Safety and Efficacy of Liraglutide in Parkinson's Disease

Phase 2

Completed

Conditions: Parkinson Disease

Interventions: Drug: Placebo
Drug: Liraglutide

Registration Number: NCT02953665

Lead Sponsor: Cedars-Sinai Medical Center

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 63

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:
1. History of pancreatitis
2. Personal or family history of medullary thyroid carcinoma
3. History of multiple endocrine neoplasia syndrome type 2
4. History of alcoholism
5. Severe gastrointestinal disease, including gastroparesis
6. Treatment with immunosuppressive medications (e.g., systemic corticosteroids) within the last 90 days or chemotherapeutic agents for malignancy within the last 2 years
7. Severe renal insufficiency (CrCl <30)
8. Moderate or severe hepatic impairment
9. 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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo will be self-administered subcutaneously once daily according to the same schedule.
Liraglutide	Liraglutide	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.

Primary Outcome Measures

Name	Time	Method
Change in the Mattis Dementia Rating Scale (DRS-2) From Baseline to the End of Double-Blind Maintenance Period	From Baseline (Week 0) to the end of Maintenance Period (up to 54 weeks)	The DRS-2 assesses individuals in five areas resulting in five sub-scale scores. These scores are used to determine the overall score and level of cognitive functioning ability. The five areas include: Attention - measured using eight items Construction - measured using six items Conceptualization - measured using six items Initiation/Preservation - measured using eleven items Memory - measured using five items Higher raw scores indicate better cognitive status, with scores ranging from 0 to 144. Normative data in healthy subjects range from 137 to 144.
Change in Unified Parkinson's Disease Rating Scale (UPDRS Part III Motor Examination) During "OFF" Time From Baseline to the End of Double-Blind Maintenance Period	From Baseline (Week 0) to end of Maintenance Period (up to 54 weeks)	The UPDRS Part III (motor symptoms sub-scale) Assessment consists of 17 items, measured on a 5-Point scale (0-Normal to 4-Severe), addressing speech, facial expression, tremor at rest, action tremor, rigidity, finger taps, hand movements, hand pronation and supination, leg agility, arising from chair, posture, gait, postural stability, and body bradykinesia. The participant's score is calculated as a sum of the scores of the 17 individual questions. This sum score ranges from 0 to 108. Higher scores denote greater disability. A participant has been considered "OFF" when he/she has been off L-dopa for greater than 12 hours. During "OFF" time, the participant will not report feeling the effects of their anti-Parkinson's medication. The participant recorded the exact time of L-dopa intake. Assessment was only conducted greater than 12 hours after dosing with the participant reportedly feeling "OFF."
Change in the Non-Motor Symptoms Scale (NMSS) Total Score From Baseline to the End of the Double-Blind Maintenance Period	From Baseline (Week 0) to the End of Maintenance Period (up to Week 54)	The NMSS is a 30-item rater-based scale to assess a wide range of non-motor symptoms in patients with Parkinson's disease. The NMSS measures severity and frequency of non-motor symptoms across nine dimensions (cardiovascular, sleep/fatigue, mood/apathy, perceptual problems/hallucinations, attention/memory, gastrointestinal, urinary, sexual function, and miscellaneous which includes pain, taste/smell, weight change, and excessive sweating). Higher scores indicate a higher burden of these symptoms on the patient. There are 30 items to be scored, and the item scores are calculated as the product of severity and frequency; the total score is obtained by summing the item scores. The NMSS total score ranges from 0 to 360 with a lower score indicating fewer symptoms; a negative change from baseline indicates improvement in symptoms.

Secondary Outcome Measures

Name	Time	Method
Change in the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Index From Baseline to the End of Maintenance Period	From Baseline (Week 0) to end of Maintenance Period (up to 54 weeks)	Peripheral insulin resistance was assessed using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Index. The HOMA-IR tool is a validated, non-invasive tool to assess the relationship between glucose and insulin. A score less than 1 means indicates insulin-sensitivity (Optimal). Greater than 1.9 indicates early insulin resistance, and a score greater than 2.9 indicates significant insulin resistance. An increase in one's HOMA-IR score may indicate increased insulin resistance.
Change in the Unified Parkinson's Disease Rating Scale Total Score From Baseline to the End of Double-Blind Maintenance Period	From Baseline (Week 0) to end of Maintenance Period (up to 54 weeks)	Total UPDRS Score (Parts I, II, III, and IV; administered in the ON condition) Change from Baseline to End of Maintenance Period. UPDRS I evaluation of mentation, behavior, and mood UPDRS II self-evaluation of the activities of daily life (ADLs) including speech, swallowing, handwriting, dressing, hygiene, falling, salivating, turning in bed, walking, and cutting food UPDRS III clinician-scored monitored motor evaluation UPDRS IV evaluation of complications in therapy and motor fluctuations, including OFF time and dyskinesia The UPDRS I, II, III, and IV scores and subscores are calculated as the sum of all individual items. Subscales have 0-4 ratings, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe The final cumulative score will range from 0 (no disability) to 260 (total disability). A decrease in the mean indicates global improvement in the UPDRS score.
Change in The Parkinson's Disease Questionnaire (PDQ-39) From Baseline to the End of Double-Blind Maintenance Period	From Baseline (Week 0) to end of Maintenance Period (up to 54 weeks)	The Parkinson's Disease Questionnaire (PDQ-39) is a 39-item patient-reported rating scale that measures Parkinson's disease-specific health related quality of life. It covers 8 areas: mobility, activities of daily living (ADL), emotional well-being, stigma, social support, cognition, communication and bodily discomfort. Lower scores indicate better health related quality of life. PDQ-39 total scores range from 0 to 800. The total score can be summarised into the PDQ-39 summary index score (range of scores 0 to 100). A mean change in the PDQ-39 summary index score of about 1.6 points relates to feeling 'a little worse' and is likely to represent a clinically important difference.