Jan Lindhe. Clinical Periodontology

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THE USE OF ANTISEPTICS IN PERIODONTAL THERAPY • 4

there is the potential of interaction between toothpaste

and mouthrinse, which could be additive but in most

cases is more likely negative for effects on mouthrinse

ingredients (Owens et al. 1997, Sheen et al. 2001, 2002).

Compliance in home use studies can also be a problem

and difficult to accurately determine. In short-term

studies compliance can be guaranteed through super

vision but this is difficult if not impossible in home use

studies. Finally, particularly in toothpaste studies, the

control product will have some inherent plaque in-

hibitory action consequent upon ingredients such as

detergents (Addy et al. 1983). If the appropriate con-

trol products have been used in the screening plaque

inhibitory and experimental gingivitis models this

should not pose a problem. However, there is no

doubt, and this will be discussed, that the choice of

control toothpaste, whereby to compare an active

toothpaste, could considerably influence the outcome

and therefore the conclusions concerning a potential

antiplaque toothpaste.

CLINICAL TRIAL DESIGN

CONSIDERATIONS

Clinical trials involving human patients, subjects or

healthy volunteers should conform to the Guidelines

for Good Clinical Practice (ICH 1996) including the

Declaration of Helsinki (World Medical Association

1996). These guidelines were introduced not only to

protect the well-being of the participants but also the

interest of those organizing, supporting and conduct-

ing the trials. An additional purpose for the guidelines

was to limit the possibility for falsification of data.

Broadly, the guidelines are concerned with all aspects

of a clinical trial and, in particular, the ethical require

ments, the design and conduct of the trial, data collec

tion and record keeping, data analysis and reporting

of the findings. Requirements of ethical committees

will vary locally, nationally and internationally; how-

ever, common to all is a need for a detailed protocol

covering all aspects of the clinical trial, subject or

patient information and consent. Written indemnifi-

cation and/or insurance cover from the appropriate

source or sources for the subjects or patients is re-

quired, although the details may vary both nationally

and internationally. For example, in the UK most ethi

cal committees would adopt the indemnification prin-

ciples as set out by the Association of British Pharma

ceutical Industries.

The basic requirements of a clinical trial are that it

should be blind, randomized and suitably controlled.

These three aspects of clinical trial design are inti-

mately related and are there to remove, limit or allow

adjustment for possible influences that might con-

found the outcome of a clinical trial and thereby re-

duce or completely obviate the scientific value of any

particular study. These three design features will be

discussed individually.

Blindness

All clinical studies must be, at least, single, examiner

blind. Single blindness requires that any investigator

collecting data from the patients or subjects should not

know the identity of the treatments used by any par-

ticular individual. Single blindness should eliminate

bias in data collection. Examiner blindness, however,

can be compromised to a variable degree if a particular

treatment produces changes within the oral cavity,

which can be perceived by the examiner. Such an

example could be extrinsic staining of the teeth

and/or oral mucosa like chlorhexidine formulations.

The use of objective measures, which reduce or re-

move the requirement for the subjective judgement of

the examiner, can improve the likelihood of single

blindness but such objective methods are not common

to the recording of plaque, gingivitis and periodontal

disease parameters. Double blindness is the ideal

when neither the examiner nor subject or patient is

aware of the treatment being used by the individual.

Numerous factors will influence whether the subjects

or patients can be maintained totally blind to their

treatment(s), including whether the study is parallel

or cross-over (to be discussed later), prior experience

with treatments and the presentation, taste and ap-

pearance of the treatments, particularly controls. Sub

ject blindness, although ideal, is less important where

the treatment outcome measures are out of the imme

diate control of the subject, e.g. plaque accumulation

and gingivitis; assuming, that is, that lack of subject

blindness does not influence compliance. Subject

blindness becomes highly important where the sub-

ject is required to make a valid judgement of the effects

of the treatment, for example the effects of treatments

on symptoms such as pain.

Randomization

The order in which treatments are received by each

subject in a cross-over study, or into which treatment

group subjects are placed in a parallel study, should

be according to a randomized schedule. Randomiza-

tion provides several important safety aspects to the

study design in that firstly it is an essential part of

examiner blindness, secondly in a cross-over study

randomization should remove the potential con-

founding effects of the order of product use, the so-

called period effects. Thirdly, the use of balanced ran-

domization designs allows for potential carry-over in

cross-over design studies (Newcombe 1992, New-

combe et al. 1995). Finally, where the effects of a treat

ment on a disease state are to be assessed, randomiza

tion improves the chances that parallel treatment

groups should be as similar as possible in baseline

disease levels and, if relevant, demographic data. Ran

domization schedules, which use subject matching for

demographic and disease status or stratification for

486 • CHAPTER 22

level of disease, can be employed to improve balanc-

ing of parallel groups.

Controls

The use of appropriate control treatments is essential

to the evaluation of the benefits of a particular agent

or product. Without such controls, studies essentially

become no more than case report data at best and

anecdotal at worst, particularly when a particular

treatment is evaluated alone for effects on particular

parameters. However, the choice of controls can vary

depending on the aim of the study and the level of

evaluation of an agent or product within a program of

research. The choice of controls could therefore be one

or more of the following.

Placebo control

Here the control is a substance without any expected

pharmacological action, e.g. water. This is useful

when assessing a new agent or positioning an agent

or formulation between a positive or benchmark con-

trol. Placebo controls are particularly valuable where

a condition or symptom may be perceived by the

subject or patient to have improved, so-called placebo

response, or where a condition appears to improve

naturally over time, the so-called regression to the

mode. Both of these phenomena are common to stud

ies of the treatment of dentine hypersensitivity where

pain is a primary outcome measure, but they are of

course unlikely to occur in studies where the outcome

measure are levels of plaque and gingivitis.

Minus

active control (negative

control)

This type of control is commonly employed to deter-

mine whether an agent provides activity over and

above its vehicle. It is particularly useful in the initial

assessment of formulations such as toothpastes which

have included a new active. In the later stages of

development, perhaps at the product level, the use of

minus active controls in home use studies is of less

value since minus active controls are not normally

used by the general public.

Bench mark control

This term is usually used to define a control which is

a commercially available product commonly used by

the general public. Such controls would appear more

sensible for home use studies rather than minus active

products when, for example, a new toothpaste prod-

uct is formulated to promote gingival health benefits.

In this case it would seem reasonable to determine

whether efficacy is superior to conventional fluoride

toothpaste rather than the minus active toothpaste.

Positive control

Positive control is an agent or formulation presently

considered the most effective agent available. In this

case chlorhexidine mouthrinses are arguably consid-

ered the standard antiplaque agent and are frequently

used as the positive control by which to compare and

position the efficacy of agents and formulations. Usu-

ally chlorhexidine mouthrinses as positive controls

are used in the early no oral hygiene study protocols.

Depending on the aims and constraints of a clinical

study, more than one of the aforementioned controls

may be used; for example, in the short-term studies it

is not unusual to position an agent or formulation for

plaque and gingivitis efficacy between a positive con-

trol, chlorhexidine, and a placebo, water.

Study groups

Study designs for oral hygiene products are usually

either parallel or cross-over. Parallel group studies

require that each individual uses only one of the for-

mulations (active or control) during the duration of

the study. Parallel designs can be used for any of the

previously described oral hygiene study methods;

however they are more commonly used when the

study duration is protracted to weeks or months. Par

allel designs require that the study groups are large in

number to provide sufficient power for statistical

analysis. Indeed, the power of any particular study to

demonstrate a statistically significant difference be-

tween treatments should be calculated prior to the

study, although this may be compromised by lack of

data as to the likely outcome or by difficulty in decid-

ing the clinical relevance of any difference found.

Advice from a statistician is important and group sizes

can be calculated based on expected differences be-

tween test and control formulations. It must be re-

membered that small differences can be found statis-

tically significant merely by using large group sizes.

Cross-over studies randomly allocate subjects to

use all of the agents or formulations under test. Since

each individual acts as their own control, paired sta-

tistical analytical techniques mean that the power to

detect differences is markedly increased compared to

parallel designs, and thereby the total study cohort of

subjects can be relatively small. Furthermore, a con-

siderable number of formulations can be compared,

although this will be limited by the duration of each

study period which, in itself, will have a knock-on

effect to acceptability to and compliance of the sub-

jects. Cross-over studies require a wash-out period

between each treatment period and this will depend

on the known, or expected, carry-over effect of a treat

ment or a condition into the next period. Random

incomplete block designs can be used, in which each

subject only uses so many of the agents under test.

The relationship between statistical significance

and clinical significance is always difficult to resolve.

Statistical significance is a mathematical concept

which, with varying levels of probability, supports the

idea that any difference between treatments is not due

to chance. Clinical significance, on the other hand, is

conceptual and attempts to define the benefit to the

THE USE OF ANTISEPTICS IN PERIODONTAL THERAPY • 4

patient of any particular treatment. Clinical signifi-

cance could be:

Bench mark equivalent:

when a formulation per-

forms as well as an established formulation or

product.

Bench mark superior:

when a formulation performs

significantly better than an established formula-

tion.

Disease related:

when a formulation has an effect

an etiological factor such that the related signs

or symptoms of the associated disease are reduced

a significantly greater extent than the control, e.

plaque reduction which reduced gingivitis to a

greater extent than control.

Positive:

when a formulation produced the effect

significantly greater than the most effective agent

today, e.g. the antiplaque effect is greater than

chlorhexidine.

Proportional superiority:

when from the outset of a

study a minimum percentage improvement over

the control group is set down as clinically signifi-

cant.

Conclusions

•

Terminology concerning oral hygiene products

needs to be standardized and defined.

•

Claims for efficacy, which are implied or rely on

inferences to be drawn, should be avoided.

•

Studies

in vitro

can provide supportive data to clini-

cal investigations but cannot stand alone as proof of

efficacy

in vivo.

•

Research and development of oral hygiene prod-

ucts needs to be step-by-step processed, making

available a body of knowledge supporting the effi-

cacy of a final formulation.

•

Clinical proof should be largely dependent on data

from blind, randomized, controlled, clinical trials

conducted to the Guideline for Good Clinical Prac-

tice (GCP).

•

In reporting clinical trials the clinical significance of

the finding should be considered.

•

Statistical significance should not necessarily be

taken as proof

per se

of the benefit of an oral hygiene

product to the general public.

•

Clinical outcome, when possible, should be evalu-

ated against side effects and the cost-benefit ratio

should be determined.

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CHAPTER 23

The Use of Antibiotics in

Periodontal Therapy

ANDREA MOMBELLI

Principles for antibiotic therapy

The limitations of mechanical therapy

Specific characteristics of the periodontal infection

Infection concepts and treatment goals

Drug delivery routes

Evaluation of antimicrobial agents for

periodontal therapy

Systemic antimicrobial therapy in clinical trials

Local antimicrobial therapy in clinical trials

Comparison of treatment methods

Overall conclusion

PRINCIPLES FOR ANTIBIOTIC

THERAPY

The limitations of mechanical therapy. Can

antimicrobial agents help?

Accumulation of bacteria on hard oral surfaces is the

primary cause of gingivitis and periodontitis. There-

fore, regular mechanical removal of bacterial plaque

from all non-shedding oral surfaces is considered the

primary means to prevent and stop the progression of

periodontal disease. Longitudinal studies have

shown

the efficacy of the standard treatment approach

consisting of the combination of systematic scaling

and planing of the root surfaces, the patient's daily

meticulous oral hygiene and regular maintenance vis

its to remove newly formed subgingival deposits. In

most cases, periodontal disease can be treated success

fully in this way and results can be maintained over

prolonged periods of time. The main adverse effects

this approach are irreversible hard tissue damage

and

gingival recession, ensuing from repetitive me-

chanical brushing and scraping of tooth surfaces. Sub

stantial hard tissue trauma may occasionally arise

from repeated treatment of sites that are locally unre-

sponsive or have recurrent disease (Fig. 23-1).

A closer look at the composition of plaque reveals

that mechanical treatment is targeted at a variable

mixture of different bacteria. Although the number of

different species and subspecies occasionally identi-

fied in samples from human plaque by far exceeds one

hundred, only relatively few organisms show a dis-

tinctive pattern of association with disease. Possible

pathogens have been suggested among these organ-

isms based on their animal pathogenicity and the

demonstration of virulence factors (for review see

Chapter 4). Certain species, notably

Actinobacillus act-

inomycetemcomitans

and

Porphyromonas gingivalis,

have

attracted particular attention because longitudi

nal

and retrospective studies have indicated an in-

creased risk for periodontal breakdown in positive

sites and because results of treatment have been better

if the organisms could no longer be detected at follow

up (Bragd et al. 1987, Carlos et al. 1988, Haffajee et al.

1991, Grossi et al. 1994, Haffajee & Socransky 1994).

periodontal disease is in fact caused by a limited number of

bacterial species, then non-specific continuous plaque sup-

pression is not the only possibility for prevention and ther-

apy. Specific elimination or reduction of pathogenic bacteria

from plaque becomes a valid alternative.

Mechanical treatment may not predictably elimi-

nate putative pathogens, such as

A. actinomycetem-

comitans,

from the subgingival area. The pathogens

may be inaccessible by mechanical interventions due

to their ability to invade periodontal tissues or dentin

tubules (Adriaens et al. 1988) or because they reside

in sites inaccessible for periodontal instruments. This

may be the case in the presence of root concavities or

in furcation. In addition, successfully treated sites

may be recolonized by periodontal pathogens persist-

ing in non-dental areas such as the dorsum of the

tongue or the tonsils. Although we know that me-

chanical periodontal therapy may be clinically suc-

cessful in many patients even if all putative pathogens