A Phase 3 interventional study of dextromethorphan hydrobromide 20 mg and quinidine sulfate 10 mg and dextromethorphan hydrobromide 30 mg and quinidine sulfate 10 mg in Pseudobulbar Affect (PBA), sponsored by Avanir Pharmaceuticals. Completed at 62 sites in 3 countries. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2017-04-12.
Sponsored by Avanir Pharmaceuticals (part of Otsuka Holdings Co., Ltd.) · Phase 3, Interventional, and Treatment
Objectives of the study are to evaluate the safety, tolerability, and efficacy of two different doses of AVP-923 (capsules containing either 30 mg of dextromethorphan hydrobromide and 10 mg of quinidine sulfate [AVP-923-30] or 20 mg of dextromethorphan hydrobromide and 10 mg of quinidine sulfate [AVP-923-20]) when compared to placebo, for the treatment of PBA in a population of patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS) over a 12-week period. An additional objective is to determine the pharmacokinetic parameters of the two different doses of AVP-923 in a subset of the study population.
Pseudobulbar Affect (PBA) is a condition characterized by involuntary, sudden and frequent episodes of laughing and/or crying out of proportion or incongruous to the underlying emotion of happiness or sadness Other terms used to describe this condition include emotional lability, emotionalism, emotional incontinence, emotional discontrol, excessive emotionalism, and pathological laughing and crying. The outbursts can occur spontaneously or in response to provocative stimuli such as questions or events.
A body of evidence suggests that PBA can be modulated through pharmacologic intervention.
Dextromethorphan (DM) is a low-affinity uncompetitive antagonist of the N-Methyl-D-aspartate (NMDA) receptor, reducing the level of excitatory activity. DM also acts at the phencyclidine-binding site, which is part of the NMDA receptor complex. DM is a sigma receptor agonist, suppressing the release of excitatory neurotransmitters.
Quinidine (Q) is a known potent inhibitor of cytochrome P450 2D6 (CYP2D6), that decreases the metabolism of dextromethorphan and helps to achieve sustained and therapeutic levels of this drug.
978 studies on the registry are indexed under Amyotrophic Lateral Sclerosis; 277 are open to participants now.
This study's enrollment of 326 is above the median of 38 across 662 interventional studies indexed under Amyotrophic Lateral Sclerosis.
Browse Amyotrophic Lateral Sclerosis studies →Avanir Pharmaceuticals is the lead sponsor of 13 studies on the registry; none are open to participants now.
First submitted before Avanir Pharmaceuticals became part of Otsuka Holdings Co., Ltd..
Counted across the registry records on this site, refreshed daily.
Main Inclusion Criteria:
Main Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
QT and QTc
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
AVP-923-30/10 Capsules (30 mg dextromethorphan/10 mg quinidine)administered once daily for 1 week and then twice daily for 11 weeks
Drug: dextromethorphan hydrobromide 30 mg and quinidine sulfate 10 mg
AVP-923-20/10 Capsules (20 mg dextromethorphan/10 mg quinidine)administered once daily for 1 week and then twice daily for 11 weeks
Drug: dextromethorphan hydrobromide 20 mg and quinidine sulfate 10 mg
Placebo Capsules once daily for 1 week and then twice daily for an additional 11 weeks
Drug: Placebo
Drug page: Dextromethorphan
Dextromethorphan hydrobromide (DM) and quinidine sulfate (Q) capsules (AVP-923 capsules), containing DM 20 mg/ Q 10 mg, taken once daily for 1 week and then twice daily for 11 consecutive weeks to complete a 12-week period
Also known as: AVP-923, Nuedexta™, DM 20 mg/ Q 10 mg, DMQ
Drug page: Dextromethorphan
Dextromethorphan hydrobromide (DM) and quinidine sulfate (Q) capsules (AVP-923 capsules), containing DM 30 mg/ Q 10 mg taken once daily for 1 week and then twice daily for 11 consecutive weeks to complete a 12-week period
Also known as: AVP-923, DM 30 mg/ Q 10 mg, DMQ
Placebo capsules (identical in appearance to AVP-923 capsules being studied in this trial), taken once daily for 1 week and then twice daily for 11 consecutive weeks to complete a 12-week period
PBA Episode Rate Ratio (Post/Pre), Regression Adjusted
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
Mean Change From Baseline in CNS-LS Total Score by Visit
Center for Neurologic Studies-Lability Scale (CNS-LS) is an instrument for the measurement of PBA that has been validated for the use in patients with ALS and MS. It is a 7-item self-report questionnaire that measures the frequency and severity of PBA episodes, including assessments of labile laughter and labile tearfulness,and provides a score for total PBA (total score can range from 7-35). The following 5-point scoring was used: 1=Applies never, 2=Applies rarely, 3=Applies occasionally, 4=Applies frequently, 5=Applies most of the time. A score of 13 or higher may suggest PBA, and the higher the score the more severe the episodes.
Time frame: Baseline, Day 15, Day 29, Day 57, Day 84
Mean Change From Baseline to Day 84 in Neuropsychiatric Inventory (NPI-Q) Frequency and Severity Score (EE Population)
The NPI is a retrospective (to 1 month) caregiver-informant interview assessing frequency and severity of 12 neuropsychiatric symptom domains. The NPI score is based on the sum of the severity ratings (0=absent, 1=mild, 3=severe). The 12 symptom domains include delusions, hallucinations, agitation/aggression, dysphoria/depression, anxiety, euphoria/elation, apathy/indifference, disinhibition, irritability/lability, aberrant motor behaviors, nighttime behavioral disturbances, and appetite/eating abnormalities. The NPI severity score is based on severity ratings (0=absent, 1=mild to 3=severe).
Time frame: Baseline to Day 84
Mean Change From Baseline to Day 84 in Neuropsychiatric Inventory (NPI-Q) Frequency and Severity Score (ITT Population)
The NPI is a retrospective (to 1 month) caregiver-informant interview assessing frequency and severity of 12 neuropsychiatric symptom domains. The NPI score is based on the sum of the severity ratings (0=absent, 1=mild, 3=severe). The 12 symptom domains include delusions, hallucinations, agitation/aggression, dysphoria/depression, anxiety, euphoria/elation, apathy/indifference, disinhibition, irritability/lability, aberrant motor behaviors, nighttime behavioral disturbances, and appetite/eating abnormalities. The NPI severity score is based on severity ratings (0=absent, 1=mild to 3=severe).
Time frame: Baseline to Day 84
Mean Change From Baseline at Day 84 in SF-36 (Short-Form) Health Survey Medical Outcome Score by Category
The SF-36 is designed to examine a person's perceived health status. The SF-36 includes one multi-item scale measuring eight health concepts: vitality, physical functioning, bodily pain, general health perceptions, physical role-, emotional role-, social role functioning, and mental health. Answers to each question are scored and summed to produce raw scale scores for each health concept which are then transformed to a 0 - 100 scale, a high score defining a more favorable health state. An aggregate summary measure is calculated by averaging the scores from the eight health concepts.
Time frame: Baseline and Day 84
Mean Change From Baseline at Day 84 in Beck Depression Inventory (BDI-II) Total Score
The BDI-II is a 21-item self report instrument intended to assess the existence and severity of symptoms of depression, summed to give a single score. The BDI-II uses a 4-point for each item ranging from 0 to 3. A total score of 0-13 is considered minimal range, 14 to 19 is mild, 20 to 28 is moderate, and 29 to 63 is severe.
Time frame: Baseline and Day 84
Mean Change From Baseline to Day 84 in Pain Rating Scale (PRS) of MS Subjects
Subjects with MS were instructed to also record daily the pain they experienced using the PRS. After evaluating the subject's ability to comply with these requirements, the investigator determined if a caregiver should complete the study diary and assessments. Subjects rated their pain over the past 12 hours on a scale of 0 to 10 (0=none, 10=worst pain ever experienced).
Time frame: Baseline, Day 15, Day 29, Day 57, Day 84
Subjects diagnosed with pseudobulbar affect (PBA) secondary to amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS).
| Milestone | 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 |
| Withdrew: Lost to follow-up | 1 | 3 | 2 |
| Withdrew: Exacerbation of ms symptoms | 1 | 0 | 1 |
| Withdrew: Adverse event | 1 | 5 | 0 |
| Withdrew: Serious adverse event (ae) | 2 | 3 | 1 |
| Withdrew: Medication refusal due to ae | 2 | 2 | 0 |
| Withdrew: Withdrawal by subject | 2 | 2 | 7 |
| Withdrew: Protocol violation | 0 | 2 | 1 |
| Withdrew: Other | 0 | 2 | 3 |
| Milestone | AVP-923-30 | AVP-923-20 | Placebo |
|---|---|---|---|
| Started | 253 | 0 | 0 |
| Subjects with pba secondary to als | 146 | 0 | 0 |
| Subjects with pba secondary to ms | 107 | 0 | 0 |
| Completed | 235 | 0 | 0 |
| Not completed | 18 | 0 | 0 |
| Withdrew: Lost to follow-up | 1 | 0 | 0 |
| Withdrew: Exacerbation of ms symptoms | 2 | 0 | 0 |
| Withdrew: Adverse event | 3 | 0 | 0 |
| Withdrew: Serious adverse event | 5 | 0 | 0 |
| Withdrew: Withdrawal by subject | 3 | 0 | 0 |
| Withdrew: Protocol violation | 2 | 0 | 0 |
| Withdrew: Other | 2 | 0 | 0 |
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.
| Unit-free (ratio of episodes/week) | AVP-923-30 | AVP-923-20 | Placebo |
|---|---|---|---|
| PBA Episode Rate Ratio (Post/Pre), Regression Adjusted | 0.247 ± 3.447 | 0.237 ± 6.048 | 0.465 ± 6.642 |
Center for Neurologic Studies-Lability Scale (CNS-LS) is an instrument for the measurement of PBA that has been validated for the use in patients with ALS and MS. It is a 7-item self-report questionnaire that measures the frequency and severity of PBA episodes, including assessments of labile laughter and labile tearfulness,and provides a score for total PBA (total score can range from 7-35). The following 5-point scoring was used: 1=Applies never, 2=Applies rarely, 3=Applies occasionally, 4=Applies frequently, 5=Applies most of the time. A score of 13 or higher may suggest PBA, and the higher the score the more severe the episodes.
| Scores on a Scale | AVP-923-30 | AVP-923-20 | Placebo |
|---|---|---|---|
| Day 15 (Visit2) | -6.77 ± 5.239 | -6.27 ± 5.552 | -4.58 ± 4.982 |
| Day 29 (Visit 3) | -8.03 ± 5.591 | -7.62 ± 5.421 | -5.70 ± 5.034 |
| Day 57 (Visit 4) | -8.59 ± 5.745 | -8.89 ± 5.501 | -5.66 ± 5.038 |
| Day 84 (Visit 5) | -8.17 ± 6.104 | -8.24 ± 6.126 | -5.72 ± 5.280 |
The NPI is a retrospective (to 1 month) caregiver-informant interview assessing frequency and severity of 12 neuropsychiatric symptom domains. The NPI score is based on the sum of the severity ratings (0=absent, 1=mild, 3=severe). The 12 symptom domains include delusions, hallucinations, agitation/aggression, dysphoria/depression, anxiety, euphoria/elation, apathy/indifference, disinhibition, irritability/lability, aberrant motor behaviors, nighttime behavioral disturbances, and appetite/eating abnormalities. The NPI severity score is based on severity ratings (0=absent, 1=mild to 3=severe).
| Scores on a Scale | AVP-923-30 | AVP-923-20 | Placebo |
|---|---|---|---|
| Frequency Score | -1.68 ± 4.102 | -3.09 ± 6.241 | -1.25 ± 4.860 |
| Severity Score | -0.80 ± 3.109 | -1.81 ± 4.206 | -0.91 ± 4.026 |
The NPI is a retrospective (to 1 month) caregiver-informant interview assessing frequency and severity of 12 neuropsychiatric symptom domains. The NPI score is based on the sum of the severity ratings (0=absent, 1=mild, 3=severe). The 12 symptom domains include delusions, hallucinations, agitation/aggression, dysphoria/depression, anxiety, euphoria/elation, apathy/indifference, disinhibition, irritability/lability, aberrant motor behaviors, nighttime behavioral disturbances, and appetite/eating abnormalities. The NPI severity score is based on severity ratings (0=absent, 1=mild to 3=severe).
| Scores on a Scale | AVP-923-30 | AVP-923-20 | Placebo |
|---|---|---|---|
| Frequency Score | -1.62 ± 4.110 | -2.56 ± 6.205 | -1.33 ± 4.837 |
| Severity Score | -0.74 ± 3.102 | -1.59 ± 4.128 | -0.98 ± 4.008 |
The SF-36 is designed to examine a person's perceived health status. The SF-36 includes one multi-item scale measuring eight health concepts: vitality, physical functioning, bodily pain, general health perceptions, physical role-, emotional role-, social role functioning, and mental health. Answers to each question are scored and summed to produce raw scale scores for each health concept which are then transformed to a 0 - 100 scale, a high score defining a more favorable health state. An aggregate summary measure is calculated by averaging the scores from the eight health concepts.
| Scores on a Scale | AVP-923-30 | AVP-923-20 | Placebo |
|---|---|---|---|
| Physical Functioning Scale | -0.90 ± 17.336 | -5.30 ± 15.652 | -4.05 ± 16.381 |
| Role Physical Scale | 3.47 ± 36.747 | -4.26 ± 39.764 | -1.75 ± 40.084 |
| Bodily Pain Scale | 4.09 ± 20.861 | 5.84 ± 20.437 | -1.13 ± 21.782 |
| General Health Scale | -1.47 ± 17.273 | -2.95 ± 16.266 | -1.28 ± 15.824 |
| Vitality Scale | -0.90 ± 17.336 | -5.30 ± 15.652 | -4.05 ± 16.381 |
| Social Functioning Scale | 9.34 ± 25.105 | 1.42 ± 28.577 | -3.09 ± 28.908 |
| Role Emotional Scale | 11.55 ± 47.711 | -1.81 ± 45.924 | 2.36 ± 45.984 |
| Mental Health Scale | 5.53 ± 17.067 | 3.09 ± 16.877 | -0.28 ± 13.720 |
The BDI-II is a 21-item self report instrument intended to assess the existence and severity of symptoms of depression, summed to give a single score. The BDI-II uses a 4-point for each item ranging from 0 to 3. A total score of 0-13 is considered minimal range, 14 to 19 is mild, 20 to 28 is moderate, and 29 to 63 is severe.
| Scores on a Scale | AVP-923-30 | AVP-923-20 | Placebo |
|---|---|---|---|
| Mean Change From Baseline at Day 84 in Beck Depression Inventory (BDI-II) Total Score | -1.59 ± 5.294 | -1.03 ± 5.183 | -0.02 ± 6.320 |
Subjects with MS were instructed to also record daily the pain they experienced using the PRS. After evaluating the subject's ability to comply with these requirements, the investigator determined if a caregiver should complete the study diary and assessments. Subjects rated their pain over the past 12 hours on a scale of 0 to 10 (0=none, 10=worst pain ever experienced).
| Scores on a Scale | AVP-923-30 | AVP-923-20 | Placebo |
|---|---|---|---|
| Mean Change From Baseline to Day 84 in Pain Rating Scale (PRS) of MS Subjects | -1.0 ± 2.39 | -0.7 ± 1.84 | -0.4 ± 2.61 |
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| AVP-923-30 (Double-blind) | — | 8/110 (7.3%) | 66/110 (60%) |
| AVP-923-20 (Double-blind) | — | 9/107 (8.4%) | 65/107 (60.7%) |
| Placebo (Double-blind) | — | 10/109 (9.2%) | 63/109 (57.8%) |
| AVP-923-30 (Open Label) | — | 14/253 (5.5%) | 123/253 (48.6%) |
| Event | AVP-923-30 (Double-blind) | AVP-923-20 (Double-blind) | Placebo (Double-blind) | AVP-923-30 (Open Label) |
|---|---|---|---|---|
| RESPIRATORY FAILURERespiratory, thoracic and mediastinal disorders | 3/110 | 1/107 | 1/109 | 2/253 |
| DYSPHAGIAGastrointestinal disorders | 1/110 | 0/107 | 2/109 | 1/253 |
| DEEP VEIN THROMBOSISVascular disorders | 0/110 | 0/107 | 2/109 | 0/253 |
| PULMONARY EMBOLISMRespiratory, thoracic and mediastinal disorders | 1/110 | 1/107 | 0/109 | 0/253 |
| RESPIRATORY DEPRESSIONRespiratory, thoracic and mediastinal disorders | 0/110 | 1/107 | 0/109 | 0/253 |
| BRONCHOSPASMRespiratory, thoracic and mediastinal disorders | 0/110 | 1/107 | 0/109 | 0/253 |
| INGUINAL HERNIAGastrointestinal disorders | 0/110 | 1/107 | 0/109 | 0/253 |
| CONSTIPATIONGastrointestinal disorders | 0/110 | 1/107 | 0/109 | 0/253 |
| ABDOMINAL PAINGastrointestinal disorders | 0/110 | 1/107 | 0/109 | 0/253 |
| MUSCLE SPASTICITYNervous system disorders | 0/110 | 1/107 | 0/109 | 0/253 |
| Event | AVP-923-30 (Double-blind) | AVP-923-20 (Double-blind) | Placebo (Double-blind) | AVP-923-30 (Open Label) |
|---|---|---|---|---|
| FALLInjury, poisoning and procedural complications | 22/110 | 14/107 | 22/109 | 40/253 |
| DIZZINESSNervous system disorders | 20/110 | 11/107 | 6/109 | 17/253 |
| HEADACHENervous system disorders | 15/110 | 15/107 | 17/109 | 27/253 |
| DIARRHOEAGastrointestinal disorders | 11/110 | 14/107 | 7/109 | 0/253 |
| NAUSEAGastrointestinal disorders | 14/110 | 8/107 | 10/109 | 15/253 |
| FATIGUEGeneral disorders | 9/110 | 11/107 | 10/109 | 30/253 |
| SOMNOLENCENervous system disorders | 11/110 | 9/107 | 10/109 | 16/253 |
| MUSCLE SPASMSMusculoskeletal and connective tissue disorders | 7/110 | 3/107 | 10/109 | 0/253 |
| CONSTIPATIONGastrointestinal disorders | 7/110 | 6/107 | 9/109 | 17/253 |
| NASOPHARYNGITISInfections and infestations | 9/110 | 6/107 | 8/109 | 14/253 |
| Age, Continuous(Years) | AVP-923-30 | AVP-923-20 | Placebo | Total |
|---|---|---|---|---|
| Mean | 53.08 ± 11.016 | 50.81 ± 11.114 | 50.27 ± 11.939 | 51.39 ± 11.356 |
| Sex: Female, Male(Participants) | AVP-923-30 | AVP-923-20 | Placebo | Total |
|---|---|---|---|---|
| Female | 64 | 54 | 59 | 177 |
| Male | 46 | 53 | 50 | 149 |
The record gives a start of Dec 2007, a primary completion of Jun 2009 and a completion of Sep 2009. It does not say whether these dates are actual or estimated.
Results were first posted in Jul 2013, 4 years 1 month after primary completion.
How these figures are worked out, and which studies are left out of them.
This study is completed, as verified in Mar 2017. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: Dextromethorphan
Amyotrophic Lateral Sclerosis →