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

Avanir Pharmaceuticals

Status and phase: Completed; Phase 3

Conditions: Pseudobulbar Affect (PBA)

Treatments: Drug: dextromethorphan hydrobromide 20 mg and quinidine sulfate 10 mg; Drug: dextromethorphan hydrobromide 30 mg and quinidine sulfate 10 mg; Drug: Placebo

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT00573443

07-AVR-123

Details and patient eligibility

About

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.

Enrollment: 326 patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Main Inclusion Criteria:

• The patient has a diagnosis of Amyotrophic Lateral Sclerosis (according to El Escorial Criteria, WFN, 1998) and the time from diagnosis of ALS is not be longer than 30 months, or the patient has a diagnosis of multiple sclerosis or probable multiple sclerosis (according to McDonald criteria, 2001)
• The patient has a clinical history and clinical relevant symptoms of Pseudobulbar Affect (PBA)
• CNS-LS score at baseline is 13 or greater

Main Exclusion Criteria:

• Patients with myasthenia gravis
• Any personal history of complete heart block, QTc prolongation, or torsades de pointes
• Any family history of congenital QT interval prolongation syndrome
• Patients with known sensitivity to quinidine, dextromethorphan or opiate drugs (codeine, etc.)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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326 participants in 3 patient groups, including a placebo group

DM 30 mg/Q 10 mg

Experimental group

Description:

AVP-923-30/10 Capsules (30 mg dextromethorphan/10 mg quinidine)administered once daily for 1 week and then twice daily for 11 weeks

Treatment:

Drug: dextromethorphan hydrobromide 30 mg and quinidine sulfate 10 mg

DM 20 mg/ Q 10 mg

Experimental group

Description:

AVP-923-20/10 Capsules (20 mg dextromethorphan/10 mg quinidine)administered once daily for 1 week and then twice daily for 11 weeks

Treatment:

Drug: dextromethorphan hydrobromide 20 mg and quinidine sulfate 10 mg

Placebo

Placebo Comparator group

Description:

Placebo Capsules once daily for 1 week and then twice daily for an additional 11 weeks

Treatment:

Drug: Placebo