Trial Outcomes & Findings for Staccato Alprazolam Abuse Liability (NCT NCT00603980)

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

31 participants

Primary outcome timeframe

End of day for each of the 7 crossover treatments

Results posted on

2020-01-02

Participant Flow

Each participants was to receive all 7 interventions in a randomized order in a crossover design

Participant milestones

Participant milestones
Measure	All Subjects Entering All subjects entering the crossover qualification period
Study Qualification STARTED	31
Study Qualification COMPLETED	15
Study Qualification NOT COMPLETED	16
Main Study STARTED	15
Main Study COMPLETED	14
Main Study NOT COMPLETED	1

Reasons for withdrawal

Reasons for withdrawal
Measure	All Subjects Entering All subjects entering the crossover qualification period
Study Qualification Protocol Violation	3
Study Qualification Inconsistent data reporting	13
Main Study 14th subject completed trial	1

Baseline Characteristics

Staccato Alprazolam Abuse Liability

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Qualifying Session (Includes Crossover Group) n=31 Participants 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
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	31 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Age, Continuous	38.032 years STANDARD_DEVIATION 38.032 • n=5 Participants
Sex: Female, Male Female	9 Participants n=5 Participants
Sex: Female, Male Male	22 Participants n=5 Participants
Region of Enrollment United States	31 participants n=5 Participants

PRIMARY outcome

Timeframe: End of day for each of the 7 crossover treatments

Population: 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.

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

Outcome measures

Outcome measures
Measure	Placebo n=14 Participants Inhaled Staccato Placebo +oral placebo	Oral Alprazolam 1 mg n=14 Participants Oral alprazolam 1 mg + inhaled placebo	Oral Alprazolam 2 mg n=14 Participants Oral alprazolam 2 mg + inhaled placebo	Oral Alprazolam 4 mg n=14 Participants Oral alprazolam 4 mg + inhaled placebo	Inhaled Alprazolam 0.5 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Alprazolam 1 mg n=14 Participants Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Alprazolam 2 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Response to EDQ Question Number 5, "Rate the Degree to Which You Would Like to Take the Drug Again"	0 units on a scale Standard Error 0.349	1.714 units on a scale Standard Error 0.349	2.143 units on a scale Standard Error 0.349	2.286 units on a scale Standard Error 0.349	1.00 units on a scale Standard Error 0.349	1.714 units on a scale Standard Error 0.349	2.214 units on a scale Standard Error 0.349

SECONDARY outcome

Timeframe: End of day for each of the 7 crossover treatments

Population: 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.

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

Outcome measures

Outcome measures
Measure	Placebo n=14 Participants Inhaled Staccato Placebo +oral placebo	Oral Alprazolam 1 mg n=14 Participants Oral alprazolam 1 mg + inhaled placebo	Oral Alprazolam 2 mg n=14 Participants Oral alprazolam 2 mg + inhaled placebo	Oral Alprazolam 4 mg n=14 Participants Oral alprazolam 4 mg + inhaled placebo	Inhaled Alprazolam 0.5 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Alprazolam 1 mg n=14 Participants Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Alprazolam 2 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
EDQ Question Number 2 "Rate Your Overall Liking of the Drug Effect"	1.679 Rank across the 7 treatments Standard Error 0.349	4.214 Rank across the 7 treatments Standard Error 0.349	4.429 Rank across the 7 treatments Standard Error 0.349	4.607 Rank across the 7 treatments Standard Error 0.349	2.571 Rank across the 7 treatments Standard Error 0.349	4.857 Rank across the 7 treatments Standard Error 0.349	5.643 Rank across the 7 treatments Standard Error 0.349

SECONDARY outcome

Timeframe: End of day for each of the 7 crossover treatments

Population: 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.

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".

Outcome measures

Outcome measures
Measure	Placebo n=14 Participants Inhaled Staccato Placebo +oral placebo	Oral Alprazolam 1 mg n=14 Participants Oral alprazolam 1 mg + inhaled placebo	Oral Alprazolam 2 mg n=14 Participants Oral alprazolam 2 mg + inhaled placebo	Oral Alprazolam 4 mg n=14 Participants Oral alprazolam 4 mg + inhaled placebo	Inhaled Alprazolam 0.5 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Alprazolam 1 mg n=14 Participants Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Alprazolam 2 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
EDQ Question Number 6 " Estimate the Amount of Money You Think the Drug You Took Today Would be Worth on the Street".	1.750 Dollars ($) Standard Error 0.402	3.571 Dollars ($) Standard Error 0.402	7.071 Dollars ($) Standard Error 0.402	8.714 Dollars ($) Standard Error 0.402	2.857 Dollars ($) Standard Error 0.402	4.286 Dollars ($) Standard Error 0.402	8.571 Dollars ($) Standard Error 0.402

SECONDARY outcome

Timeframe: End of day for each of the 7 crossover treatments

Population: 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.

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 1. Possible mild effect, but not sure 2. Definite mild effect 3. Moderate strong drug effect 4. Very strong drug effect Thus a higher rank means a stronger drug effect and a lower rank a lesser drug effect

Outcome measures

Outcome measures
Measure	Placebo n=14 Participants Inhaled Staccato Placebo +oral placebo	Oral Alprazolam 1 mg n=14 Participants Oral alprazolam 1 mg + inhaled placebo	Oral Alprazolam 2 mg n=14 Participants Oral alprazolam 2 mg + inhaled placebo	Oral Alprazolam 4 mg n=14 Participants Oral alprazolam 4 mg + inhaled placebo	Inhaled Alprazolam 0.5 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Alprazolam 1 mg n=14 Participants Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Alprazolam 2 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
EDQ Question Number 1, "Rate the Overall Strength of the Drug Effect"	1.429 Rank across the 7 treatments Standard Error 0.317	3.536 Rank across the 7 treatments Standard Error 0.317	4.821 Rank across the 7 treatments Standard Error 0.317	5.429 Rank across the 7 treatments Standard Error 0.317	2.893 Rank across the 7 treatments Standard Error 0.317	4.143 Rank across the 7 treatments Standard Error 0.317	5.750 Rank across the 7 treatments Standard Error 0.317

SECONDARY outcome

Timeframe: End of day for each of the 7 crossover treatments

Population: 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.

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

Outcome measures

Outcome measures
Measure	Placebo n=14 Participants Inhaled Staccato Placebo +oral placebo	Oral Alprazolam 1 mg n=14 Participants Oral alprazolam 1 mg + inhaled placebo	Oral Alprazolam 2 mg n=14 Participants Oral alprazolam 2 mg + inhaled placebo	Oral Alprazolam 4 mg n=14 Participants Oral alprazolam 4 mg + inhaled placebo	Inhaled Alprazolam 0.5 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Alprazolam 1 mg n=14 Participants Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Alprazolam 2 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
EDQ Question Number 7,"What Would You be Willing to Pay for Today's Drug?"	1.607 Dollars ($) Standard Error 0.387	3.821 Dollars ($) Standard Error 0.387	4.571 Dollars ($) Standard Error 0.387	5.179 Dollars ($) Standard Error 0.387	2.964 Dollars ($) Standard Error 0.387	4.107 Dollars ($) Standard Error 0.387	5.750 Dollars ($) Standard Error 0.387

SECONDARY outcome

Timeframe: DEQ was assessed at the 10 time points (predose through 9 hours)

Population: 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.

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

Outcome measures

Outcome measures
Measure	Placebo n=14 Participants Inhaled Staccato Placebo +oral placebo	Oral Alprazolam 1 mg n=14 Participants Oral alprazolam 1 mg + inhaled placebo	Oral Alprazolam 2 mg n=14 Participants Oral alprazolam 2 mg + inhaled placebo	Oral Alprazolam 4 mg n=14 Participants Oral alprazolam 4 mg + inhaled placebo	Inhaled Alprazolam 0.5 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Alprazolam 1 mg n=14 Participants Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Alprazolam 2 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Maximum of DEQ Question 1 "Rate the Strength of the Drug Effect" (at the 10 Time Points, Predose Through 9 Hours)	1.571 Rank across the 7 treatments Standard Error 0.340	3.143 Rank across the 7 treatments Standard Error 0.340	4.714 Rank across the 7 treatments Standard Error 0.340	5.536 Rank across the 7 treatments Standard Error 0.340	3.036 Rank across the 7 treatments Standard Error 0.340	4.250 Rank across the 7 treatments Standard Error 0.340	5.750 Rank across the 7 treatments Standard Error 0.340

SECONDARY outcome

Timeframe: DEQ was assessed at the 10 time points (predose through 9 hours)

Population: 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.

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

Outcome measures

Outcome measures
Measure	Placebo n=14 Participants Inhaled Staccato Placebo +oral placebo	Oral Alprazolam 1 mg n=14 Participants Oral alprazolam 1 mg + inhaled placebo	Oral Alprazolam 2 mg n=14 Participants Oral alprazolam 2 mg + inhaled placebo	Oral Alprazolam 4 mg n=14 Participants Oral alprazolam 4 mg + inhaled placebo	Inhaled Alprazolam 0.5 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Alprazolam 1 mg n=14 Participants Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Alprazolam 2 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Maximum of DEQ Question 2 "Rate Your Liking of the Drug Effect" at the 10 Time Points (Predose Through 9 Hours)	1.607 Rank across the 7 treatments Standard Error 0.343	3.500 Rank across the 7 treatments Standard Error 0.343	4.536 Rank across the 7 treatments Standard Error 0.343	5.536 Rank across the 7 treatments Standard Error 0.343	2.893 Rank across the 7 treatments Standard Error 0.343	4.250 Rank across the 7 treatments Standard Error 0.343	5.679 Rank across the 7 treatments Standard Error 0.343

SECONDARY outcome

Timeframe: ORQ was assessed at the 10 time points (predose through 9 hours)

Population: 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.

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

Outcome measures

Outcome measures
Measure	Placebo n=14 Participants Inhaled Staccato Placebo +oral placebo	Oral Alprazolam 1 mg n=14 Participants Oral alprazolam 1 mg + inhaled placebo	Oral Alprazolam 2 mg n=14 Participants Oral alprazolam 2 mg + inhaled placebo	Oral Alprazolam 4 mg n=14 Participants Oral alprazolam 4 mg + inhaled placebo	Inhaled Alprazolam 0.5 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Alprazolam 1 mg n=14 Participants Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Alprazolam 2 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Observer Rated Questionnaire 1) Maximum of Sedation/Sleepiness	2.250 Rank across the 7 treatments Standard Error 0.313	3.679 Rank across the 7 treatments Standard Error 0.313	4.607 Rank across the 7 treatments Standard Error 0.313	4.714 Rank across the 7 treatments Standard Error 0.313	3.929 Rank across the 7 treatments Standard Error 0.313	4.000 Rank across the 7 treatments Standard Error 0.313	4.821 Rank across the 7 treatments Standard Error 0.313

SECONDARY outcome

Timeframe: ORQ was assessed at the 10 time points (predose through 9 hours)

Population: 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.

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

Outcome measures

Outcome measures
Measure	Placebo n=14 Participants Inhaled Staccato Placebo +oral placebo	Oral Alprazolam 1 mg n=14 Participants Oral alprazolam 1 mg + inhaled placebo	Oral Alprazolam 2 mg n=14 Participants Oral alprazolam 2 mg + inhaled placebo	Oral Alprazolam 4 mg n=14 Participants Oral alprazolam 4 mg + inhaled placebo	Inhaled Alprazolam 0.5 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Alprazolam 1 mg n=14 Participants Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Alprazolam 2 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Observer Rated Questionnaire 2) Maximum of Muscle Relaxation Locomotor	2.464 Rank across the 7 treatments Standard Error 0.287	2.964 Rank across the 7 treatments Standard Error 0.287	4.643 Rank across the 7 treatments Standard Error 0.287	6.357 Rank across the 7 treatments Standard Error 0.287	2.821 Rank across the 7 treatments Standard Error 0.287	3.571 Rank across the 7 treatments Standard Error 0.287	5.179 Rank across the 7 treatments Standard Error 0.287

SECONDARY outcome

Timeframe: ORQ was assessed at the 10 time points (predose through 9 hours)

Population: 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.

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

Outcome measures

Outcome measures
Measure	Placebo n=14 Participants Inhaled Staccato Placebo +oral placebo	Oral Alprazolam 1 mg n=14 Participants Oral alprazolam 1 mg + inhaled placebo	Oral Alprazolam 2 mg n=14 Participants Oral alprazolam 2 mg + inhaled placebo	Oral Alprazolam 4 mg n=14 Participants Oral alprazolam 4 mg + inhaled placebo	Inhaled Alprazolam 0.5 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Alprazolam 1 mg n=14 Participants Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Alprazolam 2 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Observer Rated Questionnaire 3) Maximum of Muscle Relaxation Non-locomotor	2.536 units on a scale Standard Error 0.282	3.036 units on a scale Standard Error 0.282	4.607 units on a scale Standard Error 0.282	6.393 units on a scale Standard Error 0.282	2.714 units on a scale Standard Error 0.282	3.786 units on a scale Standard Error 0.282	4.929 units on a scale Standard Error 0.282

SECONDARY outcome

Timeframe: ORQ was assessed at the 10 time points (predose through 9 hours)

Population: 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.

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

Outcome measures

Outcome measures
Measure	Placebo n=14 Participants Inhaled Staccato Placebo +oral placebo	Oral Alprazolam 1 mg n=14 Participants Oral alprazolam 1 mg + inhaled placebo	Oral Alprazolam 2 mg n=14 Participants Oral alprazolam 2 mg + inhaled placebo	Oral Alprazolam 4 mg n=14 Participants Oral alprazolam 4 mg + inhaled placebo	Inhaled Alprazolam 0.5 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Alprazolam 1 mg n=14 Participants Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Alprazolam 2 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Observer Rated Questionnaire 4) Maximum of Muscle Relaxation Posture	2.750 Rank across the 7 treatments Standard Error 0.337	2.893 Rank across the 7 treatments Standard Error 0.337	3.964 Rank across the 7 treatments Standard Error 0.337	6.250 Rank across the 7 treatments Standard Error 0.337	2.929 Rank across the 7 treatments Standard Error 0.337	2.929 Rank across the 7 treatments Standard Error 0.337	2.929 Rank across the 7 treatments Standard Error 0.337

SECONDARY outcome

Timeframe: ORQ was assessed at the 10 time points (predose through 9 hours)

Population: 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.

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

Outcome measures

Outcome measures
Measure	Placebo n=14 Participants Inhaled Staccato Placebo +oral placebo	Oral Alprazolam 1 mg n=14 Participants Oral alprazolam 1 mg + inhaled placebo	Oral Alprazolam 2 mg n=14 Participants Oral alprazolam 2 mg + inhaled placebo	Oral Alprazolam 4 mg n=14 Participants Oral alprazolam 4 mg + inhaled placebo	Inhaled Alprazolam 0.5 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Alprazolam 1 mg n=14 Participants Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Alprazolam 2 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Observer Rated Questionnaire 5) Maximum of Speech	2.214 Rank across the 7 treatments Standard Error 0.284	2.893 Rank across the 7 treatments Standard Error 0.284	4.786 Rank across the 7 treatments Standard Error 0.284	6.393 Rank across the 7 treatments Standard Error 0.284	3.071 Rank across the 7 treatments Standard Error 0.284	3.071 Rank across the 7 treatments Standard Error 0.284	5.357 Rank across the 7 treatments Standard Error 0.284

SECONDARY outcome

Timeframe: ORQ was assessed at the 10 time points (predose through 9 hours)

Population: 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.

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

Outcome measures

Outcome measures
Measure	Placebo n=14 Participants Inhaled Staccato Placebo +oral placebo	Oral Alprazolam 1 mg n=14 Participants Oral alprazolam 1 mg + inhaled placebo	Oral Alprazolam 2 mg n=14 Participants Oral alprazolam 2 mg + inhaled placebo	Oral Alprazolam 4 mg n=14 Participants Oral alprazolam 4 mg + inhaled placebo	Inhaled Alprazolam 0.5 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Alprazolam 1 mg n=14 Participants Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Alprazolam 2 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Observer Rated Questionnaire 6) Maximum of Confusion/Disorientation	1.929 Rank across the 7 treatments Standard Error 0.282	2.821 Rank across the 7 treatments Standard Error 0.282	4.893 Rank across the 7 treatments Standard Error 0.282	6.429 Rank across the 7 treatments Standard Error 0.282	3.393 Rank across the 7 treatments Standard Error 0.282	3.107 Rank across the 7 treatments Standard Error 0.282	5.429 Rank across the 7 treatments Standard Error 0.282

SECONDARY outcome

Timeframe: ORQ was assessed at the 10 time points (predose through 9 hours)

Population: 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.

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

Outcome measures

Outcome measures
Measure	Placebo n=14 Participants Inhaled Staccato Placebo +oral placebo	Oral Alprazolam 1 mg n=14 Participants Oral alprazolam 1 mg + inhaled placebo	Oral Alprazolam 2 mg n=14 Participants Oral alprazolam 2 mg + inhaled placebo	Oral Alprazolam 4 mg n=14 Participants Oral alprazolam 4 mg + inhaled placebo	Inhaled Alprazolam 0.5 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo	Inhaled Alprazolam 1 mg n=14 Participants Inhaled Staccato alprazolam 1 mg + oral placebo	Inhaled Alprazolam 2 mg n=14 Participants Inhaled Staccato alprazolam 0.5 mg + oral placebo placebo
Observer Rated Questionnaire 7) Maximum of Stimulation/Arousal	3.964 Rank across the 7 treatments Standard Error 0.087	3.964 Rank across the 7 treatments Standard Error 0.087	3.964 Rank across the 7 treatments Standard Error 0.087	3.964 Rank across the 7 treatments Standard Error 0.087	3.964 Rank across the 7 treatments Standard Error 0.087	3.964 Rank across the 7 treatments Standard Error 0.087	4,214 Rank across the 7 treatments Standard Error 0.087

SECONDARY outcome

Timeframe: ORQ was assessed at the 10 time points (predose through 9 hours)

Population: 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.

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