CLINICAL TRIALS PROFILE FOR DEXTROMETHORPHAN HYDROBROMIDE AND QUINIDINE SULFATE

All Clinical Trials for DEXTROMETHORPHAN HYDROBROMIDE AND QUINIDINE SULFATE

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT02153502 ↗	Efficacy, Safety, and Tolerability Study of AVP-786 as an Adjunctive Therapy in Patients With Major Depressive Disorder With an Inadequate Response to Antidepressant Treatment	Completed	Avanir Pharmaceuticals	Phase 2	2014-07-01	The objectives of this 10-week study are to evaluate the efficacy, safety, and tolerability of AVP 786 as an adjunctive therapy compared with placebo in patients with major depressive disorder (MDD) who have shown an inadequate response to standard antidepressant treatment. A secondary objective of this study is to assess the pharmacokinetics (PK) of AVP-786 and potential correlations with pharmacodynamic effects.
NCT02174822 ↗	A Phase 1, Drug Interaction Study Between AVP-786 and Paroxetine and Between AVP-786 and Duloxetine in Healthy Subjects	Completed	Avanir Pharmaceuticals	Phase 1	2014-01-01	To assess steady state pharmacokinetics (PK), safety and tolerability between AVP-786 (deuterated [d6] dextromethorphan hydrobromide [DM]/quinidine sulfate [Q]) and paroxetine and between AVP-786 and duloxetine.
NCT00573443 ↗	Safety and Efficacy of AVP-923 in PBA Patients With ALS or MS	Completed	INC Research	Phase 3	2007-12-01	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.
NCT00573443 ↗	Safety and Efficacy of AVP-923 in PBA Patients With ALS or MS	Completed	Syneos Health	Phase 3	2007-12-01	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.
NCT00573443 ↗	Safety and Efficacy of AVP-923 in PBA Patients With ALS or MS	Completed	Avanir Pharmaceuticals	Phase 3	2007-12-01	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.

Clinical Trial Conditions for DEXTROMETHORPHAN HYDROBROMIDE AND QUINIDINE SULFATE

Condition Name

Condition Name for DEXTROMETHORPHAN HYDROBROMIDE AND QUINIDINE SULFATE
Intervention	Trials
Agitation in Patients With Dementia of the Alzheimer's Type	3
Pseudobulbar Affect (PBA)	1
Schizophrenia	1
Agitation in Alzheimer's Disease	1

Condition MeSH

Condition MeSH for DEXTROMETHORPHAN HYDROBROMIDE AND QUINIDINE SULFATE
Intervention	Trials
Alzheimer Disease	3
Psychomotor Agitation	3
Dementia	3
Motor Neuron Disease	1

Clinical Trial Locations for DEXTROMETHORPHAN HYDROBROMIDE AND QUINIDINE SULFATE

Trials by Country

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Trials by Country for DEXTROMETHORPHAN HYDROBROMIDE AND QUINIDINE SULFATE
Location	Trials
United States	138
Brazil	6
Argentina	4
Canada	3
Australia	2

Trials by US State

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Trials by US State for DEXTROMETHORPHAN HYDROBROMIDE AND QUINIDINE SULFATE
Location	Trials
Florida	7
Massachusetts	6
Illinois	6
Georgia	6
California	6

Clinical Trial Progress for DEXTROMETHORPHAN HYDROBROMIDE AND QUINIDINE SULFATE

Clinical Trial Phase

Clinical Trial Phase for DEXTROMETHORPHAN HYDROBROMIDE AND QUINIDINE SULFATE
Clinical Trial Phase	Trials
Phase 4	1
Phase 3	4
Phase 2	2

Clinical Trial Status

Clinical Trial Status for DEXTROMETHORPHAN HYDROBROMIDE AND QUINIDINE SULFATE
Clinical Trial Phase	Trials
Completed	9
Recruiting	1
Terminated	1

Clinical Trial Sponsors for DEXTROMETHORPHAN HYDROBROMIDE AND QUINIDINE SULFATE

Sponsor Name

Sponsor Name for DEXTROMETHORPHAN HYDROBROMIDE AND QUINIDINE SULFATE
Sponsor	Trials
Avanir Pharmaceuticals	11
INC Research	1
Syneos Health	1

Sponsor Type

Sponsor Type for DEXTROMETHORPHAN HYDROBROMIDE AND QUINIDINE SULFATE
Sponsor	Trials
Industry	11
Other	2

Dextromethorphan Hydrobromide and Quinidine Sulfate: Clinical Trials, Market Analysis, and Projections

Introduction

Dextromethorphan hydrobromide and quinidine sulfate, marketed as Nuedexta, is a combination drug approved by the US Food and Drug Administration (FDA) for the treatment of pseudobulbar affect (PBA). This article delves into the clinical trials, market analysis, and future projections for this medication.

Clinical Trials Overview

FDA Approval and Initial Studies

Nuedexta was approved in 2010 based on clinical trials conducted in patients with amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). These trials, notably the STAR trial, demonstrated that the combination of dextromethorphan and quinidine significantly reduced the frequency of PBA episodes compared to placebo[2][4].

STAR Trial Findings

The STAR trial, a double-blind, placebo-controlled study, showed that patients receiving dextromethorphan (20 or 30 mg) and quinidine (10 mg) had a significant reduction in PBA episodes. Specifically, the 20 mg/10 mg group reported an 82% mean weekly episode reduction from baseline, compared to a 47% reduction in the placebo group[2][4].

Additional Studies and Populations

Subsequent studies have explored the use of Nuedexta in other patient populations. For example, a 10-week phase 2 trial in patients with Alzheimer's disease found that those treated with dextromethorphan-quinidine had a greater reduction in agitation scores compared to placebo[1].

Mechanism of Action

Pharmacokinetics and Pharmacodynamics

The combination of dextromethorphan and quinidine works by inhibiting the rapid metabolism of dextromethorphan by the CYP2D6 enzyme, thereby increasing its bioavailability. Dextromethorphan acts as an uncompetitive NMDA receptor antagonist and a sigma-1 receptor agonist, while quinidine extends the plasma concentrations of dextromethorphan[2][4].

Market Analysis

Prescribing Patterns

Despite its initial approval for PBA in patients with ALS and MS, Nuedexta is predominantly prescribed for patients with dementia and/or Parkinson's disease. A population-based cohort study revealed that the number of patients receiving this medication increased significantly from 2011 to 2016, with associated Medicare spending rising from $3.9 million to $200.4 million[1].

Economic Impact

The economic impact of Nuedexta is substantial. The increased prescribing and associated costs highlight the drug's widespread use beyond its original approved indications. However, it remains unclear whether Nuedexta is superior to other agents for treating PBA, which could affect its long-term market position[1][2].

Market Projections

Growing Demand

Given the expanding use of Nuedexta in various neurological conditions, the demand for this medication is expected to continue growing. The increasing prevalence of dementia and Parkinson's disease, coupled with the lack of effective alternatives for PBA, suggests a stable and potentially growing market for Nuedexta.

Competitive Landscape

While Nuedexta has a strong market presence, the absence of direct comparator trials leaves questions about its efficacy relative to other treatments. Future studies comparing Nuedexta to other agents could impact its market share. However, its unique mechanism of action and established efficacy in clinical trials position it as a leading treatment for PBA[2][4].

Safety and Side Effects

Common Side Effects

Clinical trials have identified common side effects of Nuedexta, including dizziness, diarrhea, and urinary tract infections. The drug also has a potential proarrhythmic risk associated with quinidine, which was a concern during the FDA approval process[2][5].

QT Interval Concerns

Thorough QT studies have evaluated the effect of Nuedexta on the QT interval, showing a minimal increase in QTcF intervals. This suggests that, at the recommended doses, the risk of significant QT interval prolongation is manageable[2][5].

Off-Label Uses

Current Trends

Despite its FDA approval for PBA, Nuedexta is often prescribed off-label for conditions like dementia and Parkinson's disease. This trend highlights the need for further research to validate its efficacy in these populations and to ensure safe and effective use[1].

Future Research Directions

Pediatric Studies

There is a lack of data on the safety and efficacy of Nuedexta in pediatric populations. Future studies are needed to address this gap, particularly under the Pediatric Research Equity Act (PREA)[3].

Comparative Studies

To solidify Nuedexta's position in the market, comparative studies against other treatments for PBA are essential. These studies will help determine whether Nuedexta offers superior efficacy and safety compared to alternative therapies[2][4].

Key Takeaways

• Clinical Efficacy: Nuedexta has demonstrated significant efficacy in reducing PBA episodes in clinical trials, particularly in patients with ALS and MS.
• Market Trends: The drug is predominantly prescribed for patients with dementia and Parkinson's disease, indicating a broader market than initially approved for.
• Economic Impact: The medication has a substantial economic impact, with significant increases in prescribing and associated costs.
• Safety Profile: Common side effects include dizziness, diarrhea, and urinary tract infections, with a manageable risk of QT interval prolongation.
• Future Research: Needed studies include pediatric trials and comparative studies against other PBA treatments.

FAQs

What is the primary indication for Nuedexta?

Nuedexta is primarily indicated for the treatment of pseudobulbar affect (PBA), although it is often prescribed off-label for other conditions.

How does Nuedexta work?

Nuedexta works by inhibiting the rapid metabolism of dextromethorphan by the CYP2D6 enzyme, thereby increasing its bioavailability and enhancing its pharmacological effects.

What are the common side effects of Nuedexta?

Common side effects include dizziness, diarrhea, and urinary tract infections.

Is Nuedexta used in pediatric populations?

Currently, there is no approved indication for Nuedexta in pediatric populations, and further research is needed to assess its safety and efficacy in this group.

What are the future research directions for Nuedexta?

Future research should focus on comparative studies against other PBA treatments and pediatric studies to expand its approved indications and validate its use in broader populations.

Sources

1. JAMA Internal Medicine: Combined Dextromethorphan and Quinidine in Patients With Pseudobulbar Affect.
2. VA PBM: Dextromethorphan Hydrobromide and Quinidine Sulfate (Nuedexta) Drug Monograph.
3. FDA: Nuedexta (Dextromethorphan Hydrobromide and Quinidine Sulfate) NDA 021879.
4. VA PBM: Dextromethorphan Hydrobromide and Quinidine Sulfate (Nuedexta) Drug Monograph.
5. FDA: Nuedexta (Dextromethorphan Hydrobromide and Quinidine Sulfate) NDA 021879 Administrative Correspondence.