A Randomized Double-blind Placebo-controlled Multicentre Study to Assess Safety, Tolerability, Pharmacokinetics and Efficacy of Radotinib in Parkinson's Disease
Overview
- Phase
- Phase 2
- Intervention
- Placebo
- Conditions
- Parkinson Disease
- Sponsor
- Il-Yang Pharm. Co., Ltd.
- Enrollment
- 40
- Locations
- 7
- Primary Endpoint
- Evaluation of safety parameters: Adverse Events
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
This is a safety, tolerability, pharmacokinetic and efficacy study in subjects with Parkinson's disease
Detailed Description
This study is will be conducting to determine if Radotinib is safe and can be tolerated by patients with Parkinson's disease (PD) and to learn if Radotinib can be potential therapeutic agents for the treatment of PD. Radotinib has been approved by Ministry of Food \& Drug Safety of Korea to treat Chronic Myeloid Leukemia (CML) but it has not been approved for PD. In nonclinical efficacy study, therapeutic effect of Radotinib HCl, c-Abl inhibitor, which exhibits improved pharmacokinetic properties and BBB penetration compared to nilotinib and other c-Abl inhibitors, was tested in a preclinical α-synuclein preformed fibrils (PFF) model of sporadic PD. As a result, the treatment of Radotinib HCl protects the α-synuclein PFFs-induced neuronal toxicity, reduces the PFFs-induced LB/LN-like pathology, and inhibits the PFFs-induced c-Abl activation in neurons. In vivo studies demonstrate that administration of Radotinib HCl prevents dopamine neuron loss and behavioral deficits following α-synuclein PFFs-induced toxicity. Taken together, these findings indicate that Radotinib HCl has beneficial neuroprotective effects in PD and provides strong evidence that selective and brain permeable c-Abl inhibitors can be potential therapeutic agents for the treatment of PD. These data are very compelling to evaluate the effects of Radotinib in a phase II, randomized, double-blind, placebo-controlled trial in patients with PD.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male and Female from 40 to 80 years old;
- •Diagnosed with "Clinically Probable Parkinson's Disease" according to the MDS clinical diagnostic criteria, with documented onset of symptoms per treating physician's records within three years of the screening visit;
- •Positive DAT-scan (e.g. a striatal dopamine transporter deficit on dopamine transporter imaging by DaT-SPECT, characterized by crescent-shaped areas of asymmetrical aspect, or of symmetrical aspect but of uneven intensity, between the right and the left brain hemisphere) confirmed by local reading;
- •Hoehn \& Yahr stage ≤ 2.5;
- •Without previous symptomatic treatment for PD disease and with current clinical state not requiring started dopaminergic therapy within 6 months from Baseline;
- •Absence of a parkinsonian syndrome and other neurovascular comorbidities, confirmed by MRI
- •Female subjects must be not of childbearing potential, e.g., documented evidence that they are surgically sterile (e.g., hysterectomy, partial hysterectomy, bilateral oophorectomy, bilateral tubal ligation), or postmenopausal (at least 12 months since last menses) or using highly effective method of birth control defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly, such as combined hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intra uterine devices (IUDs), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, condom, until at least one month after the last drug intake associated to a negative pregnancy test at screening;
- •Covered by Health Insurance System;
- •Able to understand and to sign the informed consent prior to screening;
- •Blood Pressure (BP) and Heart Rate (HR) considered NCS by Investigator;
Exclusion Criteria
- •Atypical Parkinsonism or drug-induced Parkinsonism;
- •Current, or within 60 days of screening, use of any prescription, investigational, or over the counter medication for the symptomatic treatment of PD or to slow the progression of PD.
- •Prior use of dopaminergic therapy (e.g., levodopa, dopamine agonist, amantadine, rasagiline) for 30 or more days any time in the past;
- •Cognitive impairment (MMSE ≤ 24);
- •Active psychiatric disorder (mood disorders, hallucinations or delirium with strong functional impact and not controlled by medication or which happened during the last 3 months before inclusion);
- •Severe or uncontrolled chronic disease;
- •Significant medical history of congenital or acquired bleeding disorders;
- •Treatment by Deep Brain Stimulation or continuous infusion of apomorphin/dopa gel;
- •Any below impaired cardiac function:
- •LVEF \<45% or \< lower bound of normal limit of study site (whichever higher), confirmed by echocardiogram (if the subject has already carried out this examination during the last month before inclusion, he/she will be exempted from retaking this examination, but he/she will have to present the echocardiogram as well as the cardiologist's report. If not, this exam should be performed during the screening period)
Arms & Interventions
Placebo: Dose escalation
Forty (40) subject will be recruited and randomized into 4 dosing groups. In each dosing group, ten (10) will be randomized and 8 of 10 will receive the active product (Radotinib) and 2 subjects will receive the matching placebo orally once daily for 6 months at each escalating dose level.
Intervention: Placebo
Radotinib HCl: Dose escalation
Forty (40) subject will be recruited and randomized into 4 dosing groups. In each dosing group, ten (10) will be randomized and 8 of 10 will receive the active product (Radotinib) and 2 subjects will receive the matching placebo orally once daily for 6 months at each escalating dose level. The inclusion of subjects in the next dose level will be decided by the sponsor in consultation with a Data Monitoring Committee (DMC).
Intervention: Radotinib HCl 50 mg
Outcomes
Primary Outcomes
Evaluation of safety parameters: Adverse Events
Time Frame: 12 months after dose administration
Incidence and severity of treatment emergent AEs
Secondary Outcomes
- Pharmacokinetics assessments of Radotinib HCl: Cmax(14 days after dose administration)
- Pharmacokinetics assessments of Radotinib HCl: AUC0-12h(14 days after dose administration)
- Subject's clinical global impression of change.(12 months)
- Change in health related quality of life as measured by a quality of life questionnaire (PDQ-39)(12 months)
- Pharmacokinetics assessments of Radotinib HCl: AUCt(14 days after dose administration)
- Pharmacokinetics assessments of Radotinib HCl: t1/2(14 days after dose administration)
- Pharmacokinetics assessments of Radotinib HCl: Vd/F(14 days after dose administration)
- Pharmacokinetics assessments of Radotinib HCl: CL/F(14 days after dose administration)
- Change from Baseline in the sum of MDS-UPDRS Parts I, II and III(6 months)
- Time from baseline to initiation of dopamine-replacement medication.(6 months)
- Pharmacokinetics assessments of Radotinib HCl: Tmax(14 days after dose administration)
- Pharmacokinetics assessments of Radotinib HCl: AUCinf(14 days after dose administration)
- Pharmacokinetics assessments of Radotinib HCl: Ctrough(14 days after dose administration)