Trial results for the Phase IIb ZEAL-UNLOCK study (NCT06269484) investigating dapagliflozin in combination with zibotentan for participants with cirrhosis were posted on ClinicalTrials.gov on 2026-01-20. The study, primarily evaluating safety, reported 14 participants in both the combination and zibotentan monotherapy arms experienced components of a fluid retention composite endpoint, compared to 6 participants in the placebo arm.
Background
Dapagliflozin is a medication that was investigated in combination with zibotentan for patients with liver cirrhosis in the ZEAL-UNLOCK study.
Trial design
The ZEAL-UNLOCK study (NCT06269484) was a Phase IIb, multicentre, randomised, double-blind, parallel-group, placebo-controlled study. It enrolled 73 participants with liver cirrhosis. The study evaluated the safety of zibotentan/dapagliflozin in combination, as well as zibotentan monotherapy, compared to placebo. The intervention arms included placebo, zibotentan + placebo, and zibotentan + dapagliflozin.
Key results
The trial evaluated several outcomes related to safety and physiological changes. For the composite endpoint measuring fluid retention-related events (defined as >2kg increase in body weight, >2 L increase in total body water, increase in 2 or more loop-diuretic equivalents, or a fluid retention adverse event):
- 14 participants in the zibotentan + dapagliflozin arm experienced components of this endpoint.
- 14 participants in the zibotentan monotherapy arm experienced components of this endpoint.
- 6 participants in the placebo arm experienced components of this endpoint.
Analysis of this composite endpoint showed a Risk Difference (RD) of 0.33 (90.0% CI: 0.09 to 0.55) when comparing zibotentan + dapagliflozin to placebo, and an RD of 0.33 (90.0% CI: 0.09 to 0.55) when comparing zibotentan monotherapy to placebo. The RD between zibotentan + dapagliflozin and zibotentan monotherapy was 0.0 (90.0% CI: -0.24 to 0.24).
Regarding changes from baseline in body weight:
- The least squares mean change for zibotentan + dapagliflozin was -1.08 kg.
- The least squares mean change for zibotentan monotherapy was 0.64 kg.
- The least squares mean change for placebo was -0.53 kg.
A Mixed Models Analysis showed a Mean Difference (Net) in body weight of -1.72 (90.0% CI: -2.82 to -0.62) for zibotentan + dapagliflozin compared to zibotentan monotherapy. The Mean Difference (Net) for zibotentan + dapagliflozin compared to placebo was -0.55 (90.0% CI: -1.66 to 0.56). The Mean Difference (Net) for zibotentan monotherapy compared to placebo was 1.17 (90.0% CI: 0.09 to 2.25).
For change from baseline in body fat mass:
- The least squares mean change for zibotentan + dapagliflozin was -1.68 kg.
- The least squares mean change for zibotentan monotherapy was -0.23 kg.
- The least squares mean change for placebo was -0.30 kg.
For change from baseline in total body water:
- The least squares mean change for zibotentan + dapagliflozin was 0.36 L.
- The least squares mean change for zibotentan monotherapy was 0.66 L.
- The least squares mean change for placebo was -0.36 L.
What this means
The results from the ZEAL-UNLOCK trial indicate that both zibotentan + dapagliflozin and zibotentan monotherapy were associated with a higher incidence of fluid retention-related events compared to placebo in participants with cirrhosis. This suggests a potential safety concern regarding fluid management in this vulnerable patient population. While the combination therapy showed a decrease in body weight and body fat mass, the increase in total body water in active treatment arms further supports the observation of fluid retention. These findings are important for understanding the safety profile of these treatments in patients with liver cirrhosis.
Source
The information regarding these trial results was obtained from ClinicalTrials.gov, a public database of clinical studies. The results for study NCT06269484, titled "A Phase IIb Study to Evaluate the Safety of Zibotentan/Dapagliflozin in Participants With Cirrhosis-ZEAL-UNLOCK," were posted on 2026-01-20 on clinicaltrials.gov.