Compounds with a graded row

Ordered by rung, strongest first. The rung rates the study design; the chip beside it says what the study measured. Both are needed.

1. Cerebrolysin

   human RCT Direct outcome Not approved for this condition

   Who was studied

   adults 18-80 with moderate-to-severe TBI enrolled within 30 days of injury, single centre in Romania, n=93 randomised across three arms (86 in the intention-to-treat analysis), followed 180 days; mild TBI was excluded

   This double-blind three-arm trial gave intravenous cerebrolysin with or without repetitive transcranial magnetic stimulation against saline and measured ten cognitive tests including MoCA, Stroop, Trail Making and CANTAB; no statistically significant difference was found on the primary outcome measures, and the authors list small sample size, single-centre design and short follow-up as limitations. A 2019 systematic review and meta-analysis of cerebrolysin in moderate and severe TBI pooled 5,685 participants across five studies but only one was a randomised trial, the other four being cohorts; it reported improvement on the Glasgow Outcome Scale (SMD 0.30, 95% CI 0.18 to 0.42) and the modified Rankin Scale while grading the body of evidence Level II and citing heterogeneity in dose, timing and injury severity, and the reviewers noted the lack of standard clinical trials as the reason the level of evidence is limited. Cerebrolysin has no FDA or EMA marketing authorisation for any indication; it is marketed under national registrations in Russia, China and other countries, and we did not locate a regulator's own document stating a TBI indication.

   Source PubMed Central 2 primary sources read for this row

2. BPC-157

   animal in vivo Direct outcome Not approved for this condition

   Who was studied

   mice, weight-drop closed head injury of escalating severity, 24 hour observation; group sizes not reported in the abstract

   Mice given BPC 157 intraperitoneally (10 microgram/kg and 10 nanogram/kg) after weight-drop head injury had less subarachnoid and intraventricular haemorrhage, less brain oedema and lower early mortality over 24 hours than controls. This is a rodent closed head injury model observed for one day, not human TBI, and no human study of BPC-157 in traumatic brain injury is on file.

   Source sciencedirect.com 1 primary source read for this row

3. P21

   animal in vivo Direct outcome Not approved for this condition

   Who was studied

   adult male C57Bl/6 mice, controlled cortical impact at 1.5 mm penetration (mild to moderate injury), 30 days of treatment; group sizes not reported in the abstract

   Mice given 50 nmol/day of the compound for 30 days after controlled cortical impact performed better on a hippocampus-dependent memory task and showed less neuronal loss in CA1 and parietal cortex than saline controls. The molecule tested was Peptide 6, the ciliary neurotrophic factor fragment from which the shorter tetrapeptide sold as P021 or P21 is derived, so this is evidence about a related but not identical peptide; the model is a mouse model of TBI and no human study of either peptide in traumatic brain injury is on file.

   Source PubMed 1 primary source read for this row

4. Thymosin Beta-4

   animal in vivo Direct outcome Not approved for this condition

   Who was studied

   adult rats, controlled cortical impact over the left parietal cortex; delayed-treatment experiment n=6 sham, 9 saline, 10 thymosin beta-4; outcomes to day 35

   Rats given thymosin beta-4 intraperitoneally after controlled cortical impact showed better spatial learning on the Morris water maze and improved modified neurological severity scores than saline controls, with reduced hippocampal cell loss; early dosing reduced cortical lesion volume while delayed dosing did not. Controlled cortical impact is a rodent model of TBI, not human TBI, and no human trial of thymosin beta-4 in traumatic brain injury is on file.

   Source PubMed Central 1 primary source read for this row

Checked, and nothing recorded

3 compounds were checked against traumatic brain injury and produced no gradeable row.

• Cortexin — checked, no row on file
• Dihexa — checked, no row on file
• Semax — checked, no row on file

A compound is here because someone looked and the sources did not support a row — not because nobody looked. Under the rubric, uncertainty resolves to no row, and a row resting on a vendor page or a clinic blog is worse than no row at all.