Famotidine for Levodopa-induced Dyskinesia in PD

Dyskinesia Clinical Trial

Official title:

An 'N-of-1' Study of the Histamine H@ Antagonist, Famotidine in Levodopa-induced Dyskinesia in Parkinson's Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01937078
• Other study ID #: MDC FAM 2010
• Status: Completed
• Phase: Phase 2
• First received: July 26, 2012
• Last updated: May 1, 2014
• Start date: April 2011
• Est. completion date: March 2014

Study information

• Verified date: May 2014
• Source: University Health Network, Toronto
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health Canada
• Study type: Interventional

Clinical Trial Summary

Levodopa-induced dyskinesia is a common problem in Parkinson's disease (PD). In particular, targeting non-dopaminergic systems may be an option for reducing dyskinesia without worsening motor symptoms. One such target may be histamine. The central histaminergic system is involved in diverse biological functions including thermoregulation, eating, and sleep; a role in motor activity is suggested by strong histaminergic innervation of the basal ganglia. Histamine H2 receptors are highly expressed in the striatum, particularly on the GABAergic striatal-pallidal and striatal-nigral pathways Histamine H2 stimulation modulates acetylcholine release. Previous studies have demonstrated that blocking acetylcholine with anticholinergic agents can induce chorea. The investigators propose that histamine H2 receptor stimulation decreases acetylcholine in the striatum and increases activity of the direct striatal output pathway, a key component of the neural mechanisms underlying dyskinesia.

The investigators hypothesise that H2 antagonists would reduce activity of the direct striatopallidal pathway and so potentially reduce levodopa-induced chorea

Famotidine has also been assessed in schizophrenia in a small cases series to treat schizophrenia, with tolerability. Clinical experience thus suggests the suitability of using this agent as a histamine H2 antagonist in clinical studies for PD.

Description:

The proposed study will be composed of multiple N -of 1 studies performed in a randomized, double-blind, placebo-controlled multiple (4) crossover fashion. Twelve PD patients (thus 12 N-of-1 trials) with levodopa-induced dyskinesia will complete 4 treatment phases; one phase at each of the 3 doses of famotidine and one of placebo. The treatment doses will be: famotidine 40mg/day, 80mg/day, and 120mg/day. The phases will occur in a random order, but each subject will receive each of the treatment doses during the course of the study. After each phase of treatment (14 days), there will be a washout period (7 days, over 10 half-lives of famotidine) followed by a crossover. The primary outcome will be the change in Unified Dyskinesia Rating Scale (UDysRS) between placebo and famotidine at the end of each treatment phase and secondary outcomes will be Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) parts III and IV, Clinical Global Impression (CGI), Lang-Fahn activities of daily living dyskinesia scale (LFADLDS) and assessment of adverse effects.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 7
• Est. completion date: March 2014
• Est. primary completion date: March 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:Eligible patients, male and female, will be less than 80 years of age and be on stable levodopa. Subjects must have stable, bothersome dyskinesia and have an MDS-UPDRS score 2 or greater, on item 4.2. All anti-parkinsonian medications must be unchanged for at least one month prior to study enrollment. Subjects may be taking amantadine at a stable dose for at least one month prior to study onset -

Exclusion Criteria:are prior surgery for PD, Hoehn and Yahr score of 5 when off-medication, history of moderate to severe renal impairment (creatinine clearance <25 millilitres per minute, dementia (defined by Montreal Cognitive Scale < 2518 , allergic reaction to lactose, famotidine or other histamine H2 antagonists

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Dyskinesia
• Dyskinesias

Intervention

Drug:
• Famotidine
Each patient will receive 4 randomized treatment phases - three famotidine (one at each of the dose levels) and one placebo. Each treatment phase will last for 14 days. Doses of drug will be titrated upwards, starting at 40mg once daily on day one, 40mg twice daily on day two, and 80mg twice daily (or placebo + drug equivalent) from day three and then continue on this dose for the next 12 days. Regardless of treatment phase, subjects will take 2 tablets twice daily, with varying ratios of active famotidine to placebo. Thus famotidine 80mg/d will consist of 1 tablet of 40 mg famotidine plus 1 tablet of placebo twice a day; 120 mg /d famotidine will be 2 tablets at 40 mg morning and 1 tablet famotidine 40 mg plus 1 tablet placebo evening; famotidine 160 mg/d will be famotidine 40 mg tablets, 2 tablets twice a day. The placebo phase will consist of 2 placebo tablets twice a day.

Locations

Country	Name	City	State
Canada	Toronto Western Hospital	Toronto	Ontario

Sponsors (1)

Lead Sponsor	Collaborator
University Health Network, Toronto

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Dyskinesia severity using Unified Dyskinesia Rating Scale		on days 1;14;21;35;42;56;63;77	No
Secondary	Subject-rated dyskinesia severity using Unified Dyskinesia Rating Scale and Lang-Fahn Activities of Daily Living Scale		on days 1;14;21;35;42;56;63;77	No
Secondary	Parkinsonian disability using UPDRS (blinded investigator-rated		on days 1;14;21;35;42;56;63;77	Yes
Secondary	Adverse events	Number of Participants with Adverse Events as a Measure of Safety and Tolerability	on days 1;14;21;35;42;56;63;77	Yes