End-Stage Renal Disease, Hepatitis C
Conditions
Keywords
Renal, Transplants, Hepatitis C, HCV-negative, Infected, Donors
Brief summary
In this study, individuals without hepatitis C infection who are on the kidney transplant waitlist will receive a kidney from a deceased donor with hepatitis C infection and will be treated for hepatitis C at the same time. Treatment will include Grazoprevir (GZR) 100 mg/Elbasvir (EBR) 50 mg administered on-call to the operating room for the renal transplant procedure and continued for 12 weeks post-renal transplant.
Detailed description
In this study, individuals without hepatitis C infection who are on the kidney transplant waitlist will receive a kidney from a deceased donor with hepatitis C infection and will be treated for hepatitis C at the same time. Hepatitis C treatment will include Grazoprevir (GZR) 100 mg/Elbasvir (EBR) 50 mg administered on-call to the operating room for the renal transplant procedure and continued for 12 weeks post-renal transplant. The donor hepatitis C genotype will be tested. If the donor has genotype 1a without resistance or genotype 1b treatment will remain GZR/EBR for 12 weeks. If the donor has genotype 1a with resistance variants, then Ribavirin will be added and treatment will be given for 16 weeks starting from the date ribavirin was added. If the donor has hepatitis C genotype 2 or 3, Sofosbuvir will be added and treatment will be for 12 weeks from the date Sofosbuvir was added.
Interventions
DRUGZepatier
Fixed dose Grazoprevir 100 mg/Elbasvir 50 mg by mouth daily for 12 weeks
DRUGRibavirin
Ribavirin 1200 mg/d (\> 75 kg) or 1000 mg/d (\< 75 kg) by mouth daily in two divided doses
DRUGSofosbuvir
Sofosbuvir 400 mg daily
Sponsors
Merck Sharp & Dohme LLC
Johns Hopkins University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants ≥ 50 years old * On the deceased donor kidney waiting list at Johns Hopkins Hospital * Awaiting a first kidney transplant * No available living kidney donors * On hemodialysis or peritoneal dialysis or stage 5 chronic kidney disease (CKD) defined as a glomerular filtration rate \< 15 ml/min for ≥ past 90 days * HCV-uninfected (by both antibody and RNA PCR) and without any behavioral risk factors for contracting HCV other than being on hemodialysis. * Calculated panel reactive anti-human leukocyte antigen (HLA) antibody (cPRA) below 20 percent * Female who is: * practicing total abstinence from sexual intercourse (minimum 1 complete menstrual cycle) * sexually active with female partners only * not of childbearing potential: defined as postmenopausal for at least 2 years prior to screening defined as amenorrheic for longer than 2 years, age appropriate, and confirmed by a follicle-stimulating hormone level indicating a postmenopausal state, or surgically sterile: defined as bilateral tubal ligation, bilateral oophorectomy or hysterectomy or has a vasectomized partner(s); * of childbearing potential and sexually active with male partner(s): currently using at least one effective method of birth control at the time of screening and agree to practice two effective methods of birth control while receiving study drug (as outlined in the participant information and consent form starting with Study Day 1 and for 30 days after stopping study drug, or for 6 months after stopping study drug if receiving RBV (Note: Estrogen-containing hormonal contraceptives, including oral, injectable, implantable, patch and ring varieties, may not be used during study drug treatment). * Males who are not surgically sterile and are sexually active with female partner(s) of childbearing potential must agree to practice two effective forms of birth control (as outlined in the participant information and consent form) throughout the course of the study, starting with starting with Study Day 1 and for 30 days after stopping study drug, or for 6 months after stopping study drug if receiving ribavirin (RBV)
Exclusion criteria
* Plan to receive a multi-organ transplant * Plan to receive a dual kidney transplant (including en bloc) * Prior solid organ transplant * Participating in another study that involves an intervention or investigational product * Plan to receive a blood type incompatible kidney * History of human immunodeficiency (HIV), hepatitis C (HCV), or active hepatitis B (HBV) infection defined as being on active antiviral treatment for HBV, detectable hepatitis B surface Ag or detectable hepatitis B DNA * Active or unresolved bacterial, viral, or fungal infection that is clinically significant * History of cirrhosis or pre-existing liver disease such as non-alcoholic steatohepatitis * History of illicit drug use or alcohol abuse within 12 months prior to screening * Psychiatric or physical illness that in the opinion of the investigator would make it unsafe to proceed with transplantation or interfere with the ability of the subject to participate in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Grade 3 or Higher Treatment-related Adverse Events as US Department of Health and Human Services Common Terminology of Adverse Events (CTCAE) Version 4 | 12 weeks after transplant | Proportion of participants with grade 3 or higher treatment-related adverse events (AE) as assessed by US Department of Health and Human Services Common Terminology of AEs version 4. An AE is an unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5. Grade 3 Severe or medically significant but not life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. The investigator will determine if the AE is related to the treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Antibody Development | 12 weeks | Number of kidney transplant recipients who become reactive for HCV antibody |
| Number of Participants With Nonstructural Protein 5A (NS5A) Resistance Mutations in the HCV Population From the Deceased Donors | Baseline | Number of participants with NS5A resistance mutations in the HCV population from the deceased donors. Number of donors with NS5A resistance mutations |
| Viral Response | 12 weeks after completing treatment | This is the number of participants with undetectable hepatitis C RNA in the blood at 12 weeks after stopping treatment. Proportion of kidney transplant recipients with HCV RNA \< Lower Limit Of Quantification (LLOQ) at week 12 |
| Kidney Function at 6 Months | 6 months following transplantation | Serum creatinine mg/dL at 6 months following transplantation |
| Kidney Function at 12 Months | 12 months following transplantation | Serum creatinine mg/dL at 12 months following transplantation |
| IP-10 Elevations | 12 weeks | Measurement of interferon (IFN)-gamma inducible protein 10 (IP-10) a marker of acute hepatitis C infection. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Donor Genotype 1a no Resistance or 1b Participants who receive donors found to have hepatitis C genotype 1a without resistance Zepatier one tablet daily for 12 weeks
Zepatier: Fixed dose Grazoprevir 100 mg/Elbasvir 50 mg by mouth daily for 12 weeks | 7 |
| Donor Genotype 1a With Resistance Participants who receive donors found to have hepatitis C genotype 1a with nonstructural protein 5A associated resistance mutations Zepatier one tablet daily for 16 weeks Ribavirin weight based dosing for 16 weeks
Zepatier: Fixed dose Grazoprevir 100 mg/Elbasvir 50 mg by mouth daily for 12 weeks
Ribavirin: Ribavirin 1200 mg/d (\> 75 kg) or 1000 mg/d (\< 75 kg) by mouth daily in two divided doses | 0 |
| Donor Genotype 2 or 3 Participants who receive donors found to have hepatitis C genotype 2 or 3 Zepatier one tablet daily for 12 weeks Sofosbuvir 400 mg daily for 12 weeks
Zepatier: Fixed dose Grazoprevir 100 mg/Elbasvir 50 mg by mouth daily for 12 weeks
Sofosbuvir: Sofosbuvir 400 mg daily | 3 |
| Total | 10 |
Baseline characteristics
| Characteristic | Donor Genotype 1a no Resistance or 1b | Donor Genotype 1a With Resistance | Donor Genotype 2 or 3 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 0 Participants | 1 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Age, Continuous | 71 years | — | 61 years | 71 years |
| Hepatitis C virus (HCV) antibody negative | 7 Participants | 0 Participants | 3 Participants | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 0 Participants | 2 Participants | 8 Participants |
| Region of Enrollment United States | 7 participants | — | 3 participants | 10 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 6 Participants | 0 Participants | 2 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 0 | 0 / 3 |
| other Total, other adverse events | 0 / 7 | 0 / 0 | 0 / 3 |
| serious Total, serious adverse events | 3 / 7 | 0 / 0 | 1 / 3 |
Outcome results
Primary
Number of Participants With Grade 3 or Higher Treatment-related Adverse Events as US Department of Health and Human Services Common Terminology of Adverse Events (CTCAE) Version 4
Proportion of participants with grade 3 or higher treatment-related adverse events (AE) as assessed by US Department of Health and Human Services Common Terminology of AEs version 4. An AE is an unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5. Grade 3 Severe or medically significant but not life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. The investigator will determine if the AE is related to the treatment.
Time frame: 12 weeks after transplant
Population: There were no participants who received donors found to have hepatitis C genotype 1a with resistance enrolled.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Donor Genotype 1a no Resistance or 1b | Number of Participants With Grade 3 or Higher Treatment-related Adverse Events as US Department of Health and Human Services Common Terminology of Adverse Events (CTCAE) Version 4 | 0 Participants |
| Donor Genotype 1a With Resistance | Number of Participants With Grade 3 or Higher Treatment-related Adverse Events as US Department of Health and Human Services Common Terminology of Adverse Events (CTCAE) Version 4 | 0 Participants |
| Donor Genotype 2 or 3 | Number of Participants With Grade 3 or Higher Treatment-related Adverse Events as US Department of Health and Human Services Common Terminology of Adverse Events (CTCAE) Version 4 | 0 Participants |
Secondary
Antibody Development
Number of kidney transplant recipients who become reactive for HCV antibody
Time frame: 12 weeks
Population: There were no participants who received a kidney from a donor with genotype 1a infection and resistance. Therefore this population is zero.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Donor Genotype 1a no Resistance or 1b | Antibody Development | 3 Participants |
| Donor Genotype 1a With Resistance | Antibody Development | 0 Participants |
| Donor Genotype 2 or 3 | Antibody Development | 2 Participants |
Secondary
IP-10 Elevations
Measurement of interferon (IFN)-gamma inducible protein 10 (IP-10) a marker of acute hepatitis C infection.
Time frame: 12 weeks
Population: Data were not collected
Secondary
Kidney Function at 12 Months
Serum creatinine mg/dL at 12 months following transplantation
Time frame: 12 months following transplantation
Population: There were no participants who received a kidney from a donor with genotype 1a infection and resistance. Therefore this population is zero.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Donor Genotype 1a no Resistance or 1b | Kidney Function at 12 Months | 1.0 mg/dL |
| Donor Genotype 2 or 3 | Kidney Function at 12 Months | 1.3 mg/dL |
Secondary
Kidney Function at 6 Months
Serum creatinine mg/dL at 6 months following transplantation
Time frame: 6 months following transplantation
Population: There were no participants who received a kidney from a donor with genotype 1a infection and resistance. Therefore this population is zero.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Donor Genotype 1a no Resistance or 1b | Kidney Function at 6 Months | 1.12 mg/dL |
| Donor Genotype 2 or 3 | Kidney Function at 6 Months | 0.9 mg/dL |
Secondary
Number of Participants With Nonstructural Protein 5A (NS5A) Resistance Mutations in the HCV Population From the Deceased Donors
Number of participants with NS5A resistance mutations in the HCV population from the deceased donors. Number of donors with NS5A resistance mutations
Time frame: Baseline
Population: There were no participants who received a kidney from a donor with genotype 1a infection and resistance. Therefore this population is zero.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Donor Genotype 1a no Resistance or 1b | Number of Participants With Nonstructural Protein 5A (NS5A) Resistance Mutations in the HCV Population From the Deceased Donors | 0 Participants |
| Donor Genotype 1a With Resistance | Number of Participants With Nonstructural Protein 5A (NS5A) Resistance Mutations in the HCV Population From the Deceased Donors | 0 Participants |
| Donor Genotype 2 or 3 | Number of Participants With Nonstructural Protein 5A (NS5A) Resistance Mutations in the HCV Population From the Deceased Donors | 0 Participants |
Secondary
Viral Response
This is the number of participants with undetectable hepatitis C RNA in the blood at 12 weeks after stopping treatment. Proportion of kidney transplant recipients with HCV RNA \< Lower Limit Of Quantification (LLOQ) at week 12
Time frame: 12 weeks after completing treatment
Population: There were no participants who received a kidney from a donor with genotype 1a infection and resistance. Therefore this population is zero.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Donor Genotype 1a no Resistance or 1b | Viral Response | 7 Participants |
| Donor Genotype 1a With Resistance | Viral Response | 0 Participants |
| Donor Genotype 2 or 3 | Viral Response | 3 Participants |