Eliminate Placebos To Encourage Participation

[jimcaster]

After thousands of double blind studies making use of placebos to determine whether a particular drug or treatment is effective, it seems that there should be an objective way to determine how "effective" placebos typically are for Parkinson's patients. It seems to me that trial participation would increase dramatically if everyone was assured that they were receiving the active ingredient being trialed. There are several trials which are enticing, but the prospect of having a 33% chance of receiving nothing but a placebo dampens my enthusiasm greatly. Drugs or treatments being trialed should be compared against a mean or average placebo response and it shouldn't have to be examined over and over and over again. What do you think?

[LagLag37]

I agree.

[Drummer67]

You would think it would speed up the process which would be positive

[kevowpd]

What has previously occurred to me is having one placebo arm for a whole load of treatment arms. So instead of needing a placebo arm per trial, you can test 4 different treatments of similar nature (say, a pill) against one placebo pill arm.

The challenge is probably getting the treatments lined up at the same time and figuring out who is paying for what. Yet another reason for public funding, maybe.

I don't agree with abolishing it all-together for the simple reason that we lack objective measurements of progression or even symptom severity. You really need the same trial coordinators measuring placebo and the treatment arms to eliminate differences in measurement approaches.

I think the two biggest obstacles to participation are:

- a lack of national/international coordination as to who has been diagnosed and when (Im not aware of any national PD databases that are complete or close to it); and

- PD fatigue.

Not much to be done about the second but the first should be manageable.

[Stillstandingstill in reply to kevowpd]

Look up the EJS ACT-PD trial. Supposedly recruiting this year here in the UK but also a model they hope to roll out to other countries.

[park_bear]

The usual way of dealing with this is with an open label extension where everybody gets to partake of the test drug. No placebos at all would be insufficient evidence because Parkinson's is subject to the placebo effect.

[jimcaster in reply to park_bear]

I agree that the drug or treatment being tested to be compared with a placebo. I just thought by now we'd know what the typical response to a placebo is so we don't have to keep wasting time and money. Especially for trials when people undergo sham surgeries, it inhibits my desire to participate.

[Raphaekg in reply to jimcaster]

Placebo responses are not fixed. Surgery may have a bigger placebo effect than a medication. Exotic handling of a drug (see Laurie Mischley's trial on intranasal glutathione, where the placebo effect was more powerful than the active drug effect: content.iospress.com/articl... or patient procedures can lead to larger placebo effects. Mishley also reports on the % of patients getting active vs placebo drug who thought that they were getting active drug. I wish that more placebo-effect trials did this, since patients inherently try to 'break the blind' and guess correctly whether they were getting placebo or not.

It also irritates me when I see results from new pharma trials where a "new" drug is a variant of an existing drug: the FDA only requires that the new drug is tested against placebo. A more clinically relevant question is whether the "new" drug is better than an existing drug for which the new drug is a variant. For example, I don't care to know whether Gocovri or Osmolex ER --both extended release forms of Amantadine-- are better than placebo in reducing Off Times or dyskinesias. I want to know whether they are better than generic Amantadine. This is especially important for patient information, since patented drugs are extremely expensive.

[House2]

Placebo is the sacred cow of mainstream medicine. There is a contrarian thought that instead of placeo being a factual "thing" it is merely an artifact of scientific studies. How could that be? Well if 100 members in this group charted our symptoms every day for 30 days, and we looked at the symptom scores, we'd see some us had our symptoms increase, others would fluctuate downward, and many would stay the same. This is merely chance fluctuation of symptoms that is common in members of groups with similar diagnosis.

Now let's take 50 of us and give us a placebo pill (we are blinded,meaning we don't know we got the sugar pill). The other lucky dogs got the real deal (ParkAway tm). Same 30 day diary.

What do we hope to find? Well if ParkAway really does cure PD, we expect to see many more improved diaries in group taking the drug when compared to the group taking the placebo. We find 40/50 people taking ParkAway record improvement. Those of us taking the placebo, not so much-only 20 out of 50.

Yeah, twice the number of people taking ParkAway got better than those taking placebo, Yippie!! We have found a cure!

Now let's take a look at the little blue placebo pill. Wow pretty strong placebo effect. Twenty people taking the placebo pill were made better by the amazing power of the placebo. That's why you always need to control for people getting better by placebo treatment. (Spoiler Alert)

Hey I wonder what would happen if we compared the diaries we all did while we were waiting to start the actual study (often called the waiting list group, intent to treat group or simply, the no treatment at all group)?

Amazingly, there were 18 diaries that showed improvement in the group that received "no treatment at all, not ParkAway and not placebo" while they were anxiously waiting on the waiting list.

ParkAway 40 improved meaningful improvement over placebo

Placebo 20 improved meaningless improvement over no treatment

No Treatment 18 improved placebo does not exist and produces no clinical benefit

Moral of the story, with the possible exception of pain relief, there is no evidence that placebo treatments produce objective improvements that are meaningful.

Very long story short, skip the placebo and test the treatment against "waiting list" "intention to treat scores."

Melt down from members with a science degree in 3..2..1 😀

[Bolt_Upright]

Great point Jim! They should have different treatments in each arm.

I posted this 2 years ago: Professor Thomas Borody Interview: Comments on Trial Designs and Ethics of Clinical Trials healthunlocked.com/cure-par...

Dr Borody, as most of us know, is the Godfather of FMT (and a genius). The first 6 minutes of this interview are dynamite, but I set it to start at 5:50 to queue up something I think is very important: The idea that a single substance is going to cure a complex condition is not likely, and also that having placebo arms for fatal diseases is immoral.

youtu.be/POfIMGS2D6A?t=350(Not working as expected?)

[Buckholt]

If the only way to measure whether a drug has worked, is through careful statistical analysis , then I would say for most of us it’s not the one! Maybe I’m being too optimistic, but surely what we are hoping for is a treatment where the improvement in condition is so noticeable, so obvious that you don’t need any clever maths to tell you that you feeling better, doing better!

[kevowpd in reply to Buckholt]

If a treatment stopped your progression altogether (by blocking further protein aggregation or something) but had no impact on your current symptoms, i suspect you would still want it even though the fact that it's 'working' would not be at all obvious to you in the fashion you describe.

[CuriousMe12]

It's crazy that success/failure is judged on a 20% cut off between placebo and actual.

This bbc video of an expensive GDNF trial shows some excellent results but failed next stage due to the 20% barrier

youtu.be/u7zwRNyRz24?si=xEu...(Not working as expected?)

It also raises a question in my mind as to whether theres a nocebo effect ie if a patient negatively starts to think they're on placebo ( even if they're on the real thing) could they effect what might have been a more positive outcome ?

[House2 in reply to CuriousMe12]

That’s why you need objective not subjective outcomes.

[CuriousMe12 in reply to House2]

It's why they need to be open and flexible to successful outcomes and not bin a good approach because it doesn't fit a predefined formulae

[MBAnderson]

JIm,

What are the trials that entice you?

[jimcaster in reply to MBAnderson]

The Glutamic Acid Decarboxylase Gene Transfer trial for one...

[MBAnderson in reply to jimcaster]

Looks good, but I'm not eligible because I don't take PD drugs.

(At Yale and U of Mich only)

[Boscoejean in reply to MBAnderson]

My husband was refused for participation in one clinical trial because he did not take Parkinsons medication and another one because of taking macuna for a couple months with compounded carbidopa with no levodopa since they did not want anyone who had taken any kind of medication for more than 28 days. This is the new clinical trial that seems to be aimed at halting or at least slowing progression.

classic.clinicaltrials.gov/...

He was refused for the Oregon glove study due to being in a clinical trial in Texas that is done this month even though some people will not start this study until February. He has his last visit for the clinical trial which is just a physical on January 30th. We believe he was in the placebo group.

It has been a bit frustrating that at every turn there is some way to exclude a person from something that has the potential to be very helpful.

[MBAnderson in reply to Boscoejean]

Yeah, I'm pretty dissatisfied with the rules of clinical trials.

[Smittybear7]

I agree.

[Ctime]

JimCaster,

I agree, it does seem that there is more that could be done with modern data analysis tools as well as wearables to reduce the # of placebo controls needed, or in cases like Ambroxol or Terazosin and other approved medications, eliminate the need for long studies by just analyzing existing data.

At the risk of sounding tedious though, I think the odds of getting something that is going to fix an individual's case of Parkinson's by participating in clinical trials is really quite small anyway. Probability of Success (POS) of a new drug targeting the central nervous system from Phase 2 to approval is only 20% according to this study academic.oup.com/biostatist...

Then there is the drug to availability delays, open label delays, dosage, plus odds of placebo, blah blah, and it is truly unlikely that a pill that a participant gets in Phase 2 that might be disease modifying is going to help them that much faster.

I suppose though that Stem Cell and sham surgery are a whole different calculus because it really could be a one and done cure.

When I was first diagnosed, I joined a support group and the leader/facilitator was a big fan of medical trial. He stressed that he got involved for 2 reasons. Volunteering is the only way TO MOVE THE WHOLE PROCESS ALONG FASTER and typically a good way to get better personal care though more visits with care providers.

It works for me. Starting the next gig a week from tomorrow!

Onward.

Charles

[LAJ12345]

with hubby’s permission I do n= 1 trials of various things without telling him he is trying something new, then watch for any change in behaviours.

He seems unable to tell himself if he is feeling better as he never seems to remember how he was feeling. I watch for signs of improvement like he starts folding washing, he empties dishwasher, he starts playing music, in particular welsh football crowds singing hymns for some reason. Also he starts booking holidays and looking for concerts to go to and starts saying yes when I suggest doing something.

By not telling him he is trying something new I can put him on something then remove it again to see what happens.

Not sure what kind of trial that is.

[Zella23]

I wrote a post earlier on here about Rory Cellan-Jones, a U.K. journalist who now has PD, visiting the Francis Crick Institute in London

He was interviewing Dr Sonia Ghandi a Neuroscientist who leads the Francis Crick Institute neurodegeneration laboratory as well as being a leading Neurologist at the hospital my husband attends.

It’s an interesting read about her innovative ideas as regards drugs trials. Let’s hope they come to fruition.

healthunlocked.com/cure-par....

[MBAnderson in reply to Zella23]

Dr. Gandhi has the same thinking as Jim C.

"... the idea is to build a multi-arm system with many drugs being tested at once. “You have one control , and four or five drug arms. You run them all together and then you do what's called an interim analysis and anything that's not positive you just drop out and take on a new drug." There are no gaps and the trial machinery remains in place."

[Stillstandingstill in reply to MBAnderson]

They are hopefully recruiting this year. UK at first but a model that could be used more widely.

[House2]

Placebo interventions are often claimed to substantially improve patient-reported and observer-reported outcomes in many clinical conditions, but most reports on effects of placebos are based on studies that have not randomised patients to placebo or no treatment. Two previous versions of this review from 2001 and 2004 found that placebo interventions in general did not have clinically important effects.

[adding additional studies published from 2004 to 2010 the authors concluded...]

Conclusions: We did not find that placebo interventions have important clinical effects in general. However, in certain settings placebo interventions can influence patient-reported outcomes, especially pain and nausea,

pubmed.ncbi.nlm.nih.gov/200...

[Manypony]

my gloves trial was 4 months long. I was told 2 months would be placebo. I’ve heard the new gloves trial is 8 months long! 4 months placebo! Geesh! I can attest the gloves helped even in the first generation, there has to be a more humane approach to testing helpful technology.

[Despe]

If and when I read/hear that the silver bullet is found, then I will get the silver bullet, Jim. I will pay in GOLD, silver is cheaper.

[skybluepink]

Have you considered unfocussed ultrasound if not too late ,it can be expensive but can have amzing results .