Many clinical trials are underway with molecules that attempt to demonstrate a disease modifying effect (DME) in Parkinson's disease.1 A critical point is that, to date, the best methodology for measuring disease progression is unclear. And this involves both the primary endpoint and the proper methodology of the ideal clinical trial. Evidence of DME is based on clinical trial designs such as staggered start and delayed withdrawal or with parallel designs incorporating combined clinical outcomes and correlated biomarker evidence of an effect on the underlying pathophysiological processes of the disease.2 DME does not involve curing the disease or even stopping it. DME refers to a permanent change in the disease trajectory that will delay the onset of symptoms or slow progression in symptomatic patients. A major problem is that to clearly observe whether there is a difference in the progression of a neurodegenerative disease between a group receiving a drug and a control group, it would be necessary to wait a long time (e.g., ≥3–5 years).3,4 A comparison in the long term of the treated group with an external group may be an alternative but with many biases.5
We propose a new methodological concept based on two consecutive double-blind phases. In the first phase, the arm receiving the drug would be compared to the placebo arm (Fig. 1, Phase 1), as has been routinely done so far. In the second phase (Fig. 1, Phase 2), and this is the novel concept, three arms would be included after a second randomization without breaking the blind: (i) early-start drug arm; (ii) late-start drug arm; (iii) placebo arm. Since patients will not be deprived of symptomatic treatment if necessary, there would be no ethical conflict. This point is crucial. Given that patients are receiving an investigational treatment that aims to demonstrate whether it can slow disease progression, that there is no other currently available treatment approved for this purpose, and that they could also receive symptomatic medication as needed, it is not a problem to not know the type of intervention (neither patient nor medical team) if the patient agrees to it. Another key point is that in the second phase, there will be a new randomization so that those who initially received the drug will continue with it, and half of the other group will receive the drug and the other half will continue with the placebo. However, because it would be double-blind, there will be no bias due to differences in expectations in the long term based on the treatment received. In this context, it would be necessary to define the primary endpoint to be measured at the end of the first phase as well as the follow-up time, with the possibility of measuring the long-term differences in progression between the 3 arms defined from the second phase onwards (Fig. 1, green arrows). On the other hand, some limitations could be costs and time. Firstly, and due to the need to compare three arms in the long term, it would be necessary to include many patients. Secondly, the follow-up time to observe differences will probably be long, with at least 5 years being recommended. Both points will inevitably lead to an increase in costs. However, because the placebo is not broken throughout the duration of the trial, phase 1 could be extended further (primary endpoint), and interim analyses performed in any case to analyze the relevance of continuing the study, planning the DME trial as a phase 2/3 trial with the inclusion of a very large population and very long-term follow-up. Of course, the analysis should consider adjustment for symptomatic medication received, as is currently the case.
New methodological proposal of a disease-modifying therapy trial with two consecutive double-blind phases. In the first phase (on the left), the arm receiving the drug (in red) would be compared to the placebo arm (in blue). In the second phase (on the right), three arms would be includen a fter a second randomization without breaking the blind: (i) early-start drug arm (red-red); (ii) late-start drug arm (blue-red); (iii) placebo arm (blue-blue). The green arrows show the long-term measurement of progression comparing the 3 proposed arms.
It is currently unclear what the appropriate endpoint or method of measuring PD progression should be, and the primary endpoint in DME trials differs from one to another. Even when a clinical scale is used, it is not clear whether it is better to use a quantitative (change from baseline to the final visit comparing the active arm vs. placebo arm in the Movement Disorder Society – sponsored revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS] total score; change in the MDS-UPDRS part III score; change in the MDS-UPDRS part II score; change in the MDS-UPDRS part II+part III score) or qualitative variable (5-point increase in the MDS-UPDRS part III score; 7-point increase in the MDS-UPDRS part III score; 2-point increase in the MDS-UPDRS part II score). What does seem clear is that an insufficiently long initial placebo phase can result in a negative trial. If we consider the effect of the therapy, not symptomatic but DME, a very long follow-up period is necessary to be truly certain of the modifying effect. And even more so if we take into account a very important bias in these trials, which is the inclusion of patients with minimally affected conditions in an initial stage with no provision for modifying treatment at least a year after their inclusion. This explains why the long-term progression of patients treated with the investigational drug has been compared with patients from an external cohort with similar characteristics.5 With our proposal, we would eliminate important biases such as potential calendar time bias, geographic bias, selection bias (the enrollment of people in clinical trials that are different from those in clinical practice), differences in clinic visit frequency, bias related to the retrospective nature of defining the external comparator arm, confounding factors (e.g., diet and exercise) and data quality issues, and of course, a potential placebo effect only in the group of patients who are participating in the trial.5
In summary, we propose a new methodological concept for clinical trials based on two consecutive phases with a placebo arm and unbroken blinding, with the aim of reducing biases and allowing for a more accurate analysis of whether the investigational drug can actually slow disease progression. Although the focus of the discussion is on Parkinson's disease, it could be extended to other neurodegenerative diseases without a disease-modifying alternative.
Financial disclosures for the previous 12 monthsDiego Santos-García has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, Italfarmaco, Teva, Archímedes, Esteve, Stada, financial compensation for INIBIC/Fundación Professor Novoa Santos in relation to activity as a PI in phase 2 to phase 4 clinical trials for Parkinson's disease and other movement disorders, and grants from the “Fundación Professor Novoa Santos” as a result of the “CONVOCATORIA DE AYUDAS PARA LA REALIZACIÓN DE PROYECTOS DE INVESTIGACIÓN PARA GRUPOS EMERGENTES Y ASOCIADOS DEL INIBIC (2023/2024)”. Ángella Solleiro has nothing to report. Tania M. Figueiras Vázquez has nothing to report.
Funding sourcesNone.
Conflict of interestNone.
