Annually, approximately 100,000 patients in the USA suffer from intracerebral hemorrhage (ICH), which is associated with high mortality rates and poor long-term cognitive and physical recovery. At present, no pharmacological therapies have been demonstrated to improve functional outcomes after ICH. However, we have successfully demonstrated that CN-105, a pentapeptide derived from the receptor binding surface of the apolipoprotein E (apoE), is a highly promising therapy for improving recovery after ICH. CN-105 was rationally designed to mimic the LRP-1 receptor binding face of the apoE holoprotein, which binds the cell surface low density lipoprotein-related (LRP1) receptor, reducing microglial activation, neuroinflammation, and neuronal excitotoxicity. We demonstrated that CN-105 has excellent CNS penetration, is well tolerated, and retains the anti-inflammatory and neuroprotective effects of endogenous apoE holoprotein. In the Phase 1 of this STTR, we demonstrated CN-105's preclinical efficacy across species, sex, age, and hypertensive comorbidity, as evidence to support efficacy phase clinical trials. Our preclinical work with CN-105 has led to the successful completion of an IND and translation to a Phase 1 single- and multiple-escalating dose study (NCT02670824), where CN-105 demonstrated excellent clinical safety profile and linear pharmacokinetics. Based on the successful completion of the Phase 1 trial and after consultation with and funding from the FDA, we completed and recently published the CN-105 in participants from the Acute supraTentorial intraCerebral Hemorrhage (CATCH) trial, a multisite open-label safety study in patients with acute ICH (NCT03168581)1, which demonstrated early efficacy, and completed a parallel randomized placebo-controlled clinical trial in patients with ICH in Singapore (S-CATCH; NCT03711903). Together the CATCH and S-CATCH trials will allow insight into target engagement and therapeutic efficacy of CN-105 via analyses of serologic proteins and radiographic surrogates. Given the orphan drug status of CN- 105, our preliminary data are critical to rationally inform the development of a larger and definitive ICH study. In the current proposal, we will design an adaptive Phase 2b/3 clinical trial to evaluate CN-105 efficacy, in collaboration with StrokeNet and the Duke Clinical Research Institute (DCRI) (Milestone 1). To form the basis for trial adaptation, we will utilize radiographic and serologic data already collected in the completed CATCH and S-CATCH trials to characterize an algorithm for screening treatment response to CN-105 (Milestone 2).