Early Use of Long-acting Tacrolimus in Lung Transplant Recipients

NCT04469842 | Recruiting Early Phase 1 DMC FDA Drug

• 1 other identifier: VEL-IIS-2020-085
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

Lung transplantation is a life-saving therapy for patients with advanced lung disease, however, necessitates the use of life-long immunosuppressive therapy for the prevention of acute and chronic rejection. The backbone of immunosuppression is the calcineurin-inhibitor class, with tacrolimus being the preferred drug due to its potency and improved side-effect profile. Nevertheless, tacrolimus is associated with several side effects including increased risk for infection and malignancy, tremors, headaches, seizures, hypertension, leukopenia and renal dysfunction. In fact, by 6 months post-transplant, 50% of patients will have a 50% decline in eGFR and by 5 years post-transplant \~10% of patients will have advanced renal disease that may require renal replacement therapy and/or kidney transplantation. Tacrolimus induces a nephropathy in two ways- acute calcineurin inhibitor nephrotoxicity (CIN) is mediated by afferent arteriolar vasoconstriction, whereas chronic CIN is due to interstitial nephritis and fibrosis. Immunosuppressive regimens that spare or dose-reduce calcineurin inhibitors have been shown to have a modest impact on preserving renal function, but are limited by timing. Although most studies support implementing renal preserving protocols early on, this is balanced by the potential for acute cellular rejection, antibody mediated rejection and anastomotic dehiscence. Long-acting Tacrolimus (LCP-tacrolimus) may have the potential to bridge the balance of providing potent immunosuppression, while sparing renal function, due to the better systemic dose levels and improved concentration/dose ration achieved with it compared to IR-tacrolimus, evidenced in the renal transplant population. There is limited experience with LCP-tacrolimus in lung transplantation. Several case reports chronicling the late conversion from IR-tacrolimus to LCP-tacrolimus due to absorption issues or side-effect intolerance, have demonstrated safety and tolerability. The investigators seek to determine whether early use of LCP-tacrolimus in lung transplant recipients following the index hospitalization is acceptable, and propose a single-center prospective, randomized, controlled pilot study of early-use LCP-tacrolimus in lung transplant recipients to assess safety, tolerability and side-effects of LCP-tacrolimus.

Conditions

Lung Transplant; Complications

Keywords

Lung Transplantation; Calcineurin inhibitor; LCP-tacrolimus (Envarsus XR); Calcineurin-inhibitor nephrotoxicity (CIN)

Outcome Measures

Primary Outcomes (1)

• Safety and Tolerability

  Composite of mortality, allograft failure, potential drug induced liver injury, supra-therapeutic trough levels (\>20 ng/mL), sub-therapeutic trough levels (\<5 ng/mL), seizures, encephalopathy, thrombotic microangiopathy and serious hyperkalemia associated with use of LCP-tacrolimus, compared to matched historical controls administered IR-tacrolimus.

  6 months

Secondary Outcomes (5)

• Median change in eGFR at 9 months post-transplant.

  9 months

• Headache frequency and severity

  9 months

• Quality of life related to tremor

  9 months

• Incidence of acute cellular rejection

  9 months

• Incidence of de novo donor-specific anti-HLA antibodies

  9 months

Study Arms (2)

Immunosuppression with Extended-Release Tacrolimus

EXPERIMENTAL

LCP-tacrolimus administered daily to target a goal trough level of 10-14 ng/mL x 7 months (with Mycophenolate mofetil and prednisone). Additional standard immunosuppression with either mycophenolate mofetil (500-1500mg twice daily) OR Azathioprine (up to 2mg/kg daily) AND Prednisone (5-10mg daily) will be administered.

Drug: Tacrolimus Extended Release Oral Tablet [Envarsus]; Drug: Mycophenolate Mofetil Hydrochloride; Drug: Prednisone; Drug: Azathioprine

Immunosuppression with Intermediate Release Tacrolimus

ACTIVE COMPARATOR

IR-tacrolimus administered twice daily to target a goal trough level of 10-14 ng/mL x 7 months (with Mycophenolate mofetil and prednisone). This is currently the standard of care at Vanderbilt University Medical Center and most other lung transplant centers (ISHLT Registry 2019). Additional standard immunosuppression with either mycophenolate mofetil (500-1500mg twice daily) OR Azathioprine (up to 2mg/kg daily) AND Prednisone (5-10mg daily) will be administered.

Drug: Tacrolimus; Drug: Mycophenolate Mofetil Hydrochloride; Drug: Prednisone; Drug: Azathioprine

Interventions

Tacrolimus Extended Release Oral Tablet [Envarsus] DRUG

Immunosuppression regimen with Tacrolimus Extended Release as the backbone.

Also known as: Envarsus XR

Immunosuppression with Extended-Release Tacrolimus

Tacrolimus DRUG

Standard Immunosuppression regimen with Intermediate-Release Tacrolimus.

Also known as: Intermediate Release Tacrolimus, Prograf, FK506

Immunosuppression with Intermediate Release Tacrolimus

Mycophenolate Mofetil Hydrochloride DRUG

Standard immunosuppression of the anti-proliferative class.

Also known as: MMF, CellCept

Immunosuppression with Extended-Release Tacrolimus; Immunosuppression with Intermediate Release Tacrolimus

Prednisone DRUG

Standard immunosuppression (corticosteroid class).

Also known as: Deltasone

Immunosuppression with Extended-Release Tacrolimus; Immunosuppression with Intermediate Release Tacrolimus

Azathioprine DRUG

Standard immunosuppression of the anti-proliferative class.

Also known as: Imuran

Immunosuppression with Extended-Release Tacrolimus; Immunosuppression with Intermediate Release Tacrolimus

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Status-post single or bilateral lung transplantation
• Participant is able to give informed consent for participation in the study.
• Male or female age 18 years or above.
• Actively receives care at VUMC and is adherent with medical therapies.

You may not qualify if:

• History of prior organ transplantation
• History of tacrolimus use prior to transplantation
• Intolerance of tacrolimus (that precludes use)
• Having DSA pre-transplant (Positive virtual crossmatch)
• Active infection with Hepatitis B or C
• Active infection with Human Immunodeficiency Virus (HIV)
• Baseline AST / ALT \> three times upper limit normal
• Primary graft dysfunction grade 3 at 72 hours
• Acute kidney injury during index hospitalization that does not resolve to two times the pre-transplant baseline value.
• Contraindication to PO (per os) intake of medications
• Impaired GI absorption (defined as sublingual administration of IR-tacro)
• History of frequent headaches
• Seizure history
• Cannot provide consent (at least verbally)
• Pregnancy or breast-feeding

Sponsors & Collaborators

• Vanderbilt University Medical Center: lead
• Veloxis Pharmaceuticals: collaborator

Study Sites (1)

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

RECRUITING

Related Publications (38)

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  BACKGROUND

• Monnier A, Kummel T, Collage O, et al. Prevalence of Acute and Chronic Renal Failure After Lung Transplantation. In. Vol 34. Journal Heart Lung Transplantation 2015:S261.

  RESULT

• McCurry KA,Fitzgerald LJ, Chan JM, Jia S. Conversion from Tacrolimus IR (Twice Daily) or Cyclosporine to Tacrolimus XR (Envarsus®, Once Daily) in Lung Transplant Recipients. J Heart Lung Transplant. 2020; 39(4): S505

  RESULT

MeSH Terms

Interventions

Tacrolimus; Mycophenolic Acid; Prednisone; Azathioprine

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Thionucleosides; Sulfur Compounds; Mercaptopurine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Anil J Trindade, MD

  Vanderbilt University Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Anil J Trindade, MD

CONTACT

615-875-1380; anil.trindade@vumc.org

Haley Hoy, PhD, NP

CONTACT

615-202-8576; haley.hoy@vumc.org

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Model Details: Prospective, randomized, controlled pilot study.

Study Record Dates

• First Submitted: July 9, 2020
• First Posted: July 14, 2020
• Study Start: December 1, 2023
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: March 10, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)