Publications by authors named "Rajat Mohindra"

10 Publications

  • Page 1 of 1

FULFIL Trial: Once-Daily Triple Therapy for Patients with Chronic Obstructive Pulmonary Disease.

Am J Respir Crit Care Med 2017 08;196(4):438-446

1 GlaxoSmithKline, King of Prussia, Pennsylvania.

Rationale: Randomized data comparing triple therapy with dual inhaled corticosteroid (ICS)/long-acting β-agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) are limited.

Objectives: We compared the effects of once-daily triple therapy on lung function and health-related quality of life with twice-daily ICS/LABA therapy in patients with COPD.

Methods: The FULFIL (Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy) trial was a randomized, double-blind, double-dummy study comparing 24 weeks of once-daily triple therapy (fluticasone furoate/umeclidinium/vilanterol 100 μg/62.5 μg/25 μg; ELLIPTA inhaler) with twice-daily ICS/LABA therapy (budesonide/formoterol 400 μg/12 μg; Turbuhaler). A patient subgroup remained on blinded treatment for up to 52 weeks. Co-primary endpoints were change from baseline in trough FEV and in St. George's Respiratory Questionnaire (SGRQ) total score at Week 24.

Measurements And Main Results: In the intent-to-treat population (n = 1,810) at Week 24 for triple therapy (n = 911) and ICS/LABA therapy (n = 899), mean changes from baseline in FEV were 142 ml (95% confidence interval [CI], 126 to 158) and -29 ml (95% CI, -46 to -13), respectively, and mean changes from baseline in SGRQ scores were -6.6 units (95% CI, -7.4 to -5.7) and -4.3 units (95% CI, -5.2 to -3.4), respectively. For both endpoints, the between-group differences were statistically significant (P < 0.001). There was a statistically significant reduction in moderate/severe exacerbation rate with triple therapy versus dual ICS/LABA therapy (35% reduction; 95% CI, 14-51; P = 0.002). The safety profile of triple therapy reflected the known profiles of the components.

Conclusions: These results support the benefits of single-inhaler triple therapy compared with ICS/LABA therapy in patients with advanced COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02345161).
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http://dx.doi.org/10.1164/rccm.201703-0449OCDOI Listing
August 2017

Safety and efficacy of ozanezumab in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled, phase 2 trial.

Lancet Neurol 2017 03 28;16(3):208-216. Epub 2017 Jan 28.

Neurosciences Therapy Area Unit, GlaxoSmithKline, Uxbridge, UK. Electronic address:

Background: Neurite outgrowth inhibitor A (Nogo-A) is thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). A monoclonal antibody against Nogo-A showed a positive effect in the SOD1 mouse model of ALS, and a humanised form of this antibody (ozanezumab) was well tolerated in a first-in-human trial. Therefore, we aimed to assess the safety and efficacy of ozanezumab in patients with ALS.

Methods: This randomised, double-blind, placebo-controlled, phase 2 trial was done in 34 centres in 11 countries. Patients aged 18-80 years with a diagnosis of familial or sporadic ALS were randomly assigned (1:1), centrally according to a computer-generated allocation schedule, to receive ozanezumab (15 mg/kg) or placebo as intravenous infusions over 1 h every 2 weeks for 46 weeks, followed by assessments at week 48 and week 60. Patients and study personnel were masked to treatment assignment. The primary outcome was a joint-rank analysis of function (ALS Functional Rating Scale-Revised) and overall survival, analysed at 48 weeks in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01753076, and with GSK-ClinicalStudyRegister.com, NOG112264, and is completed.

Findings: Between Dec 20, 2012, and Nov 1, 2013, we recruited 307 patients, of whom 303 were randomly assigned to receive placebo (n=151) or ozanezumab (n=152). The adjusted mean of the joint-rank score was -14·9 (SE 13·5) for the ozanezumab group and 15·0 (13·6) for the placebo group, with a least squares mean difference of -30·0 (95% CI -67·9 to 7·9; p=0·12). Overall, reported adverse events, serious adverse events, and adverse events leading to permanent discontinuation of study drug or withdrawal from study were similar between the treatment groups, except for dyspepsia (ten [7%] in the ozanezumab group vs four [3%] in the placebo group), depression (11 [7%] vs five [3%]), and diarrhoea (25 [16%] vs 12 [8%]). Respiratory failure was the most common serious adverse event (12 [8%] vs seven [5%]). At week 60, the number of deaths was higher in the ozanezumab group (20 [13%]) than in the placebo group (16 [11%]), mainly as a result of respiratory failure (ten [7%] vs five [3%]). Two deaths were considered related to the study drug (bladder transitional cell carcinoma in the ozanezumab group and cerebrovascular accident in the placebo group).

Interpretation: Ozanezumab did not show efficacy compared with placebo in patients with ALS. Therefore, Nogo-A does not seem to be an effective therapeutic target in ALS.

Funding: GlaxoSmithKline.
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http://dx.doi.org/10.1016/S1474-4422(16)30399-4DOI Listing
March 2017

A phase III randomised controlled trial of single-dose triple therapy in COPD: the IMPACT protocol.

Eur Respir J 2016 08 13;48(2):320-30. Epub 2016 Jul 13.

Respiratory Medicines Development Centre, GSK, Brentford, UK William Harvey Institute, Barts & The London School of Medicine and Dentistry, London, UK.

Patients with symptomatic advanced chronic obstructive pulmonary disease (COPD) who experience recurrent exacerbations are particularly at risk of poor outcomes and present a significant burden on healthcare systems. The relative merits of treating with different inhaled combination therapies e.g. inhaled corticosteroids (ICS)/long-acting β2-agonist (LABA), LABA/long-acting muscarinic antagonists (LAMA), ICS/LABA/LAMA, in this patient group are poorly understood, as is reflected in current guidelines. The InforMing the PAthway of COPD Treatment (IMPACT) study will evaluate the efficacy and safety of fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) versus FF/VI or UMEC/VI over a 52-week treatment period. The study has been designed with a focus on understanding the comparative merits of each treatment modality in different phenotypes/endotypes.This is a phase III, randomised, double-blind, three-arm, parallel-group, global multicentre study comparing the rate of moderate and severe exacerbations between FF/UMEC/VI and FF/VI or UMEC/VI over a 52-week treatment period. The study aims to recruit 10 000 patients from approximately 1070 centres. Eligible patients are aged ≥40 years, with symptomatic advanced COPD (Global initiative for chronic Obstructive Lung Disease (GOLD) group D) and an exacerbation in the previous 12 months.The first patients were recruited to the IMPACT study (ClinicalTrials.gov: NCT02164513) in June 2014 and the anticipated completion date is July 2017.
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http://dx.doi.org/10.1183/13993003.02165-2015DOI Listing
August 2016

An adaptive design to investigate the effect of ketoconazole on pharmacokinetics of GSK239512 in healthy male volunteers.

J Clin Pharmacol 2015 May 4;55(5):505-11. Epub 2015 Feb 4.

GSKR R&D, Shanghai, China.

This open label drug-drug interaction (DDI) study investigated the effect of a strong CYP3A inhibitor ketoconazole on the PK and safety profile of GSK239512. To mitigate the tolerability concerns of high GSK239512 exposures resulting from CYP3A inhibition, a 2-cohort adaptive design was used to facilitate a stepwise selection of dose levels and subject numbers. In Cohort 1, 6 subjects received a single dose of 20 μg GSK239512 alone and then 10 μg GSK239512 in combination with repeated once daily doses of 400 mg ketoconazole. The results from Cohort 1 demonstrated an approximately 1.5-fold increase in GSK239512 exposure with a good tolerability profile. This led to the adoption of a 3-session option in Cohort 2, in which 16 subjects received sequential single doses of 20 μg GSK239512 alone, 40 μg GSK239512 alone, and a single dose of 40 μg GSK239512 in combination with repeated once daily doses of 400 mg ketoconazole. The 2-cohort adaptive design proved effective in mitigating any potentially significant DDI risk to healthy subjects. Final results showed a 1.3-fold increase in GSK239512 exposure with ketoconazole, suggesting that in vivo metabolism of GSK239512 by CYP3A is unlikely to be the primary route of GSK239512 elimination.
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http://dx.doi.org/10.1002/jcph.441DOI Listing
May 2015

Mechanical breakdown and intraembolus thrombolysis in massive pulmonary embolism.

Indian Heart J 2005 Jul-Aug;57(4):364-5

Department of Cardiology, Dayanand Medical College and Hospital, Ludhiana.

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January 2006

Gastrointestinal bleed after leeching in a patient on aspirin therapy.

Indian J Gastroenterol 2005 Jul-Aug;24(4):170

Department of Medicine, Dayanand Medical College and Hospital, Ludhiana, India.

Leeches ( Hirudo medicinalis ) have been used in health care for their property of bloodletting. Bleed occurring from the site of leech attachment has been well documented. We report a 50-year-old man who was on aspirin therapy for coronary artery disease, and presented with GI bleed after leech treatment for his knee pain.
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August 2006

Syncope in a middle aged male due to acute rheumatic fever.

Indian Heart J 2004 Nov-Dec;56(6):668-9

Dayanand Medical College and Hospital, Ludhiana, Punjab.

Rheumatic fever is a multi system disease which occurs following infection with group A beta hemolytic streptococcus. It is commonest in the age group of 5-15 years but can occur in adults also. First degree atrioventricular block is a common manifestation of acute rheumatic fever and is included in the Jones criteria but Wenckebacks phenomena and complete heart block are relatively rare manifestations of rheumatic fever. Syncope occurring in acute rheumatic fever is also infrequently reported. We report the case of a 38-year-old male with rheumatic carditis who had advanced atrioventricular block which resulted in syncope and required a temporary pacemaker insertion.
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March 2005
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