Ribavirin for Hemorrhagic Fever With Renal Syndrome in Germany — HFRS  

Hemorrhagic Fever With Renal Syndrome Clinical Trial

Official title: A Phase 2 Treatment Protocol of Intravenous Ribavirin in Adult Subjects With Hemorrhagic Fever With Renal Syndrome (HFRS) in Landstuhl Regional Medical Center (Landstuhl, Germany) IND 16,666

Status Withdrawn

Clinical Trial Summary

This is a treatment protocol using IND Ribavirin-there is no control group. Hemorrhagic Fever with Renal Syndrome (HFRS) is caused by a virus acquired by contact with chronically infected rodent hosts. HFRS is present throughout Europe and caused mainly by Puumala and Dobrava viruses. 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 (determination if the disease is caused by Puumala or Dobrava virus is helpful) 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.

Clinical Trial Description

This is a Phase 2, open label study of the safety of IV Ribavirin treatment in individuals with HFRS admitted to the Landstuhl Regional Medical Center, Germany. The study will also monitor the 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 and meet entry criteria with a 7 day course of IV Ribavirin and a 28-60 day follow up period after the 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 the Principal Investigator, attending physicians or consultants who manage the subject's care at LRMC. Up to 50 subjects could potentially be enrolled in a five year time period with an expected accrual of 0-5 subjects per year. 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.

Hemorrhagic fever with renal syndrome (HFRS) is caused by viruses in the genus Hantavirus of the family Bunyaviridae. There are four known Hantaviruses that cause HFRS: Hantaan, Seoul, Puumala, and Dobrava viruses. Hantaan virus is a spherical, enveloped virus and has been designated the prototype for the Hantavirus genus family Bunyaviridae (Schmaljohn, 1983). Serologic, morphologic, and biochemical studies have established that this virus is related to Puumala virus, Seoul virus, and other Hantaviruses (Schmaljohn, 1985). HFRS is acquired by contact with chronically infected rodent hosts, most commonly from inhalation of infected rodent excreta (urine, saliva, and feces) but also reported from rodent bites. In Europe, HFRS is caused mainly by Puumala and Dobrava viruses, with Puumala virus responsible for most cases. Puumala virus, the cause of nephropathia epidemica (NE) in Scandinavia (also France, Germany, Belgium, Scotland, and Italy), is transmitted by Clethrionomys glareolus (mole) [HFRS manual Niklasson]. HFRS from Puumala virus is associated with a mortality rate of <0.5%. Oliguria is reported in 40% of cases, and severe renal insufficiency is generally observed in 3 to 9% cases [HFRS manual Lahdevirta]. However, a report from HFRS due to Puumala virus in Germany was associated with severe renal disease necessitating dialysis in 4/15 (26% cases) [Rasche et al, 2004)].

Dobrava virus, the cause of a severe form of HFRS mainly in the Balkan Peninsula (Hungary, Bulgaria, Albania, the former Yugoslavia, and Greece) but also in Russia in areas west of the Ural Mountains, is transmitted by the rodent host Apodemus flavicollis (yellow-necked field mouse), and associated with a mortality rate of 5%-35% {HFRS manual Tatjana; HFRS manual Tkachenko]. Less data is available on Dobrava virus, but the morbidity and mortality is expected to be similar to HFRS caused by Hantaan virus, or perhaps more severe. In one study of HFRS in Greece felt to be secondary to Dobrava virus, 37% cases required dialysis and 15% cases resulted in death (Antoniadis et al, 1989).

Disease from Dobrava virus has a similar severity and presentation as disease from Hantaan virus. However, HFRS from Puumala has a lower death rate and dialysis rate and the risk of IV Ribavirin in treatment for HFRS, in particular, must be measured against the benefit of treatment. The decision to start IND IV Ribavirin will be based on whether the HFRS is likely to be Dobrava virus versus Puumala virus based on epidemiological data of past or ongoing outbreaks of HFRS in that geographical area. Observation with supportive care without the use of IND IV Ribavirin is the generally recommended medical management of HFRS from Puumala virus due to the lower morbidity and mortality associated with HFRS from Puumala virus.

While most cases in HFRS in Europe will be from Puumala and Dobrava viruses, the experience with IV ribavirin has been mainly with HFRS caused by Hantaan and Seoul viruses in Southeast Asia. All hantaviruses have in vitro sensitivity to IV ribavirin. The data for IV ribavirin for HFRS caused by hantaviruses in Europe is based on the experience with HFRS from Hantaan and Seoul viruses.

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 is not licensed in the U.S. IV Ribavirin for the treatment of HFRS is used under IND 16,666. ;

Related Conditions & MeSH terms

• Fever
• Hemorrhagic Fever With Renal Syndrome
• Syndrome

• NCT number: NCT00868946
• Study type: Interventional
• Source: U.S. Army Medical Research and Development Command
• Status: Withdrawn
• Phase: Phase 2
• Start date: October 2009
• Completion date: September 2016