PRO-ACT:: Prevention of De Novo HCV With Antiviral HCV Therapy Post-Liver and Post-Kidney Transplant

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT03619837
• Collaborator: (none)
• Enrollment: 122
• Locations: 6
• Arm: 1
• Actual Duration (Months): 25
• Patients Per Site: 20.3
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

In this study, subjects that do not have Hepatitis C virus (HCV) will be transplanted with livers or kidneys from donors who do have HCV. Medications that are used to treat HCV will be given to the study subjects shortly after transplant to protect them from developing the problems HCV can cause to the liver.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis C; Transplantation Disease Transmission	Drug: Sofosbuvir/Velpatasvir; Drug: Sofosbuvir/Velpatasvir/Voxilaprevir	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 122 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: PRO-ACT: Prevention of De Novo HCV With Antiviral HCV Therapy Post-Liver
• Actual Study Start Date: Jul 15, 2018
• Actual Primary Completion Date: Dec 21, 2019
• Actual Study Completion Date: Aug 13, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment Arm Single Arm: Sofosbuvir/Velpatasvir Dosage: 400mg/100mg. Once daily for 12 weeks.	Drug: Sofosbuvir/Velpatasvir; Sofosbuvir/Velpatasvir starting early post-transplant for total of 12 weeks.; Drug: Sofosbuvir/Velpatasvir/Voxilaprevir; Only for patients who fail initial treatment with Sofosbuvir/Velpatasvir. Dosage: 400mg/100mg/100mg daily for 12 weeks.

Outcome Measures

Primary Outcome Measures

1. Proportion of Participants With HCV RNA Level Below Limits of Quantification (LOQ) [12 weeks after end of treatment]

   The primary outcome was sustained virologic response, defined as HCV RNA below the lower limit of quantification 12 weeks after treatment completion (SVR12). Secondary outcomes included the proportion of patients with SVR24 defined as HCV RNA < lower limit of quantification 24 weeks after the end of treatment; with viral relapse defined as HCV RNA <LLOQ at end of treatment with subsequent quantifiable HCV RNA; and with on-treatment virologic breakthrough defined as > 1 log increase in viral RNA after treatment week 1. Safety was measured as the adverse events and serious adverse events attributed by the investigator to HCV infection or antiviral therapy; the proportion of recipients who prematurely discontinued antiviral therapy before the planned end of treatment; and patient and graft survival at 6 months post-transplant.

Secondary Outcome Measures

1. Safety as Measured by the Proportion of Participants Who Prematurely Discontinue Antiviral Therapy Before the Planned End of Treatment [12 weeks after start of treatment]

   1 of 23 patients prematurely discontinued antiviral therapy due to intercurrent graft-versus-host disease that progressed to multiorgan failure.

Other Outcome Measures

1. Survival Rate of Patients and Their Allografts 6 Months Post Transplant [6 months from time of liver transplant]

   Graft and patient survival at 24 weeks after transplant

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adult (≥ 18 year-old), wait-listed for primary kidney or liver transplant without a potential suitable living donor or for simultaneous liver kidney transplant;

• HCV non-infected at the time of transplant. Subjects who were previously HCV infected but who have had documented SVR12 are eligible to participate;

• Agree to use two methods of birth control during the study;

• Donor characteristics: serum HCV NAT-positive and negative for hepatitis B surface antigen. For liver transplant: pre-donation liver biopsy with no fibrosis (F0) or minimal fibrosis (F1). For kidney transplant: kidney donor profile index < 85%.

Exclusion Criteria:

• Donor and/or recipient HIV infection

• Subject pregnant or nursing

• Donor and/or recipient Hepatitis B surface antigen positive

• Kidney-pancreas transplant

• Single organ liver recipients who received hemodialysis for more than 7 days prior to liver transplantation

• Kidney recipients: on dialysis for > 5 years at time of Screening; subjects sensitized with panel reactive antibody > 80%; for single organ kidney transplant, subjects with advanced liver fibrosis (Knodell stage 3) or cirrhosis

• Individuals being treated with and needing to continue rifabutin, rifampin, carbamazepine, phenytoin, phenobarbital, oxcarbazepine, St. John's wort (Hypericum perforatum), medium- or high-dose rosuvastatin or atorvastatin, or high-dose proton pump inhibitors (See Concomitant Medications).

• Individuals treated with amiodarone within 42 days of organ transplant.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Francisco	San Francisco	California	United States	94143
2	University of Colorado Denver	Aurora	Colorado	United States	80045
3	Piedmont Research Institute	Atlanta	Georgia	United States	30309
4	Columbia University	New York	New York	United States	10032
5	Baylor University Medical Center - Dallas	Dallas	Texas	United States	75246
6	Houston Methodist Hospital	Houston	Texas	United States	77030

Sponsors and Collaborators

• University of California, San Francisco

Investigators

• Principal Investigator: Claus Niemann, MD, University of California, San Francisco

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 18, 2018
• Informed Consent Form - Mar 19, 2018

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT03619837
• Other Study ID Numbers: 18-24323
• First Posted: Aug 8, 2018
• Last Update Posted: Mar 3, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Additional relevant MeSH terms: Hepatitis C; Sofosbuvir; Velpatasvir; Sofosbuvir-velpatasvir drug combination

Study Results

Participant Flow

Recruitment Details	From July 13, 2018, to December 21, 2019, 122 patients were recruited from 6 U.S. transplant centers and completed the first part of the informed consent and were enrolled in this trial, and 24 (20%) of these received organs from HCV-viremic donors completed the second consent to receive transplant: 13 liver transplants and 11 kidney transplants.

Arm/Group Title	Treatment Arm
Arm/Group Description	Single Arm: Sofosbuvir/Velpatasvir Dosage: 400mg/100mg. Once daily for 12 weeks. Sofosbuvir/Velpatasvir: Sofosbuvir/Velpatasvir starting early post-transplant for total of 12 weeks. Sofosbuvir/Velpatasvir/Voxilaprevir: Only for patients who fail initial treatment with Sofosbuvir/Velpatasvir. Dosage: 400mg/100mg/100mg daily for 12 weeks.
Period Title: Screening
STARTED	122
COMPLETED	24
NOT COMPLETED	98
Period Title: Screening
STARTED	24
COMPLETED	24
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Transplant Recipients
Arm/Group Description	Single Arm: Sofosbuvir/Velpatasvir Dosage: 400mg/100mg. Once daily for12 weeks. Sofosbuvir/Velpatasvir:Sofosbuvir/Velpatasvir starting early post-transplant for total of 12 weeks. Sofosbuvir/Velpatasvir/Voxilaprevir:Only for patients who fail initial treatment with Sofosbuvir/Velpatasvir. [no patients failed initial treatment] Dosage: 400mg/100mg/100mg daily for12 weeks.
Overall Participants	24
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	22 91.7%
>=65 years	2 8.3%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	57
Sex: Female, Male (Count of Participants)
Female	11 45.8%
Male	13 54.2%
Race/Ethnicity, Customized (Count of Participants)
White	20 83.3%
Black	3 12.5%
Asian	1 4.2%
Region of Enrollment (participants) [Number]
United States	24 100%
Etiology of end-stage disease (Count of Participants)
nonalcohol steatohepatitis	5 20.8%
alcohol	4 16.7%
HCV/alcohol	2 8.3%
alpha-1-anti-trypsin deficiency	1 4.2%
hemochromatosis	1 4.2%
hypertension	4 16.7%
diabetes	1 4.2%
polycystic disease	2 8.3%
chronic nephritis	2 8.3%
immunoglobulin A nephropathy	2 8.3%

Outcome Measures

1. Primary Outcome

Title	Proportion of Participants With HCV RNA Level Below Limits of Quantification (LOQ)
Description	The primary outcome was sustained virologic response, defined as HCV RNA below the lower limit of quantification 12 weeks after treatment completion (SVR12). Secondary outcomes included the proportion of patients with SVR24 defined as HCV RNA < lower limit of quantification 24 weeks after the end of treatment; with viral relapse defined as HCV RNA <LLOQ at end of treatment with subsequent quantifiable HCV RNA; and with on-treatment virologic breakthrough defined as > 1 log increase in viral RNA after treatment week 1. Safety was measured as the adverse events and serious adverse events attributed by the investigator to HCV infection or antiviral therapy; the proportion of recipients who prematurely discontinued antiviral therapy before the planned end of treatment; and patient and graft survival at 6 months post-transplant.
Time Frame	12 weeks after end of treatment

Outcome Measure Data

Analysis Population Description

All patients with HC viremia documented post-transplant. 1 participant did not develop HCV viremia post transplant therefore was not included in the count of participants for this outcome.

Arm/Group Title	Treatment Arm
Arm/Group Description	Single Arm: Sofosbuvir/Velpatasvir Dosage: 400mg/100mg. Once daily for 12 weeks. Sofosbuvir/Velpatasvir: Sofosbuvir/Velpatasvir starting early post-transplant for total of 12 weeks. Sofosbuvir/Velpatasvir/Voxilaprevir: Only for patients who fail initial treatment with Sofosbuvir/Velpatasvir. Dosage: 400mg/100mg/100mg daily for 12 weeks.
Measure Participants	23
Count of Participants [Participants]	23 95.8%

2. Secondary Outcome

Title	Safety as Measured by the Proportion of Participants Who Prematurely Discontinue Antiviral Therapy Before the Planned End of Treatment
Description	1 of 23 patients prematurely discontinued antiviral therapy due to intercurrent graft-versus-host disease that progressed to multiorgan failure.
Time Frame	12 weeks after start of treatment

Outcome Measure Data

Analysis Population Description

1 participant did not develop HCV viremia post transplant therefore was not included in the count of participants for this outcome.

Arm/Group Title	Treatment Arm
Arm/Group Description	Single Arm: Sofosbuvir/Velpatasvir Dosage: 400mg/100mg. Once daily for 12 weeks. Sofosbuvir/Velpatasvir: Sofosbuvir/Velpatasvir starting early post-transplant for total of 12 weeks. Sofosbuvir/Velpatasvir/Voxilaprevir: Only for patients who fail initial treatment with Sofosbuvir/Velpatasvir. Dosage: 400mg/100mg/100mg daily for 12 weeks.
Measure Participants	23
Count of Participants [Participants]	1 4.2%

3. Other Pre-specified Outcome

Title	Survival Rate of Patients and Their Allografts 6 Months Post Transplant
Description	Graft and patient survival at 24 weeks after transplant
Time Frame	6 months from time of liver transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Arm
Arm/Group Description	Single Arm: Sofosbuvir/Velpatasvir Dosage: 400mg/100mg. Once daily for 12 weeks. Sofosbuvir/Velpatasvir: Sofosbuvir/Velpatasvir starting early post-transplant for total of 12 weeks. Sofosbuvir/Velpatasvir/Voxilaprevir: Only for patients who fail initial treatment with Sofosbuvir/Velpatasvir. Dosage: 400mg/100mg/100mg daily for 12 weeks.
Measure Participants	24
Count of Participants [Participants]	23 95.8%

Adverse Events

Time Frame	6 months
Adverse Event Reporting Description	AEs were graded using the Common Terminology Criteria for Adverse Events, Version 4.03, published June 2010
Arm/Group Title	Transplant Recipients
Arm/Group Description	Treatment Arm Single Arm: Sofosbuvir/Velpatasvir Dosage: 400mg/100mg. Once daily for 12 weeks.
All Cause Mortality
	Transplant Recipients
	Affected / at Risk (%)	# Events
Total	1/24 (4.2%)
Serious Adverse Events
	Transplant Recipients
	Affected / at Risk (%)	# Events
Total	13/24 (54.2%)
Cardiac disorders
cardiomyopathy	1/24 (4.2%)	1
Supraventricular tachycardia	1/24 (4.2%)	1
Gastrointestinal disorders
Colitis	1/24 (4.2%)	1
Gastrointestinal bleeding	1/24 (4.2%)	1
Hepatobiliary disorders
Biliary sclerosis	1/24 (4.2%)	1
Cholangitis	2/24 (8.3%)	2
Immune system disorders
GVHD	1/24 (4.2%)	1
Rejection	1/24 (4.2%)	1
Infections and infestations
Fever	5/24 (20.8%)	7
Musculoskeletal and connective tissue disorders
Fracture	2/24 (8.3%)	2
Renal and urinary disorders
Delayed graft function	1/24 (4.2%)	1
Ureteral stricture	1/24 (4.2%)	1
hyperkalemia	1/24 (4.2%)	1
Surgical and medical procedures
Bleeding	2/24 (8.3%)	2
Pancreatitis	1/24 (4.2%)	1
Other (Not Including Serious) Adverse Events
	Transplant Recipients
	Affected / at Risk (%)	# Events
Total	7/24 (29.2%)
Blood and lymphatic system disorders
anemia	1/24 (4.2%)	1
leukopenia	1/24 (4.2%)	1
Gastrointestinal disorders
nausea	1/24 (4.2%)	1
Hepatobiliary disorders
abnormal liver tests	5/24 (20.8%)	5
Renal and urinary disorders
hematuria	1/24 (4.2%)	1
Elevated creatinine	1/24 (4.2%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.