At the recent ORATORIO-HAND investigators’ meetings in Barcelona and Athens, several investigators’ made the point that it may be hard to retain people with PPMS in this trial because ocrelizumab has already been licensed to treat MS. I said YES and NO.
For one a lot of neurologists, HCPs and payers don’t think the original ORATORIO trial was positive. They think the trial was driven by the 25% or so of the subjects with PPMS who had active disease, i.e. those with Gad-enhancing lesions at baseline. I have even heard some people claim that this trial was positive because it was contaminated by relapsing patients. This was not the case, all subjects had to have PPMS to get into this study. Any history of previous relapse excluded them from the trial. As a result of this doubt, many countries and insurance companies have not agreed to license or reimburse ocrelizumab for PPMS. To convince the naysayers, laggards and sceptics we need another PPMS trial to confirm the original results and extend the findings into pwPPSM with more advanced disease to show that ocrelizumab has a treatment effect in older and more disabled pwPPMS. This is why our age cutoff for the ORATORIO-HAND study is 65 and EDSS cut-off is 8.0 (wheelchair users). In the original ORATORIO study, these cutoffs were 55 years and EDSS of 6.5 (bilateral support, but still mobile).
Statisticians will tell you that when you only do one trial, which is positive, there is about a 1 in 20 to 40 (2.5% to 5%) chance that result could be positive by chance. In statistical jargon, this is referred to as a false-positive result or type 1 error. This is why the regulators usually require two positive trials to license a product; the first trial to test the hypothesis and the second to confirm the results of the first trial. If one trial is positive and the second trial is negative, or vice versa, this usually results in a third trial being required. This is what happened with laquinimod in RRMS; you may recall the third trial (CONCERTO) turning out to be negative so the laquinimod MS development programme was halted. Herein lies a hidden danger. If ORATORIO-HAND is negative and does not confirm a significant treatment effect in PPMS it could be used by regulatory authorities to question the result of the ORATORIO trial and potentially withdraw the license. A negative result will justify payers refusal to reimburse the costs of ocrelizumab to treat PPMS. I am confident this is not going to happen, but we need your help to makes sure this does not happen.
The ORATORIO-HAND is a very well-designed study and is adequately powered to give a positive result. The scientific principles underpinning this study are sound. However, if too many subjects drop-out to accept being treated with ocrelizumab when it is reimbursed in their countries or game the trial, i.e. find a way to unbind themselves, and drop-out this could potentially result in the study being underpowered, i.e. there are too few subjects to show a significant result when comparing placebo and active treatment groups. If this happens it could not only jeopardise treatment for themselves but the whole PPMS community. This is why I am appealing to all potential ORATORIO-HAND trial subjects if you are not sure about your longterm commitment to the trial you should not volunteer.
We are very aware that half the trial subjects will be allocated to placebo. Someone investigators asked why didn’t we make the randomisation 2:1, i.e. for every one person on placebo two people would be allocated ocrelizumab. The logic is that by having a 2-out-of-3 chance of being on active treatment the more likely pwPPMS are likely to volunteer for the study and to stay the distance. There are two reasons for the one-to-one randomisation ratio; time and possibly cost. Increasing the time it takes to recruit study participants is important. We estimate to recruit another 500 subjects, to allow a 2:1 ratio, would take another 12-15 months, which means we would be exposing a third of the subjects to placebo for an additional 12-15 months and potentially denying many pwPPMS across the world earlier access to the ocrelizumab. A 12-15 month extension to the recruitment phase means 12-15 month delay for drug getting to wider PPMS population. These are the factors that convinced the steering committee to choose the 1:1 randomisation ratio. Although cost is an obvious potential consideration we didn’t even ask senior management at Roche the question.
At the end of the day, we are asking pwPPMS to be altruistic. We are asking you to volunteer for a study and have a 50% chance of being randomised to a placebo knowing that ocrelizumab may be available to you as part of routine clinical practice or could become available to you during the trial. I know some people will ask does it have to be a randomised double-blind controlled trial? Could we generate the evidence in another way? The answer is no; the regulators will only change the label of ocrelizumab if the study is done to their standards. As you are aware it is virtually impossible to get a healthcare system-wide adoption of an MS treatment without a marketing authorisation from the appropriate regulatory body.
There are also other advantages to being in a trial. We don’t know why but trial participants tend to do better than non-trial participants even if you are randomised to placebo. This may relate to better care offered in a trial or participating in a trial has psychological benefits that can’t be quantified. I favour the latter explanation. There is evidence that people who have a purpose, a sense of belonging and are valued have better health outcomes than people without. Being a trial participant gives you a sense of purpose and being valued in that they are contributing the greater good. I have also noticed over the years that trial participation expands social capital; trial participants get to know the trial staff and other trial participants. I even know of two study subjects from one of the early trials who ended up marrying each other. Others have become friends and see each other outside the trial unit; I have bumped into two of trials participants in a local east curry house together. These intangibles can’t be quantified, but they definitely exist.
In countries in which ocrelizumab is not licensed or reimbursed for treating PPMS the advantages of participating in the ORATORIO-HAND study are obvious. But even in countries where ocrelizumab is reimbursed receiving it as part of a trial may help as well. Although we can’t pay for you to participate in the trial all of your out-of-pocket expenses related to travel will be covered.
I want to emphasise the positive of ORATORIO-HAND. For decades pwPPMS have felt neglected, ignored and left to smoulder away. Not anymore. The fact that the first ORATORIO trial was positive has shifted the goalposts and there will now be a flurry of PPMS trials. If ORATORIO-HAND fully recruits and is completed without too many dropouts the study will change the playing field for good. It will mean that PPMS is truly modifiable regardless of disease activity and potentially even people in wheelchairs will benefit. Getting a license for ocrelizumab in wheelchair users will affect the DMT stopping criteria, in other words even if you have to start using a wheelchair the treatment will have to be continued to preserve your arm and hand function. More importantly, it will get the whole MS community to say ‘Yes, we now agree that ocrelizumab works in PPMS’ and will allow pwPPMS across the world to access treatment.
We acknowledge that there are many legitimate reasons for why study subjects dropouts in clinical trials. We have factored this into the power calculations. What I am focusing on here is excess drop-outs over and above what we expect to occur from experience of other ocrelizumab trials.
This post is simply rehearsing some of the reasons for pwPPMS who volunteer for the ORATORIO-HAND study to stay the distance and complete the study. Please let me know if you agree, or disagree, with these points. I am also keen to find other reasons to help the many participating centres retain their patients in this trial.
CoI: multiple; importantly, I am the principal investigator on the ORATORIO-HAND study and I want to give this trial the maximum chance of being successful. Our #ThinkHand campaign will only be judged a success if and when we get a DMT licensed to protect upper limb and hand function in pwMS.