Prognostic Enrichment Design in Clinical Trials for Autosomal Dominant Polycystic Kidney Disease: The TEMPO 3:4 Clinical Trial

Abstract

IntroductionPatients with slowly progressive autosomal dominant polycystic kidney disease (ADPKD) are unlikely to experience outcomes during randomized controlled trials (RCTs). An image classification of ADPKD into typical (diffuse cyst distribution) class 1A to E (by age- and height-adjusted total kidney volume [TKV]) and atypical (asymmetric cyst distribution) class 2 was proposed for prognostic enrichment design, recommending inclusion of only classes 1C to 1E in RCTs.MethodsA post hoc exploratory analysis was conducted of the TEMPO 3:4 Trial, a prospective, randomized, double-blinded, controlled clinical trial in adult subjects with ADPKD, an estimated creatinine clearance >60 ml/min and total kidney volume >750 ml.ResultsDue to the entry criteria, the study population of TEMPO 3:4 was enriched for classes 1C-E (89.5 % of 1436 patients with baseline magnetic resonance images) compared to unselected populations (e.g., 60.5% of 590 Mayo Clinic patients). The effects of tolvaptan on TKV and eGFR slopes were greater in classes 1C to E than in 1B. In TEMPO 3:4, tolvaptan reduced TKV and eGFR slopes from 5.51% to 2.80% per year and from −3.70 to −2.78 ml/min/1.73 m2 per year, and lowered the risk for a composite endpoint of clinical progression events (hazard ratio = 0.87). Restricting enrollment to classes 1C to E would have reduced TKV and eGFR slopes from 5.78% to 2.91% per year and from −3.93 to −2.82 ml/min/1.73 m2 per year, and the risk of the composite endpoint (hazard ratio = 0.84, P = 0.003), with 10.5% fewer patients.DiscussionPrognostic enrichment strategies such as the entry criteria used for TEMPO 3:4 or preferably the proposed image classification should be used in RCTs for ADPKD to increase power and to reduce cost.

Age- and height-adjusted total kidney volume growth rate in autosomal dominant polycystic kidney diseases

“…The MIC model depends on the assumption of exponential growth of the kidney volume at a rate of α (%/year) from an HtTKV 0 of 150 mL/m at age 0. The MIC prediction model selected patients at high risk for rapid disease progression and improved clinical designs [23]. The present study confirmed that MIC subgroups were significantly correlated with the disease severity (Table 1), eGFR slope (Table 2; Fig.…”

A Practical Guide for Treatment of Rapidly Progressive ADPKD with Tolvaptan

“…The Mayo imaging classification has been validated by an independent study 25 and shown to be informative in post hoc analyses of several clinical trials. 24,26 In most patients, the ellipsoid equation using coronal, sagittal, and transverse diameters (obtained by various imaging modalities) provides a fairly accurate estimation of TKV, image class, and eligibility for treatment. We prefer a computed tomography (CT) scan (including contrast enhancement in patients with eGFR.60 ml/min per 1.73 m 2 ) or MRI scan without contrast (in patients with reduced eGFR).…”

Can we further enrich autosomal dominant polycystic kidney disease clinical trials for rapidly progressive patients? Application of the PROPKD score in the TEMPO trial

“…Two recent studies evaluating an enrichment strategy using the MIC have been published [ 31 , 32 ]. The first post hoc analysis was conducted in early disease in the HALT-PKD study, a randomized controlled trial that studied the effect of rigorous versus standard blood pressure control on rates of TKV increase and eGFR decline in ADPKD subjects ages 15–49 years with preserved renal function (eGFR > 60 mL/min/1.73 m 2 ) at inclusion [ 33 ].…”