title: New composite endpoints to assess efficacy in periodontal therapy clinical trials.
abstract: BACKGROUND
  Clinical attachment level (CAL) and bone height (radiographic or clinical) are two well-accepted endpoint measures for periodontal clinical trials; however, neither one has been shown to be more predictive of long-term success than the other. We propose using a composite endpoint analysis combining clinical and radiological parameters to assess the beneficial effects on both hard and soft tissues following periodontal therapy using a single statistical test. To address this need, two composite endpoint alternatives are offered as a yardstick for clinical success; each includes the improvement in CAL and either improvement in linear bone growth or percent bone fill.
  
  
  METHODS
  The data for composite endpoint analyses were derived from a clinical trial evaluating two concentrations of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) with beta-tricalcium phosphate (beta-TCP) compared to beta-TCP plus buffer as follows: group I, beta-TCP + 0.3 mg/ml rhPDGF-BB; group II, beta-TCP + 1.0 mg/ml rhPDGF-BB; and group III, beta-TCP + buffer. The construction of composite endpoints was based on the greatest values for change, accepted by the U.S. Food and Drug Administration (FDA), for clinical attachment level (DeltaCAL), mean change in radiographic linear bone gain (LBG), and mean radiographic percent bone fill (%BF), with the following dual standards defining a successful clinical result: CAL gain > or =2.67 mm and radiographic LBG > or =1.1 mm at 6 months and CAL gain > or =2.67 mm and radiographic %BF > or =14.1% at 6 months.
  
  
  RESULTS
  Group I (beta-TCP + 0.3 mg/ml rhPDGF-BB) demonstrated statistically significant differences from group III (active control) for both composite endpoints. For the CAL/LBG composite endpoint, 61.7% of sites in group I versus 30.4% of sites in group III met the composite endpoint benchmarks (P <0.001). For the CAL/%BF composite endpoint, 70% of sites in group I versus 44.6% of sites in group III met the composite endpoint benchmarks (P = 0.003). A non-significant trend was observed for group II versus group III with 37.9% (P = 0.20) and 55.2% (P = 0.13) of sites meeting the CAL/LBG and CAL/%BF composite endpoints, respectively. These results are further emphasized by findings demonstrating a low correlation between the individual efficacy endpoints (DeltaCAL and %BF; DeltaCAL and LBG) for each of the three treatment groups.
  
  
  CONCLUSIONS
  Composite endpoints are advantageous in periodontal clinical trials where no single efficacy endpoint has been established as the most important. A composite endpoint, combining outcome measures of both hard and soft tissue components of the periodontium, may be preferable for assessing efficacy of periodontal regenerative therapies. Two composite endpoints are offered to meet this need.
authors.affiliation: BioMimetic Therapeutics, Franklin, TN 37067, USA. es@biomimetics.com
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Lynch
authors.forename: Philip T
authors.initials: PT
authors.lastname: Lavin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Genco
authors.forename: William G
authors.initials: WG
authors.lastname: Beasley
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Wisner-Lynch
mesh_terms: D016301:Alveolar Bone Loss / Q000000981:diagnostic imaging / Q000601:surgery / Q000628:therapy*; D000077214:Becaplermin; D001861:Bone Regeneration; D018786:Bone Substitutes / Q000627:therapeutic use; D002130:Calcium Phosphates / Q000627:therapeutic use; D006801:Humans; D017622:Periodontal Attachment Loss / Q000601:surgery / Q000628:therapy*; D010518:Periodontitis / Q000628:therapy*; D010982:Platelet-Derived Growth Factor / Q000627:therapeutic use; D020574:Proto-Oncogene Proteins c-sis; D011859:Radiography; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D018786:Bone Substitutes; D002130:Calcium Phosphates; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; D000077214:Becaplermin; C018392:tricalcium phosphate