# Lung Transplant Clinical Trial Network (LT-CTN)

> **NIH NIH U01** · DUKE UNIVERSITY · 2022 · $2,975,390

## Abstract

ABSTRACT
This Lung Transplant Clinical Trials Network (LT-CTN) CTOT-CA consortium includes eight of the leading high-
volume, research-oriented adult and pediatric lung transplant programs in North America. Long-term survival
after lung transplantation is limited by chronic lung allograft dysfunction (CLAD), the final manifestation of chronic
lung transplant rejection. CLAD is not effectively prevented by lung transplant immunosuppression, as over 50%
of transplant patients develop CLAD within five years. Growing evidence suggests upregulation of inflammatory
cytokines in the lung allograft contributes to CLAD development through innate immunity and allorecognition-
driven adaptive immune responses. Our preliminary data demonstrate that post-transplant acute rejection (AR),
lymphocytic bronchiolitis (LB), organizing pneumonia (OP), or acute lung injury (ALI) increase CLAD risk and are
associated with elevations of Types I & II cytokines in the lung fluid. Because Type I/II cytokines share signaling
through the Janus Kinase (JAK) family, blocking the relevant JAKs could be an effective strategy to limit
inflammatory cytokine responses and prevent CLAD. Our data demonstrate that itacitinib, a selective JAK1 and
partial JAK2 inhibitor being tested in patients with bone marrow transplant, is effective in preventing AR in a fully
mismatched murine orthotopic lung transplant model, and that JAK1 is highly overexpressed in human lung
transplant CLAD. Thus, we hypothesize that addition of itacitinib to standard post-transplant immunosuppression
will reduce inflammation due to cytokine signaling, diminish further innate and adaptive immune responses, and
prevent CLAD. To test this, we propose to complete the INhIBIT-CLAD (ItacitiNIB randomized, multi-center,
double-blind, placebo-controlled trial to reduce lung Inflammation and prevenT CLAD) study, enrolling 450
bilateral lung transplant recipients over two years and randomizing 280 of those at higher CLAD risk (evidence
of AR, LB, OP, or ALI) to treatment with itacitinib or placebo and follow-up over three to five years, to detect the
primary outcome of CLAD. We also will collect biospecimens from all enrolled participants and conduct
mechanistic studies using lung fluid and tissue from randomized patients to determine how innate immunity and
adaptive immune responses that contribute to CLAD development are mitigated by selective JAK inhibition with
itacitinib. Finally, as Cytomegalovirus (CMV) is another key CLAD risk factor – and preventable – we propose a
multi-center infectious disease study targeting prevention of CMV infection after lung transplant using novel
measures of CMV-specific immunity to personalize antiviral prophylaxis duration. Our highly qualified team of
investigators bring longstanding, collaborative, highly relevant experience, including leading the adult CTOT-20
and-22 and the pediatric CTOTC-03, -05, -08, and -11 studies. Successfully completed, the studies now
proposed have poten...

## Key facts

- **NIH application ID:** 10469461
- **Project number:** 5U01AI163099-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** JOHN A BELPERIO
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,975,390
- **Award type:** 5
- **Project period:** 2021-08-13 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469461

## Citation

> US National Institutes of Health, RePORTER application 10469461, Lung Transplant Clinical Trial Network (LT-CTN) (5U01AI163099-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10469461. Licensed CC0.

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