Pulmonary HypertensionPhase 1NCT01409122
Safety, Tolerability, and PK Parameters of Sodium Nitrite Inhalation Solution in Healthy Subjects
A Phase 1 study testing 15 mg sodium nitrite inhalation solution, 90 mg sodium nitrite inhalation solution and 45 mg sodium nitrite inhalation solution in people with Pulmonary Hypertension and Pulmonary Arterial Hypertension, run by Aires Pharmaceuticals, Inc. at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 56 yearsHealthy volunteers can take part
- Conditions the study is for
- Pulmonary Hypertension, Pulmonary Arterial Hypertension
- What is being tested?
- 15 mg sodium nitrite inhalation solution, 90 mg sodium nitrite inhalation solution and 45 mg sodium nitrite inhalation solution
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 42 participants
- Where
- 1 siteUnited States
- Study dates
- Jul 2011to Jan 2012
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 56 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
Who cannot join
- 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)
Show all 31Show fewer
- 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:
- systemic hormonal contraceptive (oral, implant, injection, or patch)
- intrauterine device
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
PAREXEL International Early Phase Clinical Unit - Baltimore
Baltimore, Maryland, 21225
About this study
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
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).
Read the detailed description
Pulmonary hypertension (PH) is an increase in the blood pressure (BP) in the small pulmonary vessels, arteries, veins or capillaries that results in progressive increases in right ventricular afterload, often leading to right ventricular failure and death. Pulmonary hypertension can result from a multitude of pathologies, including arterial etiologies, venous, chronic hypoxia related, thromboembolic, and other miscellaneous etiologies. In the recent Dana Point Classification, pulmonary arterial hypertension (PAH) was classified as Group 1. In Group 1 PAH, the pathologic lesion is localized to the small muscular pulmonary arteries, resulting in luminal narrowing and resistance to blood flow. Group 1 PAH includes idiopathic or sporadic PAH and heritable PAH which includes those with a family history of PAH. Associated PAH includes disease associated with connective tissue disease as well as PAH associated with congenital systemic to pulmonary shunts, portal hypertension, and human immunodeficiency virus (HIV) infection. Drug and toxin induced PAH is also in Group 1. Untreated, patients with PAH have an average life expectancy of 3 years, which declines to approximately 1 year if right heart failure is present.
Inhaled nitric oxide (NO) is a potent acute vasodilator. Its acute administration results in improved hemodynamics in the 10 to 15% of patients with PAH who demonstrate acute vasoreactivity. However, the usefulness of NO for chronic therapy is limited by the need for continuous inhalation. In patients who demonstrate vasoreactivity during an acute challenge with inhaled NO or a prostanoid challenge, therapy with calcium channel blockers has been demonstrated to result in improved symptoms and survival. In patients who do not demonstrate an acute vasodilator response, available therapies for PAH include prostanoids, endothelin receptor antagonists (ERA), and phosphodiesterase type-5 (PDE-5) inhibitors. However, the route and frequency of administration of the prostanoids, the hepatotoxicity of the ERAs, and concerns about the sustained efficacy of both the ERAs and PDE-5 inhibitors suggests that many patients with PAH could benefit from an effective therapy which offers ease of administration and a favorable toxicity profile.
Aires Pharmaceuticals, Inc. is developing a novel therapeutic, AIR001, for the treatment of PAH. The active ingredient in AIR001 is sodium nitrite, formulated in a buffered, pH-adjusted solution for nebulization. Preclinical data suggest that under the hypoxic, acidotic conditions present in the pulmonary hypertensive lung, inhaled sodium nitrite serves as a sustained release source of NO which will act as an acute pulmonary vasodilator. In addition, because decreased levels of NO have been shown to stimulate vascular remodeling, the increased NO resulting from nitrite inhalation is postulated to attenuate or reverse the pulmonary arterial remodeling process, resulting in both symptomatic improvement and pulmonary hemodynamic improvement in patients with PAH.
Preclinical experiments have shown that AIR001 by oral, IV, and inhalation routes of administration is effective in treating PAH induced by hypoxia or monocrotaline when administered as infrequently as once weekly at doses that generate plasma concentrations of approximately 1 to 10 uM and above. While the precise mechanism by which AIR001 exerts anti-hypertensive actions in PAH models remains to be elucidated, nitrite itself has been demonstrated to be metabolized to NO in animals and humans.
Single doses of AIR001 have been shown to be well tolerated in humans at dose levels that generate peak plasma concentrations (Cmax) in the target range established in preclinical models and no safety issues have been identified. AIR001 reduced PH induced by hypoxic gas inhalation in healthy volunteers at doses that are well tolerated. Preclinical and clinical data support further clinical investigation of inhaled AIR001 for the treatment of PAH. Before progressing to studies in patients with PAH, the safety and tolerability of multiple dose administration of AIR001 will be evaluated in Part A of the current study.
The PDE-5 inhibitor, sildenafil, is approved for use in patients with PAH and commonly used in the initial treatment for PAH. AIR001 is converted to NO, which increases cGMP dependent vasodilatation. Because PDE-5 inhibitors prevent the catabolism of cGMP by phosphodiesterase, it is possible that an exaggerated drug effect could be observed when AIR001 is administered to patients being treated with sildenafil. Therefore, combination safety and tolerability (in particular orthostatic effects) of escalating single doses of AIR001 will also be evaluated in combination with steady-state sildenafil in Part B of the study.
A cohort of patients with previously diagnosed PAH on stable background therapy will be assessed for safety and tolerability of multiple doses of AIR001 in Part C of the study.
Part D of the study will assess the PK, safety and tolerability of single dose AIR001 with each of three different nebulizers in a randomized crossover design.
- Being tested
- 15 mg sodium nitrite inhalation solution, 90 mg sodium nitrite inhalation solution, 45 mg sodium nitrite inhalation solution, 120 mg sodium nitrite inhalation solution, 25% MTD sodium nitrite inhalation solution
- Keywords
- vasodilator, nitric oxide, sodium nitrite, sildenafil, PDE-5, pulmonary hypertension, pulmonary arterial hypertension
- Medical subject headings
- Hypertension, Pulmonary, Pulmonary Arterial Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
15 mg sodium nitrite inhalation solutionDrug
15 mg sodium nitrite inhalation solution Q8H
90 mg sodium nitrite inhalation solutionDrug
90 mg sodium nitrite inhalation solution Q8H
45 mg sodium nitrite inhalation solutionDrug
45 mg sodium nitrite inhalation solution Q8H
120 mg sodium nitrite inhalation solutionDrug
120 mg sodium nitrite inhalation solution or placebo Q8H
25% MTD sodium nitrite inhalation solutionDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Part A Multiple Dose | Experimental | Ascending multiple dose administration (every 8 hours, [Q8H]) of AIR001 or placebo for 16 consecutive doses Receives: 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) Receives: 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. Receives: 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. Receives: Drug: 90 mg sodium nitrite inhalation solution |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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
Measured: 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.
Measured: 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.
Measured: following each dose of AIR001 with three different nebulizers
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Aug 2011 (estimated)
- Study startJul 2011
- Primary completionJan 2012
- Study completionJan 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Pulmonary HypertensionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 42 participants (actual)
Sponsor and investigators
- Lead sponsor
- Aires Pharmaceuticals, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Azra Hussaini, MD, Principal investigator, PAREXEL International - Baltimore
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01409122
- Sponsor's protocol ID
- AIR001-CS04
- Status last verified
- Nov 2012
- First submitted
- 1 Aug 2011
- Last updated
- 9 Nov 2012
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 9 Nov 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01409122
- Acronym / sponsor ID
- AIR001-CS04
- Keywords
- vasodilator, nitric oxide, sodium nitrite, sildenafil, PDE-5, pulmonary hypertension, pulmonary arterial hypertension
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 42 participants (actual)
- Lead sponsor
- Aires Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
- Study start
- Jul 2011
- Primary completion
- Jan 2012 (actual)
- Study completion
- Jan 2012 (actual)
- First posted
- 4 Aug 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Detailed description
Pulmonary hypertension (PH) is an increase in the blood pressure (BP) in the small pulmonary vessels, arteries, veins or capillaries that results in progressive increases in right ventricular afterload, often leading to right ventricular failure and death. Pulmonary hypertension can result from a multitude of pathologies, including arterial etiologies, venous, chronic hypoxia related, thromboembolic, and other miscellaneous etiologies. In the recent Dana Point Classification, pulmonary arterial hypertension (PAH) was classified as Group 1. In Group 1 PAH, the pathologic lesion is localized to the small muscular pulmonary arteries, resulting in luminal narrowing and resistance to blood flow. Group 1 PAH includes idiopathic or sporadic PAH and heritable PAH which includes those with a family history of PAH. Associated PAH includes disease associated with connective tissue disease as well as PAH associated with congenital systemic to pulmonary shunts, portal hypertension, and human immunodeficiency virus (HIV) infection. Drug and toxin induced PAH is also in Group 1. Untreated, patients with PAH have an average life expectancy of 3 years, which declines to approximately 1 year if right heart failure is present.
Inhaled nitric oxide (NO) is a potent acute vasodilator. Its acute administration results in improved hemodynamics in the 10 to 15% of patients with PAH who demonstrate acute vasoreactivity. However, the usefulness of NO for chronic therapy is limited by the need for continuous inhalation. In patients who demonstrate vasoreactivity during an acute challenge with inhaled NO or a prostanoid challenge, therapy with calcium channel blockers has been demonstrated to result in improved symptoms and survival. In patients who do not demonstrate an acute vasodilator response, available therapies for PAH include prostanoids, endothelin receptor antagonists (ERA), and phosphodiesterase type-5 (PDE-5) inhibitors. However, the route and frequency of administration of the prostanoids, the hepatotoxicity of the ERAs, and concerns about the sustained efficacy of both the ERAs and PDE-5 inhibitors suggests that many patients with PAH could benefit from an effective therapy which offers ease of administration and a favorable toxicity profile.
Aires Pharmaceuticals, Inc. is developing a novel therapeutic, AIR001, for the treatment of PAH. The active ingredient in AIR001 is sodium nitrite, formulated in a buffered, pH-adjusted solution for nebulization. Preclinical data suggest that under the hypoxic, acidotic conditions present in the pulmonary hypertensive lung, inhaled sodium nitrite serves as a sustained release source of NO which will act as an acute pulmonary vasodilator. In addition, because decreased levels of NO have been shown to stimulate vascular remodeling, the increased NO resulting from nitrite inhalation is postulated to attenuate or reverse the pulmonary arterial remodeling process, resulting in both symptomatic improvement and pulmonary hemodynamic improvement in patients with PAH.
Preclinical experiments have shown that AIR001 by oral, IV, and inhalation routes of administration is effective in treating PAH induced by hypoxia or monocrotaline when administered as infrequently as once weekly at doses that generate plasma concentrations of approximately 1 to 10 uM and above. While the precise mechanism by which AIR001 exerts anti-hypertensive actions in PAH models remains to be elucidated, nitrite itself has been demonstrated to be metabolized to NO in animals and humans.
Single doses of AIR001 have been shown to be well tolerated in humans at dose levels that generate peak plasma concentrations (Cmax) in the target range established in preclinical models and no safety issues have been identified. AIR001 reduced PH induced by hypoxic gas inhalation in healthy volunteers at doses that are well tolerated. Preclinical and clinical data support further clinical investigation of inhaled AIR001 for the treatment of PAH. Before progressing to studies in patients with PAH, the safety and tolerability of multiple dose administration of AIR001 will be evaluated in Part A of the current study.
The PDE-5 inhibitor, sildenafil, is approved for use in patients with PAH and commonly used in the initial treatment for PAH. AIR001 is converted to NO, which increases cGMP dependent vasodilatation. Because PDE-5 inhibitors prevent the catabolism of cGMP by phosphodiesterase, it is possible that an exaggerated drug effect could be observed when AIR001 is administered to patients being treated with sildenafil. Therefore, combination safety and tolerability (in particular orthostatic effects) of escalating single doses of AIR001 will also be evaluated in combination with steady-state sildenafil in Part B of the study.
A cohort of patients with previously diagnosed PAH on stable background therapy will be assessed for safety and tolerability of multiple doses of AIR001 in Part C of the study.
Part D of the study will assess the PK, safety and tolerability of single dose AIR001 with each of three different nebulizers in a randomized crossover design.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Double blind (participant, investigator)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Part A Multiple Dose | Experimental | 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 solutionAscending multiple dose administration (every 8 hours, [Q8H]) of AIR001 or placebo for 16 consecutive doses |
| Part B Single Dose with Sildenafil | Experimental | Drug: 25% MTD sodium nitrite inhalation solutionSingle escalating doses of AIR001 or placebo (Q8H, Day 4-6) administered in combination with steady-state sildenafil administration (Q8H, Days 1-6) |
| Part C, administration of AIR001 to patients with PAH | Experimental | Drug: 90 mg sodium nitrite inhalation solutionFour doses of AIR001 will be administered via nebulization to patients with PAH. |
| Part D, device crossover study | Experimental | Drug: 90 mg sodium nitrite inhalation solutionPK, safety and tolerability of single doses of AIR001 administered in a randomized order with three different nebulizers. |
Who may qualify
- Ages
- 18 to 56 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (31 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 15 mg sodium nitrite inhalation solution15 mg sodium nitrite inhalation solution Q8H | Drug | Part A Multiple Dose |
| 90 mg sodium nitrite inhalation solution90 mg sodium nitrite inhalation solution Q8H | Drug | Part A Multiple Dose, Part C, administration of AIR001 to patients with PAH, Part D, device crossover study |
| 45 mg sodium nitrite inhalation solution45 mg sodium nitrite inhalation solution Q8H | Drug | Part A Multiple Dose |
| 120 mg sodium nitrite inhalation solution120 mg sodium nitrite inhalation solution or placebo Q8H | Drug | Part A Multiple Dose |
| 25% MTD sodium nitrite inhalation solutionMultiple 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. | Drug | Part B Single Dose with Sildenafil |
Primary outcome
Safety and tolerability of ascending multiple dose AIR001 (Part A)
Time frame: 16 doses administered Q8H over 5 days
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
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
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
: 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
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
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
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
Cmax, tmax, AUC0-T, AUC0-inf, AUC%extrap, t½, CL/F, and Vz/F.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Nov 2012.
Related trials for Pulmonary Hypertension
Not yet recruitingPhase 2/3
An Open-Label Extension Study to Evaluate Inhaled Treprostinil SMI in Participants With Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease (PH-COPD)
Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease
Not yet recruitingPhase 2
Study of Treprostinil Administered Via Soft Mist Inhaler (SMI) in Participants With Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease (PH-COPD)
Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease
Active, not recruitingPhase 1
A Pilot Study of Microbiota Transplant With Antibiotic Preconditioning and Fiber Supplementation in Pulmonary Arterial Hypertension (GUT RESTORE-PAH)
Pulmonary Arterial Hypertension
RecruitingObservational study
Natural History Study of Biomarkers in Pulmonary Arterial Hypertension
Pulmonary Disease, Pulmonary Hypertension
Active, not recruitingPhase 1
Study of Intravenous ZMA001 in Healthy Subjects
Pulmonary Arterial Hypertension PAH
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Azra Hussaini, MD principal investigator
PAREXEL International - Baltimore
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing 15 mg sodium nitrite inhalation solution, 90 mg sodium nitrite inhalation solution and 45 mg sodium nitrite inhalation solution in people with Pulmonary Hypertension and Pulmonary Arterial Hypertension, run by Aires Pharmaceuticals, Inc. at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Nov 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Safety and tolerability of ascending multiple dose AIR001 (Part A) (time frame: 16 doses administered Q8H over 5 days). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Nov 2012.