AimThis study aimed to evaluate and compare the results of combination therapy involving bone grafting and two different resorbable collagen membranes in 1-, 2- and 3-wall infrabony defects.MethodsA total of 174 patients with infrabony defects (>= 7 mm periodontal probing depth) were randomized to receive deproteinized bovine bone mineral (DBBM) with either a native porcine non-crosslinked collagen membrane (N-CM, control, n = 87) or a novel porcine crosslinked collagen membrane (C-CM, test, n = 87). Clinical parameters, including periodontal probing depth (PPD), clinical attachment level (CAL), and gingival recession (GR), were recorded at baseline, 12 weeks, and 24 weeks. Radiographic evaluations measured linear bone gain (LBG) and percentage of bone fill (%BF) at baseline and 24 weeks. Generalized Estimating Equations (GEE) were used to identify predictors of clinical outcomes. The primary outcome was the total effectiveness rate based on a composite outcome score integrating clinical and radiographic parameters at 24 weeks.ResultsOne hundred seventy three patients completed the study. At 24 weeks, mean improvements in PPD were 4.17 +/- 1.48 mm and 4.16 +/- 0.97 mm for the control and test groups, respectively, while CAL gains were 3.69 +/- 1.32 mm and 3.60 +/- 1.81 mm. Radiographic linear bone gain was 3.12 +/- 2.19 mm in the control group and 3.00 +/- 1.92 mm in the test group. Subgroup analysis showed trends favoring the test group for PPD (p = 0.046) and CAL (p = 0.042) improvements in 1-wall defects. The total effectiveness rate was 96.55% in the control group and 95.35% in the test group, with a difference of -1.2% (95% CI: -5.88% to 3.47%). Among those with effective results, the test group had a higher proportion achieving significantly effective outcomes compared to the control group (96.5% vs. 86.2%, p = 0.032). Regression analysis identified treatment group, defect morphology, and baseline defect depth as significant predictors of PPD and CAL outcomes.ConclusionThe novel porcine crosslinked collagen membrane demonstrated non-inferiority to the native non-crosslinked membrane in periodontal regeneration. Regression analysis highlighted defect morphology and baseline defect depth as key predictors of outcomes, while subgroup analysis suggested potential advantages of the C-CM in challenging defect morphologies, such as 1-wall defects. These findings provide valuable insights into clinical decision-making. However, the findings are limited by the short-term nature of the study (24 weeks), and further long-term investigations are needed to confirm these preliminary results and assess their clinical relevance.Trial RegistrationClinicalTrials.gov identifier: NCT04851847