No existing treatment for multiple sclerosis (MS) is known to resolve “chronic active” white matter lesions, which play a role in disease progression and are identifiable on high-field MRI as so-called “paramagnetic rim lesions (PRL). We report investigator-initiated, open-label trials of two agents postulated to modulate microglial activity in these lesions, representing a new Phase IIa clinical trial paradigm in MS. The first tests short-term anakinra, an FDA-approved recombinant human interleukin-1 receptor antagonist, at up to 300 mg/day. It will enroll up to 10 patients with progressive or stable MS, ≥1 PRL, and no new lesions or relapse within the prior year. Patients will receive daily self-administered subcutaneous injections with scheduled dose escalation for 12 weeks. The second trial uses tolebrutinib, an investigational, orally available, brain-penetrant, Bruton’s tyrosine kinase (BTK) inhibitor. This study has 2 cohorts: (1) 10 patients, stable on anti-CD20 antibody therapy and within 3 months of their most recent dose, who will initiate treatment with tolebrutinib 60 mg daily and forego further anti-CD20 or other disease-modifying therapy for the duration of the trial; (2) a non-randomized comparison cohort of 10 patients who choose to stay on anti-CD20 antibody therapy rather than receive tolebrutinib. Both cohorts will be followed for 96 weeks, with 7-tesla MRI every 6 months and the primary outcome (PRL disappearance) assessed in blinded fashion at 48 weeks. Secondary outcome measures will include clinical scales, analysis of immune cell populations, single-cell cerebrospinal fluid (CSF) and blood RNA sequencing, and biomarkers such as neurofilament light chain. The anakinra study (NCT04025554) is underway. The tolebrutinib study is undergoing regulatory review at the time of this submission. In summary, we aim to induce therapeutic disruption of the dysregulated equilibrium at the edge of chronic active lesions, visualized as either complete or partial resolution of the paramagnetic rim on MRI. These studies are the first steps toward a novel trial design to explore an emerging outcome measure that may address a critical but unmet clinical need in MS.