Hemorrhagic Fever With Renal SyndromePhase 2HFRSNCT00868946
Ribavirin for Hemorrhagic Fever With Renal Syndrome in Germany
A Phase 2 study testing Virazole (Ribavirin) in people with Hemorrhagic Fever With Renal Syndrome, run by U.S. Army Medical Research and Development Command at 1 site in Germany.
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. Read more about this study
- Who is it for?
- Ages 17 to 65 years
- Conditions the study is for
- Hemorrhagic Fever With Renal Syndrome
- What is being tested?
- Virazole (Ribavirin)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteGermany
- Study dates
- Oct 2009to Sep 2016
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 17 to 65 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Meets the case definition for a probable or suspected case.
- 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 Event, Serious and Unexpected Adverse Events which may or may not be associated with administration of the drug for the duration of the study.
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- Agrees to a follow-up visit and to donate blood and urine specimens at day 10, day 14 and between days 28 and 60 after their 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 has a negative pregnancy test and agrees not to become pregnant during treatment and for 7 months after receiving Ribavirin. Treatment will be a maximum of 25 doses given over a one week time period. At least two reliable forms of effective contraception, including one barrier method, must be utilized during treatment and during the 7 months post-treatment period.
- Man agrees not to have intercourse with a pregnant woman during treatment and for 7 months after receiving Ribavirin, and take precautions to avoid producing pregnancies in female partners during and for 7 months after receiving Ribavirin.
- Treatment will be a maximum of 25 doses given over a one week time period. At least two reliable forms of effective contraception, including one barrier method, must be utilized during the treatment and during the 7 month post-treatment period.
- Has a hemoglobin of 10 g/dL or higher before starting IV Ribavirin.
Who cannot join
- Has know intolerance to Ribavirin
- Is pregnant
- 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 history of hemoglobinopathies (i.e., sickle-cell anemia or thalassemia major)
- Has history of autoimmune hepatitis
- Has a calculated serum creatinine clearance of < 20 mL/min
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- Has hemoglobin less than 10 g/dL that cannot be corrected to 10 g/dL before initiation of IV Ribavirin.
- Is considered as New York Heart Association Cardiac functional capacity of Class II or greater for ASHD and CHF.
- Has known cardiac conduction defects that may predispose to arrhythmias such as Wolfe-Parkinson-White Syndrome (WPW); or a history of bradyarrhythmias such as sick sinus syndrome or second degree heart block and no pacemaker.
- Has 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). If an individual develops heart rate of less than 35 beats per minute while on IV Ribavirin, the IV Ribavirin may be discontinued by the physician.
- Is currently being treated with Didanosine (ddI). DdI must be discontinued before starting IV Ribavirin.
- Relative exclusion criteria:
- History of gout or tophaceous gout
- Use of drugs known to result in bradyarrhythmias (certain betablockers and calcium channel blockers)
- Creatinine clearance of 20 to 30 mL/min
Trial locations and contacts
1 site in 1 country.
About this study
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
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.
Read the detailed 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.
- Conditions
- Hemorrhagic Fever With Renal Syndrome
- Being tested
- Virazole (Ribavirin)
- Keywords
- Ribavirin, Hemorrhagic Fever with Renal Syndrome, Dobrava Virus, Puumala Virus
- Medical subject headings
- Hemorrhagic Fever with Renal Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Virazole (Ribavirin)Drug
Also called Ribavirin
Duration of Subject Participation:7-day course of treatment with follow-up 28 - 60 days after first dose of IV ribavirin Route of Administration and Regimen:The drug is administered IV in a volume of 50-100 mL of normal saline to be infused over 30-40 minutes.
Ribavirin Loading dose, 33 mg/kg (maximum dose: 2.64 g), followed by a dose of 16 mg/kg (maximum dose: 1.28 g) every 6 hours for the first 4 days (15 doses), and 8 mg/kg (maximum dose: 0.64 g) every 8 hours for the subsequent 3 days (9 doses).
| Study group | Role | What they receive |
|---|---|---|
| Treatment with IND Ribavirin | Experimental | All consented subjects who meet all inclusion and no exclusion criteria will enter this open label protocol and be treated with IND Virazole (Ribavirin) for 7 days with multiple dosing regime based on weight and dosage day. Receives: Drug: Virazole (Ribavirin) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of subject who develop oliguria
Number of subject who develop oliguria (≤ 400 mL of urine in a 24-hour period), who require hemodialysis, who have cardiac arrhythmias, or who experience severe hemorrhage [results in hypotension (< 90 mm Hg systolic blood pressure) or hemorrhagic shock]. Subject mortality will be evaluated.
Measured: 5 years
Number of mortalities
Measured: 5 years
Secondary outcomes (1)
Number and type of adverse events for all subjects.
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Mar 2009 (estimated)
- Study startOct 2009
- Primary completionSep 2016
- Study completionSep 2016
Why it stopped: Lack of enrollment
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Hemorrhagic Fever With Renal SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- U.S. Army Medical Research and Development Command
- Sponsor type
- US federal agency
- Responsible party
- Sponsor
- Investigators
- Elizabeth Rini, Principal investigator, Landstuhl Regional Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00868946
- Sponsor's protocol ID
- A-15314
- Other IDs
- BAMC HUC C.2008.197, USAMRIID HUC FY05-18
- Acronym
- HFRS
- Status last verified
- Dec 2019
- First submitted
- 24 Mar 2009
- Last updated
- 2 Jan 2020
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 2 Jan 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00868946
- Acronym / sponsor ID
- HFRS / A-15314
- Conditions
- Hemorrhagic Fever With Renal Syndrome
- Keywords
- Ribavirin, Hemorrhagic Fever with Renal Syndrome, Dobrava Virus, Puumala Virus
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Lack of enrollment
- Enrolment
- 0 participants (actual)
- Lead sponsor
- U.S. Army Medical Research and Development CommandUS federal agency
- Study start
- Oct 2009
- Primary completion
- Sep 2016 (actual)
- Study completion
- Sep 2016 (actual)
- First posted
- 25 Mar 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Treatment with IND Ribavirin | Experimental | Drug: Virazole (Ribavirin)All consented subjects who meet all inclusion and no exclusion criteria will enter this open label protocol and be treated with IND Virazole (Ribavirin) for 7 days with multiple dosing regime based on weight and dosage day. |
Who may qualify
- Ages
- 17 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (11 listed)
- Meets the case definition for a probable or suspected case.
- 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.
Key exclusion criteria (15 listed)
- Has know intolerance to Ribavirin
- Is pregnant
- 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 history of hemoglobinopathies (i.e., sickle-cell anemia or thalassemia major)
- Has history of autoimmune hepatitis
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Virazole (Ribavirin)Also: RibavirinDuration of Subject Participation:7-day course of treatment with follow-up 28 - 60 days after first dose of IV ribavirin Route of Administration and Regimen:The drug is administered IV in a volume of 50-100 mL of normal saline to be infused over 30-40 minutes. Ribavirin Loading dose, 33 mg/kg (maximum dose: 2.64 g), followed by a dose of 16 mg/kg (maximum dose: 1.28 g) every 6 hours for the first 4 days (15 doses), and 8 mg/kg (maximum dose: 0.64 g) every 8 hours for the subsequent 3 days (9 doses). | Drug | Treatment with IND Ribavirin |
Primary outcome
Number of subject who develop oliguria
Time frame: 5 years
Number of subject who develop oliguria (≤ 400 mL of urine in a 24-hour period), who require hemodialysis, who have cardiac arrhythmias, or who experience severe hemorrhage [results in hypotension (< 90 mm Hg systolic blood pressure) or hemorrhagic shock]. Subject mortality will be evaluated.
Number of mortalities
Time frame: 5 years
1 secondary outcome
Number and type of adverse events for all subjects.
Time frame: 5 years
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jan 2020.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Elizabeth Rini principal investigator
Landstuhl Regional Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Virazole (Ribavirin) in people with Hemorrhagic Fever With Renal Syndrome, run by U.S. Army Medical Research and Development Command at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 2 Jan 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of subject who develop oliguria (time frame: 5 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jan 2020.