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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; expected RIC-related skin petechiae (16.6% vs 0%) and transient pain (5.2% vs 0.4%)
  • Pre-specified secondary imaging outcomes showed greater haematoma volume reduction with RIC; a post-hoc haematoma resolution rate calculation at day 7 favoured RIC; an exploratory analysis showed a lower rate of subsequent surgical intervention 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): RIC 57 (IQR 51-67) vs Sham 60 (IQR 51-70)

Female %: RIC 29.7% vs Sham 28.8%

Hypertension: RIC 68.1% vs Sham 63.8%

Diabetes mellitus: RIC 10.0% vs Sham 10.5%

Previous antiplatelet therapy: RIC 5.2% mono / 0% dual vs Sham 8.3% mono / 0.4% dual

Baseline NIHSS, median (IQR): RIC 10 (7-13) vs Sham 9 (6-12)

Baseline haematoma volume (mL, median IQR): RIC 13.0 (8.5-18) vs Sham 11.6 (7.9-17.3)

Haematoma >20 mL, %: RIC 19.3% vs Sham 16.6%

Location — basal ganglia: RIC 90% vs Sham 93%

Location — lobar: RIC 9.2% vs Sham 6.6%

Baseline GCS, median (IQR): RIC 14 (13-15) vs Sham 14 (13-15)

Time from onset to randomisation (h, median IQR): RIC 35.7 (29.1-41.3) vs Sham 34.4 (29.4-40)

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 daysSecondaryRIC 124/229 (54.1%) vs sham 121/229 (52.8%); adjusted RR 1.03 (95% CI 0.89-1.20), p=0.66
Excellent functional outcome (mRS 0-1) at 180 daysSecondaryRIC 144/229 (62.9%) vs sham 148/229 (64.6%); adjusted RR 0.98 (95% CI 0.86-1.11), p=0.70
Favourable functional outcome (mRS 0-2) at 180 daysSecondaryRIC 169/229 (73.8%) vs sham 175/229 (76.4%); adjusted RR 0.97 (95% CI 0.88-1.07), p=0.57
Good functional outcome (mRS 0-3) at 90 daysSecondaryRIC 188/229 (82.1%) vs sham 190/229 (83.0%); adjusted RR 0.99 (95% CI 0.92-1.07), p=0.80
Good functional outcome (mRS 0-3) at 180 daysSecondaryRIC 198/229 (86.5%) vs sham 197/229 (86.0%); adjusted RR 1.00 (95% CI 0.94-1.08), p=0.90
Shift analysis across full range of mRSSecondary90 days: adjusted cOR 0.99 (95% CI 0.71-1.40), p=0.94; 180 days: adjusted cOR 1.02 (95% CI 0.73-1.45), p=0.90 — no significant difference
Change in NIHSS within 7 days post-randomisationSecondaryNo statistically significant differences between groups in adjusted analyses at 24 h, 72 h, or 7 days/discharge (e.g., 7 d adjusted MD -0.01, 95% CI -0.69 to 0.66, p=0.97)
Haematoma volume at follow-up (day 7)SecondaryRIC 5.6 mL (IQR 3.4-8.2) vs sham 6.7 mL (IQR 4.0-9.6); adjusted mean difference -1.80 mL (95% CI -2.42 to -1.17), p<0.001
Haematoma volume reduction from baseline to day 7SecondaryRIC 6.9 mL (IQR 4.7-9.9) vs sham 4.4 mL (IQR 3.1-6.8); adjusted mean difference 2.04 mL (95% CI 1.45-2.62), p<0.001
Haematoma resolution rate at day 7 (post-hoc, not prespecified)SecondaryRIC 58.1% (IQR 47.4-66.6) vs sham 40.9% (IQR 33.7-50.5); adjusted mean difference 14.07 (95% CI 11.21-16.94), p<0.001
Death within 90 daysSafetyRIC: 7/227 (3.1%) · Sham: 6/226 (2.7%) · Adjusted RD 0.3% (95% CI -2.7 to 3.3), p=0.84
Death within 180 daysSafetyRIC: 7/225 (3.1%) · Sham: 9/224 (4.0%) · Adjusted RD -1.0% (95% CI -4.4 to 2.4), p=0.57
Haematoma expansion within 7 days (≥33% relative or ≥6 mL absolute increase)SafetyRIC: 7/229 (3.1%) · Sham: 12/229 (5.2%) · Adjusted RD -2.2% (95% CI -5.0 to 2.0), p=0.41
Neurological deterioration within 24 h / 48 h / 72 h / 7 daysSafetyRIC: 24 h 5/229 (2.2%); 48 h 6/229 (2.6%); 72 h 2/229 (0.9%); 7 d 3/229 (1.3%) · Sham: 24 h 2/229 (0.9%); 48 h 4/229 (1.7%); 72 h 2/229 (0.9%); 7 d 1/229 (0.4%) · No statistically significant differences between groups at any timepoint (adjusted p values 0.21-0.99)
Subsequent surgical intervention for index ICH (exploratory)SafetyRIC: 2/229 (0.9%) · Sham: 9/229 (3.9%) · Adjusted RD -3.3% (95% CI -6.1 to -0.5), p=0.02
RIC-related skin petechiaeSafetyRIC: 38/229 (16.6%) · Sham: 0/229 (0.0%) · Adjusted RD 16.8% (95% CI 12.0-21.6), p<0.001
RIC-related transient painSafetyRIC: 12/229 (5.2%) · Sham: 1/229 (0.4%) · Adjusted RD 4.8% (95% CI 1.9-7.8), p=0.001
Serious adverse events within 90 daysSafetyRIC: 16/229 (7.0%) · Sham: 12/229 (5.2%) · Adjusted RD 1.7% (95% CI -2.7 to 6.0), p=0.45
Serious adverse events within 180 daysSafetyRIC: 19/229 (8.3%) · Sham: 20/229 (8.7%) · Adjusted RD -0.4% (95% CI -5.4 to 4.8), p=0.91
Deaths attributable to RIC interventionSafetyNone
Serious Adverse Events (90 days) - RICAdverse16/229 (7.0%)
Serious Adverse Events (90 days) - ShamAdverse12/229 (5.2%)
Serious Adverse Events (180 days) - RICAdverse19/229 (8.3%)
Serious Adverse Events (180 days) - ShamAdverse20/229 (8.7%)
Death (90 days) - RICAdverse7/227 (3.1%)
Death (90 days) - ShamAdverse6/226 (2.7%)
Death (180 days) - RICAdverse7/225 (3.1%)
Death (180 days) - ShamAdverse9/224 (4.0%)
Skin petechiae (RIC-related) - RICAdverse38/229 (16.6%)
Skin petechiae (RIC-related) - ShamAdverse0/229 (0.0%)
Transient pain (RIC-related) - RICAdverse12/229 (5.2%)
Transient pain (RIC-related) - ShamAdverse1/229 (0.4%)
Haematoma expansion (7 days) - RICAdverse7/229 (3.1%)
Haematoma expansion (7 days) - ShamAdverse12/229 (5.2%)
Subsequent surgical intervention - RICAdverse2/229 (0.9%)
Subsequent surgical intervention - ShamAdverse9/229 (3.9%)
RIC-attributable DeathsAdverse0

Subgroup Analysis

Pre-specified subgroup analyses of the primary outcome (Fig. 3) showed no evidence of effect modification. Interaction P values: sex 0.42; age (≤60 vs >60) 0.65; baseline NIHSS (≤10 vs >10) 0.92; baseline haematoma volume (≤20 vs >20 mL) 0.39; pre-stroke antiplatelet therapy 0.86; haematoma location (basal ganglia vs lobar) 0.63; side of haemorrhage (left vs right) 0.41; diabetes mellitus 0.38; history of hypertension 0.56. Point estimates were directionally consistent; the largest (non-significant) trend favouring sham was seen in patients with baseline haematoma volume >20 mL (RR 1.26, 95% CI 0.80-1.98).

Criticisms

  • Trial population restricted to moderate-volume haematomas (10-30 mL) and excluded surgical candidates, IVH, and SAH — limits generalisability
  • Conducted exclusively in China in Han Chinese participants; external validity to other populations uncertain
  • Perihaematomal oedema (pre-specified secondary imaging outcome) not assessed due to CT measurement limitations
  • Haematoma resolution rate (post-hoc) and subsequent surgical intervention (exploratory) findings are 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; regimen (unilateral, once daily) differed from protocols used in ischaemic stroke RIC trials
  • 30 mmHg sham cuff pressure may not have perfectly matched sensory experience of 200 mmHg active RIC, risking partial unblinding
  • ABC/2 method used at enrolment tends to overestimate irregular haematoma volumes, potentially including patients with true volumes below the 10-30 mL target range

Funding

National Natural Science Foundation of China; Beijing Natural Science Foundation for Outstanding Young Scholars; Beijing Nova Program; National Key R&D Program of China; Outstanding Young Talents Program of Capital Medical University

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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