A Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of anle138b in Parkinson's Disease

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety, tolerability and blood levels of orally administered anle138b as well as the effect of food and early signs of efficacy in patients with mild to moderate Parkinson´s disease.

Detailed Description
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This is a two centre, double-blind, randomised, placebo-controlled, multiple ascending dose study in patients with mild to moderate Parkinson´s disease. It is planned to enrol up to 5 cohorts. Cohorts A-C consist of up to 8 subjects. In Cohorts A and B, subjects will be randomly assigned to receive multiple ascending oral doses of anle138b or matching placebo (6 active investigational medicinal product [IMP], 2 placebo per cohort in cohorts A-C) for 7 days in a sequential escalating manner. Subjects in cohort A and B will be dosed once dialy and subjects in cohort C will be dosed twice a day. Subjects in Cohorts A and B will also receive an additional single oral dose of active IMP or matching placebo on Day 9 of the study for an assessment of the effect of food on the PK of anle138b in PD patients. Subjects in cohort D will be randomly assigned to receive QD doses of anle138b or matching placebo (placebo vs 150 mg vs 300 mg; 1:1:1) for 7 days in fasted state. Subjects in Cohort E will be randomly assigned to receive QD doses of either 300 mg anle138b or matching placebo (1:1) for 28 days taken in the non-fasted state.

Official Title
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A Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Oral Doses of anle138b, and to Characterise the Effect of Food of anle138b in Mild to Moderate Parkinson's Disease

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: anle138b
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females with a diagnosis of idiopathic PD as defined by the Movement Disorders Society criteria (either fulfilling criteria for Clinically Established PD or for Clinically Probable PD). Body mass index (BMI) 18.5 to 35.0 kg/m2 or 18.5 to <40.0 kg/m2 (Cohorts D and E) as measured at screening. Hoehn and Yahr stage I-III (able to walk unaided). Stable medication for PD for 1 month prior to screening at Quotient and anticipated over the study period. No history of dementia. Must be willing and able to communicate and participate in the whole study. Must provide written informed consent. Must agree to adhere to the contraception requirements defined in the study protocol. Exclusion Criteria: Subjects who have received any IMP in a clinical research study within the 90 days prior to Day 1. Subjects who are, or are immediate family members of, a study site or sponsor employee. Evidence of current SARS-CoV-2 infection. History of any drug or alcohol abuse in the past 2 years. Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 units = 125 mL glass of wine, depending on type). A confirmed positive alcohol breath test at screening or admission. Current smokers and those who have smoked within the last 12 months. A confirmed breath carbon monoxide reading of greater than 10 ppm at screening or admission (Cohorts A to C only). Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months (Cohorts A to C only). Females of childbearing potential including those who are pregnant or lactating (all female subjects must have a negative highly sensitive serum or urine pregnancy test). A woman is considered of childbearing potential unless she is permanently sterile (hysterectomy, bilateral salpingectomy, and bilateral oophorectomy) or is postmenopausal (had no menses for 12 months without an alternative medical cause and a serum follicle-stimulating hormone [FSH] concentration ≥40 IU/L). Male subjects with pregnant or lactating partners. Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator or delegate at screening. Clinically significant abnormal coagulation (Cohort E only), clinical chemistry, haematology or urinalysis as judged by the investigator. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) antibody results. History of clinically significant cardiovascular, renal, hepatic, dermatological, chronic respiratory or gastrointestinal disease or psychiatric disorder, as judged by the investigator. Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients. Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active. Donation of blood or plasma within the previous 3 months or loss of greater than 400 mL of blood. Subjects who are taking, or have taken, any prescribed or over-the-counter drug or herbal remedies other than their regular medication according to the referral letter from NUH, and/or up to 2 g of paracetamol per day and/or HRT, in the 14 days before IMP administration. Subjects who are taking, or have taken, in the 14 days before IMP administration the drug warfarin. Subjects who are taking, or have taken, in the 14 days before IMP administration any drug that is considered to interfere with the objectives of the study, as determined by the concomitant medication oversight committee. Subjects who have participated in Cohorts A to C of this study will not be allowed to participate in Cohorts D or E, and subjects who have participated in Cohort D will not be allowed to participate in Cohort E. Failure to satisfy the investigator of fitness to participate for any other reason. Subjects who have a new headache with features suggestive of raised intracranial pressure, including papilloedema, vomiting, posture-related headache, or headache on waking from sleep (Cohort E only). Subjects who have a new headache with focal neurological symptoms, or non-focal neurological symptoms such as change in personality or memory, or an unexplained headache that becomes progressively severe, or an unexplained headache in anyone previously diagnosed with cancer (Cohort E only). Medical history or evidence of mass occupying lesion in brain or spinal cord or history of spinal cord injury, which could preclude the procedure of lumbar puncture and CSF collection (Cohort E only).

Ages Eligible for Study
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Minimum Age: 40 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: anle138b<br>150 mg and higher dosage | Drug: anle138b<br>* capsule containing excipient and anle138b<br>|
| Placebo Comparator: Placebo<br>Matching placebo dosage | Drug: Placebo<br>* matching placebo capsule containing excipient<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D). | Adverse events | Day 1 to day 14-16: cohorts A-C; day 1 to week 6 post dosing: cohort D | 
| Incidence of treatment-emergent adverse events in PD patients with multiple ascending doses of anle138b taken in the fed state (Cohorts A and B). | Adverse events | From fed dosing (day 9) to day 12-14 | 
| Incidence of treatment-emergent changes in vital signs in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D). | Blood pressure | Day 1 to week 1 post dosing: cohorts A-C; day 1 to week 6 post dosing: cohort D | 
| Incidence of treatment-emergent changes in vital signs in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D). | Heart rate | Day 1 to week 1 post dosing: cohorts A-C; day 1 to week 6 post dosing: cohort D | 
| Incidence of treatment-emergent changes in vital signs in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D). | Oral temperature | Day 1 to week 1 post dosing: cohorts A-C; day 1 to week 6 post dosing: cohort D | 
| Incidence of treatment-emergent changes in vital signs in PD patients with multiple ascending doses of anle138b taken in the fed state (Cohorts A and B). | Blood pressure | From fed dosing to 1 week post dosing | 
| Incidence of treatment-emergent changes in vital signs in PD patients with multiple ascending doses of anle138b taken in the fed state (Cohorts A and B). | Heart rate | From fed dosing to 1 week post dosing | 
| Incidence of treatment-emergent changes in vital signs in PD patients with multiple ascending doses of anle138b taken in the fed state (Cohorts A and B). | Oral temperature | From fed dosing to 1 week post dosing | 
| Incidence of treatment-emergent ECG changes in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D). | Electrocardiogram (ECG) parameters including QT interval corrected for heart rate using Fridericia's formula (QTcF) | Day 1 to week 1 post dosing: cohorts A-C; day 1 to week 6 post dosing: cohort D | 
| Incidence of treatment-emergent ECG changes in PD patients with multiple ascending doses of anle138b taken in the fed state (Cohorts A and B). | Electrocardiogram (ECG) parameters including QT interval corrected for heart rate using Fridericia's formula (QTcF) | From fed dosing to 1 week post dosing | 
| Incidence of treatment-emergent changes in physical examination in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D). | Physical examination findings | Day 1 to week 1 post dosing: cohorts A-C; day 1 to week 6 post dosing: cohort D | 
| Incidence of treatment-emergent changes in physical examination in PD patients with multiple ascending doses of anle138b taken in fed state (Cohorts A and B). | Physical examination findings | From fed dosing to 1 week post dosing | 
| Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D). | Clinical laboratory Tests: Hematology | Day 1 to day 8 | 
| Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D). | Clinical chemistry: Renal function tests | Day 1 to day 8 | 
| Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D). | Clinical chemistry: Hepatic enzymes | Day 1 to day 8 | 
| Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D). | Clinical chemistry: Electrolytes | Day 1 to day 8 | 
| Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D). | Clinical chemistry: Creatine kinase | Day 1 to day 8 | 
| Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken in fed state (Cohorts A and B). | Clinical laboratory Tests: Hematology | From fed dosing to 24 hours post dosing | 
| Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken in fed state (Cohorts A and B). | Clinical chemistry: Renal function tests | From fed dosing to 24 hours post dosing | 
| Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken in fed state (Cohorts A and B). | Clinical chemistry: Hepatic enzymes | From fed dosing to 24 hours post dosing | 
| Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken in fed state (Cohorts A and B). | Clinical chemistry: Electrolytes | From fed dosing to 24 hours post dosing | 
| Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken in fed state (Cohorts A and B). | Clinical chemistry: Creatine kinase | From fed dosing to 24 hours post dosing | 
| Incidence of treatment-emergent adverse events in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E). | Adverse events | Day 1 to week 6 post dosing | 
| Incidence of treatment-emergent changes in vital signs in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E). | Blood pressure | Day 1 to week 6 post dosing | 
| Incidence of treatment-emergent changes in vital signs in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E). | Heart rate | Day 1 to week 6 post dosing | 
| Incidence of treatment-emergent changes in vital signs in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E). | Oral temperature | Day 1 to week 6 post dosing | 
| Incidence of treatment-emergent changes in vital signs in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E). | Electrocardiogram (ECG) parameters including QT interval corrected for heart rate using Fridericia's formula (QTcF) | Day 1 to week 6 post dosing | 
| Incidence of treatment-emergent changes in physical examination in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E). | Physical examination findings | Day 1 to week 6 post dosing | 
| Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E). | Clinical laboratory Tests: Hematology | Day 1 to 24 hours post dosing | 
| Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E). | Clinical chemistry: Renal function tests | Day 1 to 24 hours post dosing | 
| Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E). | Clinical chemistry: Hepatic enzymes | Day 1 to 24 hours post dosing | 
| Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E). | Clinical chemistry: Electrolytes | Day 1 to 24 hours post dosing | 
| Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E). | Clinical chemistry: Creatine kinase | Day 1 to 24 hours post dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the fasted state (cohorts A-C + D). | PK parameter: Tlag for anle138b. | Day 1 to day 9 | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the fasted state (cohorts A-C + D). | PK parameter: Tmax for anle138b. | Day 1 to day 9 | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the fasted state (cohorts A-C + D). | PK parameter: Cmax for anle138b. | Day 1 to day 9 | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the fasted state (cohort B). | PK parameter: C12 for anle138b. | Day 1 to day 9 | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the fasted state (cohorts A-C + D). | PK parameter: C24 for anle138b. | Day 1 to day 9 | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the fasted state (cohorts A-C + D). | PK parameter: AUC(0-tau) for anle138b. | Day 1 to day 9 | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the fasted state (cohorts A-C + D). | PK parameter: Lambda-z for anle138b. | Day 1 to day 9 | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the fasted state (cohorts A-C + D). | PK parameter: T1/2 for anle138b. | Day 1 to day 9 | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the fasted state (cohorts A-C + D). | PK parameter: Accumulation ratio for Cmax (Day 7) for anle138b. | Day 1 to day 9 | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the fasted state (cohorts A-C + D). | PK parameter: Accumulation ratio for AUC (Day 7) for anle138b. | Day 1 to day 9 | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the fed state (Cohorts A and B). | PK parameter: Cmax for anle138b. | From fed dosing to 48 hours post dosing. | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the fed state (Cohorts A and B). | PK parameter: AUC(0-24) for anle138b. | From fed dosing to 48 hours post dosing. | 
| Effect of multiple ascending doses of anle138b on the motor status of PD patients | Changes from baseline in the Movement Disorder Society-sponsored revision of the Unified PD Rating Scale (MDS-UPDRS) ranging from 0 to 260 points with less points meaning less severity. | Admission to follow-up visit (days 14-16 for cohorts A and B; days 12-14 for cohort C; week 6 for cohorts D and E) | 
| Effect of multiple doses of anle138b on the CSF levels of anle138b in PD patients | Quantification of anle138b | single time point 3 hours post dose on dosing day 5 (cohort B) | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the non-fasted state (cohort E) | PK parameter: Tlag for anle138b | Day 1 to day 30 | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the non-fasted state (cohort E) | PK parameter: Tmax for anle138b | Day 1 to day 30 | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the non-fasted state (cohort E) | PK parameter: Cmax for anle138b | Day 1 to day 30 | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the non-fasted state (cohort E) | PK parameter: C12 for anle138b | Day 1 to day 30 | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the non-fasted state (cohort E) | PK parameter: C24 for anle138b | Day 1 to day 30 | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the non-fasted state (cohort E) | PK parameter: AUC(0-tau) for anle138b | Day 1 to day 30 | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the non-fasted state (cohort E) | PK parameter: Lambda-z for anle138b | Day 1 to day 30 | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the non-fasted state (cohort E) | PK parameter: T1/2 for anle138b | Day 1 to day 30 | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the non-fasted state (cohort E) | PK parameter: Accumulation ratio for Cmax for anle138b | Day 1 to day 30 | 
| Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the non-fasted state (cohort E) | PK parameter: Accumulation ratio for AUC for anle138b | Day 1 to day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anle138b, alpha-Synuclein, Oligomer modulator, Multiple System Atrophy, Parkinson Disease, Alzheimer Disease, Neurodegenerative diseases, Tauopathies, Amyloid