Exenatide Once Weekly Over 2 Years as a Potential Disease Modifying Treatment for Parkinson's Disease

Study Overview
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Brief Summary
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This study is a clinical trial in patients with Parkinson's disease (PD), of a drug called exenatide, which is already licensed for the treatment of patients with type 2 diabetes. There have been several groups that have confirmed that exenatide has beneficial effects of nerve cells when tested in the laboratory, which raises the possibility that exenatide may slow down or stop the degeneration of PD. In an open label trial in patients with PD who self administered the drug for a period of 48 weeks, the investigators have previously shown that the drug is well tolerated and shows encouraging effects on the movement and non-movement aspects of the disease. A double blind placebo controlled trial involving 60 participants was then conducted which indicated that exenatide may be a neuroprotective drug, i.e. one that stops the nerve cells dying in PD. The next step is therefore to confirm this neuroprotective effect and to see whether this effect can be reproduced in a multi-centre setting including a larger number of participants. An important objective is to explore whether any positive effects remain static or increase when the treatment is continued over a 96 week period. In order to explore this, a randomised, double blind, parallel group, placebo controlled, Phase 3 trial of Exenatide is being undertaken (Exenatide-PD3).

Detailed Description
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This study is a clinical trial in patients with Parkinson's disease (PD), of a drug called exenatide, which is already licensed for the treatment of patients with type 2 diabetes. There have been several groups that have confirmed that exenatide has beneficial effects of nerve cells when tested in the laboratory, which raises the possibility that exenatide may slow down or stop the degeneration of PD. In an open label trial in patients with PD who self administered the drug for a period of 48 weeks, investigators have previously shown that the drug is well tolerated and shows encouraging effects on the movement and non-movement aspects of the disease. A double blind placebo controlled trial involving 60 participants was then conducted which indicated that exenatide may be a neuroprotective drug, i.e. one that stops the nerve cells dying in PD. The next step is therefore to confirm this neuroprotective effect and to see whether this effect can be reproduced in a multi-centre setting including a larger number of participants. An important objective is to explore whether any positive effects remain static or increase when the treatment is continued over a 96 week period.

Official Title
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A Randomised, Double Blind, Parallel Group, Placebo Controlled, Phase 3 Trial of Exenatide Once Weekly Over 2 Years as a Potential Disease Modifying Treatment for Parkinson's Disease

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Drug: Exenatide extended release 2mg (Bydureon)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Parkinson's disease. Hoehn and Yahr stage ≤2.5 in the ON medication state. Between 25 and 80 years of age. On dopaminergic treatment for at least 4 weeks before enrolment. Ability to self-administer, or to arrange carer administration of trial medication. Documented informed consent to participate. Exclusion Criteria: Diagnosis or suspicion of other cause for Parkinsonism. Patients unable to attend the clinic visits in the practically defined OFF medication state. Body mass index <18.5. Known abnormality on CT or MRI brain imaging considered likely to compromise compliance with trial protocol. Significant cognitive impairment defined by a score <21 on the Montreal Cognitive Assessment. Concurrent severe depression defined by a score ≥16 on the Patient Health Questionnaire (PHQ-9). Prior intra-cerebral surgical intervention for Parkinson's disease. Previous participation in one of the following Parkinson's disease trials (Biogen SPARK trial, Prothena Pasadena trial, Sanofi Genzyme MOVES-PD trial, UDCA-PD UP Study or any other trial still considered to involve a potentially PD modifying agent). Participation in another clinical trial of a device, drug or surgical treatment within the last 30 days Previous exposure to exenatide. Impaired renal function with creatinine clearance <50ml/min. History of pancreatitis. Type 1 or Type 2 diabetes mellitus. Severe gastrointestinal disease (e.g. gastroparesis) Hyperlipidaemia. History or family history of medullary thyroid cancer (MTC). Multiple endocrine neoplasia 2 (MEN2) syndrome. Hypersensitivity to any of exenatide's excipients. Females that are pregnant or breast feeding. WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire trial period and up to 3 months after the last dose of trial medication. Participants who lack the capacity to give informed consent Any medical or psychiatric condition or previous conventional/experimental treatment which in the investigator's opinion compromises the potential participant's ability to participate.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 80 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
Interventional Model Description: A randomised, double blind, parallel group, placebo controlled, Phase 3 trial of Exenatide once weekly over 2 years as a potential disease modifying treatment for Parkinson's disease.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Exenatide<br>Exenatide extended release 2mg (Bydureon) once weekly for 96 weeks n=100 | Drug: Exenatide extended release 2mg (Bydureon)<br>* Subcutaneous Injection<br>|
| Placebo Comparator: Placebo<br>Exenatide extended release placebo once weekly for 96 weeks n=100 | Drug: Exenatide extended release 2mg (Bydureon)<br>* Subcutaneous Injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part 3 | Comparison of MDS-UPDRS part 3 motor sub-score in the practically defined OFF medication state at 96 weeks between participants according to treatment allocation. Min value- 0 Max Value- 108. Higher score indicative of worse outcome. | 96 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Movement Disorder Society Unified Parkinson's Disease Rating Scale part 1,2, and 4 ON medication scores. | Questionnaire. Section I: 16 points; Section II: 52; Section IV: 23. Higher score indicative of worse outcome. | 96 weeks | 
| Timed Walk assessment ON and OFF medication | Assessment with research team | 96 weeks | 
| Montreal Cognitive Assessment | Questionnaire. Maximum Score= 30. Lower scores indicative of worse outcome. | 96 weeks | 
| Unified Dyskinesia Rating Scale (UDysRS) | Questionnaire. The UDysRS has four parts: I: Historical Disability (patient perceptions) of On-Dyskinesia impact (maximum 44 points); II: Historical Disability (patient perceptions) of Off-Dystonia impact (maximum 16 points); III: Objective Impairment (dyskinesia severity, anatomical distribution over seven body regions, and type (choreic or dystonic) based on four activities observed or video-recorded (28 points); IV: Objective Disability based on Part III activities (maximum 16 points). Higher scores= worse outcomes | 96 weeks | 
| Patient Health Questionnaire-9 (PHQ-9) | Questionnaire. Depression Severity: 0-4 none, 5-9 mild, 10-14 moderate, 15-19 moderately severe, 20-27 severe. Max Score= 27. Higher Score= worse outcome | 96 weeks | 
| Parkinson's Disease 39 item Quality of life questionnaire | This questionnaire assesses how often people affected by Parkinson's experience difficulties across 8 dimensions of daily living. The 39 item questionnaire offers a patient reported measure of health status and quality of life and is the most frequently used disease-specific health status measure. Higher score= worse outcome. | 96 weeks | 
| Non-Motor Symptoms Scale (NMSS) | Questionnaire. The Non-Motor Symptoms Scale (NMSS) is a 30-item rater-based scale to assess a wide range of non-motor symptoms in patients with Parkinson's disease (PD). The NMSS measures the severity and frequency of non-motor symptoms across nine dimensions. The scale can be used for patients at all stages of PD. Higher score indicative of worse outcome. NMSS total score is 0 to 360. | 96 weeks | 
| Levodopa Equivalent Dose | Assessment with Research Team | 96 weeks | 
| 3 day Hauser diary of Parkinson's Disease State | Participant take Home questionnaire. (Time-On, Off, Non troublesome Dyskinesia, Troublesome dyskinesia, Asleep). Higher total scores indicate more severe motor signs of Parkinson's. | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in pulse (bpm) | Vital Signs | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in blood pressure (mmHg) | Vital Signs | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Body Mass Index (weight and height will be combined to report BMI in kg/m^2) | Vital Signs | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Red Blood Cell Count (10^12/L) | Full Blood Count | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in White Blood Cell Count (10^9/L) | Full Blood Count | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Haemoglobin (g/dL) | Full Blood Count | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Haematocrit (%) | Full Blood Count | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Platelets (10^9/L) | Full Blood Count | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Neutrophils (10^9/L) | Full Blood Count | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Eosinophils (10^9/L) | Full Blood Count | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Basophils (10^9/L) | Full Blood Count | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Lymphocytes (10^9/L) | Full Blood Count | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Monocytes (10^9/L) | Full Blood Count | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Prothrombin Time (secs) | Blood Tests (Coagulation) | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in International Normalized Ratio (Calculated from Prothrombin Time) | Blood Tests (Coagulation) | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Activated Partial Thromboplastin Time (secs) | Blood Tests (Coagulation) | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Thrombin Time (secs) | Blood Tests (Coagulation) | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Fibrinogen (g/L) | Blood Tests (Coagulation) | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Glycated Haemoglobin (% of Haemoglobin) | Blood Tests (Blood Sugar Levels / Diabetes Testing) | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Sodium (mmol/L) | Biochemistry | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Potassium (mmol/L) | Biochemistry | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Urea (mmol/L) | Biochemistry | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Creatinine (µmol/L) | Biochemistry | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Creatinine Clearance (ml/min) | Biochemistry | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Total Bilirubin (µmol/L) | Biochemistry | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Alkaline phosphatase (IU/L) | Biochemistry | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Alanine transaminase (IU/L) | Biochemistry | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Aspartate Aminotransferase (IU/L) | Biochemistry | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Serum Amylase (U/L) | Biochemistry | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Thyroid Stimulating Hormone (mIU/L) | Biochemistry | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Thyroxin (T4) (pmol/L) | Biochemistry | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Triglycerides (mg/dL) | Biochemistry (Fasting) | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Cholesterol (mg/dL) | Biochemistry (Fasting) | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Glucose (mmol/L) | Biochemistry (Fasting) | 96 weeks | 
| Safety and tolerability of exenatide as indicated by changes in Insulin (IU/L) | Biochemistry (Fasting) | 96 weeks | 
| Safety and tolerability of exenatide as indicated by the occurrence / severity of Adverse Events | Ongoing Safety Reporting | 96 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's Disease, Exenatide, Parkinson's research