Phase 1, Open Label, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Stabilized Isoamyl Nitrite (SIAN) Nasal Spray in Healthy Adults
Overview
- Phase
- Phase 1
- Intervention
- Stabilized Isoamyl Nitrite (SIAN)
- Conditions
- Cyanide Poisoning
- Sponsor
- Emergent BioSolutions
- Enrollment
- 47
- Locations
- 2
- Primary Endpoint
- Related Serious Adverse Events (SAEs)
- Status
- Completed
- Last Updated
- 11 months ago
Overview
Brief Summary
This study is designed to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of Stabilized Isoamyl Nitrite (SIAN) nasal spray in healthy subjects.
Detailed Description
This is a Phase 1, open label, single ascending dose (SAD) study of Stabilized Isoamyl Nitrite (SIAN) nasal spray to assess safety, PK and PD. The study will consist of seven cohorts, with up to 10 subjects planned per cohort, for a total of 70 subjects. Each cohort will include 10 healthy male or non-pregnant female subjects, aged 18 to 45 years inclusive. There will be a screening period from Day -28 to Day -2 for all study subjects. Subjects will stay overnight at the site the day prior to dosing (Day -1) and the day of dosing (Day 1). They will be evaluated until 24 hours after dosing (Day 2) prior to discharge from the phase 1 clinic. Subjects will return for an End of Study Visit at Day 8 after dosing. Within cohorts one and two, the first two subjects will be dosed as sentinels, while cohorts three to seven will dose the first three subjects as sentinels. Upon completion of the Day 8 (end of study/early withdrawal) visit, safety data, including clinical and laboratory data, and raw PD/PK data will be reviewed by the Principal Investigator (PI) and Medical Monitor (MM) and Safety Monitoring Committee (SMC). If exposure is evident based on raw IAA PK data and PD response signals are detected, the remaining subjects (eight subjects for cohorts one and two and seven subjects for cohorts three to seven) will be dosed. If no exposure and/or PD response signals are detected during sentinel dosing, escalation to the next cohort may be permitted by the SMC. For cohorts where all 10 subjects are dosed, the SMC will review the entire cohort data through each subject's Day 8 visit and provide a recommendation on either, (a) dose escalation to the next cohort, (b) lowering the next dose level, or (c) stopping enrollment based on dose-limiting toxicity. Each new cohort will be dosed following the same procedure as the prior cohort.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Able and willing to provide informed consent (and assent as applicable) voluntarily signed by subject/guardian/legally acceptable representative.
- •Generally healthy, in the opinion of the PI, medical history, physical examination, vital signs, ECG and laboratory assessments at Screening.
- •Male or non-pregnant female.
- •Aged 18-45 years, inclusive, at the time of informed consent.
- •Have adequate venous access for phlebotomies.
- •For Women who are EITHER A or B:
- •A. Not of childbearing potential: surgically sterile (at least six weeks post bilateral tubal ligation, bilateral oophorectomy or hysterectomy); or post-menopausal (defined as ≥50 years of age with a history of ≥12 consecutive months without menses prior to randomization in the absence of other pathologic or physiologic causes and screening follicle-stimulating hormone \[FSH\] \> 30 mIU/mL)
- •B. Women of childbearing potential who are not planning to be pregnant during the study period and who meet criteria i - iv: i. Negative serum pregnancy test at Screening Visit ii. Negative urine pregnancy test prior to dosing at Day -1 (Baseline) iii. Not currently breastfeeding iv. Using one of the following highly effective methods of contraception during the study period:
- •Combined estrogen and progestogen, or progestogen-only hormonal contraception associated with inhibition of ovulation (e.g. implants, pills, patches) initiated ≥30 days prior to Day 1
- •Intrauterine device (IUD) inserted ≥30 days prior to Day 1
Exclusion Criteria
- •Acute disease not resolved at least 4 weeks before Baseline (Day -1).
- •Any chronic clinical condition that requires active treatment of any kind. However, subjects that are on thyroid hormone replacement therapy are eligible if clinically euthyroid and on a stable dose of thyroxine for at least 2 years.
- •Medical history of cardiovascular (including symptomatic or asymptomatic aortic or mitral valvular disease, hypertension), renal, pulmonary and neurological conditions.
- •Active treatment for erectile dysfunction, continuous or on demand, within 4 weeks of baseline.
- •Orthostatic hypotension (at any time prior to dosing) or history of syncope of any cause.
- •Clinically significant ocular condition, other than a requirement for corrective lenses.
- •Any cancer other than the following:
- •Any non-metastatic cancer (excluding hematologic malignancies) or melanoma of which the subject has been disease-free for at least five years; or
- •Localized skin cancer that has been resected at least 4 weeks prior to Screening (including squamous cell and basal cell carcinomas).
- •History of intolerance to nitrites, nitrates or IAN and/or any of the study drug components (including ELSO (Epoxidized linseed oil)).
Arms & Interventions
Cohort 1 SIAN
SIAN dose of 0.28 mg/kg (20 μL) will be administered from a single syringe-based spray device into left nostril.
Intervention: Stabilized Isoamyl Nitrite (SIAN)
Cohort 2 SIAN
SIAN dose of 0.73 mg/kg (50 μL) will be administered from a single syringe-based spray device into left nostril.
Intervention: Stabilized Isoamyl Nitrite (SIAN)
Cohort 3 SIAN
SIAN dose of 1.45 mg/kg (100 μL) will be administered from a single syringe-based spray device into left nostril.
Intervention: Stabilized Isoamyl Nitrite (SIAN)
Cohort 4 SIAN
SIAN dose of 2.18 mg/kg (150 μL) will be administered from a single syringe-based spray device into left nostril.
Intervention: Stabilized Isoamyl Nitrite (SIAN)
Cohort 5 SIAN
SIAN dose of 2.90 mg/kg (200 μL) will be administered in two syringe-based spray devices, each containing 100 μL, with dose administered in left then right nostril, one device per nostril. For doses of 2.90 milligram/kilogram (200 microliter) and higher, the dose will be split equally between the two nostrils to avoid drug overflow from the nose (using two syringe-based spray devices one immediately followed by the other). Lower doses will be administered by a single device to one nostril.
Intervention: Stabilized Isoamyl Nitrite (SIAN)
Cohort 6 SIAN
SIAN dose of 3.63 mg/kg (250 μL) will be administered in two syringe-based spray devices, each containing 125 μL, with dose administered in left then right nostril, one device per nostril.
Intervention: Stabilized Isoamyl Nitrite (SIAN)
Cohort 7 SIAN
SIAN dose of 4.35 mg/kg (300 μL) will be administered in two syringe-based spray devices, each containing 150 μL, with dose administered in left then right nostril, one device per nostril.
Intervention: Stabilized Isoamyl Nitrite (SIAN)
Outcomes
Primary Outcomes
Related Serious Adverse Events (SAEs)
Time Frame: Through Day 8
Incidence of related SAEs
Methemoglobin (MetHb) level
Time Frame: Through 360 minutes post-dose
To determine the dose that will result in a 6-10% MetHb level
Secondary Outcomes
- PD Endpoint: for BP maximum change from baseline (Emax)(Through 8 hours post dose)
- PD Endpoint: Time of reaching Emax (TEmax) of MetHb(Through 360 minutes post-dose)
- PK Endpoint: Area under the concentration-time curve from time 0 to the last quantifiable concentration (AUC 0-last) of IAA(Through 59 minutes post-dose)
- PD Endpoint: Cmax of MetHb(Through 360 minutes post-dose)
- PK Endpoint: Time at which Cmax occurs (Tmax) of IAA(Through 59 minutes post-dose)
- PK Endpoint: Maximum observed concentration (Cmax) of Isoamyl Alcohol (IAA metabolite)(Through 59 minutes post-dose)
- PK Endpoint: Apparent first order terminal elimination half-life (t 1/2) of IAA(Through 59 minutes post-dose)
- PK Endpoint: Area under the concentration-time curve from time 0 to 10 minutes post-dose (AUC 0-10min) of IAA(Through 59 minutes post-dose)
- PD Endpoint: AUC0-t of MetHb(Through 360 minutes post-dose)
- PD Endpoint: t1/2 of MetHb(Through 360 minutes post-dose)
- PD Endpoint: The maximum change from baseline (Emax) of MetHb(Through 360 minutes post-dose)
- PK Endpoint: AUC 0-t plus the additional area extrapolated to infinity (AUC 0-inf) of IAA(Through 59 minutes post-dose)
- PD Endpoint: Area under the effect curve (AUEC(0-t)) of the fraction of MetHb (%)(Through 360 minutes post-dose)
- PD Endpoint: Time to recovery to baseline values for BP (mm Hg)(Through 8 hours post dose)
- Safety Endpoint: Toxicity grade 1 or higher of vital signs(Through Day 8)
- PD Endpoint: Time to recovery to baseline values of MetHb(Through 360 minutes post-dose)
- PD Endpoint: for BP maximum change from TEmax(Through 8 hours post dose)
- PD Endpoint: Emax for SpO2 by pulse oximetry(Through 8 hours post dose)
- PD Endpoint: TEmax for SpO2 by pulse oximetry(Through 8 hours post dose)
- PD Endpoint: Time to recovery to baseline SpO2 (%)(Through 8 hours post dose)
- PD Endpoint: Time to recovery to baseline for HR (beats/min)(Through 8 hours post dose)
- Safety Endpoint: Adverse Events (AEs)(Through Day 8)
- Safety Endpoint: Toxicity grade 1 or higher of clinical laboratories(Through Day 8)
- PD Endpoint: Emax for HR (heart rate) (beats/min)(Through 8 hours post dose)
- Safety Endpoint: Orthostatic Hypotension(Through 60 minutes Post-Dose)
- PD Endpoint: TEmax for HR (beats/min)(Through 8 hours post dose)