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

NCT01409122 | Completed Phase 1

• 1 other identifier: AIR001-CS04
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Pulmonary Hypertension; Pulmonary Arterial Hypertension

Keywords

vasodilator; nitric oxide; sodium nitrite; sildenafil; PDE-5; pulmonary hypertension; pulmonary arterial hypertension

Outcome Measures

Primary Outcomes (8)

• Safety and tolerability of ascending multiple dose AIR001 (Part A)

  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

  16 doses administered Q8H over 5 days

• Safety and tolerability of single escalating doses of AIR001 with sildenafil (Part B)

  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

  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(Part A)

  Cmax, tmax, AUC0-T, AUC0-inf, AUC%extrap, t½, CL/F, and Vz/F.

  following 1st dose of AIR001 on Day 1 and final dose on Day 6

• Composite PK for Plasma Nitrite and Nitrate in the presence of steady state Sildenafil(Part B)

  : Cmax, tmax, AUC0-T, AUC0-inf, AUC%extrap, t½,CL/F, and Vz/F.

  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)

  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

  Multiple doses of sodium nitrite inhalation solution over 10 min for a total of 4 doses

• Safety and tolerability of single doses of AIR001 administered to healthy subjects with each of three different nebulizers (PART D)

  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

  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)

  Cmax, tmax, AUC0-T, AUC0-inf, AUC%extrap, t½, CL/F, and Vz/F.

  following 1st dose of AIR001 on Day 1 and final dose on Day 2

• Composite PK for Plasma Nitrite and Nitrate(Part D)

  Cmax, tmax, AUC0-T, AUC0-inf, AUC%extrap, t½, CL/F, and Vz/F.

  following each dose of AIR001 with three different nebulizers

Study Arms (4)

Part A Multiple Dose

EXPERIMENTAL

Ascending multiple dose administration (every 8 hours, \[Q8H\]) of AIR001 or placebo for 16 consecutive doses

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

Part B Single Dose with Sildenafil

EXPERIMENTAL

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

Part C, administration of AIR001 to patients with PAH

EXPERIMENTAL

Four doses of AIR001 will be administered via nebulization to patients with PAH.

Drug: 90 mg sodium nitrite inhalation solution

Part D, device crossover study

EXPERIMENTAL

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

Interventions

15 mg sodium nitrite inhalation solution DRUG

15 mg sodium nitrite inhalation solution Q8H

Part A Multiple Dose

90 mg sodium nitrite inhalation solution DRUG

90 mg sodium nitrite inhalation solution Q8H

Part A Multiple Dose; Part C, administration of AIR001 to patients with PAH; Part D, device crossover study

45 mg sodium nitrite inhalation solution DRUG

45 mg sodium nitrite inhalation solution Q8H

Part A Multiple Dose

120 mg sodium nitrite inhalation solution DRUG

120 mg sodium nitrite inhalation solution or placebo Q8H

Part A Multiple Dose

25% MTD sodium nitrite inhalation solution DRUG

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.

Part B Single Dose with Sildenafil

Eligibility Criteria

• Age: 18 Years - 56 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Aires Pharmaceuticals, Inc.: lead

Study Sites (1)

PAREXEL International Early Phase Clinical Unit - Baltimore

Baltimore, Maryland, 21225, United States

Location

MeSH Terms

Conditions

Hypertension, Pulmonary; Pulmonary Arterial Hypertension

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases

Study Officials

• Azra Hussaini, MD

  PAREXEL International - Baltimore

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 1, 2011
• First Posted: August 4, 2011
• Study Start: July 1, 2011
• Primary Completion: January 1, 2012
• Study Completion: January 1, 2012
• Last Updated: November 9, 2012

Record last verified: 2012-11

Locations

US (1)