Guest post: will the COMBAT-MS study disrupt the MS market?

You may be aware that people living with MS in resource-poor environments are often not treated with disease-modifying therapies. To address this we have been promoting a Barts-MS Essential Off-label list of DMTsThe problem with this list is that it is often not backed by a so-called 'class 1 evidence'. 

To address this lack of evidence, trials such as COMBAT-MS are being performed to provide data from real-life practice to support off-label prescribing. We are therefore privileged to have a guest post from the team running the COMBAT-MS trial explaining what the trial is about.


We keep getting at least one new approved MS disease-modifying drug per year. You might think this would help tailor therapy to individual needs. Unfortunately, this doesn't really seem to be the case. Patients are switching therapies now more than ever. MS experts can't seem to agree which drug is the best even for the same types of patients. Treatment practices vary widely, not only across countries but all the way down to regions, clinics and even individual doctors. Perhaps the most important cause of these wide variations in care is the lack of long-term real-world data. 

Loads of money has been invested into randomized clinical trials and they are really important. However, randomized controlled trials don't give the whole picture. These trials are conducted over a relatively short period of time, in mostly treatment-naive patients who are otherwise healthy and do not want to get pregnant. The drugs are usually compared only to placebo rather than to the other drugs patients have to choose from. These studies also do not consider patient-reported outcomes like quality of life. 

In the real world, many patients don't fit this picture. They may have tried other therapies before, have health issues other than MS, want to get pregnant soon and/or (of course) value the impact the drug may have on their quality of life (QoL). Short of a cure, they desire a highly effective treatment, that is reasonably safe and well-tolerated even if they need to take it for decades. Unfortunately, we can´t rely on the pharmaceutical industry to support us in answering these questions. And academic registry-based studies have inherent weaknesses that prevent them from satisfactorily addressing these issues. 

Aside from a prohibitively expense and complex randomized controlled trial, is there a middle way? Yes, perhaps. The US federally-funded Patient-Centered Outcomes Research Institute (PCORI) last year gave a big award to a US-Swedish initiative for a hybrid study between a traditional retrospective cohort and a structured, prospective cohort study. Sweden has a nationwide MS registry which includes >90% of patients and nearly complete information on MS drugs used, physical disability outcomes and the ability to link to national health registries to detect major safety signals. However, much of the other key variables like patient-reported outcomes and MRI data have over 20% missing data, which would make effects of treatments on these outcomes difficult to interpret. Therefore, a prospective trial (COMBAT-MS; NCT03193866) has recently launched. 

We aim to recruit up to 3,700 MS patients at all of Sweden´s seven university clinics (serving about 50% of the total population) who are starting their first MS therapy or switching therapies. By doing the same structured follow-ups with annual disability scorings, MRIs and patient-reported QoL outcomes the study will generate high quality, real-world long-term efficacy outcomes. This will help us sort out which drugs work or don’t work so well in real-world MS patients. To address safety concerns, we will obtain data from Swedish national healthcare registries, as well as from Kaiser Permanente Southern California. By combining these resources, we will be able to address major risks, such as cancer, as well as transient treatable concerns like recurring bladder infections and bothersome skin rashes. So, which of the approved MS drugs will be the winner? Perhaps none! 

Over the last few years, there has been a dramatic shift in Sweden and Kaiser Permanente toward rituximab. One in two MS patients in Sweden now chooses to start rituximab. The data produced so far show that rituximab beats all approved MS drugs in terms of providing MS patients with an effective, safe and tolerable drug. The fact that rituximab is much cheaper than other MS drugs also makes it an attractive option in resource-limited countries, where access to brand name MS drugs is out of reach for most patients. 

Fredrik Piehl, Annette Langer-Gould, Jessica Smith and Anna Fogdell Hahn on behalf of the COMBAT-MS investigators and steering committee


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