A Clinical Study Evaluating Efficacy of Pirepemat on Falls Frequency in Patients With Parkinson's Disease (PD)

A Randomised, Placebo-controlled, Multicentre Phase IIb Study Evaluating the Efficacy of Pirepemat on Falls Frequency in Patients With Parkinson's Disease

This is a Phase 2b study investigating the efficacy and safety of pirepemat as adjunct therapy on falls frequency in patients with Parkinson disease. Pirepemat is taken for 84 days.

At the screening visit consenting patients will be screened for eligibility according to study specific inclusion/exclusion criteria within 6 weeks before start of Investigational Medicinal Product (IMP) administration. Patients will be asked to complete a fall diary for at least 4 consecutive weeks during the screening period and to be eligible for randomization, the patient should have experienced at least 2 falls during the 4 weeks preceding the baseline visit.

At the baseline visit, patients will be randomized to receive one of two doses of Pirepemat (dose 1 or dose 2) or placebo t.i.d. (1:1:1). Dosing will start with half the dose for the first week of treatment and then continue with full dose until Week 11. Dosing will be de-escalated according to pre-specified schedule during the last week of study treatment, ending with the last dose on Day 84.

The treatment allocation will be double-blind, i.e. it will not be disclosed to the patients, the site staff or the Sponsor.

During the treatment period, patients will capture falls at home using a fall diary and changes in cognitive, postural, motor and mental functions will be assessed using the Montreal Cognitive Assessment (MoCA), Movement Disorder Society - Unified Parkinson´s Disease Rating Scale (MDS-UPDRS), Neuropsychiatric Inventory (NPI) (Apathy/Indifference part), Single Leg Stance Test, Tandem walking test, and Clinician's Global Impression of Severity (CGI-S) and Improvement (CGI-I).

Blood samples for pharmacokinetic (PK) analysis will be collected at visit 5 (week 6) and visit 8 (week 11).

Following the last IMP dose, a safety follow-up period (including laboratory assessments at 3 instances) of approximately 1 month will take place.

Inclusion Criteria:

1. Male or female 55-85 years of age, inclusive.
2. Diagnosis of idiopathic Parkinson's disease, according to the UK Parkinson's disease Society Brain Bank criteria.
3. Montreal Cognitive Assessment (MoCA) score of ≥10 and <26 at screening.
4. A modified Hoehn & Yahr score of ≥2.5 in "on".
5. Having experienced recurrent falls during the past 3 months (based on interview with the patient and/or caregiver) and at least 2 falls during the past 4 weeks before baseline.
6. On a stable regimen of anti-Parkinson's medications for at least 30 days prior to baseline, and willing to continue the same doses and regimens during study participation.
7. Able to cooperate and participate in study related procedures. This includes the ability to accurately complete a fall diary. The fall diary may also be completed by a responsible caregiver. For patients meeting DSM-IV TR criteria for Parkinson's disease dementia, the fall diary should be completed by the caregiver.
8. Availability of a responsible caregiver at least five days per week at least 2 hours per day. For patients meeting DSM-IV TR criteria for Parkinson's disease dementia, availability of a responsible live-in caregiver is required.
9. Female patients must be of non-childbearing potential (defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or post-menopausal females defined as 12 months of amenorrhoea [in questionable cases a blood sample with simultaneous follicle stimulation hormone (FSH) 25-140 IE/L and oestradiol <200 pmol/L is confirmatory]).
10. Fertile male patients must be willing to use condom and refrain from donating sperm during the study and until 3 months after last dosing of IMP and ensure that their fertile female partners are using contraceptive methods to prevent pregnancy .
11. Written informed consent for participation in the study given by the patient and the responsible caregiver.

Exclusion Criteria:

1. Any of the following potential hepatic conditions:

   1. known history of alcohol abuse, chronic liver or biliary disease, with the exception of Gilbert's syndrome
   2. total bilirubin greater than the upper limit of the normal range (unless associated with isolated instances of suspected Gilbert's syndrome)
   3. alkaline phosphatase (ALP) greater than 1.5 times the upper limit of the normal range
   4. aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 2 times the upper limit of the normal range
   5. history of repeated unexplained upper right quadrant abdominal pain and/or nausea, or jaundice

2. A positive Hepatitis B surface antigen or a positive Hepatitis C antibody result.

3. A score of 5 (wheelchair bound or bedridden) in the "on"-state on the modified Hoehn & Yahr scale.

4. Uncontrolled symptomatic orthostatic hypotension.

5. Clinically significant polyneuropathy.

6. Weight <55 kg at Screening.

7. Patients with current or past treatment with deep brain stimulation (DBS) or patients with previous history of stereotaxic brain surgery for PD.

8. A current diagnosis of any primary neurodegenerative disorder other than idiopathic PD.

9. A current diagnosis of any treatable dementia (hypothyroidism, syphilis, vitamin B12 or folate deficiency) that is verified by the investigator to be the cause of dementia.

10. A current diagnosis of a major depressive episode according to DSM-IV criteria.

11. Patient has delirium.

12. Any history of a heart condition, including prolonged QTc (>450 ms for males and > 470 ms for females, QTcF and/or QTcB), cardiac arrhythmias, any repolarisation deficits or any other clinically significant abnormal ECG as judged by the Investigator.

13. Severe or ongoing unstable medical condition including a history of poorly controlled diabetes; obesity associated with metabolic syndrome; uncontrolled hypertension; cerebrovascular disease, or any form of clinically significant cardiac disease; renal failure, history of abnormal renal function.

14. History of seizures within two years of screening.

15. History of cancer within five years prior to screening, with the following exceptions: adequately treated non-melanomatous skin cancers, localised bladder cancer, non-metastatic prostate cancer or in situ cervical cancer.

16. History of severe allergy/hypersensitivity or on-going allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to pirepemat.

17. Creatinine clearance <30 mL/min (calculated according to the Cockroft-Gault formula).

18. Treatment with Warfarin within three months before study treatment.

19. Treatment with Amantadine within 6 weeks before study treatment.

20. Treatment with Selegiline within 6 weeks before study treatment.

21. Administration of another new chemical entity (defined as a compound which has not been approved for marketing) or has participated in any other clinical study that included drug treatment with less than three months between administration of last dose and first dose of IMP in this study.

22. Current or history of drugs of abuse according to DSM-IV criteria.

23. Any planned major surgery within the duration of the study.

24. Any other condition or symptoms preventing the patient from entering the study, according to the Investigator's judgement.