Impact of disease progression on individual IPSS trajectories and consequences of immediate versus delayed start of treatment in patients with moderate or severe LUTS associated with BPH

Abstract

Purpose: Despite superiority of tamsulosin-dutasteride combination therapy versus monotherapy for lower urinary tract symptoms due to benign prostatic hyperplasia (LUTS/BPH), patients at risk of disease progression are often initiated on α-blockers. This study evaluated the impact of initiating tamsulosin monotherapy prior to switching to tamsulosin-dutasteride combination therapy versus immediate combination therapy using a longitudinal model describing International Prostate Symptom Score (IPSS) trajectories in moderate/severe LUTS/BPH patients at risk of disease progression.

Methods: Clinical trial simulations (CTS) were performed using data from 10,238 patients from Phase III/IV dutasteride trials. The effect of varying disease progression rates was explored by comparing profiles on- and off-treatment. CTS scenarios were investigated, including a reference (immediate combination therapy) and six alternative virtual treatment arms (delayed combination therapy of 1-24 months). Clinical response (≥ 25% IPSS reduction relative to baseline) was analysed using log-rank test. Differences in IPSS relative to baseline at various on-treatment time points were assessed by t tests.

Results: Delayed combination therapy initiation led to significant (p < 0.01) decreases in clinical response. At month 48, clinical response rate was 79.7% versus 74.1%, 70.3% and 71.0% and IPSS was 6.3 versus 7.6, 8.1 and 8.0 (switchers from tamsulosin monotherapy after 6, 12 and 24 months, respectively) with immediate combination therapy. More patients transitioned from severe/moderate to mild severity scores by month 48.

Conclusions: CTS allows systematic evaluation of immediate versus delayed combination therapy. Immediate response to α-blockers is not predictive of long-term symptom improvement. Observed IPSS differences between immediate and delayed combination therapy (6-24 months) are statistically significant.

Keywords: Benign prostatic hyperplasia; Clinical trial simulation; Drug–disease modelling; Dutasteride; Lower urinary tract symptoms; Tamsulosin.

Fig. 1

a Schematic diagram of CTS based on the longitudinal model describing individual IPSS trajectories [13]. b Mean IPSS changes from baseline (left panels) and predicted response rate (% responders) (right panels) stratified by treatment scenario according to a parallel-study design. From top to bottom, each panel depicts the predicted profiles for tamsulosin monotherapy (green dotted line), tamsulosin–dutasteride combination therapy (red solid line), and treatment arm switching to combination therapy (blue dashed line) at 1, 3, 6, 12 and 24 months. The lines depicting tamsulosin monotherapy and tamsulosin–dutasteride combination therapy are constant and represent these treatments being applied throughout 48 months. The dashed vertical lines indicate time of switch to combination therapy. Graphical summaries and statistical analysis refer to the results of a single replicate trial. In these simulations, the placebo effect was assumed to occur only immediately after enrolment into the study. Placebo effect is a key component of the initial response and can last longer than 6 months, as assessed by its half-life. No studies included a placebo treatment arm for > 2 years, so it was not possible to establish whether inter-individual differences might allow for a longer placebo effect

Fig. 1

a Schematic diagram of CTS based on the longitudinal model describing individual IPSS trajectories [13]. b Mean IPSS changes from baseline (left panels) and predicted response rate (% responders) (right panels) stratified by treatment scenario according to a parallel-study design. From top to bottom, each panel depicts the predicted profiles for tamsulosin monotherapy (green dotted line), tamsulosin–dutasteride combination therapy (red solid line), and treatment arm switching to combination therapy (blue dashed line) at 1, 3, 6, 12 and 24 months. The lines depicting tamsulosin monotherapy and tamsulosin–dutasteride combination therapy are constant and represent these treatments being applied throughout 48 months. The dashed vertical lines indicate time of switch to combination therapy. Graphical summaries and statistical analysis refer to the results of a single replicate trial. In these simulations, the placebo effect was assumed to occur only immediately after enrolment into the study. Placebo effect is a key component of the initial response and can last longer than 6 months, as assessed by its half-life. No studies included a placebo treatment arm for > 2 years, so it was not possible to establish whether inter-individual differences might allow for a longer placebo effect

Fig. 1

a Schematic diagram of CTS based on the longitudinal model describing individual IPSS trajectories [13]. b Mean IPSS changes from baseline (left panels) and predicted response rate (% responders) (right panels) stratified by treatment scenario according to a parallel-study design. From top to bottom, each panel depicts the predicted profiles for tamsulosin monotherapy (green dotted line), tamsulosin–dutasteride combination therapy (red solid line), and treatment arm switching to combination therapy (blue dashed line) at 1, 3, 6, 12 and 24 months. The lines depicting tamsulosin monotherapy and tamsulosin–dutasteride combination therapy are constant and represent these treatments being applied throughout 48 months. The dashed vertical lines indicate time of switch to combination therapy. Graphical summaries and statistical analysis refer to the results of a single replicate trial. In these simulations, the placebo effect was assumed to occur only immediately after enrolment into the study. Placebo effect is a key component of the initial response and can last longer than 6 months, as assessed by its half-life. No studies included a placebo treatment arm for > 2 years, so it was not possible to establish whether inter-individual differences might allow for a longer placebo effect