Safety and Efficacy of Liraglutide in Parkinson's Disease

Study Overview
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Brief Summary
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The purpose of this study is to test the efficacy and safety of liraglutide in the treatment of patients with idiopathic Parkinson's disease (PD).

Detailed Description
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This single center, double-blind, placebo-controlled study will enroll 57 participants with a diagnosis of idiopathic PD. Subjects enrolled in the study will be randomized to receive once daily self-administered injections of liraglutide (1.2 or 1.8 mg, as tolerated) or placebo at the same dose range in a 2:1 study design. Liraglutide has been approved by the Food and Drug Administration (FDA) to treat adults with Type 2 Diabetes (T2D) and to treat obesity, but it is considered investigational in this study, as it has not been approved for use in patients with PD. Liraglutide belongs to a class of medications able to stimulate receptors of glucagon-like peptide 1 (GLP-1), a naturally occurring peptide found throughout much of the brain and able to increase the incretin effect in patients with T2D, stimulating the release of insulin. Liraglutide can reduce systemic and brain insulin resistance, an abnormality that could help drive PD pathogenesis. Indeed, impaired insulin signaling in the brain can cause or exacerbate many brain pathologies and behavioral abnormalities seen in PD. Another GLP-1 agonist, named exenatide, has been evaluated in patients with PD, showing significant improvement of motor and cognitive symptoms. There is reason to believe that liraglutide may prove superior to exenatide in treating PD. Eligible participants will be followed for up to 14 months and will be expected to complete 9 in-person visits and 2 telephone visits. The study will measure liraglutide effects on motor (assessed by changes in the MDS-UPDRS part III) and non-motor symptoms of PD (assessed by the NMSS and MDRS-2) after 52 weeks of treatment. The secondary outcomes include measures of the association between liraglutide's effects on peripheral insulin resistance, PD symptoms and safety. Collection of blood and urine samples will be obtained to monitor drug safety.

Official Title
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A Phase II, Randomized, Double-blinded, Placebo-controlled Trial of Liraglutide in Parkinson's Disease

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: Liraglutide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of idiopathic PD according to the United Kingdom Parkinson's Disease Society Brain Bank (UKPDSBB) criteria for at least 2 years Responsive to levodopa or dopaminergic treatment Male or female between 25 and 85 years of age at time of enrollment Women of child-bearing potential (WOCBP) must agree to use a reliable method of contraception (e.g., oral contraceptive or long-term injectable or implantable hormonal contraceptive, double barrier methods (such as condom plus diaphragm, condom plus spermicide foam, condom plus sponge), or intra-uterine devices) throughout the duration of the trial period and must have a negative serum pregnancy test at screening Male patients with female partners who have child bearing potential must agree to use adequate contraception throughout the duration of the trial period Capacity to give informed consent Ability to self-administer, or to arrange a care partner to administer trial drug, to comply with trial protocol, and to attend necessary clinic visits off medication Exclusion Criteria: Diagnosis or suspicion of other causes for Parkinsonism, including drug- or toxin-induced parkinsonism and other neurodegenerative conditions, including multiple system atrophy, progressive supranuclear palsy, Huntington's disease, Wilson's disease, or Alzheimer's disease Active treatment with anticholinergic medications (e.g., trihexyphenidyl, tricyclic antidepressants) Known abnormality on CT or MRI brain imaging considered to cause symptoms or signs of neurological dysfunction, or considered likely to compromise compliance with trial protocol Concurrent dementia defined by a score lower than 120 on the MADRS-2 and/or inability to complete scale per neuropsychologist discretion Concurrent severe depression defined by a score greater than 29 on the Beck Depression Inventory Prior intracerebral surgical intervention for PD, including deep brain stimulation, lesional surgery, growth factor administration, gene therapy, or cell transplant Already actively participating in a trial of a device, drug, or surgical treatment for PD, or trial participation within 30 days prior to the baseline visit Diagnosis of diabetes mellitus of any type, established historically or by: Fasting plasma glucose levels equal or above 126 mg/dl Hemoglobin A1c equal or above 6.5% Active treatment with oral antidiabetic medications History of severe cardiac disease (e.g., angina, myocardial infarction, or cardiac surgery) in the preceding year Significant systemic illness likely to result in deterioration of the patient's condition or, in the Investigator's opinion, affect the patient's safety during the study, including in particular: History of pancreatitis Personal or family history of medullary thyroid carcinoma History of multiple endocrine neoplasia syndrome type 2 History of alcoholism Severe gastrointestinal disease, including gastroparesis Treatment with immunosuppressive medications (e.g., systemic corticosteroids) within the last 90 days or chemotherapeutic agents for malignancy within the last 2 years Severe renal insufficiency (CrCl <30) Moderate or severe hepatic impairment Severe hypertriglyceridemia (triglycerides >500 mg/dl) Females who are pregnant or breast feeding Prior serious hypersensitivity reaction to Victoza or any of the product components 10) Body Mass Index <18.5

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Liraglutide<br>Liraglutide 6 mg/ml (Novo Nordisk A/S) will be self-administered subcutaneously once daily at a maximum dose of 1.8 mg after a 2 week titration schedule. | Drug: Liraglutide<br>* Liraglutide 6 mg/ml once daily at a maximum dose of 1.8 mg<br>* Other names: Saxenda;|
| Placebo Comparator: Placebo<br>Placebo will be self-administered subcutaneously once daily according to the same schedule. | Drug: Placebo<br>* Placebo (for Liraglutide) 6 mg/ml once daily at a maximum dose of 1.8 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Motor Function | Efficacy of liraglutide on the motor symptoms of Parkinson disease will be determined by the change in the motor (Part III) Movement Disorders Society-Unified Parkinson Disease Rating Scale (MDS-UPDRS) score in the active treatment arm versus placebo between baseline, 28 and 54 week visit. | 54 weeks | 
| Non-Motor Function | Efficacy of liraglutide on the non-motor symptoms of Parkinson disease will be determined by the change in the Non-Motor Symptoms Scale (NMSS) score in the active treatment arm versus placebo between baseline, 28 and 54 week visit. | 54 weeks | 
| Cognitive Function | Efficacy of liraglutide on the cognitive symptoms of Parkinson disease will be determined by the change in the Mattis Dementia Rating Scale (MADRS-2) score in the active treatment arm versus placebo between baseline, 28 and 54 week visit. | 54 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peripheral Insulin Resistance | Efficacy of liraglutide on peripheral insulin resistance will be determined by the change in the Homeostasis Model Assessment (HoMA-IR) index in the active treatment arm versus placebo between baseline, 28 and 54 week visit. | 54 weeks | 
| Total MDS-UPDRS | Efficacy of liraglutide on Parkinson disease will be determined by the change in the total Movement Disorders Society-Unified Parkinson Disease Rating Scale (MDS-UPDRS) score in the active treatment arm versus placebo between baseline, 28 and 54 week visit. | 54 weeks | 
| Functional status and quality of life | Efficacy of liraglutide on Functional status and quality of life in patients with Parkinson disease will be determined by the change in the Parkinson Disease Questionnaire (PDQ39) score in the active treatment arm versus placebo between baseline, 28 and 54 week visit. | 54 weeks | 
| Adverse events frequency | Safety will be monitored with changes in vital signs, weight, clinical laboratory measures, and adverse events. Routine laboratory studies performed at the beginning and the end of the study will include complete blood count (CBC), renal function, liver function, serum amylase, lipase, calcitonin, and fasting serum glucose and insulin. In addition, an ECG will be performed at screening and follow-up visits. | every visit up to 58 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's Disease, Liraglutide, Antidiabetic agents, GLP-1 agonists, Insulin resistance