It’s an announcement that no one foresaw, not the doctors involved in the trial, nor the patients taking part; the major clinical trial of Neridronate for Complex Regional Pain Syndrome has been immediately halted as the results aren’t showing that it has any greater effect than placebo.
Why has the trial been stopped?
To understand what that means, it’s important to explain how the trial was being conducted: the participants, who all suffer from CRPS, were randomly assigned to two different groups, one of which would receive Neridronate and the other a harmless placebo. Neither the doctors running the trial nor the participants knew which group they were in. Participants were then asked to keep a diary of their reaction to treatment: did their pain decrease, did they suffer any side effects etc. What the researchers were hoping to see was a clear difference between the groups receiving the real medicine and the group receiving placebo, showing that the Neridronate was definitely more effective in helping to calm the symptoms of CRPS. Shockingly, we’ve now discovered that the first interrogation of the data, performed at 3 months into the study, didn’t show any real difference between the two.
That means this study has failed to provide evidence that Neridronate is any more of an effective treatment for CRPS than placebo. Considering that this treatment is marketed by private doctors in Italy as an expensive ‘cure to CRPS’ and that the FDA in the US designated it a ‘breakthrough treatment’ and fast-tracked its development it’s a truly shocking revelation.
Does this mean that the medicine is a failure?
It’s an interesting question. I spoke with Dr Stuart Ratcliffe, one of the main researchers running this study, and his impression is that the medicine probably is effective. That would jibe with what I’ve heard from CRPS patients who’ve either had the treatment in Italy or have taken part in this clinical trial. After all, there are many patients who’ve paid thousands to have Neridronate infusions in Italy and many of them report that it’s definitely helped them: surely not all of them can have experienced the same high level of placebo effect?
So what could have gone wrong here?
When I spoke with Dr Ratcliffe his feeling was very much that this trial could actually be a victim of its own design. It’s notable that this crucial review of data leading to a stark Go/No Go decision on the whole trial was conducted at only three months after the first patient infusions; anecdotally, there have been patients who’ve experienced a positive effect from receiving Neridronate infusions in Italy, but they’ve only experienced this benefit around six months after they had the treatment. It could be that the positive impact researchers were expecting to see may occur in the months to come, after the trial has been shut down.
The design of the trial is crucial
It’s useful to remember that, dependent on the design of a drug trial, you can create all kinds of strange results; Dr Ratcliffe shared with me details of a trial he ran years ago, testing the efficacy of Tramadol as a painkiller for post-surgical pain. Anyone who’s taken Tramadol will likely tell you that it’s an effective painkiller; I’ve had it myself several times and it definitely worked for me, even though it’s a medicine I really dislike taking (but that’s a story for another time). Likewise, Dr Ratcliffe’s colleagues were all convinced that the trial would show that it was highly effective as they’d seen it work many times. Imagine their surprise, then, when the results came back to show that this very widely-used painkiller was no more effective than placebo as a single dose in helping with post-surgical pain. What they’d failed to account for when designing the study is that Tramadol is taken by mouth and is therefore slower acting; as a single dose it will always be beaten by anything containing 1g of Paracetamol which acts much faster.
Might they have reviewed the Neridronate trial data too soon?
The takeaway is that the test setting must be absolutely correct to show accurately how a medicine works. And it’s important to realise here that the three month data doesn’t show that Neridronate has no positive impact: it merely shows that the impact is no more positive than that of placebo. It’s entirely possible that another trial that first reviewed the data at six months might have a different result, although of course it’s equally possible that it wouldn’t. The large-scale trial of a very similar drug was halted for exactly the same reasons last year. After the immunoglobulin study back in 2016 failed too, it’s all looking a bit bleak for new treatments for CRPS sufferers.
I asked Dr Ratcliffe whether he would try to follow up with their participants after the official completion of the trial and he confirmed that he would request permission from the individuals involved to do so; let’s wait and see what happens with that. Personally, I’ve heard from a participant who’s experienced huge improvement since receiving infusions and is devastated the trial is coming to an end. I’m sure they’re not the only one.
What does this mean for the doctors providing private Neridronate infusions in Italy?
It’s an interesting question. They say they’ve treated more than 10,000 patients and make some very big claims (the following is taken verbatim from their website):
“Doctors state that Neridronate is the right path towards an actual cure. If caught on time, in 80% of cases, CRPS actually disappears and none of the patients notices a return of the symptoms after the treatment. Ninety-seven percent of patients showed much improvement after Neridronate infusions.”
It sounds completely amazing, right? The problem is though, that they haven’t published scientifically valid data to back it up. The only clinical trial data they cite is a 2012 study of 82 CRPS type 1 patients that does show impressive results and I’ve written about it at length before here. I wrote that article back in 2016 and they’ve not published anything new since then; if they’re achieving the remarkable results they claim on their website then why on earth aren’t they doing the research that would validate their approach and get this treatment fast-tracked to other countries and other patients living with this awful life-destroying disease who lack the thousands required to get to Italy for infusions? There are several potential answers to this question. The ones that interest me are a) they can’t back their data up with scientifically rigorous testing or b) they don’t want this treatment to be fast-tracked elsewhere as then they’ll lose their monopoly and stop making so much money through treating patients. I hope the truth is neither of those two, but I’ll leave it up to you to decide what you think.
So what does the future hold for CRPS sufferers?
There’s no doubt that drug companies will continue to try and create effective treatments for CRPS and we will definitely see more clinical trials in the not-so-distant future. It’s a horrible illness that is notoriously difficult to treat and, alongside the altruistic element, it could make a lot of money for the company that finds a true way to do something more than managing the symptoms. I have no problem with that financial incentive; if that motivates companies to try and find a way of reducing the hideous pain I and many others live with 24/7 then that’s just fine by me. And having spoken to the doctors in charge of this trial in the UK several times, I am entirely convinced that they are extremely committed to helping sufferers.
I don’t think Neridronate is dead in the water. It wouldn’t surprise me if we see it come back with a different trial set up in the not so distant future; maybe one where the data is initially assessed at six months. The only sticking point there is that the 2010 Italian study I mentioned earlier showed a positive benefit at only 20 days versus placebo; why hasn’t that been replicated in any of the bisphosphonate trials that have taken place since? I don’t know the answer to that, but it’s a topic I will continue to follow closely. Watch this space.