Clinical trial NCT02408562: Study on Tolerability of Repeat i.c.v. Administration of sNN0031 Infusion Solution in Patients With PD
Official title: A Phase 1, Multicentre, Randomised, Double-blind Study to Assess Safety and Tolerability of Repeated Intracerebroventricular Administration of sNN0031 Infusion Solution to Patients With Parkinson's Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Parkinson's Disease
Lead sponsor: Newron Sweden AB
Sponsor class: INDUSTRY
Collaborators: name: European Union
First posted: 2015-04-03
Enrollment: 1
Sex: ALL
Minimum age (years): 30
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a phase I, randomised, placebo-controlled study to assess the safety and tolerability of two 2-weeks cycles of i.c.v. administration of sNN0031 infusion solution to patients with PD of moderate severity with persisting on-off symptoms in spite of other PD medications.


Eligibility criteria: Main Inclusion Criteria:

1. Disease duration ≥ 5 years (diagnosis based on medical history and neurological examination).
2. Male or female, age 30 - 75 years inclusive.
3. Motor fluctuations, with OFF-time \>1.5 hours during the day
4. A Hoehn and Yahr stage of 2 to 4 during OFF phase
5. Score \>22 on the UPDRS part III during ON phase
6. Patients should be L-dopa responsive and demonstrate at least a 30% decrease in the UPDRS part III score after administration of L-dopa (L-dopa challenge test)
7. Optimised and stable anti-Parkinson treatment for at least 3 months before screening

Main Exclusion Criteria:

1. The patient has any indication of forms of parkinsonism other than idiopathic Parkinson's disease
2. The patient is in a late stage of Parkinson's disease, and is experiencing severe, disabling peak-dose or biphasic dyskinesia and/or unpredictable or widely swinging fluctuations in their symptoms
3. Patients who are on treatment with Duodopa or Apomorphine pump at the time of screening
4. The patient has an implanted shunt for the drainage of CSF or an implanted Central Nervous System (CNS) catheter, or have received neurosurgical intervention related to PD (e.g. deep brain stimulation, thalamotomy etc.) or is scheduled to do so during the trial period
5. Concurrent diagnoses of dementia with a score of 24 or lower on Mini-Mental State Examination (MMSE).
6. The patient is depressed, as indicated by a Hamilton Depression Rating Scale (GRID-HAMD, 17-item scale) score \> 17
7. Patients who are at high risk of suicide as judged by the rating of the Columbia Symptoms Suicide Rating Scale (C-SSRS)
8. Patients with a history of increased intracranial pressure
9. Ophthalmologic examination (funduscopy and visual acuity by Early Treatment of Diabetic Retinopathy Study (EDTRS) and perimetry) with clinically significant findings that imply safety concerns for this study
10. The patient has a current clinically significant gastrointestinal, renal, hepatic, endocrine, pulmonary or cardiovascular disease
11. The patient has heart problems or a significant ECG abnormality
12. Uncontrolled hypertension.
13. The patient has in the past experienced psychotic symptoms (e.g. schizophrenia or psychotic depression)
14. The patient has a mental or physical condition which would preclude performing study assessments
15. Alcohol or substance dependence within the prior 12 months, or abuse within 3 months, with the exceptions of nicotine
16. MRI examination with findings of tumours or potential sources of pathological bleedings, or any abnormality that may put the patient at risk
17. History of structural brain disease including tumours and hyperplasia
18. Ongoing or suspected primary or recurrent malignant disease (currently active or in remission for less than one year)
19. Any disorder that precludes a surgical procedure, alters wound healing or renders chronic i.c.v. delivery or device implants medically unsuitable
20. The patient has a history or a current diagnosis of HIV, Hepatitis B or C.
21. Increased susceptibility to infections
22. Women who are pregnant or breast feeding or unwilling to use adequate contraception during the trial (only women of child bearing potential)

Primary outcomes:
measure: Tolerability of sNN0031 [Number of Adverse Events (AE) and Serious Adverse Events (SAE) occurring in each group over the study duration]
timeFrame: 10 months
Secondary outcomes:
measure: Peak concentrations of sNN0031 in cerebrospinal fluid during two 14 day continuous infusion cycles
timeFrame: 14 days x 2
measure: Pump flow error rate
timeFrame: 10 months
measure: Number of patients with AEs related to the Implanted Infusion System
timeFrame: 10 months
Other outcomes:
measure: Explorative evaluation of changes to the Modified Hoehn &Yahr stage following two cycles of sNN0031
timeFrame: 10 monhts
measure: Explorative evaluation of changes to the Unified Parkinson's disease rating scale (UPDRS) following two cycles of sNN0031
timeFrame: 10 monhts
measure: Explorative evaluation of changes to the Parkinson's disease questionnaire (PDQ-39) following two cycles of sNN0031
timeFrame: 10 monhts
measure: Explorative evaluation of changes to the Dyskinesia rating scale (DRS) following two cycles of sNN0031
timeFrame: 10 monhts
measure: Explorative evaluation of changes to the o Non-motor symptom scale (NMSS 30) following two cycles of sNN0031
timeFrame: 10 monhts
measure: Changes in presynaptic dopamine transporter (DAT) binding
timeFrame: 10 months
measure: Explorative evaluation of potentially relevant biomarkers (inflammatory mediators) in plasma and CSF during and after two cycles of sNN0031
timeFrame: 10 months
measure: Explorative evaluation of potentially relevant biomarkers (urate) in plasma and CSF during and after two cycles of sNN0031
timeFrame: 10 months
measure: Explorative evaluation of potentially relevant biomarkers (DJ-1/Park7) in plasma and CSF during and after two cycles of sNN0031
timeFrame: 10 months
measure: Explorative evaluation of potentially relevant biomarkers (alpha-synuclein) in plasma and CSF during and after two cycles of sNN0031
timeFrame: 10 months
measure: Explorative evaluation of potentially relevant biomarkers (haemoglobin) in plasma and CSF during and after two cycles of sNN0031
timeFrame: 10 months
measure: Explorative evaluation of potentially relevant biomarkers (nitrite/nitrate) in plasma and CSF during and after two cycles of sNN0031
timeFrame: 10 months
Locations:
city: Bremerhaven
country: Germany
facility: Klinikum-Bremerhaven
city: Lund
country: Sweden
facility: Lund University Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital Huddinge
city: London
country: United Kingdom
facility: King's College Hospital
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
Study officials:
affiliation: Lund University Hospital
name: Håkan Widner, Prof
role: PRINCIPAL_INVESTIGATOR
References: