Operational Strategies That Strengthened the NIMBLE Trial Design

In a recent video interview with Applied Clinical Trials, Umesh Chaudhari, executive medical director, global program head of the C5 programs, Regeneron, discussed recently released data from the Phase III NIMBLE clinical trial (NCT05070858), which evaluated the efficacy of cemdisiran monotherapy and a combination of cemdisiran and pozelimab in generalized myasthenia gravis (gMG). The study showed a 2.3-point reduction in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score, indicating improved daily functioning. The combination therapy had a 17% worsening rate, compared to 1% in the cemdisiran monotherapy group. Chaudhari highlighted the trial's robust design, including double-blind, double-dummy protocols, and standardized assessments, which ensured high data quality. The findings suggest that lower complement inhibition levels may be optimal for efficacy, with implications for future research in autoimmune diseases.

ACT: The NIMBLE trial used a randomized, double-blind, placebo-controlled design with both monotherapy and combination arms. What operational strategies were key to maintaining blinding and protocol adherence across these treatment regimens?

Chaudhari: I'll go through multiple components, but the first component I'll start off with is, is the administration of the study treatment, the study drug. The study treatment was administered as double-blind double dummy. As I mentioned, there's three arms, there's a combination. There was a pozelimab plus cemdisiran combination, then the cemdisiran monotherapy, and then the placebo. We matched the placebo control with the monoclonal antibody, the pozelimab, and then there's a separate placebo for cemdisiran. We ensure that patients got matching drugs, it was completely blinded, and it was administered at the same frequency throughout that 24-week treatment period, meaning they came into the clinic, to the site, every four weeks to get injections. For instance, in the cemdisiran, it's given every 12 weeks. In between those visits every four weeks, so week four and week eight, they received matching placebos, and then at week 12, they got their some cemdisiran dose, so that's one aspect.

The other layer that improved the robustness, or added to the robustness of this data set was the assessments. These assessments are subject to some bias because they're PROs, patient-reported outcomes and clinician assessments, and it's critical to reduce bias so you have robust and valid data. One of the ways we did that was by training sites, qualifying them, the investigators trying to ask sites to have the same investigator perform the assessments throughout this period, as well as, hopefully the same time of day, we also had some communication from the site to patients to hold certain background medications that may impact the results of these endpoints, and that was also done throughout the trial.