As the age of personalised medicine approaches, innovative researchers are rethinking the way we conduct clinical studies. “Rethinking” in radical ways – think: individualised clinical trials!
One obvious question is: Can you really conduct a clinical trial involving just one participant?
In this post, we will look at some of the ideas and evaluate the strengths and weaknesses these approaches.
A Nobel prize medal. Source: Motley
In the annals of Nobel prize history, there are a couple winners that stands out for their shear….um, well,…audacity.
One example in particular, was the award given to physician Dr Werner Forssmann. In 1956, Andre Cournand, Dickinson Richards and Forssmann were awarded the Nobel Prize in Physiology or Medicine “for their discoveries concerning heart catheterisation and pathological changes in the circulatory system”. Forssmann was responsible for the first part (heart catheterisation).
In 1929, at the age of 25, Forssmann performed the first human cardiac catheterisation – that is a procedure that involves inserting a thin, flexible tube directly into the heart via an artery (usually in the arm, leg or neck). It is a very common procedure performed on a daily basis in any hospital today. But in 1929, it was revolutionary. And the audacious aspect of this feat was that Forssmann performed the procedure on himself!
And if you think that is too crazy to be true, please read on.
But be warned: this particular story gets really bonkers.
Today there was a lot of Parkinson’s related activity in the news… well, more than usual at least.
Overnight there was the publication of a blood test for Parkinson’s disease, which looks very sensitive. And this afternoon, Acorda Therapeutics announced positive data for their phase three trial.
In this post, we’ll look at what it all means.
Blood cells. Source: Reference.com
Today we found out about an interesting new study from scientists at Lund University (Sweden), where they are developing a test that can differentiate between different types of Parkinsonisms (See our last post about this) using a simple blood test.
We have previously reported about an Australian research group working on a blood test for Parkinson’s disease, but they had not determined whether their test could differentiate between different kinds of neurodegenerative conditions (such as Alzheimer’s disease). And this is where the Swedish study has gone one step further…
Title: Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder
Authors: Hansson O, Janelidze S, Hall S, Magdalinou N, Lees AJ, Andreasson U, Norgren N, Linder J, Forsgren L, Constantinescu R, Zetterberg H, Blennow K, & For the Swedish BioFINDER study
Journal: Neurology, Published online before print February 8, 2017
PMID: N/A (This article is OPEN ACCESS if you would like to read it)
The research group in Lund had previously demonstrated that they could differentiate between people with Parkinson’s disease and other types of Parkinsonism to an accuracy of 93% (Click here to read more on this). That is a pretty impressive success rate – equal to basic clinical diagnostic success rates (click here for more on this).
The difference was demonstrated in the levels of a particular protein, neurofilament light chain (or Nfl). NfL is a scaffolding protein, important to the cytoskeleton of neurons. Thus when cells die and break up, Nfl could be released. This would explain the rise in Nfl following injury to the brain. Other groups (in Germany and Switzerland) have also recently published data suggesting that Nfl could be a good biomarker of disease progression (Click here to read more on this).
There was just one problem: that success rate we were talking about above, it required cerebrospinal fluid. That’s the liquid surrounding your brain and spinal cord, which can only be accessed via a lumbar puncture – a painful and difficult to perform procedure.
Lumbar puncture. Source: Lymphomas Assoc.
Not a popular idea.
This led the Swedish researchers to test a more user friendly approach: blood.
In the current study, the researchers took blood samples from three sets of subjects:
- A Lund set (278 people, including 171 people with Parkinson’s disease (PD), 30 people with Multiple system atrophy (MSA), 19 people with Progressive Supranuclear Palsy (PSP), 5 people with corticobasal syndrome (CBS), and 53 people who were neurologically healthy (controls).
- A London set (117 people, including 20 people with PD, 30 people with MSA, 29 people with PSP, 12 people with CBS, and 26 neurologically healthy controls
- An early disease set (109 people, including 53 people with PD, 28 people with MSA, 22 people with PSP, 6 people with CBS). All of the early disease set had a disease duration less than 3 years.
When the researchers looked at the levels of NfL in blood, they found that they could distinguish between people with PD and people with PSP, MSA, and CBS with an accuracy of 80-90% – again a very impressive number!
One curious aspect of this finding, however, is that the levels of Nfl in people with PD are very similar to controls. So while this protein could be used to differentiate between PD and other Parkinsonisms, it may not be a great diagnostic aid for determining PD verses non-PD/healthy control.
In addition, what could the difference in levels of Nfl between PD and other Parkinsonisms tell us about the diseases themselves? Does PD have less cell death, or a more controlled and orderly cell death (such as apoptosis) than the other Parkinsonisms? These are questions that can be examined in follow up work.
Like we said at the top, it’s been a busy day for Parkinson’s disease: Good news today for Acorda Therapeutics, Inc.
They announced positive Phase 3 clinical trial results for their inhalable L-dopa treatment, called CVT-301, which demonstrated a statistically significant improvement in motor function in people with Parkinson’s disease experiencing OFF periods.
We have previously discussed the technology and the idea behind this approach to treating Parkinson’s disease (Click here for that post).
The ARCUS inhalation technology. Source: ParkinsonsLife
Basically, the inhaler contains capsules of L-dopa, which are designed to break open so that the powder can escape. By sucking on the inhaler (see image below), the open capsule starts spinning, releasing the levodopa into the air and subsequently into the lungs. The lungs allow for quicker access to the blood system and thus, the L-dopa can get to the brain faster. This approach will be particularly useful for people with Parkinson’s disease who have trouble swallowing pills/tablets – a common issue.
The Phase 3, double-blind, placebo-controlled clinical trial evaluated the efficacy and safety of CVT-301 when compared with a placebo in people with Parkinson’s disease who experience motor fluctuations (OFF periods). There were a total of 339 study participants, who were randomised and received either CVT-301 or placebo. Participants self-administered the treatment (up to five times daily) for 12 weeks.
The results were determined by assessment of motor score, as measured by the unified Parkinson’s disease rating scale III (UPDRS III) which measures Parkinson’s motor impairment. The primary endpoint of the study was the amount of change in UPDRS motor score at Week 12 at 30 minutes post-treatment. The change in score for CVT-301 was -9.83 compared to -5.91 for placebo (p=0.009). A negative score indicates an improvement in overall motor ability, suggesting that CVT-301 significantly improved motor score.
The company will next release 12-month data from these studies in the next few months, and then plans to file a New Drug Application (NDA) with the Food and Drug Administration (FDA) in the United States by the middle of the year and file a Marketing Authorization Application (MAA) in Europe by the end of 2017. This timeline will depend on some long-term safety studies – the amount of L-dopa used in these inhalers is very high and the company needs to be sure that this is not having any adverse effects.
All going well we will see the L-dopa inhaler reaching the clinic soon.
The banner for today’s post was sourced from the Huffington Post
Last week there was a press release from La Trobe University in Melbourne, Australia regarding the development of a new blood test for Parkinson’s disease. The announcement is a little bit odd as the results of the study are still being peer-reviewed (press announcements usually come after the publication of results). But the Parkinson’s community is excited by the idea of new diagnostic aids, especially those that can maybe tell us something new about the disease.
In this post, we will review what we know at present, and we will follow up this post once the results are eventually published.
As we have previously written, the diagnosis of Parkinson’s is rather difficult, with a 10-15% error rate becoming apparent when brains are analysed at the postmortem stage. Thus any new diagnostic tools/tests that can aid in this effort would be greatly appreciated.
A group at La Trobe University in Melbourne have been studying the blood of people with neurodegenerative conditions, and have now announced that they may have a blood test for Parkinson’s disease.
The La Trobe University team: (left to right) Professor Paul Fisher, Dr Sarah Annesley and Dr Danuta Loesch-Mdzewska. Source: La trobe
So what do we know thus far?
The test has been conducted on blood taken from a total of 38 people (29 people with Parkinson’s disease and 9 in a control group). Professor Paul Fisher – one of the lead scientists in the study – has reported that the tests have proven ‘very reliable’.
What does the test measure?
The test is apparently looking at the mitochondria in the blood cells.
And what are mitochondria?
A mitochondrion (singular) is a small structure inside a cell that is responsible for respiration and energy production. It is one of the powerhouses of the cell. Cells have lots of mitochondria (plural) because cells need lots of energy. But when the mitochondria start failing, the cell dies. As the mitochondria fails, they send out toxic chemical signals that tell the cell to begin shutting down.
A schematic of a mitochondria, and where they are inside a cell. Source: Shmoop
The researchers at La Trobe found in their blood tests that there was no damage to the mitochondria of patients with Parkinson’s disease. That in itself is an interesting observation, but what they found next has larger implications:
“Based on the current literature we were expecting reduced oxygen consumption in the mitochondria, which leads to a buildup of toxic byproducts, but what we saw was the exact opposite,” Prof Fisher was quoted as saying. “We were able to show the mitochondria were perfectly normal but were working four times as hard, which also leads to increased production of poisonous byproducts to occur.”
A test that can measure these ‘hyperactive’ mitochondria is very useful as it can both identify people with Parkinson’s disease, but it may also help us to better understand the condition. Prof Fisher and his colleagues, in addition to taking the test forward, are also trying to understand the underlying mechanisms of the ‘hyperactive mitochondria’ – what is causing them to become the way they are.
What is going to happen now?
The scientists at La Trobe would like to repeat and expand on the results (after they are published), and the Michael J Fox foundation and Shake It Up Australia have given La Trobe University more than $640,000 to further develop the research. The plan is to now test 100 subjects – 70 people with Parkinson’s disease and a control group of 30. Prof Fisher is hoping that a test may be available for the clinic in five years time.
What about other neurodegenerative conditions?
So here’s the catch with the information provided thus far – the researchers have not had the funding to test whether this hyperactivity in the mitochondria is occurring exclusively in people with Parkinson’s. That is to say, they haven’t tested whether the effect is also present in people with other neurodegenerative diseases, such as Alzheimer’s, Huntington’s, or ALS. And this is where a little bit of the excitement comes out of the announcement.
But even if the hyperactivity in the mitochondria is shared between certain neurodegenerative diseases, a test highlighting the effect would still be very useful, especially if it can aid us in early detection of these conditions.
As we said above, we will be following this story closely and will report back here as and when information becomes available.