Safety Evaluation of Intravenous Talineuren (TLN) in Parkinson's Disease-affected Patients

Study Overview
=================
Brief Summary
-----------------
This study is an open-label, single ascending dose escalation followed by a multiple administration dose at the maximal suitable dose (MSD). The investigational Medicinal Product (IMP) is given as an add-on therapy. Talineuren consists of GM1 (monosialotetrahexosylganglioside), the pharmacologically active ingredient, associated with a proprietary lipid formulation assembled as liposomes. The primary objective is to demonstrate the safety of TLN administration intravenously in Parkinson patients. Secondary objectives are the determination of the maximal suitable dose based on the safety profile and preliminary efficacy, as well as the determination of the pharmacokinetics (PK) profile.

Detailed Description
-----------------
The ganglioside lipid GM1 has been described in the literature as a neuroprotective agent. Several clinical studies have shown that GM1 improves the condition of Parkinson's disease patients. Talineuren consists of the pharmacologically active ingredient GM1, associated with a proprietary lipid formulation assembled as liposomes. Talineuren has been developed to improve the delivery and bioavailability of GM1. The primary objective of this trial is to demonstrate the feasibility and safety of intravenous Talineuren administration in Parkinson's disease patients. The secondary objectives are: The determination of the recommended phase 2 dose based on the safety profile and preliminary efficacy. The determination of the pharmacokinetics (PK) profile. This trial aims to investigate the safety of the novel formulation of GM1, Talineuren. To that extent a three-part trial was designed: Part 1- Dose escalation Part 2- Dose consolidation Part 3- Dose consolidation with intrapatient dosing Part 1- rapid dose escalation scheme from 6 mg to 720 mg of Talineuren formulated GM1 in 3 patients. Optional treatment prolongations for 8 weeks (Amendment 1), 16 weeks (Amendment 2), 8 months (Amendment 3), and 4 months (Amendment 4). Part 2- multiple dosing of Talineuren over 8 weeks in 9 patients to validate the safety profile of the maximum suitable dose. Optional treatment prolongations for 16 weeks (Amendment 2), 8 months (Amendment 3), and 4 months (Amendment 4). Part 3- rapid dose escalation scheme from 6 mg to 720 mg of Talineuren followed by multiple doses of 720mg Talineuren for up to 8 months in 10 patients (Amendment 3).

Official Title
-----------------
Safety Evaluation of Intravenous Talineuren (TLN) in Parkinson's Disease-affected Patients

Conditions
-----------------
Parkinson Disease

Intervention / Treatment
-----------------
* Drug: Talineuren


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Informed consent as documented by signature. Confirmed Parkinson's disease according to British brain bank criteria. Hoehn and Yahr Stage 0 - 2.5 on medication. Stable on PD treatment for a month at least. Absence of dementia confirmed by cognitive testing (MoCA >25). Exclusion Criteria: Contraindications to the class of drugs under study, e.g., known hypersensitivity or allergy to class of drugs or the investigational product. Women who are pregnant or breast feeding, or planning to become pregnant during the course of the trial or in the 3 months following the trial. Lack of safe contraception in women with childbearing potential Other clinically significant concomitant disease states (e.g., renal failure, hepatic dysfunction, cardiovascular disease, etc) that is not under stable control. Subject has an atypical parkinsonian syndrome or secondary parkinsonism. Patients with comorbidity that may interfere with the course of the trial.

Ages Eligible for Study
-----------------
Minimum Age: 30 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Part 1: dose escalation phase, 3 patients with Parkinson's disease, (2 cohorts as in 1+2 patients, sequential inclusion between the first and 2nd patient) Part 2: repeated dose administration phase, 9 patients with Parkinson's disease (1 cohort) Part 3: Dose consolidation with intrapatient dosing, 10 patients with Parkinson's disease (1 cohort)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Talineuren dose escalation<br>14 doses of GM1 Ganglioside 6, 12, 60, 120, 180, 240, 300, 360, 420, 480, 540, 600, 660, 720 mg. Optional treatment prolongations for 16 weeks (Amendment 2), 8 months (Amendment 3), and 4 months (Amendment 4) . | Drug: Talineuren<br>* Talineuren is a liposomal formulation of the GM1 Ganglioside for intravenous administration<br>* Other names: liposomal GM1;|
| Experimental: Talineuren repeated dose<br>8 repeated doses of GM1 Ganglioside tbd from the escalation dose (maximum suitable dose). Optional treatment prolongations for 16 weeks (Amendment 2), 8 months (Amendment 3) and 4 months (Amendment 4) . | Drug: Talineuren<br>* Talineuren is a liposomal formulation of the GM1 Ganglioside for intravenous administration<br>* Other names: liposomal GM1;|
| Experimental: Talineuren dose consolidation with intrapatient dosing<br>8 months repeated doses of 720mg GM1 Ganglioside (Amendment 3). | Drug: Talineuren<br>* Talineuren is a liposomal formulation of the GM1 Ganglioside for intravenous administration<br>* Other names: liposomal GM1;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurence of adverse events (safety) | Number and kinds of adverse events (AEs) | 8 to 86 weeks | 
| Occurence of serious adverse events (safety) | Number and kinds of serious adverse events (SAEs) | 8 to 86 weeks | 
| Occurence of other safety-related signs (safety) | Number and kinds of other safety-related signs | 8 to 86 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Levodopa challenge (LDC) test | Assessing the patients' condition via the LDC test (MDS-UPDRS-3 score) | 8 to 86 weeks | 
| Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) | Assessing the patients' condition via the test | 8 to 86 weeks | 
| Epworth Sleepiness Scale (ESS) | Assessing the patients' condition via the test | 8 to 86 weeks | 
| Parkinson's Disease Questionnaire (PDQ-39) | Assessing the patients' condition via the test | 8 to 86 weeks | 
| Change in Parkinson's medication | Assessing the patients' condition via the change in their pre-existing Parkinson's medication | 8 to 86 weeks | 
| Starkstein Apathy Scale (SAS) | Assessing the patients' condition via the test | 8 to 86 weeks | 
| Montreal Cognitive Assessment (MoCA) | Assessing the patients' condition via the test | 8 to 86 weeks | 
| Beck's Depression Inventory (BDI) | Assessing the patients' condition via the test | 8 to 86 weeks | 
| Non-Motor Symptoms Questionnaire (NMSQuest) | Assessing the patients' condition via the test | 8 to 86 weeks | 
| Maximum Observed Drug Concentration (Cmax) in serum | Pharmacokinetics (PK) of total GM1 in serum over the first 96 h | 8 to 15 weeks | 
| Time of Maximum Drug Concentration (Tmax) in serum | Pharmacokinetics (PK) of total GM1 in serum over the first 96 h | 8 to 15 weeks | 
| Area Under the Curve to infinity (AUCinf.) in serum | Pharmacokinetics (PK) of total GM1 in serum over the first 96 h | 8 to 15 weeks | 
| half-life (t1/2) | Pharmacokinetics (PK) of total GM1 in serum over the first 96 h | 8 to 15 weeks | 
| Clearance (CL) | Pharmacokinetics (PK) of total GM1 in serum over the first 96 h | 8 to 15 weeks | 
| Volume of distribution (Vd) | Pharmacokinetics (PK) of total GM1 in serum over the first 96 h | 8 to 15 weeks |