It seems like we should encourage someone like Bryan Johnson to test this out for cognitive enhancement…
Here is an outline of what a formal clinical trial might look like, but a person (depending on their risk / reward profile) could choose from the dosing schedule options here and proceed by working with his or her longevity doctor:
From CGPT5:
Here’s a pragmatic, regulator-friendly Phase 1/2a clinical protocol outline for recombinant PF4 (rPF4) targeting age-related cognitive decline. I’ve leaned on what’s known from prior human rPF4 exposure (heparin-reversal studies up to 5 mg/kg IV) and the 2023 mouse cognition papers (short courses and intermittent “pulses” worked), while building in robust HIT-axis safety.
Trial title
First-in-Indication, Phase 1/2a, Randomized, Placebo-Controlled, Multiple-Ascending-Dose Study of Recombinant Platelet Factor-4 (rPF4) in Older Adults With Age-Related Cognitive Impairment
Objectives
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Primary (Phase 1): Safety/tolerability, DLTs, PK/PD, immunogenicity (anti-PF4 antibodies) of rPF4 with short-course and intermittent schedules.
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Primary (Phase 2a): Efficacy signal on a hippocampal-dependent cognitive composite at 6–8 weeks.
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Secondary: Additional cognitive domains, patient-reported outcomes, functional measures (IADL), MRI biomarkers, fluid biomarkers of neuroinflammation/synaptic function, durability (follow-up to 12–16 weeks).
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Exploratory: Platelet/immune signatures linked to PF4 mechanism (CXCR3 axis), neurogenesis/plasticity proxies, digital cognitive phenotyping, actigraphy, exercise-interaction signal.
Population
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Inclusion: Age 65–85; subjective + objective age-related cognitive decline (e.g., early aMCI range: MoCA 18–25 or equivalent), preserved basic ADLs; stable meds ≥8 weeks.
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Exclusion (safety-critical): Prior HIT/VITT or anti-PF4 antibody positivity; active thrombosis or hypercoagulable state; therapeutic anticoagulation or planned heparin exposure during study; platelets <150k/µL or >450k/µL; recent major surgery/MI/stroke (<6 months); uncontrolled HTN; eGFR <45; significant hepatic disease; active cancer therapy; strong autoimmune disease requiring immunosuppression.
Study design overview
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Phase 1 (MAD, Bayesian model-assisted): 3 sequential schedules (A/B/C) with dose escalation within each; rPF4 vs placebo (3:1) with sentinel dosing.
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Phase 2a (signal-seeking): Randomized, double-blind, placebo-controlled, parallel cohorts testing the two best schedules/doses from Phase 1.
Phase 1: arms, schedules, and dose grid
Three scheduling archetypes reflecting preclinical signals (short “priming” course vs intermittent pulses):
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Schedule A — Short course (Priming): Daily IV infusion x 7 days.
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Schedule B — Intermittent (Twice-weekly): IV infusion on Days 1, 4, 8, 11, 15, 18 (6 doses over 3 weeks).
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Schedule C — Weekly pulse: IV infusion weekly x 6.
Route/infusion: IV over 10 min (slower than historical 2–3 min to minimize infusion reactions). Consider SC feasibility in a parallel PK sub-arm after IV safety is established.
Starting dose rationale: Prior human rPF4 exposures up to 5 mg/kg IV (heparin reversal) without major safety signals; cognition likely needs far lower exposure (mouse cognition used micro-mg/kg pulses). Start orders of magnitude belowprior clinical ceiling, then escalate.
Dose levels (all mg/kg):
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Level 1: 0.03
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Level 2: 0.10
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Level 3: 0.30
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Level 4: 1.00
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Level 5 (optional): 2.50 (only if lower levels are clean and PK indicates room)
(Each schedule escalates through the same levels; escalation may diverge per schedule based on safety/PK.)
Cohort size & randomization: 8 participants/level (rPF4:placebo = 6:2). Sentinel pair (1 active, 1 placebo) dosed ≥48 h before remainder.
Bayesian escalation rules (model-assisted, e.g., BOIN/CRM):
- Target DLT rate 15–25%.
- Escalate/de-escalate based on posterior probability of exceeding target.
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Intra-schedule expansion at an “acceptable risk” level to n=16 if PK/PD promising.
DLT window: From first dose to 14 days after last dose (schedule-dependent).
DLT definitions (safety-critical for HIT/thrombosis):
- Platelet drop ≥30% from baseline confirmed within 48 h or platelets <100k/µL.
- New anti-PF4 antibody seroconversion with positive platelet activation assay (e.g., serotonin-release) or any arterial/venous thrombosis.
- Grade ≥3 treatment-related AE (CTCAE v5).
- Sustained aPTT/PT pathologic shift, or D-dimer/TAT surge with clinical concern.
- Serious infusion reaction requiring vasopressors.
Automatic individual stop/hold:
- Any anti-PF4 ELISA OD > threshold + clinical lab changes; any thrombotic symptom; platelet fall trigger.
- Any heparin exposure anticipated → participant pauses/withdraws to avoid PF4–heparin immune complexes.
Cohort-level stop:
- ≥2 DLTs in a cohort (≤8 pts) → de-escalate and/or close schedule at that level.
Data Safety Monitoring Board (DSMB): Reviews after each cohort and ad hoc for safety triggers.
Manufacturing & product notes
- rPF4 GMP-grade, low endotoxin; rigorous aggregates/polyanion control; vialed for single use.
- Consider a modified rPF4 (reduced polyanion clustering) as a backup program to lower HIT risk; same protocol shell with an added sentinel arm once tox package complete.
Rationale for dose selection & schedules
- Human rPF4 has prior IV safety exposure up to 5 mg/kg (heparin reversal). Cognition signals in mice emerged with short courses or intermittent low-dose pulses; benefits persisted off-drug. Starting low (0.03–0.10 mg/kg) with careful immune/thrombotic surveillance is conservative yet practical; PK/PD will determine whether 0.3–1.0 mg/kg is needed for target engagement.
