RE-OPEN: Randomised trial of biosimilar TNK versus TPA during endovascular therapy for acute ischaemic stroke due to large vessel occlusions.

Rationale: Rapid and timely treatment with intravenous thrombolysis and endovascular treatment (EVT) in patients with acute ischaemic stroke (AIS) and large vessel occlusion (LVO) significantly improves patient outcomes. Bridging therapy is the current standard of care in these patients. However, an incompletely answered question is whether one thrombolytic agent is better than another during bridging therapy. Aim: The current study aims to understand if one thrombolytic agent is superior to the other during bridging therapy in the treatment of AIS and LVO. Sample size estimates: Using 80% power and an alpha error of 5 %, presuming a 10% drop out rate, a total of 372 patients will be recruited for the study. Methods and design: This study is a prospective, randomised, multicentre, open-label trial with blinded outcome analysis design. Study outcomes: The primary outcomes include proportion of patients who will be independent at 3 months (modified Rankin score (mRS) ≤2 as good outcome) and proportion of patients who achieve recanalisation modified thrombolysis in cerebral infarction grade 2b/3 at first angiography run at the end of EVT. Secondary outcomes include proportion of patients with early neurological improvement, rate of symptomatic intracerebral haemorrhage (ICH), rate of any ICH, rate of any systemic major or minor bleeding and duration of hospital stay. Safety outcomes include any intracranial bleeding or symptomatic ICH. Discussion: This trial is envisioned to confirm the theoretical advantages and increase the strength and quality of evidence for use of tenecteplase (TNK) in practice. Also, it will help to generate data on the efficacy and safety of biosimilar TNK. Trial registration number: CTRI/2022/01/039473.

Impact of the COVID-19 Pandemic on the Frequency, Clinical Spectrum and Outcomes of Pediatric Guillain-Barré Syndrome in India: A Multicentric Ambispective Cohort Study.

Objective: To study impact of COVID-19 pandemic on frequency, clinical/electrophysiological profile and treatment outcomes in pediatric Guillain-Barré syndrome (GBS). Background: GBS is the most frequent cause of pediatric acute flaccid paralysis. The effect of the COVID-19 pandemic on pediatric GBS is unclear in the literature. Methods: We conducted an ambispective, multicentric, cohort study involving 12 of 27 centres in GBS Consortium, during two periods: pre-COVID-19 (March-August 2019) and during COVID-19 (March-August 2020). Children ≤12 years who satisfied National Institute of Neurological Diseases and Stroke criteria for GBS/variants were enrolled. Details pertaining to clinical/laboratory parameters, treatment and outcomes (modified Rankin Scale (mRS) at discharge, GBS Disability score at discharge and 3 months) were analysed. Results: We enrolled 33 children in 2019 and 10 in 2020. Children in 2020 were older (median 10.4 [interquartile range 6.75-11.25] years versus 5 (2.5-8.4) years; P = 0.022) and had more sensory symptoms (50% versus 18.2%; P = 0.043). The 2020 group had relatively favourable mRS at discharge (median 1 (1-3.5) versus 3 (2-4); P = 0.042) and GBS disability score at 3 months (median 0 (0-0.75) versus 2 (0-3); P = 0.009) compared to 2019. Multivariate analysis revealed bowel involvement (P = 0.000) and ventilatory support (P = 0.001) as independent predictors of disability. No child in 2020 had preceding/concurrent SARS-CoV2 infection. Conclusions: The COVID-19 pandemic led to a marked decline in pediatric GBS presenting to hospitals. Antecedent illnesses, clinical and electrophysiological profile of GBS remained largely unchanged from the pre-pandemic era.

Impact of COVID-19 on Guillain-Barre Syndrome in India: A Multicenter Ambispective Cohort Study.

Introduction/Aims: Studies conducted during the coronavirus disease 2019 (COVID-19) pandemic have reported varied data regarding the incidence of Guillain-Barre syndrome (GBS). The present study investigated demographic and clinical features, management, and outcomes of patients with GBS during a specified period of the COVID-19 pandemic, and compared these features to those of GBS in the previous year. Methods: A multicenter, ambispective cohort study including 26 centers across India was conducted. Data from a pre-COVID-19 period (March 1 to August 31, 2019) were collected retrospectively and collected ambispectively for a specified COVID-19 period (March 1 to August 31, 2020). The study was registered with the Clinical Trial Registry India (CTRI/2020/11/029143). Results: Data from 555 patients were included for analysis: pre-COVID-19 (n = 334) and COVID-19 (n = 221). Males were more commonly affected during both periods (male:female, 2:1). Gastroenteritis was the most frequent antecedent event in 2019 (17.4%), whereas fever was the most common event in 2020 (10.7%). Paraparesis (21.3% versus [vs.] 9.3%, P = 0.001) and sensory involvement (51.1% vs. 41.3%; P = 0.023) were more common during COVID-19 in 2020, whereas back pain (26.3% vs. 18.4%; P = 0.032) and bowel symptoms (20.7% vs. 13.7%; P = 0.024) were more frequent in the pre-COVID period. There was no difference in clinical outcomes between the two groups in terms of GBS disability score at discharge and 3 months after discharge. Independent predictors of disability in the pre-COVID period included areflexia/hyporeflexia, the requirementfor intubation, and time to bulbar weakness; in the COVID-19 period, independent predictors included time from onset to admission, intubation, and intubation requirement. The mortality rate was 2.3% during the entire study period (13/555 cases). Discussion: Results of this study revealed an overall reduction in the frequency of GBS during the pandemic. The lockdown likely reduced the risk for antecedent infections due to social distancing and improved hygiene, which may have resulted in the reduction of the frequency of GBS.

INSTRuCT: Protocol, Infrastructure, and Governance.

Background and Purpose: Very few large scale multicentric stroke clinical trials have been done in India. The Indian Council of Medical Research funded INSTRuCT (Indian Stroke Clinical Trial Network) as a task force project with the objectives to establish a state-of-the-art stroke clinical trial network and to conduct pharmacological and nonpharmacological stroke clinical trials relevant to the nation and globally. The purpose of the article is to enumerate the structure of multicentric stroke network, with emphasis on its scope, challenges and expectations in India. Methods: Multiple expert group meetings were conducted by Indian Council of Medical Research to understand the scope of network to perform stroke clinical trials in the country. Established stroke centers with annual volume of 200 patients with stroke with prior experience of conducting clinical trials were included. Central coordinating center, standard operating procedures, data and safety monitoring board were formed. Discussion: In first phase, 2 trials were initiated namely, SPRINT (Secondary Prevention by Structured Semi-Interactive Stroke Prevention Package in India) and Ayurveda treatment in the rehabilitation of patients with ischemic stroke in India (RESTORE [Rehabilitation of Ischemic stroke Patients in India: A Randomized controlled trial]). In second phase, 4 trials have been approved. SPRINT trial was the first to be initiated. SPRINT trial randomized first patient on April 28, 2018; recruited 3048 patients with an average of 128.5 per month so far. The first follow-up was completed on May 27, 2019. RESTORE trial randomized first patient on May 22, 2019; recruited 49 patients with an average of 3.7 per month so far. The first follow-up was completed on August 30, 2019. Conclusions: In next 5 years, INSTRuCT will be able to complete high-quality large scale stroke trials which are relevant globally. REGISTRATION: URL: http://www.ctri.nic.in/; Unique Identifier: CTRI/2017/05/008507.

Efficacy and Safety of Intravenous Tenecteplase Bolus in Acute Ischemic Stroke: Results of Two Open-Label, Multicenter Trials.

BACKGROUND: Tenecteplase (TNK-tPA) is a promising third-generation plasminogen activator, because of its greater fibrin specificity and longer half-life than alteplase. There is a paucity of studies on intravenous thrombolysis using TNK-tPA in developing countries. The present study has been undertaken to compare the efficacy and safety of TNK-tPA with alteplase. METHODS: Two studies were conducted. Study I was an open-label, randomized study in which two doses of TNK-tPA (0.1 and 0.2 mg/kg) were compared. Study II was an open-label study in which TNK-tPA 0.2 mg/kg bolus was compared with historical controls. The primary endpoint for study I and study II was an improvement of ≥ 8 points or a score of 0 on the National Institutes of Health Stroke Scale (NIHSS) [major neurological improvement (MNI)] at 24 h. Secondary endpoints for both studies were neurological improvement as assessed using the NIHSS score, modified Rankin Scale (mRS) score and the Barthel Index (BI) on days 7, 30 and 90. Minimal disability was defined as an mRS score of 0 or 1 and good functional recovery as a BI score of 50-90. Safety was assessed by the proportion of patients having symptomatic intracranial hemorrhage (sICH) within 36 h and asymptomatic intracranial hemorrhage at 48 h after treatment. RESULTS: In study I, 20 patients received 0.1 mg/kg and 30 received 0.2 mg/kg TNK-tPA. There was no significant difference in MNI at 24 h between 0.1 and 0.2 mg/kg TNK-tPA doses. The patients given 0.2 mg/kg TNK-tPA had a significantly better 3-month outcome (minimal disability, p = 0.007). There was no sICH in study I. In study II, 62 patients (one lost to follow-up) received 0.2 mg/kg TNK-tPA. MNI was noted in ten patients (16.4%), 3-month minimal disability was noted in 37 patients (60.7%), and good functional recovery was seen in 33 patients (54.1%). sICH occurred in one patient, and four patients died. Pooled data of patients in study I and study II receiving 0.2 mg/kg TNK-tPA were compared with data from the historical National Institute of Neurological Disorders and Stroke (NINDS) trial. For comparison, the primary endpoint of the NINDS trial (improvement on NIHSS of ≥ 4 points or a score of 0 at 24 h) was taken. The primary endpoint though was not significantly different (58.2% vs. 47%, p = 0.08), but with TNK-tPA, greater neurological improvement, minimal disability (70.3 vs. 39%, p < 0.001) and good functional recovery (36.3 vs. 16%, p < 0.001) was noted at 3 months. There was a lower incidence of sICH (1.1 vs. 6.4%, p = 0.05) and lower 3-month mortality (5.5 vs. 17%, p = 0.01) noted with TNK-tPA compared with alteplase. CONCLUSIONS: Intravenous TNK-tPA 0.2 mg/kg administered within 3 hours of symptom onset seems to be well tolerated and effective option in patients with acute ischemic stroke. TRIAL REGISTRATION: Clinical Trials Registry-India, www.ctri.nic.in ; unique identifiers: CTRI/2009/091/000251 and CTRI/2015/02/005556.

Shoulder taping reduces injury and pain in stroke patients: randomized controlled trial.

OBJECTIVES: We aimed to study the effectiveness of shoulder taping and conventional treatment vs sham taping and conventional treatment in prevention of shoulder injuries in patients with acute stroke. METHODS: This study was a multicenter, interventional, prospective, randomized, outcome-blinded trial (PROBE design). All first-ever stroke patients were included within 48 hours of stroke onset (August 2009-October 2011). The treatment group included shoulder taping and conventional treatment, and the control group received sham taping and conventional treatment. Primary outcomes were changes in visual analog scale (VAS) and shoulder pain and disability index (SPADI), and secondary outcomes were changes in shoulder range of motion (flexion and abduction) at days 14 and 30. Clinical trials registration no. NCT 01062308. RESULTS: There were 80 patients in the treatment arm and 82 in the control arm. There was a better reduction of VAS (on day 14: mean difference 3.7 mm, p = 0.45; on day 30: 11.9 mm, p = 0.03) and SPADI scores (on day 14: mean difference 3.5, p = 0.33; on day 30: 9.3, p = 0.04) in the treatment arm. CONCLUSIONS: Although there was a trend toward pain reduction and functional improvement associated with shoulder taping for 2 weeks after acute stage of stroke, this did not reach statistical significance. The long-term effects of taping need to be studied in large trials. CLASSIFICATION OF EVIDENCE: This study provided Class III evidence that tri-pull shoulder taping was ineffective in significantly reducing shoulder pain in patients with acute stoke.

Complications in acute stroke in India (CAST-I): a multicenter study.

The prognosis and final outcome in patients who sustain stroke are significantly affected by medical complications occurring during the acute phase of stroke. Only limited information is available from India and other developing countries regarding acute complications of stroke. This study examined the frequency of acute stroke and the factors associated with complications of stroke in India. In this prospective multicenter study, running from March 2008 to September 2009, 6 hospitals collected information on complications of first-ever stroke during admission. Complications were defined in accordance with standard criteria. Outcome at 30 days poststroke was assessed using the modified Rankin Scale. Stroke characteristics, length of hospital stay, and stroke severity (based on the National Institutes of Health Stroke Scale) were documented. Hematologic (ie, hemoglobin) and biochemical (ie, total proteins and albumin) parameters also were obtained. A total of 449 patients out of the recruited 476 completed follow-up. The mean age was 58.1 ± 13.7 years (range, 16-96 years), and the majority were men (n = 282; 62.8%). The mean National Institutes of Stroke Scale score was 10.2 ± 5.3. Overall, 206 patients (45.9%) experienced complications during admission. In the logistic regression analysis, limb weakness (odds ratio [OR], 0.12; 95% confidence interval [CI], 0.02-0.67; P = .01), anemia (OR, 0.35; 95% CI, 0.15-0.81; P = .01), length of hospital stay (OR, 0.89; 95% CI, 0.85-0.94; P < .0001), and stroke severity (OR, 0.27; 95% CI, 0.10-0.72; P = .01) were the variables associated with complications. Such complications as urinary tract infection (OR, 0.31; 95% CI, 0.13-0.78; P = .01), chest infection (OR, 1.81; 95% CI, 1.12-2.93; P = .02), bedsores (OR, 3.52; 95% CI, 1.02-12.08; P = .05), other pain (OR, 0.21; 95% CI, 0.09-0.49; P < .0001), and depression (OR, 2.22; 95% CI, 1.30-3.80; P < .01) were associated with poor outcome. Our study shows high rates of complication in acute stroke. Limb weakness, stroke severity, length of hospital stay, and anemia were the factors associated with complications. Other complications, such as urinary tract infection, chest infection, bedsores, other pain, and depression, can lead to poor outcome.

Premorbid nutrition and short term outcome of stroke: a multicentre study from India.

BACKGROUND: Little is known about the impact of premorbid undernutrition on stroke outcome in developing countries. AIM: To study the impact of premorbid undernutrition status, measured by the Subjective Global Assessment (SGA) tool, on short term stroke outcome. METHODS: First ever stroke patients admitted to six major hospitals in North and South India participated in this study from 1 March 2008 to 30 September 2009. The SGA tool was administered within 48 h of stroke onset, and 6 months premorbid nutritional status was rated as well nourished (A rating) and undernourished (B and C ratings) using this tool. Stroke outcome was assessed after 30 days using the modified Rankin scale (mRs), and a mRs score >3 was defined as a poor outcome. Statistical analyses were performed using SPSS Statistics V.17.0. RESULTS: Of 477 patients enrolled, 448 patients were included in the analyses. Mean age was 58.1±13.7 years (range 16-96) and 281 (62.7%) patients were men. At admission, premorbid undernutrition was found in 121 (27.2%) patients. Older age (OR 4.99, CI 1.26 to 19.64, p=0.021), hypertension (OR 1.99, CI 1.04 to 3.79, p=0.037) and patients from Andhra Pradesh State (OR 1.87, CI 1.05 to 3.32, p=0.032) were predictors of undernutrition in multiple logistic regression analysis. Premorbid undernutrition (OR 1.99, CI 1.20 to 3.31, p=0.007) and length of hospital stay (OR 3.41, CI 1.91 to 6.06, p<0.0001) were the independent predictors of poor outcome in the multiple logistic regression model. CONCLUSIONS: High rates of premorbid undernutrition in stroke patients were found. Age, hypertension and patients from Andhra Pradesh State were predictors of premorbid undernutrition. Premorbid undernutrition was associated with poor stroke outcome. The results provide opportunities for primary prevention and improving stroke outcome.

Stroke and thrombolysis in developing countries.

BACKGROUND: Over the past few decades, the burden of stroke in developing countries has grown to epidemic proportions. Two-thirds of global stroke occurs in low- and middle-income countries. We have found that little information is obtainable concerning the availability of thrombolysis therapy in developing countries. SUMMARY OF REVIEW: The epidemiology of stroke is well investigated in the developed world; however, in the developing world stroke is less well documented. Most of the available stroke data from these countries are hospital-based. Stroke thrombolysis is currently used in few developing countries like Brazil, Argentina, Senegal, Iran, Pakistan, China, Thailand, and India. The two main barriers for implementation of thrombolysis therapy in developing countries are the high cost of tissue plasminogen activator and lack of proper infrastructure. Most of the centers with the infrastructure to deliver thrombolysis for stroke are predominantly private sector, and only available in urban areas. CONCLUSION: Until a more cost-effective thrombolytic agent and the proper infrastructure for widespread use of thrombolysis therapy are available, developing nations should focus on primary and secondary stroke prevention strategies and the establishment of stroke units wherever possible. Such multi-faceted approaches will be more cost-effective for developing countries than the use of thrombolysis.