Ribavirin for Hemorrhagic Fever With Renal Syndrome

This study is enrolling participants by invitation only.
Sponsor:
Information provided by (Responsible Party):
U.S. Army Medical Research and Materiel Command
ClinicalTrials.gov Identifier:
NCT00623168
First received: February 13, 2008
Last updated: July 2, 2014
Last verified: July 2014
  Purpose

Hemorrhagic Fever with Renal Syndrome (HFRS) is caused by a virus acquired by contact with chronically infected rodent hosts. HFRS is present throughout Korea. Treatment consists mainly of supportive care with careful attention to control of blood pressure and fluid balance and/or dialysis. Early initiation of IND Intravenous Ribavirin has been shown to be an effective treatment for HFRS and may prevent the need for dialysis. It is important to initiate therapy based on a diagnosis consistent with HFRS and a history that makes exposure likely. This study will monitor the clinical events that occur with HFRS as well as the safety and efficacy of Ribavirin.


Condition Intervention Phase
Hemorrhagic Fever With Renal Syndrome
Drug: Ribavirin
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 2 Treatment Protocol of Intravenous Ribavirin in Adult Subjects With Hemorrhagic Fever With Renal Syndrome (HFRS) in the 121st Combat Support Hospital (Seoul, Korea)

Resource links provided by NLM:


Further study details as provided by U.S. Army Medical Research and Materiel Command:

Primary Outcome Measures:
  • To monitor the morbidity and mortality of subjects with HFRS who are treated with IV Ribavirin. To evaluate the safety of IV Ribavirin treatment in subjects with a probable case of hemorrhagic fever with renal syndrome (HFRS). [ Time Frame: indefinite ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Number of subjects who develop oliguria; Number of subjects who require hemodialysis; Number of subjects with severe hemorrhage. Number subject deaths. Frequency and nature of adverse events will be evaluated for all subjects. [ Time Frame: indefinite ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 50
Study Start Date: February 2008
Estimated Study Completion Date: February 2018
Estimated Primary Completion Date: February 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment Only
All consented subjects who meet all inclusion and no exclusion criteria will enter this open label protocol and be treated with Ribavirin.
Drug: Ribavirin
7 Day multiple dosing regime based on weight and dosage day

Detailed Description:

Hemorrhagic Fever with Renal Syndrome (HFRS) is caused by viruses in the genus Hantavirus of the family Bunyaviridae. There are four known Hantavirus that cause HFRS: Hantaan, Seoul, Puumala and Dobrava viruses. HFRS is acquired by contact with chronically infected rodent hosts, most commonly from inhalation of infected rodent excreta. Hemorrhagic fever with renal syndrome is characterized clinically by the triad of fever, hemorrhage and renal insufficiency. HFRS typically consists of five consecutive but frequently overlapping clinical phases: febrile, hypotensive, oliguric, diuretic and convalescent. DoD operations have resulted in the deployment of personnel in Europe and Southeast Asia, areas endemic for HFRS, a viral hemorrhagic fever. Early initiation of therapy with intravenous Ribavirin has been shown to be an effective treatment for HFRS. It is therefore important to initiate therapy based on a clinical diagnosis consistent with viral hemorrhagic fever and with an epidemiological history for risk of exposure to the hantavirus. Ribavirin is a nucleoside (guanosine) analog with activity against a wide variety ribonucleic acid and deoxyribonucleic acid viruses. Mechanism of action is not fully defined. The mechanism may be related to alteration of cellular nucleotide pools and of viral messenger RNA formation, but recent data suggest the mechanism of Ribavirin in HFRS may be to serve as a RNA virus mutagen resulting in an "extinction catastrophe" error, as a result of incorporation in the viral RNA genome.

Ribavirin is licensed in the United States in aerosol form for the treatment of severe lower respiratory tract infection in children and in the oral formulation in combination with recombinant interferon alpha for the treatment of chronic hepatitis C infection. The intravenous formulation of ribavirin in not licensed in the United States. IV Ribavirin for the treatment of HFRS is used under IND 16,666.

This is a Phase 2, open-label study of the safety of IV Ribavirin treatment in individuals with Hemorrhagic Fever with Renal Syndrome (HFRS) admitted to the 121st Combat Support Hospital, Seoul, Republic of Korea. The study will also monitor morbidity and mortality of subjects with HFRS who are treated with IV Ribavirin. The study population will include all subjects with a probable or suspected clinical diagnosis of HFRS, at least 18 years of age (age 17 if active military) but not greater than 65 years of age. The Investigators intend to treat all individuals who present with a tentative diagnosis of HFRS (and within 7 days of onset of illness) and meet entry criteria with a 7 day course of IV Ribavirin and a 28-60 day follow up period after first dose of Ribavirin. In addition to treatment with Ribavirin, all subjects will be given standard supportive and symptomatic care as determined by the clinical judgment of attending physicians or consultants who manage the subject's care at the 121 CSH. Up to 50 subjects could potentially be enrolled in a five year time period with an expected accrual of 0-5 subjects per year, but the number may be higher (10 to 20 persons in a year) if an HFRS outbreak should occur. Specific inclusion/exclusion/relative exclusion criteria are a part of the protocol. Safety procedures required during 7 days of treatment include continuous cardiac monitoring, daily lab work, physical exams and vital signs.

  Eligibility

Ages Eligible for Study:   17 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Have read and signed the Informed Consent (see Exception for Emergency Treatment, Section 12.0).
  • Are at least 18 years of age (17, if active military) and not greater than 65 years of age.
  • Meet the case definition for a probable or suspected case (see Section 5.0).
  • Have a blood sample drawn and a type and cross-match ordered for transfusion.
  • Agree to collection of required specimens.
  • Agree to report any Adverse Events, Serious and Unexpected Adverse Events for the duration of the study.
  • Agree to a follow-up visit and to donate blood and urine specimens at day 10, day 14 and between days 28 and 60 after the first dose of IV Ribavirin and to all follow-up visits for anemia or other medical conditions as required by the attending physician.
  • Women of childbearing age must have a negative pregnancy test and agree not to become pregnant for 7 months after receiving Ribavirin. Women will be counseled concerning the risks of IV Ribavirin.
  • Men agree not to have intercourse with pregnant women for 7 months after receiving Ribavirin, and take precautions to avoid producing pregnancies for 7 months after receiving Ribavirin.
  • Have a hemoglobin greater than or equal to10 g/dL before starting IV Ribavirin.

Exclusion Criteria:

  • A known intolerance to Ribavirin.
  • Are irreversibly ill on presentation, as defined by presence of profound shock, which does not respond to supportive therapy within 3 hours after admission.
  • A positive pregnancy test.
  • An estimated creatinine clearance < 20 ml/minute.
  • A history of hemoglobinopathies (i.e., sickle-cell anemia or thalassemia major).
  • A history of autoimmune hepatitis.
  • A hemoglobin less than 10 g/dL that cannot be corrected to ≥10 g/dL before initiation of IV Ribavirin.
  • A New York Heart Association Cardiac functional capacity of Class II or greater for ASHD and CHF.
  • Known cardiac conduction defects that may predispose the subject to arrhythmias, such as second or third degree heart block or sick sinus syndrome (and no pacemaker), or Wolfe-Parkinson-White Syndrome.
  • A sinus bradycardia of less than 40 beats per minute (or sinus bradycardia less than 50 beats per minute if the individual is not known to have a low resting heart rate related to physical conditioning).
  • Concurrent therapy with Didanosine (ddI). DdI must be discontinued before starting the IV Ribavirin.

Relative Exclusion Criteria: PI's discretion to use IND Ribavirin with caution. The PI should make the decision concerning enrollment of subjects with relative exclusion criteria based on risk versus benefit of the drug.

  • Creatinine clearance is 20 - 30 mL/minute
  • History of gout or tophaceous gout
  • On any drug that may decrease heart rate (beta-blockers, calcium channel blockers, digoxin IV Ribavirin should be avoided in severe renal insufficiency, and its use with a creatinine clearance between 20 to 30 mL/min should be based on the risk versus benefit. If used, the drug should be discontinued if the creatinine clearance decreases to 20 mL/min or lower.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00623168

Locations
Korea, Republic of
Brian Allgood Army Community Hospital (121st Combat Support)
Seoul, Korea, Republic of
Sponsors and Collaborators
U.S. Army Medical Research and Materiel Command
Investigators
Principal Investigator: Laura M Cashin, DO Brian Allgood Army Community Hospital (121st Combat Support), Seoul, Republic of Korea
  More Information

No publications provided

Responsible Party: U.S. Army Medical Research and Materiel Command
ClinicalTrials.gov Identifier: NCT00623168     History of Changes
Other Study ID Numbers: A-14474, TAMC HUC 23H07
Study First Received: February 13, 2008
Last Updated: July 2, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by U.S. Army Medical Research and Materiel Command:
Ribavirin
Hemorrhagic Fever with Renal Syndrome

Additional relevant MeSH terms:
Syndrome
Fever
Hemorrhagic Fevers, Viral
Hemorrhagic Fever with Renal Syndrome
Disease
Pathologic Processes
Body Temperature Changes
Signs and Symptoms
RNA Virus Infections
Virus Diseases
Hantavirus Infections
Bunyaviridae Infections
Ribavirin
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 18, 2014