Combination therapy of Epidermal Growth Factor and Growth Hormone-Releasing Hexapeptide in acute ischemic stroke: a phase I/II non-blinded, randomized clinical trial

 So with further research suggested will your competent? doctor and hospital ensure it gets done? Oh, you don't have a functioning stroke doctor or hospital that even knows about this, much less get more research done?

Combination therapy of Epidermal Growth Factor and Growth Hormone-Releasing Hexapeptide in acute ischemic stroke: a phase I/II non-blinded, randomized clinical trial

Francisco Hernández-Bernal^1,2†‡Donner Estenoz-García^3‡Juan H. Gutiérrez-Ronquillo^4‡Yenima Martín-Bauta^1‡Karen Catasús-Álvarez^1‡Mario Gutiérrez-Castillo^4‡Marbelys Guevara-Rodríguez^4‡Aliuska Castro-Jeréz^5‡Yoandra Fuentes-González^5‡Yulemis Pinto-Cruz^3‡Carmen Valenzuela-Silva^6‡Verena L. Muzio-González^1‡Héctor Pérez-Saad^7‡Nelvys Subirós-Martínez^7‡Gerardo E. Guillén-Nieto^8,9‡Diana Garcia-del-Barco-Herrera^7,9,*†‡ on behalf of the COURAGE (COmbined therapeUtic appRoAch durinG acute strokE) Research Group

• ¹Clinical Trial Direction, Center for Genetic Engineering and Biotechnology, Havana, Cuba
• ²Department of Comprehensive General Medicine, Latin American School of Medicine (ELAM), Havana, Cuba
• ³Neurology Department, “Antonio Luaces” Hospital, Ciego de Ávila, Cuba
• ⁴Neurology Department, “Arnaldo Milián” Hospital, Santa Clara, Villa Clara, Cuba
• ⁵Neurology Department, “Celia Sánchez” Hospital, Manzanillo, Gramma, Cuba
• ⁶Institute of Cybernetics, Mathematics, and Physics, Havana, Cuba
• ⁷Neuroprotection Project, Biomedical Research Direction, Center for Genetic Engineering and Biotechnology, Havana, Cuba
• ⁸Biomedical Research Direction, Center for Genetic Engineering and Biotechnology, Havana, Cuba
• ⁹Department of Physiology, Latin American School of Medicine (ELAM), Havana, Cuba

Objective: This study tested the hypothesis that a neuroprotective combined therapy based on epidermal growth factor (EGF) and growth hormone-releasing hexapeptide (GHRP6) could be safe for acute ischemic stroke patients, admitting up to 30% of serious adverse events (SAE) with proven causality.

Methods: A multi-centric, randomized, open-label, controlled, phase I-II clinical trial with parallel groups was conducted (July 2017 to January 2018). Patients aged 18–80 years with a computed tomography-confirmed ischemic stroke and less than 12 h from the onset of symptoms were randomly assigned to the study groups I (75 μg rEGF + 3.5 mg GHRP6 i.v., n=10), II (75 μg rEGF + 5 mg GHRP6 i.v., n=10), or III (standard care control, n=16). Combined therapy was given BID for 7 days. The primary endpoint was safety over 6 months. Secondary endpoints included neurological (NIHSS) and functional [Barthel index and modified Rankin scale (mRS)] outcomes.

Results: The study population had a mean age of 66 ± 11 years, with 21 men (58.3%), a baseline median NIHSS score of 9 (95% CI: 8–11), and a mean time to treatment of 7.3 ± 2.8 h. Analyses were conducted on an intention-to-treat basis. SAEs were reported in 9 of 16 (56.2%) patients in the control group, 3 of 10 (30%) patients in Group I (odds ratio (OR): 0.33; 95% CI: 0.06–1.78), and 2 of 10 (20%) patients in Group II (OR: 0.19; 95% CI: 0.03–1.22); only two events in one patient in Group I were attributed to the intervention treatment. Compliance with the study hypothesis was greater than 0.90 in each group. Patients treated with EGF + GHRP6 had a favorable neurological and functional evolution at both 90 and 180 days, as evidenced by the inferential analysis of NIHSS, Barthel, and mRS and by their moderate to strong effect size. At 6 months, proportion analysis evidenced a higher survival rate for patients treated with the combined therapy. Ancillary analysis including merged treated groups and utility-weighted mRS also showed a benefit of this combined therapy.

Conclusion: EGF + GHRP6 therapy was safe. The functional benefits of treatment in this study supported a Phase III study.

Clinical Trial Registration: RPCEC00000214 of the Cuban Public Registry of Clinical Trials, Unique identifier: IG/CIGB-845I/IC/1601.

1 Introduction

Ischemic stroke remains an important target for novel preventive and therapeutic strategies. It is estimated that 15 million people worldwide are affected by stroke every year, 5 million of them die and another 5 million of them suffer from long-term disability (1). The global population aged 65 years and over is growing faster than all other age groups, with a concomitant increase in stroke incidence (2). Furthermore, stroke among COVID-19 patients is associated with a significant risk of early mortality (3).

Currently, reperfusion therapy with thrombolytic drugs or endovascular thrombectomy represents the only approved therapeutic approach for acute stroke (4, 5). However, these approaches are associated with a narrow therapeutic window, increased risk of hemorrhagic transformation, and the high cost required to deliver these treatments (6), which limit their suitability for patients (~3%−6%), particularly in low-income countries (7). Moreover, despite treatment, recovery may be incomplete in a significant proportion of patients (8), as the vascular dynamics following recanalization do not invariably reduce tissue injury or reverse functional deficits (9, 10), and there remains scope for additional pharmacological-based neuroprotective interventions in addition to recanalization in acute ischemic stroke.

Considering the strong interdependence of elements in the neurovascular unit (11) and the limitations of neuron-protective strategies in clinical trials (12, 13), the scientific community has moved to combination strategies that seek to enhance endogenous mechanisms of neuroprotection (14). Combined therapies for stroke are likely to be more effective as they simultaneously target multiple levels of the ischemic pathophysiological cascade. However, few clinical trials have been published to date (2).

Molecules that trigger cytoprotective effects can be considered candidates for combined therapies (8). Particularly, a combined therapy based on epidermal growth factor (EGF) and growth hormone-releasing hexapeptide (GHRP6) has demonstrated benefit in preclinical contexts by activating pleiotropic endogenous mechanisms of survival and brain protection (15–19). Both molecules cross the blood-brain barrier (20–23), and their receptors are widely distributed in brain tissues (24, 25). EGF and GHRP6 share common properties such as anti-apoptotic (26, 27) and anti-excitotoxic effects (28, 29). In addition, both molecules have independent biological effects. Specifically, EGF promotes neurogenesis and remyelination (30), while GHRP6 induces endogenous neuroprotective factors such as growth hormone and insulin, like growth factor 1 (31).

Previous results of our group demonstrated the therapeutic benefits of this combination in animal models of multiple sclerosis (15), proximal axonopathy mimicking ALS, and focal and global ischemic stroke (16). Later, EGF+GHRP6 combined therapy improved both clinical and pathological aspects as it reduced neurological symptoms and brain infarct volume, preserving neuronal density (17). Additionally, EGF+GHRP6 combined therapy achieved similar results in a preclinical context when compared to therapeutic hypothermia (18). Moreover, both active ingredients exhibited a high safety profile in preclinical and clinical trials (32, 33).

Supported by these data, a phase I/II randomized clinical trial was designed to test the hypothesis that administration of a combined therapy based on rEGF and GHRP6 at two dose levels is safe for acute ischemic stroke (AIS) patients, admitting up to 30% of serious adverse events (SAE) in relation to proven causality. The therapeutic effect was assessed as a secondary endpoint. The current report has been written in compliance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines for randomized controlled trials (34, 35).

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