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TRANSEURO Open Label Transplant Study in Parkinson's Disease (TRANSEURO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01898390
Recruitment Status : Active, not recruiting
First Posted : July 12, 2013
Last Update Posted : April 19, 2019
Sponsor:
Collaborators:
Lund University
Cardiff University
Imperial College London
University College, London
University Hospital Freiburg
Life Science Governance Institute
Assistance Publique - Hôpitaux de Paris
Institut National de la Santé Et de la Recherche Médicale, France
Life Technologies Ltd, part of Thermo Fisher Scientific
Inomed
Cambridge Cognition Ltd
Skane University Hospital
Imanova Limited
Information provided by (Responsible Party):
Prof Roger Barker, University of Cambridge

Tracking Information
First Submitted Date  ICMJE July 9, 2013
First Posted Date  ICMJE July 12, 2013
Last Update Posted Date April 19, 2019
Study Start Date  ICMJE May 2012
Estimated Primary Completion Date March 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 11, 2013)
UPDRS change [ Time Frame: 36 months post transplantation ]
The change in motor Unified Parkinson's Disease Rating Scale (UPDRS)in a defined "OFF" state at 36 months post transplantation. "OFF" being defined as receiving no dopamine (DA) therapy for 12 hours prior to assessment or longer in the case of long acting dopamine agonists (e.g. Ropinirole slow release).
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01898390 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 11, 2013)
  • Change in timed motor tasks [ Time Frame: 36 months post transplantation ]
    Change in timed motor tasks at 36 months post transplantation
  • Dyskinesias [ Time Frame: 36 months post transplantation ]
    The number of patients with dyskinesias (including L-dopa and graft induced dyskinesias) at 36 months post transplantation
  • L-dopa equivalent medication [ Time Frame: 36 months post transplantation ]
    L-dopa equivalent medication doses at 36 months post transplantation.
  • L-dopa therapy [ Time Frame: 36 months post transplant ]
    Number of patients on L-dopa therapy at 36 months post transplantation.
  • Off time [ Time Frame: 36 months post transplantation ]
    The amount of 'off' time 36 months post transplantation
  • Quality of life [ Time Frame: 36 months post transplantation ]
    Quality of life (change) 36 months post transplantation
  • F-DOPA PET changes [ Time Frame: 36 months post transplantation ]
    Changes in F-DOPA PET in transplanted patients 36 months post transplantation
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: July 11, 2013)
  • AE/SAE's [ Time Frame: 0-36 months post treatment ]
    The number of adverse events and serious adverse events associated with the neural transplant
  • Laboratory Parameters [ Time Frame: 0-36 months post treatment ]
    Any reported changes in haematology, biochemistry or urinalysis measures outside the normal range
  • Other Safety parameters [ Time Frame: 0-36 months post treatment ]
    Vital signs, Physical Exam - new abnormalities will be recorded as an adverse event
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE TRANSEURO Open Label Transplant Study in Parkinson's Disease
Official Title  ICMJE An Open Label Study to Assess the Safety and Efficacy of Neural Allo-Transplantation With Fetal Ventral Mesencephalic Tissue in Patients With Parkinson's Disease
Brief Summary

The Transeuro Transplant study is a trial which will involve grafting foetal tissue into the brain of patients with Parkinson's disease, who are already been followed in the observational study. The tissue inserted in the brain is to help replace and rebuild lost dopamine from the brain due to Parkinson's disease.

Update April 2019:

A total of 11 PD patients were grafted in Cambridge, UK and Lund, Sweden. No further surgeries are planned. The final patient will complete the study's clinical endpoint (36 months post-graft) in 2021. We continue to assess these patients bi-annually alongside a control group which did not receive any intervention.

Detailed Description

Clinical trials of cell therapy in PD patients were first performed in Lund in the late 1980s, followed by a number of similar, small trials in other European and North American centres. These initial studies performed on small groups of advanced PD patients were all open label but firmly established safety of the procedure. The results obtained in these trials have shown that the grafted dopaminergic [DA] neurons can survive and function long-term, over more than 10 years, and that some patients have shown clear clinical benefits, especially with respect to their bradykinesia and rigidity, with reductions in L-dopa requirements. Using functional imaging it has also been shown that the grafted DA neurons can restore striatal DA release and provide a sustained re-activation of motor cortical areas, i.e. key areas that were underactive prior to grafting.

Post-mortem studies have shown excellent long-term survival of the grafted DA neurons, notwithstanding the observation that some of the long-term surviving transplants (at 12-15 years after grafting) have now been shown to contain signs of PD-related pathologies, i.e. neuronal Lewy-bodies and alpha-synuclein positive inclusions in the grafts. However, such changes have been observed only in some and not in all patients and when seen the extent of the pathology is limited to a small number of the grafted DA cells and the clinical consequence, if any, not known.

However, the outcomes of two NIH sponsored double blind placebo controlled trials, which published their main findings in 2001 and 2003, have raised major concerns. In both these trials the grafted patients did not show any significant improvement overall compared to sham-operated controls at 1 and 2 years post grafting. Furthermore, a significant number of patients in both trials developed GIDs, which in some cases were so severe that further neurosurgery was needed to remedy the situation.

The reasons for the variable, and overall poor, outcome in these trials, including the generation of GIDs, have been the subject of much debate but have recently centred on three key elements, with an additional possible fourth element:

  • The selection of patients in terms of clinical phenotype, disease stage and pattern of striatal dopaminergic denervation at the time of grafting;
  • The differences in immunosuppressive regimes and the risk that incomplete immunosuppression in combination with the use of solid graft methods may lead to the development of detrimental immune/inflammatory reactions at the graft site with compromise of the grafted dopamine cell function;
  • The mode of engraftment and differences in graft cell survival, and the risk for inhomogeneous delivery of dopaminergic neurons and the generation of potentially dyskinesia-inducing "patchy" innervations in the host striatum;
  • A final possible element is the composition of the grafted tissue and the ratio of serotoninergic to dopaminergic neurons within the graft. There is emerging evidence that serotoninergic neurons can release dopamine in a relatively unregulated fashion given they lack transporters for it, and as such may use L-dopa as a false transmitter which may not only underlie the development of L-dopa induced dyskinesia's but may also contribute to GIDs.

Failure of the NIH trials to demonstrate any overall clinical benefits in the grafted patients, and the unexpected and worrisome development of GIDs in a significant number of patients in these trials has represented a major hurdle for the future development of cell based therapies for PD and it is in this and related areas that this project seeks to move the field forward and go beyond the current state of the art for this treatment approach.

This project has gathered together all the available expertise in this area to resolve or reduce the risk of the previous complications seen with VM transplants in patients with PD. We will conduct a new round of clinical trials, involving a step-by-step optimisation of all technical aspects of the grafting procedure and patient selection and assessment, in order to improve clinical efficiency and consistency, in the absence of troublesome dyskinesia's.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Parkinson's Disease
Intervention  ICMJE Procedure: Transplant
Bilateral Neural Allo-Transplantation with Fetal Ventral Mesencephalic Tissue
Study Arms  ICMJE
  • Experimental: Transplant
    Neural Allo-Transplantation with Fetal Ventral Mesencephalic Tissue
    Intervention: Procedure: Transplant
  • No Intervention: Control
    comparison group of controls, will receive the same observational and scanning assessments but will not receive any surgical procedures
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: July 11, 2013)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2021
Estimated Primary Completion Date March 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients must meet ALL of the following criteria to be considered for the enrolment into this study:

    • PD as defined using Queen's Square Brain Bank criteria.
    • Disease duration ≥ 2 years and ≤ 13 years.
    • Aged ≥ 30 years and ≤ 68 years at the time of grafting.
    • Hoehn & Yahr stage 2.5 or better when 'on'.
    • On standard anti PD medication without significant LIDs defined as a score of >2 on the AIMS dyskinesia rating scale, in any body part.
    • Patients must be right handed.

Exclusion Criteria:

  • Any of the following will exclude patients from being enrolled in the study:

    • Atypical or secondary parkinsonism including F-DOPA PET patterns consistent with this.
    • Clinically significant response to Levodopa (as evaluated by the clinician) and/or apomorphine challenge.
    • Mini-Mental State Examination (MMSE) score of less than 26.
    • Unable to do normal copying of interlocking pentagons and semantic fluency score for naming animals of less than 20 over 90 seconds as these have recently been associated with the earlier onset of dementia in PD.
    • Ongoing major medical or psychiatric disorder including depression and psychosis.
    • Other concomitant treatment with neuroleptics (inc. Atypical neuroleptics) and cholinesterase inhibitors.
    • Significant drug induced dyskinesia defined as a score of >2 on the AIMS dyskinesia rating scale, in any body part.
    • Previous neurosurgery, cell therapy or organ transplantation.
    • Unable to be imaged using MRI.
    • Any contraindication to immunosuppression therapy.
    • Patients on anticoagulants
    • Patients who are left handed
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 30 Years to 68 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01898390
Other Study ID Numbers  ICMJE TRANSEURO
FP7-242003 ( Other Grant/Funding Number: European Community Seventh Framework Programme )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Prof Roger Barker, University of Cambridge
Study Sponsor  ICMJE University of Cambridge
Collaborators  ICMJE
  • Lund University
  • Cardiff University
  • Imperial College London
  • University College, London
  • University Hospital Freiburg
  • Life Science Governance Institute
  • Assistance Publique - Hôpitaux de Paris
  • Institut National de la Santé Et de la Recherche Médicale, France
  • Life Technologies Ltd, part of Thermo Fisher Scientific
  • Inomed
  • Cambridge Cognition Ltd
  • Skane University Hospital
  • Imanova Limited
Investigators  ICMJE
Principal Investigator: Roger Barker, Prof Department of Clinical Neurosciences, University of Cambridge
PRS Account University of Cambridge
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP