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Pre-Transplant Treatment to Prevent Recurrence of Hepatitis C After Liver Transplantation (LADR)

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ClinicalTrials.gov Identifier: NCT00135798
Recruitment Status : Completed
First Posted : August 26, 2005
Results First Posted : April 4, 2013
Last Update Posted : April 23, 2013
Sponsor:
Collaborators:
Schering-Plough
Ortho Biotech Clinical Affairs, L.L.C.
Information provided by (Responsible Party):
Averell Sherker, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Hepatitis C
Intervention Drug: LADR Treatment
Enrollment 79
Recruitment Details Persons were enrolled from October 2005 to January 2009, and followed through December 2009. Patients were enrolled at 7 clinical transplant centers in the United States.
Pre-assignment Details No pre-assignment events. Randomization occurred immediately after enrollment.
Arm/Group Title Standard Clinical Care: Genotypes 1, 4, 6 LADR Treatment: Genotypes 1, 4, 6 LADR Treatment: Genotypes 2 or 3
Hide Arm/Group Description Subjects randomized to non-treatment group 1:2 compared to treatment group. Low Accelerating Dose Regimen (LADR): Subjects randomized to LADR treatment group 2:1 compared to standard care. Patients in this subgroup were all assigned to LADR treatment.
Period Title: Overall Study
Started 16 31 32
Completed 16 31 32
Not Completed 0 0 0
Arm/Group Title Standard Clinical Care: Genotypes 1, 4, 6 LADR Treatment: Genotypes 1, 4, 6 LADR Treatment: Genotypes 2 or 3 Total
Hide Arm/Group Description Subjects randomized to non-treatment group 1:2 compared to treatment group. Low Accelerating Dose Regimen (LADR): Subjects randomized to LADR treatment group 2:1 compared to standard care. Patients in this subgroup were all assigned to LADR treatment. Total of all reporting groups
Overall Number of Baseline Participants 16 31 32 79
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 16 participants 31 participants 32 participants 79 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
15
  93.8%
30
  96.8%
27
  84.4%
72
  91.1%
>=65 years
1
   6.3%
1
   3.2%
5
  15.6%
7
   8.9%
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 16 participants 31 participants 32 participants 79 participants
56.1  (5.4) 54.6  (7.4) 56.6  (6.5) 55.7  (6.7)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 16 participants 31 participants 32 participants 79 participants
Female
3
  18.8%
10
  32.3%
7
  21.9%
20
  25.3%
Male
13
  81.3%
21
  67.7%
25
  78.1%
59
  74.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 16 participants 31 participants 32 participants 79 participants
16 31 32 79
1.Primary Outcome
Title Patients Who Are Negative for Hepatitis C Virus (HCV) RNA at 3 Months Post-transplant: Intent-to-Treat Analysis (ITT)
Hide Description Post-transplant virologic response (pTVR) defined as undetectable HCV RNA at week 12 after liver transplantation.
Time Frame 3 months post-transplant
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat (ITT) analyses of Transplanted patients assigned to treatment. Outcome is pTVR (post-transplant viral response)
Arm/Group Title Standard Care Group: Genotypes 1, 4, 6 LADR Treatment Group: Genotypes 1, 4, 6 LADR Treatment Group: Genotypes 2, 3
Hide Arm/Group Description:
Randomization 2:1 LADR vs. Standard care in Genotypes 1,4,6
Randomization 2:1 LADR vs. Standard care in Genotypes 1,4,6
All patients with Genotypes 2,3 received LADR treatment.
Overall Number of Participants Analyzed 13 24 22
Measure Type: Number
Unit of Measure: participants
0 5 6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Standard Care Group: Genotypes 1, 4, 6, LADR Treatment Group: Genotypes 1, 4, 6, LADR Treatment Group: Genotypes 2, 3
Comments ITT analysis of pTVR: 0/13 Standard care vs. 11/46 Combined LADR-treated groups
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0477
Comments One-sided test
Method Fisher Exact
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection LADR Treatment Group: Genotypes 1, 4, 6, LADR Treatment Group: Genotypes 2, 3
Comments ITT analysis of LADR-treated: 5/24 Genotypes 1,4,6 vs 6/22 Genotypes 2,3
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6090
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
2.Primary Outcome
Title Patients Who Are Negative for HCV RNA at 3 Months Post-transplant: Per-Protocol Analysis (PP)
Hide Description Post-transplant virologic response (pTVR) defined as undetectable HCV RNA at week 12 after liver transplantation, analysed among patients who received treatment.
Time Frame 3 months post-transplant
Hide Outcome Measure Data
Hide Analysis Population Description
Per-Protocol (PP) analyses of Transplanted patients who received treatment. Outcome is pTVR (post-transplant viral response)
Arm/Group Title Standard Care Group: Genotypes 1, 4, 6 LADR Treatment Group: Genotypes 1, 4, 6 LADR Treatment Group: Genotypes 2, 3
Hide Arm/Group Description:
Randomization 2:1 LADR vs. Standard care in Genotypes 1,4,6
Randomization 2:1 LADR vs. Standard care in Genotypes 1,4,6
All patients with Genotypes 2,3 received LADR treatment.
Overall Number of Participants Analyzed 13 23 21
Measure Type: Number
Unit of Measure: participants
0 5 6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Standard Care Group: Genotypes 1, 4, 6, LADR Treatment Group: Genotypes 1, 4, 6, LADR Treatment Group: Genotypes 2, 3
Comments PP analysis of pTVR: 0/13 Standard care vs. 11/44 Combined LADR-treated groups
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0274
Comments One-sided test
Method Fisher Exact
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection LADR Treatment Group: Genotypes 1, 4, 6, LADR Treatment Group: Genotypes 2, 3
Comments PP analysis of LADR-treated: 5/23 G1,4,6 vs 6/21 G2,3
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6011
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
3.Secondary Outcome
Title Patients With Combined Virologic Response (CVR): Intent-to-Treat Analyses (ITT)
Hide Description Intent-to-Treat (ITT) analyses of all patients. Combined Virologic Response (CVR), which includes both sustained virologic response pre-transplant (SVR) and post-transplant virologic response (pTVR)
Time Frame Pre-transplant and 3 months post-transplant
Hide Outcome Measure Data
Hide Analysis Population Description
All study patients
Arm/Group Title Standard Care Group: Genotypes 1, 4, 6 LADR Treatment Group: Genotypes 1, 4, 6 LADR Treatment Group: Genotypes 2, 3
Hide Arm/Group Description:
Randomization 2:1 LADR vs. Standard care in Genotypes 1,4,6
Randomization 2:1 LADR vs. Standard care in Genotypes 1,4,6
All patients with Genotypes 2,3 received LADR treatment.
Overall Number of Participants Analyzed 16 31 32
Measure Type: Number
Unit of Measure: participants
1 6 6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Standard Care Group: Genotypes 1, 4, 6, LADR Treatment Group: Genotypes 1, 4, 6, LADR Treatment Group: Genotypes 2, 3
Comments ITT analysis of CVR: 1/16 Standard care vs. 12/63 Combined LADR-treated groups
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2014
Comments One-sided test
Method Fisher Exact
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection LADR Treatment Group: Genotypes 1, 4, 6, LADR Treatment Group: Genotypes 2, 3
Comments ITT analysis of LADR-treated: 6/31 Genotypes 1,4,6 vs 6/32 Genotypes 2,3
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9513
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
4.Secondary Outcome
Title Patients With Combined Virologic Response (CVR): Per-Protocol Analysis (PP)
Hide Description Per-Protocol (PP) analyses of all patients. Combined Virologic Response (CVR)includes both sustained virologic response pre-transplant (SVR) and post-transplant virologic response (pTVR), analysed among patients who received treatment.
Time Frame Pre-transplant and 3 months post-transplant
Hide Outcome Measure Data
Hide Analysis Population Description
All study patients
Arm/Group Title Standard Care Group: Genotypes 1, 4, 6 LADR Treatment Group: Genotypes 1, 4, 6 LADR Treatment Group: Genotypes 2, 3
Hide Arm/Group Description:
Randomization 2:1 LADR vs. Standard care in Genotypes 1,4,6
Randomization 2:1 LADR vs. Standard care in Genotypes 1,4,6
All patients with Genotypes 2,3 received LADR treatment.
Overall Number of Participants Analyzed 20 30 29
Measure Type: Number
Unit of Measure: participants
0 7 6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Standard Care Group: Genotypes 1, 4, 6, LADR Treatment Group: Genotypes 1, 4, 6, LADR Treatment Group: Genotypes 2, 3
Comments PP analysis of CVR: 0/20 Standard care vs. 13/59 Combined LADR-treated groups
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0153
Comments One-sided test
Method Fisher Exact
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection LADR Treatment Group: Genotypes 1, 4, 6, LADR Treatment Group: Genotypes 2, 3
Comments PP analysis of LADR-treated: 7/30 G1,4,6 vs 6/29 G2,3
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8065
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Time Frame Serious Adverse Events (SAE) were collected pre-transplant, and through 1 year post-transplant.
Adverse Event Reporting Description Other [non-serious] adverse events were not collected or assessed as part of this study.
 
Arm/Group Title Standard Clinical Care: Genotypes 1, 4, 6 LADR Treatment (All Genotypes)
Hide Arm/Group Description Subjects who received no LADR treatment (Per Protocol analysis) This group combines all who received LADR treatment (Per Protocol analysis) for all Genotypes 1,4,6 and 2,3
All-Cause Mortality
Standard Clinical Care: Genotypes 1, 4, 6 LADR Treatment (All Genotypes)
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
Standard Clinical Care: Genotypes 1, 4, 6 LADR Treatment (All Genotypes)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   11/20 (55.00%)      40/59 (67.80%)    
Blood and lymphatic system disorders     
Pre-LT Cytopenia   0/20 (0.00%)  0 8/59 (13.56%)  11
Post-LT (first 30 days) Cytopenia   0/13 (0.00%)  0 0/44 (0.00%)  0
Post-LT (30 days-1 year) Cytopenia   1/13 (7.69%)  2 0/44 (0.00%)  0
General disorders     
Death   2/20 (10.00%)  2 9/59 (15.25%)  9
Pre-LT Other   1/20 (5.00%)  1 10/59 (16.95%)  11
Post-LT (first 30 days) Other   1/13 (7.69%)  1 6/44 (13.64%)  7
Post-LT (30 days-1 year) Other   2/13 (15.38%)  2 10/44 (22.73%)  13
Hepatobiliary disorders     
Pre-LT Liver-related   3/20 (15.00%)  3 6/59 (10.17%)  8
Post-LT (first 30 days) Liver-related   1/13 (7.69%)  1 3/44 (6.82%)  3
Post-LT (first 30 days) Rejection   0/13 (0.00%)  0 1/44 (2.27%)  1
Post-LT (30 days-1 year) Liver-related   0/13 (0.00%)  0 1/44 (2.27%)  2
Post-LT (30 days-1 year) Rejection   0/13 (0.00%)  0 0/44 (0.00%)  0
Infections and infestations     
Pre-LT Infection   0/20 (0.00%)  0 3/59 (5.08%)  7
Post-LT (first 30 days) Infection   0/13 (0.00%)  0 3/44 (6.82%)  4
Post-LT (30 days-1 year) Infection   3/13 (23.08%)  3 7/44 (15.91%)  9
Surgical and medical procedures     
Post-LT (first 30 days) Surgical complication   0/13 (0.00%)  0 1/44 (2.27%)  2
Post-LT (30 days-1 year) Surgical complication   0/13 (0.00%)  0 6/44 (13.64%)  8
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Standard Clinical Care: Genotypes 1, 4, 6 LADR Treatment (All Genotypes)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/0      0/0    
Failure to reach target of 84 transplanted patients (47 achieved); Inability to complete planned 12 weeks of treatment for some; Incomplete HCV RNA follow up; Inconsistent limits of detection of HCV RNA; Noncompliance with assigned treatment.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Gregory T. Everson, M.D., Director of Hepatology
Organization: University Colorado, Denver
Phone: 720-848-2245
EMail: greg.everson@UCDenver.edu
Layout table for additonal information
Responsible Party: Averell Sherker, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT00135798    
Other Study ID Numbers: A2ALL LADR Protocol 62498(IND)
U01DK062498 ( U.S. NIH Grant/Contract )
U01DK062536 ( U.S. NIH Grant/Contract )
U01DK062444 ( U.S. NIH Grant/Contract )
U01DK062467 ( U.S. NIH Grant/Contract )
U01DK062483 ( U.S. NIH Grant/Contract )
U01DK062484 ( U.S. NIH Grant/Contract )
U01DK062494 ( U.S. NIH Grant/Contract )
U01DK062496 ( U.S. NIH Grant/Contract )
U01DK062505 ( U.S. NIH Grant/Contract )
U01DK062531 ( U.S. NIH Grant/Contract )
CRADA through NIH-NIDDK ( Other Identifier: Schering-Plough )
CTA through NIH-NIDDK ( Other Identifier: Ortho-Biotech )
HRSA ( Other Identifier: Health Resources and Services Administration )
ASTS ( Other Identifier: American Society of Transplant Surgeons )
First Submitted: August 24, 2005
First Posted: August 26, 2005
Results First Submitted: June 13, 2012
Results First Posted: April 4, 2013
Last Update Posted: April 23, 2013