A Phase 2 study to evaluate the safety, tolerability and initial efficacy of pramipexole ER, given with aprepitant in patients with parkinsonian type disorders

Methodology:

This is an initial Phase 2, rising-dose, single-blind, out-patient, sequential-treatment study in up to 24 patients with idiopathic Parkinson's disease of about 5 months duration. All participants will have idiopathic Parkinson's disease (PD).

Subjects will sign a consent form prior to any study related procedure and will complete baseline screening assessments.

The study will be conducted in three parts:

Part 1: All eligible patients switch from their dopaminergic treatment to the equivalent dose of pramipexole ER in the judgement of the investigator. Then, pramipexole ER is titrated alone up to the patients' optimal dose or to the protocol maximum allowed dose for Part 1 of 4.5 mg/day.

Part 2: Add-on aprepitant and continue the titration of pramipexole ER from the optimal dose (or 4.5 mg/day) determined in Part 1 to the optimal dose not to exceed the protocol limit of 9.0mg/day, given in combination with aprepitant.

Part 3: Maintain the dose of pramipexole ER found in Part 2 given in combination with aprepitant for 3 months with periodic safety and efficacy checks.

During Parts 1 and 2, subjects will be evaluated at in-clinic visits for safety and tolerability at intervals not to exceed once weekly ± 2 days and additionally by telephone or in-clinic visits, as considered clinically appropriate, at each dose change.

During Part 3, this optimal pramipexole ER/aprepitant regimen will be stably maintained for 3 months in association with monthly in-clinic laboratory and clinical evaluations. Safety and tolerability will continue to be evaluated by telephone or in-clinic visits, as deemed clinically appropriate.

Pramipexole ER tablets will be administered with or without aprepitant, orally once daily in the morning. Subjects will take 1-3 pramipexole ER tablets daily.

Aprepitant will be administered orally in a fixed daily dose by means of a single capsule containing 80 mg.

At study completion (or at other times in accordance with Stopping Rules given below), study medications will be discontinued, and participants will be returned to their pre-admission therapeutic regimen as considered medically appropriate. Investigators will always have the option of making necessary and appropriate changes to protocol dose optimization schedules in consultation with the Sponsor.

An independent DSMB will be appointed to have responsibility for safeguarding the interests of the trial subjects and assessing the safety and tolerability of the study treatments during the trial. The DSMB will meet when 10 patients complete the study and when all patients complete the study.

Inclusion Criteria:

1. Patient must have signed an Institutional Review Board (IRB) approved informed consent document indicating that they understand the purpose of and procedures required by the study and are willing to participate in the study and comply with all study procedures and restrictions. Informed consent must be obtained from the patient and/or a designated representative prior to initiating screening procedures to evaluate eligibility of the study.
2. Males and females aged 40 - 80 years inclusive.
3. Meet criteria for the diagnosis of possible/ probable idiopathic Parkinson's disease (PD; Postuma RB, et al. 2015)
4. Have not previously been treated with CD/LD.
5. PD severity in the Hoehn & Yahr 2 to 3 range.

Exclusion Criteria:

1. Women who are pregnant or may become pregnant.

2. Nursing mothers.

3. Individuals who have taken a study medication (pramipexole and/or aprepitant) within 3 months of study admission.

4. Moderate and severe renal impairment (Creatinine Clearance: < 60 mL/min calculated by Cockcroft and Gault equation)

5. Severe hepatic impairment (Child-Pugh C)

6. Hypersensitivity to any component of either study medication

7. Being treated with the following medications:

   • Pramipexole
   • Centrally acting dopamine antagonists during preceding month
   • Pimozide
   • Strong CYP3A4 inducer or inhibitor
   • Warfarin (a CYP2C9 substrate)
   • Hormonal contraceptives

8. Patients considered unlikely to co-operate in the study, and/or poor compliance anticipated by the investigator.

9. Patients who have any clinically significant hypotension or ECG abnormality.

10. Any other clinically relevant acute or chronic diseases which could interfere with patients' safety during the trial, or expose them to undue risk, or which could interfere with study objectives.

11. Patients who have participated in another clinical trial with an investigational drug within previous 30 days.