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Staccato Loxapine Single Dose PK

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00444028
Recruitment Status : Completed
First Posted : March 7, 2007
Results First Posted : November 20, 2018
Last Update Posted : November 20, 2018
Sponsor:
Information provided by (Responsible Party):
Alexza Pharmaceuticals, Inc.

Brief Summary:
The objective of this study was to assess the safety, tolerability and pharmacokinetics of a single inhaled dose of (administered in 1 or 2 puffs) Staccato Loxapine in healthy volunteers.

Condition or disease Intervention/treatment Phase
Schizophrenia Drug: inhaled Loxapine 0.625 mg Drug: inhaled Loxapine 1.25 mg Drug: inhaled Loxapine 2.5 mg Drug: inhaled Loxapine 5 mg Drug: inhaled Loxapine 10 mg Drug: inhaled Placebo (0 mg) Phase 1

Detailed Description:

Safety and pharmacokinetic data obtained from 50 subjects (between the ages of 18 to 55 years) entered into this randomized, placebo-controlled study. To obtain 50 enrolled subjects, screening procedures and inclusion/exclusion criteria were evaluated for 126 subjects during a variable screening period of up to 21 days. Once enrolled, subjects were randomized to either Staccato Loxapine or Staccato placebo.

Plasma samples for pharmacokinetic analysis were collected beginning on Day 0, pre-dose and continuing for 24 hr post dose. Blood samples for the PK analysis of loxapine and its metabolites (8-OH loxapine, 7-OH loxapine and amoxapine) were obtained at time 0 (immediately before dosing), at 30 sec, 1, 2, 3, 5, 10, 30, 45 min, 1, 2, 4, 6, 12, 24 hr after dosing. Plasma concentrations of loxapine and metabolites were used to estimate the following PK parameters for loxapine and its metabolites: area under the plasma concentration time curve from time 0 extrapolated to infinity (AUCinf), AUC from time 0 to time tlast, the last quantifiable concentration (AUClast), maximum observed plasma concentration (Cmax), observed time of Cmax (tmax), terminal phase elimination rate constant (ke), apparent terminal elimination half life calculated from ke (T½ ), apparent total body clearance / fraction absorbed calculated from AUCinf and dose (CL/F) (for loxapine and the metabolites where permitted by measurable concentrations).

Safety was evaluated by the incidence of adverse events, clinical laboratory testing (blood chemistry, hematology, and urinalysis), physical examination, vital signs, pulse oximetry, postural vital signs, 12-lead electrocardiogram, pulmonary function tests, continuous 12-lead Holter monitoring, sedation assessments, akathisia assessments.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Safety, Tolerability, and Pharmacokinetics of a Single Dose of Staccato™ Loxapine for Inhalation in Normal, Healthy Volunteers
Study Start Date : September 2005
Actual Primary Completion Date : November 2005
Actual Study Completion Date : November 2005

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia

Arm Intervention/treatment
Experimental: Cohort A: Inhaled Loxapine 0.625 mg or Placebo
Single 0.625 mg dose of inhaled loxapine or Single Placebo dose of inhaled loxapine
Drug: inhaled Loxapine 0.625 mg
Single 0.625 mg (lowest) dose of inhaled loxapine
Other Name: ADASUVE

Drug: inhaled Placebo (0 mg)
Single placebo dose of inhaled loxapine
Other Name: PLACEBO

Experimental: Cohort B: Inhaled Loxapine 1.25 mg or Placebo
Single 1.25 mg dose of inhaled loxapine or Single Placebo dose of inhaled loxapine
Drug: inhaled Loxapine 1.25 mg
Single 1.25 mg (2nd) dose of inhaled loxapine
Other Name: ADASUVE

Drug: inhaled Placebo (0 mg)
Single placebo dose of inhaled loxapine
Other Name: PLACEBO

Experimental: Cohort C: Inhaled Loxapine 2.5 mg or Placebo
Single 2.5 mg dose of inhaled loxapine or Single Placebo dose of inhaled loxapine
Drug: inhaled Loxapine 2.5 mg
Single 2.5 mg (3rd) dose of inhaled loxapine
Other Name: ADASUVE

Drug: inhaled Placebo (0 mg)
Single placebo dose of inhaled loxapine
Other Name: PLACEBO

Experimental: Cohort D: Inhaled Loxapine 5 mg or Placebo
Single 5 mg dose of inhaled loxapine or Single Placebo dose of inhaled loxapine
Drug: inhaled Loxapine 5 mg
Single 5 mg (4th) dose of inhaled loxapine
Other Name: ADASUVE

Drug: inhaled Placebo (0 mg)
Single placebo dose of inhaled loxapine
Other Name: PLACEBO

Experimental: Cohort E: Inhaled Loxapine 10 mg or Placebo
Single 10 mg dose of inhaled loxapine or Single Placebo dose of inhaled loxapine
Drug: inhaled Loxapine 10 mg
Single 10 mg (5th) dose of inhaled loxapine
Other Name: ADASUVE

Drug: inhaled Placebo (0 mg)
Single placebo dose of inhaled loxapine
Other Name: PLACEBO




Primary Outcome Measures :
  1. Tmax [ Time Frame: predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours ]
    Tmax = time from inhalation to to maximum observed loxapine concentration

  2. Half-life [ Time Frame: predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours ]
    Half-life of the terminal elimination phase of loxapine concentrations

  3. ke [ Time Frame: predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours ]
    elimination rate constant

  4. Clearance [ Time Frame: predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours ]
    clearance (CL/F) of lozxapine

  5. Cmax [ Time Frame: predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours ]
    maximum concentration of loxapine observed

  6. Dose Proportionality (AUCinf) by Power Analysis [ Time Frame: predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours ]
    Dose proportionality by power analysis examines the linear regression of the log-AUC versus log-Dose on a by-patient basis across all doses administered. The slope and 90% confidence interval (CI) provide a clear, quantitative (best practices) assessment of the relationship of drug delivered to dose administered. The units on such analyses are generally those of slope (rise over run), with 1.000 being "perfect". Although any positive slope might be considered clinically useful, a 90% CI within the criteria of 0.800-1.250 may be considered a delivery system which is "as good as it gets".



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Male and female subjects between the ages of 18 to 55 years, inclusive.
  2. Subjects with a body mass index (BMI) ≥21 and ≤30.
  3. 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.
  4. Subjects who are willing and able to be confined to the Clinical Research Unit (CRU) for approximately 2 days and comply with the study schedule and study requirements.
  5. Subjects who are in good general health as determined by a complete medical history, physical examination, 12-lead ECG, spirometry, blood chemistry profile, hematology, and urinalysis.

Exclusion Criteria:

  1. Subjects who regularly consume large amounts of xanthine-containing substances (i.e., more than 5 cups of coffee or equivalent amounts of xanthine-containing substances per day).
  2. Subjects who have taken prescription or nonprescription medication (with the exception of vitamins and acetaminophen if medically necessary) within 5 days of Visit 2 (Baseline).
  3. Subjects who have had an acute illness within 5 days of Visit 2 (Baseline).
  4. Subjects who have received an investigational drug within 30 days (or within 5 half lives of the investigational drug, if >30 days) prior to Visit 2 (Baseline).
  5. Subjects who have smoked tobacco within the last year.
  6. Subjects who have a history within the past 2 years of drug or alcohol dependence or abuse as defined by DSM-4.
  7. Subjects with a history of HIV positivity.
  8. Subjects with a history of allergy or intolerance to dibenzoxazepines (amoxapine and loxapine).
  9. Subjects with a known history of contraindications to anticholinergics (bowel obstructions, urinary retention, acute glaucoma).
  10. Subjects with a history of pheochromocytoma, seizure disorder, Parkinson's disease, or Restless Leg Syndrome (RLS).
  11. Subjects who test positive for alcohol or have a positive urine drug screen at Visit 1 or Visit 2.
  12. Subjects who have hypotension (systolic blood pressure ≤90 mmHg, diastolic blood pressure ≤50 mmHg), or hypertension (systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg).
  13. Subjects who have a clinically significant ECG abnormality.
  14. Subjects with a history of unstable angina, syncope, coronary artery disease, myocardial infarction, congestive heart failure (CHF), stroke, transient ischemic attack (TIA), or a neurological disorder.
  15. Subjects who have a history of pulmonary disease that precludes administration of Staccato Loxapine (asthma, bronchitis, bronchospasm, emphysema).
  16. Subjects who have an FEV1 less than 80% of predicted values on spirometry assessments at Visit 1.
  17. Female subjects who are breastfeeding or have a positive pregnancy test at Visit 1 or Visit 2.
  18. Female participants of child-bearing potential or within 1 year of menopause, and sexually active are excluded unless they use a medically acceptable and effective birth control method throughout the study and for 1 week following the end of the study. Medically acceptable methods of contraception include abstinence, diaphragm with spermicide, intrauterine device (IUD), condom with foam or spermicide, vaginal spermicidal suppository, surgical sterilization, and birth control pills. Unacceptable methods include: the rhythm method, withdrawal, condoms alone, or diaphragm alone.
  19. Subjects who have any other disease or condition, by history, physical examination, or laboratory abnormalities that in the investigator's opinion, would present undue risk to the subject, or may confound the interpretation of study results.

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): NCT00444028


Locations
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United States, Indiana
Covance Clinical Research Unit Inc., d/b/a Covance GFI Research
Evansville, Indiana, United States, 47714
Sponsors and Collaborators
Alexza Pharmaceuticals, Inc.
Investigators
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Principal Investigator: Randall Stoltz, MD West Pharmaceutical Services, GFI Research Center, Evansville, IN 47714

Publications of Results:
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Responsible Party: Alexza Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT00444028    
Other Study ID Numbers: AMDC-004-101
First Posted: March 7, 2007    Key Record Dates
Results First Posted: November 20, 2018
Last Update Posted: November 20, 2018
Last Verified: March 2007
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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alexza Pharmaceuticals, Inc.:
Schizophrenia, Staccato Loxapine
Additional relevant MeSH terms:
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Schizophrenia
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Loxapine
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Psychotropic Drugs
Dopamine Antagonists
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action