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Safety and Efficacy of AVP-923 in PBA Patients With ALS or MS (STAR)

This study has been completed.
Sponsor:
Collaborator:
INC Research
Information provided by (Responsible Party):
Avanir Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT00573443
First received: December 13, 2007
Last updated: March 15, 2017
Last verified: March 2017
Results First Received: July 18, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Pseudobulbar Affect (PBA)
Interventions: Drug: dextromethorphan hydrobromide 20 mg and quinidine sulfate 10 mg
Drug: dextromethorphan hydrobromide 30 mg and quinidine sulfate 10 mg
Drug: Placebo

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Subjects diagnosed with pseudobulbar affect (PBA) secondary to amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS).

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
AVP-923-30 AVP-923 capsules containing 30 mg dextromethorphan (DM) and 10 mg quinidine (Q) taken orally once daily for 1 week and twice daily for 11 additional consecutive weeks for a 12 week double-blind (DB) period. Subjects who completed the DB period of this treatment arm could begin an optional 12 week open-label extension (OLE) period taking AVP-923 capsule containing 30 mg DM and 10 mg Q twice daily.
AVP-923-20 AVP-923 capsules containing 20 mg DM and 10 mg Q taken orally once daily for 1 week and twice daily for 11 additional consecutive weeks for a 12 week DB period. Subjects who completed the DB period of this treatment arm could begin an optional 12 week OLE period taking AVP-923 capsule containing 30 mg DM and 10 mg Q twice daily.
Placebo Capsules containing placebo once daily for 1 week and twice daily for 11 additional consecutive weeks for a 12 week DB period. Subjects who completed the DB period of this treatment arm could begin an optional 12 week OLE period taking AVP-923 capsule containing 30 mg DM and 10 mg Q twice daily.

Participant Flow for 2 periods

Period 1:   Double-Blind Phase
    AVP-923-30   AVP-923-20   Placebo
STARTED   110   107   109 
Subjects With PBA Secondary to ALS   65   68   64 
Subjects With PBA Secondary to MS   45   39   45 
COMPLETED   101   88   94 
NOT COMPLETED   9   19   15 
Lost to Follow-up                1                3                2 
Exacerbation of MS symptoms                1                0                1 
Adverse Event                1                5                0 
Serious Adverse Event (AE)                2                3                1 
Medication refusal due to AE                2                2                0 
Withdrawal by Subject                2                2                7 
Protocol Violation                0                2                1 
Not specified                0                2                3 

Period 2:   Open-Label Extension Phase
    AVP-923-30   AVP-923-20   Placebo
STARTED   253 [1]   0 [2]   0 [2] 
Subjects With PBA Secondary to ALS   146   0 [2]   0 [2] 
Subjects With PBA Secondary to MS   107   0 [2]   0 [2] 
COMPLETED   235   0 [2]   0 [2] 
NOT COMPLETED   18   0   0 
Lost to Follow-up                1                0                0 
Exacerbation of MS symptoms                2                0                0 
Adverse Event                3                0                0 
Serious Adverse Event                5                0                0 
Withdrawal by Subject                3                0                0 
Protocol Violation                2                0                0 
Not Specified                2                0                0 
[1] Subjects who completed any of the arms in the DB phase had the option to enroll in this OLE phase
[2] DB period of this arm could begin an optional 12 week OLE period taking AVP-923-30.



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
AVP-923-30 AVP-923 capsules containing 30 mg dextromethorphan (DM) and 10 mg quinidine (Q) taken orally once daily for 1 week and twice daily for 11 additional consecutive weeks for a 12 week double-blind (DB) period. Subjects who completed the DB period of this treatment arm could begin an optional 12 week open-label extension (OLE) period taking AVP-923 capsule containing 30 mg DM and 10 mg Q twice daily.
AVP-923-20 AVP-923 capsules containing 20 mg DM and 10 mg Q taken orally once daily for 1 week and twice daily for 11 additional consecutive weeks for a 12 week DB period. Subjects who completed the DB period of this treatment arm could begin an optional 12 week OLE period taking AVP-923 capsule containing 30 mg DM and 10 mg Q twice daily.
Placebo Capsules containing placebo once daily for 1 week and twice daily for 11 additional consecutive weeks for a 12 week DB period. Subjects who completed the DB period of this treatment arm could begin an optional 12 week OLE period taking AVP-923 capsule containing 30 mg DM and 10 mg Q twice daily.
Total Total of all reporting groups

Baseline Measures
   AVP-923-30   AVP-923-20   Placebo   Total 
Overall Participants Analyzed 
[Units: Participants]
 110   107   109   326 
Age 
[Units: Years]
Mean (Standard Deviation)
 53.08  (11.016)   50.81  (11.114)   50.27  (11.939)   51.39  (11.356) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
       
Female      64  58.2%      54  50.5%      59  54.1%      177  54.3% 
Male      46  41.8%      53  49.5%      50  45.9%      149  45.7% 


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   PBA Episode Rate Ratio (Post/Pre), Regression Adjusted   [ Time Frame: Baseline to Day 84 ]
  Hide Outcome Measure 1

Measure Type Primary
Measure Title PBA Episode Rate Ratio (Post/Pre), Regression Adjusted
Measure Description Episodes were counted each day and recorded in a daily diary. The outcome measure is the ratio of the episode rate over the 84-day treatment period to the rate during the baseline period, adjusted for study site, and underlying disease using longitudinal negative binomial regression.
Time Frame Baseline to Day 84  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-Treat (ITT) population - included all randomized subjects for the double-blind phase and all enrolled subjects for the open-label extension phase.

Reporting Groups
  Description
AVP-923-30 AVP-923 capsules containing 30 mg dextromethorphan (DM) and 10 mg quinidine (Q) taken orally once daily for 1 week and twice daily for 11 additional consecutive weeks for a 12 week double-blind (DB) period. Subjects who completed the DB period of this treatment arm could begin an optional 12 week open-label extension (OLE) period taking AVP-923 capsule containing 30 mg DM and 10 mg Q twice daily.
AVP-923-20 AVP-923 capsules containing 20 mg DM and 10 mg Q taken orally once daily for 1 week and twice daily for 11 additional consecutive weeks for a 12 week DB period. Subjects who completed the DB period of this treatment arm could begin an optional 12 week OLE period taking AVP-923 capsule containing 30 mg DM and 10 mg Q twice daily.
Placebo Capsules containing placebo once daily for 1 week and twice daily for 11 additional consecutive weeks for a 12 week DB period. Subjects who completed the DB period of this treatment arm could begin an optional 12 week OLE period taking AVP-923 capsule containing 30 mg DM and 10 mg Q twice daily.

Measured Values
   AVP-923-30   AVP-923-20   Placebo 
Participants Analyzed 
[Units: Participants]
 110   107   109 
PBA Episode Rate Ratio (Post/Pre), Regression Adjusted 
[Units: Unit-free (ratio of episodes/week)]
Least Squares Mean (95% Confidence Interval)
 0.247 
 (0.233 to 0.262) 
 0.237 
 (0.224 to 0.251) 
 0.465 
 (0.441 to 0.489) 


Statistical Analysis 1 for PBA Episode Rate Ratio (Post/Pre), Regression Adjusted
Groups [1] AVP-923-30 vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Longitudinal neg. binomial
P Value [4] <0.0001
Ratio of episode-rate reduction ratios [5] 0.5312
95% Confidence Interval 0.4939 to 0.5714
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis of PBA episode rates used longitudinal negative binomial regression with treatment, period, diagnosis and study site to estimate pre-post changes in log mean episode rate for each treatment group. Null hypothesis of equal pre-post episode rate reductions were tested: AVP-923-30/placebo = 1.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for PBA Episode Rate Ratio (Post/Pre), Regression Adjusted
Groups [1] AVP-923-20 vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Longitudinal neg. binomial
P Value [4] <0.0001
Ratio of episode-rate reduction ratios [5] 0.5103
95% Confidence Interval 0.4755 to 0.5477
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis of PBA episode rates used longitudinal negative binomial regression with treatment, period, diagnosis and study site to estimate pre-post changes in log mean episode rate for each treatment group. Null hypothesis of equal pre-post episode rate reductions were tested: AVP-923-20/placebo = 1.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  No text entered.



2.  Secondary:   Mean Change From Baseline in CNS-LS Total Score by Visit   [ Time Frame: Baseline, Day 15, Day 29, Day 57, Day 84 ]

3.  Secondary:   Mean Change From Baseline to Day 84 in Neuropsychiatric Inventory (NPI-Q) Frequency and Severity Score (EE Population)   [ Time Frame: Baseline to Day 84 ]

4.  Secondary:   Mean Change From Baseline to Day 84 in Neuropsychiatric Inventory (NPI-Q) Frequency and Severity Score (ITT Population)   [ Time Frame: Baseline to Day 84 ]

5.  Secondary:   Mean Change From Baseline at Day 84 in SF-36 (Short-Form) Health Survey Medical Outcome Score by Category   [ Time Frame: Baseline and Day 84 ]

6.  Secondary:   Mean Change From Baseline at Day 84 in Beck Depression Inventory (BDI-II) Total Score   [ Time Frame: Baseline and Day 84 ]

7.  Secondary:   Mean Change From Baseline to Day 84 in Pain Rating Scale (PRS) of MS Subjects   [ Time Frame: Baseline, Day 15, Day 29, Day 57, Day 84 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information