Primary: To assess the antiviral efficacy of triple combination antiviral drug (TCAD) therapy(i.e. amantadine and ribavirin co-administered with oseltamivir) compared to oseltamivirmonotherapy in immunocompromised subjects diagnosed with Influenza…
ID
Source
Brief title
Condition
- Immunodeficiency syndromes
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is clearing of viral shedding as determined by qRT-PCR
using
nasopharyngeal swabs.
Secondary outcome
1. Time to alleviation of influenza clinical symptoms based on symptom surveys
2. Proportion of subjects who enter the study with mild to moderate influenza
and progress
to severe influenza (protocol definition) during randomized study treatment
3. Proportion of subjects who meet clinical treatment failure criteria during
randomized
study treatment
4. Proportion of subjects who develop confirmed pneumonia (radiographically
with or
without laboratory/microbiological testing)
5. Proportion of subjects not shedding virus (defined as less than 103 RNA
copies per ml by
qRT-PCR) at Day 6
6. Proportion of subjects not shedding virus (defined as less than 103 RNA
copies per ml by
qRT-PCR) at Day 10
7. Proportion of subjects with a treatment-sensitive influenza A strain at
baseline who
develop a resistant strain during treatment, as measured by in vitro and/or
genotypic
assays.
8. Viral resistance as a function of drug exposure, as measured by in vitro
and/or genotypic
assays
9. Viral load as a function of time as measured by qRT-PCR.
10. Safety and tolerability (adverse events (AEs), AEs resulting in treatment
discontinuation,
and Serious AEs)
11. Survival
Background summary
The use of combinations of antiviral drugs has been studied in
non-immunocompromised subjects with the goal of minimizing emergence of
resistant variants and additive or synergistic affects on viral replication and
clinical recovery (Hayden 1996). One study prospectively studied rimantadine
versus rimantadine plus nebulized zanamivir (Ison, Gnann et al. 2003).
Although this study was underpowered to detect a difference between the two
arms, there was a trend toward more rapid resolution of symptoms.
Additionally, the two detected resistant variants to emerge on therapy were
recovered from subjects in the monotherapy arm.
Current CDC recommendations
(http://www.cdc.gov/flu/professionals/antivirals/index.htm) include combination
treatment with oseltamivir and rimantadine as an acceptable alternative for
treating H1N1 and unknown genotypes.
Study objective
Primary: To assess the antiviral efficacy of triple combination antiviral drug
(TCAD) therapy
(i.e. amantadine and ribavirin co-administered with oseltamivir) compared to
oseltamivir
monotherapy in immunocompromised subjects diagnosed with Influenza A
Secondary: To investigate the clinical efficacy, viral resistance patterns,
safety and tolerability
of triple combination antiviral drug (TCAD) therapy in comparison to
oseltamivir monotherapy
administered orally to immunocompromised subjects diagnosed with Influenza A
Study design
Eligible immunocompromised adult and pediatric subjects diagnosed with
influenza A will be randomized 1:1 to receive either TCAD therapy (amantadine
and ribavirin with oseltamivir) or oseltamivir for 10 days. Subjects will be
enrolled into the study based on a clinical diagnosis of influenza and a
positive standardized rapid antigen test (RAT) for influenza A, which will be
selected by the sponsor and used by all investigative sites.
Subjects may be enrolled with mild/moderate or severe influenza. However,
enrollment of subjects with severe influenza (see criteria below) will be
capped at 25% of total enrollment, and enrollment of HIV-positive subjects will
be capped at 50% of total enrollment. Randomization will be stratified based
on whether or not a subject has severe influenza and whether or not a subject
is HIV-positive.
Nasopharyngeal swabs will be utilized for all virology assessments..
Nasopharyngeal swab and blood samples will be taken for efficacy, resistance,
and safety evaluations made at intervals during the study. Influenza clinical
symptoms will be assessed through a brief symptom survey administered to
subjects by site personnel.
Intervention
Subjects will be randomized in a 1:1 ratio to receive either TCAD or
oseltamivir.
Group 1 - TCAD
Amantadine Hydrochloride Oral Syrup
Adult Dose: 75 mg every 8 hours
Ribavirin Oral Solution
Adult Dose: 200 mg every 8 hours
Oseltamivir Phosphate for Oral Suspension
Adult Dose: 50 mg every 8 hours
Group 2 - Comparator
Oseltamivir Phosphate for Oral Suspension
Adult Dose: 50 mg every 8 hours
Study burden and risks
The burden for the subject is mainly due to 9 visits to the hospital. Each
visit will last 30 to 60 minutes.
Th risks associated with the trial are related to side effects of any of the
study drugs:
Amantadine
The most common side effects of AMANTADINE that have reported are:
• Blurred vision and/or confusion
• Dizziness, lightheadedness, and a drop in blood pressure when standing up.
• Mood/mental changes, swelling of hands and feet, difficulty urinating and/or
shortness of breath.
• Vomiting, weakness, difficulty urinating and/or shortness of breath,
decreased sex drive.
It should be noted, that while not common, amantadine use has been noted to
cause seizures in some patients.
Ribavirin
The most serious possible side effects of ribavirin (REBETOL) that have been
reported are:
• Harm to unborn children. This drug may cause birth defects or death of an
unborn child.
• Anaemia: Anaemia is a reduction in the number of red blood cells you have and
was observed in approximately 10% of ribavirin (trade name REBETOL) treated
patients in clinical trials. It can be dangerous, especially if teh subject has
heart or breathing problems (chest pain or shortness of breath).
• Other less serious reported side effects that occur in 1% - 10% (1 in 100 - 1
in 10) of people include cough, rash and itching, hives or swelling, severe
stomach or lower back pain, bloody diarrhea or stools (feces), bruising, other
bleeding, tiredness, nausea and loss of appetite.
Oseltamivir
The most common side effects of oseltamivir (TAMIFLU) that have been reported
are:
• Mild to moderate nausea and vomiting
• Allergic reaction (hives, difficulty breathing, swelling of the face, lips,
tongue, or throat) or severe rash
• Increased risk of seizures, confusion, or abnormal behavior, especially if
teh subject sufers from flu
In addition, the subject might experience side effects from some of the study
procedures:
• Blood collection - the needle stick may cause pain, redness, swelling,
bleeding and rarely infection
• Nose and throat swabs -The side-effects of this procedure can include
tickling in the nose and/or throat, watering eyes, nasal soreness, sneezing,
coughing and gagging.
Stationsweg 163
9471 GP ZUIDLAREN
Nederland
Stationsweg 163
9471 GP ZUIDLAREN
Nederland
Listed location countries
Age
Inclusion criteria
1. Male or female, between 1 and 65 years of age, inclusive (an individual investigative site may elect to enroll adults only, per local regulations or EC determination)
2. Able to provide informed consent, or for whom consent may be provided by guardian
3. Immunocompromised, as defined by one of the following at study entry:
• Recent solid organ transplantation or hematopoietic cell transplantation (HCT) (within 2 years, all conditioning regimens, allogeneic, autologous, or syngeneic)
• Chronic GVHD requiring systemic immunosuppression
• Taking at least 2 systemic immunosuppressants (regardless of dose)
• Received systemic chemotherapy within the past 3 months
• Taking high dose corticosteroids: an average daily dose of > 30 mg of prednisone (or equivalent dose for other corticosteroids) during 30 days prior to study entry
• HIV-positive with a CD4+ cell count <500/µL within 90 days prior to study entry
4. A clinical diagnosis of influenza (mild/moderate or severe) with the presence of one or more of the following:;• Presence of fever at time of screening of >= 37.8°C (>= 100.0°F) taken orally. However, this requirement is waived if the patient has a history of fever within the 24 hours prior to screening and has been administered any antipyretic(s) (including systemic steroids) in the 24 hours prior to screening
• Presence of at least one constitutional symptom (headache, myalgia, malaise, or fatigue) of any severity
• Presence of at least one respiratory symptom (e.g. cough, or sore throat) of any severity
• Other flu-like symptoms, where the clinician orders an influenza test
Severe influenza is defined for this study as:
• O2 saturation <= 92% on room air; or
• Severe tachypnea (respiratory rate greater than or equal to 30 for ages greater than or equal to 12 years, rate greater than or equal to 40 for ages 6 to 12 years, rate greater than or equal to 45 for ages 3 to 6 years, rate greater than or equal to 50 for ages 1-3 years); or
• New infiltrate on chest X-ray (or any infiltrate if no prior chest X-ray or not known)
5. Positive rapid test for influenza A (standardized and sponsor-selected).
6. Subjects must be randomized no later than 5 days (120 hours) following estimated time of symptom onset. Note: Time of onset of illness is defined as either (1) the time when the temperature was first measured as elevated ( >= 38.0°C (>= 100.0°F)), OR (2) the time when the patient experienced the presence of at least one respiratory symptom or the presence of at least one constitutional symptom.
7. Females who are able to become pregnant (i.e. are not post-menopausal, have not undergone surgical sterilization, and are sexually active with men) must agree to use at least 2 effective forms of contraception from the date of informed consent through 24 weeks after the last dose of study drug. At least one of the methods of contraception should be a barrier method.
8. Males who have not undergone surgical sterilization and are sexually active with women must agree to use condoms plus have partner use at least one additional effective form of contraception from the date of informed consent through 24 weeks after the last dose of study drug.
Exclusion criteria
1. Received more than one (1) dose of antiviral influenza medications since onset of influenza symptoms
2. Critically ill with presence of one or more of the following signs:
• need for admission to an intensive care unit (for other than respiratory isolation)
• acute respiratory failure requiring intubation/mechanical ventilation
• signs of shock including hypotension
3. Creatinine clearance less than 80 mL/min (estimated by the Cockcroft-Gault equation using serum creatinine) or, for pediatric subjects, a GFR less than 80 mL/min/1.73 m2 BSA (estimated by Schwartz or other age-appropriate formula)
4. History of gastrointestinal malabsorption
5. History of genetic hemoglobinopathy (e.g., thalassemia major or sickle cell anemia) or autoimmune hemolytic anemia
6. History of Chronic Active Hepatitis C
7. Hemoglobin less than 10 gm/dL
8. ANC <1000 cells/cubic millimeter
9. Known hypersensitivity to amantadine, ribavirin, or oseltamivir
10. Received amantadine, rimantadine, ribavirin, or oseltamivir for any indication within 30 days prior to study entry (may have received one (1) dose of antiviral influenza medication since onset of influenza symptoms)
11. Received live attenuated virus vaccine within 3 weeks prior to study entry
12. Received stavudine (d4T) or didanosine (ddI) within 30 days prior to study entry
13. Females who are pregnant, who are attempting to become pregnant, or who are breast-feeding
14. Males whose female partners are pregnant
15. Psychiatric or cognitive illness, including depression or suicidal ideation, or recreational drug/alcohol use that would affect patient safety and/or compliance
16. Uncontrolled seizure disorder or history of seizure activity within 12 months prior to study entry
17. Subjects with significant or unstable cardiac disease including angina, complex arrthymias, decompensated congestive heart failure and active ischemic disease
18. Documented non-influenza A viral respiratory infection, including respiratory syncytial virus (RSV) or Influenza B
19. Use of any investigational drug within 30 days or 5 half-lives (whichever is longer) prior to study entry
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2009-015850-39-NL |
| CCMO | NL29784.058.09 |