Concentration-Controlled Ribavirin for the Treatment of Patients With Chronic Hepatitis C Virus Infection
Study Details
Study Description
Brief Summary
The purpose of this study is to determine if concentration-controlled ribavirin dosing can achieve a targeted level of plasma exposures and if it appears safe and effective compared with standard weight-based ribavirin dosing. Forty, previously treatment-naive participants with genotype 1 disease will be randomized to receive concentration-guided or standard weight-based ribavirin. Peginterferon alfa 2a,ribavirin, and telaprevir will be provided through the study.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 4 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Active Comparator: Standard Weight-Based Ribavirin Dosing 1000 mg daily in patients weighing <75 kg and 1200 mg daily in patients weighing ≥ 75 kg |
Drug: ribavirin
Randomization to standard weight based ribavirin dosing (1000 or 1200 mg daily) or concentration-guided dosing based on first dose AUC0-12
|
Experimental: Concentration-Controlled Ribavirin Dosing Dose adjusted based on first dose AUC0-12 |
Drug: ribavirin
Randomization to standard weight based ribavirin dosing (1000 or 1200 mg daily) or concentration-guided dosing based on first dose AUC0-12
|
Outcome Measures
Primary Outcome Measures
- Ribavirin AUC-12 Variability [steady state (~weeks 9-10)]
Demonstrate that concentration-controlled ribavirin dosing can achieve a targeted level of plasma exposure with reduced variability in the steady-state area-under-the-concentration-time curve (AUC0-12) compared with standard weight-based ribavirin dosing
Secondary Outcome Measures
- Safety - Absolute Hemoglobin Declines [from baseline through end of treatment, up to 48 weeks]
- Sustained Virologic Response (i.e., Cure) [assessed 12 weeks after stopping treatment]
Compare proportions with SVR in standard weight-based vs. concentration-guided ribavirin dosing groups. Number of participants with sustained virologic response is reported.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Chronic HCV-infected men and women
-
18-70 years
-
HCV genotype 1
-
Deemed ready for HCV treatment by hepatology provider and patient
-
Allowed medications: all those not specifically listed in the exclusion criteria below including medications for peginterferon / ribavirin - related adverse effects: acetaminophen, ibuprofen, diphenhydramine, selective serotonin reuptake inhibitors, darbepoeitin, erythropoietin, GCSF
Exclusion Criteria:
-
previous treatment with interferon, peginterferon, investigational HCV drugs, boceprevir, or ribavirin;
-
baseline absolute neutrophil count (ANC) < 1000/mm3,
-
platelets < 100,000/mm3,
-
hemoglobin < 12 g/dL for women and < 13 g/dL for men;
-
HIV positive serostatus;
-
HBV positive serostatus;
-
decompensated liver disease (i.e., ascites, history of esophageal variceal bleeding, hepatic encephalopathy);
-
autoimmune hepatitis
-
hemoglobinopathy (e.g., sickle cell anemia, thalassemia)
-
Cockcroft and Gault estimated creatinine clearance < 50 mL/min;
-
alcohol or illicit drug use that in the opinion of the investigator would interfere with study participation and/or impact study results
-
for females, active pregnancy or any intent to become pregnant during study period or for up to 6 months after completing treatment
-
for males, a pregnant female partner or intent to impregnate a female during study period or for up to 6 months after completing treatment
-
for both sexes an unwillingness to use two forms of contraception during the study period and for 6 months after completing treatment. While on telaprevir and for 2 weeks following discontinuation of telaprevir, females must use two non-hormonal forms of contraception;
-
history of significant or unstable cardiac disease including severe coronary artery disease (unstable angina, recent myocardial infarction, chest pain with exertion) or congestive heart failure;
-
receipt of an organ transplant;
-
malignant neoplastic disease;
-
chronic pulmonary disease that in the opinion of the study hepatologists would preclude treatment with peginterferon and ribavirin (e.g., pulmonary function tests ≤70% within the previous 2 years);
-
history of admission to a psychiatric facility within the previous year;
-
suicide attempt within the previous 3 years;
-
concomitant medications including: amantadine, mycophenolate mofetil, and investigational HCV compounds, alfuzosin, alfentanil, ergot derivatives (dihydroergotamine/ergotamine/ergonovine/methylergonovine), meperidine, anti-arrhythmics (quinidine, flecainide, propafenone, amiodarone, bepridil), astemizole, terfenadine, buspirone, diazepam, estazolam, oral midazolam, triazolam, budesonide, domperidone, eletriptan, eplerenone, fluticasone, pimozide, salmeterol, calcium channel blockers (diltiazem, felodipine, nifedipine, nisoldipine, verapamil), cisapride, cyclosporine, sirolimus, systemic tacrolimus, atorvastatin, lovastatin, simvistatin, sildenafil, tadalafil, verdenafil, antibiotics (clarithromycin, erythromycin, telithromycin, troleandomycin), carbamazepine, Phenobarbital, phenytoin, nefazodone, St. Johns Wort, antifungals (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole), rifampin, rifabutin, aprepitant, cholestyramine, fluvoxamine, mifepreistone, modafinil, systemic dexamethasone. With the exception of St. Johns Wort, investigators may use their discretion on use of herbal and dietary supplements.
-
Evidence of severe retinopathy or clinically relevant ophthalmologic disorders
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | University of Colorado Denver | Aurora | Colorado | United States | 80045 |
Sponsors and Collaborators
- University of Colorado, Denver
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
- Principal Investigator: Jennifer J Kiser, PharmD, University of Colorado, Denver
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 08-1198
- K23DK082621
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | Standard Weight-Based Ribavirin Dosing | Concentration-Controlled Ribavirin Dosing |
---|---|---|
Arm/Group Description | 1000 mg daily in patients weighing <75 kg and 1200 mg daily in patients weighing ≥ 75 kg ribavirin: Randomization to standard weight based ribavirin dosing (1000 or 1200 mg daily) or concentration-guided dosing based on first dose AUC0-12 | Dose adjusted based on first dose AUC0-12 ribavirin: Randomization to standard weight based ribavirin dosing (1000 or 1200 mg daily) or concentration-guided dosing based on first dose AUC0-12 |
Period Title: Overall Study | ||
STARTED | 17 | 18 |
COMPLETED | 14 | 14 |
NOT COMPLETED | 3 | 4 |
Baseline Characteristics
Arm/Group Title | Standard Weight-Based Ribavirin Dosing | Concentration-Controlled Ribavirin Dosing | Total |
---|---|---|---|
Arm/Group Description | 1000 mg daily in patients weighing <75 kg and 1200 mg daily in patients weighing ≥ 75 kg ribavirin: Randomization to standard weight based ribavirin dosing (1000 or 1200 mg daily) or concentration-guided dosing based on first dose AUC0-12 | Dose adjusted based on first dose AUC0-12 ribavirin: Randomization to standard weight based ribavirin dosing (1000 or 1200 mg daily) or concentration-guided dosing based on first dose AUC0-12 | Total of all reporting groups |
Overall Participants | 17 | 18 | 35 |
Age (years) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [years] |
47.1
(10.2)
|
53.4
(5.9)
|
50.3
(8.8)
|
Sex: Female, Male (Count of Participants) | |||
Female |
6
35.3%
|
7
38.9%
|
13
37.1%
|
Male |
11
64.7%
|
11
61.1%
|
22
62.9%
|
Ethnicity (NIH/OMB) (Count of Participants) | |||
Hispanic or Latino |
4
23.5%
|
4
22.2%
|
8
22.9%
|
Not Hispanic or Latino |
13
76.5%
|
14
77.8%
|
27
77.1%
|
Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
Race (NIH/OMB) (Count of Participants) | |||
American Indian or Alaska Native |
1
5.9%
|
0
0%
|
1
2.9%
|
Asian |
0
0%
|
0
0%
|
0
0%
|
Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
Black or African American |
1
5.9%
|
2
11.1%
|
3
8.6%
|
White |
15
88.2%
|
15
83.3%
|
30
85.7%
|
More than one race |
0
0%
|
1
5.6%
|
1
2.9%
|
Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
Region of Enrollment (participants) [Number] | |||
United States |
17
100%
|
18
100%
|
35
100%
|
Outcome Measures
Title | Ribavirin AUC-12 Variability |
---|---|
Description | Demonstrate that concentration-controlled ribavirin dosing can achieve a targeted level of plasma exposure with reduced variability in the steady-state area-under-the-concentration-time curve (AUC0-12) compared with standard weight-based ribavirin dosing |
Time Frame | steady state (~weeks 9-10) |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Standard Weight-Based Ribavirin Dosing | Concentration-Controlled Ribavirin Dosing |
---|---|---|
Arm/Group Description | 1000 mg daily in patients weighing <75 kg and 1200 mg daily in patients weighing ≥ 75 kg ribavirin: Randomization to standard weight based ribavirin dosing (1000 or 1200 mg daily) or concentration-guided dosing based on first dose AUC0-12 | Dose adjusted based on first dose AUC0-12 ribavirin: Randomization to standard weight based ribavirin dosing (1000 or 1200 mg daily) or concentration-guided dosing based on first dose AUC0-12 |
Measure Participants | 17 | 18 |
Mean (Standard Deviation) [ng*hr/mL] |
34425
(10046)
|
40903
(10953)
|
Title | Safety - Absolute Hemoglobin Declines |
---|---|
Description | |
Time Frame | from baseline through end of treatment, up to 48 weeks |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Standard Weight-Based Ribavirin Dosing | Concentration-Controlled Ribavirin Dosing |
---|---|---|
Arm/Group Description | 1000 mg daily in patients weighing <75 kg and 1200 mg daily in patients weighing ≥ 75 kg ribavirin: Randomization to standard weight based ribavirin dosing (1000 or 1200 mg daily) or concentration-guided dosing based on first dose AUC0-12 | Dose adjusted based on first dose AUC0-12 ribavirin: Randomization to standard weight based ribavirin dosing (1000 or 1200 mg daily) or concentration-guided dosing based on first dose AUC0-12 |
Measure Participants | 17 | 18 |
Mean (Standard Deviation) [g/dL] |
2.6
(1.9)
|
3.6
(1.2)
|
Title | Sustained Virologic Response (i.e., Cure) |
---|---|
Description | Compare proportions with SVR in standard weight-based vs. concentration-guided ribavirin dosing groups. Number of participants with sustained virologic response is reported. |
Time Frame | assessed 12 weeks after stopping treatment |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Standard Weight-Based Ribavirin Dosing | Concentration-Controlled Ribavirin Dosing |
---|---|---|
Arm/Group Description | 1000 mg daily in patients weighing <75 kg and 1200 mg daily in patients weighing ≥ 75 kg ribavirin: Randomization to standard weight based ribavirin dosing (1000 or 1200 mg daily) or concentration-guided dosing based on first dose AUC0-12 | Dose adjusted based on first dose AUC0-12 ribavirin: Randomization to standard weight based ribavirin dosing (1000 or 1200 mg daily) or concentration-guided dosing based on first dose AUC0-12 |
Measure Participants | 17 | 18 |
Count of Participants [Participants] |
8
47.1%
|
12
66.7%
|
Adverse Events
Time Frame | 48 Weeks | |||
---|---|---|---|---|
Adverse Event Reporting Description | ||||
Arm/Group Title | Standard Weight-Based Ribavirin Dosing | Concentration-Controlled Ribavirin Dosing | ||
Arm/Group Description | 1000 mg daily in patients weighing <75 kg and 1200 mg daily in patients weighing ≥ 75 kg ribavirin: Randomization to standard weight based ribavirin dosing (1000 or 1200 mg daily) or concentration-guided dosing based on first dose AUC0-12 | Dose adjusted based on first dose AUC0-12 ribavirin: Randomization to standard weight based ribavirin dosing (1000 or 1200 mg daily) or concentration-guided dosing based on first dose AUC0-12 | ||
All Cause Mortality |
||||
Standard Weight-Based Ribavirin Dosing | Concentration-Controlled Ribavirin Dosing | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/17 (0%) | 0/18 (0%) | ||
Serious Adverse Events |
||||
Standard Weight-Based Ribavirin Dosing | Concentration-Controlled Ribavirin Dosing | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 4/17 (23.5%) | 7/18 (38.9%) | ||
Blood and lymphatic system disorders | ||||
Hemoglobin < 8.5 g/dL | 1/17 (5.9%) | 1 | 2/18 (11.1%) | 2 |
Cardiac disorders | ||||
Chest pain | 1/17 (5.9%) | 1 | 1/18 (5.6%) | 1 |
Gastrointestinal disorders | ||||
Tooth pain and vomiting | 0/17 (0%) | 0 | 1/18 (5.6%) | 1 |
Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
Astrocytoma | 0/17 (0%) | 0 | 1/18 (5.6%) | 1 |
Nervous system disorders | ||||
Frozen arms | 1/17 (5.9%) | 1 | 0/18 (0%) | 0 |
Mood alteration | 0/17 (0%) | 0 | 1/18 (5.6%) | 1 |
Respiratory, thoracic and mediastinal disorders | ||||
pneumonia | 1/17 (5.9%) | 1 | 0/18 (0%) | 0 |
Shortness of breath | 0/17 (0%) | 0 | 1/18 (5.6%) | 1 |
Other (Not Including Serious) Adverse Events |
||||
Standard Weight-Based Ribavirin Dosing | Concentration-Controlled Ribavirin Dosing | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 14/17 (82.4%) | 12/18 (66.7%) | ||
Blood and lymphatic system disorders | ||||
Hemoglobin < 10 g/dL | 5/17 (29.4%) | 5 | 4/18 (22.2%) | 4 |
ANC < 1000/mm3 | 9/17 (52.9%) | 9 | 5/18 (27.8%) | 5 |
Platelets < 75,000/mm3 | 3/17 (17.6%) | 3 | 2/18 (11.1%) | 2 |
WBC <2000/mm3 | 2/17 (11.8%) | 2 | 3/18 (16.7%) | 3 |
Nervous system disorders | ||||
Grade 3 Depression | 1/17 (5.9%) | 1 | 1/18 (5.6%) | 1 |
Grade 3 Fatigue | 2/17 (11.8%) | 2 | 1/18 (5.6%) | 1 |
Grade 3 Insomnia | 2/17 (11.8%) | 2 | 0/18 (0%) | 0 |
Grade 3 Mood Alteration | 2/17 (11.8%) | 2 | 0/18 (0%) | 0 |
Respiratory, thoracic and mediastinal disorders | ||||
Grade 3 Shortness of Breath | 4/17 (23.5%) | 4 | 2/18 (11.1%) | 2 |
Skin and subcutaneous tissue disorders | ||||
Grade 3 Rash | 2/17 (11.8%) | 2 | 2/18 (11.1%) | 2 |
Limitations/Caveats
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.
Results Point of Contact
Name/Title | Jennifer Kiser |
---|---|
Organization | University of Colorado |
Phone | 3037246131 |
jennifer.kiser@cuanschutz.edu |
- 08-1198
- K23DK082621