Safety, Tolerability and Pharmacokinetic Study of Biota-CS-8958
Safety, Tolerability and Pharmacokinetic Study of Biota-CS-8958
This study will look at the safety, tolerability and what the body does to CS-8958 given to
 40 healthy volunteers 18-55 years old. CS-8958 is a dry-powder investigational drug that is
 breathed into the lungs through an inhaler device. The researchers will collect information
 about any problems that volunteers have while taking the drug and about changes in blood
 pressure and how the heart is working. Volunteers will have breathing tests, physical
 examinations, and blood samples collected for laboratory tests. The researchers will also
 look at how much of the medication travels throughout the body versus how much stays only in
 the lungs. Doses of the medication will be tested at one level and then at higher and higher
 levels after a safety committee reviews the safety and tolerability information on volunteers
 prior to the next higher dose being given. Each volunteer will participate for up to 6 weeks
 from initial screening to the follow up visit and spend 7 days in the clinic.
This study is a phase I, double-blind, placebo-controlled, ascending single inhaled dose,
 safety, tolerability and pharmacokinetic study of CS-8958 in healthy subjects. CS-8958 is an
 investigational drug substance, which is formulated as a dry-powder. Capsules of the dry
 powder are inserted into a FlowCaps® inhaler device. FlowCaps® is a re-fillable, dry-powder,
 breath-actuated inhaler device, which holds up to 14 capsules. Upon actuation the powder
 contained in one capsule is delivered to the respiratory tract. The primary study objective
 is to evaluate the safety and tolerability of CS-8958 (5, 10, 20, and 40 mg) in healthy
 subjects after a single dose administered via inhalation. Parameters are adverse events
 (AEs), vital signs including blood pressure/pulse rate (BP/PR) measurements, functional
 oxygen saturation of arterial haemoglobin (SpO2), electrocardiogram (ECG) examinations,
 spirometry (Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 second (FEV1), FEV
 percentage in 1 second (FEV 1%), FEV1/FVC ratio, Forced Expiratory Flow Rate (FEF) 25%-75%,
 Peak Expiratory Flow Rate (PEFR), physical examinations, mood assessments, and laboratory
 parameters. The secondary study objective is to assess the systemic exposure of CS-8958 and
 its active metabolite R-125489 after single inhaled doses of CS-8958 in healthy subjects. At
 Covance Clinical Research Unit Ltd, Leeds, UK, 40 subjects will be studied in 4 groups
 (Groups A to D) with each group consisting of 10 subjects. Healthy male and female subjects
 aged 18-55 years inclusive will be recruited for the study. There will be four
 investigational product treatment groups (Groups A, B, C, and D). Within each group, subjects
 will be randomly allocated to Arm 1 or Arm 2. The study product doses will be administered in
 an escalating manner. The Safety Monitoring Committee (SMC) will review the safety and
 tolerability data from each group, prior to administration of the next dose. Following these
 reviews, the dose increment for subsequent groups may be increased, or the doses administered
 may be reduced, and may be lower than the starting dose. The maximum dose level to be studied
 will be 40 mg. The primary outcome measures include safety and tolerability. These outcome
 measures will be addressed in terms of occurrences of treatment-emergent AEs, changes in
 vital signs including BP and PR, SpO2, oral body temperature, ECG, spirometry (FVC, FEV1, FEV
 1%, FEV1/FVC ratio, FEF 25-75% and PEFR), physical examinations, mood assessments, and
 laboratory parameters. Secondary outcome measures will include pharmacokinetic parameters.
 These parameters will be calculated for CS-8958 and R-125489 concentrations in plasma and
 urine using a non-compartmental approach.
Inclusion Criteria:

 -  Healthy male and female subjects between 18 and 55 years of age. Male subjects should
 use appropriate contraception (e.g. condoms) during the time interval between dosing
 until 3 months after dosing. Female subjects should be of non-child bearing potential.
 Female subjects 50 years of age or less must be surgically sterile or post-menopausal
 (defined as at least two years post cessation of menses and/or follicle-stimulating
 hormone (FSH) >18 mIU/mL and serum oestradiol <110 pmol/L), non-lactating and have a
 negative serum pregnancy test. Female subjects of more than 51 years of age must be
 surgically sterile or post menopausal (defined by a value of FSH >18 mIU/mL and no
 spontaneous menstruation for at least one year before investigational product
 administration), non-lactating and have a negative serum pregnancy test.

 -  Vital signs within normal limits: systolic BP between 90 and 150 mmHg, diastolic BP
 between 40 and 90 mmHg, pulse rate between 35 and 100 bpm (confirmed as sinus rhythm
 if between 35 and 40 bpm), oral temperature between 35.5°C and 37.7°C and oxygen
 saturation of at least 98%.

 -  Normal physical examination and laboratory findings. Grade 1 laboratory abnormalities
 for non-essential tests and clinical findings considered not clinically significant or
 a variant of normal may be acceptable following discussion between the Investigator
 and the Sponsor.

 -  No abnormality in the ECG; specifically QTc <450 ms and PR 120-200 ms.

 -  None of the following abnormal laboratory findings:

 -  AST >51 IU/L (males) or >46 IU/L (females) [based on 1.25 x ULN]

 -  ALT >61 IU/L (males) or >48 IU/L (females) [based on 1.25 x ULN]

 -  Serum creatinine >104 micro mol/L (males) or >84 micro mol/L (females)

 -  Glucose <3.8 or >5.5 mmol/L

 -  Potassium <3.9 or >5.3 mmol/L (males) or <3.8 or >5.4 mmol/L (females)

 -  Haemoglobin <13.5 or >18.0 g/dL (males) or <11.5 or >16 g/dL (females)

 -  Platelets <152 or >338 x 10^9/L (males) or <150 or >400 x 10^9/L (females)

 -  WBC <3.6 or >10.0 x 10^9/L (males) or <4.0 or >11.0 x 10^9/L (females)

 -  Neutrophils <1.80 x 10^9/L (males) or <2.00 x 10^9/L (females)

 -  No disease that the Investigator regards as clinically relevant.

 -  Negative results in Human Immunodeficiency Virus (HIV) antibody, Hepatitis B surface
 antigen (HBsAg) and Hepatitis C antibody tests.

 -  Individuals who have been registered with a general practitioner within the United
 Kingdom for at least 3 months before enrollment and whose general practitioners have
 replied to a medical history questionnaire.

 -  Individuals who have freely given Informed Consent in writing.

 -  Able to perform respiratory testing.

 Exclusion Criteria:

 -  Subjects who have taken any prescription medication (with the exception of hormone
 replacement therapy (HRT)) within 14 days or any non-prescription (with the exception
 of vitamin/mineral supplements) within the last 7 days prior to the administration of
 the investigational product (Day 1).

 -  Intake of any investigational drug within 4 months (new chemical entity) or 3 months
 (marketed compounds) prior to the intake of investigational product (Day 1).

 -  History of allergy or serious adverse reaction to the excipient or neuraminidase
 inhibitor.

 -  A history or clinical evidence of significant cerebrovascular, cardiovascular,
 gastrointestinal, or haematological disease, or myocardial infarction, or a previous
 history of any other serious underlying disease (including immunocompromised subjects
 and/or neutropenic subjects) that, in the opinion of the Investigator would interfere
 with the conduct of the study.

 -  A history or clinical evidence of significant respiratory disease (including asthma,
 hyper-reactive lung disease, COPD, cystic fibrosis and/or recurrent lower respiratory
 tract infection) and/or upper respiratory tract infection within the last month or
 lower respiratory tract infection within the last three months.

 -  A history or clinical evidence of renal disease (including renovascular occlusive
 disease), nephrectomy and/or renal transplant, and/or previous clinically significant
 laboratory abnormalities of renal function parameters. All subjects with serum
 creatinine outside the normal laboratory reference range at screening and before
 randomization that are regarded by the Investigator as clinically significant.

 -  A history or clinical evidence of hepatic disease and/or previous clinically
 significant laboratory abnormalities of liver function parameters. All subjects with
 alanine transaminase (ALT) and/or aspartate transaminase (AST) outside the normal
 laboratory reference range at screening and before randomization, that are regarded by
 the Investigator as clinically significant. Subjects known to have experienced
 elevated liver enzyme values in previous clinical studies will also be excluded.

 -  Psychiatric or emotional problems that would limit the ability of the subject to
 comply with study requirements.

 -  Body Mass Index (BMI) <18.5 kg/m squared or >30.0 kg/m squared.

 -  FEV1 less than or equal to 85%, FEV (1.0%) less than or equal to 70%, and/or FVC less
 than or equal to 80% of the predicted value, as calculated from standard age and
 height formula.

 -  History of alcohol and/or drug abuse (verified by drug screening).

 -  Receipt of blood or blood products or loss of 450 mL or more of blood during the last
 three months before screening.

 -  Unwillingness or inability to provide Informed Consent or to participate
 satisfactorily for the entire study period.

 -  Subjects who smoke or have been non-smokers for less than 3 months prior to Screening.

 -  Subjects who were previously enrolled in this study.

 -  Subjects who in the opinion of the investigating physician are unable to use the
 inhaler device after training.

 -  Poor veins, or fear of venipuncture or sight of blood.