ADASUVE-Lorazepam Drug-Drug Interaction

Study Overview
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Brief Summary
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This study will compare the safety and effects over time for giving both ADASUVE and lorazepam (intramuscular) compared to that of each agent given alone.

Detailed Description
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The objective of this study is to compare the safety and pharmacodynamic profiles of concomitant administration of a single dose of ADASUVE and lorazepam (IM) compared to that of each agent administered alone. Respiratory pharmacodynamics will be monitored through recordings of respirations/minute and pulse oximetry. Other pharmacodynamic safety measures will include effects on blood pressure, heart rate, sedation and psychomotor measures of attention, information processing speed, reaction time, and coordination. Initially, 4 subjects will receive lorazepam 1 mg IM + ADASUVE 10 mg open label to validate the dose regimen. After the safety data are reviewed and the dose regimen confirmed, 18 non-obese, healthy male or female volunteers between the ages of 18 and 50 will be enrolled in this double-blinded, double-dummy, randomized, 3-period cross-over drug interaction study.

Official Title
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ADASUVE®-Lorazepam Drug-Drug Interaction Study

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Lorazepam 1 mg IM
* Drug: Inhaled loxapine 10 mg
* Drug: Inhaled Placebo
* Drug: Placebo IM


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects between the ages of 18 to 50 years, inclusive. Body mass index (BMI) ≥18 and ≤32. Subjects who are willing and able to comply with the study schedule and requirements, and stay at the CRU for 9 days. Subjects who speak, read, and understand English and are willing and able to provide written informed consent on an IRB approved form prior to the initiation of any study procedures. Subjects who are in good general health prior to study participation as determined by a detailed medical history, physical examination, 12-lead ECG, blood chemistry profile, hematology, urinalysis, and in the opinion of the Principal Investigator. Female participants (if of child-bearing potential and sexually active) who agree to use a medically acceptable and effective birth control method throughout the study and for 30 days following the end of the study Male participants (if sexually active with a partner of child-bearing potential) who agree to use a medically acceptable and effective birth control method from the first dose and for 90 days following last dose of study drug. Male participants must refrain from donating sperm for the same period. Exclusion Criteria: Subject history, which includes: any cardiovascular disease or disorder; asthma, chronic obstructive lung disease, or any use of an inhaler prescribed for wheezing or bronchospasm must be excluded; sleep apnea; acute narrow-angle glaucoma; any neurological, gastrointestinal, hepatic, renal, hematologic, endocrine and/or metabolic disease or disorder; psychiatric illness or mental disorder except for short term situational anxiety or depression of < 2 years duration; any substance abuse or addiction within the last 2 years; pregnancy within the past 6 months. Subjects who have taken prescription or nonprescription medication within 7 days of Visit 2. Subjects who have had an acute illness within the last 7 days of Visit 2. Subjects who have a history of HIV positivity. Subjects who test positive for alcohol or have a positive urine drug screen. Subjects who have a history of allergy or intolerance to loxapine or amoxapine. Subjects who have a history of allergy or intolerance to lorazepam or any other benzodiazepine. Subjects who have a history of allergy or intolerance to polyethylene glycol, propylene glycol, or benzyl alcohol Female subjects who have a positive pregnancy test at screening or at admission to Visit 2, or are breastfeeding. Subjects who have received an investigational drug within 30 days prior to the Screening Visit. Subjects who have any other disease(s), by history, physical examination, or laboratory abnormalities that, in the investigator's opinion, presents undue risk to the subject or may confound the interpretation of study results. Subjects who are considered by the investigator, for any reason, to be an unsuitable candidate for receiving lorazepam or ADASUVE.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Open Label (lorazepam 1 mg + Inhaled loxapine 10 mg)<br>Inhaled Staccato loxapine 10 mg + IM lorazepam 1 mg to confirm tolerability of combined treatment | Drug: Lorazepam 1 mg IM<br>* Lorazepam 1 mg intramuscular<br>* Other names: Ativan 1 mg IM;Drug: Inhaled loxapine 10 mg<br>* Inhaled Staccato loxapine 10 mg<br>* Other names: ADASUVE 10 mg;|
| Other: Treatment Sequence ABC<br>Treatment: A = Lorazepam 1 mg IM + inhaled placebo, B = Lorazepam 1 mg IM + inhaled loxapine 10 mg, C= Placebo IM + inhaled loxapine 10 mg | Drug: Lorazepam 1 mg IM<br>* Lorazepam 1 mg intramuscular<br>* Other names: Ativan 1 mg IM;Drug: Inhaled loxapine 10 mg<br>* Inhaled Staccato loxapine 10 mg<br>* Other names: ADASUVE 10 mg;Drug: Inhaled Placebo<br>* Inhaler with no drug in it to mimic the ADASUVE inhaler<br>* Other names: Staccato Placebo;Drug: Placebo IM<br>* intramuscular placebo to mimic lorazepam 1 mg IM<br>* Other names: Saline;|
| Other: Treatment Sequence ACB<br>Treatment: A = Lorazepam 1 mg IM + inhaled placebo, B = Lorazepam 1 mg IM + inhaled loxapine 10 mg, C= Placebo IM + inhaled loxapine 10 mg | Drug: Lorazepam 1 mg IM<br>* Lorazepam 1 mg intramuscular<br>* Other names: Ativan 1 mg IM;Drug: Inhaled loxapine 10 mg<br>* Inhaled Staccato loxapine 10 mg<br>* Other names: ADASUVE 10 mg;Drug: Inhaled Placebo<br>* Inhaler with no drug in it to mimic the ADASUVE inhaler<br>* Other names: Staccato Placebo;Drug: Placebo IM<br>* intramuscular placebo to mimic lorazepam 1 mg IM<br>* Other names: Saline;|
| Other: Treatment Sequence BCA<br>Treatment: A = Lorazepam 1 mg IM + inhaled placebo, B = Lorazepam 1 mg IM + inhaled loxapine 10 mg, C= Placebo IM + inhaled loxapine 10 mg | Drug: Lorazepam 1 mg IM<br>* Lorazepam 1 mg intramuscular<br>* Other names: Ativan 1 mg IM;Drug: Inhaled loxapine 10 mg<br>* Inhaled Staccato loxapine 10 mg<br>* Other names: ADASUVE 10 mg;Drug: Inhaled Placebo<br>* Inhaler with no drug in it to mimic the ADASUVE inhaler<br>* Other names: Staccato Placebo;Drug: Placebo IM<br>* intramuscular placebo to mimic lorazepam 1 mg IM<br>* Other names: Saline;|
| Other: Treatment Sequence BAC<br>Treatment: A = Lorazepam 1 mg IM + inhaled placebo, B = Lorazepam 1 mg IM + inhaled loxapine 10 mg, C= Placebo IM + inhaled loxapine 10 mg | Drug: Lorazepam 1 mg IM<br>* Lorazepam 1 mg intramuscular<br>* Other names: Ativan 1 mg IM;Drug: Inhaled loxapine 10 mg<br>* Inhaled Staccato loxapine 10 mg<br>* Other names: ADASUVE 10 mg;Drug: Inhaled Placebo<br>* Inhaler with no drug in it to mimic the ADASUVE inhaler<br>* Other names: Staccato Placebo;Drug: Placebo IM<br>* intramuscular placebo to mimic lorazepam 1 mg IM<br>* Other names: Saline;|
| Other: Treatment Sequence CAB<br>Treatment: A = Lorazepam 1 mg IM + inhaled placebo, B = Lorazepam 1 mg IM + inhaled loxapine 10 mg, C= Placebo IM + inhaled loxapine 10 mg | Drug: Lorazepam 1 mg IM<br>* Lorazepam 1 mg intramuscular<br>* Other names: Ativan 1 mg IM;Drug: Inhaled loxapine 10 mg<br>* Inhaled Staccato loxapine 10 mg<br>* Other names: ADASUVE 10 mg;Drug: Inhaled Placebo<br>* Inhaler with no drug in it to mimic the ADASUVE inhaler<br>* Other names: Staccato Placebo;Drug: Placebo IM<br>* intramuscular placebo to mimic lorazepam 1 mg IM<br>* Other names: Saline;|
| Other: Treatment Sequence CBA<br>Treatment: A = Lorazepam 1 mg IM + inhaled placebo, B = Lorazepam 1 mg IM + inhaled loxapine 10 mg, C= Placebo IM + inhaled loxapine 10 mg | Drug: Lorazepam 1 mg IM<br>* Lorazepam 1 mg intramuscular<br>* Other names: Ativan 1 mg IM;Drug: Inhaled loxapine 10 mg<br>* Inhaled Staccato loxapine 10 mg<br>* Other names: ADASUVE 10 mg;Drug: Inhaled Placebo<br>* Inhaler with no drug in it to mimic the ADASUVE inhaler<br>* Other names: Staccato Placebo;Drug: Placebo IM<br>* intramuscular placebo to mimic lorazepam 1 mg IM<br>* Other names: Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Level of Sedation for Lorazepam 1 mg IM + ADASUVE 10 mg | Determine the maximum level of sedation for Lorazepam 1 mg IM + ADASUVE 10 mg based on the 100 mm Visual Analog Scale (VAS) ranging from (0=sleepy to 100=wide awake) | 24 hours | 
| Relative Pharmacodynamic Effect on Respiration Rate for Combined vs Individual (Lorazepam, Loxapine) | LS Mean ratio (90% CI) of the area under the curve for 0 to 24 hours (AUC 0-24) for respiration rate following administration of Lorazepam+Loxapine compared to the same measure following each control drug given alone (Lorazepam, Loxapine) | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative Pharmacodynamic Effect on Systolic Blood Pressure for Combined vs Individual (Lorazepam, Loxapine) | LS Means ratio (90% CI) of the area under the curve for 0 to 24 hours (AUC 0-24) for systolic blood pressure following administration of Lorazepam+Loxapine compared to the same measure following each control drug (Lorazepam, Loxapine) given alone | 24 hours | 
| Relative Pharmacodynamic Effect on Sedation for Combined vs Individual (Lorazepam, Loxapine) | LS Means ratio (90% CI) of the area under the curve for 0 to 24 hours (AUC 0-24) for sedation based on a 100 mm Visual Analog Scale (VAS) ranging from (0=sleepy to 100=wide awake) following administration of Lorazepam+Loxapine compared to the same measure following each control drug given alone (Lorazepam, Loxapine) | 24 hours | 
| Relative Pharmacodynamic Effect on Pulse Oximetry for Combined vs Individual (Lorazepam, Loxapine) | LS Means ratio (90% CI) of the area under the curve for 0 to 24 hours (AUC 0-24) for pulse oximetry following administration of Lorazepam+Loxapine compared to the same measure following each control drug (Lorazepam, Loxapine) given alone | 24 hours | 
| Relative Pharmacodynamic Effect on Heart Rate for Combined vs Individual (Lorazepam, Loxapine) | LS Means ratio (90% CI) of the area under the curve for 0 to 24 hours (AUC 0-24) for heart rate following administration of Lorazepam+Loxapine compared to the same measure following each control drug (Lorazepam, Loxapine) given alone | 24 hours | 
| Relative Pharmacodynamic Effect on Diastolic Blood Pressure for Combined vs Individual (Lorazepam, Loxapine) | LS Means ratio (90% CI) of the area under the curve for 0 to 24 hours (AUC 0-24) for diastolic blood pressure following administration of Lorazepam+Loxapine compared to the same measure following each control drug (Lorazepam, Loxapine) given alone | 24 hours | 
| Relative Pharmacodynamic Effect on Cogscreen Pathfinder Response for Combined vs Individual (Lorazepam, Loxapine) | LS Means ratio (90% CI) of the area under the curve for 0 to 24 hours (AUC 0-24) for Cogscreen Pathfinder Response following administration of Lorazepam+Loxapine compared to the same measure following each control drug (Lorazepam, Loxapine) given alone | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ADASUVE, inhaled loxapine, drug drug interaction, lorazepam, acute treatment of agitation