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This week an announcement was made regarding The Edmond J. Safra Accelerating Clinical Treatments for Parkinson’s Disease (EJS-ACT PD) Initiative.

It is hoping to revolutionise the way clinical trials for potentially disease-modifying drugs for Parkinson’s are conducted.

The project is focused on the setting up a multi-arm, multi-stage (MAMS) platform for evaluating new therapies for PD.

In today’s post, we will discuss what MAMS trials involve and the current details of the EJS-ACT PD initiative.

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Source: Motionarray

This week I boarded a train for the first time in 16 months and made my way down to London. It felt a wee bit surreal.

I arrived at Liverpool street station and was immediately shocked by the lack of crowds, the lack of face masks (seriously?!? I’ve had my two jabs as well, but I’m still wearing my mask – you are nuts if you don’t!), and the large number of empty shops. How the world has changed.

In the early morning light, I walked across central London towards St Pancras station – the weather was spectacular and it was an incredible pleasure to stroll through some old stomping grounds.

Source: Parksandgardens

At St Pancras station, I made my way to the enormous Francis Crick institute, where a group of Parkinson’s researchers and advocates were gathering for a really intriguing meeting.

Source: Timeshighereducation

What was the meeting about?

The meeting was the kick-off event for a major new project being funded by the Edmund J. Safra Foundation.

Mr Safra was a banker/philanthropist who lived with Parkinson’s during the last years of his life, and his family charity is now a major funder of Parkinson’s-related research efforts.

Edmond J. Safra. Source: Edmondjsafrafoundation

What is the major new project?

The kick-off event was for the Accelerating Clinical Treatments for Parkinson’s Disease project — which will be known as the Edmond J. Safra ACT-PD Initiative (Press release).

What is the EJS-ACT PD initiative going to do?

As the leadership team of the project – Prof Tom Foltynie, Prof Sonia Gandhi, and Dr Camille Carroll – explained, the aim of the project is to set up a MAMS platform for evaluating potentially disease modifying therapies for Parkinson’s.

What is a MAMS platform?

A Multi-Arm Multi-Stage (or MAMS) clinical trial is a study that allows for the assessment of several potential therapies at the same time. It also shifts participants seamlessly from a Phase II (safety and efficacy) study to a Phase III trial, by regular within study measures (or interim analyses).

Can we go back a moment please? Could you explain how clinical trials are currently conducted?


Here is how it currently work:

First, there is the setting up of the trial.

When it is determined (from a great deal of preclinical research) that “therapy A” is worthy of clinical testing in humans with Parkinson’s, investigators will begin to organise a study. They firstly need to find a sponsor (this is a research/medical institute that is prepared to accept the responsibility for ensuring that there are proper arrangements to manage and finance a research study).

Next, the researchers seek funding to conduct the study. And this is no easy task – trials cost a lot of money and applying for funding can take a long time. Funding applications are enormous and take a very long time to process (peer review opinions, etc). Once a sponsor and funding is in place, the researchers must still request ethical and regulatory approval for the study – in the UK all trials require approval by the Health Research Authority (HRA) which involves a review by a local Research Ethics Committee.

This first part of the clinical trial process can require years of work, and it takes place for every study (even when the same drug is being tested across two different studies, the same sequence must be followed).

Once the green light is given for starting a clinical trial of ‘therapy A’, participants in a clinical study will typically be assessed and if they are found to fit the inclusion criteria for the study, they will then be randomly assigned to one of multiple treatment groups (for example, the experimental treatment or the control group).

Next, they will be followed and assessed over a fixed period of time (such as 12 months), at the end of which the researchers will pool together all of the data and ‘lock’ it for statistical analysis. Sometimes there is also a ‘washout’ period to see what happens to the participants in the absence of the treatment.

Hang on a second, why do they wait till the end of the study to analyse the data?!?

That is correct. Current clinical trials all wait to the end of treatment before analysing the results.

The data analysis can take several months and then the investigators will write a report which they will submit for publication in a medical journal. The peer-review process is a necessary part of the scientific process, but it can be a frustratingly long tale of woe – journal editors declaring that the study isn’t worthy of their prestigious journal (a business decision), peer reviewers using the anonymous system to attack competitors (in a bid to “improve the quality of the report”), etc. Big sigh!

Source: Elsevier

Thankfully, now there are preprint databases such as MedRxiv which are being used by increasingly being used by researchers to make results available earlier as they go through the peer-review process.

But the peer-review process can take a long time (6-12 months with all the back-and-forth of correspondence and edits/revisions), which delays the clinical trial process further. And this causes further frustration for the Parkinson’s community who would like to learn about the results (and see the  whole process speed up).

And during this process of disseminating the results, the investigators will be deciding whether to further investigate the experimental therapy or not. If they chose to do so, they have to go through this entire process again – which can result in long delays between the phases of clinical trials.

What do you mean “phases” in the clinical trial process?

There are 5 Phases involved with getting a new treatment approved for clinical use:

Source: Cancer

To begin with, there is the long, labourious process of discovering and testing a new treatment/compound. This is the preclinical phase. Once a compound/treatment has been identified, validated in various preclinical models of a medical condition, and a basic pharmacological profile has been established in animals (this involves determining if the treatment is toxic and investigating how long the treatment lasts in the body of a lab animal), then investigators will go through the process described above to organise a clinical study.

The first test is called a Phase I clinical trial.

Source: Closerlookatstemcells

The goal of Phase I trials is to determine if the drug is safe. Efforts will also be made to assess the ideal dose for further clinical testing. Phase I trials will often be in healthy individuals (perhaps 20-50 people), involve a single or multiple doses of the treatment, and they are usually very quick (think weeks or a few months).

If the treatment is found to be safe in Phase I, the investigative team will shift their efforts to a Phase II trial,… and again, they will need to go through the same long process for setting up a clinical trial that we described above – resulting in a delay between Phase 1 and Phase 2 of several months-years.

Source: Closerlookatstemcells

The goal of a Phase II clinical trial is to determine if the drug is safe in your patient population of interest and attempt to provide proof of efficacy (that is, try to provide evidence that the treatment is doing what it is supposed to). Phase II trials usually involve 50 – 100 individuals being on the treatment for a long period of time (they can last up to 12 months).

If the treatment is found to be safe in the cohort of interest and have an effect in Phase II clinical trials (an example in Parkinson’s of this is the Exenatide study – Click here and here to read more about this), the investigative team will then set up for a large Phase III clinical trial.

And again, this requires going through the same long process for setting up a clinical trial that we described above – resulting in a delay between Phase 2 and Phase 3 of several years (bigger trials take longer to set up and finance).

Source: Closerlookatstemcells

The goal of a Phase III trial is to determine efficacy in a large group of the patient population of interest (200-300+ participants). These are huge, expensive trials that will involve 1-2 years of treatment and assessments on average in the case of a slowly progressing condition like Parkinson’s.

There is also a Phase IV clinical trial which comes after a drug is approved by regulators. This involves companies/clinicians/researchers continually following the use of the treatment and collecting information in the clinical setting. This is outside of the scope of our interest here as it has nothing to do with getting treatments to the clinic.

As you can hopefully see, clinical trials are long, slow projects.

But this is crazy! Whose idea was this?

I’m not sure. And I doubt many people would put up their hand to take credit for it.

The trial system (and industry surrounding it) was set up to make sure that treatments entering the medical usage are 1. safe, and 2. thoroughly characterised (ideally, they also provide some improved benefit on previous therapies, but this seems to be less important recently).

One of the biggest problems, however, is that the current system of clinical trialing is not keeping up with the extremely rapid advances being made in the biomedical research field.

“With the ever increasing pace of research, including in vitro and in vivo screening systems, advances in virtual drug modelling and bioinformatics approaches, the number of suitable drug candidates for clinical evaluation as potential disease modifying therapies is on the rise” (Source: iospress)

The way we currently conduct clinical trials is too slow.

An observer (I can’t recall who right now) once described the current system of clinical trials as being analogous to building a football stadium for just one game and then tearing it down again, before planning another stadium for a different game.

Building stadiums for a single game of football. Source: WWM

What we really need is a new way of conducting clinical trials that is more adapted to the current rapid progress of preclinical research. And this is where we come back to the idea of a Multi-Arm Multi-Stage clinical trial.


RECAP #1:  Clinical trials are long and expensive processes for determining if a new treatment is safe and effective for a particular medical condition.

The current approach to testing a new therapy is to compare it with a placebo treatment over a long period of time, and only analyse the results of the study once all of the participants have finished being evaluated.


Ok, so how is a MAMS platform going to change this?

Multi-Arm Multi-Stage (or MAMS) trials involve multiple agents being tested at the same time within a single trial. Each therapy is tested in one group (or arm) of participants. In this fashion, the MAMS design provides a quicker and ultimately cheaper option for testing new therapies than the conventional individual trial approach. But critically it requires interim analyses in order to determine which drugs are working.

Rather than waiting till the end of the study to find out whether a therapy actually work, the investigators must have the data being constantly assessed by an independent monitoring group which can tell them if an agent is demonstrating any signs of efficacy.

Source: Eupati

These regular assessments of the data as the trial is being conducted are needed so that decisions can be made about which therapies should be carried forward into Phase 3, and which should be stopped.

Below is an example of how a MAMS study could function:

Source: iospress

In the schematic provided above, 12 drugs (D1-D12) have been Phase 2 tested (or trial initiated) over the 5 year course of the study. Of these, eight have been determined to be having no effect and terminated (based on the interim analysis) while 2 (D1 and D8) have proceeded seamlessly into Phase 3 trials. Such a plan allows for 10 therapies to be Phase 2 tested in the span of 5 years.

Now compare that to the current system which tests drugs individually.

You can see why MAMS is an attractive idea.

And beyond the testing of drugs, consider all of the data about Parkinson’s that would be collected along the way (clinical, genetic, brain imaging, biomarkers, etc data could be collected from very large cohorts).

At the kick-off meeting for the EJS-ACT PD project at the Crick this week, Prof Mahesh ‘Max’ Parmar started the presentations by demonstrating a powerful example of a MAMS platform.

Prof Parmar. Source: Twitter

Prof Parmar is director of both the MRC Clinical Trials Unit and the Institute of Clinical Trials and Methodology at University College London. And he is also a really nice guy!

Prof Parmar is renowned in the world of clinical trials as he is intimately involved with the STAMPEDE trial.

What is the STAMPEDE trial?

Since opening in October 2005, the STAMPEDE trial has not only improved standard of care for prostate cancer by increasing life-expectancy, but it has also become a gold standard for researchers in other disease areas seeking to initiate MAMS trials.

The STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trial has involved more than 11,000 men with advanced prostate cancer thus far and it is still going.

Like Parkinson’s with levodopa, the main treatment for prostate cancer – long-term hormone therapy – was discovered in the middle of last century and since then there had been no new treatments for advanced prostate cancer. But since the start of STAMPEDE, the standard treatment for advanced prostate cancer (which is used in the placebo arm of STAMPEDE) has been improved 4 times (3 of those by research within the STAMPEDE trial itself!), improving the survival of men with advanced prostate cancer.

Not a bad outcome from this impressive project.

Source: ScienceDirect

The STAMPEDE study aims to continue improve standard treatment for advanced prostate cancer until at least 2030, and the EJS-ACT PD project is seeking to replicate some of this success for the treatment of Parkinson’s.

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RECAP #2:  Multi-Arm Multi-Stage (or MAMS) trials involve multiple agents being tested at the same time within a single trial. Each therapy is tested in one group (or arm) of participants. Rather than waiting until the end of the study, data collected from the study is continuously being analysed, allowing for the investigators to adapt the study as required (terminating treatments that are not working).

MAMS also allow for seamless transition between Phase 2 and Phase 3, thus speeding up the clinical trial process..

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Sounds like a good idea. Where do I sign up?

Well, the meeting this week was to initiate the EJS-ACT PD project. But there is a great deal of planning required to set up the MAMS trial platform.

And that planning process started even before the Edmund J. Safra Foundation awarded their grant. Over the last 12 months, Dr Camille Carroll (part of the EJS-ACT PD leadership) and her research team at Plymouth University have been conducting a Delphi process focused on MAMS.

Dr Camille Carroll. Source: Eurekalert

What is a Delphi process?

A Delphi process is a method for structuring a group communication process to build a consensus. It typically involves multiple rounds of questionnaires being sent to a panel of experts, and the anonymous responses are aggregated and shared with the group after each round. In this fashion, multiple points of view can help to build estimates on the likelihood and outcome of future events (such as whether a MAMS trial platform should be set up for Parkinson’s).

A Delphi process – funded by Cure Parkinson’s – was conducted to help build consensus around what a MAMS platform for Parkinson’s might look like.

The results of that process (which are being prepared for publication) were presented at the EJS-ACT PD kick off meeting and will serve as a useful resource for guiding the work groups in their efforts.

So what happened at the EJS-ACT PD kick off meeting?

At the meeting a large number of researchers and advocates gathered (safely – everyone wore face masks and we all had PCR testing for COVID-19 before the meeting). Everyone involved in part of a work group.

What are the work groups going to do?

There are 6 work groups involved with the EJS-ACT PD project:

  • Trial Design
  • Outcome Measures
  • Treatment Identification and Selection
  • Infrastructure
  • Funding and Sustainability
  • PPI Engagement

Each group is in charge of a specific part of the MAMS platform. Your truly is a keen member of the “Treatment Identification and Selection” work group. And at the meeting we had a two hour session sitting in our teams discussing various aspects of the work ahead. In the treatment identification and selection team, we discussed many of the various experimental treatments that could be considered for the MAMS platform – and these were not restricted to drug therapies (the group is open to all possibilities).

After these work group sessions, the attendees of the meeting came back together in the main conference hall and shared summaries of their discussions.

At the end of the meeting there were suggestions made during the final discussion that were quite insightful. Prof Huw Morris noted the need for an Open Science approach to the project, citing a similar philosophy is being used by the Aligning Science with Parkinson’s (ASAP) initiative (Click here to read a previous SoPD post about that project) and the related Global Parkinson’s Genetics Program (GP2).

Open science is a movement to make scientific research and its dissemination accessible to all levels of an inquiring society – making “data and other research objects discoverable, publicly available, and fully integrated into the PD data ecosystem” (Source). By making everything fully transparent and sharing new data/tools/resources, the hope is to facilitate and democratise research everywhere. There was favourable agreement regarding this from the audience at the kick off meeting and white papers are going to be produced by many of the working groups to help encourage this.

Over the next few years the working groups will focus on each aspect of the project – cross communicating with other work groups and feeding back to the steering committee of the project. The goal is for all of this effort to come together and to have the MAMS platform in a position to be conducting clinical trials.

Interesting. Has anyone ever tried MAMS for Parkinson’s before?

No, not that I am aware of.

The closest we get is the The Australian Parkinson’s Mission which is a clinical trial program built around multi arm studies, but they are not being designed to be multi stage (Click here to read a previous SoPD post on this topic).

In the first trial of the Australian Parkinson’s Mission project, 240 individuals with Parkinson’s are being recruited and randomised into four groups (3 of those groups will receive one of 3 repurposed drugs while the fourth group will be administered a placebo treatment).

Source: Eupati

Other neurodegenerative conditions are exploring MAMS platforms, particularly multiple sclerosis and motor neurone disease.

The MS Society in the UK has previously conducted a multi-arm trial – investigating 3 potentially disease modifying drugs – that was called the “MS-Secondary Progressive Multi-Arm Randomisation Trial” (or MS SMART).

The results of the MS SMART trial have now been published (Click here to read those). Despite not demonstrating a positive outcome, the MS SMART project has served as a foundation upon which the MS Society are now designing and building a clinical MAMS trial platform.

That new MAMS platform is called the Octopus.

Prof Jeremy Chataway (the lead investigator of the Octopus project) was at the EJS-ACT PD project kick off meeting and gave a presentation regarding their experience of setting up a MAMS platform, outlining the challenges and successes of their project thus far.

A second neurodegenerative MAMS platform being set up is the “Motor Neurone Disease Systematic Multi-Arm Adaptive Randomised Trial” (or MND SMART), which is being sponsored by the University of Edinburgh and funded by a collection of charitable organisations.

To aid recruitment to the MAMS platform, MND SMART is using a network set up by Scotland’s CARE-MND integrated care and research programme, which aims to integrate “clinical care, audit, research and evaluation to provide ongoing comprehensive monitoring of every person living with MND in Scotland“.

So what does it all mean?

The way we conduct clinical trials is slow and time/resource consuming.

It does not serve the Parkinson’s community or the health care system that depends of new research. Multi-Arm Multi-Stage (or MAMS) platforms represent a new way of doing clinical trials that the Parkinson’s community must explore. By conducting adaptive studies of multiple therapies, that can seamless shift from Phase 2 to Phase 3 testing, we will hopefully speed up the search for new treatments that may slow down the progression of the condition.

Thanks to a major new grant from the Edmund J. Safra Foundation, a MAMS platform is now being set up in the UK. A MAMS platform is a massive undertaking, requiring involvement at all levels across the community, and significant preparation time. It will be interesting to follow the progress of this project.

Stay tuned for updates.

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EDITOR’S NOTE: The author of this post is an employee of Cure Parkinson’s which was the funder of the Delphi process mentioned in this post and a supporter of the EJS-ACT PD project. Neither Cure Parkinson’s nor the EJS-ACT PD project leadership have asked for this post to be written. The author has written this post as he thought it might be of interest to the Parkinson’s community.

The banner for today’s post was sourced from the SoPD’s Twitter account.

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