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

ADX48621 for the Treatment of Levodopa Induced Dyskinesia in Patients With Parkinson’s Disease

Status: 
Completed
Sponsor: 
Addex Pharma
Enrollment: 
83
Study Design: 
Phase 2, Randomized, Double-blind, Placebo-controlled, Parallel Group, Multicenter Study to Evaluate the Safety, Tolerability and Efficacy of ADX48621 (dipraglurant). The trial design contained a dose escalation from 50mg once daily up to 100mg three times a day.
Rationale: 
The primary outcome measure was the number of participants with abnormal safety and tolerability assessment parameters after 4 weeks. Secondary outcome measures were the severity of dyskinesia as measured by the modified Abnormal Involuntary Movement Scale (mAIMS) after 4 weeks; change in PD severity as measured by participant diary at weeks 1, 2, 3 and 4, UPDRS part III at weeks 2 and 4, UPDRS total score at week 4; and participant and clinician-rated global impression of change in dyskinesia and PD at 4 weeks.
Comments: 
The dipraglurant treatment group of 52 participants had a higher incidence of adverse events (AEs) – 88.5% – than the placebo group of 24 (75%). While most participants completed the dose escalation, 2 participants in the active group discontinued due to AEs. No treatment effects were seen in safety monitoring variables. Dipraglurant had a statistically significant effect against placebo as measured by mAIMS on day 1 (19.9% vs 4.1%). By day 28 a strong placebo response (21.5%) compared to the dipraglurant measure (31.4%) meant that statistical significance was not achieved at the end of the study. The clinician-rated global impression of change showed a statistically significant improvement with dipraglurant (71.2%) versus placebo (49.9%). According to participant diaries, daily on time with dyskinesia reduced and on time without dyskinesia increased. Two pivotal Phase 3 studies are scheduled to start by the end of 2019. Both studies plan the same enrolment (200 participants) split equally between dipraglurant and placebo, with the same primary and secondary outcomes. The first study (#301) will start an open label extension (OLE) after 3 months; the second study (#302) starts the OLE after 6 months. The Phase 3 studies are expected to report results in the third quarter of 2021. As with other experimental therapies for dyskinesia, dipraglurant has been granted orphan drug status by the US FDA, allowing seven years of market exclusivity.

A Study in Parkinson’s Disease in paTients with mOderate to seveRe dyskInesiA (ASTORIA)

Status: 
Not Yet Recruiting
Sponsor: 
Contera Pharma
Enrollment: 
81
Study Design: 
Randomized, double-blind, double dummy, placebo-controlled, parallel group study. This Phase 2 study is comparing two dose levels of JM-010 with placebo - 4mg buspirone/0.8mg zolmitriptan and 8mg buspirone/0.8mg zolmitriptan. The time period will be 12 weeks with a further 2 weeks follow up for safety purposes. There will also be a pharmacokinetic (PK) sub-study. There are three sub-groups in the study with participants randomised in a 1:1:1 ratio. Group 1 will receive the first active dose plus a placebo; group 2 the second active dose plus a placebo; and group 3 two placebos. The study is seeking PwP between the ages of 18 and 80 on a stable regimen of levodopa. Inclusion criteria also include stable peak effect dyskinesia and at least one hour of ON state dyskinesia during waking hours, with no more than six administrations of levodopa per day. Exclusively diphasic, OFF state, myoclonic, dystonic, or akathetic dyskinesia without peak-dose dyskinesia are all excluded.
Rationale: 
Primary - the efficacy of JM-010 compared to placebo using the UDysRS over 12 weeks. Secondary outcomes are also focused on efficacy: 1. UDysRS total score changes from baseline to weeks 2, 4 and 8; 2. MDS-UPDRS Parts I to IV from baseline to week 2, 4, 8, 12; 3. Clinician’s Global Impression of Change (CGIC) score at week 12; 4. Change in ON time with troublesome dyskinesia, ON time with non-troublesome dyskinesia, ON time without dyskinesia, and OFF time as measured by Hauser patient diaries at weeks 2, 4, 8 and 12.
Results: 
The first trial specifically explores the anti-dyskinetic benefit of buspirone and is monitoring its effect on parkinsonism as well. The 2nd study explores if buspirone potentiates the anti-dyskinetic effect of amantadine and the last study tests the synergistic effect of buspirone with zolmitriptan. All studies are studying a lower dose of buspirone, unlikely to worsen parkinsonism. Whether buspirone will deliver on the results as an anti-dyskinetic is yet to be seen.

Efficacy and Tolerability of IRL790 in Parkinson’s Disease Dyskinesia

Status: 
Recruiting
Sponsor: 
Integrative Research Laboratories
Enrollment: 
74
Study Design: 
Randomized, double blind, placebo controlled, multi-centre (20 locations) assessing a 2.5mg capsule of IRL-790. Inclusion criteria require PwP between the ages of 18 and 79 on a stable regimen of anti-parkinsonian medication. They must display waking day dyskinesia of >25% determined as a score of >2 on question 4.1 of the UPDRS part IV. One intriguing inclusion criterion is that participants must be willing and able to avoid direct exposure to sunlight from day 1 to day 28.
Rationale: 
Primary outcome: the UDysRS score at 4 weeks. Secondary outcomes are also focused on efficacy, all measured at 4 weeks: 1. UDysRS parts III and IV; 2. Participant diaries assessing change in daily off time, measured every half hour during 24 hours at visit 1; 3. UPDRS part III; 4. UPDRS part IV questions 4.1 and 4.2 related to dyskinesia.
Comments: 
This study is a Phase 2a study to further assess efficacy of IRL-790 in the reduction of dyskinesia. The trial is still in the early stages but it will be interesting to see if D3 antagonism can deliver anti dyskinetic benefits without compromising motor control.

A 14-week, Double-blind, Randomized, Three-arm, Parallel-Group Study to Assess the Efficacy and Safety of Two Doses of Pridopidine Versus Placebo for the Treatment of Levodopa-induced Dyskinesia in Patients With Parkinson’s Disease (gLIDe)

Status: 
Recruiting
Sponsor: 
Prilenia Therapeutics
Enrollment: 
135
Study Design: 
This is a multicentre, double-blind, randomized, three-arm, parallel-group Phase 2 study evaluating the efficacy and safety of two doses of pridopidine vs placebo for dyskinesia in PD participants. The study will include participants with a clinical diagnosis of PD between the ages of 30 and 85 years. Mild to moderate dyskinesia is a prerequisite. Participants are required to be on a stable medication regimen (PD and non-PD) for at least 28 days prior to the study start date and be able to maintain that through the study duration. Standard exclusionary criteria apply. Participants with surgical intervention such as DBS are excluded. The participants will be randomized to one of 3 parallel arms: Arm 1- dose 1 in the form of oral capsules for 12 weeks following a 2 week titration period; Arm 2- dose 2 in the form of oral capsules for 12 weeks following a 2-week titration period; Arm 3- placebo in the form of oral capsules for 14 weeks. The study is currently recruiting participants at two sites in the USA.
Rationale: 
The primary outcome measure explores the change in dyskinesia from baseline to week 14. The score is calculated as a sum of parts 1, 3, and 4 of the UdysRS. No secondary outcomes have been posted.
Comments: 
The pharmacology of the molecule and data from animal studies are promising. Given an established safety profile, it is one step ahead in the development for dyskinesia. Physiologically its effect is similar to GDNF growth factors in terms of neuronal dopamine protection and sprouting in the nigrostriatal axons. Though it failed to show efficacy for the HD population, its effect on dyskinesia is yet to be determined.

Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, 4-way Crossover, Dose-finding Study of Eltoprazine Safety, Tolerability, and Efficacy in the Treatment of Levodopa-induced Dyskinesia in Patients With Parkinson’s Disease

Status: 
Active
Sponsor: 
Amarantus BioScience Holdings, Inc.
Enrollment: 
60
Study Design: 
This is a double blind, placebo-controlled, crossover, dose range finding interventional study designed to assess the safety, tolerability, and efficacy of Eltoprazine on dyskinesia in PD participants. They are exploring 3 treatment doses and will assess their efficacy as compared to the placebo on the severity of dyskinesia, parkinsonian symptoms and participant function along with safety and tolerability. The study uses standard scales as noted below along with motion sensors and electronic diaries. The inclusion criteria require individuals between 30 to 85 years of age with a diagnosis of PD of at least 3 years duration and should be on stable dose of levodopa for 4 weeks prior to screening visit. The dyskinesia is required to be: 1. moderate to severely disabling; 2. present during 25% of the waking day on an average; and 3. present for at least 3 months prior to study entry. Standard exclusionary criteria are applied. Participants with surgical treatment for PD namely DBS are not blindly excluded but will be, if the procedure was done within the last 6 months of study inclusion or is planned during the study. There are 4 study arms as noted here, all with dosing for 3 weeks: 1. Eltoprazine HCl 2.5mg BID (5mg/day); 2. Eltoprazine HCl 5mg BID (10mg/day); 3. Eltoprazine 7.5mg BID (15mg/day); 4. Placebo capsules BID. Participants will be randomly assigned to each of the 4 arms. They will complete the 3-week treatment cycle before crossing over to the next study arm. The study is being conducted in USA at the Parkinson’s Disease and Movement Disorders Center at Boca Raton, FL.
Rationale: 
The primary outcome measure is the change in the total UDysRS score. This will be assessed at the end of each treatment period on days 21, 42, 63 and 84. Secondary outcome measures will include: 1. Effect on PD motor symptoms as assessed by MDS-UPDRS, participant diaries and physiological meas-urement using the motion sensor system after 84 days; 2. Change in dyskinesia severity using the physiological motion sensor system after 84 days; 3. Participant function using the questionnaires in MDS-UPDRS and UDyRS to quantify dyskinesia and par-kinsonian motor symptoms. This will also be assessed after 84 days; 4. Lastly, safety and tolerability as assessed by adverse events, physical and neurological exams, safe labor-atory values, vital signs and ECG. This will be assessed after 94 days.
Comments: 
The molecule carries potential for meaningful benefit in dyskinesia. The design of the Phase 1/2a study limits any effective assessment of efficacy. In 2016, the US FDA granted the molecule orphan drug designation status for PD. Since 2017, Eltoprazine’s development has been handled by Elto Pharma, Inc., a joint venture between Amanrantus and PsychoGenics. Elto Pharma recently entered into agreement with Coeptis Pharmaceuticals, Inc. regarding further development. Though the results from the phase 2b study were expected by now, given the delay, we will have to wait to find out whether the molecule is truly efficacious for dyskinesia without compromising the levodopa benefits.

Buspirone Treatment of Iatrogenic Dyskinesias in Advanced Parkinson’s Disease. Multicenter, International, Placebo-controlled, Randomised, Double-Blind Trial

Status: 
Recruiting
Sponsor: 
Assistance Publique – Hopitaux de Paris
Enrollment: 
100
Study Design: 
The study is a phase 3 multicenter, randomized, placebo-controlled, double-blind trial looking at the efficacy of buspirone in reducing dyskinesia in PD participants. They aim to enrol 100 clinically diagnosed PD participants between 35 to 80 years of age. The dyskinesia is required to be moderately disabling and to be present more than 25% of the waking time. The participant should be able to identify dyskinesia, ON and OFF periods. They should be on stable antiparkinsonian medications and be considered optimally treated at the time of inclusion. Standard exclusionary criteria are applied. Participants with DBS can be included if the procedure was done 12 months before inclusion and they are on stable stimulation parameters for at least 4 weeks prior to the first visit. The study will randomly assign participants to two study arms. Arm 1 will receive buspirone orally in escalating doses. For the first two weeks, they will be on 10mg daily morning dose followed by 10mg twice a day for the next two weeks to finally build up to 10mg three times a day from week 5 to 12. Arm 2 will receive capsules of placebo and administered in escalating doses to match the arm 1. Assessments will be done every 2 weeks and at the end of the study.
Rationale: 
The primary outcome evaluates change in the UdysRS between the placebo and treatment arm from baseline to week 12. Secondary outcomes include: 1. Comparison of efficacy between the two arms as measured by MDS-UPDRS parts 3 and 4 at different time points within the period of 13 weeks treatment duration; 2. Comparison of quality of life between the two arms as measured by MDS-UPDRS parts 1 and 2 at different time points within the 13 weeks treatment duration; 3. Comparison between the two arms as measured by side effects profile at different time points within the 13 weeks treatment duration; 4. The maximum dose tolerated by the participants at different time points within the 13 weeks treatment duration.
Comments: 
None.

Buspirone, in Combination With Amantadine, for the Treatment of Levodopa-induced Dyskinesia

Status: 
Recruiting
Sponsor: 
Oregon Health and Science University
Enrollment: 
15
Study Design: 
This is a phase 1, single-center, double-blinded, randomized, placebo-controlled, two-period cross-over study designed to assess the safety, tolerability, and efficacy of combination therapy of buspirone and amantadine on dyskinesia. They are enrolling PD participants between 18 to 99 years of age on a stable medication regimen. Participants should have mild to severe dyskinesia and should be on amantadine (200-500mg/day) with insufficient control. Standard exclusionary criteria are applied. This study will not include participants with DBS. Included participants will be randomized to one of the two study arms. Arm 1: Buspirone titrated up over the course of 2 weeks to reach 30mg/day for a week. Arm 2: Placebo titrated up to match arm 1. Participants will be crossed over the treatment sequence. Monitoring is done every 2 weeks for safety, tolerance, compliance and dyskinesia assessment.
Rationale: 
The primary outcome measure will assess the: 1. Area under the curve – measurements for dyskinesia for a 6-hr levodopa dose cycle; 2. Change in UdysRS up to 6 weeks; 3. Safety and tolerability assessment by monitoring adverse events for up to 6 weeks. No secondary outcomes have been specified.
Comments: 
None.

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.

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 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.

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