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RICH-2

Remote ischaemic conditioning in patients with supratentorial intracerebral haemorrhage (RICH-2): a multicentre, randomised, sham-controlled phase 3 trial in China

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Year of Publication: 2026

Authors: Zhao W, Wang J, Yu X, ..., for the RICH-2 Investigators

Journal: eClinicalMedicine

Citation: eClinicalMedicine 2026;95:103900

Link: https://doi.org/10.1016/j.eclinm.2026.103900

Clinical Question

Does adjunctive remote ischaemic conditioning improve 90-day functional outcomes in adults with acute supratentorial intracerebral haemorrhage managed without surgery?

Bottom Line

In patients with acute supratentorial ICH not requiring surgery, adding RIC to standard medical management did NOT improve 90-day functional outcomes (mRS 0-2: 68.1% vs 71.2%; adjusted RR 0.97, p=0.61). RIC was safe and feasible, but should not be adopted as routine therapy in this population. Further investigation may be warranted in selected subpopulations (e.g., larger haematomas or surgical patients) with optimised protocols.

Major Points

  • First adequately powered, multicentre, randomised, sham-controlled, outcome-blinded phase 3 trial of RIC in supratentorial ICH not requiring surgery
  • RIC did NOT improve the primary outcome of favourable functional outcome (mRS 0-2) at 90 days: 68.1% RIC vs 71.2% sham; adjusted RR 0.97 (95% CI 0.87-1.08), p=0.61
  • RIC was safe and well-tolerated: SAEs within 180 days 8.3% vs 8.7%; no deaths attributable to RIC
  • Post-hoc analyses suggested greater reduction in haematoma volume, enhanced haematoma resolution at 7 days, and lower subsequent surgical intervention rates with RIC
  • Findings argue against routine adoption of RIC for non-surgical supratentorial ICH but support further study in selected populations (larger haematomas, surgical decompression) and optimised protocols

Design

Study Type: Multicentre, randomised, sham-controlled, parallel-group, outcome-blinded phase 3 trial

Randomization: 1

Blinding: Outcome-blinded; participants, treating physicians, outcome assessors, and study investigators were blinded to treatment assignment; RIC and sham devices had identical appearances with treatment-related parameters disabled on screens

Allocation: 1:1, real-time internet-based system, stratified by baseline NIHSS (≤10 vs >10) and baseline haematoma volume (≤20 mL vs >20 mL), with fixed block size of six

Enrollment Period: April 22, 2021 to April 30, 2024

Follow-up Duration: 180 days

Centers: 20

Countries: China

Sample Size: 458

Analyzed: 458

Analysis: Intention-to-treat for primary efficacy outcome; safety analysis in the safety set (participants receiving ≥1 cycle of RIC or sham)

Power Calculation: Assumed 30% favourable outcome (mRS 0-2) at 90 days in sham group and 43% in RIC group (from pilot data); two-sided alpha 0.05, 80% power, 1:1 allocation → 215 per group (430 total), inflated to 452 to account for 5% loss to follow-up

Registration: ClinicalTrials.gov NCT04657133

Inclusion Criteria

  • Adults aged 18-80 years
  • Imaging-confirmed supratentorial intracerebral haemorrhage
  • Randomisable and treatable within 24-48 hours of symptom onset
  • NIHSS score 6-20 (moderate-to-severe neurological impairment)
  • Haematoma volume 10-30 mL (assessed by ABC/2 method)
  • Glasgow Coma Scale >8

Exclusion Criteria

  • Surgery performed or planned (haematoma evacuation or decompressive craniectomy)
  • Concomitant subarachnoid haemorrhage or intraventricular haemorrhage
  • Conditions precluding RIC procedures (severe soft tissue injury, fracture, or peripheral vascular disease involving the upper limb)
  • Estimated life expectancy <6 months due to severe comorbid condition

Baseline Characteristics

Median Age (years): 58 (IQR 51-68)

Female %: 29.3%

Total Enrolled: 458

RIC Group: 229

Sham Group: 229

Arms

FieldRemote Ischaemic Conditioning (RIC)Control
N229229
InterventionUpper-limb blood pressure cuff inflated to 200 mmHg, 5 cycles of 5-min inflation followed by 5-min deflation (total ~45 min/session), once daily for 7 consecutive days, started within 10 min of randomisation, plus standard medical managementUpper-limb cuff inflated to 30 mmHg, 5 cycles of 5-min inflation/deflation, once daily for 7 consecutive days, plus standard medical management
Duration7 days7 days

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Favourable functional outcome defined as modified Rankin Scale (mRS) score of 0-2Primary163/229 (71.2%)156/229 (68.1%)0.970.61
Excellent functional outcome (mRS 0-1) at 90 and 180 daysSecondaryNot reported in available text
Favourable functional outcome (mRS 0-2) at 180 daysSecondaryNot reported in available text
Good functional outcome (mRS 0-3) at 90 and 180 daysSecondaryNot reported in available text
Shift analysis across full range of mRS at 90 and 180 daysSecondaryNot reported in available text
Change in NIHSS within 7 days post-randomisationSecondaryNot reported in available text
Haematoma volume at baseline and day 7 and change from baselineSecondaryPost-hoc analysis suggested greater haematoma volume reduction and enhanced haematoma resolution at 7 days with RIC
Serious adverse events within 180 daysSafetyRIC: 19/229 (8.3%) · Sham: 20/229 (8.7%)
Deaths attributable to RIC interventionSafetyNone
Subsequent surgical intervention for index ICH (exploratory)SafetyLower incidence in RIC group (post-hoc)
Serious Adverse Events (180 days) - RICAdverse19/229 (8.3%)
Serious Adverse Events (180 days) - ShamAdverse20/229 (8.7%)
RIC-attributable DeathsAdverse0

Subgroup Analysis

Not detailed in the extracted text; authors suggest future research focus on populations more likely to benefit (e.g., patients with large haematomas or those undergoing surgical decompression)

Criticisms

  • Trial population restricted to moderate-volume haematomas (10-30 mL) and excluded surgical candidates, IVH, and SAH — limits generalisability
  • Conducted exclusively in China; external validity to other populations uncertain
  • Perihaematomal oedema (pre-specified secondary imaging outcome) not assessed due to CT measurement limitations
  • Haematoma resolution / lower surgical intervention findings are post-hoc and hypothesis-generating only
  • Sham group favourable outcome (71.2%) far exceeded the assumed 30% used for power calculation, suggesting the trial may have been underpowered to detect a modest treatment effect in a population with better-than-expected prognosis
  • Treatment initiation window (24-48 h) may have missed an earlier therapeutic window for RIC's mechanism

Funding

National Natural Science Foundation of China; Beijing Natural Science Foundation; National Key R&D Program of China

Based on: RICH-2 (eClinicalMedicine, 2026)

Authors: Zhao W, Wang J, Yu X, ..., for the RICH-2 Investigators

Citation: eClinicalMedicine 2026;95:103900

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