Barts-MS rose-tinted-odometer: ★★★★★ (seeing turquoise; creative turquoise Friday)
She was 42 years of age and had had MS for 16 years. After a relapse in 2016, she was switched from interferon-beta to fingolimod. Despite being NEDA-2 ( no relapses or focal MRI activity) since starting fingolimod her disability has worsened with her EDSS going from 4.5 (walking unaided for more than 300m) to 6.0 (needing a walking stick to walk 100m). Clearly, fingolimod is doing what it should do, i.e. keeping relapse and MRI activity at bay. What can we add-on to fingolimod to stop worsening disability?
To answer this question we need to tackle smouldering MS in a creative way; one way is to use the so-called “Simon 2-stage, single-centre, phase 2, single-arm futility trial”. The Simon design comes from oncology and allows multiple treatment regimens to be compared. The idea is to screen treatments using an initial futility study and if you pass this phase you can then stop for futility but you don’t stop if there is evidence for an overwhelming effect on the outcome. A non-futile treatment can be taken forward for further testing in a phase 2b study.
The Simon 2-stage design provides initial evidence supporting or opposing a specific treatment, which then requires confirmation. I can see us using this trial design to test the long list of potential repurposed add-on treatments we have to tackle smouldering MS. I see no reason why we can’t use this trial design in a factorial way to test combination therapies, i.e. to build a MS-MDT sandwich.
The study below uses the Simon 2-stage design to test oral domperidone, an anti-nausea drug, in SPMS. The hypothesis was that the increase in the hormone prolactin-induced as a side-effect of domperidone would stimulate remyelination, which will improve or at least slowdown disability progression. Sadly it didn’t but it shows that this route is feasible.
I wonder if we could set up a ‘disruptive Simon-stage-2 trial platform’ for pwMS to run their own trials of over-the-counter medications and/or supplements. The platform will screen patients online and assess trial eligibility using PROMs (patient-related outcomes) and then randomise them to different treatment arms. The trial platform will then follow them up via smartphones using the futility design. The primary and secondary outcomes will all be self-monitored using smartphone technology. Wouldn’t it be cool if patients with progressive MS took control of their own trials and generated the evidence to support taking some of the supplements or medication a lot of pwMS take anyway; an example could be alpha-lipoic acid.
You may remember that Patients Like-Me did something similar with lithium in motor neuron disease a few years ago. The article by Paul Wicks ‘Patient Study Thyself’ highlighted below explains the process and is really asking people with disease to disrupt the status quo. I would urge you to go for it!
Koch et al. Repurposing Domperidone in Secondary Progressive Multiple Sclerosis: A Simon 2-Stage Phase 2 Futility Trial. Neurology. 2021 May 4;96(18):e2313-e2322.
Objective: To assess whether treatment with the generic drug domperidone can reduce the progression of disability in secondary progressive multiple sclerosis (SPMS), we conducted a phase 2 futility trial following the Simon 2-stage design.
Methods: We enrolled patients in an open-label, Simon 2-stage, single-center, phase 2, single-arm futility trial at the Calgary Multiple Sclerosis Clinic if they met the following criteria: age of 18 to 60 years, SPMS, screening Expanded Disability Status Scale score of 4.0 to 6.5, and screening timed 25-ft walk (T25FW) of ≥9 seconds. Patients received domperidone 10 mg 4 times daily for 1 year. The primary outcome was worsening of disability, defined as worsening of the T25FW performance by ≥20% at 12 months compared to baseline. This trial is registered with ClinicalTrials.gov (NCT02308137).
Results: Between February 13, 2015, and January 3, 2020, 110 patients were screened, 81 received treatment, and 64 completed follow-up, of whom 62 were analyzed. The study did not meet its primary endpoint: 22 of 62 (35%) patients experienced significant worsening of disability, which is close to the expected proportion of 40% and above the predefined futility threshold. Patients with higher prolactin levels during the study had a significantly lower risk of disability progression, which may warrant further investigation. Domperidone treatment was reasonably well tolerated, but adverse events occurred in 84% and serious adverse events in 15% of patients.
Conclusions: Domperidone treatment could not reject futility in reducing disability progression in SPMS. The Simon 2-stage trial model may be a useful model for phase 2 studies in progressive MS.
Trial registration information: ClinicalTrials.gov Identifier: NCT02308137.
Classification of evidence: This study provides Class III evidence that in individuals with SPMS participating in a futility trial, domperidone treatment could not reject futility in reducing disability progression at 12 months.
Paul Wicks. Patient, study thyself. BMC Medicine volume 16, Article number: 217 (2018).
The past 15 years have seen the emergence of a new paradigm in medical research, namely of people living with medical conditions (whether patients, parents, or caregivers) using digital tools to conduct N-of-1 trials and scientifically grounded research on themselves, whilst using the Internet to form communities of like-minded individuals willing to self-experiment. Prominent examples can be found in amyotrophic lateral sclerosis/motor neurone disease (the ‘lithium study’ on PatientsLikeMe), Parkinson’s disease (‘digital patient’ Sara Riggare), and diabetes (the ‘open artificial pancreas’ of the #WeAreNotWaiting movement). Through transparency, data sharing, open source code, and publication in the peer-reviewed scientific literature, such activities conform to expected scientific conventions. However, other conventions, such as ethical oversight, regulation, professionalization, and the ability to translate this new form of relatively biased data into generalizable decisions, remain challenged. While critics worry such participant-led research merely muddies the waters of high-quality medical research and exposes patients to new harms, the potential is there to enroll millions of active minds in unravelling the wicked problems of complex medical disorders that degrade the human health span.
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.