Gradual Withdrawal of Immune System Suppressing Drugs in Patients Receiving a Liver Transplant

Browse trials for

• Hepatitis A 2,709
• Hepatitis C 2,321
• Hepatitis C, Chronic 1,073
• Hepatitis 3,380
• Liver Failure 445

Keywords

• hepatitis
• hepatitis C
• HCV
• liver
• liver disease
• liver transplant
• liver transplantation
• transplant
• hepatic
• hepatic transplantation
• immunosuppression
• rejection

Hepatitis A

2,709 studies on the registry are indexed under Hepatitis A; 142 are open to participants now.

This study's enrollment of 275 is above the median of 100 across 1,886 interventional studies indexed under Hepatitis A.

Lead sponsor

National Institute of Allergy and Infectious Diseases (NIAID) is the lead sponsor of 2,401 studies on the registry; 179 are open to participants now.

Of its 396 completed or terminated interventional studies of FDA-regulated products, 294 (74%) have results posted.

Study arms

• Experimental
  Immunosuppression Withdrawal

  Subjects may randomize to this group at 12 to 24 months after transplantation. This is followed by tapered withdrawal of calcineurin inhibitor-based immunosuppression therapy over the course of 1 year.

  Drug: calcineurin inhibitor-based immunosuppression · Procedure: liver transplant · Drug: corticosteroids · Other: immunosuppression withdrawal

• Active comparator
  Immunosuppression Maintenance

  Liver transplant, followed by maintenance doses of continuous calcineurin inhibitor-based immunosuppression therapy.

  Drug: calcineurin inhibitor-based immunosuppression · Procedure: liver transplant · Drug: corticosteroids

Interventions

• Drugcalcineurin inhibitor-based immunosuppression

  May be cyclosporine, mycophenolate mofetil, or tacrolimus

• Procedureliver transplant

  Occurs at study entry

  Also known as: liver transplantation

• Drugcorticosteroids

  3-month course of corticosteroids

  Also known as: prednisone

• Otherimmunosuppression withdrawal

  One year after transplantation, participants eligible for withdrawal are randomly assigned in a 4 to 1 ratio to immunosuppression withdrawal or to maintenance.

Primary outcomes

1. Number of Participants With Clinical Complications Usually Attributed to Immunosuppression

   This is a composite endpoint comprising clinical complications related to immunosuppression and is defined as the occurrence of any of the following: death or graft loss, grade 4 secondary malignancy (graded by Common Terminology Criteria for Adverse Events \[CTCAE\] version 3.0), grade 4 opportunistic infection (graded by CTCAE version 3.0), stage 3 or higher fibrosis, or decrease in renal function. Decrease in renal function is defined as: a) the estimated glomerular filtration rate (eGFR) using creatinine obtained prior to and closest to randomization will be considered the baseline and will be compared to the eGFR using creatinine obtained at 24 months +/- 3 months after randomization; b) for those with a baseline eGFR 30-90 ml per min per 1.73 meter-squared, a 25% decrease in eGFR; c) for those with a baseline eGFR greater than 90 ml per min per 1.73 meter-squared, a 25% decrease in eGFR and a decrease in eGFR to less than 90 ml per min per 1.73 meter-squared.

   Time frame: Randomization to 2 years post-randomization

Secondary outcomes

1. Number of Participants Who Qualify for Random Assignment

   Time frame: One to two years post-transplantation

2. Number of Participants Who Successfully Stop Taking Immunosuppression for at Least 6 Months

   Time frame: Randomization until study completion or participant termination (up to six years post-transplant)

3. Immunosuppression-free Duration

   Time (in days) from withdrawing off of all immunosuppressive drugs to re-starting immunosuppression or study termination/completion.

   Time frame: Discontinuation of all immunosuppression to end of trial participation or to time of restarting immunosuppression, whichever came first, assessed up to two years

4. Number of Hepatitis C Infected Participants With Progression of Hepatitis C Related Liver Disease, Defined as Stage 4 or Higher Fibrosis on the Ishak Scale

   Number of subjects with a biopsy showing stage 4 fibrosis or higher on the Ishak scale. Stage 4 represents at least 13.7% fibrosis measurement with a description of fibrous expansion of portal areas with marked bridging (P-P) as well as portal to central (P-C). Stage 5 is marked bridging (P-P and/or P-C), with occasional nodules (incomplete cirrhosis) and stage 6 is cirrhosis, probable or definite.

   Time frame: Randomization to 2 years post-randomization.

5. Number of Participants Experiencing Graft Loss or Death

   Number of participants with graft loss or death. Graft loss is defined as subject death or re-transplantation.

   Time frame: Randomization to 2 years post-randomization.

6. Total Immunosuppression From Month 21 to Month 24 Post-randomization

   Daily immunosuppression score in units per day averaged over the 3-month period from Month 21 to Month 24 post-randomization. Daily doses were assigned a score of 1 unit as follows: tacrolimus 1 mg, cyclosporine 100 mg, Sirolimus 1 mg, mycophenolate mofetil 1000 mg, Mycophenolic acid 720 mg, azathioprine 50 mg, and prednisone 5 mg. Any antibody use equaled 20 units. Unit scores based on Vasudev (Vasudev B, Hariharan S, Hussain SA, Zhu YR, Bresnahan BA et al. BK virus nephritis: risk factors, timing, and outcome in renal transplant recipients. Kidney Int. 2005; 8(4):1834-1839.)

   Time frame: Month 21 to Month 24 post-randomization

7. Total Burden of Immunosuppression From Random Assignment to Month 24

   Total immunosuppression score in units taken as the sum of units per day over the 2-year period from randomization to Month 24 post-randomization. Daily doses were assigned a score of 1 unit as follows: tacrolimus 1 mg, cyclosporine 100 mg, Sirolimus 1 mg, mycophenolate mofetil 1000 mg, Mycophenolic acid 720 mg, azathioprine 50 mg, and prednisone 5 mg. Any antibody use equaled 20 units. Unit scores based on Vasudev (Vasudev B, Hariharan S, Hussain SA, Zhu YR, Bresnahan BA et al. BK virus nephritis: risk factors, timing, and outcome in renal transplant recipients. Kidney Int. 2005; 8(4):1834-1839.).

   Time frame: Randomization to Month 24 post-randomization

Baseline characteristics

Publications

• Shaked A, DesMarais MR, Kopetskie H, Feng S, Punch JD, Levitsky J, Reyes J, Klintmalm GB, Demetris AJ, Burrell BE, Priore A, Bridges ND, Sayre PH. Outcomes of immunosuppression minimization and withdrawal early after liver transplantation. Am J Transplant. 2019 May;19(5):1397-1409. doi: 10.1111/ajt.15205. Epub 2018 Dec 31. Erratum In: Am J Transplant. 2019 Aug;19(8):2393. doi: 10.1111/ajt.15491. PubMed 30506630 ↗
• Muthukumar T, Akat KM, Yang H, Schwartz JE, Li C, Bang H, Ben-Dov IZ, Lee JR, Ikle D, Demetris AJ, Tuschl T, Suthanthiran M. Serum MicroRNA Transcriptomics and Acute Rejection or Recurrent Hepatitis C Virus in Human Liver Allograft Recipients: A Pilot Study. Transplantation. 2022 Apr 1;106(4):806-820. doi: 10.1097/TP.0000000000003815. PubMed 33979314 ↗

Related links

• Click here for the Immune Tolerance Network website ↗