Restoring Awareness

The study will evaluate the safety and preliminary efficacy of saxagliptin in treating prolonged DoC through a randomized, placebo-controlled, double-blind, delayed start Phase IIA trial. Twenty-four (24) patients with prolonged DOC (≥28 days post-injury) will be enrolled at Rehabilitation Hopsital's Center for Disorders of Consciousness (C³DoC).

Twelve patients will be randomized to receive placebo for 15 days followed by saxagliptin 5 mg for 15 days (Delayed Start Group), and 12 will receive saxagliptin 5 mg for the full 30 days (Full Treatment Group). Patients will be under continuous medical monitoring within C³DoC throughout their approximately 4-week admission. Validated behavioral biomarkers of consciousness (CRS-R) will be collected by blinded certified assessors at baseline (days -7 and 0), day 15, and day 30, with portable EEG-based AI biomarker assessments to corroborate behavioral findings. Follow-up DRS-PI assessments will be conducted at days 60 and 90.

A pre-planned adaptive dose escalation design will be employed. The first 6 patients (sentinel cohort) will receive 5 mg (or placebo per delayed start). Upon cohort completion, the independent Safety Monitoring Board (SMB), chaired by a Medical doctor , will review unblinded safety data. If IRB and FDA IND Exemption approval is obtained for dose escalation, and excellent safety criteria are met (zero SAEs, no Grade 2+ AEs, zero hypoglycemia), the SMB will direct escalation to 10 mg for subsequent patients (up to 400 mg/day has been shown to be well-tolerated in humans); otherwise, 5 mg continues. Investigators and patients remain blinded throughout.

When individuals suffer a severe brain injury and do not completely regain their previous functional abilities, frequently develop a Disorder of Consciousness (DoC). This refers to a collection of interconnected conditions characterized by reduced awareness and alertness, such as the Vegetative State (VS) and the Minimally Conscious State(MCS). When these conditions persist over time, there are currently no authorized pharmacological interventions available to enhance their recovery. Only one medication, amantadine, has Class II evidence for DOC, offering modest benefit with no group difference versus placebo at trial end . Eight drugs, which are indicated for other conditions, have previously shown some promise in improving alertness and awareness in some DoC patients. These drugs are amantadine, apomorphine, baclofen, bromocriptine, desipramine, levodopa, methylphenidate, and zolpidem. In order to identify new potential drugs for DoC, investigators trained a deep neural network to predict the efficacy of these eight drugs, as well as 288 other drugs known to be ineffective (from prior research and patient records), based on their molecular structure. This phenotypic AI screening was trained on both acute coma and prolonged DOC cases. Investigators then used this trained network to predict the efficacy of all other FDA-approved drugs in chronic DoC. This in silico drug screen identified a new, FDA-approved medication with promise in ameliorating chronic DoC: the type 2 diabetes medication saxagliptin. This finding has since been supported by a retrospective study of 4,047 ICU acute coma patients matched by age, sex, Glasgow Coma Scale score, etiology, and glycemic status, in which incretin-based therapies (including DPP-4 inhibitors) yielded significantly higher recovery rates versus non-incretin diabetes medications (P=0.0331), patients without diabetes (P=0.0272), and amantadine-treated patients (P=0.0364) (Toker et al., 2025). Recovery rates with incretin-based drugs were consistent across coma etiologies: TBI (76.5%), stroke (73.7%), and anoxic (74.9%); saxagliptin-treated patients showed 89% recovery. A new preclinical study also demonstrated saxagliptin significantly improved neurobehavioral outcomes and attenuated neuropathologies in severe TBI in non-diabetic rats .

In the present study, investigators propose to evaluate the safety and preliminary efficacy of saxagliptin in treating prolonged DoC through a randomized, placebo-controlled, double-blind, delayed start Phase IIA trial. Twenty-four (24) patients with prolonged DOC (≥28 days post-injury) will be enrolled at Rehabilitation Hospital's Center for Disorders of Consciousness (C³DoC).

Twelve patients will be randomized to receive placebo for 15 days followed by saxagliptin 5 mg for 15 days (Delayed Start Group), and 12 will receive saxagliptin 5 mg for the full 30 days (Full Treatment Group). Patients will be undercontinuous medical monitoring within C³DoC throughout their approximately 4-week admission. Validated behavioral biomarkers of consciousness (CRS-R) will be collected by blinded certified assessors at baseline (days -7 and 0), day 15, and day 30, with portable EEG-based AI biomarker assessments to corroborate behavioral findings. Follow-up DRS-PI assessments will be conducted at days 60 and 90. A pre-planned adaptive dose escalation design will be employed. The first 8 patients (sentinel cohort) will receive 5 mg (or placebo per delayed start). Upon cohort completion, the independent Safety Monitoring Board (SMB),chaired by a Medical Doctor, will review unblinded safety data. If IRB and FDA IND Exemption approval is obtained for dose escalation, and excellent safety criteria are met (zero SAEs, no Grade 2+ AEs, zero hypoglycemia), the SMB will direct escalation to 10 mg for only the remaining 6 patients in the full treatment arm; All 12 Delayed-Start patients will remain at 5 mg during active treatment (up to 400 mg/day has been shown to be well-tolerated in humans); otherwise, 5 mg continues. Investigators and patients remain blinded throughout. No confirmed adverse events of special interest (AESIs), no permanent study-drug discontinuations for safety reasons, completion of treatment and follow-up through Day 44 before escalation review.