Research Article: Item Response Theory Modeling of the International Prostate Symptom Score in Patients with Lower Urinary Tract Symptoms Associated with Benign Prostatic Hyperplasia

Date Published: August 27, 2020

Publisher: Springer International Publishing

Author(s): Yassine Kamal Lyauk, Daniël M. Jonker, Trine Meldgaard Lund, Andrew C. Hooker, Mats O. Karlsson.

http://doi.org/10.1208/s12248-020-00500-w

Abstract

Item response theory (IRT) was used to characterize the time course of lower urinary tract symptoms due to benign prostatic hyperplasia (BPH-LUTS) measured by item-level International Prostate Symptom Scores (IPSS). The Fisher information content of IPSS items was determined and the power to detect a drug effect using the IRT approach was examined. Data from 403 patients with moderate-to-severe BPH-LUTS in a placebo-controlled phase II trial studying the effect of degarelix over 6 months were used for modeling. Three pharmacometric models were developed: a model for total IPSS, a unidimensional IRT model, and a bidimensional IRT model, the latter separating voiding and storage items. The population-level time course of BPH-LUTS in all models was described by initial improvement followed by worsening. In the unidimensional IRT model, the combined information content of IPSS voiding items represented 72% of the total information content, indicating that the voiding subscore may be more sensitive to changes in BPH-LUTS compared with the storage subscore. The pharmacometric models showed considerably higher power to detect a drug effect compared with a cross-sectional and while-on-treatment analysis of covariance, respectively. Compared with the sample size required to detect a drug effect at 80% power with the total IPSS model, a reduction of 5.9% and 11.7% was obtained with the unidimensional and bidimensional IPSS IRT model, respectively. Pharmacometric IRT analysis of the IPSS within BPH-LUTS may increase the precision and efficiency of treatment effect assessment, albeit to a more limited extent compared with applications in other therapeutic areas.

Partial Text

Benign prostate hyperplasia (BPH) is a common condition in the aging male and is estimated to affect 50% of males by age 60 years and 90% by age 85 years (1,2). The clinical manifestations of BPH are known as lower urinary tract symptoms (LUTS) and are characterized by an increased: sensation of incomplete emptying of the bladder following urination, urination frequency, urination intermittency, urgency to urinate, weakness of the urinary stream, straining to start urination, and nocturia. LUTS are associated with adverse health effects such as significantly diminished quality of life and depression, as well as impairment in activities of daily living (3–5). In approximately 10% of patients, the condition may lead to severe complications such as acute urinary retention, urosepsis, and kidney failure (2,6). The severity of BPH-LUTS is commonly measured by the International Prostate Symptom Score (IPSS) (also known as the American Urological Association score) (7), which consists of seven questions describing the severity of each of the clinical manifestations of LUTS. The IPSS questionnaire is considered the gold standard measure for assessing BPH-LUTS, and its use is widespread in the clinic, as a primary or secondary endpoint in clinical trials, and in urology research (8).

Table I shows the subject characteristics at baseline. In total, 3117 summary IPSS and 21,836 item-level IPSS responses from 403 patients were available for analysis. The distribution of responses is shown in Supplemental Fig. S1. Three hundred and sixty-nine of the 403 randomized patients completed the 6-month treatment period. Figure 1 shows the mean summary IPSS time course in each trial arm as well as the distribution of responses for each IPSS item. A marked drop in total IPSS was observed in all treatment arms following dosing, and there was a similar distribution of item-level IPSS responses at the three key trial visits (baseline, the landmark time point, and end-of-trial) in both the placebo arm and the pooled treatment arms. From Fig. 1, there was no apparent dose-response for the effect of degarelix on the IPSS.Table IBaseline Demographic and International Prostate Symptom Score (IPSS) Characteristics in Clinical Trial CS36VariablePlaceboDegarelix 10 mgDegarelix 20 mgDegarelix 30 mgNumber of patients9810199105Age in years (median [range])65.0 [50.0, 86.0]65.0 [50.0, 81.0]66.0 [52.0, 82.0]65.0 [50.0, 87.0]Body weight in kg (median [range])86.4 [60.0, 128.0]87.0 [54.1, 126.2]85.0 [57.0, 141.2]84.0 [55.0, 183.8]Body mass index in kg/m/m (median [range])28.5 [20.1, 40.2]27.8 [18.9, 40.5]27.7 [21.4, 38.9]27.7 [19.8, 58.1]Total IPSS (median [range])18.0 [13.0, 33.0]18.0 [11.0, 33.0]19.0 [13.0, 33.0]19.0 [13.0, 35.0]IPSS storage subscore (median [range])8.0 [3.0, 15.0]8.0 [3.0, 15.0]8.0 [4.0, 15.0]8.0 [2.0, 15.0]IPSS voiding subscore (median [range])10.0 [4.0, 20.0]11.0 [0.0, 20.0]11.0 [3.0, 20.0]11.0 [4.0, 20.0]Quality of life score (median [range])4.0 [2.0, 6.0]4.0 [1.0, 6.0]4.0 [2.0, 6.0]4.0 [3.0, 6.0]BPH Impact Index score (median [range])7.0 [0.0, 13.0]7.0 [0.0, 12.0]7.0 [0.0, 12.0]7.0 [0.0, 12.0]Voided volume in mL (median [range])175.5 [77.0, 466.0]188.1 [125.0, 632.0]185.0 [57.0, 505.0]186.0 [106.4, 484.0]Voiding time in s (median [range])37.0 [19.0, 121.0]40.0 [21.0, 128.0]42.0 [15.0, 112.0]39.0 [20.6, 344.5]Post void residual volume in mL (median [range])39.1 [0.0, 230.0]50.5 [0.0, 246.6]45.0 [0.0, 189.0]56.3 [0.0, 999.0]Average flow rate in mL/s (median [range])5.0 [2.6, 10.4]5.0 [2.6, 9.5]5.3 [2.7, 10.6]5.0 [2.3, 8.5]Maximum urine flow in mL/s (median [range])10.0 [4.6, 16.4]10.0 [4.4, 19.2]10.0 [5.4, 50.0]9.9 [5.1, 16.0]Flow time including time to maximum flow in s (median [range])33.0 [18.0, 113.0]36.0 [20.0, 120.0]37.4 [13.0, 101.0]37.0 [20.6, 100.4]Total prostate volume in mL (median [range])39.1 [16.8, 102.0]38.4 [14.2, 128.0]38.3 [17.0, 155.7]36.1 [9.8, 135.9]Prostate specific antigen in ng/mL (median [range])2.0 [0.2, 9.6]1.8 [0.1, 9.0]2.3 [0.3, 9.6]1.8 [0.3, 7.8]Serum testosterone in ng/mL (median [range])4.1 [1.0, 10.2]4.3 [0.2, 13.6]4.3 [2.0, 8.0]4.3 [0.6, 12.2]Region North America (N, %)57 (58.2)60 (59.4)60 (60.6)63 (60.0)Region Europe (N, %)41 (41.8)41 (40.6)39 (39.4)42 (40.0)Fig. 1The mean International Prostate Symptom Score (IPSS) in each CS36 trial arm along with the standard error of the mean at each visit. The distribution of item-level IPSS at the baseline visit, landmark time point (3 months post-dose), and end of trial (6 months post-dose) is shown for the placebo arm as well as the pooled degarelix dose arms

Pharmacometric models were developed based on item-level and summary-level IPSS, respectively, to describe the time course of underlying disability and total IPSS in patients with moderate-to-severe BPH-LUTS in a clinical trial setting. IRT analysis revealed that voiding IPSS items combined contained the majority of the information content, which may have implications for the analysis of IPSS subscores. The unidimensional IRT model showed slightly higher power to detect a drug effect compared with the composite score model, while the bidimensional IRT model further increased the power. Taking the multidimensional nature of the IPSS into account in a pharmacometric IRT framework may hence allow for more precise quantification of drug effects and optimization of statistical power.

 

Source:

http://doi.org/10.1208/s12248-020-00500-w

 

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