Prognostic enrichment design in clinical trials for autosomal dominant polycystic kidney disease: the HALT-PKD clinical trial

Abstract

Background: Patients with mild autosomal dominant polycystic kidney disease (ADPKD) are less likely to be informative in randomized clinical trials (RCTs). We previously developed an imaging classification of ADPKD (typical diffuse cyst distribution Class 1A-E and atypical cyst distribution Class 2) for prognostic enrichment design in RCTs. We investigated whether using this classification would have increased the power to detect a beneficial treatment effect of rigorous blood pressure (BP) control on HALT-PKD participants with early disease (Study A).

Methods: Post hoc analysis of the early disease HALT-PKD study, an RCT that studied the effect of rigorous versus standard BP control on rates of total kidney volume (TKV) increase and estimated glomerular filtration rate (eGFR) decline in ADPKD patients with eGFR >60 mL/min/1.73 m2.

Results: Five hundred and fifty-one patients were classified by two observers (98.2% agreement) into Class 1A (6.2%), 1B (20.3%), 1C (34.1%), 1D (22.1%), 1E (11.8%) and 2 (5.4%). The TKV increase and eGFR decline became steeper from Class 1A through 1E. Rigorous BP control had been shown to be associated with slower TKV increase, without a significant overall effect on the rate of eGFR decline (faster in the first 4 months and marginally slower thereafter). Merging Classes 1A and 2 (lowest severity), 1B and 1C (intermediate severity) and 1D and 1E (highest severity) detected stronger beneficial effects on TKV increase and eGFR decline in Class 1D and E with a smaller number of patients.

Conclusions: Strategies for prognostic enrichment, such as image classification, should be used in the design of RCTs for ADPKD to increase their power and reduce their cost.

Keywords: HALT-PKD study; autosomal dominant polycystic kidney disease; eGFR; image classification; total kidney volume.

FIGURE 1

Coronal T₂-weighted MRIs from patients with Class 1A (49-year-old male PKD2), 2A (49-year-old male PKD2), 1B (38-year-old male PKD1), 1C (37-year-old male PKD1), 1D (37-year-old male PKD1) and 1E (37-year-old male PKD1) ADPKD. Classes 1A and 2A are considered mild, 1B and 1C intermediate and 1D and 1E severe disease.

FIGURE 2

Distribution of Class 1 early ADPKD HALT study patients at baseline based on HtTKV limits for their age. Limits are defined based on estimated kidney growth rates of 1.5, 3.0, 4.5 and 6.0%.

FIGURE 3

Distribution of (A) gender and (B) genotype of early ADPKD HALT study patients by baseline classes. (A) The male:female ratio increased from 1A to 1E (0.36, 0.49, 1.24, 1.49 and 2.25); N = total number of patients per class. (B) Similarly, the PKD1:PKD2 case ratio increased from Class 1A through 1E (0.64, 2.0, 6.55, 14.14 and 52.0). Proportionately to the total in each class, Class 1A had the highest NMD rate (37.9%), but this decreased and remained similar through Classes 1B to 1E (1B, 7.7%; 1C, 6.7%; 1D, 6.2%; 1E, 7.1%); N = number of patients with genetic analysis per class.