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SM-1 vs 2 Comparators and Placebo in Participants With a History of Transient Insomnia.

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ClinicalTrials.gov Identifier: NCT03331042
Recruitment Status : Completed
First Posted : November 6, 2017
Results First Posted : June 5, 2019
Last Update Posted : June 5, 2019
Sponsor:
Information provided by (Responsible Party):
Sequential Medicine Ltd

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Transient Insomnia
Interventions Drug: SM-1
Drug: D+Z
Drug: D+L
Drug: Placebo
Enrollment 85
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Sequence 1 Sequence 2 Sequence 3 Sequence 4
Hide Arm/Group Description

SM-1 (Treatment Period 1), D+Z (Treatment Period 2), D+L (Treatment Period 3), Placebo (Treatment Period 4).

SM-1: 3-drug combination product containing 50-mg diphenhydramine, 5-mg delayed-release zolpidem and 0.5-mg delayed-release lorazepam.

D+Z: 2-drug combination comparator product containing 50-mg diphenhydramine and 5-mg delayed-release zolpidem.

D+L: 2-drug combination comparator product containing 50-mg diphenhydramine and 0.5-mg delayed-release lorazepam.

Placebo: Identical in appearance to SM-1, D+Z and D+L and has the same excipients, but no diphenhydramine, zolpidem, lorazepam or delayed-release coating materials.

D+Z (Treatment Period 1), D+L (Treatment Period 2), Placebo (Treatment Period 3), SM-1 (Treatment Period 4).

SM-1: 3-drug combination product containing 50-mg diphenhydramine, 5-mg delayed-release zolpidem and 0.5-mg delayed-release lorazepam.

D+Z: 2-drug combination comparator product containing 50-mg diphenhydramine and 5-mg delayed-release zolpidem.

D+L: 2-drug combination comparator product containing 50-mg diphenhydramine and 0.5-mg delayed-release lorazepam.

Placebo: Identical in appearance to SM-1, D+Z and D+L and has the same excipients, but no diphenhydramine, zolpidem, lorazepam or delayed-release coating materials.

D+L (Treatment Period 1), Placebo (Treatment Period 2), SM-1 (Treatment Period 3), D+Z (Treatment Period 4).

SM-1: 3-drug combination product containing 50-mg diphenhydramine, 5-mg delayed-release zolpidem and 0.5-mg delayed-release lorazepam.

D+Z: 2-drug combination comparator product containing 50-mg diphenhydramine and 5-mg delayed-release zolpidem.

D+L: 2-drug combination comparator product containing 50-mg diphenhydramine and 0.5-mg delayed-release lorazepam.

Placebo: Identical in appearance to SM-1, D+Z and D+L and has the same excipients, but no diphenhydramine, zolpidem, lorazepam or delayed-release coating materials.

Placebo (Treatment Period 1), SM-1 (Treatment Period 2), D+Z (Treatment Period 3), D+L (Treatment Period 4).

SM-1: 3-drug combination product containing 50-mg diphenhydramine, 5-mg delayed-release zolpidem and 0.5-mg delayed-release lorazepam.

D+Z: 2-drug combination comparator product containing 50-mg diphenhydramine and 5-mg delayed-release zolpidem.

D+L: 2-drug combination comparator product containing 50-mg diphenhydramine and 0.5-mg delayed-release lorazepam.

Placebo: Identical in appearance to SM-1, D+Z and D+L and has the same excipients, but no diphenhydramine, zolpidem, lorazepam or delayed-release coating materials.

Period Title: Overall Study
Started 22 21 21 21
Completed 21 21 20 20
Not Completed 1 0 1 1
Reason Not Completed
Protocol Violation             1             0             0             0
Physician Decision             0             0             1             0
Lost to Follow-up             0             0             0             1
Arm/Group Title Sequence 1 Sequence 2 Sequence 3 Sequence 4 Total
Hide Arm/Group Description

SM-1 (Treatment Period 1), D+Z (Treatment Period 2), D+L (Treatment Period 3), Placebo (Treatment Period 4).

SM-1: 3-drug combination product containing 50-mg diphenhydramine, 5-mg delayed-release zolpidem and 0.5-mg delayed-release lorazepam.

D+Z: 2-drug combination comparator product containing 50-mg diphenhydramine and 5-mg delayed-release zolpidem.

D+L: 2-drug combination comparator product containing 50-mg diphenhydramine and 0.5-mg delayed-release lorazepam.

Placebo: Identical in appearance to SM-1, D+Z and D+L and has the same excipients, but no diphenhydramine, zolpidem, lorazepam or delayed-release coating materials.

D+Z (Treatment Period 1), D+L (Treatment Period 2), Placebo (Treatment Period 3), SM-1 (Treatment Period 4).

SM-1: 3-drug combination product containing 50-mg diphenhydramine, 5-mg delayed-release zolpidem and 0.5-mg delayed-release lorazepam.

D+Z: 2-drug combination comparator product containing 50-mg diphenhydramine and 5-mg delayed-release zolpidem.

D+L: 2-drug combination comparator product containing 50-mg diphenhydramine and 0.5-mg delayed-release lorazepam.

Placebo: Identical in appearance to SM-1, D+Z and D+L and has the same excipients, but no diphenhydramine, zolpidem, lorazepam or delayed-release coating materials.

D+L (Treatment Period 1), Placebo (Treatment Period 2), SM-1 (Treatment Period 3), D+Z (Treatment Period 4).

SM-1: 3-drug combination product containing 50-mg diphenhydramine, 5-mg delayed-release zolpidem and 0.5-mg delayed-release lorazepam.

D+Z: 2-drug combination comparator product containing 50-mg diphenhydramine and 5-mg delayed-release zolpidem.

D+L: 2-drug combination comparator product containing 50-mg diphenhydramine and 0.5-mg delayed-release lorazepam.

Placebo: Identical in appearance to SM-1, D+Z and D+L and has the same excipients, but no diphenhydramine, zolpidem, lorazepam or delayed-release coating materials.

Placebo (Treatment Period 1), SM-1 (Treatment Period 2), D+Z (Treatment Period 3), D+L (Treatment Period 4).

SM-1: 3-drug combination product containing 50-mg diphenhydramine, 5-mg delayed-release zolpidem and 0.5-mg delayed-release lorazepam.

D+Z: 2-drug combination comparator product containing 50-mg diphenhydramine and 5-mg delayed-release zolpidem.

D+L: 2-drug combination comparator product containing 50-mg diphenhydramine and 0.5-mg delayed-release lorazepam.

Placebo: Identical in appearance to SM-1, D+Z and D+L and has the same excipients, but no diphenhydramine, zolpidem, lorazepam or delayed-release coating materials.

Total of all reporting groups
Overall Number of Baseline Participants 22 21 21 21 85
Hide Baseline Analysis Population Description
Subjects were randomized to one of four possible planned order of treatments (Sequences) given in the protocol.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 22 participants 21 participants 21 participants 21 participants 85 participants
38.7  (13.68) 39.3  (13.29) 36.1  (11.68) 41.6  (11.77) 38.9  (12.57)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 22 participants 21 participants 21 participants 21 participants 85 participants
Female
13
  59.1%
10
  47.6%
9
  42.9%
11
  52.4%
43
  50.6%
Male
9
  40.9%
11
  52.4%
12
  57.1%
10
  47.6%
42
  49.4%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 22 participants 21 participants 21 participants 21 participants 85 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
3
  13.6%
0
   0.0%
1
   4.8%
1
   4.8%
5
   5.9%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
12
  54.5%
13
  61.9%
10
  47.6%
15
  71.4%
50
  58.8%
White
7
  31.8%
6
  28.6%
7
  33.3%
4
  19.0%
24
  28.2%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
2
   9.5%
3
  14.3%
1
   4.8%
6
   7.1%
1.Primary Outcome
Title Total Sleep Time (TST)
Hide Description TST efficacy of SM-1 versus placebo, combination product diphenhydramine plus zolpidem and combination product diphenhydramine plus lorazepam measured by polysomnography (PSG)-defined total sleep time (TST)
Time Frame 8 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set consisted of all subjects who were randomized to a treatment sequence, and had taken any study drug.
Arm/Group Title SM-1 Diphenhydramine Plus Zolpidem Diphenhydramine Plus Lorazepam Placebo
Hide Arm/Group Description:
Subjects received a single dose of the triple drug combination
Subjects received a single dose of the 2-drug product containing Diphenhydramine plus Zolpidem; i.e., SM-1 without Lorazepam
Subjects received a single dose of the 2-drug product containing Diphenhydramine plus Lorazepam; i.e., SM-1 without Zolpidem
Subjects received a single dose of a Placebo matching the appearance of the active treatments but containing no active drug components
Overall Number of Participants Analyzed 84 83 83 83
Mean (Standard Deviation)
Unit of Measure: minutes
401.82  (68.074) 404.83  (47.252) 397.28  (56.982) 307.38  (107.365)
2.Secondary Outcome
Title Latency to Persistent Sleep (LPS)
Hide Description Efficacy of SM-1 versus placebo, combination product diphenhydramine plus zolpidem and combination product diphenhydramine plus lorazepam measured by polysomnography (PSG)-measured sleep induction, the amount of time it takes the subject to fall asleep.
Time Frame 8 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set consisted of all subjects who were randomized to a treatment sequence, and had taken any study drug.
Arm/Group Title SM-1 Diphenhydramine and Zolpidem Diphenhydramine and Lorazepam Placebo
Hide Arm/Group Description:
Triple drug combination
Diphenhydramine and zolpidem
diphenhydramine and lorazepam
Placebo
Overall Number of Participants Analyzed 84 83 83 83
Mean (Standard Deviation)
Unit of Measure: minutes
18.59  (18.548) 23.10  (29.145) 23.55  (29.125) 39.25  (73.961)
3.Secondary Outcome
Title Number of Awakenings (NAW)
Hide Description NAW efficacy of SM-1 versus placebo, combination product diphenhydramine plus zolpidem and combination product diphenhydramine plus lorazepam measured by polysomnography (PSG)-measured sleep maintenance.
Time Frame 8 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set consisted of all subjects who were randomized to a treatment sequence, and had taken any study drug.
Arm/Group Title SM-1 Diphenhydramine and Zolpidem Diphenhydramine and Lorazepam Placebo
Hide Arm/Group Description:
Triple drug combination
Diphenhydramine and zolpidem
diphenhydramine and lorazepam
Placebo
Overall Number of Participants Analyzed 84 83 83 83
Mean (Standard Deviation)
Unit of Measure: awakenings
11.0  (6.06) 10.7  (6.22) 11.0  (5.91) 8.6  (5.06)
4.Secondary Outcome
Title Wakefulness After Sleep Onset (WASO)
Hide Description WASO efficacy of SM-1 versus placebo, combination product diphenhydramine plus zolpidem and combination product diphenhydramine plus lorazepam measured by polysomnography (PSG)-measured sleep maintenance as the amount of time spent awake after falling asleep.
Time Frame 8 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set consisted of all subjects who were randomized to a treatment sequence, and had taken any study drug.
Arm/Group Title SM-1 Diphenhydramine and Zolpidem Diphenhydramine and Lorazepam Placebo
Hide Arm/Group Description:
Triple drug combination
Diphenhydramine and zolpidem
diphenhydramine and lorazepam
Placebo
Overall Number of Participants Analyzed 84 83 83 83
Mean (Standard Deviation)
Unit of Measure: minutes
64.11  (66.673) 58.83  (41.834) 63.91  (49.841) 140.06  (99.366)
5.Secondary Outcome
Title Karolinska Sleepiness Scale (KSS) of Morning Alertness.
Hide Description Morning alertness measured by Karolinska Sleepiness Scale (KSS). KSS ranges from 1-9, with higher numbers indicating sleepier and lower numbers more alert.
Time Frame Up to Visit 5
Hide Outcome Measure Data
Hide Analysis Population Description
The Safety Population included all subjects that received any study drug, and were grouped by actual treatment.
Arm/Group Title SM-1 Diphenhydramine and Zolpidem Diphenhydramine and Lorazepam Placebo
Hide Arm/Group Description:
Triple drug combination
Diphenhydramine and zolpidem
diphenhydramine and lorazepam
Placebo
Overall Number of Participants Analyzed 84 83 83 83
Mean (Standard Deviation)
Unit of Measure: units on a scale
4.2  (1.99) 3.9  (2.01) 3.9  (2.02) 3.9  (2.01)
6.Secondary Outcome
Title Number Correct on Digit Symbol Substitution Test (DSST)
Hide Description Morning alertness measured by DSST. The digit symbol substitution test assesses attention, psychomotor speed, complex scanning, visual tracking, and immediate memory. This test consists of 4 rows each with 25 small blank squares; above each square is a number between 1 and 9. At the top is a 'key,' which pairs each number (1 through 9) with an unfamiliar symbol. The participant has 90 seconds to work as quickly as possible (left to right across the rows) to fill in each blank square with the appropriate symbol based on the number above the square. Results are presented as total number correct; therefore, lower numbers indicate greater impairment. Scores on the DSST range from 0-93
Time Frame Up to Visit 5
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population included all subjects that received any study drug, and were grouped by actual treatment.
Arm/Group Title SM-1 Diphenhydramine and Zolpidem Diphenhydramine and Lorazepam Placebo
Hide Arm/Group Description:
Triple drug combination
Diphenhydramine and zolpidem
diphenhydramine and lorazepam
Placebo
Overall Number of Participants Analyzed 84 83 83 83
Mean (Standard Deviation)
Unit of Measure: number correct
56.0  (14.21) 57.6  (14.98) 58.3  (16.20) 60.4  (16.81)
7.Secondary Outcome
Title Subjective Total Sleep Time (sTST)
Hide Description Subject reported TST from Post-Sleep Questionnaire (PSQ).
Time Frame Up to 22 days.
Hide Outcome Measure Data
Hide Analysis Population Description
All subjects who were randomized to a treatment sequence, and had taken any study drug.
Arm/Group Title SM-1 Diphenhydramine and Zolpidem Diphenhydramine and Lorazepam Placebo
Hide Arm/Group Description:
Triple drug combination
Diphenhydramine and zolpidem
diphenhydramine and lorazepam
Placebo
Overall Number of Participants Analyzed 84 83 82 83
Mean (Standard Deviation)
Unit of Measure: minutes
441.1  (55.97) 419.0  (79.60) 422.9  (83.63) 368.7  (107.47)
8.Secondary Outcome
Title Subjective Sleep Onset Latency (sSOL)
Hide Description Subject reported SOL, the amount of time the subject felt it took to fall asleep, from Post-Sleep Questionnaire (PSQ).
Time Frame Up to 22 days.
Hide Outcome Measure Data
Hide Analysis Population Description
All subjects who were randomized to a treatment sequence, and had taken any study drug.
Arm/Group Title SM-1 Diphenhydramine and Zolpidem Diphenhydramine and Lorazepam Placebo
Hide Arm/Group Description:
Triple drug combination
Diphenhydramine and zolpidem
diphenhydramine and lorazepam
Placebo
Overall Number of Participants Analyzed 84 83 82 83
Mean (Standard Error)
Unit of Measure: minutes
22.7  (24.30) 27.7  (34.29) 26.6  (51.81) 34.8  (55.53)
9.Secondary Outcome
Title Subjective Number of Awakenings (sNAW)
Hide Description Subject reported NAW from Post-Sleep Questionnaire (PSQ).
Time Frame Up to 22 days.
Hide Outcome Measure Data
Hide Analysis Population Description
All subjects who were randomized to a treatment sequence, and had taken any study drug.
Arm/Group Title SM-1 Diphenhydramine Plus Zolpidem Diphenhydramine Plus Lorazepam Placebo
Hide Arm/Group Description:
Triple drug combination
Diphenhydramine plus Zolpidem
Diphenhydramine plus Lorazepam
Placebo
Overall Number of Participants Analyzed 84 83 80 82
Mean (Standard Deviation)
Unit of Measure: awakenings
2.0  (1.73) 2.2  (2.19) 2.2  (1.47) 2.8  (1.83)
10.Secondary Outcome
Title Number of Participants According to Sleep Quality
Hide Description Subject reported sleep quality, how well the subject felt he or she slept, from Post-Sleep Questionnaire (PSQ).
Time Frame Up to 22 days.
Hide Outcome Measure Data
Hide Analysis Population Description
All subjects who were randomized to a treatment sequence, and had taken any study drug.
Arm/Group Title SM-1 Diphenhydramine and Zolpidem Diphenhydramine and Lorazepam Placebo
Hide Arm/Group Description:
Triple drug combination
Diphenhydramine and zolpidem
diphenhydramine and lorazepam
Placebo
Overall Number of Participants Analyzed 84 83 83 83
Measure Type: Count of Participants
Unit of Measure: Participants
1 = poor
5
   6.0%
3
   3.6%
7
   8.4%
15
  18.1%
2 = fair
13
  15.5%
17
  20.5%
15
  18.1%
39
  47.0%
3 = good
43
  51.2%
48
  57.8%
49
  59.0%
21
  25.3%
4 = excellent
23
  27.4%
15
  18.1%
12
  14.5%
8
   9.6%
11.Other Pre-specified Outcome
Title Number of Minutes of Sleep in Stages N1, N2, N3, Rapid Eye Movement (REM) and Latency to REM Onset.
Hide Description Effect of SM-1 and the two 2-drug combination products (diphenhydramine plus zolpidem and diphenhydramine plus lorazepam) on sleep stage distribution.
Time Frame 8 hours
Outcome Measure Data Not Reported
Time Frame From Day 1 until 7 days after the last dose of study drug.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title SM-1 Diphenhydramine Plus Zolpidem Diphenhydramine Plus Lorazepam Placebo
Hide Arm/Group Description Triple drug combination Diphenhydramine plus Zolpidem Diphenhydramine plus Lorazepam Placebo
All-Cause Mortality
SM-1 Diphenhydramine Plus Zolpidem Diphenhydramine Plus Lorazepam Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/84 (0.00%)      0/83 (0.00%)      0/83 (0.00%)      0/83 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
SM-1 Diphenhydramine Plus Zolpidem Diphenhydramine Plus Lorazepam Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/84 (0.00%)      0/83 (0.00%)      0/83 (0.00%)      0/83 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
SM-1 Diphenhydramine Plus Zolpidem Diphenhydramine Plus Lorazepam Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/84 (3.57%)      2/83 (2.41%)      1/83 (1.20%)      1/83 (1.20%)    
Gastrointestinal disorders         
abdominal pain  3 [1]  0/84 (0.00%)  0 1/83 (1.20%)  1 0/83 (0.00%)  0 0/83 (0.00%)  0
General disorders         
asthenia  4 [2]  1/84 (1.19%)  1 0/83 (0.00%)  0 1/83 (1.20%)  1 0/83 (0.00%)  0
fatigue  5 [3]  0/84 (0.00%)  0 0/83 (0.00%)  0 1/83 (1.20%)  1 0/83 (0.00%)  0
Nervous system disorders         
nightmare  1 [4]  1/84 (1.19%)  1 0/83 (0.00%)  0 0/83 (0.00%)  0 0/83 (0.00%)  0
somnolence  2 [5]  1/84 (1.19%)  1 1/83 (1.20%)  1 0/83 (0.00%)  0 1/83 (1.20%)  1
1
Term from vocabulary, nightmare
2
Term from vocabulary, somnolence
3
Term from vocabulary, abdominal pain
4
Term from vocabulary, asthenia
5
Term from vocabulary, fatigue
Indicates events were collected by systematic assessment
[1]
upper abdominal pain
[2]
asthenia
[3]
fatigue
[4]
Nightmare
[5]
somnolence
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Thomas Dahl
Organization: Sequential Medicine Ltd
Phone: 617-818-2735
EMail: tadahl@outlook.com
Layout table for additonal information
Responsible Party: Sequential Medicine Ltd
ClinicalTrials.gov Identifier: NCT03331042     History of Changes
Other Study ID Numbers: SM-A-05
First Submitted: October 29, 2017
First Posted: November 6, 2017
Results First Submitted: April 16, 2019
Results First Posted: June 5, 2019
Last Update Posted: June 5, 2019