TL;DR: ⚪ Phase 2 signal didn't replicate — ilofotase alfa did not improve 28-day survival in sepsis-associated AKI, despite a promising phase 2 mortality/MAKE90 signal; a cautionary drug-development example.
1. Publication
- Title: Phase-3 trial of recombinant human alkaline phosphatase for patients with sepsis-associated acute kidney injury (REVIVAL)
- Acronym: REVIVAL
- Year & Journal: Intensive Care Medicine, published January 3, 2024 (50(1):68-78; correction April 2024)
- Citation: Pickkers P, Angus DC, Bass K, et al; REVIVAL investigators. Intensive Care Med. 2024;50(1):68-78. doi:10.1007/s00134-023-07271-w
2. Context & Rationale
Background: Sepsis-associated AKI (SA-AKI) has high short-term mortality and frequently progresses to chronic kidney disease, with no established disease-modifying pharmacotherapy. Ilofotase alfa (recombinant human alkaline phosphatase) dephosphorylates endotoxin and extracellular ATP, plausibly reducing inflammatory signaling, endothelial injury, and tubular stress. A phase 2 trial (301 patients) missed its primary endpoint (7-day endogenous creatinine clearance) but showed longer-term creatinine clearance improvement, a survival benefit, and reduced MAKE90 (26% reduction) — motivating this confirmatory phase 3 trial.
Research Question/Hypothesis: In critically ill SA-AKI patients, does ilofotase alfa improve 28-day survival compared with placebo?
3. Design & Methods
- Study Type: International, double-blind, randomized, placebo-controlled phase 3 trial
- Population: SA-AKI patients enrolled <72h on vasopressor and <24h of AKI (including a distinct "COVID-19 population" cohort)
- Intervention: Ilofotase alfa (recombinant human alkaline phosphatase)
- Comparator: Placebo
- Randomization: Stratified by site and modified SOFA (≤9 vs >9, excluding neurological component)
- Statistical Power & Follow-Up: Primary: 28-day all-cause mortality. Secondary: MAKE90, days alive and free of organ support through day 28, days alive and out of ICU through day 28, time to death through day 90.
4. Key Results
Outcome | Ilofotase Alfa | Placebo | Notes |
28-day survival (primary) | Not improved | — | Primary endpoint not met — clear null |
MAKE90 (secondary) | Possibly reduced | — | Suggestive signal, not the primary confirmed result |
Safety | No concerns identified | — | Reassuring safety profile |
5. Internal Validity Assessment
International, double-blind, placebo-controlled phase 3 confirmatory trial with prespecified stratification. Overall: Strong — a well-designed, definitive confirmatory trial following a promising but not fully positive phase 2 signal; the clear null on the primary (survival) endpoint, despite a possible MAKE90 secondary signal, provides high-confidence evidence against the drug's primary hypothesized benefit.
6. External Validity Assessment
International, multi-country SA-AKI population including a distinct COVID-19 subgroup — broadly representative of severe SA-AKI populations in critical care.
7. Strengths & Limitations
Strengths: Rigorous phase 3 confirmatory design directly testing the phase 2 trial's survival-benefit hypothesis; international, multi-site; reassuring safety profile.
Limitations: Primary endpoint (28-day survival) not met, representing a failure to replicate the phase 2 signal; MAKE90 secondary signal is suggestive only, not a confirmed primary finding.
8. Interpretation & Practice Impact
Does not support ilofotase alfa for improving survival in SA-AKI — the phase 2 survival-benefit signal did not replicate in this larger, definitive phase 3 trial, though a possible MAKE90 benefit leaves some residual interest in kidney-specific (rather than mortality) outcomes.
9. Controversies & Subsequent Evidence
The trial explicitly represents a case where a promising phase 2 signal (survival benefit, MAKE90 reduction) did not fully replicate at phase 3 — a recurring, important pattern in critical care drug development that argues for cautious interpretation of phase 2 data before assuming efficacy. The REVIVAL investigators and manufacturer (AM-Pharma) disclosures are noted, given the drug's continued commercial interest despite the null primary result.
10. Summary & Executive Takeaway
Summary: REVIVAL, an international phase 3 trial, randomized SA-AKI patients to ilofotase alfa (recombinant alkaline phosphatase) or placebo. 28-day survival, the primary endpoint, was not improved, though MAKE90 events may have been reduced (secondary signal); no safety concerns were identified.
Overall Takeaway: Ilofotase alfa did not confirm the survival benefit suggested by its phase 2 trial — a cautionary example of a promising early-phase signal failing to replicate in a larger, definitive confirmatory trial, though the drug's safety profile and a possible kidney-specific (MAKE90) signal leave some residual research interest short of a mortality benefit.
11. Bibliography
- Pickkers P, et al. Phase 2 trial of recombinant alkaline phosphatase in SA-AKI (STOP-AKI). JAMA. 2018;320(19):1998-2009.