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ADASUVE-Lorazepam Drug-Drug Interaction

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ClinicalTrials.gov Identifier: NCT01877642
Recruitment Status : Completed
First Posted : June 14, 2013
Results First Posted : December 13, 2017
Last Update Posted : December 13, 2017
Sponsor:
Information provided by (Responsible Party):
Alexza Pharmaceuticals, Inc.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Healthy Volunteers Drug: Lorazepam 1 mg IM Drug: Inhaled loxapine 10 mg Drug: Inhaled Placebo Drug: Placebo IM Phase 4

Detailed Description:

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 22 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Other
Official Title: ADASUVE®-Lorazepam Drug-Drug Interaction Study
Study Start Date : June 2013
Actual Primary Completion Date : July 2013
Actual Study Completion Date : July 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Drug Reactions

Arm Intervention/treatment
Open Label (lorazepam 1 mg + Inhaled loxapine 10 mg)
Inhaled Staccato loxapine 10 mg + IM lorazepam 1 mg to confirm tolerability of combined treatment
Drug: Lorazepam 1 mg IM
Lorazepam 1 mg intramuscular
Other Name: Ativan 1 mg IM

Drug: Inhaled loxapine 10 mg
Inhaled Staccato loxapine 10 mg
Other Name: ADASUVE 10 mg

Treatment Sequence ABC
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
Lorazepam 1 mg intramuscular
Other Name: Ativan 1 mg IM

Drug: Inhaled loxapine 10 mg
Inhaled Staccato loxapine 10 mg
Other Name: ADASUVE 10 mg

Drug: Inhaled Placebo
Inhaler with no drug in it to mimic the ADASUVE inhaler
Other Name: Staccato Placebo

Drug: Placebo IM
intramuscular placebo to mimic lorazepam 1 mg IM
Other Name: Saline

Treatment Sequence ACB
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
Lorazepam 1 mg intramuscular
Other Name: Ativan 1 mg IM

Drug: Inhaled loxapine 10 mg
Inhaled Staccato loxapine 10 mg
Other Name: ADASUVE 10 mg

Drug: Inhaled Placebo
Inhaler with no drug in it to mimic the ADASUVE inhaler
Other Name: Staccato Placebo

Drug: Placebo IM
intramuscular placebo to mimic lorazepam 1 mg IM
Other Name: Saline

Treatment Sequence BCA
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
Lorazepam 1 mg intramuscular
Other Name: Ativan 1 mg IM

Drug: Inhaled loxapine 10 mg
Inhaled Staccato loxapine 10 mg
Other Name: ADASUVE 10 mg

Drug: Inhaled Placebo
Inhaler with no drug in it to mimic the ADASUVE inhaler
Other Name: Staccato Placebo

Drug: Placebo IM
intramuscular placebo to mimic lorazepam 1 mg IM
Other Name: Saline

Treatment Sequence BAC
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
Lorazepam 1 mg intramuscular
Other Name: Ativan 1 mg IM

Drug: Inhaled loxapine 10 mg
Inhaled Staccato loxapine 10 mg
Other Name: ADASUVE 10 mg

Drug: Inhaled Placebo
Inhaler with no drug in it to mimic the ADASUVE inhaler
Other Name: Staccato Placebo

Drug: Placebo IM
intramuscular placebo to mimic lorazepam 1 mg IM
Other Name: Saline

Treatment Sequence CAB
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
Lorazepam 1 mg intramuscular
Other Name: Ativan 1 mg IM

Drug: Inhaled loxapine 10 mg
Inhaled Staccato loxapine 10 mg
Other Name: ADASUVE 10 mg

Drug: Inhaled Placebo
Inhaler with no drug in it to mimic the ADASUVE inhaler
Other Name: Staccato Placebo

Drug: Placebo IM
intramuscular placebo to mimic lorazepam 1 mg IM
Other Name: Saline

Treatment Sequence CBA
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
Lorazepam 1 mg intramuscular
Other Name: Ativan 1 mg IM

Drug: Inhaled loxapine 10 mg
Inhaled Staccato loxapine 10 mg
Other Name: ADASUVE 10 mg

Drug: Inhaled Placebo
Inhaler with no drug in it to mimic the ADASUVE inhaler
Other Name: Staccato Placebo

Drug: Placebo IM
intramuscular placebo to mimic lorazepam 1 mg IM
Other Name: Saline




Primary Outcome Measures :
  1. Maximum Level of Sedation for Lorazepam 1 mg IM + ADASUVE 10 mg [ Time Frame: 24 hours ]
    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)

  2. Relative Pharmacodynamic Effect on Respiration Rate for Combined vs Individual (Lorazepam, Loxapine) [ Time Frame: 24 hours ]
    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)


Secondary Outcome Measures :
  1. Relative Pharmacodynamic Effect on Systolic Blood Pressure for Combined vs Individual (Lorazepam, Loxapine) [ Time Frame: 24 hours ]
    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

  2. Relative Pharmacodynamic Effect on Sedation for Combined vs Individual (Lorazepam, Loxapine) [ Time Frame: 24 hours ]
    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)

  3. Relative Pharmacodynamic Effect on Pulse Oximetry for Combined vs Individual (Lorazepam, Loxapine) [ Time Frame: 24 hours ]
    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

  4. Relative Pharmacodynamic Effect on Heart Rate for Combined vs Individual (Lorazepam, Loxapine) [ Time Frame: 24 hours ]
    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

  5. Relative Pharmacodynamic Effect on Diastolic Blood Pressure for Combined vs Individual (Lorazepam, Loxapine) [ Time Frame: 24 hours ]
    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

  6. Relative Pharmacodynamic Effect on Cogscreen Pathfinder Response for Combined vs Individual (Lorazepam, Loxapine) [ Time Frame: 24 hours ]
    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



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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01877642


Locations
United States, Indiana
Covance-Evansville
Evansville, Indiana, United States, 47710
Sponsors and Collaborators
Alexza Pharmaceuticals, Inc.
Investigators
Principal Investigator: Randall R Stoltz, MD Medical Director, Covance-Evansville, Evansville, IN 47710

Publications of Results:
Responsible Party: Alexza Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT01877642     History of Changes
Other Study ID Numbers: AMDC-204-402
First Posted: June 14, 2013    Key Record Dates
Results First Posted: December 13, 2017
Last Update Posted: December 13, 2017
Last Verified: July 2013
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD submitted to regulatory authorities. Others may contact Alexza Pharmaceuticals, Inc. Please send your request to ClinicalTrialsInfo@alexza.com

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Alexza Pharmaceuticals, Inc.:
ADASUVE
inhaled loxapine
drug drug interaction
lorazepam
acute treatment of agitation

Additional relevant MeSH terms:
Lorazepam
Loxapine
Anticonvulsants
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Hypnotics and Sedatives
Central Nervous System Depressants
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antipsychotic Agents
Dopamine Antagonists
Dopamine Agents