pocket>5mm) will be recorded
for each quadrant. The dmft/ DMFT (decayed missing filled teeth) index will be used for
recording caries experience. Mucosal status will be investigated by recording presence
of ulcers, blisters, white patches, speckled areas and masses. Saliva samples and plaque
samples will be collected. At the baseline visit, a calibrated dental examiner will
perform a more detailed assessment, consisting of collection of full-mouth measurements
of probing pocket depth (PPD), clinical attachment level (CAL), gingival bleeding on
probing gingival crevicular fluid sampling and assessment of plaque levels (simplified
visible biofilm index).
5.8 Dental sampling A series of samples will be collected from the patients' oral cavity
(sample of saliva, GCF and subgingival plaque biofilm). GCF will be taken by gentle
insertion of 4 paper-strips in the gingival crevice of the mesio-buccal aspect of 4
teeth (3 first molars and 1 incisor). Subgingival plaque will be collected by the
examiners following gentle insertion of a curette at the base of 3 first molars and 1
first incisor sites (one in each quadrant). In case of absence of permanent molars, the
samples will be collected from the second deciduous molars. The 4 subgingival samples
will be pooled together.
5.9 Definition of periodontal disease
Following the periodontal examination, children will be diagnosed as:
- Healthy: no attachment loss (measured as no CAL>3mm or CAL>3mm in <2 non-adjacent
teeth) and no/minimal gingival inflammation (measured as <15 sites bleeding on probing)
- Gingivitis: no attachment loss (measured as no CAL>3mm or CAL>3mm in <2 non-adjacent
teeth) and presence of gingival inflammation (≥15 sites bleeding on probing)
- Periodontitis: attachment loss (measured as CAL>3mm in ≥2 non-adjacent teeth)
5.10 Dental radiographs If a BPE code 3 or more is detected, bite-wings or long cone
parallel periapical radiographs (more indicated for a BPE of 4) using Rinn holders will
be taken to detect marginal bone levels, according to clinical needs. The distance
between coronal and apical bone levels and cemento-enamel junction will be analysed as
described previously, also taking into account age of the patient, tooth eruption stage
and presence of primary, mixed or permanent dentition. Radiographs will then be
digitized for future analysis using an image-analysis software.
5.11 Non-surgical periodontal treatment All children will be offered an oral hygiene and
tooth scaling and polishing session. For children affected by periodontal disease,
subgingival debridement will also be performed according to needs, with the aim to
disrupt the subgingival biofilm responsible for the onset and progression of the
periodontal pathology. This can be accompanied, when appropriate, by the use of local
anaesthesia and adjunctive antimicrobials (systemic or locally applied subgingivally),
according to the clinical presentation and the child's medical conditions. In addition,
when required, nitrous oxide sedation (NOS) could be used before treatment. NOS is a
safe and widely-used technique in paediatric dentistry. It is administered by inhalation
via a nasal mask and is used to reduce dental anxiety along with behaviour management
techniques. There are very few contra-indications. It is not suitable for patients who
have nasal congestion or severe dental anxiety. NOS will be conducted following the
guidelines by Standards for Conscious Sedation in the Provision of Dental Care and
appropriate clinical consent forms will be obtained before its use.
Accurate supra- and sub-gingival removal of calculus and dental plaque will be performed
both with ultrasonic and/or manual instruments. The necessary sub-gingival debridement
will be performed in 1 to 4 visits (either full mouth treatment, half-mouth treatment or
quadrant-wise treatment) depending on patient preference and practical considerations,
using manual (Gracey curettes, Hu-Friedy) and ultrasonic devices (EMS). Caries will be
treated as necessary (shared care with the general dental practitioners / community
dental services). Children with mucosal lesions requiring treatment will be given a
letter for their GDP suggesting referral to a collaborating expert in Oral Medicine
(Prof. Stephen Porter).
6. Missing data The inclusion of very young subjects in the present study introduces the
risk of missing data, owing to the difficulty in data and sample collection in some
children (due to their unwillingness to be examined or sampled). The Investigators will
endeavor to complete data and sample collection with minimal discomfort to each subject.
However, should dental and periodontal examination not be achievable, the subjects will
be exited from the study. Once the main variable outcome of the study (presence of
periodontal disease by means of collection of BPE) is recorded, the subject will not be
excluded from analysis, even if some of the other data are not collected. For example,
if a child tolerated periodontal probing (hence collection of BPE) but refuses to
provide a plaque sample, he/she will still be included in the study until the last
visit. The final study analyses and report/publications will take into account possible
missing data and reasons why they were not collected.
5.7 Repeatability Prior to initiation of the study, the designated examiner will participate
in a training and repeatability exercise. For the repeatability exercise, the examiner will
score 5 subjects for PPD and REC and then perform repeated examinations of the same subjects
on the same day after at least 15 minutes separation. Upon completion of all measurements,
intra-examiner repeatability for PPD measurements will be assessed. The reproducibility of
the examiner will be tested using the Bland-Altman approach and by calculating Lin's
concordance correlation coefficient. A co-efficient of repeatability less than ± 2 mm in 95%
of the cases is considered acceptable.
5.8 Laboratory analyses Samples will initially be stored at -70° to -80° for analysis.
Microbiological analysis will involve next generation sequencing of the 16S rRNA metagenome
at QMUL. GCF samples will be eluted and will undergo analysis of inflammatory markers as
described before.
9. PARTICIPANTS' COMPLETION AND WITHDRAWAL 9.1Reasons for withdrawal
Participants will be informed that they have the right to withdraw from the study at any time
for any reason, without prejudice to their medical care. The investigator also has the right
to withdraw participants from the study for any of the following reasons:
- Occurrence of an unacceptable adverse event/illness
- Participant/parent/guardian request
- Protocol violations
- Administrative reasons
- Failure to return for follow-up
- General or specific changes in the Participant's condition unacceptable for further
treatment in the judgment of the investigator
9.2 Completion/Withdrawal Procedures At the time of withdrawal, all study procedures outlined
for the end of study visit should be concluded. The primary reason for a participant's
withdrawal from the study is to be recorded on the CRF.
10. ADVERSE EVENT REPORTING 7.1 Adverse Events (AEs) An adverse event includes any noxious,
pathological or unintended change in anatomical, physiological or metabolic functions as
indicated by physical signs, symptoms and/or laboratory changes occurring in any phase of the
clinical study, whether associated with the study or not. This includes exacerbation of
pre-existing conditions or events, inter-current illnesses, drug interaction or the
significant worsening of the disease under study. For all adverse events, the investigator
must pursue and obtain information adequate both to determine the outcome of the adverse
event and to assess whether it meets the criteria for classification as a serious adverse
event requiring immediate notification to the sponsor or its designated representative. For
all adverse events, sufficient information should be obtained by the investigator to
determine the causality of the adverse event.
Clinically significant symptoms following NSPT include those that are outside a normally
accepted range (as judged by the clinician). This would include:
- Excessive or progressively increasing pain or discomfort
- Excessive swelling
- Signs of infection (e.g. suppuration)
- Excessive bleeding
Moreover we shall record if the participants take any drugs as a result of these adverse
events.
7.2 Serious Adverse Events definition
A serious adverse event or serious adverse drug reaction is any untoward medical occurrence
at any dose which:
- results in death
- is life-threatening (immediate risk of death)
- requires participant hospitalization or prolongation of existing hospitalization
- results in persistent or significant disability/incapacity
- results in congenital anomaly/birth defect.
Medical and scientific judgment should be exercised in determining whether an event is an
important medical event. An important medical event may not be immediately life-threatening
and/or result in death or hospitalization. However, if it is determined that the event may
jeopardize the participant and may require intervention to prevent one of the other outcomes
listed in the definition above, the important medical event should be reported as serious.
7.3 Reporting of Serious Adverse Events Because of the need to report to health authorities
all suspected unexpected serious adverse reactions (SUSARs) in a timely manner, it is vitally
important that the investigator reports immediately any adverse events which would be
considered serious. Any serious adverse event (including death) due to any cause, which
occurs during the course of this clinical study, whether or not related to the study, must be
reported immediately to the Principal Investigator or its designee.
7.4 Reporting period The nature of each individual adverse event, date and time of onset,
duration, severity and relationship to treatment and corrective treatment must be established
by the investigator and recorded in the CRF. Adverse events will be recorded following
signing of the first consent form up to the last study visit. Any serious adverse event
occurring any time after the reporting period must be promptly reported if a causal
relationship to the investigational product is suspected and all SUSARs will be followed up
until resolution.
8 STATISTICAL PROCEDURES 6.1 Sample size estimation A convenience sample of 50 children
(based on current estimation of numbers of children with neutrophil defects seen yearly at
GOSH) is proposed for this study, since no formal power calculation could be performed owing
to the lack of similar studies in the literature. However, hypothesising that subgingival
presence of bacterium A.actinomycetemcomitans at baseline could discriminate between
responders and non-responders to periodontal treatment (difference 0.5mm ± 0.5 mm mean
clinical attachment gain), 41 children (including 20% drop-outs) who undergo periodontal
therapy would give 80% power to prove or disprove this hypothesis.
6.2 Statistical analysis All data derived from the study will be anonymised and entered in a
dedicated database. The initial plan of analysis will describe the prevalence of periodontal
diseases in the study cohort (divided by medical diagnosis). Appropriate summary statistics
will be determined separately for affected and non-affected subjects. Differences in
demographic and systemic parameters (diagnosis, current treatment) between affected and
non-affected subjects will be assessed by the two-sample t-test or Mann-Whitney test as
appropriate. Explorative logistic regression analyses will be performed to detect the effect
of microbiological and inflammatory parameters (e.g. presence of periodontopathogenic
bacterium A.actinomycetemcomitans or cytokine concentrations in the GCF) on groups, taking
into account that many children may be on long-term antimicrobial therapy. Response to
therapy will be assessed by comparing clinical periodontal parameters at baseline and
follow-ups by random effects analysis taking time points as repeated measures. This will be
then associated to patients' demographics, compliance and microbiological and inflammatory
factors.
7 ADMINISTRATIVE REQUIREMENTS 9.1 Good clinical practice The study will be conducted in
accordance with the International Conference on Harmonisation (ICH) for Good Clinical
Practice (GCP) and the appropriate regulatory requirement(s). Essential clinical documents
will be maintained to demonstrate the validity of the study and the integrity of the data
collected. Master files should be established at the beginning of the study, maintained for
the duration of the study, and retained according to the appropriate regulations.
9.2 Ethical considerations The study will be conducted in accordance with ethical principles
founded in the Declaration of Helsinki. The Research Ethics Committee will review all
appropriate study documentation in order to safeguard the rights, safety, and well-being of
the participants. The study will be conducted only at sites where Research Ethics Committee
approval has been obtained. The protocol, informed consent, advertisements (if applicable),
written information given to the participants, safety updates, progress reports, and any
revisions to these documents will be provided to the Research Ethics Committee by the
investigator.
9.3 Participant Information and Informed Consent During the first screening session and the
enrolment visit, written informed consent will be obtained from all
participants/guardians/parents. The method of obtaining and documenting the informed consent
and the contents of the consent will comply with ICH-GCP and all applicable regulatory
requirement(s).
9.4 Participant confidentiality In order to maintain participant privacy, all CRFs, study
reports and communications will identify the participant by initials and the assigned
participant number. The participant's confidentiality will be maintained and will not be made
publicly available to the extent permitted by the applicable laws and regulations.
9.5 Protocol compliance The investigator will conduct the study in compliance with the
protocol and given approval/favorable opinion by the Research Ethics Committee and the
appropriate regulatory authority(ies). Changes to the protocol will require written Research
Ethics Committee approval/favourable opinion prior to implementation, except when the
modification is needed to eliminate an immediate hazard(s) to participants.
9.6 Study monitoring Monitoring and auditing procedures developed by the investigator will be
followed, in order to comply with GCP guidelines. On-site checking of the CRFs for
completeness and clarity, cross-checking with source documents, and clarification of
administrative matters will be performed. The study will be monitored by a clinical trial
coordinator or its designee.
9.7 Case report form completion Case report forms will be completed for each study
participant. It is the investigator's responsibility to ensure the accuracy, completeness,
and timeliness of the data reported in the participant's CRF. Source documentation supporting
the CRF data should indicate the participant's participation in the study and should document
the dates and details of study procedures, adverse events and participant status.
The investigator, or designated representative, should complete the CRF pages as soon as
possible after information is collected, preferably on the same day that a study participant
is seen for an examination, treatment, or any other study procedure. Any outstanding entries
must be completed immediately after the final examination. An explanation should be given for
all missing data. The investigator must sign and date the Investigator's Statement at the end
of the CRF to endorse the recorded data.
9.8 Premature closure of the study This study may be prematurely terminated, if in the
opinion of the investigator there is sufficient reasonable cause. Written notification,
documenting the reason for study termination, will be provided to the investigator by the
terminating party.
Circumstances which may warrant termination include, but are not limited to:
- Determination of unexpected, significant, or unacceptable risk to participants
- Failure to enter participants at an acceptable rate
- Insufficient adherence to protocol requirements
- Insufficient data
9.9 Complaints and indemnity
- Complaints. In the event of complaint about the conduct of the study, the hosting NHS-
Great Ormond Street Hospital for Children NHS Foundation - complaints policy should
apply as the research subject is recruited through an NHS Trust.
- Indemnity QMUL holds insurance against claims from participants for harm caused by their
participation in this clinical study. Participants may be able to claim compensation if
they can prove that QMUL has been negligent. However, if this clinical study is being
carried out in a hospital, the hospital continues to have a duty of care to the
participant of the clinical study. QMUL does not accept liability for any breach in the
hospital's duty of care, or any negligence on the part of hospital employees. This
applies whether the hospital is an NHS Trust or otherwise.
