The multi-domain responder index: a novel analysis tool to capture a broader assessment of clinical benefit in heterogeneous complex rare diseases

Abstract

In traditional clinical trial design, efficacy is typically assessed using a single primary endpoint in a randomized controlled trial to detect an expected treatment effect of a therapy in a narrowly selected patient population. This accepted paradigm is based on clinical evaluations that may not actually capture the breadth of the impact of a disease, which is especially true in the setting of complex, multisystem, rare diseases with small, extremely heterogeneous patient populations. The multi-domain responder index (MDRI) is a novel approach that accommodates complex and heterogeneous disease manifestations and evaluates a broad array of clinical disease without impairing the power or rigor of a study to fully understand a treatment. The MDRI sums the scores corresponding to clinically significant thresholds of change for each component domain in each individual patient, capturing the mean clinically meaningful change across multiple domains within individuals. This novel approach combines and then sums the results of independent domain endpoint responder analyses into one responder score to provide a broad basis for the assessment of efficacy. The impact of a treatment across multiple, physiologically independent domains, can be assessed clinically, reducing the adverse impact of heterogeneity on trial outcomes and allowing eligibility criteria to enroll a wider range of patients, ultimately resulting in efficacy and safety assessments of a therapy across a broad group of heterogeneous patients in rare disease programs.Trial registration The following studies are referenced within this manuscript (CLINICALTRIALS.GOV registration numbers): NCT00912925; NCT00146770; NCT00067470; NCT00104234; NCT00069641; NCT02230566; NCT02377921; NCT02432144.

Keywords: Laronidase; MDRI; MPS; Mucopolysaccharidosis; Multi-domain responder index; Vestronidase alfa.

Conflict of interest statement

PKT and EDK are employees and shareholders of Ultragenyx Pharmaceutical Inc.

Figures

Fig. 1

MDRI example construction and calculation

Fig. 2

MDRI response using heat map approach in the Phase 3 Laronidase study

Fig. 3

Net change in domains from a Phase 3 study of Laronidase versus Placebo

Fig. 4

Mean (± SE) MDRI score during the Vestronidase blind-start and extension studies* [27]

Fig. 5

Patient-level MDRI at baseline and week 48 in the extension study* [27]

Fig. 6

Clinical Global Impression (CGI) Scale rating of severity at baseline in Angelman syndrome