Encephalopathy Connectomic Collapse Atlas (ECCA-HEP) | First-in-Human (FIH) Clinical Trial Design — Hepatic Encephalopathy

SCF-ECCA-HEP-FIH-CTD-0002

First-in-Human (FIH) Clinical Trial Design

Hepatic Encephalopathy

SCF Multi-Omics Neuroimmune Connectomic Reconstruction Platform

Adaptive Biomarker-Guided Precision Acupuncture Clinical Administration Protocol

Encephalopathy Connectomic Collapse Atlas (ECCA-HEP)

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I. TRIAL OVERVIEW

Study Title

A First-in-Human Adaptive Biomarker-Guided Precision Acupuncture Study for Hepatic Encephalopathy Utilizing the SCF Encephalopathy Connectomic Collapse Atlas (ECCA-HEP).

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Study Phase

Phase 0/Ia

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Trial Design

• Prospective
• Adaptive
• Biomarker-guided
• Open-label
• Dose-escalation neuromodulation study
• Safety and feasibility primary objective
• Integrated real-time biomarker monitoring
• Continuous hepatic-neuroimmune-connectomic surveillance

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Study Duration

Total Duration

16 Weeks

Screening

2 Weeks

Active Treatment

12 Weeks

Follow-Up

2 Weeks

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II. PRIMARY OBJECTIVES

Safety

Evaluate:

• Serious adverse events (SAEs)
• Hepatic decompensation
• Hepatic coma progression
• New-onset seizures
• Cognitive worsening
• Autonomic instability
• Variceal bleeding events
• Ascites progression

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Feasibility

Determine:

• Treatment adherence
• Biomarker collection feasibility
• Continuous monitoring compliance
• Neuromodulation tolerability

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III. SECONDARY OBJECTIVES

Evaluate:

• Hyperammonemia reduction
• Neuroimmune normalization
• Astrocyte injury reduction
• Connectomic restoration
• Autonomic stabilization
• Cognitive recovery
• Quality-of-life improvement
• Hospitalization reduction

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IV. TARGET POPULATION

Eligible Hepatic Encephalopathy Types

Minimal Hepatic Encephalopathy (MHE)

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Overt Hepatic Encephalopathy

Grade I

Grade II

Grade III (stable only)

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Cirrhosis-Associated Hepatic Encephalopathy

• Viral cirrhosis
• Alcoholic cirrhosis
• NASH-associated cirrhosis
• Cryptogenic cirrhosis

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Recurrent Hepatic Encephalopathy

≥2 episodes within previous year

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V. INCLUSION CRITERIA

Age:

18–80

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Confirmed hepatic encephalopathy

West Haven Grade 0–III

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Ammonia elevation

Above laboratory reference range

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MoCA:

10–28

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Stable standard-of-care treatment

Minimum 14 days

Including:

• Lactulose
• Rifaximin
• Nutritional support

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SCF Hepatic Connectomic Collapse Score

20–80

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VI. EXCLUSION CRITERIA

• Acute liver failure
• Active GI bleeding
• Active spontaneous bacterial peritonitis
• Hepatorenal syndrome requiring dialysis
• Mechanical ventilation
• Uncontrolled epilepsy
• Intracranial hemorrhage
• Liver transplantation within 90 days
• Pregnancy

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VII. SCF HEPATIC ENCEPHALOPATHY REAL-TIME BIOMARKER PANEL

Tier 1 Hyperammonemia Panel

Primary Endpoint

Hyperammonemia Severity Index (HSI)

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Tier 2 Liver Function Panel

Endpoint

Hepatic Function Stability Index (HFSI)

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Tier 3 Astrocyte Injury Panel

Endpoint

Astrocytic Dysfunction Index (ADI)

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Tier 4 Neuroaxonal Injury Panel

Endpoint

Neuroaxonal Injury Index (NAII)

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Tier 5 Neuroimmune Activation Panel

Endpoint

Neuroimmune Amplification Index (NAI)

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Tier 6 Connectomic Monitoring Panel

Endpoint

Connectomic Collapse Index (CCI)

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Tier 7 Autonomic Monitoring Panel

Endpoint

Autonomic Collapse Index (ACI)

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VIII. ACUPUNCTURE ADMINISTRATION PROTOCOL

Cohort A

Low Intensity

Frequency:

2 Sessions/Week

Duration:

20 Minutes

Primary Points:

• GV20
• PC6
• ST36
• SP6
• HT7

Goal:

Initial neuro-autonomic stabilization

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Cohort B

Moderate Intensity

Frequency:

3 Sessions/Week

Duration:

30 Minutes

Additional Points:

• GV24
• LI11
• LV3
• CV12

Goal:

Neuroimmune and hepatic-connectomic modulation

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Cohort C

High Intensity

Frequency:

5 Sessions/Week

Duration:

40 Minutes

Additional Points:

• Sishencong
• CV17
• KI3
• LR14
• Auricular Shenmen

Goal:

Maximum connectomic restoration protocol

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IX. REAL-TIME ESCALATION RULES

Escalation Criteria

Must Meet ALL Conditions for 14 Consecutive Days

Hyperammonemia

Plasma ammonia reduction

≥20%

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Neuroimmune Activity

IL-6 reduction

≥20%

AND

TNF-α reduction

≥15%

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Astrocyte Injury

GFAP stable or reduced

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Connectomics

qEEG connectivity improvement

≥10%

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Cognition

MoCA improvement

≥2 points

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Autonomics

HRV SDNN increase

≥10%

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Escalation Action

Advance to next cohort

within 7 days

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X. DE-ESCALATION RULES

Immediate De-Escalation

If ANY occur

Hyperammonemia

Ammonia increase

≥25%

from baseline

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Liver Decompensation

MELD increase

≥20%

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Astrocyte Injury

GFAP increase

≥25%

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Neuroaxonal Injury

NfL increase

≥25%

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Connectomics

EEG deterioration

≥20%

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Cognition

MoCA decline

≥3 points

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Clinical

New Grade III/IV HE episode

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Action

Return to previous cohort

Repeat biomarker assessment

within 24–48 hours

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XI. STOPPING RULES

Immediate Trial Suspension

Any of the Following

• Hepatic coma
• ICU admission
• Acute liver failure
• Variceal hemorrhage
• Sepsis
• Status epilepticus
• Unexpected SAE

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Subject Withdrawal

If:

Plasma ammonia doubles from baseline

OR

GFAP doubles from baseline

OR

MELD increases >30%

OR

SCF Hepatic Connectomic Collapse Score worsens >30%

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XII. PRIMARY ENDPOINTS

Safety Endpoints

• SAE incidence
• Hepatic decompensation
• Hospitalization
• Cognitive deterioration
• Autonomic instability

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Biomarker Safety Endpoints

• Ammonia stabilization
• GFAP stabilization
• NfL stabilization
• Cytokine stabilization

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XIII. SECONDARY ENDPOINTS

Connectomic Restoration

• qEEG connectivity
• rs-fMRI connectivity
• DTI FA

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Cognitive Recovery

• MoCA
• Psychometric Hepatic Encephalopathy Score (PHES)
• Trail Making Test A/B

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Autonomic Recovery

• HRV
• COMPASS-31

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Hepatic Improvement

• MELD
• Bilirubin
• INR
• Albumin

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Quality of Life

• CLDQ
• EQ-5D-5L

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XIV. COMPOSITE SCF HEPATIC ENCEPHALOPATHY RESPONSE SCORE (SCF-HERS)

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Interpretation

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XV. TRANSLATIONAL DECISION GATES

GO

Requirements:

• No SAE signal
• Ammonia reduction ≥20%
• Improved qEEG connectivity
• Improved MoCA
• Stable MELD

Proceed to Phase Ib

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CONDITIONAL GO

Requirements:

• Acceptable safety
• Mixed biomarker response
• Stable hepatic function

Protocol optimization required

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NO-GO

Requirements:

• Hepatic decompensation signal
• Biomarker worsening
• Connectomic deterioration
• Increased hospitalization frequency

Terminate development

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XVI. FDA-ALIGNED REAL-TIME SAFETY DASHBOARD

Green Zone

• Ammonia ↓ ≥20%
• GFAP stable
• NfL stable
• MELD unchanged/improved
• HRV improved

Continue protocol

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Yellow Zone

• Ammonia fluctuation ±15%
• Mild cytokine increase
• Mild EEG deterioration

Increase monitoring frequency

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Red Zone

• Ammonia ↑ ≥25%
• MELD ↑ ≥20%
• GFAP ↑ ≥25%
• NfL ↑ ≥25%
• New Grade III/IV HE episode

Immediate de-escalation or withdrawal evaluation

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NEXT CLINICAL ADMINISTRATION PROTOCOL

SCF-ECCA-PVLC-FIH-CTD-0003

Post-Viral / Long COVID Encephalopathy FIH Clinical Trial Design

MASTER REGISTRY INDEX

• SCF-ECCA-HEP-FIH-CTD-0002 — Hepatic Encephalopathy FIH Clinical Trial Design
• SCF-ECCA-HEP-BIO-0002 — Hepatic Encephalopathy Biomarker Panel
• SCF-ECCA-HEP-ACU-0002 — Hepatic Encephalopathy Acupoint Neuro-Circuit Atlas
• SCF-ECCA-0001 — Encephalopathy Connectomic Collapse Atlas
• SCF-CLINDEV-0001 — SCF Clinical Development Framework
• SCF-BIOMARKER-ENDPOINTS-0001 — SCF Biomarker Endpoint Validation Framework
• SCF-ACU-NEURO-ATLAS-0001 — SCF Neural Mapping Schema
• SCF-HEPATIC-CONNECTOME-0001 — Hepatic Neuroimmune Connectomic Reconstruction Framework