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Famotidine for Levodopa-induced Dyskinesia in PD

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01937078
Recruitment Status : Completed
First Posted : September 9, 2013
Last Update Posted : May 5, 2014
Sponsor:
Information provided by (Responsible Party):
Susan Fox, University Health Network, Toronto

Study Description
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Brief 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.


Condition or disease Intervention/treatment Phase
Dyskinesia Drug: Famotidine Phase 2

Detailed 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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 7 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: An 'N-of-1' Study of the Histamine H@ Antagonist, Famotidine in Levodopa-induced Dyskinesia in Parkinson's Disease
Study Start Date : April 2011
Actual Primary Completion Date : March 2014
Actual Study Completion Date : March 2014

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Active Comparator: active
Famotidine will be administered at total daily doses of 80, 120mg, or 160mg per day. Each patient will be randomized to receive each active dose of famotidine (80, 120, or 160mg/d and placebo). Each patient will receive 4 randomized treatment phases - three famotidine (one at each of the dose levels) and one placebo.
 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.


Outcome Measures
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Primary Outcome Measures :
  1. Change in Dyskinesia severity using Unified Dyskinesia Rating Scale [ Time Frame: on days 1;14;21;35;42;56;63;77 ]

Secondary Outcome Measures :
  1. Subject-rated dyskinesia severity using Unified Dyskinesia Rating Scale and Lang-Fahn Activities of Daily Living Scale [ Time Frame: on days 1;14;21;35;42;56;63;77 ]
  2. Parkinsonian disability using UPDRS (blinded investigator-rated [ Time Frame: on days 1;14;21;35;42;56;63;77 ]
  3. Adverse events [ Time Frame: on days 1;14;21;35;42;56;63;77 ]
    Number of Participants with Adverse Events as a Measure of Safety and Tolerability


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

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Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01937078


Locations
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Canada, Ontario
Toronto Western Hospital
Toronto, Ontario, Canada
Sponsors and Collaborators
University Health Network, Toronto
Investigators
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Principal Investigator: Susan Fox University Health Network, Toronto
More Information
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Responsible Party: Susan Fox, PI, University Health Network, Toronto
ClinicalTrials.gov Identifier: NCT01937078    
Other Study ID Numbers: MDC FAM 2010
First Posted: September 9, 2013    Key Record Dates
Last Update Posted: May 5, 2014
Last Verified: May 2014
Additional relevant MeSH terms:
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Dyskinesias
Movement Disorders
Central Nervous System Diseases
Nervous System Diseases
Neurologic Manifestations
Famotidine
Anti-Ulcer Agents
 Gastrointestinal Agents
Histamine H2 Antagonists
Histamine Antagonists
Histamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs