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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Aires Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
NCT01409122
First received: August 1, 2011
Last updated: November 8, 2012
Last verified: November 2012
  Purpose

This is a four-part study of the safety, tolerability, and PK profile of sodium nitrite inhalation solution (AIR001) of ascending multiple doses (Part A) and of escalating doses with steady-state sildenafil (Part B) to healthy male and female subjects, as well as assessment of the safety and tolerability of multiple doses of AIR001 to patients with pulmonary arterial hypertension (part C) with a single dose PK study of AIR001 utilizing three different nebulizers (Part D).


Condition Intervention Phase
Pulmonary Hypertension
Pulmonary Arterial Hypertension
Drug: 15 mg sodium nitrite inhalation solution
Drug: 90 mg sodium nitrite inhalation solution
Drug: 45 mg sodium nitrite inhalation solution
Drug: 120 mg sodium nitrite inhalation solution
Drug: 25% MTD sodium nitrite inhalation solution
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official 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

Resource links provided by NLM:


Further study details as provided by Aires Pharmaceuticals, Inc.:

Primary Outcome Measures:
  • Safety and tolerability of ascending multiple dose AIR001 (Part A) [ Time Frame: 16 doses administered Q8H over 5 days ] [ Designated as safety issue: Yes ]

    To evaluate the safety and tolerability of ascending multiple dose administration (every 8 hours, [Q8H]) of AIR001 for 16 consecutive doses

    • Adverse Events
    • 12 lead ECG
    • Vital Signs (change in supine BP, Pulse Rate and change in orthostatic BP)
    • Venous Methemoglobin
    • Spirometry
    • Percutaneous Saturation of Oxygen and Methemoglobin concentrations
    • Plasma cGMP

  • 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 ] [ Designated as safety issue: Yes ]

    To evaluate the safety and tolerability of single escalating doses of AIR001 when administered in combination with steady-state sildenafil administration.

    • Adverse Events
    • 12 lead ECG
    • Vital Signs (change in supine BP, Pulse Rate and change in orthostatic BP)
    • Venous Methemoglobin
    • Spirometry
    • Percutaneous Saturation of Oxygen and Methemoglobin concentrations
    • Plasma cGMP

  • 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 ] [ Designated as safety issue: Yes ]
    Cmax, tmax, AUC0-T, AUC0-inf, AUC%extrap, t½, CL/F, and Vz/F.

  • 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 ] [ Designated as safety issue: Yes ]
    : Cmax, tmax, AUC0-T, AUC0-inf, AUC%extrap, t½,CL/F, and Vz/F.

  • 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 ] [ Designated as safety issue: Yes ]

    To evaluate the safety and tolerability of multiple doses of AIR001 when administered in combination with steady-state background PAH medications in patients with PAH.

    • Adverse Events
    • 12 lead ECG
    • Vital Signs (change in supine BP, Pulse Rate and change in orthostatic BP)
    • Venous Methemoglobin
    • Spirometry
    • Percutaneous Saturation of Oxygen and Methemoglobin concentrations

  • 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 ] [ Designated as safety issue: Yes ]

    To evaluate the safety and tolerability of single doses of AIR001 when administered in a randomized fashion with each of three different nebulizers in healthy volunteers.

    • Adverse Events
    • 12 lead ECG
    • Vital Signs (change in supine BP, Pulse Rate and change in orthostatic BP)
    • Venous Methemoglobin
    • Spirometry
    • Percutaneous Saturation of Oxygen and Methemoglobin concentrations

  • 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 ] [ Designated as safety issue: Yes ]
    Cmax, tmax, AUC0-T, AUC0-inf, AUC%extrap, t½, CL/F, and Vz/F.

  • Composite PK for Plasma Nitrite and Nitrate(Part D) [ Time Frame: following each dose of AIR001 with three different nebulizers ] [ Designated as safety issue: Yes ]
    Cmax, tmax, AUC0-T, AUC0-inf, AUC%extrap, t½, CL/F, and Vz/F.


Enrollment: 42
Study Start Date: July 2011
Study Completion Date: January 2012
Primary Completion Date: January 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part A Multiple Dose
Ascending multiple dose administration (every 8 hours, [Q8H]) of AIR001 or placebo for 16 consecutive doses
Drug: 15 mg sodium nitrite inhalation solution
15 mg sodium nitrite inhalation solution Q8H
Drug: 90 mg sodium nitrite inhalation solution
90 mg sodium nitrite inhalation solution Q8H
Drug: 45 mg sodium nitrite inhalation solution
45 mg sodium nitrite inhalation solution Q8H
Drug: 120 mg sodium nitrite inhalation solution
120 mg sodium nitrite inhalation solution or placebo Q8H
Experimental: Part B Single Dose with Sildenafil
Single escalating doses of AIR001 or placebo (Q8H, Day 4-6) administered in combination with steady-state sildenafil administration (Q8H, Days 1-6)
Drug: 25% MTD sodium nitrite inhalation solution
Multiple oral doses of 20 mg sildenafil will be administered open-label Q8H to a single cohort of eight subjects on Days 1 to 6. A single dose of sodium nitrite inhalation solution equal to 25% of the maximum tolerated dose (MTD) identified in Part A (or placebo) will be administered on Day 4, a single dose equal to 50% of the MTD (or placebo) will be administered on Day 5, and a single dose equal to 100% of the MTD (or placebo) will be administered on Day 6.
Experimental: Part C, administration of AIR001 to patients with PAH
Four doses of AIR001 will be administered via nebulization to patients with PAH.
Drug: 90 mg sodium nitrite inhalation solution
90 mg sodium nitrite inhalation solution Q8H
Experimental: Part D, device crossover study
PK, safety and tolerability of single doses of AIR001 administered in a randomized order with three different nebulizers.
Drug: 90 mg sodium nitrite inhalation solution
90 mg sodium nitrite inhalation solution Q8H

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 56 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01409122

Locations
United States, Maryland
PAREXEL International Early Phase Clinical Unit - Baltimore
Baltimore, Maryland, United States, 21225
Sponsors and Collaborators
Aires Pharmaceuticals, Inc.
Investigators
Principal Investigator: Azra Hussaini, MD PAREXEL International - Baltimore
  More Information

No publications provided

Responsible Party: Aires Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT01409122     History of Changes
Other Study ID Numbers: AIR001-CS04
Study First Received: August 1, 2011
Last Updated: November 8, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Aires Pharmaceuticals, Inc.:
vasodilator
nitric oxide
sodium nitrite
sildenafil
PDE-5
pulmonary hypertension
pulmonary arterial hypertension

Additional relevant MeSH terms:
Hypertension, Pulmonary
Hypertension
Lung Diseases
Respiratory Tract Diseases
Vascular Diseases
Cardiovascular Diseases
Pharmaceutical Solutions
Sildenafil
Therapeutic Uses
Pharmacologic Actions
Vasodilator Agents
Cardiovascular Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents

ClinicalTrials.gov processed this record on July 31, 2014