Clinical trial NCT02579473: A Study of Weekly Subcutaneous Injections of SER-214 in Subjects With Parkinson's Disease (PD), to Determine the Safety, Tolerability and Pharmacokinetic (PK) Profile of SER-214
Official title: A Multi-center, Open-label, Multiple Ascending Dosage-ranging Cohort (MAD) Study in Early, Untreated or Stably Treated Subjects With Parkinson's Disease (PD), to Determine the Safety, Tolerability and Pharmacokinetics (PK) of Injections of SER-214 Administered Subcutaneously Once a Week for Two Weeks After 0-2 Weeks of Dose Titration
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Parkinson's Disease
Keywords: Continuous dopaminergic stimulation
Lead sponsor: Serina Therapeutics
Sponsor class: INDUSTRY
First posted: 2015-10-19
Enrollment: 20
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: SER-214 is a poly (2-ethyl-2oxazoline)(POZ) polymer conjugate of rotigotine, a potent dopamine agonist that has high affinity for the subclass of dopamine receptors in the brain that mediate dopamine signaling. SER-214 will be administered subcutaneously once a week via a standard 1 mL insulin syringe to determine the safety, tolerability and pharmacokinetic (PK) profile of released rotigotine and POZ-conjugate. Subjects in this study are eligible if they have early, stable or untreated Parkinson's disease and are still experiencing motor fluctuations.

Detailed description: Clinical evidence suggests that dopamine agonists should be considered as an initial or early symptomatic therapy for PD. Current information indicates that the early use of long-acting dopaminergic agonists may protect against the development of motor complications by stimulating dopamine receptors in a non-pulsatile manner and by delaying the introduction of levodopa. In pre-clinical primate studies, L-dopa (short-acting, pulsatile) and dopaminergic agonists (long-acting; non pulsatile) provide comparable clinical benefit but with agonists inducing significantly less dyskinesia.

Chronic L-dopa treated animals develop gene changes that are associated with abnormal neuronal firing patterns and dyskinesias which are not seen with long-acting dopamine agonists. Based on pre-clinical and clinical study results, treatment of Parkinson's patients with long-acting levodopa or dopamine agonists should provide symptomatic benefit, and significantly delay the onset of motor complications. This can be accomplished with duodopa or continuous sc apomorphine but these treatments are associated with significant side effects. To date, no practical method of providing continuous drug delivery using a dopaminergic agent for therapy of patients with early PD to prevent the development of motor complications has been advanced through clinical trials.

SER-214 is being developed as a weekly sc injection that provides prompt onset of dopaminergic stimulation. Continuous levels of released rotigotine within the therapeutic window for relief of motor fluctuations have been observed in MPTP-treated cynomolgus macaques. PK determinations in normal monkeys for up to 13 weeks of treatment show that weekly injections of SER-214 provide continuous drug delivery of released plasma rotigotine within a predictable therapeutic range.

Eligibility criteria: Inclusion Criteria:

1. Female or male subjects 40-80 years of age inclusive
2. A diagnosis of idiopathic Parkinson's disease (PD) consistent with UK brain bank criteria
3. De novo PD patients and those on a stable regimen of anti-Parkinson's drugs for at least 4weeks prior to screening including anticholingerics, amantadine, MAO-B inhibitors, COMT inhibitors or levodopa, but not dopamine agonists
4. Free of clinically significant motor complications as determined by the investigator
5. Ability to complete up to four weeks of dosing once per week with two weeks of terminal "wash-out" PK
6. Ability to return to the clinic for blood sampling, clinical and laboratory assessment on scheduled days, based upon cohort
7. Mini Mental State Exam (MMSE) \> 26
8. Women of child-bearing potential (WOCBP) must use a reliable method of contraception (e.g., oral contraceptive or long-term injectable or implantable hormonal contraceptive, double-barrier methods \[such as condom plus diaphragm, condom plus spermicidal foam, condom plus sponge\], or intra-uterine devices), and must have a negative serum pregnancy test at Screening and negative urine pregnancy test at baseline
9. Willing and able to comply with the study requirements including follow-up
10. Provide written informed consent
11. Cognitively intact sufficient to understand and provide informed consent
12. Approved by a central Eligibility Monitoring Committee (EMC) confirmed by EMC signature on the Enrollment Authorization Form (EAF)

Exclusion Criteria:

1. Subject has previously participated in this study.
2. Myocardial infarction within the past six months from screening
3. Ischemic stroke or transient ischemic event within the past two years from screening
4. Known sensitivity to dopamine agonists including nausea/vomiting, orthostatic hypotension, excessive sleep or impulse control disorder
5. Any major organ disease that substantially impairs life expectancy
6. History of cancer, other than basal cell carcinoma, within the past 10 years or subjects with any laboratory or physical exam or diagnostic procedure finding suggestive of current malignancy
7. Subjects who are known to be immunosuppressed or are receiving chronic treatment with immunosuppressive drugs
8. Subject with an atypical or secondary Parkinsonian (e.g., due to drugs, metabolic neurogenetic disorders, encephalitis, cerebrovascular disease or degenerative disease)
9. Any clinically significant medical, surgical, or psychiatric condition, laboratory value, or concomitant medication which, in the opinion of the Investigator, makes the subject unsuitable for study entry or potentially unable to complete all aspects of the study.
10. Subject has moderate renal impairment (creatine \> 2.5)
11. Subject has moderate (Child-Pugh categorization B, score 7-9) or severe (Child-Pugh categorization C, score 10-15) hepatic impairment.
12. Subject has a lifetime history of suicide attempt (including an active attempt, interrupted attempt or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a positive response ('Yes') to either Question 4 or Question 5 of the Columbia-Suicide Severity Rating Scale (CSSRS) at Screening
13. Subject has known hypersensitivity to rotigotine or to any components or excipients of the study drug
14. Subject has a history of psychosis or hallucinations within the previous 12 months
15. Subject has received an investigational drug within 30 days of screening or is currently participating in an investigational drug or investigational device trial
16. Subject, who, for any reason, is judged by the Investigator to be inappropriate for this study, including a subject who is unable to communicate or cooperate with the Investigator or who has/had a clinically significant illness or abnormal physical examination that may compromise safety of the subject during the trial or affect ability of the subject to adhere to study procedures

Primary outcomes:
measure: Safety - Adverse Events and Serious Adverse Events
timeFrame: From initial sc dose of SER-214 up to six weeks of follow-up
measure: Percentage of patients in each cohort who discontinued therapy due to any adverse events {Tolerability}
timeFrame: From initial sc dose of SER-214 up to six weeks of follow-up
measure: Safety - Vital Signs
timeFrame: From initial sc dose of SER-214 up to six weeks of follow-up
measure: Safety - Abnormal Laboratory Results
timeFrame: From initial sc dose of SER-214 up to six weeks of follow-up
measure: Safety - Treatment-Emergent Adverse Events
timeFrame: From initial sc dose of SER-214 up to six weeks of follow-up
measure: Safety - ECG Changes
timeFrame: From initial sc dose of SER-214 up to six weeks of follow-up
Secondary outcomes:
measure: Fluctuation index
timeFrame: On injection days plasma samples will be taken at time 0, 1, 2, 4 and 8 hours
measure: Maximum plasma concentration [C(max)]
timeFrame: On injection days plasma samples will be taken at time 0, 1, 2, 4 and 8 hours
measure: Time to maximum concentration [T(max)]
timeFrame: On injection days plasma samples will be taken at time 0, 1, 2, 4 and 8 hours
measure: Dose-adjusted area under the curve (AUC)
timeFrame: On injection days plasma samples will be taken at time 0, 1, 2, 4 and 8 hours
measure: Unified Parkinson's Disease Rating Scale
timeFrame: From Screening up to six weeks of follow-up
measure: Unified Parkinson's Disease Rating Scale - Motor Part III Only
timeFrame: From Screening up to six weeks of follow-up
measure: Epworth Sleepiness Scale (ESS)
timeFrame: From Screening up to six weeks of follow-up
measure: Columbia Suicide Severity Rating Scale (C-SSRS)
timeFrame: From Screening up to six weeks of follow-up
measure: Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease (QUIP)
timeFrame: From screening up to six weeks of follow-up
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Birmingham
state: Alabama
city: Hallandale Beach
country: United States
facility: MD Clinical
state: Florida
city: Augusta
country: United States
facility: Georgia Regents University
state: Georgia
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
Study officials:
affiliation: Univeristy of Alabama-Birmingham School of Medicine, Division of Neurology
name: David G Standaert, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Eskow Jaunarajs KL, Standaert DG, Viegas TX, Bentley MD, Fang Z, Dizman B, Yoon K, Weimer R, Ravenscroft P, Johnston TH, Hill MP, Brotchie JM, Moreadith RW. Rotigotine polyoxazoline conjugate SER-214 provides robust and sustained antiparkinsonian benefit. Mov Disord. 2013 Oct;28(12):1675-82. doi: 10.1002/mds.25625. Epub 2013 Sep 3.