UMIN-CTR Clinical Trial

Public title

Heterogeneous Treatment Effects of Early High-Dose Rehabilitation in Acute Ischemic Stroke: Target Trial Emulation and Causal Forests

Acronym

Heterogeneous Treatment Effects of Early High-Dose Rehabilitation in Acute Ischemic Stroke

Scientific Title

Heterogeneous Treatment Effects of Early High-Dose Rehabilitation in Acute Ischemic Stroke: Target Trial Emulation and Causal Forests

Scientific Title:Acronym

Heterogeneous Treatment Effects of Early High-Dose Rehabilitation in Acute Ischemic Stroke

Region

Japan

Condition

Ischemic Stroke

Classification by specialty

Neurology	Neurosurgery	Rehabilitation medicine

Classification by malignancy

Others

Genomic information

NO

Narrative objectives1

This study aims to operationally define and evaluate an "early high-dose" regimen (initiated <48 hours, duration 7 days) for acute ischemic stroke within the Target Trial Emulation (TTE) framework. In addition to estimating the average causal effect, we will use Causal Forests to identify Conditional Average Treatment Effects (CATE) tailored to patient characteristics.

Focusing on the clinically feasible first 7 days of hospitalization, we will compare dose designs to identify "high-benefit populations" (maximizing benefit while minimizing harm), thereby providing evidence to establish individualized rehabilitation strategies.

Basic objectives2

Safety,Efficacy

Basic objectives -Others

Trial characteristics_1

Confirmatory

Trial characteristics_2

Developmental phase

Not applicable

Primary outcomes

Barthel Index at discharge

Key secondary outcomes

modified Rankin Scale (mRS) score at discharge (including
achievement of mRS 0-3)

Study type

Observational

Basic design

Randomization

Randomization unit

Blinding

Control

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

Purpose of intervention

Type of intervention

Interventions/Control_1

Interventions/Control_2

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

18

years-old

<=

Age-upper limit

Not applicable

Gender

Male and Female

Key inclusion criteria

Eligibility criteria were as follows: (1) ischemic stroke (ICD-10: I63*) identified in the DPC data as either the reason for admission or the principal diagnosis; (2) age >= 18 years; (3) pre-admission modified Rankin Scale (mRS) score <= 4; and (4) confirmed stay in a stroke care unit (SCU) on the day of admission (Day 1-SCU). Time zero was defined as the admission date (Day 1). Day 1-SCU was identified using a claims-based proxy definition: the first billing date of an SCU-related management fee in the DPC data coinciding with the admission date.

Key exclusion criteria

Exclusion criteria were: (1) cases suggestive of in-hospital onset; (2) cases with clear evidence of long-term care (LTC) residence prior to admission; and (3) cases with an explicit contraindication to rehabilitation immediately after admission (e.g., immediately after decompressive craniectomy, ventricular drainage/external ventricular drain [EVD] placement, initiation of extracorporeal membrane oxygenation [ECMO], or initiation of high-dose vasopressors).

Target sample size

40000

Name of lead principal investigator

1st name	Hirofumi
Middle name
Last name	Nagayama

Organization

Kanagawa University of Human Services

Division name

Department of Occupational therapy, The School of Rehabilitation

Zip code

2388522

Address

1-10-1 Heiseicho, Yokosuka, Kanagawa, Japan

TEL

046-828-2724

Email

nagayama-ktr@kuhs.ac.jp

Name of contact person

1st name	Hirofumi
Middle name
Last name	Nagayama

Organization

Kanagawa University of Human Services

Division name

Department of Occupational therapy, The School of Rehabilitation

Zip code

2388522

Address

1-10-1 Heiseicho, Yokosuka, Kanagawa, Japan

TEL

046-828-2724

Homepage URL

Email

nagayama-ktr@kuhs.ac.jp

Institute

Mie University

Institute

Department

Personal name

Organization

Ministry of Education, Culture, Sports, Science and Technology

Organization

Division

Category of Funding Organization

Japanese Governmental office

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

Ethics approval: Not applicable; ethics review was not required for this study.

Address

Ethics approval: Not applicable; ethics review was not required for this study.

Tel

Ethics approval: Not applicable; ethics review was

Email

Ethics approval: Not applicable; ethics review was not required for this study.

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

三重大学

Date of disclosure of the study information

2026

Year

04

Month

30

Day

URL releasing protocol

Publication of results

Unpublished

URL related to results and publications

Number of participants that the trial has enrolled

Results

Results date posted

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Participant flow

Adverse events

Outcome measures

Plan to share IPD

IPD sharing Plan description

Recruitment status

Preinitiation

Date of protocol fixation

2026

Year

02

Month

21

Day

Date of IRB

Anticipated trial start date

2026

Year

02

Month

22

Day

Last follow-up date

2026

Year

03

Month

31

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

The aim of this study is, within a target trial emulation (TTE) framework, to operationally define an "early high-dose" rehabilitation regimen initiated within 48 hours and evaluated over the first 7 hospital days among patients with acute ischemic stroke, and to rigorously estimate its average causal effect. In addition, we will use causal forests to identify heterogeneity of treatment effects according to patient characteristics, expressed as conditional average treatment effects (CATE). We focus on a 7-day regimen from admission because it is clinically feasible to implement, and we will compare implementable dose designs and clarify a "high-benefit" subgroup from the perspective of maximizing benefit and minimizing harm, thereby generating evidence to inform personalized rehabilitation strategies.

[Protocol amendment: 2026-05-25]
Following consultation among the co-authors, the analytical scope of this study has been refined to focus on the core effectiveness outcomes, and the secondary outcomes have been reduced to mRS at discharge only.
[Removed secondary outcomes]
- BI shift categories (0-39, 40-59, 60-84, 85-100)
- Achievement of BI >=60 at discharge
- Safety outcomes (in-hospital mortality, new-onset aspiration pneumonia, and trauma/injury)
[Rationale]
This is a retrospective analysis of an existing DPC database, with data collection completed prior to registration. After review of the analytical plan among the co-authors, we decided to focus the methodological scope of this study on the primary effectiveness outcome (discharge BI) and the heterogeneity of treatment effect (HTE) analysis.
[Unchanged]
- Primary outcome (Barthel Index at discharge)
- Study design (Target Trial Emulation + Causal Forest)
- Eligibility criteria and intervention definition

Registered date

2026

Year

02

Month

03

Day

Last modified on

2026

Year

05

Month

25

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000068230