Treatment of Viral Hemorrhagic Fevers With Intravenous Ribavirin in Military Treatment Facilities
Treatment of Viral Hemorrhagic Fevers With Intravenous Ribavirin in Military Treatment Facilities
This is a Phase 2 study of the safety and efficacy of Intravenous (IV) Ribavirin in treating
 patients presenting with a probable or suspected case of viral hemorrhagic fever (either
 Crimean Congo or Lassa Fever) at a military medical treatment hospital. All patients will be
 treated with a 10 day course of IV Ribavirin if they meet all the inclusion and none of the
 exclusion criteria.
Department of Defense operations have resulted in the deployment of personnel to areas
 endemic for Viral Hemorrhagic Fever (VHF): Crimean-Congo Hemorrhagic Fever (CCHF) or Lassa
 Fever. Unfortunately, beyond supportive care, there is no approved therapy for treating
 either infection. Previous studies with intravenous (IV) Ribavirin have shown IV Ribavirin as
 a promising treatment for both infections. This study will provide experience in U.S.
 Department of Defense associated treatment facilities in the use of IV Ribavirin for the
 experimental treatment of viral hemorrhagic fevers primarily among U.S. Service personnel
 deployed to disease-endemic areas.

 The rationale for conducting the study is a) to allow the DoD to gain experience in treating
 VHF b) to offer this experimental but promising therapy to patients with probable or
 suspected VHF c) to collect safety data while obtaining experience using Ribavirin.
Inclusion Criteria:

 An individual will be enrolled in this study if the patient:

 -  Meets the case definition for a probable or a suspected case of CCHF or LF (see
 below).

 -  Has read and signed the Informed Consent.

 -  Is at least 18 years of age (17, if active military) and not greater than 65 years of
 age.

 -  Has a blood sample drawn and a type and cross-match ordered for transfusion.

 -  Agrees to collection of required specimens.

 -  Agrees to report any Adverse Events, Serious and Unexpected Adverse Events for the
 duration of the study.

 -  Agrees to a follow-up visit and to donate blood and urine specimens at day 14 (±2
 days) and once 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.

 -  Woman of childbearing age must have a pregnancy test performed. If negative, she must
 agree not to become pregnant during treatment and for 7 months after receiving
 Ribavirin. She also must agree to not breast feed during treatment and for 7 months
 after receiving Ribavirin. Two reliable forms of effective contraception must be used
 including one barrier method during treatment and during the 7 month post-treatment
 period. She will be counseled concerning the risks of IV Ribavirin versus no treatment
 if the pregnancy test is positive.

 -  Man agrees not to have intercourse with pregnant woman during treatment and for 7
 months after receiving Ribavirin, and take precautions to avoid producing pregnancies
 during treatment and for 7 months after receiving Ribavirin. At least two reliable
 forms of effective contraception must be used including one barrier method during
 treatment and during the 7 month post-treatment period to avoid a pregnancy.

 -  Has a hemoglobin greater than or equal to10 g/dL before starting IV Ribavirin

 Note: Malaria should be excluded as a possibility for illness in patients suspected to have
 VHF.

 Probable Case of Crimean-Congo Hemorrhagic Fever:

 All subjects will have a history of possible exposure to CCHF, either having:

 -  Worked or slept outdoors in the CCHF endemic area within 2 weeks of illness onset,
 with or without a history of tick-bite or tick exposure, (Endemic area includes, but
 not necessarily limited to: Saudi Arabia, Kuwait, Oman, United Arab Emirates, Iran,
 Iraq, Turkey, Greece, Bulgaria, Albania, Montenegro, the Kosovo region of Serbia,
 Bosnia-Herzegovina, Macedonia, the whole of Africa, India, Pakistan, Afghanistan,
 Kazakhstan, Uzbekistan, Kyrgyzstan, Tajikistan, Turkmenistan, Azerbaijan, Georgia, the
 Crimean region of the Ukraine, Rostov-Don and Astrakhan regions of Russia, and the
 Xinjiang [northwestern] region of the People's Republic of China), OR

 -  Handled blood or freshly butchered meat of domestic livestock in CCHF endemic area
 during 2 weeks before the onset of illness, OR

 -  Had direct contact with blood, tissues, secretions, or excretions of a CCHF patient
 (suspected or confirmed), including laboratory specimens, OR

 -  Worked with the virus in the laboratory setting and have a clinical syndrome
 consistent with CCHF as defined by:

 -  Acute illness with fever and at least two of these symptoms: myalgia, low back
 pain, and headache,

 -  And the appearance of three or more of the following five groups of
 signs/symptoms:

 -  Hemorrhage (one or more petechiae, ecchymoses, purpura, gingival bleeding,
 epistaxis, gastrointestinal tract bleeding),

 -  Elevated AST levels (above the upper limits of normal for the laboratory),

 -  Thrombocytopenia (below the lower limits of normal),

 -  Hypotension (systolic pressure < 90 mm Hg), or

 -  Azotemia, renal failure (serum creatinine above the upper limits of normal).

 -  Prognostic indicators exist for subjects at increased risk of severe CCHF. Any of
 these indicators occurring in the first 5 days of illness, predict a mortality greater
 than 90% (Swanepoel et al., 1989). Patients with these prognostic indicators may
 benefit most from drug therapy, if resources become limiting:

 -  WBC > 10,000/mm3

 -  Platelet count < 20 x 103/mm3

 -  AST > 200 U/L

 -  ALT > 150 U/L

 -  APTT > 60 seconds

 -  Fibrinogen < 110 mg/dL

 Probable Case of Lassa Fever:

 All subjects will have a history of possible exposure to Lassa fever, either having:

 -  By residence or travel in an endemic area where contact with rodents was possible
 within 3 weeks of onset of illness, (Endemic area includes, but not necessarily
 limited to: Sierra Leone, Liberia, Nigeria, Mali, Central African Republic, and
 Guinea.) or

 -  Contact with a suspect patient or their body fluids (including laboratory specimens)
 within 3 weeks of symptom onset, or

 -  Worked with the virus in the laboratory setting. And have

 -  A negative malaria smear. And have

 -  Signs and symptoms compatible with Lassa fever, either:

 -  Fever plus pharyngitis plus retrosternal pain plus proteinuria (positive
 predictive value of 81% when these three criteria are met, McCormick et al.,
 1987a,b),OR

 -  Fever plus unexplained mucosal bleeding, OR

 -  Fever plus unexplained edema of the face and neck, OR

 -  Suspected Case of CCHF or LF

 -  Have a clinical syndrome consistent with CCHF or LF, meeting most of the above
 criteria of a probable case and the patient has an epidemiological history of
 potential exposure to the bunyavirus or arenavirus (i.e., recent field duty and/or
 other individuals in his troop have CCHF or LF).

 Exclusion Criteria:

 -  Has known intolerance to Ribavirin.

 -  Is irreversibly ill on presentation, as defined by presence of profound shock (shock
 which does not respond to supportive therapy within 3 hours after admission).

 -  Has hemoglobin less than 10 g/dL that cannot be corrected to 10 g/dL before initiation
 of IV Ribavirin

 -  Has history of hemoglobinopathies (i.e., sickle-cell anemia or thalassemia major).

 -  Has history of autoimmune hepatitis.

 -  Has a calculated serum creatinine clearance of < 30 mL/min.

 -  History of such as second or third degree heart block or sick sinus syndrome and
 without a pacemaker and no capability of a pacemaker placement or
 Wolfe-Parkinson-White Syndrome.

 -  A sinus bradycardia of less than 40 beats per minute.

 -  Is currently being treated with Didanosine (ddI). ddI must be discontinued before
 starting IV Ribavirin.

 Relative Exclusion Criteria:

 At the principal investigator's (PI) discretion, an individual may be treated with IV
 Ribavirin, with caution, if one of these criteria is present:

 -  A positive pregnancy test. The individual will be informed of the risk and benefit of
 treatment with IV Ribavirin versus no treatment with IV Ribavirin in CCHF (generally
 associated with high mortality) and severe cases of Lassa fever with high mortality
 rates versus mild cases of Lassa fever with low mortality rates.

 -  A New York Heart Association Cardiac functional capacity of Class II or greater for
 ASHD and CHF.

 -  Known cardiac defects that my predispose the subject to bradyarrhythmias, such as
 second or third degree heart block or sick sinus syndrome without a pacemaker, but
 capability of pacemaker placement, if needed.

 -  Sinus bradycardia of 41-49 beats per minutes if the individual is not known to have a
 low resting heart rate related to physical conditioning.

 -  Use of drugs known to result in bradyarrhythmias (certain betablockers and calcium
 channel blockers, digoxin).

 f. History of gout or tophaceous gout.