Study on Tolerability of Repeat i.c.v. Administration of sNN0031 Infusion Solution in Patients With PD

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

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.

Study Overview

• Status: Terminated
• Conditions: Parkinson's Disease
• Intervention / Treatment: Other: i.c.v. infusion of sNN0031 by an Implanted infusion system; Other: i.c.v. infusion of aCSF by an Implanted infusion system

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Bremerhaven, Germany, DE-27574
    • Klinikum-Bremerhaven
• Sweden
  • Lund, Sweden, 22185
    • Lund University Hospital
  • Stockholm, Sweden, 141 86
    • Karolinska University Hospital Huddinge
• United Kingdom
  • London, United Kingdom, SE5 9RS
    • King's College Hospital
  • Oxford, United Kingdom, OX3 9DU
    • John Radcliffe Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: sNN0031; sNN0031 Infusion Solution (in aCSF) for intracerebroventricular (i.c.v.) administration by an implanted infusion pump	Other: i.c.v. infusion of sNN0031 by an Implanted infusion system; I.c.v. infusion during 2 12d cycles separated by 3 mo. 6 mo follow-up after 2nd cycle.; Other Names: rhPDGF-BB; Medtronic SynchroMed® II Infusion System
PLACEBO_COMPARATOR: Placebo; Articifial Cerebro Spinal Fluid (aCSF) for intracerebroventricular (i.c.v.) administration by an implanted infusion pump	Other: i.c.v. infusion of aCSF by an Implanted infusion system; I.c.v. infusion during 2 12d cycles separated by 3 mo. 6 mo follow-up after 2nd cycle.; Other Names: Medtronic SynchroMed® II Infusion System; Placebo, Artificial Cerebrospinal fluid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerability of sNN0031 [Number of Adverse Events (AE) and Serious Adverse Events (SAE) occurring in each group over the study duration]	Number of AEs and SAEs occurring in each group over the study duration	10 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak concentrations of sNN0031 in cerebrospinal fluid during two 14 day continuous infusion cycles	To explore peak concentrations of Platelet Derived Growth Factor-BB (PDGF-BB) levels in cerebrospinal fluid (CSF) during two different treatment cycles of 70 μg sNN0031 each separated by 3 months	14 days x 2
Pump flow error rate	Performance of the Medtronic SynchroMed® II Infusion System - Pump flow error rate within 25%	10 months
Number of patients with AEs related to the Implanted Infusion System	Number of AEs and SAEs related to the Medtronic SynchroMed® II Infusion System occurring in each group over the study duration	10 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Explorative evaluation of changes to the Modified Hoehn &Yahr stage following two cycles of sNN0031	To explore the change from baseline in relevant efficacy related variables: o Modified Hoehn &Yahr stage	10 monhts
Explorative evaluation of changes to the Unified Parkinson's disease rating scale (UPDRS) following two cycles of sNN0031	To explore the change from baseline in relevant efficacy related variables: o Unified Parkinson's disease rating scale (UPDRS)	10 monhts
Explorative evaluation of changes to the Parkinson's disease questionnaire (PDQ-39) following two cycles of sNN0031	To explore the change from baseline in relevant efficacy related variables: o Parkinson's disease questionnaire (PDQ-39)	10 monhts
Explorative evaluation of changes to the Dyskinesia rating scale (DRS) following two cycles of sNN0031	To explore the change from baseline in relevant efficacy related variables: o Dyskinesia rating scale (DRS)	10 monhts
Explorative evaluation of changes to the o Non-motor symptom scale (NMSS 30) following two cycles of sNN0031	To explore the change from baseline in relevant efficacy related variables: o Non-motor symptom scale (NMSS 30)	10 monhts
Changes in presynaptic dopamine transporter (DAT) binding	To explore changes in presynaptic dopamine transporter (DAT) binding in basal ganglia by using DaTscan	10 months
Explorative evaluation of potentially relevant biomarkers (inflammatory mediators) in plasma and CSF during and after two cycles of sNN0031	To explore potentially relevant biomarkers in plasma and CSF - inflammatory mediators.	10 months
Explorative evaluation of potentially relevant biomarkers (urate) in plasma and CSF during and after two cycles of sNN0031	To explore potentially relevant biomarkers in plasma and CSF - urate.	10 months
Explorative evaluation of potentially relevant biomarkers (DJ-1/Park7) in plasma and CSF during and after two cycles of sNN0031	To explore potentially relevant biomarkers in plasma and CSF - DJ-1/Park7.	10 months
Explorative evaluation of potentially relevant biomarkers (alpha-synuclein) in plasma and CSF during and after two cycles of sNN0031	To explore potentially relevant biomarkers in plasma and CSF - alpha-synuclein.	10 months
Explorative evaluation of potentially relevant biomarkers (haemoglobin) in plasma and CSF during and after two cycles of sNN0031	To explore potentially relevant biomarkers in plasma and CSF - haemoglobin.	10 months
Explorative evaluation of potentially relevant biomarkers (nitrite/nitrate) in plasma and CSF during and after two cycles of sNN0031	To explore potentially relevant biomarkers in plasma and CSF - nitrite/nitrate.	10 months

Collaborators and Investigators

• Sponsor: Newron Sweden AB
• Collaborators: European Union
• Investigators: Principal Investigator: Håkan Widner, Prof, Lund University Hospital

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (ACTUAL): October 1, 2015
• Study Completion (ACTUAL): October 1, 2015

Study Registration Dates

• First Submitted: March 5, 2015
• First Submitted That Met QC Criteria: March 31, 2015
• First Posted (ESTIMATE): April 3, 2015

Study Record Updates

• Last Update Posted (ESTIMATE): January 27, 2016
• Last Update Submitted That Met QC Criteria: January 26, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Physiological Effects of Drugs; Angiogenesis Modulating Agents; Growth Substances; Anticoagulants; Angiogenesis Inducing Agents; Becaplermin
• Other Study ID Numbers: sNN0031-004