Primary:To evaluate the effects of pirepemat on falls frequency as compared to placebo.Secundary:To evaluate the effects of pirepemat on Parkinson's disease motor symptoms as compared to placebo.To evaluate the effects of pirepemat on apathy as…
ID
Source
Brief title
Condition
- Movement disorders (incl parkinsonism)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change in falls frequency from baseline period (1 month prior to randomisation)
to the end of treatment visit as assessed by fall diary.(1 month prior to dose
se-escalation)
Secondary outcome
Secundary:
Change in the total score of MDS-UPDRS part 2 (M-EDL) from baseline to Week 11.
Change in total score (Frequency*Severity) and Caregiver distress of NPI Item G
(Apathy/Indifference) from baseline to Week 11.
Tertiary/exploratory endpoint variables
- Change in MDS-UPDRS part I from baseline to Week 11.
- Change in MDS-UPDRS part II from baseline to Week 11.
- Change in MDS-UPDRS part III from baseline to Week 11.
- Change in MDS-UPDRS part IV from baseline to Week 11.
- Change in MDS-UPDRS part IV item 4.3 (Time spent in the off state) from
baseline to Week 11.
- Change in sum score of MDS-UPDRS items 2.13 (Freezing) and 3.11 (Freezing of
gait) from baseline to Week 11.
- Change in individual scores from baseline to Week 11for the following
MDS-UPDRS part I items: 1.2 (Hallucinations and psychosis), 1.3 (Depressed
mood), 1.5 (Apathy), 1.6 (Features of dopamine dysregulation syndrome), 1.8
(Daytime sleepiness), 1.9 (Pain and other sensations), 1.13 (Fatigue).
- Change in individual scores from baseline to Week 11for the following
MDS-UPDRS part II items: 2.1 (Speech), 2.12 (Walking and balance).
- Change in modified Hoehn & Yahr score from baseline to Week 11.
Change in scores from baseline to Week 11for the following tests:
- Single leg stance test
- Tandem walking test
As measured by subject incident of treatment-emergent adverse events,
clinically significant changes in vital signs and physical examination,
clinical laboratory safety tests, and ECGs.
Background summary
Falls are a frequent and serious complication of Parkinson*s disease (PD).
Prospective studies report that 60% of people with PD have at least one fall
per year and 39% fall recurrently. The risk of experiencing falls in PD
increases with disease severity. In a prospective study the 7 year cumulative
incidence of falls in non-falling patients diagnosed with PD at baseline was
57.5%, with a relative risk to controls of at least 3.1. Consequences of falls
in PD include fractures and injury, fear of future falls, hospital admission,
and increased caregiver burden, with falls cited as one of the worst aspects of
the disease.
The cause of the high propensity for falls in PD is likely to be
multifactorial. The major contributing risk factors for falls have been shown
to be fall history, freezing, impaired postural function and cognitive
deterioration.
The major causes underlying falls in PD seem not to be amenable to standard
anti-Parkinson therapy. Postural instability is a cause of significant
morbidity that worsens as PD advances and rarely improves with dopaminergic or
surgical therapy. However, whilst axial motor features such as postural
instability and freezing of gait have been associated with falls in PD, the
relationship with overall motor severity is complex and there is little
available detailed quantitative information on individual axial and nonaxial
items and their relative potential to cause falls.
It is suggested that postural instability and other poorly dopa-responsive
symptoms in PD are likely to be the results of other *extranigral* lesions,
possible involving a lack of cortical control. Affected neurotransmitters
include, among others, norepinephrine, acetylcholine and serotonin. In
particular, cell loss of noradrenergic input from the locus coeruleus has been
implicated to underly postural instability in PD. It is likely that not only
subcortical cell loss is underlying axial motor impairment in PD, since
cognitive impairment, including measures of global and executive function, have
also been associated with falls in PD.
Pirepemat displays a novel pharmacological profile which addresses pathological
dysregulations occurring in multiple cortical transmitter systems implicated in
axial motor impairment and dementias. Neurochemical data show that pirepemat
combines therapeutically useful effects on monoaminergic, cholinergic and
glutamatergic neurotransmission in the cerebral cortex leading to activation of
synaptic activity both in the cortex and in the basal ganglia suggesting
strengthening of cortical and cortico-striatal connectivity. At the integrated
level the specific regional effects on biogenic amines, acetylcholine and
down-stream effects related to synaptic activation, gives rise to a behavioural
profile indicating cognitive and behavioural benefits without psychomotor
stimulant like, or antipsychotic like inhibitory, properties. Hence, pirepemat
targets several of the key neurochemical features suggested to be underlying
risk factors for falls in PD, without causing unwanted adverse effects on the
motor system.
Study objective
Primary:
To evaluate the effects of pirepemat on falls frequency as compared to placebo.
Secundary:
To evaluate the effects of pirepemat on Parkinson's disease motor symptoms as
compared to placebo.
To evaluate the effects of pirepemat on apathy as compared to placebo.
Other:
To evaluate the effects of pirepemat on Parkinson's disease symptoms and
severity as compared to placebo.
To evaluate the effects of pirepemat on postural dysfunction as compared to
placebo.
To evaluate the effects of pirepemat on cognitive function as compared to
placebo
To evaluate the safety and tolerability of pirepemat
To examine the relationship between dose and plasma concentration of pirepemat
and pharmacodynamic effects.
Study design
This will be a randomised, double-blind, placebo-controlled multi-centre study.
Intervention
Patients will take three daily oral doses (at approximately 8 am, 2 pm and 8
pm) of pirepemat or placebo for 84 consecutive days. Dosing will start with
half maximum dose for the first week of treatment and de-escalated according to
pre-specified schedule during the last week of study treatment.
Study burden and risks
there are no direct benefits expected for the participant.
The following side effects of the study drug under investigation are common:
- Headache
- Thinking and memory problems
- Confusion
- Hallucinations
- Tremors
- Falls
- Increase in PD symptoms
- Constipation
- Pain in the upper abdomen
- Urinary tract infection
- Pain in the extremities (hands and feet)
- Sweating
The following side effects are uncommon but may be serious:
A few patients with PD who were treated with Pirepemat had short-term increases
of certain enzymes in their blood. These enzymes are large molecules that help
important chemical reactions in the liver to occur. If the levels of these
enzymes in the blood are higher or lower than normal, they can indicate liver
problems. All patients will be closely monitored during the study. In case of
any abnormal liver values, the participants study participation may be
terminated, and they will receive appropriate treatment and be closely followed
up.
Since it is possible for drugs that affect the central nervous system to lead
to people feeling depressed or having suicidal thoughts, the study doctor will
ask the participant and the participants caregiver at each visit whether the
participant has experienced this.
Arvid Wallgrens Backe 20
Göteborg 413 46
SE
Arvid Wallgrens Backe 20
Göteborg 413 46
SE
Listed location countries
Age
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
falls diary. The falls diary may also be completed by a responsible caregiver.
For patients meeting DSM-IV TR criteria for Parkinson*s disease dementia, the
falls 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.
Exclusion criteria
1. Any of the following potential hepatic conditions: a. known history of
alcohol abuse, chronic liver or biliary disease, with the exception of
Gilbert*s syndrome b. total bilirubin greater than the upper limit of the
normal range (unless associated with isolated instances of suspected Gilbert*s
syndrome) c. alkaline phosphatase (ALP) greater than 1.5 times the upper limit
of the normal range d. aspartate aminotransferase (AST) or alanine
aminotransferase (ALT) greater than 2 times the upper limit of the normal range
e. 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. Where the clinical significance of an abnormal Screening test result
(lab or any other tests) is considered uncertain, the test may be repeated
once, at the discretion of the Investigator, as long as the repeat test result
is available within the 6 weeks screening period to determine eligibility.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-002627-16-NL |
| Other | IRL752C003 |
| CCMO | NL82410.091.22 |