Concentration-Controlled Ribavirin for the Treatment of Patients With Chronic Hepatitis C Virus Infection

Sponsor
University of Colorado, Denver (Other)
Overall Status
Completed
CT.gov ID
NCT01097395
Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
35
Enrollment
1
Location
2
Arms
65.9
Duration (Months)
0.5
Patients Per Site Per Month

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 DiseaseIntervention/TreatmentPhase
Phase 4

Study Design

Study Type:
Interventional
Actual Enrollment :
35 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Concentration-Controlled Ribavirin for the Treatment of Patients With Chronic Hepatitis C Virus Infection
Study Start Date :
Feb 1, 2010
Actual Primary Completion Date :
Aug 1, 2015
Actual Study Completion Date :
Aug 1, 2015

Arms and Interventions

ArmIntervention/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

  1. 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

  1. Safety - Absolute Hemoglobin Declines [from baseline through end of treatment, up to 48 weeks]

  2. 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

Ages Eligible for Study:
18 Years to 70 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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

SiteCityStateCountryPostal Code
1University of Colorado DenverAuroraColoradoUnited States80045

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.
Responsible Party:
University of Colorado, Denver
ClinicalTrials.gov Identifier:
NCT01097395
Other Study ID Numbers:
  • 08-1198
  • K23DK082621
First Posted:
Apr 1, 2010
Last Update Posted:
Sep 16, 2021
Last Verified:
Aug 1, 2021
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.:
No
Keywords provided by University of Colorado, Denver
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail
Arm/Group TitleStandard Weight-Based Ribavirin DosingConcentration-Controlled Ribavirin Dosing
Arm/Group Description1000 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 AUC0-12Dose 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
STARTED1718
COMPLETED1414
NOT COMPLETED34

Baseline Characteristics

Arm/Group TitleStandard Weight-Based Ribavirin DosingConcentration-Controlled Ribavirin DosingTotal
Arm/Group Description1000 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 AUC0-12Dose 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 AUC0-12Total of all reporting groups
Overall Participants171835
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

1. Primary Outcome
TitleRibavirin AUC-12 Variability
DescriptionDemonstrate 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 Framesteady state (~weeks 9-10)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group TitleStandard Weight-Based Ribavirin DosingConcentration-Controlled Ribavirin Dosing
Arm/Group Description1000 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 AUC0-12Dose 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 Participants1718
Mean (Standard Deviation) [ng*hr/mL]
34425
(10046)
40903
(10953)
2. Secondary Outcome
TitleSafety - Absolute Hemoglobin Declines
Description
Time Framefrom baseline through end of treatment, up to 48 weeks

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group TitleStandard Weight-Based Ribavirin DosingConcentration-Controlled Ribavirin Dosing
Arm/Group Description1000 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 AUC0-12Dose 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 Participants1718
Mean (Standard Deviation) [g/dL]
2.6
(1.9)
3.6
(1.2)
3. Secondary Outcome
TitleSustained Virologic Response (i.e., Cure)
DescriptionCompare proportions with SVR in standard weight-based vs. concentration-guided ribavirin dosing groups. Number of participants with sustained virologic response is reported.
Time Frameassessed 12 weeks after stopping treatment

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group TitleStandard Weight-Based Ribavirin DosingConcentration-Controlled Ribavirin Dosing
Arm/Group Description1000 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 AUC0-12Dose 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 Participants1718
Count of Participants [Participants]
8
47.1%
12
66.7%

Adverse Events

Time Frame48 Weeks
Adverse Event Reporting Description
Arm/Group TitleStandard Weight-Based Ribavirin DosingConcentration-Controlled Ribavirin Dosing
Arm/Group Description1000 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 AUC0-12Dose 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 DosingConcentration-Controlled Ribavirin Dosing
Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total0/17 (0%) 0/18 (0%)
Serious Adverse Events
Standard Weight-Based Ribavirin DosingConcentration-Controlled Ribavirin Dosing
Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total4/17 (23.5%) 7/18 (38.9%)
Blood and lymphatic system disorders
Hemoglobin < 8.5 g/dL1/17 (5.9%) 12/18 (11.1%) 2
Cardiac disorders
Chest pain1/17 (5.9%) 11/18 (5.6%) 1
Gastrointestinal disorders
Tooth pain and vomiting0/17 (0%) 01/18 (5.6%) 1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Astrocytoma0/17 (0%) 01/18 (5.6%) 1
Nervous system disorders
Frozen arms1/17 (5.9%) 10/18 (0%) 0
Mood alteration0/17 (0%) 01/18 (5.6%) 1
Respiratory, thoracic and mediastinal disorders
pneumonia1/17 (5.9%) 10/18 (0%) 0
Shortness of breath0/17 (0%) 01/18 (5.6%) 1
Other (Not Including Serious) Adverse Events
Standard Weight-Based Ribavirin DosingConcentration-Controlled Ribavirin Dosing
Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total14/17 (82.4%) 12/18 (66.7%)
Blood and lymphatic system disorders
Hemoglobin < 10 g/dL5/17 (29.4%) 54/18 (22.2%) 4
ANC < 1000/mm39/17 (52.9%) 95/18 (27.8%) 5
Platelets < 75,000/mm33/17 (17.6%) 32/18 (11.1%) 2
WBC <2000/mm32/17 (11.8%) 23/18 (16.7%) 3
Nervous system disorders
Grade 3 Depression1/17 (5.9%) 11/18 (5.6%) 1
Grade 3 Fatigue2/17 (11.8%) 21/18 (5.6%) 1
Grade 3 Insomnia2/17 (11.8%) 20/18 (0%) 0
Grade 3 Mood Alteration2/17 (11.8%) 20/18 (0%) 0
Respiratory, thoracic and mediastinal disorders
Grade 3 Shortness of Breath4/17 (23.5%) 42/18 (11.1%) 2
Skin and subcutaneous tissue disorders
Grade 3 Rash2/17 (11.8%) 22/18 (11.1%) 2

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.

Results Point of Contact

Name/TitleJennifer Kiser
OrganizationUniversity of Colorado
Phone3037246131
Emailjennifer.kiser@cuanschutz.edu
Responsible Party:
University of Colorado, Denver
ClinicalTrials.gov Identifier:
NCT01097395
Other Study ID Numbers:
  • 08-1198
  • K23DK082621
First Posted:
Apr 1, 2010
Last Update Posted:
Sep 16, 2021
Last Verified:
Aug 1, 2021