Predictors of Individual Response to Placebo or Tadalafil 5mg among Men with Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia: An Integrated Clinical Data Mining Analysis

<div><p>Background</p><p>A significant percentage of patients with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) achieve clinically meaningful improvement when receiving placebo or tadalafil 5mg once daily. However, individual patient characteristics associated with treatment response are unknown.</p><p>Methods</p><p>This integrated clinical data mining analysis was designed to identify factors associated with a clinically meaningful response to placebo or tadalafil 5mg once daily in an individual patient with LUTS-BPH. Analyses were performed on pooled data from four randomized, placebo-controlled, double-blind, clinical studies, including about 1,500 patients, from which 107 baseline characteristics were selected and 8 response criteria. The split set evaluation method (1,000 repeats) was used to estimate prediction accuracy, with the database randomly split into training and test subsets. Logistic Regression (LR), Decision Tree (DT), Support Vector Machine (SVM) and Random Forest (RF) models were then generated on the training subset and used to predict response in the test subset. Prediction models were generated for placebo and tadalafil 5mg once daily Receiver Operating Curve (ROC) analysis was used to select optimal prediction models lying on the ROC surface.</p><p>Findings</p><p>International Prostate Symptom Score (IPSS) baseline group (mild/moderate vs. severe) for active treatment and placebo achieved the highest combined sensitivity and specificity of 70% and ~50% for all analyses, respectively. This was below the sensitivity and specificity threshold of 80% that would enable reliable allocation of an individual patient to either the responder or non-responder group</p><p>Conclusions</p><p>This extensive clinical data mining study in LUTS-BPH did not identify baseline clinical or demographic characteristics that were sufficiently predictive of an individual patient response to placebo or once daily tadalafil 5mg. However, the study reaffirms the efficacy of tadalalfil 5mg once daily in the treatment of LUTS-BPH in the majority of patients and the importance of evaluating individual patient need in selecting the most appropriate treatment.</p></div

Definition of treatment response on the IPSS, BII and PGI-I after 12 weeks treatment with tadalafil or placebo as used in the clinical data mining analysis.

<p>BII, BPH Impact Index; IPSS, International Prostate Symptom Score; PGI-I, Patient Global Impression of Improvement; QoL, quality of life.</p><p>Definition of treatment response on the IPSS, BII and PGI-I after 12 weeks treatment with tadalafil or placebo as used in the clinical data mining analysis.</p

Exploratory Results.

<p>Models were generated on dataset excluding testosterone, alcohol frequency, Qmax, SHBG, Albumin, PGI, and PSA</p><p>BII, BPH Impact Index; CI, confidence interval; DT, Decision Tree; IPSS, International Prostate Symptom Score; MCID, Minimally Clinically Important Differences; PGI-I, Patient Global Impression of Improvement; PSA, prostate specific antigen; Q_max, maximal flow rate; QoL, quality of life; RF, Random Forest; SHBG, sex hormone binding globulin.</p><p>Exploratory Results.</p

Secondary Results (Tadalafil 5mg once daily).

<p>*Model on ROC surface with best performance if false positive and false negative errors are equally important.</p><p>** Alpha-Blockers, beta-blockers, calcium channels blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers and diuretics.</p><p>BII, BPH Impact Index; CI, confidence interval; IIEF, International Index of Erectile Function; IPSS, International Prostate Symptom Score; N, no; PGI, Patient Global Impression of Improvement; Q_max, maximal flow rate; QoL, quality of life; ROC, Receiver Operating Curve; Y, yes.</p><p>Secondary Results (Tadalafil 5mg once daily).</p

Primary results for both treatment groups.

<p>*Model on ROC surface with best performance if false positive and false negative errors are equally important.</p><p>CI, confidence interval; ED, erectile dysfunction; IPSS, International Prostate Symptom Score; MCID, Minimal Clinically Important Differences; N, no; PSA, prostate specific antigen; ROC, Receiver Operating Curve; Y, yes.</p><p>Primary results for both treatment groups.</p

Secondary Results (Placebo).

<p>*Model on ROC surface with best performance if false positive and false negative errors are equally important.</p><p>** Alpha-Blockers, beta-blockers, calcium channels blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers and diuretics.</p><p>BII, BPH Impact Index; CI, confidence interval; ED, erectile dysfunction; IIEF, International Index of Erectile Function; IPSS, International Prostate Symptom Score; N, no; PGI-I, Patient Global Impression of Improvement; PGISS, Patient Global Incontinence Severity Score; QoL, quality of life; ROC, Receiver Operating Curve; SHBG, sex hormone binding globulin; Y, yes.</p><p>Secondary Results (Placebo).</p