“split-mouth” clinical trials methodological challenges in the design and analysis introduction...

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“Split-Mouth” Clinical Trials Methodological Challenges in

the Design and Analysis

Introduction

Bruce L. Pihlstrom, DDS, MSBethesda, Maryland USAbpihls@verizon.net

Professor Emeritus, University of MinnesotaAdjunct Professor, Oregon Health Sciences UniversityIndependent Oral Health Research Consultant

Presentation Outline

• History and Development

• Advantages / Disadvantages

• Limitations

• Recommendations

Parallel Arm Trial DesignEffect of NaFl rinse on caries

Such experimental designs are particularly well suited to farmers. Treatments can be laid out in strips, with length of the plots determined by the length of the field and the width by the equipment you use.

Randomized InterventionExample

Y

X

0.05% NaFl Daily RinseVs

Placebo Daily Rinse

Randomize Subject

Randomize Subject

0.05% NaFl Daily Rinse

Placebo Daily Rinse

History and Development

Split-Mouth Design

Derived from Split-Plot Agricultural Research ?? Evaluates multiple agricultural methods by

dividing fields (sampling units) into main plots & sub-plots

Split Plot Trial DesignEffect of two soil treatments on crop yield

Such experimental designs are particularly well suited to farmers. Treatments can be laid out in strips, with length of the plots determined by the length of the field and the width by the equipment you use.

Fertilizer 1 = 20 lb Nitrogen / acreFertilizer 2 = 40 lb Nitrogen / acre

X = Conservative TillageY = Intensive Tillage

YX

Main plot factor:Randomize Fertilizer

Sub-plot factor:Randomize Tillage to subplots

Y

X

Y X

Randomize Main Treatment (Fertilizer per Acre)

Plot

Plot

Analogous Split Mouth Trial DesignEffect of two treatments on caries

Such experimental designs are particularly well suited to farmers. Treatments can be laid out in strips, with length of the plots determined by the length of the field and the width by the equipment you use.

X = Sealants PlacedY = No Sealants Placed

YX

Main subject factor:Randomize fluoride use

Sub-subject factor:Randomize sealantsto dentition segments

Y

X

Y X

NaFl: 0.05% daily rinseNaFl: 0.24% daily toothpaste

Subject

Subject

Randomize Main Treatment

(Fluoride Rinse)

Common Split Mouth Trial DesignEffect of one treatment on caries

Such experimental designs are particularly well suited to farmers. Treatments can be laid out in strips, with length of the plots determined by the length of the field and the width by the equipment you use.

X Y

Randomized Intervention

X = Sealants PlacedY = No Sealants Placed

Randomize intervention to dentition segments (½ mouths) in each subject

Randomize intervention to dentition segments (½ mouths) in each subject

Y X

History of Split Mouth Trials

• Introduced in 1968 by Ramfjord, Nissle, Shick, et al.1

Randomly assigned subgingival curettage or surgical pocket elimination to ½ mouths divided by mid-sagittal plane between central incisors

• Later, definition enlarged by others to include randomly assigned treatments to quadrants / sextants for other

dental diseases

• 11 different variants found in periodontal literature by Hujoel and Loesche in 19902

1. J Periodontol 1968;39:1672. J Clin Periodontol 1990;17:722

Potential Advantage of Split Mouth Trials*

Achieves increased efficiency by:

Reduced inter-subject variability (error variance) and therefore:

• Increase power

• Increase precision of estimated treatment effect

*Hujoel P. and DeRouen, J Clin Periodontol 1992;19:625-627

Example of a Small Randomized Clinical Trial

Surgical vs. Non-surgical Periodontal Therapy

J Periodontol. 1981 May;52(5):227-42.

Hujoel & Loesche*

Efficiency of Split Mouth Designs

1. Baseline data from 69 patients with periodontal disease investigated for disease similarity and suitability for 11 different split mouth designs based on disease:

• Amount (mean PD & CAL)• Distribution (variance of PD & CAL)• Severity (presence of PD 4-6mm; > 6 mm)

2. Subset of 38 patients received scaling and root planing in all within-subject experimental units

3. Re-evaluated at 6 weeks to determine relative efficiency of 11 different split mouth designs

* J Periodontol 1990; 17:722-728

Hujoel & Loesche*Homogeneity Within Experimental Units

* J Periodontol 1990; 17:722-728

Split Mouth Design

Within-Patient

Experimental Units

Disease AmountPocket Depth

MeanDifferences (p-values)

Disease Amount Clinical Att. Loss Mean Differences

(p-values)

Ipsi-lateral Quadrants 2 0.08 0.89

Ipsi-lateral Sextants 2 0.03 0.25

Contra-lateral Quadrants 2 0.80 0.33

Contra-lateral Sextants 2 0.76 0.45

Quadrants 4 0.0001

0.23

Posterior Sextants 4 0.1 0.0001

Sextants 6 0.0001 0.0001

Hujoel & Loesche*Variability within Experimental Units

* J Periodontol 1990; 17:722-728

Split Mouth Design

Within-Patient Experimental

Units

Probing Depth Variance

(p-values)

Clinical Attachment

Level Variance(p-values)

Ipsi-lateral Quadrants 2 0.11 0.19

Ipsi-lateral Sextants 2 0.03 0.006

Contra-lateral Quadrants 2 0.83 0.01

Contra-lateral Sextants 2 0.98 0.26

Quadrants 4 0.02

0.001

Posterior Sextants 4 0.04 0.0007

Sextants 6 0.0001 0.002

Hujoel & Loesche*Distribution & Asymmetry Within Experimental Units

* J Periodontol 1990; 17:722-728

Split Mouth Design

Patients with asymmetric probing depths 4-6 mm (%)

Patients with asymmetric probing depths > 6mm (%)

Ipsi-lateral Quadrants 0 % 17%

Ipsi-lateral Sextants 0 19

Contra-lateral Quadrants 0 15

Contra-lateral Sextants 0 16

Quadrants 0 55

Posterior Sextants 9 68

Sextants 14 83

Hujoel & Loesche*Relative Efficiencies of Split Mouth Designs

Additional Patients needed for whole mouth design = Split-mouth design x Efficiency Factor Gain

* Ratios of full mouth vs. split mouth error variance J Periodontol 1990; 17:722-728

Split Mouth Design

Efficiency Factor Gain

4-6 mm probing depths

Efficiency Factor Gain

> 6 mm probing depths

Ipsi-lateral Quadrants (2) 3.2 0.8

Ipsi-lateral Sextants (2) 1.9 0.8

Contra-lateral Quadrants (2) 4.8 1.7

Contra-lateral Sextants (2) 1.9 1.0

Quadrants (4) 2.0 0.8

Posterior Sextants (4) 0.9 0.7

Sextants (6) 1.0 1.0

Potential Disadvantages of Split Mouth Trials

• “Carry-cross” from one randomized segment to another may introduce unknown bias 1

• “Carry-cross” effect precludes use of this design for equivalence trials because of potential contamination across randomized segments 2,3

• Screening and recruitment may need to be increased because of need for symmetry in randomized segments; e.g. especially for trials with very restrictive inclusion criteria1

1. Hujoel PP. Community Dent Oral Epidemiol 1998;26:85-6 2. Imrey P, Chilton N. J Periodontol 1992 (Suppl); 1124-1140 3. Fleiss JL. J Periodont Res 1992;27:306-313

Potential Disadvantages of Split Mouth Trials

• More complex statistical analysis is needed to consider paired design and correlations within subjects across randomized segments1

• Depending on magnitude of within-patient correlation, may not gain efficiency; e.g. If within-patient correlation of treatment response is low, little efficiency is gained1

1. Hujoel PP. Community Dent Oral Epidemiol 1998;26:85-6

Split Mouth Trials - Recommendations

• Always consult with biostatistician who has experience in clinical trials during design phase

• Facilitate statistical analysis by not using complex designs with multiple levels of sub-patient interventions and outcomes

• Facilitate screening and recruitment by simplifying inclusion / exclusion criteria

NOTE: Always a good idea for generalizability and ease of recruitment…..

BUT simplification of inclusion criteria especially important for split

mouth trials where symmetry of disease in randomized segments is essential to gain (or maintain) efficiency

Split Mouth Trials - Recommendations

• Avoid using split mouth trials for equivalency trials

• Always consider possible “carry-cross” effect of intervention

• Never use split mouth design if carry-cross effect is likely (possible?)

• Make sure that efficiency is really being improved by screening patients for comparable amount, severity, distribution of disease within patient mouths