Safety and efficacy of transcranial direct current stimulation in addition to constraint-induced movement therapy for post-stroke motor recovery (TRANSPORT2): a phase 2, multicentre, randomised, sham-controlled triple-blind trial.

BACKGROUND: Motor impairments contribute substantially to long-term disability following stroke. Studies of transcranial direct current stimulation (tDCS), combined with various rehabilitation therapies, have shown promising results in reducing motor impairment. We aimed to evaluate the safety and efficacy of three doses of tDCS in combination with modified constraint-induced movement therapy (mCIMT) in people who have had their first ischaemic stroke in the preceding 1-6 months.

METHODS: We conducted a phase 2, multicentre, randomised, triple-blind, sham-controlled study with a blinded centrally scored primary outcome. The trial was conducted at 15 medical centres in the USA. Eligible participants were enrolled between 1 month and 6 months after their first ischaemic stroke. Inclusion criteria required participants to have a persistent motor deficit, defined as a Fugl-Meyer Upper-Extremity (FM-UE) score of 54 or lower (out of 66), and two consecutive baseline visits (separated by 7-14 days) with an absolute difference of 2 or fewer points on the FM-UE scale. Participants were randomly assigned to treatment groups by an adaptive randomisation algorithm hosted on the TRANSPORT2 WebDCU study website. Participants received either sham, 2 mA, or 4 mA of bi-hemispheric tDCS for the first 30 min and mCIMT with 120 min of active therapy time per session, administered over ten sessions during a 2-week period. The primary endpoint was the change in FM-UE score from baseline to day 15, which was analysed in all participants who have data both at baseline and post-baseline (modified intention-to-treat group). Safety outcomes were analysed in all participants. TRANSPORT2 is registered at clinicaltrials.gov (NCT03826030) and its status is completed.

FINDINGS: 129 participants were recruited between Sept 9, 2019, and June 14, 2024, and 43 participants were randomly assigned to each group. 54 (42%) of 129 participants were female, and 69 (53%) were White. Two participants in the sham plus mCIMT group withdrew consent before the day 15 assessment and were excluded from the primary analysis. The median baseline FM-UE score was 39·0 (IQR 30·0-46·0) in the sham plus mCIMT group, 39·0 (27·0-48·0) in the 2 mA plus mCIMT group, and 40·0 (27·0-48·0) in the 4 mA plus mCIMT group. For the primary outcome, the adjusted mean change from baseline to day 15 in FM-UE was 4·91 (3·00-6·82) for sham plus mCIMT, 3·87 (2·00-5·74) for 2 mA plus mCIMT, and 5·53 (3·64-7·42) for 4 mA plus mCIMT (p=0·39). No clinically important adverse events were observed in any group and no deaths were reported.

INTERPRETATION: tDCS at doses of 2 mA or 4 mA, in addition to mCIMT, did not lead to further reduction in motor impairment in patients 1-6 months after stroke, but it was safe, well tolerated, and feasible for clinical practice. tDCS at higher doses (ie, >4 mA) might be a consideration for future trials in addition to balancing known covariates affecting stroke recovery during the group allocation.

FUNDING: National Institute of Neurological Disorders and Stroke.