Phase I/II Study of the Safety, Efficacy and Dose Evaluation of ProSavin for the Treatment of Bilateral Idiopathic Parkinson's Disease
Primary Purpose
Parkinson's Disease
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
ProSavin
ProSavin
Sponsored by
About this trial
This is an interventional treatment trial for Parkinson's Disease focused on measuring ProSavin, Parkinson's Disease, Gene Therapy
Eligibility Criteria
Inclusion Criteria:
- Willing and able to give written Informed Consent
- Diagnosed with bilateral idiopathic PD
- Diagnosis of PD > five years, using diagnostic criteria from core assessment program for surgical interventional therapies CAPSIT (1999)
- Males/females between 48 and 65 years
- Women must be postmenopausal, with last menstrual period being over two years ago
- Male patients must agree to use at least two methods of contraception for at least 3 months following ProSavin administration if they and their partner is of child-bearing capacity
- Response to L-DOPA where an increase in dose is unacceptable to the patient due to potentiating the fluctuations in motor functions
- Hoehn and Yahr stage 3 and 4
- UPDRS (Part III) of between 20 and 60 in the "OFF" state
- Stable dosing of PD medication, including L-DOPA, for six weeks prior to surgery
- Positive response to dopaminergic therapy as defined by a 50% improvement in UPDRS (Part III) between the "OFF" and "ON" states
- Presence of motor fluctuations
- Willing to have current treatment withdrawn for up to 24 hours prior to surgery therefore being in an "OFF" state for surgery
- Willing to have their L-DOPA dosage reduced/withdrawn at the discretion of the principal investigator (PI) at regular intervals following surgery to allow assessment of ProSavin in the absence of concomitant anti-{Parkinsonian medication
- Affiliated with the French social security health care system (Patients enrolled in France only)
Exclusion Criteria:
- Major surgery within the 28 days prior to enrolment
- Severe disabling dyskinesias > or = 51% of the day as defined by the UPDRS (Part IV)
- History of psychosis or current treatment with dopamine blocking agents of any kind
- Severe depression as defined by a BDI score of >16. Any treatment for depression should be limited to seretonergic therapies and those that do not target the dopaminergic pathways
- Prior treatment with tolcapone within the six months prior to enrollment into the study, due to its ability to modify dopaminergic pathways in the brain
- History of epilepsy or any other co-morbid condition that the Investigator believes presents an unacceptable health risk to the patient in conjunction with the procedures in this protocol
- Life-threatening illness unrelated to PD
- History of stereotactic or other surgery for the treatment of PD
- Premenopausal women
- Alcohol or other substance abuse
- Clinically significant laboratory test abnormalities, including full blood count, chemistry panel, liver function tests, electrocardiogram (ECG), Chest X rays
- Any contraindication for undergoing an MRI scan of the head
- Intercurrent illness or infection 28 days prior to enrolment
- Abnormal MRI findings such as mega cisterna, septum pellucidum, signs of severe cortical or subcortical atrophy, brain tumours, vascular diseases, trauma or arteriovenous malformations (AVM)
- Prior regular exposure to neuroleptic agents
- History of treatment with any agent that may induce PD or PD symptoms within the last three months prior to enrollment
- Contraindications to use of anaesthesia
- Treated with dopaminergic antagonists six months prior to screening
- Concurrent antiretroviral therapy that would inactivate the investigational agent
- History of any investigational agent within 28 days prior to ProSavin administration
- Participation in a prior gene transfer therapy study
- Enrolment in any other clinical study, for any condition, including those relating to PD, throughout the duration of the ProSavin study
- Current of anticipated treatment with anticoagulant therapy or the use of anticoagulation therapy within the four weeks prior to surgery
- Diagnosis of multiple systems atrophy (MSA) following assessment of the autonomic nervous systems function (e.g. blood pressure, difficulty in urinating and sexual activity) and MRI during the screening process
- Administration of subcutaneous rescue remedy apomorphine
- Patient unable to adhere to their prescribed Parkinson's disease treatment regime.
Sites / Locations
- Henri Mondor Hospital
- Addenbrookes Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Sham Comparator
Arm Label
Dose Evaluation
Sham element
Arm Description
To assess the safety and efficacy of up to three dose levels of ProSavin
The potential use of sham comparator to confirm efficacy
Outcomes
Primary Outcome Measures
Safety as measured by the number and severity of Adverse Events
Secondary Outcome Measures
Efficacy as measured by the UPDRS
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00627588
Brief Title
Phase I/II Study of the Safety, Efficacy and Dose Evaluation of ProSavin for the Treatment of Bilateral Idiopathic Parkinson's Disease
Official Title
A Phase I/II Study of the Safety, Efficacy and Dose Evaluation of ProSavin®, Administered Using Stereotactic Injection to the Striatum of Patients With Bilateral, Idiopathic Parkinson's Disease.
Study Type
Interventional
2. Study Status
Record Verification Date
May 2013
Overall Recruitment Status
Completed
Study Start Date
January 2008 (undefined)
Primary Completion Date
August 2012 (Actual)
Study Completion Date
August 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Oxford BioMedica
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The primary objectives of the trial are to assess the safety and efficacy of ProSavin.
Patients in the trial will have been diagnosed with Parkinson's disease and will be failing on current treatment with L-DOPA but they will not have progressed to drug-induced dyskinesias. The first stage is an open-label dose escalation to evaluate up to three dose levels of ProSavin in cohorts of three patients each. Following a recommendation by the DMC the study may proceed to the second stage of the trial, a further 12 patients will be recruited to confirm efficacy of the optimal dose in the randomized phase of the study.
The efficacy of ProSavin will be assessed using the Unified Parkinson's Disease Rating Score (UPDRS). Patients will be monitored at regular intervals, with the primary endpoint being an efficacy assessment at six months after treatment. The secondary objective of the trial is to asses the extent to which patients' current therapy (L-DOPA) can be reduced following administration of ProSavin.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Parkinson's Disease
Keywords
ProSavin, Parkinson's Disease, Gene Therapy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
15 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Dose Evaluation
Arm Type
Experimental
Arm Description
To assess the safety and efficacy of up to three dose levels of ProSavin
Arm Title
Sham element
Arm Type
Sham Comparator
Arm Description
The potential use of sham comparator to confirm efficacy
Intervention Type
Biological
Intervention Name(s)
ProSavin
Intervention Description
ProSavin is a gene therapy designed to delivery three key enzymes involved in the synthesis of dopamine
Intervention Type
Biological
Intervention Name(s)
ProSavin
Intervention Description
ProSavin is a gene therapy designed to delivery three key enzymes involved in the synthesis of dopamine
Primary Outcome Measure Information:
Title
Safety as measured by the number and severity of Adverse Events
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Efficacy as measured by the UPDRS
Time Frame
6 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
48 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Willing and able to give written Informed Consent
Diagnosed with bilateral idiopathic PD
Diagnosis of PD > five years, using diagnostic criteria from core assessment program for surgical interventional therapies CAPSIT (1999)
Males/females between 48 and 65 years
Women must be postmenopausal, with last menstrual period being over two years ago
Male patients must agree to use at least two methods of contraception for at least 3 months following ProSavin administration if they and their partner is of child-bearing capacity
Response to L-DOPA where an increase in dose is unacceptable to the patient due to potentiating the fluctuations in motor functions
Hoehn and Yahr stage 3 and 4
UPDRS (Part III) of between 20 and 60 in the "OFF" state
Stable dosing of PD medication, including L-DOPA, for six weeks prior to surgery
Positive response to dopaminergic therapy as defined by a 50% improvement in UPDRS (Part III) between the "OFF" and "ON" states
Presence of motor fluctuations
Willing to have current treatment withdrawn for up to 24 hours prior to surgery therefore being in an "OFF" state for surgery
Willing to have their L-DOPA dosage reduced/withdrawn at the discretion of the principal investigator (PI) at regular intervals following surgery to allow assessment of ProSavin in the absence of concomitant anti-{Parkinsonian medication
Affiliated with the French social security health care system (Patients enrolled in France only)
Exclusion Criteria:
Major surgery within the 28 days prior to enrolment
Severe disabling dyskinesias > or = 51% of the day as defined by the UPDRS (Part IV)
History of psychosis or current treatment with dopamine blocking agents of any kind
Severe depression as defined by a BDI score of >16. Any treatment for depression should be limited to seretonergic therapies and those that do not target the dopaminergic pathways
Prior treatment with tolcapone within the six months prior to enrollment into the study, due to its ability to modify dopaminergic pathways in the brain
History of epilepsy or any other co-morbid condition that the Investigator believes presents an unacceptable health risk to the patient in conjunction with the procedures in this protocol
Life-threatening illness unrelated to PD
History of stereotactic or other surgery for the treatment of PD
Premenopausal women
Alcohol or other substance abuse
Clinically significant laboratory test abnormalities, including full blood count, chemistry panel, liver function tests, electrocardiogram (ECG), Chest X rays
Any contraindication for undergoing an MRI scan of the head
Intercurrent illness or infection 28 days prior to enrolment
Abnormal MRI findings such as mega cisterna, septum pellucidum, signs of severe cortical or subcortical atrophy, brain tumours, vascular diseases, trauma or arteriovenous malformations (AVM)
Prior regular exposure to neuroleptic agents
History of treatment with any agent that may induce PD or PD symptoms within the last three months prior to enrollment
Contraindications to use of anaesthesia
Treated with dopaminergic antagonists six months prior to screening
Concurrent antiretroviral therapy that would inactivate the investigational agent
History of any investigational agent within 28 days prior to ProSavin administration
Participation in a prior gene transfer therapy study
Enrolment in any other clinical study, for any condition, including those relating to PD, throughout the duration of the ProSavin study
Current of anticipated treatment with anticoagulant therapy or the use of anticoagulation therapy within the four weeks prior to surgery
Diagnosis of multiple systems atrophy (MSA) following assessment of the autonomic nervous systems function (e.g. blood pressure, difficulty in urinating and sexual activity) and MRI during the screening process
Administration of subcutaneous rescue remedy apomorphine
Patient unable to adhere to their prescribed Parkinson's disease treatment regime.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephane Palfi, Professor
Organizational Affiliation
Henri Mondor University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Henri Mondor Hospital
City
Paris
Country
France
Facility Name
Addenbrookes Hospital
City
Cambridge
State/Province
Cambridgeshire
ZIP/Postal Code
CB2 0QQ
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
24412048
Citation
Palfi S, Gurruchaga JM, Ralph GS, Lepetit H, Lavisse S, Buttery PC, Watts C, Miskin J, Kelleher M, Deeley S, Iwamuro H, Lefaucheur JP, Thiriez C, Fenelon G, Lucas C, Brugieres P, Gabriel I, Abhay K, Drouot X, Tani N, Kas A, Ghaleh B, Le Corvoisier P, Dolphin P, Breen DP, Mason S, Guzman NV, Mazarakis ND, Radcliffe PA, Harrop R, Kingsman SM, Rascol O, Naylor S, Barker RA, Hantraye P, Remy P, Cesaro P, Mitrophanous KA. Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial. Lancet. 2014 Mar 29;383(9923):1138-46. doi: 10.1016/S0140-6736(13)61939-X. Epub 2014 Jan 10.
Results Reference
derived
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Phase I/II Study of the Safety, Efficacy and Dose Evaluation of ProSavin for the Treatment of Bilateral Idiopathic Parkinson's Disease
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