Safety, Tolerability, and PK Parameters of Sodium Nitrite Inhalation Solution in Healthy Subjects

• Register: ClinicalTrials.gov
• Last refreshed on: 19 February 2015
• Main ID: NCT01409122
• Date of registration: 01/08/2011
• Prospective Registration: No
• Primary sponsor: Aires Pharmaceuticals, Inc.
• Public title: Safety, Tolerability, and PK Parameters of Sodium Nitrite Inhalation Solution in Healthy Subjects
• Scientific title: A Phase 1, Placebo Controlled, Blinded, Multiple Dose Escalation Study of AIR001 (Sodium Nitrite Inhalation Solution) in Healthy Subjects, an Assessment of the Tolerability in Combination With Oral Sildenafil, and an Open-Label Study of Multiple Dose AIR001 in Patients With Pulmonary Arterial Hypertension
• Date of first enrolment: July 2011
• Target sample size: 42
• Recruitment status: Completed
• URL: http://clinicaltrials.gov/show/NCT01409122
• Study type: Interventional
• Study design: Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
• Phase: Phase 1

Countries of recruitment

United States

Contacts

• Name: Azra Hussaini, MD
• Affiliation: PAREXEL International - Baltimore

Key inclusion & exclusion criteria

Inclusion Criteria:

- Be informed of the nature of the study and is able to understand and has provided
written informed voluntary consent

- Be healthy males or females, of any race, at least 18 years of age or the legal age
of consent (whichever is greater) and less than 56 years of age at the time of the
first dose of study drug (or sildenafil)

- Have a body mass index (BMI) >=18.0 and <32.0 kg/m2 and weigh at least 50 kg

- Be in good general health with no clinically relevant abnormalities based on the
medical history, physical examination, clinical laboratory evaluations (hematology,
clinical chemistry, urinalysis, methemoglobin), and 12-lead ECG that, in the opinion
of the Investigator, would affect subject safety

- Agree to comply with the study procedures and restrictions

Exclusion Criteria:

- Any disease or condition that might affect drug absorption, metabolism, or excretion,
or clinically significant cardiovascular, ocular, hematological, renal, hepatic,
pulmonary, endocrine, gastrointestinal, immunological, dermatological, neurological,
or psychiatric disease

- Clinically significant illness (including lower respiratory tract infection) or
clinically significant surgery within 4 weeks before the administration of study drug
(or sildenafil)

- Use of any commercially marketed mouthwash or oral rinse with agents other than tap
water as well as tongue brushing or scraping from screening onwards through
completion of study

- Currently a smoker or has a past history of smoking (of >10 pack years)

- History of bronchial asthma or sleep apnea

- Evidence of restrictive or obstructive lung disease (Forced Expiratory Volume in 1
second (FEV1)/Forced Vital Capacity (FVC) <70%, FEV1 <70% predicted, and/or FVC <70%
predicted)

- Family history of primary PH

- History of pulmonary embolism

- Evidence of supine hypertension or hypotension (systolic BP >180 mmHg or <90 mmHg
and/or diastolic BP> 100 mmHg or <50 mmHg) pre-dose [NOTE: BP measurements may be
repeated twice, at least 10 minutes apart]

- Orthostatic hypotension defined as a drop in systolic BP by >=20 mmHg or diastolic BP
of >=10 mmHg at screening or predose or the development of significant postural
symptoms (dizziness, lightheadedness, vertigo) when going from the supine to the
standing position

- Personal or family history of congenital or acquired methemoglobinemia

- Personal or family history of RBC CYP B5 reductase deficiency

- Personal or family history or any evidence of hemoglobinopathy

- Known or suspected hypersensitivity or allergic reaction to sodium nitrite, sodium
nitrate, or saccharin

- Glucose-6-phosphate dehydrogenase (G6PD) deficiency or any contraindication to
receiving methylene blue

- History of hypersensitivity or idiosyncratic reaction to drugs from multiple drug
classes

- If female, is pregnant or breast feeding, or has a positive pregnancy test result
pre-dose

- If a sexually active female, is not surgically sterile (defined as having had a
hysterectomy, bilateral oophorectomy, or tubal ligation at least 6 months prior to
screening) or post-menopausal (defined as amenorrhea for the past 2 years if <50
years of age or for the past 1 year if <=50 years or, if on hormone replacement
therapy [HRT], documented follicle stimulating hormone [FSH] >30 IU/L before starting
HRT), or does not agree to utilize two effective methods of contraception
consistently and as intended from screening until at least 4 weeks after the last
dose of study drug. Subjects must use a barrier method (diaphragm with intravaginal
spermicide, cervical cap with intravaginal spermicide, or partner using condoms plus
use of intravaginal spermicide) in combination with at least one of the following
methods of contraception:

1. systemic hormonal contraceptive (oral, implant, injection, or patch)

2. intrauterine device

3. or male partner who has undergone a vasectomy at least 6 months prior to
screening.

- Unless approved by the Sponsor, chronic use of any systemic medications (with the
exception of systemic hormonal contraceptives and vitamins taken at standard
supplement doses); use of a drug therapy (including herbal preparations, e.g., St.
John's wort) known to induce or inhibit hepatic drug metabolism within 30 days before
the first dose of study drug (or sildenafil); use of prescription medication within
14 days before administration of study drug (or sildenafil) or over-the-counter [OTC]
products (including natural products, vitamins) within 7 days before administration
of study drug (or sildenafil). By exception, topical products without systemic
absorption will be allowed. (NOTE: in particular, use of any PDE-5 inhibitor [e.g.,
sildenafil, tadalafil, vardenafil] is prohibited)

- Current history or evidence of drug abuse, history of regular alcohol consumption
exceeding 21 drinks/week for men and 14 drinks/week for women (1 drink = 5 ounces
[150 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor)
within 6 months of screening or a positive screen for substances of abuse or alcohol
at screening or pre-dose

- Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C antibody, or HIV
antibody

- Receipt of an investigational product or device, or participation in a drug research
study within a period of 30 days (or 5 half-lives of the drug, whichever is longer)
before the first dose of study drug (sildenafil)

- Blood loss or blood donation of >550 mL within 90 days or plasma donation >500 mL
within 14 days before administration of study drug (or sildenafil)

- Any food allergy, intolerance, restriction, or special diet that, in the opinion of
the Investigator, should preclude the subject's participation in this study

Part B Only:

- Known or suspected hypersensitivity or allergic reaction to sildenafil or other
therapeutics of similar chemical structure or any of the components of Revatio®
tablets

- Any medical condition that constitutes a contraindication or risk to taking
sildenafil, including a history of hereditary degenerative retinal disorders such as
retinitis pigmentosa

- Ingestion of grapefruit or grapefruit juice within 72 hours before sildenafil
administration



Age minimum: 18 Years
Age maximum: 56 Years
Gender: Both

Health Condition(s) or Problem(s) studied

Pulmonary Arterial Hypertension

Pulmonary Hypertension

Intervention(s)

Drug: 90 mg sodium nitrite inhalation solution

Drug: 45 mg sodium nitrite inhalation solution

Drug: 25% MTD sodium nitrite inhalation solution

Drug: 120 mg sodium nitrite inhalation solution

Drug: 15 mg sodium nitrite inhalation solution

Primary Outcome(s)

Safety and tolerability of ascending multiple dose AIR001 (Part A) [Time Frame: 16 doses administered Q8H over 5 days]

Composite PK for Plasma Nitrite and Nitrate(Part D) [Time Frame: following each dose of AIR001 with three different nebulizers]

Composite PK for Plasma Nitrite and Nitrate(Part A) [Time Frame: following 1st dose of AIR001 on Day 1 and final dose on Day 6]

Safety and tolerability of single escalating doses of AIR001 with sildenafil (Part B) [Time Frame: 20 mg sildenafil Q8H for Days 1-6, single dose sodium nitrite inhalation solution over 10 min Days 4-6]

Composite PK for Plasma Nitrite and Nitrate in the presence of steady state Sildenafil(Part B) [Time Frame: Following the third dose of AIR001 on Day 5,6,7]

Safety and tolerability of multiple doses of AIR001 administered to patients with PAH (PART C) [Time Frame: Multiple doses of sodium nitrite inhalation solution over 10 min for a total of 4 doses]

Composite PK for Plasma Nitrite and Nitrate(Part C) [Time Frame: following 1st dose of AIR001 on Day 1 and final dose on Day 2]

Safety and tolerability of single doses of AIR001 administered to healthy subjects with each of three different nebulizers (PART D) [Time Frame: Multiple doses of sodium nitrite inhalation solution over 10 min for a total of 4 doses]

Secondary ID(s)

AIR001-CS04

Source(s) of Monetary Support

Please refer to primary and secondary sponsors