A Randomized Open Label Study Comparing the Safety, Tolerability and Pharmacokinetics (PK) of Amantadine Hydrochloride and Ribavirin with Oseltamivir Phosphate (TCAD) Administered Orally Versus Oseltamivir alone Administered Orally to Influenza A Virus Infected Hospitalized Immunocompromised Patients

Influenza causes annual epidemics of acute respiratory illness. In the
Netherlands, both influenza A H1N1 and H3N2 subtypes circulate. Although the
incidence of influenza in transplant recipients has not been assessed
prospectively, large retrospective cohort studies have clearly demonstrated
that transplant recipients have more prolonged shedding of influenza and have a
higher rate of complications, including death, than immunocompetent patients;
mortality rates have been documented to be as high as 23%. The prolonged
shedding predisposes to the emergence of neuraminidase inhibitor resistant
variants. Available evidence suggests that antiviral therapy is associated with
reduced morbidity and mortality attributable to influenza in both stem cell and
solid organ transplant patients.
Available antivirals with activity against influenza include M2 inhibitors
(amantadine and rimantadine), neuraminidase inhibitors (oseltamivir and
zanamivir), and ribavirin. Among immunocompetent patients, both the M2
inhibitors and neuraminidase inhibitors reduce the severity of illness,
duration of fever, time to return to normal activity, quantity of viral
shedding, duration of impaired activity, and complications leading to
antibiotic use, particularly bronchitis.

Influenza virus resistance has been described for both the M2 inhibitors and
the neuraminidase inhibitors (NAI). Resistance to the M2 inhibitor is mediated
by mutations in the M2 ion channel and results in cross-resistance among all
drugs in the class. M2 inhibitor resistance developes rapidly during treatment
and appears to be stable and persistent.
These features have contributed to the rapid and widespread emergence of
influenza A/H3 virus resistant to M2 inhibitors that currently limits the
effectiveness of this class of drugs. On the other hand, neuraminidase
inhibitor resistance can occur as the result of mutations in either the NA or
HA gene, does not always result in cross-resistance among all neuraminidase
inhibitors, and may be more transient.

The use of combinations of antivirals has been studied in non-immunocompromised
patients with the goal of minimizing emergence of resistant variants and
potentiating effects 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 underrecruited
subjects and was therefore 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 patients in the monotherapy arm.

An additional problem is the high rates (>90%) of oseltamivir resistance among
circulating H1N1 viruses, current US CDC recommendations include combination
treatment with oseltamivir and rimantadine as an acceptable alternative for
treating H1N1 and unknown genotypes. However, given the known rapid
development of amantadine and rimantadine resistance during monotherapy with
these agents , this regimen carries a substantial risk of generating dual
resistant viruses if used for treatment of current oseltamivir-resistant H1N1
viruses.
Adamas Pharmaceuticals Inc. has reported that the triple combination therapy
(amantadine, oseltamivir, and ribavirin) is highly synergistic over specific
and physiologically-relevant concentration ranges in the in vitro models (MDCK
cells), and reduces the EC50 of the drugs significantly when compared to
monotherapy and dual therapy.

Primary: To determine the safety and tolerability of TCAD administered orally
to immunocompromised patients diagnosed with influenza A

Secondary: To assess the antiviral effect, the speed of symptom resolution, and
the influenza complication rate of combination antiviral therapy as compared to
oseltamivir monotherapy, and to evaluate its pharmacokinetics.

This open label randomized study will investigate the safety, tolerability and
virologic benefit of amantadine hydrochloride and ribavirin with oseltamivir
phosphate (TCAD) versus neuraminidase inhibitor monotherapy for the treatment
of influenza A in up to 40 immunocompromised patients infected with influenza A
(H3N2) viruses. Patients infected with influenza A (H1N1) viruses (up to 30
patients) will be treated with open-label TCAD. Reason for the distinction
between H3N2 and H1N1 viruses is that nearly 100% of currently circulating H1N1
viruses are oseltamivir-resistant. Current influenza H3N2 viruses are all
susceptible to oseltamivir.
Eligible immunocompromised patients diagnosed with influenza A (H3N2) virus
infection, as assessed by subtype specific PCR, will be randomized to receive
either TCAD (amantadine/ribavirin with oseltamivir phosphate) or oseltamivir
alone for a minimum of 10 days.
Patients diagnosed with influenza A(H1N1) virus infection will receive
open-label TCAD for a minimum of 10 days.
In all patients, the duration of study treatment may be extended for one
additional 10 day dosing period depending on duration of symptoms, continued
viral shedding (Positive Rapid Antigen or DFA), and clinician judgment.
Patients may receive study drug in the hospital or on an outpatient basis.
Outpatients will return to the Clinical Study Unit at each designated
outpatient study visit for study evaluations as outlined in the schedule of
events (Appendix A).
Assessment of viral shedding and genotypic and phenotypic drug resistance will
be performed. Nasopharyngeal swabs (or washes) and blood samples will be taken
and efficacy, resistance, and safety evaluations made at intervals during the
study. Peripheral venous blood samples for pharmacokinetic (PK) analysis of
amantadine, ribavirin and oseltamivir carboxylate will be collected on Day 3
(or Day 4 or 5 if Day 3 is not practical) at pre-dose (trough) and at 1, 2, 4,
and 8 hours following the morning dose of study drug.

Routine safety monitoring (including AE reporting, clinical laboratory tests,
vital signs, and O2 levels) will be conducted during and after dosing in all
patients. A final safety assessment will occur approximately 30 days after the
final dose of study drug. A Data Safety Monitoring Board (DSMB) will monitor
patient safety throughout the duration of the study.

- Nasopharyngeal swabs (or washes)
- Peripheral venous blood samples will be drawn from indwelling catheters or by
direct venipuncture into collection tubes
- TCAD (Amantadine 75 mg q8h orally, Ribavirin 200 mg q8h orally en Oseltamivir
50 mg q8h orally) versus Oseltamivir alone 50 mg q8h orally.

The nonclinical and clinical pharmacology, pharmacokinetics, and safety of
amantadine HCl, oseltamivir phosphate, and ribavirin have been well studied.
There do not appear to be overlapping or synergistic toxicities between the
drugs, and therefore there is no expectation that the drugs given together
should have increased safety concerns compared to the drugs given alone.

Several studies describe the safety and/or the pharmacokinetics of
double-combination therapy for the treatment of viral infections: ribavirin
with amantadine (Adinolfi, Utili et al. 2003; Engler, Flechtenmacher et al.
2004; Thuluvath, Maheshwari et al. 2004; Oguz, Cicek et al. 2005; Younossi,
McCullough et al. 2005), amantadine with oseltamivir (Morrison, Roy et al.
2007), and oseltamivir with ribavirin (Poutanen, Low et al. 2003). These
studies revealed little evidence of a clinically significant safety issues
posed by multiple administrations of this triple combination using labeled
doses of each drug product.
An open-label, single dose, parallel-group crossover study to evaluate the
safety and pharmacokinetics of single doses of amantadine 100 mg, oseltamivir
75 mg and ribavirin 600 mg and the combination of
amantadine/oseltamivir/ribavirin was conducted in 42 healthy volunteers (Adamas
Pharmaceuticals, personal communication). The study treatments in this trial
were safe and well tolerated. There were no significant treatment-emergent
adverse events, deaths, or serious adverse events. The results of this study
indicated that the single dose pharmacokinetics of amantadine, oseltamivir,
oseltamivir carboxylate, and ribavirin are not altered when the three drugs are
administered together.
From understanding the metabolism of the individual components, an acceptable
PK and safety profile is predicted with simultaneous administration of all
three drugs.
13 times Venepuncture and 13 times nasopharyngeal swab will be done. The
complications of this type interventies are minimal.