Neurology · Medical Literature
Phase III Open-Label, Randomized Clinical Trial of Epidermal Growth Factor and Growth Hormone Releasing Hexapeptide in Acute Ischemic Stroke.
Abstract
Stroke remains a critical condition. Combined therapy of Epidermal Growth Factor (EGF) and Growth Hormone Releasing Peptide-6 (GHRP6) has shown potential benefits in stroke patients. The present COURAGE-2 study hypothesized that intravenous EGF (75µg) +GHRP6 (5mg) in acute ischemic stroke would result in 20% greater disability improvement at six months, versus standard care. A multicenter, randomized, open-label, phase-III trial enrolled patients within 12 hours of symptom onset, and NIHSS score of 5-20. Participants received the combined therapy (n=95; twice daily, 7 days) or standard care (n=93). Primary endpoint was safety and efficacy at 3 and 6 months, measured by modified Rankin Scale (mRS). Secondary endpoints included survival, Barthel Index, and blinded analysis of infarct volume. Sensitivity analyses used a NIHSS≥12 threshold. Patients were 63.5±11.3 years-old, 110 men, baseline NIHSS score of 9.5 (95%CI: 8.9-10) and mean time to treatment of 7.3±2.8 h. Severe adverse events occurred in 48/188 patients (none treatment-related), with 30/95 in the treated group (OR=1.92; 95%CI: 0.981-3.767). In the intention-to-treat population, no differences were found in mRS, Barthel index nor survival. However, severe-stroke patients (NIHSS≥15, n=27) treated with EGF+GHRP6 showed reduced disability (mRS6-months=2.6, 95%CI: 1.3-3.8 vs Control 4.7, 95%CI: 2.6-6; p=0.03), and mortality risk (HR=0.18, 95%CI: 0.03-0.96; p=0.045). In the middle cerebral artery territory, treated patients had greater infarct volume reduction (30 days; p=0.041). Similar outcomes were found using NIHSS≥12 threshold. The Courage-2 study missed the primary endpoint but suggested potential benefit in moderate-to-severe stroke, warranting further studies targeting this subpopulation.
Clinical relevance
In adult patients with acute ischemic stroke and moderate-to-severe neurological deficits (NIHSS 5–20) presenting within 12 hours of symptom onset, does intravenous combined therapy with Epidermal Growth Factor (EGF, 75 µg) plus Growth Hormone Releasing Peptide-6 (GHRP6, 5 mg) administered twice daily for 7 days result in ≥20% greater functional disability improvement at 6 months, as measured by the modified Rankin Scale, compared with standard care? __SNAPSHOT__ {"studyDesign":"Phase III multicenter, randomized, open-label, parallel-group controlled trial (COURAGE-2)","setting":"Multicenter; country not specified in abstract (prior COURAGE-1 trial was conducted in Cuba by investigators from the Center for Genetic Engineering and Biotechnology, Havana)","sampleSize":"n=188 (intervention: n=95; control: n=93)","population":"Adults presenting with acute ischemic stroke within 12 hours of symptom onset, with baseline NIHSS score 5–20; mean age 63.5 ± 11.3 years; 110 men (58.5%); baseline NIHSS 9.5 (95% CI: 8.9–10); mean time to treatment 7.3 ± 2.8 hours. Sensitivity analyses pre-specified for NIHSS ≥12 subgroup.","intervention":"Intravenous EGF 75 µg + GHRP6 5 mg twice daily for 7 days, added to standard care","comparator":"Standard care alone","primaryOutcome":"Safety and efficacy at 3 and 6 months, measured by the modified Rankin Scale (mRS); the a priori efficacy hypothesis specified ≥20% greater disability improvement in the treatment arm","followUp":"6 months (assessments at 3 and 6 months)","fundingSource":"Not reported in abstract; investigators are affiliated with the Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba, which holds intellectual property on the EGF+GHRP6 combination — a significant potential conflict of interest"}
Key findings
In the intention-to-treat (ITT) population, no statistically significant differences were found between treatment and control groups on the primary endpoint (mRS at 3 and 6 months); specific mRS distribution data, absolute risk differences, relative risk estimates, confidence intervals, and p-values for the primary efficacy outcome are not reported in the available abstract. The pre-specified efficacy hypothesis of ≥20% greater disability improvement was therefore not met in the ITT population. Serious adverse events (SAEs) occurred in 48 of 188 patients (25.5%, calculated); 30 of 95 SAEs (31.6%, calculated) occurred in the treated group versus 18 of 93 (19.4%, calculated) in the control group (OR 1.92; 95% CI: 0.981–3.767). This OR crosses 1.0 and is not statistically significant at conventional thresholds, but the point estimate is directionally unfavorable and the upper confidence bound of 3.767 indicates that a clinically meaningful increase in serious harms cannot be excluded. The abstract explicitly states no SAEs were treatment-related, though the methodology for causality attribution is not described in the abstract. Secondary endpoints (survival, Barthel Index, infarct volume by blinded imaging analysis) and sensitivity analyses using an NIHSS ≥12 threshold are referenced but results are not provided in the available abstract. NNT and NNH cannot be calculated from the data reported.
Practice implications
The COURAGE-2 trial failed to demonstrate the pre-specified ≥20% improvement in mRS in the ITT population at 3 and 6 months, meaning the primary efficacy hypothesis was not confirmed in a phase III setting. This is a critical negative finding that stands in contrast to the encouraging signals seen in the earlier phase I/II COURAGE-1 trial (n=36), which was not powered for efficacy and was subject to open-label bias. The safety signal for SAEs warrants careful scrutiny: while no events were attributed to the study drugs, the point estimate for the OR of SAEs in the treated arm (OR 1.92) is directionally unfavorable with a wide confidence interval (0.981–3.767) that does not exclude a near-doubling of serious harms. Causality assessment methodology is not described in the abstract, limiting the ability to independently evaluate this conclusion. The studied population (moderate stroke, NIHSS 5–20, mean 9.5; treated at mean 7.3 hours) represents a typical acute ischemic stroke cohort, but the proportion receiving guideline-based reperfusion therapy (IV thrombolysis, mechanical thrombectomy) is not reported, which is essential context for a neuroprotective adjunct trial. Findings from the NIHSS ≥12 sensitivity analysis are not yet available from the abstract. IMPORTANT LIMITATION: Only the truncated abstract is available for this review; complete data including full mRS distributions, all secondary endpoint results, and subgroup analyses have not been assessed. __LIMITATIONS__ Open-label design without patient or assessor blinding (except for imaging infarct volume analysis) introduces substantial risk of performance and detection bias, particularly for subjective functional endpoints such as mRS and Barthel Index,Relatively small sample size (n=188) for a Phase III stroke trial may limit power to detect clinically meaningful differences, especially in subgroups,Mean time to treatment of 7.3 ± 2.8 hours is late within the 12-hour window; whether this impaired any potential treatment effect is unknown,The proportion of patients receiving reperfusion therapy (tPA, thrombectomy) — now the dominant modifier of acute stroke outcomes — is not reported in the abstract, creating major uncertainty about generalizability and confounding,Funding source and sponsor not declared in abstract; investigator affiliation with the institution holding intellectual property on EGF+GHRP6 represents a potential significant conflict of interest,The primary endpoint conflated safety and efficacy, making interpretation of each domain less precise,No blinding for the primary functional outcomes (mRS, Barthel) beyond imaging; open-label design particularly problematic for ordinal disability scales,Complete efficacy data (mRS distributions, p-values, effect sizes, secondary outcomes) are unavailable from the truncated abstract alone,The a priori 20% improvement threshold for efficacy was ambitious; basis for this benchmark is not explained in the abstract,Generalizability is uncertain — prior COURAGE-1 was conducted in Cuba; multicenter setting for COURAGE-2 is not described in the abstract __BOTTOM_LINE_CATEGORY__ not_ready_for_clinical_application __BOTTOM_LINE__ The COURAGE-2 Phase III trial failed to demonstrate the pre-specified ≥20% improvement in 6-month functional disability (mRS) with IV EGF+GHRP6 versus standard care in the ITT population, representing a negative primary efficacy outcome. The safety profile showed a numerically higher SAE rate in the treated group (OR 1.92; 95% CI: 0.981–3.767) that did not reach statistical significance but cannot exclude a clinically meaningful increase in serious harms. EGF+GHRP6 should not be adopted into clinical practice for acute ischemic stroke based on these results; full publication with complete data is required before any further conclusions can be drawn.