Table 1.
Potential end points for clinical trials in primary hyperoxaluria
| End Point | Pros | Cons |
|---|---|---|
| Clinical end points | ||
| Stone events | Affects how most patients with primary hyperoxaluria feel and function | Standards for measurement and longitudinal monitoring lacking |
| Accurate methods of measurement that do not rely on ionizing radiation are needed | ||
| Reliability in CKD stages 3b–5 unknown | ||
| Kidney failure | Important to patients, easy to measure | May not have many events in a trial, particularly if trial is conducted in the available number of patients with a reasonable length of follow-up |
| Oxalosis | Important to patients, severe morbidity | May not have many events in a trial, particularly if trial is conducted in the available number of patients with a reasonable length of follow-up |
| Surrogate end points | ||
| Worsening kidney function (GFR slope) | Accepted as surrogate end point for other conditions | May not detect change in patients with slow progression |
| Easy to measure | ||
| Rapid decline would be highly supportive of clinically meaningful benefit | ||
| Urine oxalate | Causal role in stone formation and kidney damage in CKD 1–3a and relationship between baseline urine oxalate and kidney failure | Magnitude of change needed to predict clinical benefit across primary hyperoxaluria types warrants further study |
| Available data support use of substantial change as surrogate end point for traditional approval in patients with primary hyperoxaluria type 1 with CKD 1–3a | May not be useful in CKD 3b–5 due to reduced kidney function to excrete oxalate | |
| Lesser treatment effects or effects in patients with primary hyperoxaluria without very high baseline levels reasonably likely to predict clinical benefit | ||
| Plasma oxalate | Reasonably likely to predict clinical benefit due to causal role in systemic oxalosis in CKD stages 3b–5 | Magnitude of change in plasma oxalate in CKD stages 3b–5 likely to predict clinical benefit requires further study |
| Causal role in stone formation and kidney damage (CKD stages 1–3a) | Value in CKD 1–3a for prediction of clinical outcome remains to be established | |
| Limited availability of laboratory measurement. Results vary by method | ||
Data supporting these conclusions are heavily influenced by primary hyperoxaluria type 1, which accounts for the majority of patients with primary hyperoxaluria. Small numbers of patients with primary hyperoxaluria type 2 and primary hyperoxaluria type 3 in primary hyperoxaluria registries do not yet provide a similar strength of evidence for these biomarkers in other forms of primary hyperoxaluria.