Staccato Alprazolam Abuse Liability

• Sponsor: Alexza Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00603980
• Collaborator: (none)
• Enrollment: 31
• Location: 1
• Arms: 14
• Duration (Months): 12
• Patients Per Site Per Month: 2.6

Study Details

Study Description

Brief Summary

Compare the abuse liabilities of Staccato Alprazolam, oral immediate-release alprazolam, and Staccato Placebo.

Condition or Disease	Intervention/Treatment	Phase
Abuse Liability of Staccato Alprazolam	Drug: Inhaled placebo + oral placebo; Drug: Inhaled alprazolam 0.5 mg; Drug: Inhaled alprazolam 1 mg; Drug: Inhaled alprazolam 2 mg; Drug: Oral alprazolam 1 mg; Drug: Oral alprazolam 2 mg; Drug: Oral alprazolam 4 m; Drug: Oral alprazolam 2 mg qualifying session; Drug: Oral placebo qualifying session	Phase 1

Detailed Description

The Phase 1 clinical study compared the abuse liabilities of Staccato Alprazolam, oral immediate-release alprazolam, and Staccato Placebo in 14 subjects with a history of sedative abuse. Subjects who met the inclusion/exclusion criteria received 2 mg of oral alprazolam and matching placebo over 2 sessions. Those who demonstrated greater liking for alprazolam versus placebo were eligible to participate in the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: The crossover schedule is planned according to a 7-treatment, 7-period Latin Square design due to E.J. Williams (1949), which is balanced for first-order carryover effects (Fleiss, 1986). Each subject will receive all treatments in this 7-treatment, 7- period Williams Square crossover design as suggested by Chen & Tsong (2007). This Williams Square will include one replication by 1 subject of each of the 14 sequencesThe crossover schedule is planned according to a 7-treatment, 7-period Latin Square design due to E.J. Williams (1949), which is balanced for first-order carryover effects (Fleiss, 1986). Each subject will receive all treatments in this 7-treatment, 7- period Williams Square crossover design as suggested by Chen & Tsong (2007). This Williams Square will include one replication by 1 subject of each of the 14 sequences
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: In order to reduce discrimination between placebo and active Staccato Alprazolam, taste blinding will be accomplished using a rapidly dissolving, intensely flavored product (candy, strip or breath spray). The product will be administered immediately after each oral capsule dosing (at the -60-min and 0- min time points).
• Primary Purpose: Treatment
• Official Title: Abuse Liability Study of Staccato® Alprazolam for Inhalation in Subjects With Histories of Sedative Abuse
• Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: Jan 1, 2009
• Actual Study Completion Date: Jan 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Other: Treatment sequence 1 Sequence 1: Q, 1, 2, 7, 3, 6, 4, 5; where Q=Qualifying sessions (2 mg oral alprazolam and placebo in random order), 1=placebo, 2=oral alprazolam 1 mg, 3= oral alprazolam 2 mg, 4= oral alprazolam 4 mg, 5= inhaled alprazolam 0.5 mg, 6= inhaled alprazolam 1 mg, 7= inhaled alprazolam 2 mg	Drug: Inhaled placebo + oral placebo; Inhaled Staccato placebo + oral placebo; Drug: Inhaled alprazolam 0.5 mg; Inhaled Staccato alprazolam 0.5 mg + oral placebo; Drug: Inhaled alprazolam 1 mg; Inhaled Staccato alprazolam 1 mg + oral placebo; Drug: Inhaled alprazolam 2 mg; Inhaled Staccato alprazolam 2 mg + oral placebo; Drug: Oral alprazolam 1 mg; Oral alprazolam 1 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg; Oral alprazolam 2 mg + Inhaled placebo; Drug: Oral alprazolam 4 m; Oral alprazolam 4 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg qualifying session; Qualifying session (2 mg oral alprazolam); Drug: Oral placebo qualifying session; Qualifying control session (oral placebo)
Other: Treatment sequence 2 Sequence Q, 2: 2, 3, 1, 4, 7, 5, 6; where Q=Qualifying sessions (2 mg oral alprazolam and placebo in random order), 1=placebo, 2=oral alprazolam 1 mg, 3= oral alprazolam 2 mg, 4= oral alprazolam 4 mg, 5= inhaled alprazolam 0.5 mg, 6= inhaled alprazolam 1 mg, 7= inhaled alprazolam 2 mg	Drug: Inhaled placebo + oral placebo; Inhaled Staccato placebo + oral placebo; Drug: Inhaled alprazolam 0.5 mg; Inhaled Staccato alprazolam 0.5 mg + oral placebo; Drug: Inhaled alprazolam 1 mg; Inhaled Staccato alprazolam 1 mg + oral placebo; Drug: Inhaled alprazolam 2 mg; Inhaled Staccato alprazolam 2 mg + oral placebo; Drug: Oral alprazolam 1 mg; Oral alprazolam 1 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg; Oral alprazolam 2 mg + Inhaled placebo; Drug: Oral alprazolam 4 m; Oral alprazolam 4 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg qualifying session; Qualifying session (2 mg oral alprazolam); Drug: Oral placebo qualifying session; Qualifying control session (oral placebo)
Other: Treatment sequence 3 Sequence 3: Q, 3, 4, 2, 5, 1, 6, 7; where Q=Qualifying sessions (2 mg oral alprazolam and placebo in random order), 1=placebo, 2=oral alprazolam 1 mg, 3= oral alprazolam 2 mg, 4= oral alprazolam 4 mg, 5= inhaled alprazolam 0.5 mg, 6= inhaled alprazolam 1 mg, 7= inhaled alprazolam 2 mg	Drug: Inhaled placebo + oral placebo; Inhaled Staccato placebo + oral placebo; Drug: Inhaled alprazolam 0.5 mg; Inhaled Staccato alprazolam 0.5 mg + oral placebo; Drug: Inhaled alprazolam 1 mg; Inhaled Staccato alprazolam 1 mg + oral placebo; Drug: Inhaled alprazolam 2 mg; Inhaled Staccato alprazolam 2 mg + oral placebo; Drug: Oral alprazolam 1 mg; Oral alprazolam 1 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg; Oral alprazolam 2 mg + Inhaled placebo; Drug: Oral alprazolam 4 m; Oral alprazolam 4 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg qualifying session; Qualifying session (2 mg oral alprazolam); Drug: Oral placebo qualifying session; Qualifying control session (oral placebo)
Other: Treatment sequence 4 Sequence 4: Q, 4, 5, 3, 6, 2, 7, 1; where Q=Qualifying sessions (2 mg oral alprazolam and placebo in random order), 1=placebo, 2=oral alprazolam 1 mg, 3= oral alprazolam 2 mg, 4= oral alprazolam 4 mg, 5= inhaled alprazolam 0.5 mg, 6= inhaled alprazolam 1 mg, 7= inhaled alprazolam 2 mg	Drug: Inhaled placebo + oral placebo; Inhaled Staccato placebo + oral placebo; Drug: Inhaled alprazolam 0.5 mg; Inhaled Staccato alprazolam 0.5 mg + oral placebo; Drug: Inhaled alprazolam 1 mg; Inhaled Staccato alprazolam 1 mg + oral placebo; Drug: Inhaled alprazolam 2 mg; Inhaled Staccato alprazolam 2 mg + oral placebo; Drug: Oral alprazolam 1 mg; Oral alprazolam 1 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg; Oral alprazolam 2 mg + Inhaled placebo; Drug: Oral alprazolam 4 m; Oral alprazolam 4 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg qualifying session; Qualifying session (2 mg oral alprazolam); Drug: Oral placebo qualifying session; Qualifying control session (oral placebo)
Other: Treatment sequence 5 Sequence 5: Q, 5, 6, 4, 7, 3, 1, 2; where Q=Qualifying sessions (2 mg oral alprazolam and placebo in random order), 1=placebo, 2=oral alprazolam 1 mg, 3= oral alprazolam 2 mg, 4= oral alprazolam 4 mg, 5= inhaled alprazolam 0.5 mg, 6= inhaled alprazolam 1 mg, 7= inhaled alprazolam 2 mg	Drug: Inhaled placebo + oral placebo; Inhaled Staccato placebo + oral placebo; Drug: Inhaled alprazolam 0.5 mg; Inhaled Staccato alprazolam 0.5 mg + oral placebo; Drug: Inhaled alprazolam 1 mg; Inhaled Staccato alprazolam 1 mg + oral placebo; Drug: Inhaled alprazolam 2 mg; Inhaled Staccato alprazolam 2 mg + oral placebo; Drug: Oral alprazolam 1 mg; Oral alprazolam 1 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg; Oral alprazolam 2 mg + Inhaled placebo; Drug: Oral alprazolam 4 m; Oral alprazolam 4 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg qualifying session; Qualifying session (2 mg oral alprazolam); Drug: Oral placebo qualifying session; Qualifying control session (oral placebo)
Other: Treatment sequence 6 Sequence 6: Q, 6, 7, 5, 1, 4, 2, 3; where Q=Qualifying sessions (2 mg oral alprazolam and placebo in random order), 1=placebo, 2=oral alprazolam 1 mg, 3= oral alprazolam 2 mg, 4= oral alprazolam 4 mg, 5= inhaled alprazolam 0.5 mg, 6= inhaled alprazolam 1 mg, 7= inhaled alprazolam 2 mg	Drug: Inhaled placebo + oral placebo; Inhaled Staccato placebo + oral placebo; Drug: Inhaled alprazolam 0.5 mg; Inhaled Staccato alprazolam 0.5 mg + oral placebo; Drug: Inhaled alprazolam 1 mg; Inhaled Staccato alprazolam 1 mg + oral placebo; Drug: Inhaled alprazolam 2 mg; Inhaled Staccato alprazolam 2 mg + oral placebo; Drug: Oral alprazolam 1 mg; Oral alprazolam 1 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg; Oral alprazolam 2 mg + Inhaled placebo; Drug: Oral alprazolam 4 m; Oral alprazolam 4 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg qualifying session; Qualifying session (2 mg oral alprazolam); Drug: Oral placebo qualifying session; Qualifying control session (oral placebo)
Other: Treatment sequence 7 Sequence 7: Q, 7, 1, 6, 2, 5, 3, 4; where Q=Qualifying sessions (2 mg oral alprazolam and placebo in random order), 1=placebo, 2=oral alprazolam 1 mg, 3= oral alprazolam 2 mg, 4= oral alprazolam 4 mg, 5= inhaled alprazolam 0.5 mg, 6= inhaled alprazolam 1 mg, 7= inhaled alprazolam 2 mg	Drug: Inhaled placebo + oral placebo; Inhaled Staccato placebo + oral placebo; Drug: Inhaled alprazolam 0.5 mg; Inhaled Staccato alprazolam 0.5 mg + oral placebo; Drug: Inhaled alprazolam 1 mg; Inhaled Staccato alprazolam 1 mg + oral placebo; Drug: Inhaled alprazolam 2 mg; Inhaled Staccato alprazolam 2 mg + oral placebo; Drug: Oral alprazolam 1 mg; Oral alprazolam 1 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg; Oral alprazolam 2 mg + Inhaled placebo; Drug: Oral alprazolam 4 m; Oral alprazolam 4 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg qualifying session; Qualifying session (2 mg oral alprazolam); Drug: Oral placebo qualifying session; Qualifying control session (oral placebo)
Other: Treatment sequence 8 Sequence 8: Q, 5, 4, 6, 3, 7, 2, 1; where Q=Qualifying sessions (2 mg oral alprazolam and placebo in random order), 1=placebo, 2=oral alprazolam 1 mg, 3= oral alprazolam 2 mg, 4= oral alprazolam 4 mg, 5= inhaled alprazolam 0.5 mg, 6= inhaled alprazolam 1 mg, 7= inhaled alprazolam 2 mg	Drug: Inhaled placebo + oral placebo; Inhaled Staccato placebo + oral placebo; Drug: Inhaled alprazolam 0.5 mg; Inhaled Staccato alprazolam 0.5 mg + oral placebo; Drug: Inhaled alprazolam 1 mg; Inhaled Staccato alprazolam 1 mg + oral placebo; Drug: Inhaled alprazolam 2 mg; Inhaled Staccato alprazolam 2 mg + oral placebo; Drug: Oral alprazolam 1 mg; Oral alprazolam 1 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg; Oral alprazolam 2 mg + Inhaled placebo; Drug: Oral alprazolam 4 m; Oral alprazolam 4 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg qualifying session; Qualifying session (2 mg oral alprazolam); Drug: Oral placebo qualifying session; Qualifying control session (oral placebo)
Other: Treatment sequence 9 Sequence 9: Q, 6, 5, 7, 4, 1, 3, 2; where Q=Qualifying sessions (2 mg oral alprazolam and placebo in random order), 1=placebo, 2=oral alprazolam 1 mg, 3= oral alprazolam 2 mg, 4= oral alprazolam 4 mg, 5= inhaled alprazolam 0.5 mg, 6= inhaled alprazolam 1 mg, 7= inhaled alprazolam 2 mg	Drug: Inhaled placebo + oral placebo; Inhaled Staccato placebo + oral placebo; Drug: Inhaled alprazolam 0.5 mg; Inhaled Staccato alprazolam 0.5 mg + oral placebo; Drug: Inhaled alprazolam 1 mg; Inhaled Staccato alprazolam 1 mg + oral placebo; Drug: Inhaled alprazolam 2 mg; Inhaled Staccato alprazolam 2 mg + oral placebo; Drug: Oral alprazolam 1 mg; Oral alprazolam 1 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg; Oral alprazolam 2 mg + Inhaled placebo; Drug: Oral alprazolam 4 m; Oral alprazolam 4 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg qualifying session; Qualifying session (2 mg oral alprazolam); Drug: Oral placebo qualifying session; Qualifying control session (oral placebo)
Other: Treatment sequence 10 Sequence 10: Q, 7, 6, 1, 5, 2, 4, 3; where Q=Qualifying sessions (2 mg oral alprazolam and placebo in random order), 1=placebo, 2=oral alprazolam 1 mg, 3= oral alprazolam 2 mg, 4= oral alprazolam 4 mg, 5= inhaled alprazolam 0.5 mg, 6= inhaled alprazolam 1 mg, 7= inhaled alprazolam 2 mg	Drug: Inhaled placebo + oral placebo; Inhaled Staccato placebo + oral placebo; Drug: Inhaled alprazolam 0.5 mg; Inhaled Staccato alprazolam 0.5 mg + oral placebo; Drug: Inhaled alprazolam 1 mg; Inhaled Staccato alprazolam 1 mg + oral placebo; Drug: Inhaled alprazolam 2 mg; Inhaled Staccato alprazolam 2 mg + oral placebo; Drug: Oral alprazolam 1 mg; Oral alprazolam 1 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg; Oral alprazolam 2 mg + Inhaled placebo; Drug: Oral alprazolam 4 m; Oral alprazolam 4 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg qualifying session; Qualifying session (2 mg oral alprazolam); Drug: Oral placebo qualifying session; Qualifying control session (oral placebo)
Other: Treatment sequence 11 Sequence 11: Q, 1, 7, 2, 6, 3, 5, 4; where Q=Qualifying sessions (2 mg oral alprazolam and placebo in random order), 1=placebo, 2=oral alprazolam 1 mg, 3= oral alprazolam 2 mg, 4= oral alprazolam 4 mg, 5= inhaled alprazolam 0.5 mg, 6= inhaled alprazolam 1 mg, 7= inhaled alprazolam 2 mg	Drug: Inhaled placebo + oral placebo; Inhaled Staccato placebo + oral placebo; Drug: Inhaled alprazolam 0.5 mg; Inhaled Staccato alprazolam 0.5 mg + oral placebo; Drug: Inhaled alprazolam 1 mg; Inhaled Staccato alprazolam 1 mg + oral placebo; Drug: Inhaled alprazolam 2 mg; Inhaled Staccato alprazolam 2 mg + oral placebo; Drug: Oral alprazolam 1 mg; Oral alprazolam 1 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg; Oral alprazolam 2 mg + Inhaled placebo; Drug: Oral alprazolam 4 m; Oral alprazolam 4 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg qualifying session; Qualifying session (2 mg oral alprazolam); Drug: Oral placebo qualifying session; Qualifying control session (oral placebo)
Other: Treatment sequence 12 Sequence 12: Q, 2, 1, 3, 7, 4, 6, 5; where Q=Qualifying sessions (2 mg oral alprazolam and placebo in random order), 11=placebo, 2=oral alprazolam 1 mg, 3= oral alprazolam 2 mg, 4= oral alprazolam 4 mg, 5= inhaled alprazolam 0.5 mg, 6= inhaled alprazolam 1 mg, 7= inhaled alprazolam 2 mg	Drug: Inhaled placebo + oral placebo; Inhaled Staccato placebo + oral placebo; Drug: Inhaled alprazolam 0.5 mg; Inhaled Staccato alprazolam 0.5 mg + oral placebo; Drug: Inhaled alprazolam 1 mg; Inhaled Staccato alprazolam 1 mg + oral placebo; Drug: Inhaled alprazolam 2 mg; Inhaled Staccato alprazolam 2 mg + oral placebo; Drug: Oral alprazolam 1 mg; Oral alprazolam 1 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg; Oral alprazolam 2 mg + Inhaled placebo; Drug: Oral alprazolam 4 m; Oral alprazolam 4 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg qualifying session; Qualifying session (2 mg oral alprazolam); Drug: Oral placebo qualifying session; Qualifying control session (oral placebo)
Other: Treatment sequence 13 Sequence 13: Q, 3, 2, 4, 1, 5, 7, 6; where Q=Qualifying sessions (2 mg oral alprazolam and placebo in random order), 1=placebo, 2=oral alprazolam 1 mg, 3= oral alprazolam 2 mg, 4= oral alprazolam 4 mg, 5= inhaled alprazolam 0.5 mg, 6= inhaled alprazolam 1 mg, 7= inhaled alprazolam 2 mg	Drug: Inhaled placebo + oral placebo; Inhaled Staccato placebo + oral placebo; Drug: Inhaled alprazolam 0.5 mg; Inhaled Staccato alprazolam 0.5 mg + oral placebo; Drug: Inhaled alprazolam 1 mg; Inhaled Staccato alprazolam 1 mg + oral placebo; Drug: Inhaled alprazolam 2 mg; Inhaled Staccato alprazolam 2 mg + oral placebo; Drug: Oral alprazolam 1 mg; Oral alprazolam 1 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg; Oral alprazolam 2 mg + Inhaled placebo; Drug: Oral alprazolam 4 m; Oral alprazolam 4 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg qualifying session; Qualifying session (2 mg oral alprazolam); Drug: Oral placebo qualifying session; Qualifying control session (oral placebo)
Other: Treatment sequence 14 Sequence 14: Q, 4, 3, 5, 2, 6, 1, 7; where Q=Qualifying sessions (2 mg oral alprazolam and placebo in random order), 11=placebo, 2=oral alprazolam 1 mg, 3= oral alprazolam 2 mg, 4= oral alprazolam 4 mg, 5= inhaled alprazolam 0.5 mg, 6= inhaled alprazolam 1 mg, 7= inhaled alprazolam 2 mg	Drug: Inhaled placebo + oral placebo; Inhaled Staccato placebo + oral placebo; Drug: Inhaled alprazolam 0.5 mg; Inhaled Staccato alprazolam 0.5 mg + oral placebo; Drug: Inhaled alprazolam 1 mg; Inhaled Staccato alprazolam 1 mg + oral placebo; Drug: Inhaled alprazolam 2 mg; Inhaled Staccato alprazolam 2 mg + oral placebo; Drug: Oral alprazolam 1 mg; Oral alprazolam 1 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg; Oral alprazolam 2 mg + Inhaled placebo; Drug: Oral alprazolam 4 m; Oral alprazolam 4 mg + Inhaled placebo; Drug: Oral alprazolam 2 mg qualifying session; Qualifying session (2 mg oral alprazolam); Drug: Oral placebo qualifying session; Qualifying control session (oral placebo)

Outcome Measures

Primary Outcome Measures

1. Response to EDQ Question Number 5, "Rate the Degree to Which You Would Like to Take the Drug Again" [End of day for each of the 7 crossover treatments]

   The End of Day Questionnaire (EDQ) is a 7-question computerized instrument in which subjects rate the overall effect of the drug they received that day. The primary outcome measure for this trial is the categorical response to question number 5, "Rate the degree to which you would like to take the drug again", with a numerical value assigned to each of the responses allowed: 0=Not at all, 1=A little, 2=Moderately, 3=Quite a bit, 4=Very much

Secondary Outcome Measures

1. EDQ Question Number 2 "Rate Your Overall Liking of the Drug Effect" [End of day for each of the 7 crossover treatments]

   The within patient rank (1-7) of End of Day question number 2 (of primary interest), "Rate your overall liking of the drug effect", response options range from -4 to +4: 4=Dislike very much 3=Dislike quite a bit 2=Dislike somewhat 1=Dislike, but not very much 0=NEUTRAL OR NO EFFECT 1=Like, but not very much 2=Like somewhat 3=Like quite a bit 4=Like very much Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect

2. EDQ Question Number 6 " Estimate the Amount of Money You Think the Drug You Took Today Would be Worth on the Street". [End of day for each of the 7 crossover treatments]

   EDQ question number 6 (of primary interest)," Estimate the amount of money you think the drug you took today would be worth on the street".

3. EDQ Question Number 1, "Rate the Overall Strength of the Drug Effect" [End of day for each of the 7 crossover treatments]

   The within patient rank (1-7) of End of Day question number 1, "Rate the overall strength of the drug effect", response options range from 0-4: 0=No drug effect at all Possible mild effect, but not sure Definite mild effect Moderate strong drug effect Very strong drug effect Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect

4. EDQ Question Number 7,"What Would You be Willing to Pay for Today's Drug?" [End of day for each of the 7 crossover treatments]

   EDQ question number 7," What would you be willing to pay for today's drug?"

5. Maximum of DEQ Question 1 "Rate the Strength of the Drug Effect" (at the 10 Time Points, Predose Through 9 Hours) [DEQ was assessed at the 10 time points (predose through 9 hours)]

   The within patient rank (1-7) of Drug Effect Questionnaire question number 1: Rate the STRENGTH of the drug effect you are feeling RIGHT NOW; response options range for 0 to 4: "No drug effect at all"=0, "Possible mild effect, but not sure"=1, "Definite mild effect"=2, "Moderate strong drug effect"=3, "Very strong drug effect"=4 Maximum of the 10 time points (predose through 9 hours) Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect

6. Maximum of DEQ Question 2 "Rate Your Liking of the Drug Effect" at the 10 Time Points (Predose Through 9 Hours) [DEQ was assessed at the 10 time points (predose through 9 hours)]

   The within patient rank (1-7) of maximum of the Rate your LIKING of the drug effect you are feeling RIGHT NOW; response options range from -4 to +4: "Dislike very much"=-4, "Dislike quite a bit"=-3, "Dislike somewhat"=-2, "Dislike, but not very much"=-1, "NEUTRAL OR NO EFFECT"=0, "Like, but not very much"=1, "Like somewhat"=2, "Like quite a bit"=3, "Like very much"=4 Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect

7. Observer Rated Questionnaire 1) Maximum of Sedation/Sleepiness [ORQ was assessed at the 10 time points (predose through 9 hours)]

   The within patient rank (1-7) of Maximum of Observer Rated Questionnaire (ORQ): A trained and blinded staff member completed observer ratings as the subject completed the questionnaires and psychomotor assessment testing at each time point. The observer rated the subject on sedation/sleepiness, muscle relaxation, impaired posture, impaired speech, confusion/disorientation, stimulation/arousal and strength of drug effect on a five-point scale from 0 (indicating normal or no effect) to 4 (indicating extreme drug effect). Maximum of the 10 time points (predose through 9 hours) Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect

8. Observer Rated Questionnaire 2) Maximum of Muscle Relaxation Locomotor [ORQ was assessed at the 10 time points (predose through 9 hours)]

   The within patient rank (1-7) of maximum of the observer rated the subject on muscle relaxation (locomotor) on a five-point scale from 0 (indicating normal or no effect) to 4 (indicating extreme drug effect). Maximum of the 10 time points (predose through 9 hours) Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect

9. Observer Rated Questionnaire 3) Maximum of Muscle Relaxation Non-locomotor [ORQ was assessed at the 10 time points (predose through 9 hours)]

   The within patient rank (1-7) of maximum of the observer rated the subject on muscle relaxation (non-locomotor) on a five-point scale from 0 (indicating normal or no effect) to 4 (indicating extreme drug effect). Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect

10. Observer Rated Questionnaire 4) Maximum of Muscle Relaxation Posture [ORQ was assessed at the 10 time points (predose through 9 hours)]

    The within patient rank (1-7) of maximum of the observer rated the subject on muscle relaxation (posture) on a five-point scale from 0 (indicating normal or no effect) to 4 (indicating extreme drug effect). Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect

11. Observer Rated Questionnaire 5) Maximum of Speech [ORQ was assessed at the 10 time points (predose through 9 hours)]

    The within patient rank (1-7) of maximum of the observer rated the subject on speech on a five-point scale from 0 (indicating normal or no effect) to 4 (indicating extreme drug effect). Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect

12. Observer Rated Questionnaire 6) Maximum of Confusion/Disorientation [ORQ was assessed at the 10 time points (predose through 9 hours)]

    The within patient rank (1-7) of maximum of the observer rated the subject on Confusion/Disorientation on a five-point scale from 0 (indicating normal or no effect) to 4 (indicating extreme drug effect). Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect

13. Observer Rated Questionnaire 7) Maximum of Stimulation/Arousal [ORQ was assessed at the 10 time points (predose through 9 hours)]

    The within patient rank (1-7) of maximum of the observer rated the subject on Stimulation/Arousal on a five-point scale from 0 (indicating normal or no effect) to 4 (indicating extreme drug effect). Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect

14. Observer Rated Questionnaire 8) Maximum of Drug Strength [ORQ was assessed at the 10 time points (predose through 9 hours)]

    The within patient rank (1-7) of maximum of the observer rated the subject on Drug Strength on a five-point scale from 0 (indicating normal or no effect) to 4 (indicating extreme drug effect). Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Male and female subjects between the ages of 18 to 55 years, inclusive, who have a history of substance abuse or dependence on barbiturates and/or benzodiazepine receptor agonists for their intoxicating effects

Exclusion Criteria:

• Subjects with a significant current psychiatric illness or taking any psychotropic prescription medications for therapeutic uses.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins University School of Medicine	Baltimore	Maryland	United States	21224

Sponsors and Collaborators

• Alexza Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Roland R Griffiths, PhD, Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Alexza Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT00603980
• Other Study ID Numbers: AMDC-002-102; 22 January 2008
• First Posted: Jan 29, 2008
• Last Update Posted: Jan 2, 2020
• Last Verified: Jan 1, 2009

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Alprazolam

Study Results

Participant Flow

Pre-assignment Detail	Each participants was to receive all 7 interventions in a randomized order in a crossover design

Arm/Group Title	All Subjects Entering
Arm/Group Description	All subjects entering the crossover qualification period
Period Title: Study Qualification
STARTED	31
COMPLETED	15
NOT COMPLETED	16
Period Title: Study Qualification
STARTED	15
COMPLETED	14
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Qualifying Session (Includes Crossover Group)
Arm/Group Description	All subjects received Placebo and Oral alprazolam 2 mg in a randomized order to Qualify Each subject was to receive all 7 interventions (Placebo, Oral alprazolam 1, 2 & 3 mg, Inhaled alprazolam 0.5, 1, & 2 mg) in a randomized order in a crossover design
Overall Participants	31
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	31 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	38.032 (38.032)
Sex: Female, Male (Count of Participants)
Female	9 29%
Male	22 71%
Region of Enrollment (participants) [Number]
United States	31 100%

Outcome Measures

1. Primary Outcome

Title	Response to EDQ Question Number 5, "Rate the Degree to Which You Would Like to Take the Drug Again"
Description	The End of Day Questionnaire (EDQ) is a 7-question computerized instrument in which subjects rate the overall effect of the drug they received that day. The primary outcome measure for this trial is the categorical response to question number 5, "Rate the degree to which you would like to take the drug again", with a numerical value assigned to each of the responses allowed: 0=Not at all, 1=A little, 2=Moderately, 3=Quite a bit, 4=Very much
Time Frame	End of day for each of the 7 crossover treatments

Outcome Measure Data

Analysis Population Description

Efficacy (crossover) Population, n=14. LSM & SEM are based on all 14 subjects completing all 7 treatments. PROC MIXED model used assigns the same SEM to all 7 treatments.

Arm/Group Title	Placebo	Oral Alprazolam 1 mg	Oral Alprazolam 2 mg	Oral Alprazolam 4 mg	Inhaled Alprazolam 0.5 mg	Inhaled Alprazolam 1 mg	Inhaled Alprazolam 2 mg
Arm/Group Description	Inhaled Staccato Placebo +oral placebo	Oral alprazolam 1 mg + inhaled placebo	Oral alprazolam 2 mg + inhaled placebo	Oral alprazolam 4 mg + inhaled placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Measure Participants	14	14	14	14	14	14	14
Least Squares Mean (Standard Error) [units on a scale]	0 (0.349)	1.714 (0.349)	2.143 (0.349)	2.286 (0.349)	1.00 (0.349)	1.714 (0.349)	2.214 (0.349)

2. Secondary Outcome

Title	EDQ Question Number 2 "Rate Your Overall Liking of the Drug Effect"
Description	The within patient rank (1-7) of End of Day question number 2 (of primary interest), "Rate your overall liking of the drug effect", response options range from -4 to +4: 4=Dislike very much 3=Dislike quite a bit 2=Dislike somewhat 1=Dislike, but not very much 0=NEUTRAL OR NO EFFECT 1=Like, but not very much 2=Like somewhat 3=Like quite a bit 4=Like very much Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect
Time Frame	End of day for each of the 7 crossover treatments

Outcome Measure Data

Analysis Population Description

Efficacy (crossover) Population, n=14 LS Means via SAS PROC MIXED non-parametric model (ranks within subject), treatment and period as fixed effects, ddf=72 LSM & SEM are based on the ranks of scores within each subject across all 14 subjects completing all 7 treatments. PROC MIXED model assigns the same SEM to all 7 treatments.

Arm/Group Title	Placebo	Oral Alprazolam 1 mg	Oral Alprazolam 2 mg	Oral Alprazolam 4 mg	Inhaled Alprazolam 0.5 mg	Inhaled Alprazolam 1 mg	Inhaled Alprazolam 2 mg
Arm/Group Description	Inhaled Staccato Placebo +oral placebo	Oral alprazolam 1 mg + inhaled placebo	Oral alprazolam 2 mg + inhaled placebo	Oral alprazolam 4 mg + inhaled placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Measure Participants	14	14	14	14	14	14	14
Least Squares Mean (Standard Error) [Rank across the 7 treatments]	1.679 (0.349)	4.214 (0.349)	4.429 (0.349)	4.607 (0.349)	2.571 (0.349)	4.857 (0.349)	5.643 (0.349)

3. Secondary Outcome

Title	EDQ Question Number 6 " Estimate the Amount of Money You Think the Drug You Took Today Would be Worth on the Street".
Description	EDQ question number 6 (of primary interest)," Estimate the amount of money you think the drug you took today would be worth on the street".
Time Frame	End of day for each of the 7 crossover treatments

Outcome Measure Data

Analysis Population Description

Efficacy (crossover) Population, n=14. LSM & SEM are based on all 14 subjects completing all 7 treatments. PROC MIXED model used assigns the same SEM to all 7 treatments.

Arm/Group Title	Placebo	Oral Alprazolam 1 mg	Oral Alprazolam 2 mg	Oral Alprazolam 4 mg	Inhaled Alprazolam 0.5 mg	Inhaled Alprazolam 1 mg	Inhaled Alprazolam 2 mg
Arm/Group Description	Inhaled Staccato Placebo +oral placebo	Oral alprazolam 1 mg + inhaled placebo	Oral alprazolam 2 mg + inhaled placebo	Oral alprazolam 4 mg + inhaled placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Measure Participants	14	14	14	14	14	14	14
Least Squares Mean (Standard Error) [Dollars ($)]	1.750 (0.402)	3.571 (0.402)	7.071 (0.402)	8.714 (0.402)	2.857 (0.402)	4.286 (0.402)	8.571 (0.402)

4. Secondary Outcome

Title	EDQ Question Number 1, "Rate the Overall Strength of the Drug Effect"
Description	The within patient rank (1-7) of End of Day question number 1, "Rate the overall strength of the drug effect", response options range from 0-4: 0=No drug effect at all Possible mild effect, but not sure Definite mild effect Moderate strong drug effect Very strong drug effect Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect
Time Frame	End of day for each of the 7 crossover treatments

Outcome Measure Data

Analysis Population Description

Efficacy (crossover) Population, n=14 LS Means via SAS PROC MIXED non-parametric model (ranks within subject), treatment and period as fixed effects, ddf=72 LSM & SEM are based on the ranks of scores within each subject across all 14 subjects completing all 7 treatments. PROC MIXED model assigns the same SEM to all 7 treatments.

Arm/Group Title	Placebo	Oral Alprazolam 1 mg	Oral Alprazolam 2 mg	Oral Alprazolam 4 mg	Inhaled Alprazolam 0.5 mg	Inhaled Alprazolam 1 mg	Inhaled Alprazolam 2 mg
Arm/Group Description	Inhaled Staccato Placebo +oral placebo	Oral alprazolam 1 mg + inhaled placebo	Oral alprazolam 2 mg + inhaled placebo	Oral alprazolam 4 mg + inhaled placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Measure Participants	14	14	14	14	14	14	14
Least Squares Mean (Standard Error) [Rank across the 7 treatments]	1.429 (0.317)	3.536 (0.317)	4.821 (0.317)	5.429 (0.317)	2.893 (0.317)	4.143 (0.317)	5.750 (0.317)

5. Secondary Outcome

Title	EDQ Question Number 7,"What Would You be Willing to Pay for Today's Drug?"
Description	EDQ question number 7," What would you be willing to pay for today's drug?"
Time Frame	End of day for each of the 7 crossover treatments

Outcome Measure Data

Analysis Population Description

Efficacy (crossover) Population, n=14. LSM & SEM are based on all 14 subjects completing all 7 treatments. PROC MIXED model used assigns the same SEM to all 7 treatments.

Arm/Group Title	Placebo	Oral Alprazolam 1 mg	Oral Alprazolam 2 mg	Oral Alprazolam 4 mg	Inhaled Alprazolam 0.5 mg	Inhaled Alprazolam 1 mg	Inhaled Alprazolam 2 mg
Arm/Group Description	Inhaled Staccato Placebo +oral placebo	Oral alprazolam 1 mg + inhaled placebo	Oral alprazolam 2 mg + inhaled placebo	Oral alprazolam 4 mg + inhaled placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Measure Participants	14	14	14	14	14	14	14
Least Squares Mean (Standard Error) [Dollars ($)]	1.607 (0.387)	3.821 (0.387)	4.571 (0.387)	5.179 (0.387)	2.964 (0.387)	4.107 (0.387)	5.750 (0.387)

6. Secondary Outcome

Title	Maximum of DEQ Question 1 "Rate the Strength of the Drug Effect" (at the 10 Time Points, Predose Through 9 Hours)
Description	The within patient rank (1-7) of Drug Effect Questionnaire question number 1: Rate the STRENGTH of the drug effect you are feeling RIGHT NOW; response options range for 0 to 4: "No drug effect at all"=0, "Possible mild effect, but not sure"=1, "Definite mild effect"=2, "Moderate strong drug effect"=3, "Very strong drug effect"=4 Maximum of the 10 time points (predose through 9 hours) Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect
Time Frame	DEQ was assessed at the 10 time points (predose through 9 hours)

Outcome Measure Data

Analysis Population Description

Efficacy (crossover) Population, n=14 LS Means via SAS PROC MIXED non-parametric model (ranks within subject), treatment and period as fixed effects, ddf=72 LSM & SEM are based on the ranks of scores within each subject across all 14 subjects completing all 7 treatments. PROC MIXED model assigns the same SEM to all 7 treatments.

Arm/Group Title	Placebo	Oral Alprazolam 1 mg	Oral Alprazolam 2 mg	Oral Alprazolam 4 mg	Inhaled Alprazolam 0.5 mg	Inhaled Alprazolam 1 mg	Inhaled Alprazolam 2 mg
Arm/Group Description	Inhaled Staccato Placebo +oral placebo	Oral alprazolam 1 mg + inhaled placebo	Oral alprazolam 2 mg + inhaled placebo	Oral alprazolam 4 mg + inhaled placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Measure Participants	14	14	14	14	14	14	14
Least Squares Mean (Standard Error) [Rank across the 7 treatments]	1.571 (0.340)	3.143 (0.340)	4.714 (0.340)	5.536 (0.340)	3.036 (0.340)	4.250 (0.340)	5.750 (0.340)

7. Secondary Outcome

Title	Maximum of DEQ Question 2 "Rate Your Liking of the Drug Effect" at the 10 Time Points (Predose Through 9 Hours)
Description	The within patient rank (1-7) of maximum of the Rate your LIKING of the drug effect you are feeling RIGHT NOW; response options range from -4 to +4: "Dislike very much"=-4, "Dislike quite a bit"=-3, "Dislike somewhat"=-2, "Dislike, but not very much"=-1, "NEUTRAL OR NO EFFECT"=0, "Like, but not very much"=1, "Like somewhat"=2, "Like quite a bit"=3, "Like very much"=4 Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect
Time Frame	DEQ was assessed at the 10 time points (predose through 9 hours)

Outcome Measure Data

Analysis Population Description

Efficacy (crossover) Population, n=14 LS Means via SAS PROC MIXED non-parametric model (ranks within subject), treatment and period as fixed effects, ddf=72 LSM & SEM are based on the ranks of scores within each subject across all 14 subjects completing all 7 treatments. PROC MIXED model assigns the same SEM to all 7 treatments.

Arm/Group Title	Placebo	Oral Alprazolam 1 mg	Oral Alprazolam 2 mg	Oral Alprazolam 4 mg	Inhaled Alprazolam 0.5 mg	Inhaled Alprazolam 1 mg	Inhaled Alprazolam 2 mg
Arm/Group Description	Inhaled Staccato Placebo +oral placebo	Oral alprazolam 1 mg + inhaled placebo	Oral alprazolam 2 mg + inhaled placebo	Oral alprazolam 4 mg + inhaled placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Measure Participants	14	14	14	14	14	14	14
Least Squares Mean (Standard Error) [Rank across the 7 treatments]	1.607 (0.343)	3.500 (0.343)	4.536 (0.343)	5.536 (0.343)	2.893 (0.343)	4.250 (0.343)	5.679 (0.343)

8. Secondary Outcome

Title	Observer Rated Questionnaire 1) Maximum of Sedation/Sleepiness
Description	The within patient rank (1-7) of Maximum of Observer Rated Questionnaire (ORQ): A trained and blinded staff member completed observer ratings as the subject completed the questionnaires and psychomotor assessment testing at each time point. The observer rated the subject on sedation/sleepiness, muscle relaxation, impaired posture, impaired speech, confusion/disorientation, stimulation/arousal and strength of drug effect on a five-point scale from 0 (indicating normal or no effect) to 4 (indicating extreme drug effect). Maximum of the 10 time points (predose through 9 hours) Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect
Time Frame	ORQ was assessed at the 10 time points (predose through 9 hours)

Outcome Measure Data

Analysis Population Description

Efficacy (crossover) Population, n=14 LS Means via SAS PROC MIXED non-parametric model (ranks within subject), treatment and period as fixed effects, ddf=72 LSM & SEM are based on the ranks of scores within each subject across all 14 subjects completing all 7 treatments. PROC MIXED model assigns the same SEM to all 7 treatments.

Arm/Group Title	Placebo	Oral Alprazolam 1 mg	Oral Alprazolam 2 mg	Oral Alprazolam 4 mg	Inhaled Alprazolam 0.5 mg	Inhaled Alprazolam 1 mg	Inhaled Alprazolam 2 mg
Arm/Group Description	Inhaled Staccato Placebo +oral placebo	Oral alprazolam 1 mg + inhaled placebo	Oral alprazolam 2 mg + inhaled placebo	Oral alprazolam 4 mg + inhaled placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Measure Participants	14	14	14	14	14	14	14
Least Squares Mean (Standard Error) [Rank across the 7 treatments]	2.250 (0.313)	3.679 (0.313)	4.607 (0.313)	4.714 (0.313)	3.929 (0.313)	4.000 (0.313)	4.821 (0.313)

9. Secondary Outcome

Title	Observer Rated Questionnaire 2) Maximum of Muscle Relaxation Locomotor
Description	The within patient rank (1-7) of maximum of the observer rated the subject on muscle relaxation (locomotor) on a five-point scale from 0 (indicating normal or no effect) to 4 (indicating extreme drug effect). Maximum of the 10 time points (predose through 9 hours) Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect
Time Frame	ORQ was assessed at the 10 time points (predose through 9 hours)

Outcome Measure Data

Analysis Population Description

Efficacy (crossover) Population, n=14 LS Means via SAS PROC MIXED non-parametric model (ranks within subject), treatment and period as fixed effects, ddf=72 LSM & SEM are based on the ranks of scores within each subject across all 14 subjects completing all 7 treatments. PROC MIXED model assigns the same SEM to all 7 treatments.

Arm/Group Title	Placebo	Oral Alprazolam 1 mg	Oral Alprazolam 2 mg	Oral Alprazolam 4 mg	Inhaled Alprazolam 0.5 mg	Inhaled Alprazolam 1 mg	Inhaled Alprazolam 2 mg
Arm/Group Description	Inhaled Staccato Placebo +oral placebo	Oral alprazolam 1 mg + inhaled placebo	Oral alprazolam 2 mg + inhaled placebo	Oral alprazolam 4 mg + inhaled placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Measure Participants	14	14	14	14	14	14	14
Least Squares Mean (Standard Error) [Rank across the 7 treatments]	2.464 (0.287)	2.964 (0.287)	4.643 (0.287)	6.357 (0.287)	2.821 (0.287)	3.571 (0.287)	5.179 (0.287)

10. Secondary Outcome

Title	Observer Rated Questionnaire 3) Maximum of Muscle Relaxation Non-locomotor
Description	The within patient rank (1-7) of maximum of the observer rated the subject on muscle relaxation (non-locomotor) on a five-point scale from 0 (indicating normal or no effect) to 4 (indicating extreme drug effect). Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect
Time Frame	ORQ was assessed at the 10 time points (predose through 9 hours)

Outcome Measure Data

Analysis Population Description

Efficacy (crossover) Population, n=14 LS Means via SAS PROC MIXED non-parametric model (ranks within subject), treatment and period as fixed effects, ddf=72 LSM & SEM are based on the ranks of scores within each subject across all 14 subjects completing all 7 treatments. PROC MIXED model assigns the same SEM to all 7 treatments.

Arm/Group Title	Placebo	Oral Alprazolam 1 mg	Oral Alprazolam 2 mg	Oral Alprazolam 4 mg	Inhaled Alprazolam 0.5 mg	Inhaled Alprazolam 1 mg	Inhaled Alprazolam 2 mg
Arm/Group Description	Inhaled Staccato Placebo +oral placebo	Oral alprazolam 1 mg + inhaled placebo	Oral alprazolam 2 mg + inhaled placebo	Oral alprazolam 4 mg + inhaled placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Measure Participants	14	14	14	14	14	14	14
Least Squares Mean (Standard Error) [units on a scale]	2.536 (0.282)	3.036 (0.282)	4.607 (0.282)	6.393 (0.282)	2.714 (0.282)	3.786 (0.282)	4.929 (0.282)

11. Secondary Outcome

Title	Observer Rated Questionnaire 4) Maximum of Muscle Relaxation Posture
Description	The within patient rank (1-7) of maximum of the observer rated the subject on muscle relaxation (posture) on a five-point scale from 0 (indicating normal or no effect) to 4 (indicating extreme drug effect). Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect
Time Frame	ORQ was assessed at the 10 time points (predose through 9 hours)

Outcome Measure Data

Analysis Population Description

Efficacy (crossover) Population, n=14 LS Means via SAS PROC MIXED non-parametric model (ranks within subject), treatment and period as fixed effects, ddf=72 LSM & SEM are based on the ranks of scores within each subject across all 14 subjects completing all 7 treatments. PROC MIXED model assigns the same SEM to all 7 treatments.

Arm/Group Title	Placebo	Oral Alprazolam 1 mg	Oral Alprazolam 2 mg	Oral Alprazolam 4 mg	Inhaled Alprazolam 0.5 mg	Inhaled Alprazolam 1 mg	Inhaled Alprazolam 2 mg
Arm/Group Description	Inhaled Staccato Placebo +oral placebo	Oral alprazolam 1 mg + inhaled placebo	Oral alprazolam 2 mg + inhaled placebo	Oral alprazolam 4 mg + inhaled placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Measure Participants	14	14	14	14	14	14	14
Least Squares Mean (Standard Error) [Rank across the 7 treatments]	2.750 (0.337)	2.893 (0.337)	3.964 (0.337)	6.250 (0.337)	2.929 (0.337)	2.929 (0.337)	2.929 (0.337)

12. Secondary Outcome

Title	Observer Rated Questionnaire 5) Maximum of Speech
Description	The within patient rank (1-7) of maximum of the observer rated the subject on speech on a five-point scale from 0 (indicating normal or no effect) to 4 (indicating extreme drug effect). Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect
Time Frame	ORQ was assessed at the 10 time points (predose through 9 hours)

Outcome Measure Data

Analysis Population Description

Efficacy (crossover) Population, n=14 LS Means via SAS PROC MIXED non-parametric model (ranks within subject), treatment and period as fixed effects, ddf=72 LSM & SEM are based on the ranks of scores within each subject across all 14 subjects completing all 7 treatments. PROC MIXED model assigns the same SEM to all 7 treatments.

Arm/Group Title	Placebo	Oral Alprazolam 1 mg	Oral Alprazolam 2 mg	Oral Alprazolam 4 mg	Inhaled Alprazolam 0.5 mg	Inhaled Alprazolam 1 mg	Inhaled Alprazolam 2 mg
Arm/Group Description	Inhaled Staccato Placebo +oral placebo	Oral alprazolam 1 mg + inhaled placebo	Oral alprazolam 2 mg + inhaled placebo	Oral alprazolam 4 mg + inhaled placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Measure Participants	14	14	14	14	14	14	14
Least Squares Mean (Standard Error) [Rank across the 7 treatments]	2.214 (0.284)	2.893 (0.284)	4.786 (0.284)	6.393 (0.284)	3.071 (0.284)	3.071 (0.284)	5.357 (0.284)

13. Secondary Outcome

Title	Observer Rated Questionnaire 6) Maximum of Confusion/Disorientation
Description	The within patient rank (1-7) of maximum of the observer rated the subject on Confusion/Disorientation on a five-point scale from 0 (indicating normal or no effect) to 4 (indicating extreme drug effect). Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect
Time Frame	ORQ was assessed at the 10 time points (predose through 9 hours)

Outcome Measure Data

Analysis Population Description

Efficacy (crossover) Population, n=14 LS Means via SAS PROC MIXED non-parametric model (ranks within subject), treatment and period as fixed effects, ddf=72 LSM & SEM are based on the ranks of scores within each subject across all 14 subjects completing all 7 treatments. PROC MIXED model assigns the same SEM to all 7 treatments.

Arm/Group Title	Placebo	Oral Alprazolam 1 mg	Oral Alprazolam 2 mg	Oral Alprazolam 4 mg	Inhaled Alprazolam 0.5 mg	Inhaled Alprazolam 1 mg	Inhaled Alprazolam 2 mg
Arm/Group Description	Inhaled Staccato Placebo +oral placebo	Oral alprazolam 1 mg + inhaled placebo	Oral alprazolam 2 mg + inhaled placebo	Oral alprazolam 4 mg + inhaled placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Measure Participants	14	14	14	14	14	14	14
Least Squares Mean (Standard Error) [Rank across the 7 treatments]	1.929 (0.282)	2.821 (0.282)	4.893 (0.282)	6.429 (0.282)	3.393 (0.282)	3.107 (0.282)	5.429 (0.282)

14. Secondary Outcome

Title	Observer Rated Questionnaire 7) Maximum of Stimulation/Arousal
Description	The within patient rank (1-7) of maximum of the observer rated the subject on Stimulation/Arousal on a five-point scale from 0 (indicating normal or no effect) to 4 (indicating extreme drug effect). Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect
Time Frame	ORQ was assessed at the 10 time points (predose through 9 hours)

Outcome Measure Data

Analysis Population Description

Efficacy (crossover) Population, n=14 LS Means via SAS PROC MIXED non-parametric model (ranks within subject), treatment and period as fixed effects, ddf=72 LSM & SEM are based on the ranks of scores within each subject across all 14 subjects completing all 7 treatments. PROC MIXED model assigns the same SEM to all 7 treatments.

Arm/Group Title	Placebo	Oral Alprazolam 1 mg	Oral Alprazolam 2 mg	Oral Alprazolam 4 mg	Inhaled Alprazolam 0.5 mg	Inhaled Alprazolam 1 mg	Inhaled Alprazolam 2 mg
Arm/Group Description	Inhaled Staccato Placebo +oral placebo	Oral alprazolam 1 mg + inhaled placebo	Oral alprazolam 2 mg + inhaled placebo	Oral alprazolam 4 mg + inhaled placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Measure Participants	14	14	14	14	14	14	14
Least Squares Mean (Standard Error) [Rank across the 7 treatments]	3.964 (0.087)	3.964 (0.087)	3.964 (0.087)	3.964 (0.087)	3.964 (0.087)	3.964 (0.087)	4,214 (0.087)

15. Secondary Outcome

Title	Observer Rated Questionnaire 8) Maximum of Drug Strength
Description	The within patient rank (1-7) of maximum of the observer rated the subject on Drug Strength on a five-point scale from 0 (indicating normal or no effect) to 4 (indicating extreme drug effect). Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect
Time Frame	ORQ was assessed at the 10 time points (predose through 9 hours)

Outcome Measure Data

Analysis Population Description

Efficacy (crossover) Population, n=14 LS Means via SAS PROC MIXED non-parametric model (ranks within subject), treatment and period as fixed effects, ddf=72 LSM & SEM are based on the ranks of scores within each subject across all 14 subjects completing all 7 treatments. PROC MIXED model assigns the same SEM to all 7 treatments.

Arm/Group Title	Oral Alprazolam 1 mg	Placebo	Oral Alprazolam 2 mg	Oral Alprazolam 4 mg	Inhaled Alprazolam 0.5 mg	Inhaled Alprazolam 1 mg	Inhaled Alprazolam 2 mg
Arm/Group Description	Oral alprazolam 1 mg + inhaled placebo	Inhaled Staccato Placebo +oral placebo	Oral alprazolam 2 mg + inhaled placebo	Oral alprazolam 4 mg + inhaled placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Measure Participants	14	14	14	14	14	14	14
Least Squares Mean (Standard Error) [Rank across the 7 treatments]	2.786 (0.286)	1.714 (0.286)	4.571 (0.286)	6.321 (0.286)	3.000 (0.286)	3.929 (0.286)	5.679 (0.286)

Adverse Events

Time Frame	Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment
Adverse Event Reporting Description	Adverse events (AEs) were assessed at 14 pre-specified time points for the 24-hour period after dosing, as well as whenever spontaneously reported by the subjects or study staff
Arm/Group Title	Placebo		Oral Alprazolam 1 mg		Oral Alprazolam 2 mg		Oral Alprazolam 4 mg		Inhaled Alprazolam 0.5 mg		Inhaled Alprazolam 1 mg		Inhaled Alprazolam 2 mg		Qualifying Session 2 mg Oral		Qualifying Session Oral Placebo
Arm/Group Description	Inhaled Staccato Placebo +oral placebo		Oral alprazolam 1 mg + inhaled placebo		Oral alprazolam 2 mg + inhaled placebo		Oral alprazolam 4 mg + inhaled placebo		Inhaled Staccato alprazolam 0.5 mg + oral placebo		Inhaled Staccato alprazolam 1 mg + oral placebo		Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo		Qualifying session, 2 mg oral alprazolam		Qualifying session, oral placebo (alprazolam 0 mg)
All Cause Mortality
	Placebo		Oral Alprazolam 1 mg		Oral Alprazolam 2 mg		Oral Alprazolam 4 mg		Inhaled Alprazolam 0.5 mg		Inhaled Alprazolam 1 mg		Inhaled Alprazolam 2 mg		Qualifying Session 2 mg Oral		Qualifying Session Oral Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/15 (0%)		0/14 (0%)		0/15 (0%)		0/15 (0%)		0/28 (0%)		0/28 (0%)
Serious Adverse Events
	Placebo		Oral Alprazolam 1 mg		Oral Alprazolam 2 mg		Oral Alprazolam 4 mg		Inhaled Alprazolam 0.5 mg		Inhaled Alprazolam 1 mg		Inhaled Alprazolam 2 mg		Qualifying Session 2 mg Oral		Qualifying Session Oral Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/15 (0%)		0/14 (0%)		0/15 (0%)		0/15 (0%)		0/28 (0%)		0/28 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Oral Alprazolam 1 mg		Oral Alprazolam 2 mg		Oral Alprazolam 4 mg		Inhaled Alprazolam 0.5 mg		Inhaled Alprazolam 1 mg		Inhaled Alprazolam 2 mg		Qualifying Session 2 mg Oral		Qualifying Session Oral Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)		0/14 (0%)		1/15 (6.7%)		0/14 (0%)		0/15 (0%)		0/15 (0%)		0/28 (0%)		1/28 (3.6%)
Nervous system disorders
Sedation	0/15 (0%)	0	0/15 (0%)	0	0/14 (0%)	0	1/15 (6.7%)	1	0/14 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	0/28 (0%)	0	0/28 (0%)	0
Vascular disorders
Hypertension	0/15 (0%)	0	0/15 (0%)	0	0/14 (0%)	0	0/15 (0%)	0	0/14 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	0/28 (0%)	0	1/28 (3.6%)	1

Limitations/Caveats

A limitation of the current study was the lack of assessment of drug plasma levels. The differences in abuse potential measures may be due to differences in absorption, peak drug plasma levels, or other PK parameters

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.