When this is all over and done with,
I will literally be able to leap out of bed.
That'll be fantastic.
It's 2012 and 42 men and women are about to take part
in one of the world's most ambitious medical trials...
See you later.
..a search for a cure for Parkinson's.
OK.
We're asking people to have experimental brain surgery.
So, we're going right posterior. Yeah.
We're asking people to have an experimental device
inserted into their heads.
We're going to drive the needles in, OK?
That's fine.
We're asking people to have an experimental drug.
We could do great harm here and we could genuinely make people
worse than they are before they started.
For the last six years,
cameras have been given unprecedented access to film
a clinical trial from start to finish.
A world first look behind the scenes of what it takes to get
a new drug to market.
From the scientists who believe they have a breakthrough
drug for Parkinson's...
I know the drug works.
It's more how do you get it in the right dose in the right place
at the right time.
..to the volunteers who put their lives on the line
for medical science.
This chance doesn't come along to many people,
to be part of a trial that could truly shift medicine.
It's a double-blind, placebo-controlled trial
where only half get the real drug and half just a placebo.
No one knows who's getting what...
..not even the doctors.
To have a huge operation like that and then have to have a placebo.
Is that human?
Not really, is it?
Why do we do it?
We want to live longer, that's the truth.
For some, there are remarkable transformations...
It was like a bloody miracle.
Look at my hands, they're just...
Look at that.
..for others disappointment and setback.
I felt something as I went in.
It felt like a vessel.
You know what? I hope he's not on the drug.
I thought I was going to die.
If this is as good as it gets, I'd be pissed off.
Could this be the miracle drug
millions of Parkinson's sufferers worldwide have been waiting for?
See you on the other side.
Tom Isaacs, now 44, was 27 years old when he was diagnosed
with Parkinson's, a disease of the brain that affects
his ability to move.
It's the world's second most common neurodegenerative condition
after Alzheimer's, with around 145,000 sufferers in the UK.
When I first was diagnosed, you wouldn't even know I had it
and it was like that for about the first five, six years.
Nowadays, everyone knows there's something going on.
Inflicting Parkinson's on someone you love is tough.
There are times when Lyndsey, I'm sure, thinks,
"What on Earth am I doing with this loser?
"He's just a shaking lump of jelly.
"What does he give me back in return?"
What do you think you give her back in return?
Good looks.
HE LAUGHS
I'm very conscious of being looked at.
People think I'm drunk.
And taxis don't pick me up sometimes because they're seeing the disease,
not the man.
It's October 2012.
The first day of the trial.
Come in. Hi, Lucy. Hello, Tom.
It's windy.
Come on through.
Thank you very much.
I'm going to ask you to complete some questionnaires. OK.
How are you feeling about the assessment?
Yeah, OK. Not too bad. Yeah?
Pretty cool. Good.
Tom is one of almost 200 people with Parkinson's
who've applied for the trial's 42 places...
PHONE RINGS
Hello. Parkinson's UK helpline, how can I help you?
..despite knowing that it involves complex brain surgery.
Oh, is it the GDNF trial that you're interested in?
This approach is novel and it's radical and I can't say
it's without risk. We've done everything we can to minimise that.
But, certainly, these are very brave people.
Steve Gill will be doing all of the surgeries,
but choosing the volunteers
is down to movement disorder specialist Alan Whone,
who's in overall charge of the trial.
The situation in Parkinson's is that we have therapies
that may help some of the symptoms, but, over time,
people relentlessly progress.
And we have no way of slowing that down and certainly no way
of reversing it and so that's a great unmet need.
What we're testing here is whether a drug called GDNF
has the potential to restore brain cells in Parkinson's.
What's your name?
That would really be a game changer for people with the second commonest
neurodegenerative condition in the world.
The £3 million trial straddles two NHS hospitals in Bristol
and is what's known as a Phase 2 trial.
It's taken almost 20 years of laboratory work and animal studies
to get GDNF this far.
Now to become a licensed treatment, GDNF must perform better
than a placebo drug in humans.
OK, so, if you look my finger... You can call me Tom, by the way.
OK, thanks, Tom. I'm Neil.
We're looking for people between 35 and 75...
You haven't got any pain in your arms and legs, have you?
Not at the moment.
..that have moderate stage Parkinson's.
That's brilliant. OK. Thank you very much.
Now, Parkinson's is a disease of older people, commonly,
but, against the public perception,
there are many people who develop Parkinson's at a young age.
If you just go across until you get to the very end, OK?
The shortlisted volunteers now face a series of tests.
Green, red, green, red, green...
These are designed to assess their Parkinson's
and to make sure they can cope, physically and psychologically,
with the demands of the trial.
Well done, you're doing really well.
I respond well to praise.
Parkinson's is a progressive neurodegenerative condition,
which means that brain cells are dying off in a relentless fashion...
One, two, three...
..in particular, types of brain cells that release a chemical
called dopamine, which is necessary to allow movement.
Keep on doing it until I say stop.
Parkinson's comes with more than about 60 different symptoms.
Movement symptoms, but on the other side, you've got lots of so-called
non-movement symptoms that include memory and thinking problems,
depression, anxiety, difficulties with sleep, problems with bladder
and bowel and so on.
So, there's four booklets to complete. Oh, OK.
So, we start with number one, two, three, four, so working
our way through them. There's quite a few.
At 72, Ron Johnson is the oldest volunteer
to be screened for the trial.
Smell the box and then if you can
shade in whether you think it's A, B, C or D, OK?
Righto.
I can put anything down?
Yeah, what you think it smells of.
Nothing. You can't smell anything at all? No.
Losing your sense of smell is often one of the first
symptoms of Parkinson's.
If the new drug works, this could be one of the abilities to return.
Oh, my, I can't smell bugger all.
A retired aircraft engineer, Ron was diagnosed nine years ago.
Grandad, you are very shaky. I am today.
That's very true.
Is it because you're worried or excited?
He used to enjoy an active lifestyle,
but Parkinson's has slowed him down a lot.
That's it, just put a blob in each.
His wife, May, has also noticed changes in his personality and mood.
The person that I married and have lived with all these years
is kind of slowly disappearing in a way.
Open that.
That's orange. Yellow.
It's hoped the new drug might reverse the cognitive decline
that's common in Parkinson's too.
Take some of this, without shaking.
And put it on top of the cake. You're the shaky one.
Just let me do one more.
The trial was something that he's chosen to do, so I'm kind
of going along with it, really.
I suppose hoping that I'd get the person back that he was.
I really would like to do it. Why?
The main reason is totally and absolutely selfish.
I just want to play football with my grandkids.
HE SNIFFS
Silly, isn't it?
Tom has been living with Parkinson's for 17 years.
It is with you every single second of every day.
It interferes with everything that people take for granted
in their lives.
Movement, eating food, writing.
You know, just simple things.
The most obvious symptoms of Parkinson's are slowness,
rigidity and tremor.
Initially on one side of the body, but, eventually, both.
Tom takes drugs that boost the amount of dopamine in his brain,
but they don't always work and can cause considerable side effects.
So, actually I've got too much movement
and it's involuntary movement which I can't control.
The longer you have Parkinson's, the worse it gets.
So, what's the best plan?
My days, there's no rhyme or reason to them.
I can spend the day in perfect harmony with my body.
Pretty rare these days.
OK. Thanks. Thanks a lot.
Or I can spend the day, seven hours, shaking on the floor.
Oh, God.
Inside our brains we've got two types of cells.
One are the neurons, which do the information processing,
and the other ones are glial cells and these are supporting
cells, but they're critically important for hardwiring
and maintaining our brains
and a key thing that they do is release growth factors.
One of these growth factors is called
glial cell-derived neurotrophic factor, GDNF.
Very shortly after it was discovered, it was seen it had
enormous potential to treat Parkinson's disease.
In the lab, it was found that at high concentrations, GDNF
could regenerate dopamine brain cells, the ones that die
in Parkinson's, affecting the ability to move.
In 2001,
Steve Gill became the first to successfully deliver a therapeutic
dose of GDNF to people with Parkinson's
using a tiny tube inserted directly into the brain.
Well, it was pretty astonishing, really.
We saw quite remarkable changes occurring quickly.
And it wasn't just in the movement of the patients and their stability,
but also in their well-being and cognitive function.
So, everything improved
and this is something that, you know, had never been seen before.
Steve's findings electrified neuroscience and in 2004, a major
drug company took GDNF on to a Phase 2 trial
with more patients.
But it was stopped early when very high doses of the drug
given to monkeys caused damage to their brains.
The drug company also reported that GDNF had performed no better
than a placebo, something all drugs must do to be licensed.
Steve Gill's treatment was dropped.
Even though it was very bad news,
I knew absolutely that this was a drug that was going to do the job.
Having seen the remarkable effects, that wasn't going to stop me
and I knew there were things wrong with the way they were doing it
and I already had in mind ways of improving the delivery
which was a critical element.
It's taken an international team of scientists seven years to resolve
the safety issues and to secure the key regulatory and ethics
approvals necessary to try GDNF in people again.
I know the drug works.
It's a matter of how do you get it in the right dose in the right
place at the right time.
From the almost 200 who have applied, the Bristol team
is now ready to offer 42 volunteers a place on the trial.
Take a seat. Come and have a seat.
Good to see you.
Good. How are you?
I'm fine.
I'm sure you've had time to reflect.
Very much so and I want to do it.
I want to go ahead and I want to do it.
OK. So, subject to the MRI scan, which is the next part, not showing
anything untoward in your brain which we're not expecting,
we'll be very happy to put you forward for the study,
if you would like to take part.
If that's what you'd like to hear.
Yes. OK.
I'm delighted. That's great.
Thank you very much. I look forward to seeing you probably next week.
I'll be here.
Thank you very much.
Thanks. Love you to bits.
Well done.
And you. Bye-bye, Ron.
I'll see you next time you come.
I'll come see you out. OK.
Come on.
Wow, it's windy.
Kay Cotton, an artist from Cornwall, is also offered a place.
This trial is so I can fight the war.
You know, I can't do other things, but I can do this.
I'm giving you my body and I want you to find the cure.
At 41, Nick Vallotton is the youngest volunteer
to be accepted onto the trial.
I went to see an osteopath in London for what I thought was a shoulder
injury and he said, "Is your writing getting smaller?"
And I said, "Yeah, it is."
And he said, "Well, small writing, stiff shoulder.
"Have you ever thought about Parkinson's?"
And this was a good two years
before I saw anybody else about the whole thing
and I just shrugged it off and went, "No."
You know? "It's not Parkinson's."
I'm in what they call my honeymoon period,
which sounds very nice.
My symptoms aren't too bad.
The drugs are working quite well.
But like all degenerative neurological conditions,
the future is quite bleak, you know.
I'm doing the trial because
if the trial does end up offering physiological benefits,
then getting those at 41
is probably better than getting them at 51.
For Tom, volunteering for the trial is the culmination of a quest
that started seven years ago.
Morning! Morning!
Yeah, I think you said the majority of the Parkinson's commentators...
In 2005, he gave up his career as a surveyor
and founded the Cure Parkinson's Trust
to lobby for a cure.
But having had Parkinson's for 17 years,
it may be too late for Tom himself to take part in the trial.
You want them to have enough symptoms
that you can see improvement, but at the same time,
not be so advanced that they have a lack of brain cells left
to actually regenerate.
Tonight, Tom is staying in a hotel in Bristol close to the hospital.
Everything now depends on one final test tomorrow.
I'm taking this pill. This is Sinemet.
It's a drug that helps me move.
And this is the last one I'm going to take of these
for the next 18 hours, I should think.
Normally, Tom would take a dose in the morning,
but the team needs to measure what his Parkinson's is like without it.
And this'll be the longest period I've not taken drugs for
for about 15 years.
So, this is going to be quite a shock, I should imagine,
as to how I'm going to feel.
INTERVIEWER: Do you have a picture in your head
of what life would be like if you get on the trial and GDNF works?
Such an emotional question, really.
I can think of so many places that I'd be.
8:00am, and it's 14 hours since Tom had any medication.
His symptoms are significantly worse than he expected.
For the first time ever, Tom has to accept a wheelchair
to get him into the hospital's photographic studio.
Here, his baseline Parkinson's will be videoed and scored.
You can look at the camera and tell us
just when you were diagnosed with the Parkinson's
and what your first symptoms were, please.
I was diagnosed in 1996.
My first symptoms were a tremor in my right hand.
Coming off their medication for patients
can be quite a shock the first time.
They don't realise how dependent on the tablets they are.
Smile.
Best I can do.
We can see just how stiff and slow they are,
which is reflective of how little dopamine
their brain cells may be making.
And then we can measure that severity
by having them do certain movements.
Well done. It does seem almost cruel
to ask people to stop their medication overnight
and then see them in distress and then see them struggling,
but at the present time, it's felt that that's the best way
of really understanding what's happening
at a movement level.
I think, though, through the screening visits -
both the outpatient screen and the inpatient screen -
we've probably been looking at you for about 30 hours,
and I can say that you're at the more severe end
of the inclusion criteria, but you fall within those criteria,
and therefore, we'd be very happy to include you,
and look forward to seeing you shortly
for the next part, which is the MRI scan.
Excellent. Very good news. Very good news. Very good news.
Thank you.
Do you have any questions about what we've spoken about?
I must say, I'm quite surprised. It's been quite a tough call cos...
Quite a tight one, but I'm delighted. Yeah.
Tom can now join the other 41 volunteers
accepted onto the trial.
All of them will repeat these tests every eight weeks,
helping the team work out how much improvement, if any,
they make during the course of the trial.
Around 1,000 clinical drugs trials take place in Britain every year,
but this one is especially controversial...
..not just because GDNF has failed before...
Open your eyes.
..but because you cannot give GDNF in a pill
or via injection into the bloodstream.
If you want to get GDNF into the brain,
you need to give it by surgical delivery -
a main line, if you like,
direct to the part of the brain where you want it to go.
In a world first, the Bristol team will implant four catheters
deep into the brains of 42 people with Parkinson's
and infuse GDNF or placebo
through a port in the side of their heads.
The device has been developed here in Gloucestershire by Steve Gill,
working with some of the world's leading medical engineers.
One of the big challenges we face
in treating neurological disease, such as Parkinson's disease,
is that there's a naturally occurring barrier
between the bloodstream and the brain,
which prevents poisons going across
from the bloodstream into the brain to protect us,
but equally, it stops many drugs going across.
So, when GDNF was discovered and shown to have
these amazing effects on restoring the function of dying nerve cells,
the next thing was how do you deliver the drug
into a deep part of the brain, which deteriorates in Parkinson's,
every month for the lifetime of the patient?
Steve's solution is to use a method called convection enhanced delivery.
This is where we push fluid through a tiny tube very, very slowly.
And if we do it just at the right flow rate,
we can start to drive the drug between the cells of the brain
and push it out over quite big volumes.
It's quite a complicated thing to do
down multiple tubes that we felt we needed to have,
and therefore we had to design completely new technology.
Every element of the device is unique,
from the 5mm port that has been 3-D printed from titanium powder
to the tiny catheters which will be inserted 8cm into the brain.
We're asking people to have experimental brain surgery,
we're asking people to have an experimental device
inserted into their heads,
and we're asking people to have an experimental drug.
We could do great harm here
and we could genuinely make people worse
than they were before they started.
One of the first to have surgery will be Chris Brownbill,
who was diagnosed with Parkinson's seven years ago.
Yeah, yeah, yeah. I'm just coming down tonight.
Chris is on his way to Bristol today.
OK, that's great. Thanks for that.
When he actually went through this trial,
it was quite a big shock to us all.
When he came back and said, "Ooh, yes,
"they've got to do this in my brain and they've got to do that,"
straight away, I thought, "No, I don't want him to do it."
I tend to do things and then worry about the consequences later.
So, basically, I got onto this trial,
so I'm doing this trial. That was it.
There was no discussion at all.
I'm all packed and ready to go, basically.
And I have to say that, you know, the girls were a bit dubious
and saying, "No, Dad, don't do it."
See you later, Abby. Good luck.
He's the one that's determined to do it.
I'm coming down with you. THEY LAUGH
See you. Bye, darling. I love you. Love you, too.
And I'll see you tomorrow. All right, good luck.
It's three days before Christmas
and the surgeries to fit the ports are about to begin.
You OK? Glamorous.
The procedure involves two general anaesthetics,
and this is the first, for an MRI scan
to map the geography of Tom's brain to submillimetre accuracy.
BEEPING
So, today, these scans are used for planning the operation tomorrow.
We want to see the location of this structure.
Steve will implant the catheters
into a walnut-sized part of Tom's brain called the putamen.
And we need to determine the trajectory, the path
by which they can travel to get there safely.
The hope is that GDNF will cause the surviving dopamine neurons
in the putamen to regrow and start producing more dopamine,
reversing the effects of Parkinson's.
It should make a big difference to them,
if we got all the bits right.
INTERVIEWER: Is that a big "if"? No.
We're going into the most vascular structure in the body.
It's got more blood vessels per cubic millimetre than anywhere else,
so it's a highly risky place to go.
Come on through.
The biggest risk from the procedure is,
when we put these catheters in, that we could hit a blood vessel,
and of course, bleeding.
And that's the biggest risk to you. OK.
And the consequence of that could be quite serious,
in terms of having a stroke, effectively. Yeah.
So, that's the biggest concern.
Then the other bits which are relevant is,
because you've got a cardiac stent... Right.
..you had cardiac problems, that, you know,
that still is there in the background,
and when you're undergoing a long anaesthetic,
you have a risk of cardiac problems relating to that.
And we've taken you off your aspirin... Yeah.
..so you have an increased risk of getting a clot.
OK. But we had to do that.
Otherwise, you'd have an increased risk of bleeding.
So, it's kind of one of those balance things.
Yeah, all right. Yeah?
All right? OK. OK. Anything you want to go through?
I can't think of anything right now, no.
It's a long day. Yeah, yeah, yeah.
But if it goes till whenever, don't worry. OK.
That's just how things work, you know. OK.
I'll try not to worry. All right, OK. See you. Thank you.
Which way? This way?
See you. OK.
NURSE: We'll look after him. Thank you.
It's all right. It's all right, darling.
We'll take good care of him. Promise. I know you will. Thank you.
Come on. Let's get you...
Do you need a cup of tea or anything?
Do you have any crowned, capped or loose teeth in the front there? No?
And when did you last eat or drink something?
Yesterday at midnight. Midnight. Smashing. OK.
Tom is taken down to surgery.
It's known that stress often makes symptoms worse.
You'll just feel slightly woozy in a minute or two.
See you on the other side. Yeah. You'll be fine.
Feeling good. It's good, isn't it?
OK. Bye.
We're fitting on a reference frame so that when we do an image,
we can effectively put a scale on to the position of the brain
within the reference frame,
and that's what we use to guide our instruments to the target.
It looks fairly gruesome, fairly medieval,
but obviously, we have to fix his head very rigidly,
if you're machining the skull or doing anything,
to ensure the whole thing is stable.
Computer software developed especially for the trial
combines the MRI scan Tom had yesterday
with a CT scan to build a 3-D image of his brain.
This is the putamen, which this software automatically detected.
And we need to...
These are our catheters that we need to deliver
into the back part.
This is the motor part of the structure,
and you can see the catheters there.
The 3-D image maps every detail of Tom's brain.
Yeah, you can see every single blood vessel that you want to avoid,
and it's quite a tangle, as you can see,
that we need to miss to hit this target.
But by having all this information,
we can determine exactly where to go.
This is our target - our deep target.
A 12cm incision along Tom's centre parting line
marks the start of the procedure.
The team has spent many months planning for the surgeries,
but it is still a leap into the unknown.
It's the first time the operation has been performed on humans.
Almost everything about the procedure is ground-breaking,
from bespoke instrumentation to the use of a surgical robot.
You wouldn't get on a jumbo jet without an autopilot.
However good the pilot was, you would not... You'd be crazy.
A robot works at very, very fine tolerances,
fractions of a millimetre, and it does it very quickly.
Guided by computer software,
the robot ensures the entry point into Tom's skull
is at exactly the right angle.
A fraction of a millimetre out and they will miss their target.
Steve drills through Tom's skull to the surface of the brain.
Right. So, that's through now.
We're now going to advance a probe - a rigid tungsten carbide probe -
down to the top of the putamen,
the part of the brain we want to treat.
The process is repeated three times
to create channels for all four catheters.
Tom then has a CT scan
to check that everything is in the right place.
So, the green outline is where our plan for the catheter was,
and the white shadow behind it is where the actual placement is.
So, the width of this is 0.6mm.
So, we've got 7mm accuracy,
which is what we were hoping for on this catheter.
Hello. I'm Dr Dunnet. I'm one of the anaesthetists. Have a seat.
Every surgery has to be planned individually...
Any loose teeth?
Here it goes.
..and each takes the best part of a day.
She'll send you off to sleep now, all right? OK.
You've done ever so well. Thank you.
The most technically demanding part of the procedure
is fixing the port into the skull behind the ear.
Firstly, it needs to be rigidly fixed to the bone,
and the bone behind the ear can be quite thin in some cases.
It needs to be very stable because we're fixing equipment to it.
And if you get it wrong, there's a risk of infection,
and that could be potentially life-threatening
if it tracks into the brain.
A wash here, please.
After seven hours of prep,
the time has come to implant the device.
So, we're going right posterior.
The catheters are fed down the four channels created earlier
and secured into place.
Big wash, please.
Neil, can you put the port itself in there?
The final part of the procedure
is to seat the port in the hole created earlier.
It connects to the catheters via a line fed under the scalp.
Tom, how are you feeling?
Well, I'm alive.
You're alive. You survived it all.
It all went very well, actually, so we're all very pleased.
INTERVIEWER: Can you tell how you're feeling or not?
Elation. Pure, massive elation.
That went really well, actually.
You've just got to get the juice now. Yeah. Yeah?
All right. Anyway, I think you're going to head back to the ward now.
Oh, by the way, what's that tattoo?
The one item that I'm missing in my putamen - dopamine.
Is it really? Is that what it is?
It just feels a bit numb at the moment.
Yeah, and that's quite normal, as well. All right?
I didn't know whether I could do it or not, to tell you the truth.
And I did it.
Can you grip my fingers? Bryn? Bryn?
Grip my fingers. Hard. Harder than that.
Well done. Let go.
Because he's had an operation on his brain,
we need to make sure that his cognitive function
is returning to normal,
so we ask fairly standard questions just to see how aware he is.
HE GROANS
People say to me, "Are you nervous? Are you frightened?" I'm not.
This chance doesn't come along to many people
to be part of a trial that could truly shift medicine.
Bryn Williams lives with his family in Glasgow.
He was diagnosed with Parkinson's six years ago at the age of 36.
Hold on.
He still has a good quality of life...
Sore foot. Sore foot. Bye-bye. Bye-bye.
..but today, paralysing cramps stop him from walking.
See you later.
I don't want to be encased in concrete,
trembling away, unable to function, having to be cleaned
and all that sort of carry-on.
That will not happen.
Whatever has to happen to stop that happening,
my girls will not see me do that.
Every fight I have with Parkinson's,
I'm fighting it because I want to be there for my little girls
and I want to walk them down the aisle
and I want to deliver a speech at the wedding.
After six hours in the operating theatre,
Bryn's wife Vicky has come to see him.
Hello. Hello. How are you? You've changed.
SHE LAUGHS
You haven't really. No. How have you been?
I'm good. How are you? Ah, I'm OK.
I was only out for two minutes. Were you?! Mm-hm.
So, it's all a big farce? Yeah. Was it?
Well, you've got a dirty big bandage on your head, so...
Oh, no! SHE LAUGHS
Nine of the 42 volunteers have had surgery,
and all have gone smoothly so far.
Soon, the drug infusions will begin
with no-one knowing who's getting GDNF
and who's receiving the placebo.
But first, the skin needs to heal and seal around their new ports.
Six weeks post-op and Tom's port must still be cleaned daily.
INTERVIEWER: How sore is it, Tom? Erm, on a scale of one to ten,
it's about 11, but I can take it.
Yeah. You don't normally feel anything.
I can't actually feel a thing. I'm just going to hold your head.
It's a pity I don't have a bit more hair, really.
You actually said you wanted me to get a toupee.
We thought maybe just a piece of hair,
like a well-done wig, that went around the hair,
like, the bottom part, so it looked like your own hair.
But I think your hair's going to grow over it
cos it's already kind of coming down over it.
So, as soon as the graft is all healed,
I think you won't notice it, actually.
I resisted the toupee idea.
BOTH LAUGH
Tom's scars are healing, but since the surgery,
he's been struggling with his Parkinson's symptoms.
The nights, I think, have been the worst bit.
Isn't it, Tom? Yeah. Basically, you've had to get me out of bed. Mm.
And I haven't been able to move in bed and...
It's the first time I've felt like your carer...
Sorry. For God's sake!
..not your wife. I've been your carer.
It's just been really hard. Really hard.
Cos I like to be your wife, not your carer.
But anyway...
SHE LAUGHS
Yeah, that must be quite tough, actually.
The infusions are prepared to order
in sterile conditions in the hospital's pharmacy.
Volunteers have been randomised by a computer
to receive either GDNF or a placebo fluid...
..and only one person knows who'll be receiving what.
Clearly, the pharmacist has to know what they're putting in the tubing,
so the pharmacist knows.
But outside of the pharmacy,
the staff giving the drug and the patients are blinded.
They don't know whether they're having the active drug
or the placebo.
It's March 2013.
We thought if we sat you in that chair...
It's taken three months for the skin around Tom's port to heal.
So, I'm going to start by cleaning the port.
Today, the port will be opened for the first of ten monthly infusions
of either GDNF or placebo.
Each infusion will take two hours.
The volunteers will stay on their normal
Parkinson's medication throughout
as they couldn't function without it.
Fingers crossed for me, people.
Yeah, it's a huge day.
OK. So, I'm just going to hold your head slightly firmly
just to prop that on, OK?
This week, we got quite upbeat, actually.
I think we both did. Yeah?
Certainly, I've been feeling really positive that this is it now.
Hopefully, it's GDNF. DOCTOR: That's right. Well done.
I'm just going to pop in the applications.
MACHINE BEEPS That's in.
Very well done.
Very good. Good. And relax.
THEY LAUGH
It works! You can go now. HE LAUGHS
For everyone... I can retire!
..the first few infusions go without a hitch.
Yes, but it was that thing, wasn't it? That thing, yeah.
And it was across there
and we felt like we were being interrogated.
Inevitably, speculation begins about who's on the drug
and who's on the placebo.
Oh, I do so hope he doesn't have the placebo.
I think that's a cruel, cruel thing to have a huge operation like that
and then have to have a placebo.
Is that human? Not really, is it?
Simply the effect of going to see the doctor
may begin to make you feel better,
particularly if the patient has some sense or hope
that that's going to be the case.
And on the whole, the more you're doing to patients,
the more they may anticipate benefit.
Have you ever seen him down? TOM'S WIFE: Probably once or twice.
So, if you're putting them forward for brain surgery
and then putting a port behind their ear
and then infusing them every four weeks,
the levels of anticipation may be pretty high at that stage.
Steve's original study didn't have a placebo group,
leaving it vulnerable to claims that it was belief in the treatment
rather than a true biological effect that led to improvements.
The patients look heaps better.
That said, I do genuinely believe
that that level of response could have been a placebo effect.
And so, although it may seem cruel to put people through brain surgery
and then have half of them have to have dummy,
there isn't really another way of deciding
if one is genuinely better than simply giving distilled water.
The volunteers settle into a rhythm of monthly hospital visits,
infusions and endless assessments.
I'm going to shine a light in your eye.
Everything is documented, from minor colds and headaches
to changes in sleep patterns or mood.
Do you want to do it at the present time, as well?
Well, the present time would be the same. Yeah.
Good at that.
The scale of the record-keeping is somewhat mind-blowing.
You end up with a room full of documentation,
and it's literally thousands and thousands of pieces of data.
Nine months since the start of the trial,
and after six infusions, Tom can run without any medication.
Feels like fluid again.
It feels like a pharmaceutically manufactured version of me.
Feels like the real me.
Yeah, I do think it's new. It's really exciting.
Tom's sleeping longer.
He's not requiring me to get him out of bed at night-time any more,
which he was requiring up until about a month ago.
Go on, get it!
And it's little things in the morning,
like he can move his hands, so that's really positive.
There are signs that others might be improving, too.
It'll be amazing - amazing -
to just have that freedom of choice, to...
..not be contained by it, cos it contains you.
It's December 2013,
and Chris Brownbill returns to the hospital
for an infusion and MRI scan.
During the scan, he feels unwell.
He makes it back to the clinic room afterwards,
but the medical team can tell that something is wrong.
Do you want to go through and take a seat?
What was immediately obvious, as he came through the door,
was that one side of his face was drooping.
Immediately, Chris undergoes an urgent neurological examination.
Here, we have an MRI scan cut across the brain like this,
and here, these little black holes are the tubes or catheters,
and what you're seeing around this back catheter
is this bright area,
which is suggestive of a stroke having occurred.
Chris recovers.
Well, I'm a lot better than I was.
I was quite a mess, really, both emotionally and physically.
So, it's a big improvement,
and that's why I'm feeling better within myself
because I can feel myself coming back
from quite a dark place, really.
Suddenly, there's a great unknown that puts the whole project at risk.
To date, we've only given
a relatively small number of infusions
compared with the more than 1,000
that are going to be given by the end of the study.
And so we just don't know whether this is something
we're going to keep seeing or whether it's a freak and a one-off.
And then another disaster.
Lying in bed, I rolled over onto my left side and the...
..port came loose.
I heard a crack in my ear.
Bryn becomes the first of five patients
whose ports fail to bond with the bone.
To create a seal around the base of the port,
it needs to be immobile. As soon as it starts moving,
then the skin's going to be breaking away from the port.
Then infection can travel along all the tubing
and get into the brain,
and that would be potentially a life-threatening problem.
Steve heads back to the engineers in Gloucestershire
to try and find a fix as fast as possible.
The wobbly ports and Chris's stroke
are what are known as serious adverse events.
They trigger the involvement of an independent off-site committee
whose primary concern is patient safety.
15 months since the start, the trial is stopped.
We have to understand, before we put this into anyone else,
why these events have occurred
and if it's safe and reasonable to carry on.
If the trial doesn't get going again,
the patients will have to go through further surgery
to remove their ports.
We could go to the seaside. And what else could we do?
This is the reality of certain clinical trials
that carry significant risks - that you may not get to the end.
And people have to understand that at the beginning.
Chris Brownbill's port is taken out.
It's too risky for him to continue...
That's healed nice, hasn't it? Yeah, the port site. Really nice.
..and he is taken off the trial.
I just read the happy script.
I expected to go for the trial,
get the GDNF, improve. That was my scenario.
I didn't see any other scenario than that.
Parkinson's - it's something that you know you're going to get worse
so your natural instinct is to face it.
There's nothing going to stop me trying to get rid of this condition.
But after today, I hope that we can just perhaps
get on with our lives a little bit.
Yeah.
Following weeks of discussion
and with no other incidents during an infusion,
the independent monitors conclude that Chris's stroke
is probably a one-off
and decide it's safe to restart the trial.
And the engineers have devised a fix for the wobbly ports.
Can you push me?
It means more surgery for Bryn.
A year ago this week,
Ella decided she wanted to go to see One Direction,
and she made me buy tickets.
I was going to have to go to One Direction tonight in Edinburgh.
I hate them. They're a racket. Just noise. Talentless gimps.
And I've got out of it cos of this trial...
..and she'll never, ever speak to me again.
But you know what? It's worth it.
Well, you can see it's quite wobbly, that port.
Our rescue device is a cylinder into which the old port sits.
OK.
Oh!
The cylinder has stabilisers that are anchored into the bone
so that the port can't move.
HE GROANS Nice, deep breaths, Bryn.
The way of fixing the port in is much more robust.
It'll probably go on changing a bit more.
It's just unfortunate there are people
who have to go through all they have,
as well as going through their suffering at the other end.
Morning. Morning.
After an eight-month hiatus,
the trial can now get back under way.
So, that's hopefully good news,
but obviously, I'm aware that things could still go wrong along the way.
Take a seat through to our waiting room.
It's just round here on the right-hand side.
Right, thank you. Cheers.
Somewhere in Southmead Hospital,
there's a vial with a liquid in it
which is going to go into my brain today.
If it works, I'll be a dad for the rest of my life.
If it doesn't work, I'll not be a dad worth having.
Metal. Yeah. To go at the end.
With the trial back on track,
the guessing game about who is and isn't getting the real drug
begins in earnest.
Look how well the trees are doing.
They've got so big. Lean this against that.
Pass me the hammer a minute.
Yeah, last night, it took me about 15 minutes
to unbutton my shirt when I got home.
Oh, there it is. There it is.
After five infusions,
Nick is convinced he's on the placebo.
His last assessment reveals no improvement
since he started the trial.
I'm hopeful.
I don't know. Sometimes, I think I'm clutching at straws,
but at the other end of the scale,
Bristol Southmead and all these people
wouldn't have thrown three million quid at this project.
They've done their homework.
Watch the little stream.
Can we drink the water? Mm, I wouldn't.
Why? Well, cos sometimes there's badger poo in it.
Ron Johnson has also had five infusions.
His tremors seem to have gotten worse.
And also he was very sharp-minded, you know, whereas now it's very...
..slow and sometimes quite confused.
If this is as good as it gets,
if the ultimate is what I'm going through every day...
..I'd be pissed off.
In Cornwall, Kaye is convinced her infusions are working.
The first thing that happened was I could smell.
I've started to get my smell back.
I can smell all kinds of subtleties now.
But the first thing that I smelled was my dog
who was...
He broke wind and I'm like, "Oh, what on Earth is that?"
My mum was there and she said, "What?"
I said, "What was that smell?" She said, "You can't smell."
I said, "I certainly smelled that."
Bryn also notices a difference.
Our problem was writing clearly.
Other patients are reporting improvements, too.
Some of the patients do seem to be getting better,
and whilst that's encouraging, I'm also very aware
that it could be a placebo-type response.
Nevertheless, if nobody seemed to be doing anything,
then the chances of seeing a difference, of course,
would be much lower.
In September 2014, almost two years
since the start of the trial,
the biggest pharmaceutical company in the world
decides to invest in GDNF and the Bristol delivery system.
They're taking an option out early, that if it is positive,
they've got first dibs on going forward
into a Phase 3 study.
Because of the costs of those Phase 3 studies,
even if we're successful and we show the drug works,
without that backing, it wouldn't go forward anyway,
so it makes the whole thing more meaningful.
That's about as good as it gets.
You know, this is the biggest drug company in the world.
They have all the resources, and if they are keen
to take a completely novel form of therapy forward,
that's a major advance.
The stakes are high.
The scientific community is watching.
More than ever, everything depends on the outcome of the trial.
Got to say, I feel great.
I feel really good.
Still as you like.
Come on!
Yes! Yes!
The trial is now almost at the halfway mark,
with the future of millions of people worldwide
resting on what happens next.
Yes!
Next time, the trial enters its second phase,
and everyone receives the GDNF drug.
I'm going to get this stuff.
There are extraordinary transformations.
It was like a bloody miracle.
Look at my hands. You know, they're just...
Look at that.
But there is desperation, too. HE GROANS
I thought I was going to die.
Finally, after five years...
So, here we go, eh?
..we find out if the drug works
and if GDNF is the breakthrough the world has been waiting for.
This programme contains some strong language
No qualms about going ahead? Too late now!
In 2012, a remarkable medical trial began in Bristol.
And I'll see you tomorrow.
42 volunteers have had surgery
to implant a titanium port in their skulls...
So, we're going right posterior.
..to deliver a new drug deep into their brains.
Going to drive the needles in, OK? That's fine.
The hope is that it will reverse Parkinson's -
the world's second most common neurodegenerative disorder.
We could do great harm here
and we could genuinely make people worse than they are
before they started.
It's a double blind, placebo control trial...
Screw your eyes up really tight.
..which means for nine months, half have been getting the real drug
and half a dummy drug.
I'm going to put the needles in.
Now at the halfway point,
all the volunteers start to receive the real drug...
I'm going to get this stuff.
..for the next nine months.
It didn't seem ethical to put people through having brain surgery,
having the device inserted,
without ever having the prospect of the drug.
For some, there are remarkable transformations...
The more I'm doing it, the more I'm smiling.
I'm thinking, "This ain't real. This ain't real."
And now he's back!
For others, disappointment and setback.
I felt something as I went in. It was felt like a vessel.
Shoot.
Lying there, I thought I was going to die.
Finally...
So, here we go, eh?
..after five years, we find out if the drug works...
We needed to see a 20% difference between the treated group
with GDNF versus the placebo group.
..and if GDNF is the breakthrough the world has been waiting for.
Right, and back.
The amazing thing to me is in my hands.
See? No tremor.
Well, very little tremor.
This is my hand that usually tremors a lot.
My smile's coming back.
I can taste things better.
I can go for a whole day without having a nap.
It might not seem much to you but it's a lot to me.
It's summer 2015 -
two and a half years since 42 men and women from across the UK
signed up for one of the most extraordinary clinical trials
the world has ever seen.
Going to drive the needles in, OK?
They're helping to test a new drug called GDNF
that could be the first to reverse Parkinson's -
a movement disorder one in 39 of us is destined to get.
The trial is now at the halfway point and the picture is mixed.
I hope to God that I am on the placebo.
Because...so far, I don't feel any real difference.
Just feeling crap and disabled, and non-functioning,
and I hate it.
I think it's certainly the case that we're not seeing people
turning up and saying, "I've thrown away my tablets."
So we're not seeing that magnitude of benefit or change.
But there seems to be enough improvement in some
that there may be a significant difference between the two groups.
Blimey!
For the past nine months,
the volunteers have been having monthly infusions
through a port implanted into their head
at the start of the trial.
Every two months, they are filmed
attempting a series of movement tasks
to see if they've improved.
Smile at the camera.
Screw your eyes up really tight.
So far, no-one knows if they're getting the real drug or a placebo.
Now, everything's about to change.
So we're now at the end of the first nine months where patients,
both on the placebo and the GDNF, move over,
so that everybody receives active drug for the next nine months.
DOG BARKS
In the first few months of the trial, Tom Isaacs was convinced
he was on the real drug and getting better.
Now, he thinks he's been on the placebo.
Do you know what? I hope he's not on the drug...
..because... It's worse. Yeah. Made me worse.
..it's made him worse.
Compared to this time last year before for the surgery,
I'd say I'm 20% to 30% worse than I was at that time.
Really, really, it's been the year from hell.
The assessments, where the volunteers are taken off
their regular meds, to expose their baseline Parkinson's...
Go.
..capture the change in Tom since the start of the trial.
That's it, Tom.
You want to go down or do you want...? Yeah. Go down. Yeah.
And again.
INTERVIEWER: If you could wind back the clock 12 months,
would you still embark on this trial? Yes. Of course.
Yes. Yes. It's a no-brainer, that one, isn't it?
In Parkinson's disease, there's a disconnect
between your decision to do something
and your ability to do it,
so you can't actually drive your motor system.
And it's down to a progressive loss of nerve cells -
they're involved in planning and executing movements.
The drugs currently available for Parkinson's work well
in the early years...
..but over time they become less effective...
..and they eventually cause serious side effects...
If I can get it on me...
..including uncontrollable movement called dyskinesia.
For Jeff Tottle, a maintenance man and gardener from Somerset...
..it makes earning a living very difficult.
Jeff is now at the end of the first half of the trial.
I honestly think I'm on the placebo...
..cos I'm no different whatsoever.
As the disease progresses, nothing really touches
some of the key symptoms of Parkinson's disease...
..and this is what ultimately has a major impact
on people's quality of life.
INTERVIEWER: Do you allow yourself to think about the future
if it doesn't work?
No.
I don't go as far down the road as that.
For the volunteers who think they've been on placebo
during the first half of the trial,
the start of the second nine months offers fresh hope.
Is it?
I'm going to get the stuff, I'm going to get better...
..and everything's going to be rosy
and I might even buy my wife some flowers. Woohoo!
It doesn't get much better than that.
Hello. Hiya. Hello. How are you? How are you? Are you well?
It's my first definite infusion of real thing.
Are you nervous? Mmm. Yes. Are you? Well, no.
Father-of-two Bryn Williams is also convinced he's been on placebo
since the start of the trial.
Today's a day of mixed emotion cos there's excitement...
..but there's fear that it won't work for me.
But there's no other show in town...
All right, Bryn.
..so I'm kind of banking on it.
The pencil sharpener noise now.
My mum died when I was 14...
..and I don't remember her as an adult.
I only remember her as a child.
I remember her as a mum, not as a person...
Go for 400 now. 400?
..and I want my girls to know me as a grown-up...
All right, Bryn. We're off.
..as a normal grown-up.
I can feel a warm tingling on my neck - that feels different.
Maybe I'm making it up, I don't know. I don't know!
She wouldn't tell me.
No-one will find out what they were on in the first nine months
until the end of the trial.
You don't want to artificially affect
how they feel in the second nine months
by letting them know what they were on in the first nine months.
They might have a heightened placebo response at that point
and generally it's better to keep the whole thing a secret
until you've collected all of your outcomes.
You know, I wanted to be a nun when I was younger.
Mind you, then I discovered that the shoes weren't very nice...
..or the uniform.
As before, the volunteers come for monthly infusions.
And once every two months,
they're assessed off their conventional meds to see
if there's been any improvement in their baseline Parkinson's.
The role of the second nine months is to fulfil an obligation
set at the start of the trial by an independent ethics committee,
whose job it is to decide what's reasonable to ask volunteers to do.
It didn't seem ethical to put people through having brain surgery,
having the device inserted,
without ever having the prospect of the drug.
The second half of the trial
will also provide longer term safety and efficacy data.
OK, and look directly at the camera and smile, please.
They told me from day one,
"Don't read into things."
And frown.
"Don't try and analyse it."
And relax. Screw your eyes up really tight.
So I haven't.
And clench your teeth, please.
Volunteer Darren was diagnosed with Parkinson's 11 years ago.
The lack of expression in his face
is a typical feature of the condition.
I look like somebody who has got a disability, which I don't like.
Ready? Go.
It's like I'm trapped in my own body
and I'm desperate to get out.
That's what it feels like.
I just think I've got this for a reason.
I believe you've got to have trials.
OK. All right?
I want to make a difference for somebody.
If it's not me, I want to make a difference for somebody else.
Darren thinks he was on placebo in the first half of the trial.
This is his fourth infusion of GDNF
since the start of the second nine months.
Something's happening.
I don't know what. I'm not reading into it,
but something is definitely happening.
Up... CAT MEOWS
..down, up, down, up, down,
and the more I'm doing it,
the more I'm smiling.
I'm thinking, "This ain't real. This ain't real."
And then I go downstairs and I start screaming to Jane,
"Come and see this. Come and see this." And she's going,
"What's the matter with you? What's the matter with you?
She got up and I said, "You've got to film this. This is unbelievable."
And now he's back!
Oh, dear.
I never expected none of this.
I never seen it coming.
That's pretty well amazing.
To be honest with you, it scared me a little bit.
INTERVIEWER: When was the last time you felt like that?
Before I had Parkinson's.
He's previously been quite guarded,
suddenly seems to have gone to the other end,
that he really feels this is a sort of dramatic response,
Lazarus type moment, and that he may be becoming free of Parkinson's.
Good morning. It's 6:30, would you believe?
He is now on 50% less medication
than he was on when he commenced on the double blind part of the trial.
And Darren has got me up to film him putting his socks on.
Can you believe this?
Unbelievable.
I just want to share these magic moments with her
and I think it is magic moments,
and just...just may it continue.
It seems to be starting.
A couple of things happened.
One, I just feel better, I've got a sense of wellbeing about me
and people say I'm looking better,
people say my voice sounds stronger.
One of the nurses independently said,
"Your facial expression has returned."
Can you give us a big smile?
And relax.
Can you frown?
Is this the light at the end of the tunnel?
Is this the beginning of the end?
And last of all, can you clench your teeth?
It's just awesome.
It is just awesome.
Look at my hands, you know, they're just...
I can type that, I've got dexterity
and I can throw darts right-handed to a fashion.
Not a fashion that's going to win me anything
but a fashion that keeps the wall safe.
That's not bad.
People send me up to the bar now to get drinks.
It's, er...
..a real downside, actually, that.
Going to the bar to get drinks,
that's a real downside of being cured.
It's now a year since pharmaceutical giant Pfizer expressed interest
in GDNF and the Bristol delivery system.
The support of a major drug company is critical
if GDNF is to become a licensed treatment
available to everyone with Parkinson's.
That's because it costs millions
to do the further larger scale trials
required by the drug regulatory bodies.
Pfizer will also want to know which of Parkinson's many symptoms
the drug may help...
..including the depression and cognitive decline
evident in patients like Ron Johnson.
Ron struggled in the first half of the trial.
Some days, I just...
I just don't understand what happens.
I do everything the same...
..but Parky kicks the hell out of me.
Ron has now had seven infusions of GDNF.
When I first had Parkinson's, everything was uphill.
Now it's not.
You'll need to do it from the beginning, won't you?
Can you do it from your end?
It's made him more positive.
He's more there, more present.
What I mean is, you need to tie a knot in the string between them.
I think it will be all right once it's up.
It's a good life, basically.
And I think the GDNF has made a huge difference.
On a good day, I can do anything.
I really can.
WHIRRING
That was a good one.
Oh, God. Are you all right? Yeah.
It's just hit on your scar.
What scar? "What scar?"
Your scalp thing.
Where they took my brain out? Yeah.
INTERVIEWER: Would you have been tackling the kitchen
a couple of years ago?
No way.
Absolutely no way.
Make a mess of it now, but...
It's December 2015...
..and the first volunteers to join the trial
are nearing the end of the second nine months.
There's now such optimism about GDNF's future
that Alan writes to invite them to continue their infusions
until everyone has completed their 18 months.
For some, it means several more infusions
than originally planned...
I'd like you to try and stand up out of the chair
without using your arms.
..but there is no miracle yet for Tom.
Go.
Can you push off your arms at the side?
Push up from both arms of the chair, OK?
This morning I had my assessment...
..and couldn't walk.
It led to...
No?
..today I felt that
people are taking decisions away from me,
which were really mine to make.
The thing that I can't stand about this condition is
if it takes away control of my own life...
..it's, er...
..it's very tough to justify your existence.
Ready? Both, is it? Yep, at the same time. Ready, steady, go.
I can't take much more of this.
It sucks.
I don't like this disease.
Parkinson's is caused by the progressive death of cells
in the brain that produce a chemical called dopamine.
In the lab and in animal studies,
GDNF has been shown to regrow these cells...
OK, so it's just a little step just here, mind that one.
..but Tom has now had Parkinson's for 20 years...
..and it might simply be that it's too late.
But there's one other possibility.
Are you all right? I'm very well. How are you?
Tom is taken for an MRI scan and it shows that very little GDNF
is getting to the putamen -
the area of the brain they're trying to treat...
..but it's not because of a problem in Tom's brain...
..it's the delivery device.
Nobody's ever tried to deliver drugs in this way repeatedly
in somebody with a disease
where they're moving their brain around all the time.
So we're learning as we're going along.
As one of the first to have surgery,
Tom has an early version of the device
that delivers GDNF to the brain.
Steve now has a new version -
one that will ensure that more drug reaches
and stays in the right place.
Tom is offered the new device.
To go through all that again is a very big undertaking for him,
but I think this is the only choice he has -
either he goes for this opportunity or he comes out of the trial.
I'm crazy, going back for surgery again.
Why have I got such belief in this man, Steven Gill?
I've just got a bad feeling that...
..sort of, what'll happen if I have the surgery again?
Something bad is going to happen...
..but I can't tell Lindsay that.
Just to go through why we're doing this.
The catheters that you've got at the moment a relatively vertical.
I think, because of your dyskinesia,
what happens is, the brain is moving around like this,
the catheters are also moving
and that's causing reflux.
What we have done in the interim is develop a new catheter
which performs completely differently.
And you've tried it in people who have dyskinesia? Yes. Right.
Yeah. And we put it in...
As bad as mine is?
Now that would be challenging. HE LAUGHS
Charming!
And in Tom's scan, is there anything different from the first one?
Did you not...? No, I'm just impressed by the amount
of grey matter that you have. Fantastic.
TOM CHUCKLES
See you later.
I think this will be absolutely the right thing to do.
One way or another, you absolutely have to get him right,
as best as we can.
So now, if we just bring him around this way and we can put him
on the table that way.
So, on this? Yeah. Just one point.
The new kit will be put in via the back of Tom's head,
yet another refinement.
First, the old kit has to come out through the top of Tom's head.
Later.
On ten, is it?
Yes, cutting around.
The ones we've just looked at are very good.
The procedure requires sub-millimetre accuracy.
Have you got a swab I could use, please?
Just got one more to put in.
The target is in a deep part of the brain
where hitting a major blood vessel could be fatal.
Yep, and now go that way.
After six hours, a portable CT scanner is brought in to check
that the four new catheters are in exactly the right place.
Why are we so deep?
Shoot.
The scan shows clearly that one of the catheters
has veered off target.
Oh, there it is. Yeah, you can see it there. Yeah, yeah.
Flicked about there. Yeah.
Just flicked up. That's...
That's... I think...
I think I felt something as I went in.
It felt like a vessel and there are some vessels there.
Let's have a look at this here.
Some vessels there, look. Mmm.
And that's why it's deflected off.
I hit the side of a vessel.
It's so tight, it's like a slalom.
So one is working in very, very tight area.
Look at that.
It's a major vessel in the neck that obviously could cause major
disability or could be fatal.
I mean, worst case scenario.
These are the old catheters and they had a very short trajectory
which went just down to here.
So they were about a third of the length of these very long catheters
which will now fill this whole structure up.
Tom has been in surgery for nine hours.
Can you do that?
Yeah. Yeah, perfect.
Can you wiggle your toes for me?
Have you got any pain anywhere?
We kind of blased into this one.
Having been through it already, we thought it was going to be OK
and, er...
..unfortunately Tom had quite severe post-operative complications.
To put the catheter in from the back of the head,
you have to have the patient operated on face down.
If they're there for many hours, particularly if you have,
as in Tom's case, you had to take out the old system,
so that's a big operation its own right.
And then put it in a completely new system,
it's many hours with him on his face,
and during that time, because he was quite flexed,
the intubation tube caused pressure effects inside his throat.
And so, when he woke up, he had a swollen tongue.
He had difficulty breathing and he got very distressed.
He's having a really tough time at the moment and...
..it's incredibly hard on both of us.
I will. You will.
This last little session that I've been through
has been the most appalling.
I thought I was going to die.
But I just had faith in this treatment, in the team.
Even if I'm not cured, I will strike a happy medium somewhere.
I've got nothing to fear any more.
I can deal with this silly illness,
whatever it throws at me,
as long as... The only thing I ask is I need to be able to communicate.
We always get stronger in times like this.
I think it brings us together.
INTERVIEWER: Does there come a point where you say,
"Enough is enough"?
Maybe, but not yet. Not yet.
Absolutely not.
Does that feel all right, Tom?
Yeah, that's fine. Yeah?
This port is 100% better than the original.
I cannot actually believe...
..how...
..they've managed to perfect this in such a short time,
but the first time Tom had this done, it took...
..erm, six weeks to heal.
How does it feel?
Can you feel anything on it, Tom? No, can't feel anything.
The only problem is, it's on my starboard side. Right.
Three weeks later, Tom resumes his infusions.
There are now just a few weeks of the trial to go.
The impression I'm getting is that more people are improving.
And that's perhaps not surprising,
given that everybody's now on the active drug.
Don't eat too much. We're having dinner in an hour and a half.
Who's your favourite daughter?
Favourite daughter?
You're in the top two.
And people who appear to be improving
during the first nine months are potentially improving
yet further still in the second nine months.
In Cornwall, volunteer Kay Cotton
is convinced she's been on the real thing since the start.
My Parkinson's was in my left-hand side.
I said "was" in my life-hand side cos that's what it feels like now.
Both sides feel as loose as each other
and I couldn't do this before, I hope I can do it now!
Ready, steady, go.
It's volunteer Vicky Dillon's final assessment of the trial.
And it's a revelation.
It was like...
I was almost better off my meds the longer I went on.
I can't explain it and we can't get our heads round it,
but it was like a bloody miracle!
It's not just yesterday.
The amount of people who come to me and tell me that I look better...
I know I'm better! There's no doubt in my mind.
It's now three years since Tom Isaacs started on the trial.
Despite many setbacks, his faith in the Bristol team
and in GDNF has been unshakeable.
22nd of July,
2015.
Here we are again in Bristol.
And what is happening tomorrow is another off assessment.
My second off assessment since my second bout of surgery.
And I'm hoping...
..there might be a bit of something to show for my efforts.
The date you were diagnosed on your first symptom.
I was diagnosed in 1996,
and my first symptom was a tremor in my right hand.
I've got this...
Just a little part of me
is hoping that something wonderful is going to happen.
Ready, steady, go.
Compared to when he was assessed off his regular meds four months ago...
..Tom is 50% better.
Last time I did the off assessment,
I couldn't even start the walk of death.
No.
Tomorrow, I've got a chance
I'll be able to make it
and if I do make it, it's going to be an eureka moment.
Go.
Come on! Come on!
Do this thing!
Yes!
Well done!
Love Alan,
love Steve,
love Lucy, love them all.
And when they make me better,
when they make all of us better...
..we'll have a big party
and I'm going to get very, very drunk!
July 2016.
It's now 23 years since a researcher in America put GDNF
onto a dying dopamine brain cell...
..and saw it come back to life.
It's 15 years since Steve Gill first tried the drug in humans.
And 12 years since GDNF was dropped
after a failed trial in 2004.
The drug's future and the future for the millions of people
worldwide with Parkinson's hangs in the balance.
It's results day.
Afternoon. Hello.
Big day. Very big day.
Yes.
And I'm just really relieved we've got to the point of having
the answer for the first nine months,
so that's terrific that we've got to the point,
knowing what the result is - the data will be the data.
But I'm very pleased to be here, so...
The CEO of the small bio-tech company that has
the patent on GDNF has flown in from Canada.
Erich Mohr has put millions of dollars of his own
money into the venture.
I feel good.
I mean, you know, obviously, I'm an optimist,
so hopefully, on behalf of the ten million patients, which is the
most important part, we had success today, but science will be science.
And you don't have any idea what the results are? I do not.
And you're still able to be that optimistic? I am.
Famous last words!
INDISTINCT
Mr Mohr.
Big day today. Big day, yup.
The trial steering committee includes scientists,
the medical team, engineers,
and representatives from the charities that funded the trial.
To remind you,
we needed to see a 20% difference at the end of the study
between the treated group with GDNF versus the placebo group,
so there needed to be a 20% difference and that's what
we needed to reach, statistical significance, at a group level.
And the answer is...
..that sadly we did not meet the primary endpoint.
Everybody in the room was in a state of shock. Couldn't speak.
That's how bad it was.
I've never been in any environment where that's happened like that
because there was such expectation.
It was the end of hope, I think.
That's how it felt.
Not only for me, but for the ten million or so individuals who
suffer from Parkinson's disease, this is a huge disappointment.
But it is perhaps an important reminder why
we do clinical trials the way we do them, so that they're not
done on hunches or guesses, but on objective measures.
The group on GDNF did do better than those in the placebo group...
..but it needed to be by 20%
to be considered statistically significant.
And it was only by 6%.
In other words,
the improvement could have been down to chance alone.
We hadn't just slightly missed, we'd missed by a country mile,
in statistical terms.
The negative result almost certainly means
it's the end of the road for GDNF.
It falls to Alan to tell the volunteers, via a conference call.
Now, before I go on, what I wanted to say first
was a massive thank you,
on behalf of all the trial team here, to you the participants.
We could not have done this without you.
However, unfortunately,
there was not a statistically significant improvement
in people receiving GDNF
compared to those receiving placebo at the nine month point
in their motor scores,
when assessed off regular Parkinson's medication.
I know that comes as a disappointment.
I'm going to say more now.
The group who received GDNF did not significantly do better than
the group who received placebo on this measure,
by significance we mean a statistically significant effect.
We know that individuals,
they have felt they did better to a greater or lesser extent.
I'd love to be able to talk to each of you face to face right now.
You are all incredibly dear to me.
I'm enormously grateful for what you've taken part in.
I still think it's been worth doing.
And I don't, myself,
regret a day that I've spent working on this trial.
And I wish everybody luck, including all the trial team...
Bollocks.
That is...
..slightly disappointing.
It's had a huge impact on all of us.
I just think...
..has it even been worth it?
Better start applying for my blue badge.
And, um...
..looking out for a fucking bungalow.
We know that patients said they felt better,
but we weren't able to prove it against placebo and what that means
is we haven't shown benefit, we haven't proved it, it's not enough.
But then, a more in-depth look at the data reveals some anomalies.
The trial failed because, overall,
the volunteers on GDNF didn't perform significantly better
than those on placebo when off their regular Parkinson's meds.
This is what's called the primary outcome measure.
Every trial has one and it's the measure by which the overall
success of trials are judged.
But the GDNF trial recorded much more than just movement scores.
I can do that. I'm used to shuffling!
In particular, at the start of the trial
and again after nine months, all the volunteers had a scan which
measured the amount of dopamine in their brains.
We've started scanning, OK? Just keep really still, all right?
What we see in patients prior to the trial
is that there's insufficient dopamine
in these deeper structures in the brain
and that's what we'd see generally in people with Parkinson's disease.
PET scans use a radioactive tracer to measure
the amount of dopamine nerve endings in the brain.
After nine months, those who'd been on placebo showed no change.
And then, they looked at the PET scans of those who'd been on GDNF.
Having delivered GDNF to these patients,
we've seen that signal throughout the whole of that structure
increase, by 100%.
So, that's a large effect.
The nerve endings in the putamen part of the brain have regenerated.
Whilst that doesn't mean those nerves were working well,
it does mean there was some biological response.
So, now, we've got to work out why, despite that good delivery,
achieving that biological effect, we didn't bring through a large
enough clinical benefit to see statistical significance.
The team then looks in detail at who was and wasn't on placebo.
Today, after almost three years of waiting,
I've finally come to see Alan to find out
if I was on the placebo or GDNF and to get my results.
Nick did not think he was any better at the end of the first
half of the trial
and is pretty sure he was on placebo.
So, for the first nine months, in fact, you were on placebo. OK.
Fine. OK?
In fact, there weren't many surprises.
Bryn, who had not felt better at the end of the first nine months...
I'm expecting my assessment to show my continual decline through
the first half the trial. ..was also on placebo.
I honestly think I'm on the placebo.
I haven't felt no different whatsoever.
And so was Jeff.
Vicki, who improved from the start, was on GDNF.
And so... See? No tremor. ..was Kay.
Well, very little tremor. This is my hand that usually tremors a lot.
But Ron, who was fed up in the first nine months...
If this is as good as it gets, I'll be pissed off.
..was on the real drug from the start.
Tom got significantly worse in the first nine months,
despite being on GDNF all along.
Come on! But by the end of the trial... Do this thing!
..Tom's scores were back to what they'd
been at the start of the trial, four years previously.
Potentially significant... Yes!
..because Parkinson's gets worse over time.
The higher the score, the more severe the problem. OK.
The natural course of the condition means that Nick's movement
scores should be about 3% worse than at the start of the trial.
So, you've improved by 66%... Wow!
..in your off scores by the end... Wow!
That's quite... That's quite amazing!
You know that natural progression will be about two points per year.
Four of the 41 patients who finished
the trial did not get better overall.
But Ron's motor scores improved by 11% by the end of the trial.
Bryn's by 20%.
And bring them into your chest.
And Kay was 23% better. Further apart.
And forward.
Overall, Jeff's motor scores stayed much the same,
but his walking was three times better by the end of the trial.
Darren improved across the board, by 50%.
And by the end of the trial,
Vicki had improved by more than 60%.
By the time we get to the end of the second nine months,
the average improvement was between, overall,
a moderate to a large clinical effect.
Pfizer's interest was contingent on the first nine months
being a success.
But the secondary findings are enough to keep them at the table.
Hopes rise that the volunteers could resume infusions
as part of a longer-term study.
And so everything seems to be moving gradually, gradually towards,
you know, a phase three study.
In March 2017, there's an event in Bristol
to mark the end of the trial.
It brings all the volunteers together for the first time.
Some of the Parkinson's assessments
of the trial were certainly ridiculous.
One of the questions I was asked was,
"Over the past few weeks, have you been more or less indecisive?"
To which there is only one answer - "I'm not sure."
LAUGHTER
I am here today to tell you, first of all, thank you from the bottom
of our hearts that you have embarked on this mission.
This quest, by the way, many people have likened to
a manned mission to Mars.
Well, folks, you are the travellers.
And you were the ones who had the courage, the foresight
and, really, the selflessness to say,
"Yes, I am going to volunteer for this mission and I do not know
"what's on the other side."
We do not know what Pfizer will do, but we will leave no stone unturned
until we succeed, because succeed we must
on behalf of the ten million-odd Parkinson's sufferers in the world.
So, thank you, and God bless.
After five years, 42 ground-breaking surgeries
and over 1,000 infusions
the £3 million trial is over...
..and everything now depends on what Pfizer does next.
Three months after the event,
Tom wakes up in the middle of the night, in pain.
About four o'clock in the morning, on the Wednesday morning, Tom...
SHE SOBS
He woke up, shouting.
And I said, Tom I need to call an ambulance."
And he said, "No, I'm OK."
And I said, "You're not OK."
He was doing all sorts of jokes with this lovely lady paramedic
and I thought, "Oh, OK, you're not too bad."
And then, his head had gone down and he wasn't responding.
And I was just sort of saying, "Tom, Tom,"
and he wasn't responding to me,
and they got him on a chair thing
and took him downstairs, shut the doors of the van
and started to work on him.
And I can remember sitting on the steps with the door open,
watching it, thinking, "You don't die.
"Tom, you don't... What?"
Cos I could hear the defib being zapped
and you could see the movement of them doing CPR in the van.
Tom is taken to hospital...
..where he's pronounced dead.
One of the paramedics came up to me and said,
"He wouldn't have known anything."
He didn't know a thing. So that's a nice way to go.
His mother said, when she came to see him,
that she'd forgotten that he could be still.
Cos he moved around so much near the end.
A postmortem reveals that Tom died of myocarditis,
a heart condition unrelated to Tom's Parkinson's,
or the trial, that can kill without warning.
It was a total shock, and awful...
..cos Thomas is so central to everything we've done.
And, you know, he drove me on and he was a friend
and I loved his company.
You know, I loved being with him and so on.
It was, without doubt, the worst point, for me,
of the whole experience.
I would have liked to have...
..done better for him.
So...
I know he had a tough time through the whole thing.
HE SIGHS
Yeah.
But first, news that the pharmaceutical giant Pfizer
has pulled out of research into neurodegenerative diseases
like Alzheimer's and Parkinson's.
In January 2018, Pfizer announces it's closing its
neuroscience research division.
The volunteers are told the company has dropped GDNF.
In reality, progress has been worryingly slow.
Over the last 15 years,
nearly every trial into new treatments has ended in failure.
And Pfizer's unlikely to be the only company to say, "Enough is enough."
The medical world, the scientific world, the Parkinson's world
has just written it off as if we're a load of idiots
who've just been done over.
And I want to scream, because I know this stuff works.
And I keep hearing Tom's voice all the time - all the time -
in my ear, going, "Go on, Vicki. Go on. Do something."
I don't quite know what to do,
I don't know quite how I'm going to do it...
..but I sure as hell know I'm not going to just sit here
and do nothing, and lay down and bloody die.
I found it incredible.
And they, just with a sweep of a pen, get rid of a whole division.
Pfizer maintains the move will ultimately benefit neuroscience
by freeing up money to invest in other companies'
more successful research efforts.
Of course, there have to be commercial decisions.
But, you know, this is a big one.
The impact is huge on everybody here.
We all put our necks on the line to prove, one way or another,
whether GDNF worked or not.
And here we are, five years later,
with bits of metal and plastic in our brains.
And we don't know.
The greatest thing the trial provided me was hope.
And that's...
..gone.
Why do WE do it?
We want to live longer.
That's the truth.
They do it for money.
I've got to got to the clinic again.
VOICEOVER: I'm willing to sacrifice.
You're not.
You just want to be paid.
It felt as if we were part
of something really, really ground-breaking.
But, you know, that's all come to an end.
VOICEOVER: It's as if you're of no consequence,
got no say in it at all.
After all the time and effort that people put into it.
It's now two years since Nick had his last infusion.
Almost all the volunteers want GDNF back.
But the trial results leave the scientific world divided.
Lamb's-ears.
The improvements in the second nine months could have been down
to a long-lasting placebo effect
and it's the second time GDNF has failed in a high-profile trial.
It's been eaten a bit by the caterpillar.
DR WHONE: It wouldn't be the first drug that's failed
in clinical trials and then come good, by any means.
Just give us a tug, Albert.
Oh, yeah, sure.
Often, it is a question of having to go at something a number
of times, and each time you refine the way you do it and how you do
it and to whom you do it. And, eventually, you may get there.
Yee-haw!
Although you do have to make a decision sometimes
that this, for whatever reason, isn't going to work
and you're better off putting your efforts into another area.
INDISTINCT
I know the drug works.
So where do we go from here?
It has to be a dose issue.
SHE LAUGHS
We've got ginger ones, chocolate ones,
mint chocolate ones...
New toxicology data suggests
it would be safe to increase the dose fourfold.
And we're busy trying to wave the Parkie flag,
cos we need the money for research.
So, if you'd like to buy a tombola ticket, they're a quid.
MedGenesis is now trying to raise the money needed
for a phase three trial.
Both the US and European drug regulatory bodies
say they would welcome an application for a further trial
if the money can be raised.
I'm hopeful that MedGenesis will raise the money
short shrift and we'll be back on track.
Every hour, two people in the UK are diagnosed with Parkinson's.
That is only going to progress.
Being a part of the GDNF trial
was so inspiring and gave Tom huge hope, huge hope for the future.
This has only been impossible by enormous courage of the patients.
We now have a means of safely delivering drugs into the brain.
So the contribution that everybody's made to just taking the technology
forward will have a huge effect on so many people in the future.
All the time, when you're doing clinical research,
as long as you do it well, you can learn something
and it's a bit like putting another brick in the wall.
And, eventually, something will give.
These diseases aren't just bad for the people that have them
they're very difficult and damaging to families and friends.
And you either accept that and say, "Well, that's the status quo,
"we can't do any more," or we have to keep trying.