Clinical Trials Highlights

Dear Readers,

The Clinical Trials Highlights of the Journal of Parksinon's Disease is a section devoted to raising awareness of the clinical trial landscape in Parkinson’s, promoting discussion and progress in the conduct and outcome of studies. Please help us to make a difference to the outcome of clinical trials in Parkinson’s, looking forward to a time when clinical progress matches the performance in the lab. If you feel that you would like to draw attention to a specific trial, please feel free to email us at: jpd@iospress.com.

Sincerely,

Kevin McFarthing
JPD Co-Editor of Clinical Trials Highlights
Parkinson’s Advocate, Innovation Fixer Ltd, Oxford, UK

Tanya Simuni
JPD Co-Editor of Clinical Trials Highlights
Parkinson's Disease and Movement Disorders Center
Northwestern University Feinberg School of Medicine, Chicago, USA

A Phase 1/2 Study of Intra-putaminal Infusion of Adeno-Associated Virus Encoding Human Aromatic L-Amino Acid Decarboxylase in Subjects with Parkinson’s Disease

Status: 
Recruiting
Sponsor: 
Jichi Medical University
Enrollment: 
6
Study Design: 
This study is a phase 1/2 non-randomized, single center, open label, interventional, safety and dose evaluation study of the active agent AAV-hAADC-2 being delivered intra-putaminal via stereotaxic surgery. It is being conducted at the Jichi Medical University in Japan. The target putamen is identified on the pre-operative MRI brain and then bilateral putamina are infused with the active drug at a total of 4 spots (2 on each putamen). AAV-hAADC-2 is administered via bilateral intra-putaminal infusion in either low or high dose. There are two sequential study arms. Cohort 1 receives low dose (3x1011 vector genome/subject) and is infused with a total volume of 200 μl of the drug (50 μl per site). If there are no safety concerns at 6 months, then the study moves to cohort 2. Cohort 2 will receive high dose (9x1011 vector genome/subject) with 600 μl of total infusion volume (150 μl per site). The study includes patients with clinical diagnosis of idiopathic PD aged between 35 to 75 years of age with no other known or suspected cause of parkinsonism. Patients should be levodopa responsive and should have been on it for at least 5 years. An OFF state MDS-UPDRS score between 30–100 and Hoehn and Yahr stage IV is required. Patients with a history of 3 hours or more of intensive or violent dyskinesia are excluded from the study. Standard surgical exclusionary criteria are applied.
Rationale: 
Primary outcome measures include assessment of safety of intra-putaminal infusion of AAV-hAADC-2 as measured by adverse events. Secondary outcomes include two measures: 1. The treatment effect of the drug at the end of 6 months. This is assessed by improvement in PD symptoms as recorded in subject diaries, clinical assessment and change in levodopa dosage. 2. The amount of intra-putaminal expression of AAV-hAADC-2 after 6 months, as measured by FMT-PET imaging. Investigators will continue to assess the safety for 5 years after baseline examination and long term follow up will continue for 10 years.
Comments: 
This is a phase 1/2 dose escalation safety and efficacy study. No results have been published yet.

VY-AADC02 for Parkinson’s Disease with motor fluctuations

Status: 
Recruiting
Sponsor: 
Voyager Therapeutics
Enrollment: 
42
Study Design: 
Voyager’s phase 2 study is randomized, placebo-controlled and double-blind, comparing one active dose of VY-AADC02 with a placebo of sham surgery involving a partial burr/twist hole without dura penetration.
Rationale: 
Primary outcomes will measure both efficacy and safety. The safety criteria will be evaluated at 12 months and 30 day follow up. The efficacy measures will be taken at 12 months, with enzyme activity also assessed at 45 days. The outcome measures are: a. change in patient rated motor fluctuations; b. percent coverage within the putamen at time of administration of VY-AADC02; c. change in AADC enzyme activity (distribution); d. safety of VY-AADC02 as measured by: i. number of treatment emergent adverse events, ii. changes in vital signs, iii. physical examinations and routine clinical laboratory analysis, (hematology and clinical chemistry), iv. changes in findings on brain images, v. the Columbia-Suicide Severity Rating Scale (C-SSRS), vi. change in impulse control disorders. Secondary outcomes are all related to efficacy, as measured at the twelve-month timepoint by changes in: a. activities of daily living (UPDRS II); b. PD related quality of life (PDQ-39); c. time course response to levodopa (UPDRS III); d. clinical global function (CGI); e. overall non-motor symptoms (NMSS).
Comments: 
Voyager are recruiting patients at least four years since diagnosis, although there is no explicit requirement for the presence of motor complications, despite the study title. The choice of primary and secondary outcome measures has some interesting features. The primary efficacy outcome is a patient rating of motor fluctuations, with UPDRS measures only as secondary outcomes. The assessment of coverage of the putamen on administration and distribution of enzyme activity, both already validated in the phase 1b trial, will give a good indication of target engagement and change in biological activity. The combination of a good safety profile thus far; the change in biological activity leading to significant clinical change; and a favourable regulatory review, give cause for optimism with VY-AADC02.

A Study to Assess the Safety and Efficacy of the Gastric-retentive AP-CD/LD in Advanced Parkinson’s Patients (Accordance)

Status: 
Active, No Longer Recruiting
Sponsor: 
Intec Pharma
Enrollment: 
420
Study Design: 
The phase 3 Accordance study is a multi-center (97 study locations), global, randomized, double-blind, double-dummy, active-controlled, parallel-group study in adult subjects with fluctuating PD. The study will have 2 open label titration periods of 6 weeks each prior to the double-blind maintenance period. In the open label periods, all patients will be stabilized on the active comparator, IR-CD/LD and then on AP-CD/LD. The double-blind maintenance period will be 13 weeks long.
Rationale: 
The primary outcome is change from baseline through to study completion, an average of 27 weeks, in the percentage of daily “Off time” during waking hours, based on Hauser Home Diary assessments. Secondary outcomes, all measured on the same timescale as the primary outcome, are: 1. Change in “On time” without troublesome dyskinesia during waking hours; 2. Change in the number of total daily LD doses; 3. Clinical Global Impression Improvement (CGI-I), as recorded by physician & patient; 4. Change in total UPDRS Score (sum of Parts I-III).
Comments: 
Until disease-modifying therapies are available, people with Parkinson’s will welcome any therapy that extends the duration of symptom relief and reduces motor fluctuations. The novel design of the Accordion Pill and the promising safety and efficacy data generated in phases 1 and 2, hold out great hope for the achievement of these benefits.

Study of OXB-102 (AXO-Lenti-PD) in patients with idiopathic Parkinson’s Disease (SUNRISE-PD)

Status: 
Recruiting
Sponsor: 
Axovant
Enrollment: 
32
Study Design: 
There are two parts to this phase 1/2 study. The first is an open-label phase where three escalating dose levels will be tested. The second phase will take the optimal dose from part one into a randomized, double-blind phase in which patients will receive either active AXO-Lenti-PD or an imitation surgical procedure (ISP).
Rationale: 
Primary outcomes are all related to safety at the three-month time point, as measured by: a. incidence of treatment emergent adverse events and serious adverse events; b. changes in clinical laboratory analysis; c. changes in vital signs; d. changes in brain MRI findings; e. changes in physical examination. Secondary outcomes are all related to efficacy, as measured at the six-month timepoint by changes in: a. the Unified Parkinson’s Disease Rating Scale (UPDRS) scores compared to baseline in defined “OFF” and “ON” medication states; b. motor fluctuations compared to baseline as assessed by patient diaries; c. the dyskinesia rating scale from baseline.
Comments: 
Axovant are recruiting patients at a relatively advanced stage of Parkinson’s, with at least five years since diagnosis and a Hoehn and Yahr stage of 3 or 4 in the OFF state. The patients must also be experiencing motor complications. Results from the first cohort using the lowest dose of AXO-Lenti-PD in two patients, were announced in March 2019 [3], showing efficacy greater than the highest dose of ProSavin® used in previous studies. No serious adverse events were reported. Clearly, caution must be applied given the number of patients and further results are awaited.

A Phase 1 Open-Label Dose Escalation Safety Study of Convection Enhanced Delivery (CED) of Adeno-Associated Virus Encoding Glial Cell Line-Derived Neurotrophic Factor (AAV2-GDNF) in Subjects with Advanced Parkinson’s Disease

Status: 
Active, No Longer Recruiting
Sponsor: 
National Institute of Neurological Disorders and Stroke (NINDS)
Enrollment: 
25
Study Design: 
This is a phase 1 single center, open-label, dose escalation, safety and tolerability study of the AAV2-GDNF (adeno-associated virus, serotype 2 containing the human GDNF complementary DNA). The active drug will be delivered surgically by convection-enhanced delivery to bilateral putamina. The study includes 4 cohorts to evaluate the four escalating dose levels. Each cohort will have 6 subjects. The drug level for each cohort is as follows: Cohort 1: 9 x 10 sup.10 vg; Cohort 2: 3 x 10 sup.11 vg; Cohort 3: 9 x 10 sup.11 vg; Cohort 4: 3 x 10 sup.12 vg. The study includes individuals 18 years and above with clinical idiopathic PD of at least 5 years disease duration with no other known or suspected cause for parkinsonism. An Off state UPDRS score of more than or equal to 30 and Hoehn and Yahr stage of III and IV are required for inclusion. The study also requires a 30% or greater improvement in the UPDRS total motor score on sinemet study according to the CAPSIT guidelines. The participants in the study will be followed for 5 years with 18 outpatient study visits and a 3-day stay in the hospital post-surgery. Lumbar puncture for CSF analysis will be done at the time of surgery, 6 months and 18 months after surgery.
Rationale: 
Primary outcome measure: To assess the safety and tolerability of 4 different dose levels of AAV2-GDNF over a period of 12 years. Secondary outcome measures: To obtain preliminary data regarding the potential for clinical responses of the 4 dose levels testing by assessing the magnitude and variability of any treatment effects including clinical, laboratory and neuroimaging studies.
Comments: 
GDNF and neurturin have been studied extensively as potential neuroprotective interventions in PD so far with disappointing results despite reproducibly positive data in preclinical models. It remains to be determined if lack of success in PD clinical trials reflects a lack of biological effect of intervention, limitations of the technical delivery modes (insufficient coverage of putamen, dose, etc) or failure to reverse the course of the advanced disease at the time of intervention. The ongoing study will be closely followed.

Impact of Nilotinib on Safety, Tolerability, Pharmacokinetics and Biomarkers in Parkinson’s Disease (PD Nilotinib)

Status: 
No Longer Recruiting
Sponsor: 
Georgetown University
Enrollment: 
75
Study Design: 
Out of 75 participants that will be recruited and randomly assigned 1:1:1 to the 3 groups (arms), 150mg: 300mg: placebo; all once daily. Intervention duration: 6 months and 2 months follow up (NCT03205488) and 12 months and 3 months follow up (NCT02954978).
Rationale: 
PRIMARY OUTCOME MEASURE: Safety and tolerability (both studies). SECONDARY OUTCOME MEASURES: Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III (motor function) will be evaluated to determine if Nilotinib has the potential to reduce the MDS-UPDRS motor score as well as a spectrum of motor and non-motor outcome scales, PK profile in cerebrospinal fluid and a number of exploratory biomarkers.
Comments: 
Nilotinib is a drug approved for treatment of chronic leukaemia and as such has a number of safety concerns. The current studies aim to assess safety/ tolerability of nilotinib as well as explore signals of efficacy to determine if the future studies are warranted. There are other molecules targeting the c-ABL pathway in development with potentially better safety profile and better CNS penetration, (Sun Pharma, NCT02970019).

A Phase 1, Randomized, Double-Blind, Single Ascending Dose Trial of the Safety, Tolerability and Pharmacokinetics of NPT200-11 in Healthy Subjects

Status: 
Completed
Sponsor: 
Neuropore Therapies/UCB
Enrollment: 
55
Study Design: 
Single ascending dose of orally administered capsule(s) NPT200-11 vs placebo: 15, 30, 60,120, 240, 360 and 480 mg dose.
Rationale: 
PRIMARY OUTCOME MEASURE: Safety, including adverse events, physical examinations, ECGs, clinical laboratory tests. Time Frame: Screening (28 days prior to dosing) through Day 7. SECONDARY OUTCOME MEASURES: To possibly determine the maximally tolerated dose (MTD) of orally administered NPT200-11 in healthy subjects. The number of participants with unacceptable toxicities at each dose level will determine the maximally tolerated dose.
Comments: 
An early phase SAD study was completed but the data have not been published and no information on future drug development are available.

Phenylbutyrate Response as a Biomarker for Alpha-synuclein Clearance from the Brain

Status: 
Active, No Longer Recruiting
Sponsor: 
University of Colorado, Denver
Enrollment: 
40
Study Design: 
This is a Phase I clinical trial of phenylbutyrate in 20 Parkinson patients and 20 age- and sex-matched normal control subjects to see if phenylbutyrate can increase the removal of alpha-synuclein from the brain into the bloodstream. All subjects will receive 20 grams/day of phenylbutyrate in the liquid form phenylbutyrate-triglyceride taken as one teaspoonful three times per day with meals. Blood will be drawn on two days prior to starting phenylbutyrate to measure alpha-synuclein concentrations. Phenylbutyrate-triglyceride will then be started and the change in plasma alpha-synuclein will be measured on day 1, 7, 14, and 21 days while taking phenylbutyrate. After 21 days, the drug will be stopped and a final blood sample will be measured at 28 days to see if plasma alpha-synuclein has fallen to its pre-phenylbutyrate level. No effects on Parkinson symptoms are expected during this short trial.
Rationale: 
PRIMARY OUTCOME MEASURE: Levels of α-synuclein in blood plasma. SECONDARY OUTCOME MEASURES: Not listed.
Comments: 
This is an open label proof of principle study. The study has been completed but the results have not been published. The team is pursuing a Phase II dose selection study.

A study to evaluate the efficacy of Prasinezumab (RO7046015/PRX002) in participants with early Parkinson’s Disease (PASADENA)

Status: 
No Longer Recruiting, Ongoing
Sponsor: 
Hoffmann-La Roche
Enrollment: 
300
Study Design: 
The PASADENA study has two parts, both of which are randomized, double-blind and placebo controlled. The first part has three arms: ARM 1 – high dose Prasinezumab 4500mg for participants with body-weight greater than or equal to (>/=) 65kg or 3500 mg for participants with body-weight less than (<) 65 kg; ARM 2 – low dose Prasinezumab 1500mg; ARM 3 – placebo. All three arms will receive the relevant dose through IV infusion every 4 weeks for 52 weeks. At the end of part 1, patients who have been on placebo will be randomized to either high dose or low dose Prasinezumab, joining those patients who have already been on the high or low dose. Part 2 will therefore have 2 arms: HIGH DOSE ARM - high dose group participants and placebo group participants randomized to high dose level will receive Prasinezumab at high dose level as intravenous infusion every 4 weeks for additional 52 weeks; LOW DOSE ARM - low dose group participants and placebo group participants randomized to low dose level will receive Prasinezumab at low dose level as intravenous infusion every 4 weeks for additional 52 weeks.
Rationale: 
Primary Outcome Measures: 1. Change From Baseline in Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Total Score (Sum of Parts I, II, and III) at Week 52 [Time Frame: Baseline and Week 52]. Secondary Outcome Measures: 1. Change From Baseline in Dopamine Transporter Imaging With Single Photon Emission Computed Tomography (DaT-SPECT) Signal at Week 52 [Time Frame: Baseline and Week 52]. 2. Change From Baseline in the MDS-UPDRS Motor Subscale (Part III) Score [Time Frame: Baseline and Week 52]. 3. Clinical Global Impression of Improvement (CGI-I) Score at Weeks 24 and 52 [Time Frame: Week 24 and Week 52]. 4. Patient Global Impression of Change (PGIC) Score at Weeks 24 and 52 [Time Frame: Week 24 and Week 52]. 5. Time to Start of Dopaminergic Symptomatic Treatment [Time Frame: From Baseline to Week 52]. 6. Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) [Time Frame: From Day 1 to Week 104]. 7. Percentage of Participants With Anti-Drug Antibodies (ADAs) Against RO7046015 [Time Frame: Baseline, Pre-dose (0 hours) on Weeks 4, 20, 36, 52, 56, 68, 80, and 104; at early termination (up to Week 104), and follow-up (12 weeks after last dose up to Week 116)]. 8. Systemic Clearance (CL) of RO7046015 [ Time Frame: Predose (0 hours) and end of infusion (infusion length=2 hours or less) on Day 1, Weeks 4, 20, 36, 52, 56, 68, 80, and 104; at Day 7, Day 14, early termination (up to Week 104), and follow-up (12 weeks after last dose up to Week 116)]. 9. Apparent Volume of Distribution (Vz/F) of RO7046015 [Time Frame: Predose (0 hours) and end of infusion (infusion length=2 hours or less) on Day 1, Weeks 4, 20, 36, 52, 56, 68, 80, and 104; at Day 7, Day 14, early termination (up to Week 104), and follow-up (12 weeks after last dose up to Week 116)]. 10. Area Under the Serum Concentration-Time Curve (AUC) of RO7046015 [Time Frame: Predose (0 hours) and end of infusion (infusion length=2 hours or less) on Day 1, Weeks 4, 20, 36, 52, 56, 68, 80, and 104; at Day 7, Day 14, early termination (up to Week 104), and follow-up (12 weeks after last dose up to Week 116)]. 11. Maximum Observed Serum Concentration (Cmax) of RO7046015 [Time Frame: Predose (0 hours) and end of infusion (infusion length=2 hours or less) on Day 1, Weeks 4, 20, 36, 52, 56, 68, 80, and 104; at Day 7, Day 14, early termination (up to Week 104), and follow-up (12 weeks after last dose up to Week 116)]. 12. Minimum Observed Serum Trough Concentration (Ctrough) of RO7046015 [Time Frame: Predose (0 hours) and end of infusion (infusion length=2 hours or less) on Day 1, Weeks 4, 20, 36, 52, 56, 68, 80, and 104; at Day 7, Day 14, early termination (up to Week 104), and follow-up (12 weeks after last dose up to Week 116)].
Comments: 
This is a comprehensive phase 2 study assessing both efficacy and safety/tolerability at two active dose levels of Prasinezumab.

Interventional, Randomized, Double-blind, Sequential-group, Placebo-controlled, Single-ascending-dose Study Investigating the Safety, Tolerability and Pharmacokinetic and Pharmacodynamic Properties of Lu AF82422 in Healthy Non-Japanese and Japanese Subjec

Status: 
Recruiting
Sponsor: 
H. Lundbeck A/S
Enrollment: 
44
Study Design: 
Single ascending dose study. Cohort A: A1, A2, and A3: 24 healthy subjects in active arm and in placebo, with 8 subjects per cohort per treatment arm (aiming for an equal number of men and women). Cohort A4: 12 healthy subjects per treatment arm, with 6 non-Japanese subjects and 6 Japanese subjects (aiming for an equal number of men and women). Part B: Cohort B1: 8 patients with PD in active arm: 8 in placebo.
Rationale: 
PRIMARY OUTCOME MEASURE: Adverse events. SECONDARY OUTCOME MEASURES: spectrum of pharmacokinetic and pharmacodynamic measures including free/total α-synuclein concentration in cerebrospinal fluid and plasma. Antidrug antibodies in serum will be measured as well.
Comments: 
This is an early phase Single Ascending Dose (SAD) study that will define viability of the molecule to move into the more advanced stages of the development. MEDI1341 is an α-synuclein antibody that is potentially differentiated by its high affinity, high selectivity and reduced effector function (lower interaction with the immune system). The impact of this differential profile will be determined in future studies.

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