Randomized Phase II Study of Hepatitis C Immune Globulin Intravenous (Human), Civacir(TM), in Liver Transplantation

• Sponsor: ADMA Biologics, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00473824
• Collaborator: (none)
• Enrollment: 7
• Locations: 3
• Arms: 2
• Duration (Months): 21.1
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

A Phase 2 study to evaluate safety, pharmacokinetics and efficacy of Hepatitis C Immune Globulin Intravenous (human) [Civacir(TM)] for preventing or reducing the impact of recurrent HCV infection following liver transplantation.

Condition or Disease	Intervention/Treatment	Phase
Sequelae of Viral Hepatitis; Transplantation Infection; Evidence of Liver Transplantation	Biological: Hepatitis C Immune Globulin Intravenous (Human) 5%	Phase 2

Detailed Description

Hepatitis C virus (HCV) infection is the leading single cause of liver transplantation (LT) in the US and Europe. Recurrence of HCV infection following LT is almost universal. There is currently no effective way to prevent post-transplantation HCV infection of the liver graft and related progression of HCV-related liver disease. This study is designed to evaluate a polyclonal human hepatitis C immune globulin (Civacir) given during and post liver transplantation for preventing or reducing the impact of recurrent HCV infection.

In this open-label trial, 2 subjects will be randomized to receive Civacir (standard of care treatment plus Civacir) for every 1 Control subject (standard of care treatment alone). Civacir recipients will receive 18 intravenous infusions over 24 weeks beginning at the time of liver transplantation.

Viral loads, liver enzyme assessments and liver biopsy assessments will be made at scheduled intervals during the study which will last for 48 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-Label Phase II Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Hepatitis C Immune Globulin Intravenous (Human), Civacir(TM), in Liver Transplant Recipients
• Study Start Date: May 1, 2007
• Actual Primary Completion Date: Feb 1, 2009
• Actual Study Completion Date: Feb 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Civacir Treated Hepatitis C Immune Globulin Intravenous (Human) 5% [Civacir], 18 infusions total, per schedule, of Civacir 300 or 400 mg/kg of body weight, with standard post-transplant site specific routine immunosuppressant therapy .	Biological: Hepatitis C Immune Globulin Intravenous (Human) 5%; Hepatitis C Immune Globulin Intravenous (Human) 5%, [Civacir]: 18 infusions total, per schedule, of 300 or 400 mg/kg of body weight given with standard post-transplant therapy inclusive of immunosuppressive agents.; Other Names: Civacir™
No Intervention: Observational Control Observation on standard post-transplant site specific routine immunosuppressant therapy without infusions of Hepatitis C Immune Globulin Intravenous (Human) 5% [Civacir].

Outcome Measures

Primary Outcome Measures

1. Post Transplant Reduction in Viral Load (as Measured Quantitatively by Hepatitis C Virus (HCV) Reverse Transcription-Polymerase Chain Reaction (HCV RT-PCR)). [Outcome evaluations at 1 month (Day 28) and 6 months ( 24 weeks) post-tranplant.]

   Percentage of subjects who achieve reduction in viral load from the baseline pre-transplant value. Baseline is the pre-transplant HCV viral load as measeured by RT-PCR. Post-transplant HCV viral load is determined at both 1 month and 6 months post-tranplant.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female, 18 to 75 years of age.

• Written informed consent.

• Expectation of compliance with the protocol procedures.

• If female, have a negative pregnancy test within 3 days prior to randomization and use an acceptable method of contraception or be at least one year post-menopausal or surgically sterile.

• HCV infection identified by positive, quantifiable HCV-RNA test within 3 months prior to transplantation.

• First time liver transplant recipient.

• Primary, single organ recipient (deceased donor <65 years of age).

• Normal TSH.

• Subjects with a pre-LT diagnosis of hepatocellular carcinoma (HCC) may be enrolled provided: there is no evidence of extrahepatic spread, tumor is solitary and <5cm or there are up to three tumors <3 cm.

• Agree to receive study medication as outlined in the protocol and follow all study related procedures until the conclusion of their protocol participation.

• Agree to consume no alcohol during the entire study period.

Exclusion Criteria:

• Has received an investigational agent within the last six weeks prior to liver transplantation. Exceptions include Theraspheres for hepatocellular carcinoma or rifaximin.

• Known immunoglobulin A deficiency.

• Subject weighs more than 112.5 Kg (248 pounds).

• Known history of cancer, suspected cancer, or cancer therapy within 12 months prior to the administration of the investigational product, except for treatment for basal cell carcinoma, squamous cell carcinoma, cancer of the cervix in situ, early stage prostate cancer (Gleason's grade 1 or 2), or a history of malignancy where the risk of recurrence is >= 20% within 2 years. A significant exception is hepatocellular carcinoma with predefined acceptability (see inclusion criteria).

• Has any condition judged by the study physician to preclude participation in the study, including any psychological disorder, which might hinder compliance.

• History of use of immunosuppressive or immunomodulatory drugs within 3 months prior to randomization (except low-dose physiologic replacement glucocorticoid therapy (<=10 mg of prednisone or equivalent per day).

• Recipient of liver from a living donor.

• Subjects whose liver is obtained from a non-beating heart donor.

• Subjects scheduled to receive a split liver transplantation.

• Liver transplants that were obtained from donors across ABO incompatible blood type.

• Donor liver cold ischemic time greater than 20 hours.

• Donor liver is from a hepatitis C positive donor.

• Evidence of any other unresolved infection and any unresolved opportunistic infection requiring treatment.

• Serum creatinine level >2.0 times the upper limit of normal or advanced renal disease at screening.

• Neutrophil count <1500 cells/mm3, WBC>20,000 x 109/L, Hgb <8 g/dL, or platelet count <25,000 cells/mm3.

• Planned use of T-cell depleting antibody therapies.

• Hepatitis B (sAg, cAb IgM), hepatitis A (IgM) or HIV infection.

• History of autoimmune disease (SLE, scleroderma, RA, etc.).

• Women who are pregnant or breast feeding.

• The use of colony stimulating factor agents to facilitate subject's entry into study within 2 weeks of enrollment.

• History of severe psychiatric disease, especially depression.

• Seizure disorders uncontrolled by anticonvulsants (within the last 12 mos).

• History of severe cardiac disease, unhealed gastric or duodenal ulcer, or other significant medical disease that would put the subject at risk from the volume of the infusions or significant risk of bleeding from the underlying condition.

• Evidence of alcohol and/or drug abuse within 6 months of entry or inability/unwilling-ness to abstain from alcohol throughout entire course of treatment and follow-up.

• Concomitant medication with rifabutin, pyrazinamide, isoniazid, thalidomide, oxymetholone (Anadrol).

• History of thyroid disease poorly controlled on prescribed medications.

• History or other evidence of severe illness or any other conditions which would make the subject, in the opinion of the investigator, unsuitable for Civacir treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Phoenix	Arizona	United States	85054
2	Mayo Clinic	Jacksonville	Florida	United States	32224
3	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• ADMA Biologics, Inc.

Investigators

• Study Director: Eliezer Katz, MD, Clinical Trial and Consulting Services
• Study Director: Shailesh Chavan, MD, Biotest Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: ADMA Biologics, Inc.
• ClinicalTrials.gov Identifier: NCT00473824
• Other Study ID Numbers: Nabi-3104
• First Posted: May 16, 2007
• Last Update Posted: Jul 30, 2021
• Last Verified: Jul 1, 2021

• Keywords provided by ADMA Biologics, Inc.: hepatitis C; liver transplantation; immune globulin
• Additional relevant MeSH terms: Hepatitis A; Hepatitis C; Hepatitis; Immunoglobulins; Antibodies; gamma-Globulins; Immunoglobulins, Intravenous; Rho(D) Immune Globulin

Study Results

Participant Flow

Recruitment Details	First enrollment: 14 May 2007 Last Subject completed: 16 February 2009 Three investigative sites, all Mayo Clinics
Pre-assignment Detail	This was an open label, randomized study.

Arm/Group Title	Civacir Treatment Arm	No Civacir (Control)
Arm/Group Description	Subjects received standard site specific routine post-transplant immunosuppressant therapy with Hepatitis C Immune Globulin Intravenous (Human) 5% [Civacir], 18 infusions total, per schedule, of Civacir 300 or 400 mg/kg of body weight.	Observation on standard site specific routine post-transplant immunosuppressant therapy without infusions of Hepatitis C Immune Globulin Intravenous (Human) 5%.
Period Title: Overall Study
STARTED	5	2
COMPLETED	0	2
NOT COMPLETED	5	0

Baseline Characteristics

Arm/Group Title	Civacir Treatment Arm	No Civacir (Control)	Total
Arm/Group Description	Subjects received standard site specific routine post-transplant immunosuppressant therapy with Hepatitis C Immune Globulin Intravenous (Human) 5% [Civacir], 18 infusions total, per schedule, of Civacir 300 or 400 mg/kg of body weight.	Observation on standard site specific routine post-transplant immunosuppressant therapy without infusions of Hepatitis C Immune Globulin Intravenous (Human) 5%.	Total of all reporting groups
Overall Participants	5	2	7
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	5 100%	2 100%	7 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.2 (5.0)	47 (11.3)	50 (6.5)
Sex: Female, Male (Count of Participants)
Female	1 20%	0 0%	1 14.3%
Male	4 80%	2 100%	6 85.7%
Region of Enrollment (participants) [Number]
United States	5 100%	2 100%	7 100%

Outcome Measures

1. Primary Outcome

Title	Post Transplant Reduction in Viral Load (as Measured Quantitatively by Hepatitis C Virus (HCV) Reverse Transcription-Polymerase Chain Reaction (HCV RT-PCR)).
Description	Percentage of subjects who achieve reduction in viral load from the baseline pre-transplant value. Baseline is the pre-transplant HCV viral load as measeured by RT-PCR. Post-transplant HCV viral load is determined at both 1 month and 6 months post-tranplant.
Time Frame	Outcome evaluations at 1 month (Day 28) and 6 months ( 24 weeks) post-tranplant.

Outcome Measure Data

Analysis Population Description

As the study was terminated early and since no participant in either arm achieved reduction in viral load, it was recorded that zero particpants and zero percent in each arm achieved reduction in viral load.

Arm/Group Title	Civacir Treatment Arm	No Civacir (Control)
Arm/Group Description	Subjects received Hepatitis C Immune Globulin Intravenous (Human) 5% [Civacir], 18 infusions total, per schedule, of Civacir 300 or 400 mg/kg of body weight, in addition to their standard site specific routine post-tranplant immunosuppressant therapy.	Observation on standard site specific routine post-tranplant immunosuppressant therapy without infusions of Hepatitis C Immune Globulin Intravenous (Human) 5%. Standard post-tranplant therapy includes immunosuppressive agents.
Measure Participants	5	2
Number [percentage of participants]	0 0%	0 0%

Adverse Events

Arm/Group Title	Civacir Treatment Arm		No Civacir (Control)
Arm/Group Description	Subjects received standard site specific routine post-transplant immunosuppressant therapy with Hepatitis C Immune Globulin Intravenous (Human) 5% [Civacir], 18 infusions total, per schedule, of Civacir 300 or 400 mg/kg of body weight.		Observation on standard site specific routine post-transplant immunosuppressant therapy without infusions of Hepatitis C Immune Globulin Intravenous (Human) 5%.
All Cause Mortality
	Civacir Treatment Arm		No Civacir (Control)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Civacir Treatment Arm		No Civacir (Control)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/5 (80%)		0/2 (0%)
Cardiac disorders
Hyperkalemia	1/5 (20%)	1	0/2 (0%)	0
General disorders
Chest Tightness	1/5 (20%)	1	0/2 (0%)	0
Infections and infestations
Vancomycin-Resistant Enterococcus Bacteremia	1/5 (20%)	1	0/2 (0%)	0
Osteomyelitis	1/5 (20%)	1	0/2 (0%)	0
Methicillin-resistant staph aureus (MRSA) Peritonitis	1/5 (20%)	1	0/2 (0%)	0
Respiratory, thoracic and mediastinal disorders
Adult Respiratory Distress Syndrome [ARDS]	1/5 (20%)	1	0/2 (0%)	0
Surgical and medical procedures
Mid Common Hepatic Ductal Stricture with possible Biliary Leak	1/5 (20%)	1	0/2 (0%)	0
Other (Not Including Serious) Adverse Events
	Civacir Treatment Arm		No Civacir (Control)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/5 (80%)		2/2 (100%)
Blood and lymphatic system disorders
Blood and Lymphatic System Disorders	1/5 (20%)	2	2/2 (100%)	2
Cardiac disorders
Cardiac Disorders	1/5 (20%)	1	0/2 (0%)	0
Eye disorders
Eye Disorders	0/5 (0%)	0	1/2 (50%)	1
Gastrointestinal disorders
Gastrointestinal Disorders	3/5 (60%)	14	2/2 (100%)	8
General disorders
General Disorders and Administration Site Conditions	3/5 (60%)	3	1/2 (50%)	4
Hepatobiliary disorders
Hepatobiliary Disorders	0/5 (0%)	0	1/2 (50%)	1
Injury, poisoning and procedural complications
Injury, Poisoning and Procedural Complications	2/5 (40%)	2	1/2 (50%)	1
Investigations
Investigations	0/5 (0%)	0	1/2 (50%)	1
Metabolism and nutrition disorders
Metabolism and Nutrition Disorders	3/5 (60%)	6	2/2 (100%)	4
Musculoskeletal and connective tissue disorders
Musculoskeletal and Connective Tissue Disorders	2/5 (40%)	3	2/2 (100%)	4
Nervous system disorders
Nervous System Disorders	2/5 (40%)	4	2/2 (100%)	3
Psychiatric disorders
Psychiatric Disorders	3/5 (60%)	3	2/2 (100%)	4
Renal and urinary disorders
Infections and Infestations	1/5 (20%)	2	1/2 (50%)	1
Renal and Urinary Disorders	1/5 (20%)	2	2/2 (100%)	2
Reproductive system and breast disorders
Reproductive System and Breast Disorders	1/5 (20%)	1	1/2 (50%)	2
Respiratory, thoracic and mediastinal disorders
Respiratory, Thoracic and Mediastinal Disorders	0/5 (0%)	0	1/2 (50%)	3
Skin and subcutaneous tissue disorders
Skin and Subcutaneous Tissue Disorders	1/5 (20%)	1	0/2 (0%)	0
Vascular disorders
Vascular Disorders	2/5 (40%)	2	1/2 (50%)	1

Limitations/Caveats

Early termination by sponsor due to data from the initial 7 patients of 36 planned for this study. Therefore, statistical analysis was not performed and no conclusion were reached regarding efficacy or drug safety.

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.