A Safety, Tolerability and Levodopa Pharmacokinetics Study of Repeated ND0612 in Parkinson's Disease Patients

A Phase IIa Multicenter, Randomized, Double-blind, Placebo-controlled Study Followed by an Open-label Period, to Evaluate the Safety, Tolerability, and Levodopa Pharmacokinetics in Levodopa-treated Parkinson's Disease Patients With Motor Fluctuations, Administered With Repeated Subcutaneous ND0612

This is a randomized, placebo-controlled, double-blind, 2-period study evaluating the safety and pharmacokinetics (PK) of ND0612 in Parkinson's disease (PD) patients on an optimized oral levodopa (LD) regimen and experiencing ≥2 h/day of OFF time. Safety and tolerability, PK profile, pump usability, and the potential clinical effect of ND0612 will be explored in subjects with PD and motor fluctuations.

During Period 1, patients continued on their current standard of care (SoC) levodopa/carbidopa (LD/CD) and were randomized at 2:1 ratio to 14 days of adjunct treatment with ND0612 (daily LD/CD dose of 270/63 mg) or placebo infusion. During Period 2, patients were randomized to receive 7 days open-label treatment with ND0612 or ND0612 plus oral entacapone. Patients then entered a 4-week safety follow-up period.

Inclusion Criteria:

1. Men and women with idiopathic PD whose diagnosis was confirmed by presence of at least two of the cardinal signs (resting tremor, bradykinesia, rigidity) and lacking any other known or suspected cause of parkinsonism.
2. Patients who experienced motor fluctuations averaging at least two hours daily in the "OFF" state during the waking hours (including morning akinesia), corresponding to the end-of-dose deterioration phenomenon ("wearing off") confirmed by the baseline home diaries.
3. Modified Hoehn and Yahr stage < 5 in the "OFF" state.
4. Patients who were taking optimized LD/decarboxylase inhibitor therapy (based on the investigator's judgment) that was stable for at least 14 days prior to baseline. Patients were to receive at least three daily doses of LD (which could include a bedtime dose) with at least three hours between doses.
5. Patients treated with dopaminergic agonists and other anti-PD drugs were to be on stable doses for at least 30 days prior to baseline and those doses were to remain constant throughout the study period.
6. Women who were postmenopausal, surgically sterilized, or using adequate birth control. Women of childbearing potential were to have a negative pregnancy test (beta human chorionic gonadotropin [hCG] serum) at screening.
7. Patients between the ages of 30 and 80.
8. Patients willing and able to give informed consent.
9. Patients and/or caregivers able to understand and follow instructions for use of SC delivery pump.
10. Patients who demonstrated the ability to keep accurate diaries of PD symptoms (ON-OFF diaries).

Exclusion Criteria:

1. Patients treated with controlled release formulation of LD/CD. (Note: Patients treated with Entacapone, Tolcapone, or Stalevo were allowed to participate in Period 1 but were excluded from Period 2 participation)
2. Patients with a clinically significant or unstable medical or surgical condition which would preclude safe and complete study participation. Such conditions may include gastrointestinal, cardiovascular, pulmonary, hepatic, renal, or metabolic diseases or malignancies as determined by medical history, physical exam, laboratory tests, or ECG.
3. History of melanoma or significant skin disorders.
4. Patients with significant cognitive impairment as defined by a MMSE score of < 25.
5. Patients treated with dopaminergic agonists, anticholinergics, monoamine oxidase (MAO)-B inhibitors, or antipsychotics that need dose adjustment in the 30 days prior to Study Baseline.
6. Patients with clinically significant psychiatric illness, including major depression (according to Diagnostic and Statistical Manual of Mental Disorders [DSM] IV criteria for major depressive episode) or other problems that might compromise their ability to provide consent or participate fully in the study.
7. Patients with a history of alcohol or substance abuse within the past two years.
8. Patients who have taken experimental medications within 60 days prior to baseline.
9. Patients who have undergone a neurosurgical intervention for PD (e.g. pallidotomy, thalamotomy, transplantation, or deep brain stimulation procedures).
10. Patients with severe disabling dyskinesias.
11. Patients with hearing, visual or motor impairments that prevent them from using the pump or reacting effectively to errors.