Types of studies

We will include randomised controlled trials (RCTs) evaluating any antimicrobial used systemically as an adjunct to non‐surgical therapy for the treatment of chronic or aggressive periodontitis. We will exclude quasi‐RCTs, cross‐over and split‐mouth trials.

Types of participants

We will include all individuals with clinically diagnosed untreated periodontitis (chronic/aggressive). Periodontitis and its types are shown in Figure 2.

People with the following conditions will be excluded:

• necrotizing periodontitis,

• recurrent periodontitis,

• refractory periodontitis,

• periodontitis as a manifestation of systemic disease,

• pregnancy,

• systemic disease/condition (e.g. HIV, diabetes).

Types of interventions

Interventions considering the systemic use of antimicrobials as an adjunct to scaling and root planing (SRP) compared with SRP alone or with placebo.

Interventions comparing different antimicrobials administered systemically (different drugs/different dosage regimens/different combinations/at different time periods) as an adjunct to SRP will be included.

Exclusion criteria:

• studies comparing the use of antimicrobials alone versus SRP with antimicrobial;

• studies using the application of any local antimicrobial/laser;

• studies using antibiotics at a subantimicrobial dose (e.g. subdose doxycycline).

Types of outcome measures

All of the following participants' outcomes at different follow‐up periods will be recorded.

Electronic searches

We will search the following databases for relevant trials:

• Cochrane Oral Health's Trials Register;

• the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library;

• MEDLINE Ovid (from 1946 onwards);

• Embase Ovid (previous 6 months to date).

The subject strategies for databases will be modelled on the search strategy designed for MEDLINE Ovid in Appendix 1. Where appropriate, this will be combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomised controlled trials and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.c. (Lefebvre 2011)).

Searching other resources

We will search the following trials registries:

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (http://clinicaltrials.gov/);

• World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch).

We will check the bibliographies of included studies and any relevant systematic reviews identified for further references to relevant trials. We will not perform a separate search for adverse effects of interventions. We will consider adverse effects described in included studies only.

Selection of studies

Two pairs of review authors (Shivi Khattri (SK) and Eachempati Prashanti (EP), and Kumbargere N Sumanth (KNS) and Ankita Arora (AA)) will independently screen the titles and abstracts from the electronic searches to identify potentially eligible studies that require further evaluation to determine whether they meet the inclusion criteria for this review.
We will obtain full‐text copies of all eligible and potentially eligible studies and these will be further evaluated by SK and AA to identify those studies that actually meet all the inclusion criteria. From this group, we will record those studies that do not meet the inclusion criteria in the 'Characteristics of excluded studies' table, noting the reason for exclusion. Non‐RCTs will be excluded without giving any reasons for exclusion. We will resolve disagreements by discussion. When resolution is not possible, we will consult an arbiter (KNS). We will assess articles in languages other than English by their abstracts, where possible, and if they appear to be potentially eligible, we will be requesting translators for data extraction.

Data extraction and management

Two review authors (SK and Chandan Kumar Kusum (CKK)) will independently extract the data. The review authors will not be blinded to the authors of the included studies. Disagreement will be resolved by discussion between the two review authors or, if necessary, a third review author (Giovanni Lodi (GL)) will be consulted in order to reach consensus. We will extract data using a customised data extraction form, which will first be pilot tested using a sample of the included studies. All the items in the data extraction form will be designed following guidance from the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will enter study details into the 'Characteristics of included studies' table in Review Manager (RevMan) software (RevMan 2014).

The following details will be recorded for each included trial.

• Publication details such as year of publication, language.

• Demographic details of the report.

• Inclusion and exclusion criteria.

• Type of trial, sample size, method of randomisation, allocation concealment, blinding, method of assessing the outcomes and dropouts, if any.

• Type of intervention.

• Level of expertise (specialist/general practitioner or dental hygienist or student) and intensity (in minutes or visits) for scaling and root planing.

• Details of the outcomes reported.

• Oral hygiene instruction provided/not provided.

• Duration of follow‐up.

• Results of the intervention.

• Funding details.

Assessment of risk of bias in included studies

Two review authors (KNS and SK) will independently assess the risk of bias in the included trials in seven domains:

• random sequence generation (selection bias);

• allocation concealment (selection bias);

• blinding of participants and personnel (performance bias);

• blinding (outcome assessment) (detection bias);

• incomplete outcome data (attrition bias);

• selective outcome reporting (reporting bias);

• other biases.

For each of these components, we will assign a judgement regarding the risk of bias as either high, low or unclear based on guidance in Higgins 2011. We will contact the trial authors if details are missing in the publications or are unclear. We will resolve disagreements through consensus. We will record our judgements and justifications in 'Risk of bias' tables for each included study and generate a 'Risk of bias' summary graph and figure. We will use these judgements while grading the overall quality of evidence for each comparison and outcome in the 'Summary of findings' tables.
We will summarise the risk of bias according to Higgins 2011 as follows.

Measures of treatment effect

We expect data for our primary outcome to be count data (number of closed pockets). Under secondary outcomes, CAL/RAL, PPD and patient quality of life may be expressed in the form of continuous data. Antimicrobial resistance, BOP, adverse events and patient quality of life may be expressed as dichotomous data. Patient quality of life and BOP might be measured in the form of an ordinal scale.

We will use means and standard deviations (SDs) presented in the studies to calculate mean differences (MD) and 95% confidence interval (CI) to summarize the continuous data. We will use standardized mean difference (SMD) if studies use different scales to measure the same outcome. If data expressed are in ordinal scales, we will explore the possibility of converting them to dichotomous outcomes. If outcomes are reported both at baseline and at follow‐up or at trial endpoints, we will extract both the mean change from baseline and the standard deviation of this mean for each treatment group, as well as the same for endpoint data. The end scores will be preferred a priori. However, change scores for CAL and PPD will be preferred to end scores. Count data will be treated in the same way as continuous outcome data. The intervention effect used will be the mean difference which compares the difference in the mean number of events (standardized to a unit time period) experienced by participants in the intervention group compared to control group.

If the trials provide details on the oral hygiene instructions (OHI) along with SRP, we will use the data as SRP with OHI and SRP without OHI.

Unit of analysis issues

We will consider the participant as the statistical analysis unit considering the mean value of improvement in the CAL and PPD per person in studies with a parallel design. We are not expecting to find any cluster‐randomised trials or split‐mouth designs in our review. If we find any trial with multiple treatment groups, we will combine groups to create a single pair‐wise comparison as recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). In case of dropouts, we will use what the paper reports and deal with it in the risk of bias assessment. If the search finds trials with repeated observations on participants, we will follow the methods described in Section 9.3.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). In case of multiple treatment attempts per participant, we will use the number of participants randomised to calculate the CIs (Higgins 2011). In trials where adverse effects are described as counts, we will follow the methods described in Section 9.2.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Dealing with missing data

We plan to contact study authors to obtain missing data. We will use the methods in Section 16.1.3 of the Cochrane Handbook for Systematic Reviews of Interventions to estimate missing SDs (Higgins 2011). Missing SDs will be calculated from the reported values of t, P and Chi². If it is not possible to calculate the SDs, the outcomes will be described qualitatively.

Assessment of heterogeneity

Where meta‐analyses are performed, we will assess heterogeneity using a Chi² test, where a P value < 0.1 will indicate statistically significant heterogeneity. We will quantify heterogeneity using the I² statistic as follows:

• 0% to 40% implies slight heterogeneity;

• 30% to 60% moderate heterogeneity;

• 50% to 90% substantial heterogeneity;

• 75% to 100% considerable heterogeneity.

If there is considerable heterogeneity (I² > 75%) which cannot be explained by the subgroup analyses, meta‐analysis will not be conducted.

Assessment of reporting biases

If there are more than 10 studies included in a meta‐analysis, we will assess the possible presence of reporting bias by testing for asymmetry in a funnel plot.

If present, we will carry out statistical analysis using the methods described in Section 10.4.3.1 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) for continuous and dichotomous data.

Data synthesis

We will analyze the data using RevMan software (RevMan 2014). If the data available from the studies have similar comparisons and outcomes, we will undertake meta‐analysis. Our general approach will be to use a random‐effects model. With this approach, the CIs for the average intervention effect will be wider than those obtained using a fixed‐effect approach, leading to a more conservative interpretation. We will use all change scores or end scores when available, and combine change and end scores where necessary using the criteria from Section 9.4.5.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will report the results from studies that are not suitable for inclusion in a meta‐analysis using additional tables.

Subgroup analysis and investigation of heterogeneity

If there is significant heterogeneity, we will explore the reasons by performing subgroup analyses based on participant characteristics.

• Age group.

• Severity of disease (mild, moderate, severe).

• Socioeconomic status (low‐, middle‐ and high‐income countries).

• Oral hygiene practices.

• Type of antimicrobial drug.

Sensitivity analysis

Provided there are sufficient included studies, we will undertake sensitivity analyses based on risk of bias, including only studies at low risk of bias.