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Abstract: SA-PO497

Composite End Points in ADPKD Studies: A Guide for Best Practices

Session Information

  • ADPKD: Clinical Studies
    October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


  • Mustafa, Reem, University of Kansas, Kansas City, Kansas, United States
  • Baron, David, PKD Foundation, Kansas City, Missouri, United States
  • Czerwiec, Frank S., Otsuka Pharma. Devel. & Comm., Inc., Rockville, Maryland, United States
  • Yu, Alan S.L., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Perrone, Ronald D., Tufts Medical Center, Boston, Massachusetts, United States

Group or Team Name

  • for the Polycystic Kidney Disease Outcome Consortium (PKDOC) composite outcomes subcommittee

There is considerable inconsistency in the outcomes reported in Autosomal Dominate Polycystic Kidney Disease (ADPKD) and how they are measured. In this article, we aim to highlight the appropriateness of different outcomes to be included as a component in composite outcomes


We developed guidance including a summary table for components of the composite end points in ADPKD. We utilized the results of a systematic review and discussions among the Polycystic Kidney Disease Outcome Consortium (PKDOC) composite endpoint subcommittee. The subcommittee consists of Scientists, clinicians, methodologists, manufacturers, patients, advocacy groups representatives, and critical path institute representatives, all with experience in ADPKD. The investigators assessed the face validity of the suggested guidance and used an iterative approach of feedback, revision, and testing.


Table 1 summarizes outcomes that are reported in ADPKD studies and the different ways they can be measured. It also explores pros and cons for including them as part of a composite outcome for ADPKD studies.


Composite end points will continue to be used in ADPKD studies and may be more utilized in-light of new approved treatments. Understanding the unique considerations about the different components and their use in ADPKD studies is essential in developing high quality evidence that will appropriately assess the short and long term effects of different interventions.

Table 1
EndpointFeasibility of collecting dataEvent frequencyAcceptability to regulatorsPrevious body of evidence in a clinical areaComments
DeathYesRareYesCommonly reported as a component of a composite- Likely more appropriate to use overall mortality
-Disease specific mortality requires clear definitions.
- Death rate will depend on baseline risk of mortality in the population of interest, which is low in ADPKD
-Should be considered but may not apply in all cases (e.g. children).
ESRD including preemptive transplantYesVaries depending on genotype, rate of progression and comorbiditiesYesCommonly reported as a component of a compositeEnrichment strategies are useful to increase the event rate of the outcome.
-Clear definitions of ESRD are necessary.
HospitalizationYesVaries; Can be affected by patients’ historyYesReported as an outcome but not often part of a compositeHospitalization due to disease specific Interventions or complications should be very clearly defined and adjudicated
Worsening kidney functionYesVaries/FrequentYesCommonly reported as a component of a composite-Reported using different measures (e.g. doubling of serum Cr, 50% reduction in eGFR, reduction of eGFR beyond a certain threshold)
-Important to note that the pattern of treatment effects on GFR must be examined, specifically acute effects on eGFR
-Need to be aware of hyperfiltartion as a potential confounder to the results of kidney function
HypertensionComplicated if agent affects BP and by concomitant anti-hypertensive useFrequentAccepted surrogate Reported as an outcome but not often part of a composite -could be unreliable unless very clearly defined.
-Reported using different measures (e.g. SBP, DBP, worsening hypertension as defined by “intensified therapy”)
- It is important to include the actual BP value
Chronic or acute pain / Medication? lack of reliable and responsive tools to assess pain and identify causeVaries/FrequentYes when using validated toolsReported as an outcome but not part of a composite-Reported using different measures (e.g. significant kidney pain necessitating medical leave, pharmacologic treatment or invasive intervention)
-Challenging to distinguish Kidney pain
Total Kidney VolumeVaries/ requires CT or MRIVariesVaries with different jurisdictions.
Not accepted as a clinical outcome but accepted as “reasonably likely surrogate” and “prognostic enrichment biomarker” in the united states
Reported as an outcome but not part of a composite-Earlier biomarker than worsening kidney function
-usually reported as % change of TKV over different periods
Activities of Daily Living/Quality of lifeYes/ requires validated toolsVariesYes when using validated toolsReported as an outcome but not part of a composite-Many different ADLs could be measured using validated tools.
-There are also “accepted” patient reported outcome measures that should be considered
Complicated by concomitant medication use and variability in ways to measure it
VariesNoInconsistent reporting -Not a common feature of ADPKD
-Reported using different measures (e.g. Urine protein/Creatinine ration, time to the doubling of the baseline urine protein-to-creatinine)
Radiological appearance of the kidneyNoVariesNoNot often reported and is not part of a composite-Technology not mature and validated. “Textural analysis.”
GirthYes/ requires validated toolsVariesYes, when using validated toolNot often reported and is not part of a composite-Could be well measured with a PRO
-Multiple factors affect Girth including liver size.
-Organ enlargement is only a measure of late disease
- May be considered cosmetic
Kidney stones and Kidney infectionsYesVaries but relatively infrequentYes
(clinically meaningful)
Not often reported and is not part of a composite-Infrequent and may not be a good component in a composite
Cardiovascular outcomesYesVaries depending on comorbidities but relatively infrequentYesNot often reported and is not part of a composite-Unlikely to occur in early ADPKD disease
-May be considered a safety endpoint depending on the agent being investigated