Fig 1.
(A) Study design and (B) CONSORT flow diagram. d, day; aIL18, anti-interleukin-18; m, month; mAb, monoclonal antibody.
Fig 2.
(A) Probability of a Go decision by DGF rate* (B) Sequential Go/No Go/Continue rule†. *At a maximum of 30 patients, this design yields the probability of a Go decision of 0.139 when the GSK1070806 DGF rate is 50% (i.e., null hypothesis) and 0.69 at what has been a clinically impactful GSK1070806 DGF rate of 35%. †The number in the first column indicates the number of patients who have completed study treatment. A sequential Go/No Go/Continue rule is based on the predictive probability of success. A high predictive probability (PP) of success means that GSK1070806 is likely to be efficacious by the end of the study given the observed data, whereas a low PP suggests that the treatment may not have sufficient activity. If the PP value <2% (red region) the alternative hypothesis is rejected. If the PP is >92% (green), the conclusion may be made that GSK1070806 has better efficacy than the standard of care. If the PP is 2–92% (white region), the trial will continue to the next interim or until reaching 30 completed patients. The sequential path observed in the study is represented by the orange line. Although the pathway ends in the white region, the decision to terminate the study was made as only 1 of the 7 patients completing study treatment was not on dialysis and had creatine <400 μmol/L; this suggested that it was unlikely that GSK1070806 3 mg/kg reduced the risk of DGF. DGF, delayed graft function.
Fig 3.
Simulation of drug exposure in the kidney interstitium based on IL18 suppression using PBPK modeling up to 6 hours (A) and 90 days (B) post dose. Predicted drug concentration and free/bound IL18 in the kidney interstitium up to 4 hours (C) and 1-month (D) post dose with 3 mg/kg. IL18, interleukin-18, PBPK, physiologically-based pharmacokinetic modeling.
Table 1.
Donor and recipient paired baseline demographic characteristics and DGF outcomes.
Table 2.
Baseline demographics and clinical characteristics of patients receiving GSK1070806.
Fig 4.
(A) Creatinine levels and urine output during the first 7 days following transplantation. (B) Mean serum creatinine by DGF occurrence over the study course. There was some variability between patients in timeframe and extent of data collection: Patient 1, no data collected for Days 5 and 6; Patient 5, urine output was negligible during this period; Patient 7, urine output not recorded due to patient undergoing continued dialysis during this period. Any event occurring at any time within a calendar day was charted at that study day, e.g., for Patient 4, dialysis at Day 1 as shown on the chart may have occurred at any time point during Day 1. DGF, delayed graft function.
Table 3.
Summary of drug-related adverse events by system organ class.
Fig 5.
Serum levels of (A) IL18-GSK1070806 complex, (B) total IL18, and (C) IL18-BP over the study course. BP, binding protein; IL18, interleukin-18. Figures produced post hoc.
Fig 6.
Serum cytokine levels over the study course.
(A) IFNγ, (B) IP10, (C) MIG. IFNγ, interferon-γ; IP10, IFNγ-induced protein 10 Kd; MIG, monokine induced by IFNγ. Figures produced post-hoc.
Fig 7.
Dual immunohistochemical detection.
(A) Co-distribution of GSK1070806 (pink) with IL18 (yellow) in wedge biopsies from Patient 2. Nuclei stained with hematoxylin. (B) 200x magnified region of Patient 2 biopsy, taken from the area outlined in A, showing the luminal co-distribution of GSK1070806 (pink) and IL18 (yellow) in the tubules. (C) Isotype control staining. IL18, interleukin-18.