Periodic Reporting for period 3 - PD-MIND (Parkinson Disease with Mild cognition Impairment treated with Nicotinic agonist Drug)
Okres sprawozdawczy: 2021-05-01 do 2022-04-30
Parkinson Disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease. There is an unmet clinical need to treat Parkinson disease with mild cognitive impairment (PD-MCI), i.e. Parkinson patients whose cognition is impaired, but who have not yet reached the stage of Parkinson’s Disease Dementia (PDD).
There is ample evidence from epidemiological studies as well as (pre)clinical research that Nicotinic receptors are involved in PD and cognition. Recently a clinical trial suggested that selective α7 nicotinic receptor agonist improved cognition in PD patients, as a secondary outcome measure. Hence, the main goal of PD-MIND was to show the potential of the Astrazeneca nicotinic α7 agonist AZD0328 in a randomized, placebo-controlled, international multicentre study on cognition in people diagnosed with PD-MCI. We were planning to assess Attention Intensity Index composite score (a parameter to detect changes in patient’s attention span) as a primary outcome measure and other clinical aspects (cognition, motor symptoms, health-related measures) as secondary outcomes. In addition, MRI (Magnetic Resonance Imaging) imaging and blood biomarkers were to be assessed as potential predictors of response, and as markers of target involvement. Patients (Public and Patient Involvement) and other stakeholders were to be engaged from the start to allow integration of end-user perspectives in the design and execution of the project.
PD-MIND would have put considerable effort to disseminate and exploit clinical outcome data and biomarker results, and to sustain the partnership for subsequent phase 3 clinical studies. The PD-MIND consortium consisted of world-leading PD-MCI experts in the area of clinical trials, clinical coordination, project management, data management and analysis, and biomarkers. As such the consortium was well positioned to execute the proposed work and complement the EFPIA members.
Due to complications, it was not possible to start the clinical studies under the PD-MIND project. Therefore, no results have been produced by the end of the project.
There is ample evidence from epidemiological studies as well as (pre)clinical research that Nicotinic receptors are involved in PD and cognition. Recently a clinical trial suggested that selective α7 nicotinic receptor agonist improved cognition in PD patients, as a secondary outcome measure. Hence, the main goal of PD-MIND was to show the potential of the Astrazeneca nicotinic α7 agonist AZD0328 in a randomized, placebo-controlled, international multicentre study on cognition in people diagnosed with PD-MCI. We were planning to assess Attention Intensity Index composite score (a parameter to detect changes in patient’s attention span) as a primary outcome measure and other clinical aspects (cognition, motor symptoms, health-related measures) as secondary outcomes. In addition, MRI (Magnetic Resonance Imaging) imaging and blood biomarkers were to be assessed as potential predictors of response, and as markers of target involvement. Patients (Public and Patient Involvement) and other stakeholders were to be engaged from the start to allow integration of end-user perspectives in the design and execution of the project.
PD-MIND would have put considerable effort to disseminate and exploit clinical outcome data and biomarker results, and to sustain the partnership for subsequent phase 3 clinical studies. The PD-MIND consortium consisted of world-leading PD-MCI experts in the area of clinical trials, clinical coordination, project management, data management and analysis, and biomarkers. As such the consortium was well positioned to execute the proposed work and complement the EFPIA members.
Due to complications, it was not possible to start the clinical studies under the PD-MIND project. Therefore, no results have been produced by the end of the project.
Work performed from the start of the project:
• Two annual consortium meetings were held onine.
• A successful Mid-Term review was held.
• Agreements - Clinical site agreements have been finalised by sponsor 1 (KCL) and sent for approval to co-sponsor. Once approved by co-sponsor this would have been sent to all research sites.
• Funding - The additional funding that had been agreed from Parkinson’s UK and Michael J. Fox Foundation was secured but could no longer be used for this project.
• Assessments - all license agreements for the Clinical Data Repository (CDR) were secured .
• Competent authority approval - this was obtained from UK Medicines and Healthcare products Regulatory Agency (MHRA) and the Norwegian equivalent The Norwegian Medicines Agency (NOMA). Also an amendment was submitted to UK MHRA, and approved.
• Preparations were underway for submission to the competent authority in Italy.
• Ethical approval - both Norway and UK sites had given ethical approval.
• At partner AZ work to prepare for submission to the regulatory agency in Germany was performed and submitted.
• Patient facing documents - UK-based documents were to be used as a template for translations into local languages after ethical approval had been obtained for these in the UK. Documents including document version trackers and history of version control had been made for all documents so that it was easy to see which site would have been using which version, and any local variations between documents. All patient facing documents were translated into Norwegian and approved by the local ethics committee in Norway. These were also ready to upload to the PD-MIND website once recruitment at these sites would have started. Translations were ongoing for other countries - Italy, Germany and Czech Republic.
• The randomisation system was being built.
• Cognitive tests were almost finalized.
• The MRI acquisition protocols were harmonized, SOPS (Standard Operating Procedures) for MRI scanner settings were prepared, and a data management pipeline, describing details of data acquisition and structure of acquired date (BIDS standard), was built.
• Two annual consortium meetings were held onine.
• A successful Mid-Term review was held.
• Agreements - Clinical site agreements have been finalised by sponsor 1 (KCL) and sent for approval to co-sponsor. Once approved by co-sponsor this would have been sent to all research sites.
• Funding - The additional funding that had been agreed from Parkinson’s UK and Michael J. Fox Foundation was secured but could no longer be used for this project.
• Assessments - all license agreements for the Clinical Data Repository (CDR) were secured .
• Competent authority approval - this was obtained from UK Medicines and Healthcare products Regulatory Agency (MHRA) and the Norwegian equivalent The Norwegian Medicines Agency (NOMA). Also an amendment was submitted to UK MHRA, and approved.
• Preparations were underway for submission to the competent authority in Italy.
• Ethical approval - both Norway and UK sites had given ethical approval.
• At partner AZ work to prepare for submission to the regulatory agency in Germany was performed and submitted.
• Patient facing documents - UK-based documents were to be used as a template for translations into local languages after ethical approval had been obtained for these in the UK. Documents including document version trackers and history of version control had been made for all documents so that it was easy to see which site would have been using which version, and any local variations between documents. All patient facing documents were translated into Norwegian and approved by the local ethics committee in Norway. These were also ready to upload to the PD-MIND website once recruitment at these sites would have started. Translations were ongoing for other countries - Italy, Germany and Czech Republic.
• The randomisation system was being built.
• Cognitive tests were almost finalized.
• The MRI acquisition protocols were harmonized, SOPS (Standard Operating Procedures) for MRI scanner settings were prepared, and a data management pipeline, describing details of data acquisition and structure of acquired date (BIDS standard), was built.
PD-MIND was to be a multi-centre, randomised, double-blind, placebo-controlled, phase 2 trial of a nicotinic agonist, AZD0328, in patients with PD-MCI to improve their cognitive abilities. There is currently no treatment available.
Furthermore, imaging biomarker studies were meant to provide information on targets potentially modified by AZD0328, to further elucidate the role of a nicotinic agonist in cognitive decline in PD.
The trial was meant to include 160 individuals with PD-MCI: 80 in active (AZD0328) group and 80 in control (placebo) group. On a subset of 90 participants an MRI scan at study entry and exit as part of an MRI biomarker component was to be performed.
PD-MIND was going to use a composite score across an array of cognitive measures to account for differences in cognition patterns. PD-MIND would also use biomarkers as potential early predictors for effect cognitive decline to increase the body of evidence on AZD038 efficacy and on the other hand address potentially underlying disease mechanisms affected by AZD0328.
This study was going to test for the first time the potential of a nicotinic agonist in PD-MCI, primarily on cognitive symptoms. PD-MIND was to be one of the first RCT in PD-MCI to use the recently standardized and generally accepted diagnostic criteria for PD-MCI, and would employ computerized cognitive outcome measures, using the CogPro system. Thereby, PD-MIND would contribute to establishing and validating these criteria and measures in a clinical trial context for PD-MCI. The study would also aim to identify the most relevant cognitive areas improved by AZD0328.
The study was going to assess magnetic resonance imaging (MRI) imaging biomarkers, to discover potential predictors of response to AZD0328, markers of target involvement and disease progression. There would have been the prospect of discovering new biomarkers for PD-MCI, important for detecting and monitoring the disease course in general. The MRI biomarkers that were going to be assessed could have had the potential to identify subgroups with high or low likelihood of response to nicotinic agents (i.e. “diagnostic MRI biomarker tools”). These could be further developed towards an opportunity for personalized medical interventions.
The sample size and the use of a sensitive computer-based cognitive outcome measure, which was to be administered three times in each phase without learning effect, would have promised a much improved signal-to-noise ratios and an increased likelihood to detect a treatment effect.
Being a Phase 2a study, the study was going to be an exploratory rather than a confirmatory study to assess whether a reasonably strong signal of efficacy could be achieved. Moreover, monitoring treatment effects using structural and functional MRI is in infancy. If successful, the findings would have informed phase III clinical trial designs.
Furthermore, imaging biomarker studies were meant to provide information on targets potentially modified by AZD0328, to further elucidate the role of a nicotinic agonist in cognitive decline in PD.
The trial was meant to include 160 individuals with PD-MCI: 80 in active (AZD0328) group and 80 in control (placebo) group. On a subset of 90 participants an MRI scan at study entry and exit as part of an MRI biomarker component was to be performed.
PD-MIND was going to use a composite score across an array of cognitive measures to account for differences in cognition patterns. PD-MIND would also use biomarkers as potential early predictors for effect cognitive decline to increase the body of evidence on AZD038 efficacy and on the other hand address potentially underlying disease mechanisms affected by AZD0328.
This study was going to test for the first time the potential of a nicotinic agonist in PD-MCI, primarily on cognitive symptoms. PD-MIND was to be one of the first RCT in PD-MCI to use the recently standardized and generally accepted diagnostic criteria for PD-MCI, and would employ computerized cognitive outcome measures, using the CogPro system. Thereby, PD-MIND would contribute to establishing and validating these criteria and measures in a clinical trial context for PD-MCI. The study would also aim to identify the most relevant cognitive areas improved by AZD0328.
The study was going to assess magnetic resonance imaging (MRI) imaging biomarkers, to discover potential predictors of response to AZD0328, markers of target involvement and disease progression. There would have been the prospect of discovering new biomarkers for PD-MCI, important for detecting and monitoring the disease course in general. The MRI biomarkers that were going to be assessed could have had the potential to identify subgroups with high or low likelihood of response to nicotinic agents (i.e. “diagnostic MRI biomarker tools”). These could be further developed towards an opportunity for personalized medical interventions.
The sample size and the use of a sensitive computer-based cognitive outcome measure, which was to be administered three times in each phase without learning effect, would have promised a much improved signal-to-noise ratios and an increased likelihood to detect a treatment effect.
Being a Phase 2a study, the study was going to be an exploratory rather than a confirmatory study to assess whether a reasonably strong signal of efficacy could be achieved. Moreover, monitoring treatment effects using structural and functional MRI is in infancy. If successful, the findings would have informed phase III clinical trial designs.