A Phase 2, Double-blind, Randomized, Placebo-controlled, Four-arm, Multicenter, Dose-finding Study to Assess the Safety and Efficacy of Three Dose Levels of AVP-923 (Dextromethorphan/Quinidine) in the Treatment of Central Neuropathic Pain in Patients with Multiple Sclerosis

Conditions: Central Neuropathic Pain in Multiple Sclerosis
MedDRA version: 15.1Level: LLTClassification code 10054095Term: Neuropathic painSystem Organ Class: 100000004852
Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Registration Number: EUCTR2011-002178-22-PL

Lead Sponsor: Avanir Pharmaceuticals, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 400

Inclusion Criteria

1.Males and females 18 to 85 years of age, inclusive.
2.The patient has a diagnosis of RRMS or SPMS (MS must be diagnosed according to the McDonald criteria).
3.The patient has a clinical history and clinical relevant symptoms of central neuropathic pain (dysesthetic pain) secondary to MS for at least 3 months prior to screening and expected to remain otherwise stable during the study. Patients meeting the criterion for central neuropathic pain and experiencing concomitant non-central neuropathic pain (e.g., back pain, headache, chronic visceral pain, musculoskeletal postural pain, trigeminal neuralgia or Lhermitte's sign) are allowed to participate in the study as long as central neuopathic pain of the extremities is the predominant type of pain.
4.Mean PRS score at Baseline is more or equal to 4.
5.The patient has not experienced an MS relapse within the previous 30 days.
6.The patient has stable hematologic, hepatic, and renal function, with no clinically significant symptoms, and no clinically significant clinical laboratory abnormalities.
7.The patient has a negative urine drug screening panel result (including amphetamines, barbiturates, cocaine metabolite, opiates and THC [cannabinoids]).
8.The patient has an ECG (obtained within 4 weeks prior to entry and evaluated by a certified cardiologist) with no evidence of clinically significant abnormality and with no evidence of: complete heart block, ventricular tachycardia, or frequent unifocal ventricular ectopic beats (>5 per minute).
9.If female, must not be pregnant, breast-feeding, or planning a pregnancy during the course of the study, and must have a negative urine pregnancy test at screening and at baseline.
10.If female, must have been practicing a medically-acceptable method of birth control for at least 1 month prior to randomization (oral contraceptive tablets, hormonal implant device, hormone patch, intrauterine device, diaphragm and contraceptive cream or foam, condom with spermicide, tubal ligation, or abstinence) or be surgically sterile or post-menopausal.
11.Patients currently receiving an MS disease-modifying therapy ([MS DMT] eg, interferon beta, glatiramer, natalizumab, fingolimod) are eligible provided they have been on a stable dose of these medications for at least 2 months prior to randomization.
12.Patients currently receiving fampridine/dalfampridine should be on a stable dose for at least 2 months prior to randomization.
13.Patients currently taking SSRIs (selective serotonin reuptake inhibitors) for the treatment of major depression for at least 3 months on a stable dose prior to randomization are eligible, provided the SSRI dose remains unchanged during the study.
14.Patient must not show current symptoms of a depressive disorder.
15.Patient must have a score of =19 in the BDI-II at screening and at baseline.
16.Patient must be willing to not take any prohibited medications during the study.
17.Patient signed and received a copy of an ICF after the nature and risks of study participation had been fully explained to them

Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 400
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 400

Exclusion Criteria

1.Patient (or caregiver) is unwilling or unable, in the opinion of the investigator, to comply with study instructions.
2.Other types of neuropathic pain unrelated to MS (e.g., DPN pain).
3.Patients with myasthenia gravis.
4.Any personal history of complete heart block, QTc prolongation, or torsades de pointes.
5.Any family history of congenital QT interval prolongation syndrome.
6.Patients with known sensitivity to DM, Q, or opiate drugs (codeine, etc.).
7.Patients with known sensitivity to ibuprofen.
8.Patients experiencing an MS relapse within the previous 30 days.
9.Patients who have been taking disallowed concomitant medications within 2 weeks prior to Baseline (Day 1).
10.Patients currently using, or have been using marijuana or dronabinol within 2 weeks prior to Baseline (Day 1).
11.Patients with a current or prior history of major psychiatric disorder. Exclusionary psychiatric diagnoses, to be determined by chart review and patient interview, include the following Axis I disorders (according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria): (i) current symptoms of major depression; (ii) bipolar disorder; (iii) schizophrenia or other psychotic disorder; (iv) somatoform disorders; and the Axis II disorder of borderline personality.
12.Patients with co-existent major systemic diseases that would interfere with interpretation of the results of the study (eg, malignancy [exept skin basal-cell carcinoma], poorly controlled diabetes, poorly controlled hypertension, ischemic cardiac disease, dilated cardiomyopathy, or valvular heart disease).
13.Patients who are currently participating in, or who have participated in other clinical study within the past 30 days.
14.Patients with severe and/or unstable pulmonary disease.
15.Patients who have received DM co-administered with Q within the previous 3 months.
16.Patients with symptomatic hypotension, history of postural syncope or any history of unexplained synope (evaluated on a case-by case basic).
17. Evidence of uncontrolled diabetes based on HbA1c below 53 mmol/ mol (> 7.0%)
18. Patients with a histrory of substance and/or alcohol abuse within the past 2 years.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The objectives of the study are to evaluate the safety, tolerability, and efficacy of 3 doses of AVP-923 capsules containing either 45 mg DM and 10 mg Q (AVP-923-45) or 30 mg DM 10 mg Q (AVP-923-30) or 20 mg DM and 10 mg Q (AVP-923-20) compared to placebo, for the treatment of central neuropathic pain in a population of patients with multiple sclerosis (MS) over a 12-week period.;Secondary Objective: Not Applicable;Primary end point(s): The primary efficacy endpoint is the 11 point (0-10) PRS obtained from daily patient diaries.;Timepoint(s) of evaluation of this end point: The primary analysis will be carried out using an analysis of covariance (ANCOVA) model with the PRS change from baseline to Days 57-84 as the dependent variable, treatment group as a factor, and the baseline PRS score as a covariate. The primary analysis will compare the AVP 923-45 group to the placebo group.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Secondary efficacy endpoints include the FSS, MSIS-29, PSQI, MSNQ, SDMT, BDI-II, MAS, NRS and PGIC scores;Timepoint(s) of evaluation of this end point: The primary analysis of the secondary efficacy variables will be based on the change from baseline to the Day 85 visit using an analysis of covariance (ANCOVA) model with treatment group as factors and the baseline scores as covariates.