Safety and Efficacy of AVP-923 in PBA Patients With ALS or MS
Condition: Pseudobulbar Affect (PBA)
MeSH terms: Amyotrophic Lateral Sclerosis
Intervention: dextromethorphan hydrobromide 20 mg and quinidine sulfate 10 mg; dextromethorphan hydrobromide 30 mg and quinidine sulfate 10 mg; Placebo
Intervention description: 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; 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; 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
Intervention MeSH terms: Quinidine; Quinidine gluconate; Dextromethorphan
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 326.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Amyotrophic Lateral Sclerosis (Lou Gehrig's disease, ALS); Multiple Sclerosis (MS)

Summary:

      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.
    

Eligibility 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.)