“Split-Mouth” Clinical Trials Methodological Challenges in the Design and Analysis Introduction Bruce L. Pihlstrom, DDS, MS Bethesda, Maryland USA bpihls@verizon.net Professor Emeritus, University of Minnesota Adjunct Professor, Oregon Health Sciences University Independent Oral Health Research Consultant

Presentation Outline History and Development Advantages / Disadvantages Limitations Recommendations

Parallel Arm Trial Design Effect 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. Parallel Arm Trial Design Effect of NaFl rinse on caries 0.05% NaFl Daily Rinse Vs Placebo Daily Rinse Randomized Intervention Example 0.05% NaFl Daily Rinse Randomize Subject Randomize Subject Y X 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 Design Effect 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. Split Plot Trial Design Effect of two soil treatments on crop yield Main plot factor: Randomize Fertilizer Fertilizer 1 = 20 lb Nitrogen / acre Fertilizer 2 = 40 lb Nitrogen / acre Plot Randomize Main Treatment (Fertilizer per Acre) X Y Y X Y X Plot Sub-plot factor: Randomize Tillage to subplots X = Conservative Tillage Y = Intensive Tillage

Analogous Split Mouth Trial Design Effect 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. Analogous Split Mouth Trial Design Effect of two treatments on caries Main subject factor: Randomize fluoride use NaFl: 0.05% daily rinse NaFl: 0.24% daily toothpaste Subject X Y Randomize Main Treatment (Fluoride Rinse) Subject Y X Y X Sub-subject factor: Randomize sealants to dentition segments X = Sealants Placed Y = No Sealants Placed

Common Split Mouth Trial Design Effect 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. Common Split Mouth Trial Design Effect of one treatment on caries Randomized Intervention X = Sealants Placed Y = No Sealants Placed Randomize intervention to dentition segments (½ mouths) in each subject X Y 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 J Periodontol 1968;39:167 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 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) Subset of 38 patients received scaling and root planing in all within-subject experimental units 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 Split Mouth Design Within-Patient Experimental Units Disease Amount Pocket Depth Mean Differences (p-values) Clinical Att. Loss Mean Differences Ipsi-lateral Quadrants 2 0.08 0.89 Ipsi-lateral Sextants 0.03 0.25 Contra-lateral Quadrants 0.80 0.33 Contra-lateral Sextants 0.76 0.45 Quadrants 4 0.0001 0.23 Posterior Sextants 0.1 Sextants 6 * J Periodontol 1990; 17:722-728

Hujoel & Loesche* Variability within Experimental Units Split Mouth Design Within-Patient Experimental Units Probing Depth Variance (p-values) Clinical Attachment Level Variance Ipsi-lateral Quadrants 2 0.11 0.19 Ipsi-lateral Sextants 0.03 0.006 Contra-lateral Quadrants 0.83 0.01 Contra-lateral Sextants 0.98 0.26 Quadrants 4 0.02 0.001 Posterior Sextants 0.04 0.0007 Sextants 6 0.0001 0.002 * J Periodontol 1990; 17:722-728

Hujoel & Loesche* Distribution & Asymmetry Within Experimental Units 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 19 Contra-lateral Quadrants 15 Contra-lateral Sextants 16 Quadrants 55 Posterior Sextants 9 68 Sextants 14 83 * J Periodontol 1990; 17:722-728

Hujoel & Loesche* Relative Efficiencies of Split Mouth Designs 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 Contra-lateral Quadrants (2) 4.8 1.7 Contra-lateral Sextants (2) 1.0 Quadrants (4) 2.0 Posterior Sextants (4) 0.9 0.7 Sextants (6) 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

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