Prognostic Enrichment Design in Clinical Trials for Autosomal Dominant Polycystic Kidney Disease

The TEMPO 3:4 Clinical Trial

Maria Irazabal Mira, Jaime D. Blais, Ronald D. Perrone, Ron T. Gansevoort, Arlene B. Chapman, Olivier Devuyst, Eiji Higashihara, Peter C Harris, Wen Zhou, John Ouyang, Frank S. Czerwiec, Vicente Torres

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Introduction Patients 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. Methods A 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. Results Due 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. Discussion Prognostic 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.

Original languageEnglish (US)
Pages (from-to)213-220
Number of pages8
JournalKidney International Reports
Volume1
Issue number4
DOIs
StatePublished - 2016

Fingerprint

Autosomal Dominant Polycystic Kidney
Clinical Trials
Kidney
Randomized Controlled Trials
Cysts
Controlled Clinical Trials
Population
Creatinine
Magnetic Resonance Spectroscopy
TEMPO
Costs and Cost Analysis

Keywords

  • autosomal dominant polycystic kidney disease
  • clinical trials
  • disease progression
  • image classification of ADPKD
  • kidney volume

ASJC Scopus subject areas

  • Nephrology

Cite this

Prognostic Enrichment Design in Clinical Trials for Autosomal Dominant Polycystic Kidney Disease : The TEMPO 3:4 Clinical Trial. / Irazabal Mira, Maria; Blais, Jaime D.; Perrone, Ronald D.; Gansevoort, Ron T.; Chapman, Arlene B.; Devuyst, Olivier; Higashihara, Eiji; Harris, Peter C; Zhou, Wen; Ouyang, John; Czerwiec, Frank S.; Torres, Vicente.

In: Kidney International Reports, Vol. 1, No. 4, 2016, p. 213-220.

Research output: Contribution to journalArticle

Irazabal Mira, Maria ; Blais, Jaime D. ; Perrone, Ronald D. ; Gansevoort, Ron T. ; Chapman, Arlene B. ; Devuyst, Olivier ; Higashihara, Eiji ; Harris, Peter C ; Zhou, Wen ; Ouyang, John ; Czerwiec, Frank S. ; Torres, Vicente. / Prognostic Enrichment Design in Clinical Trials for Autosomal Dominant Polycystic Kidney Disease : The TEMPO 3:4 Clinical Trial. In: Kidney International Reports. 2016 ; Vol. 1, No. 4. pp. 213-220.
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abstract = "Introduction Patients 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. Methods A 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. Results Due 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. Discussion Prognostic 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.",
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AU - Perrone, Ronald D.

AU - Gansevoort, Ron T.

AU - Chapman, Arlene B.

AU - Devuyst, Olivier

AU - Higashihara, Eiji

AU - Harris, Peter C

AU - Zhou, Wen

AU - Ouyang, John

AU - Czerwiec, Frank S.

AU - Torres, Vicente

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N2 - Introduction Patients 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. Methods A 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. Results Due 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. Discussion Prognostic 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.

AB - Introduction Patients 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. Methods A 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. Results Due 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. Discussion Prognostic 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.

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