Jacques Hebert - Academia.edu (original) (raw)

Papers by Jacques Hebert

Frontiers in Medicine, 2020

International Journal of Emergency Medicine

Background Acute airway angioedema commonly occurs through two distinct mechanisms: histamine- an... more Background Acute airway angioedema commonly occurs through two distinct mechanisms: histamine- and bradykinin-dependent. Although they respond to distinct treatments, these two potentially life-threatening states present similarly. Poor recognition of the bradykinin-dependent pathway leads to treatment errors in the emergency department (ED), despite the availability of multiple pharmacologic options for hereditary angioedema (HAE) and other forms of bradykinin-induced angioedema. Here, we consider the pathophysiology and clinical features of bradykinin-induced angioedema, and we present a systematic literature review exploring the effectiveness of the available therapies for managing such cases. Methods PubMed searches using ‘emergency’, ‘bradykinin’ and various therapeutic product names identified studies reporting the efficacy of treatments for bradykinin-induced angioedema in the ED setting. In all, 22 studies met prespecified criteria and are analysed here. Findings Whereas his...

The Journal of Allergy and Clinical Immunology: In Practice, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Pharmaceuticals, 2020

Kinins (peptides related to bradykinin, BK) are formed from circulating substrates, the kininogen... more Kinins (peptides related to bradykinin, BK) are formed from circulating substrates, the kininogens, by the action of two proteases, the kallikreins. The only clinical application of a BK receptor ligand, the B2 receptor antagonist icatibant, is the treatment of the rare hereditary angioedema (HAE) caused by the deficiency of C1-esterase inhibitor (C1-INH). Less common forms of HAE (genetic variants of factor XII, plasminogen, kininogen) are presumably mediated by increased BK formation. Acquired forms of BK-mediated angioedema, such as that associated with angiotensin-I converting enzyme (ACE) inhibition, are also known. Antibody-based analytical techniques are briefly reviewed, and support that kinins are extremely short-lived, prominently cleared by ACE. Despite evidence of continuous activation of the kallikrein–kinin system in HAE, patients are not symptomatic most of the time and their blood or plasma obtained during remission does not generate excessive immunoreactive BK (iBK)...

The Journal of Allergy and Clinical Immunology: In Practice, 2019

What is already known about this topic? We searched PubMed for reviews discussing management of p... more What is already known about this topic? We searched PubMed for reviews discussing management of patients with hereditary angioedema. Twenty-one articles described barriers to long-term prophylaxis with intravenous human C1esterase inhibitor (C1-INH) due to challenges with lifelong vascular access and attack risk. What does this article add to our knowledge? The long-term Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT) demonstrates that continuous replacement therapy with subcutaneous C1-INH provides sustained treatment effectiveness with minimal adverse effects. How does this study impact current management guidelines? This study confirms previous recommendations for subcutaneous C1-INH replacement as a safe and effective long-term prophylaxis against symptoms, attacks, and need for rescue therapy in hereditary angioedema. BACKGROUND: For the prevention of attacks of hereditary angioedema (HAE), the efficacy and safety of subcutaneous human C1-esterase inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) was established in the 16-week Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT). OBJECTIVE: To assess the long-term safety, occurrence of angioedema attacks, and use of rescue medication with C1-INH(SC). METHODS: Open-label, randomized, parallel-arm extension of COMPACT across 11 countries. Patients with frequent angioedema attacks, either study treatment-naive or who had completed COMPACT, were randomly assigned (1:1) to 40 IU/

PLOS ONE, 2017

Background Omalizumab is a non-steroidal medication indicated for the treatment of poorly control... more Background Omalizumab is a non-steroidal medication indicated for the treatment of poorly controlled moderate-to-severe allergic asthmatics. This observational study examines the "real world" effectiveness of omalizumab in this population. Methods This is a one year open-label observational study that compared clinical outcomes including total oral corticosteroid use, exacerbation history, measures of quality of life and inflammation in patients with moderate-to-severe allergic asthma, who were prescribed omalizumab as part of their treatment with the year prior to therapy. Results A total of 99 patients were enrolled at 25 sites in Canada. During the study period, the mean total annual OCS dose was reduced from 2301.5 mg (prednisone equivalents) in the year prior to omalizumab to 1130.0 mg (p<0.0001). There was a 71% reduction in asthma exacerbations and 56% of patients on omalizumab remained exacerbation free when compared to the year prior to study entry. Associated with this was reduced health care utilization. There were significant improvements in the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life questionnaire (AQLQ) Patients with an elevated FeNO at baseline showed a better response to treatment. No new safety issues were identified during the study period. Conclusion Our study demonstrates that in "real world" clinical practice, after initiating omalizumab, there is a reduction in total OCS use and exacerbation frequency in patients with moderate

Pneumologie, 2015

ABSTRACT

European Respiratory Journal, 2012

NVA237 (glycopyrronium bromide) is a once-daily long-acting muscarinic antagonist (LAMA) in devel... more NVA237 (glycopyrronium bromide) is a once-daily long-acting muscarinic antagonist (LAMA) in development for chronic obstructive pulmonary disease (COPD). The GLycopyrronium bromide in COPD airWays clinical Study 2 (GLOW2) evaluated the efficacy and safety of NVA237 in moderate-to-severe COPD over 52 weeks. Patients were randomised 2:1:1 to NVA237 50 mg, placebo or open-label tiotropium 18 mg for 52 weeks. Primary end-point was trough forced expiratory volume in 1 s (FEV1) at 12 weeks. 1,066 patients were randomised, 810 completed the study. At week 12, trough FEV1 increased significantly by 97 mL with NVA237 (95% CI 64.6-130.2; p,0.001) and 83 mL with tiotropium (95% CI 45.6-121.4; p,0.001). Compared with placebo, NVA237 produced significant improvements in dyspnoea (Transition Dyspnoea Index at week 26; p50.002) and health status (St George's Respiratory Questionnaire at week 52; p,0.001). NVA237 significantly reduced the risk of moderate-to-severe COPD exacerbations by 34% (p50.001) and the use of rescue medication (p50.039), versus placebo. NVA237-placebo and tiotropium-placebo differences were comparable for all outcomes. Safety profiles were similar across groups. NVA237 50 mg provided significant improvements in lung function, dyspnoea, health status, exacerbations and rescue medication use, versus placebo, and was comparable to tiotropium. NVA237 can potentially be an alternative choice of LAMA for COPD patients.

Allergy, Asthma & Clinical Immunology, 2010

Background: We published the Canadian 2003 International Consensus Algorithm for the Diagnosis, T... more Background: We published the Canadian 2003 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema (HAE; C1 inhibitor [C1-INH] deficiency) and updated this as Hereditary angioedema: a current state-of-the-art review: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema. Objective: To update the International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema (circa 2010). Methods: The Canadian Hereditary Angioedema Network (CHAEN)/Réseau Canadien d'angioédème héréditaire (RCAH) http://www.haecanada.com and cosponsors University of Calgary and the Canadian Society of Allergy and Clinical Immunology (with an unrestricted educational grant from CSL Behring) held our third Conference May 15th to 16th, 2010 in Toronto Canada to update our consensus approach. The Consensus document was reviewed at the meeting and then circulated for review. Results: This manuscript is the 2010 International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema that resulted from that conference. Conclusions: Consensus approach is only an interim guide to a complex disorder such as HAE and should be replaced as soon as possible with large phase III and IV clinical trials, meta analyses, and using data base registry validation of approaches including quality of life and cost benefit analyses, followed by large head-to-head clinical trials and then evidence-based guidelines and standards for HAE disease management.

Allergy, Asthma & Clinical Immunology, 2017

The 10th C1-inhibitor deficiency workshop will be held between 18 and 21 May 2017 in Budapest (20... more The 10th C1-inhibitor deficiency workshop will be held between 18 and 21 May 2017 in Budapest (2017.haenetworkshop.hu), among the picturesque surroundings of Margaret Island. As indicated by the name of this event, most of the interest focused on angioedema due to C1-inhibitor deficiency in 1999, when it was first organized. The name is unchanged, but the range of angioedemas has expanded since to include all known varieties of hereditary and acquired angioedemas with a bradykinin-mediated pathomechanism. Looking back to the agenda of this biennial conference, many questions remained unanswered and new issues have arisen despite the enormous scientific progress made. On this occasion, 318 participants have registered from 42 countriesthis is the greatest attendance in the history of the Workshop since the start of the series. Eighty-six presentations have been submitted for this 4-day long scientific forum. The scientific program sounds interesting-it comprises novel achievements by leading scientific teams in basic research into bradykinin-mediated angioedema, the new findings of diagnostics and genetics, promising therapeutic solutions awaiting introduction, and the experience accumulated with the latest therapeutic procedures. Several presentations discuss the efforts related to improving the patients' quality of life. This time, we have invited five prominent experts-namely

Annals of Allergy, Asthma & Immunology, 2008

Objective: To provide a context to understand the opportunity for novel therapeutic modalities to... more Objective: To provide a context to understand the opportunity for novel therapeutic modalities to transform the treatment of hereditary angioedema (HAE). Data Sources: MEDLINE and PubMed were searched to identify studies involving current treatment of HAE in the United States. Study Selection: Studies were selected based on their relevance to the treatment of HAE. Results: The current HAE treatment strategy is far from satisfactory, and its limitations create an unmet clinical need. Current prophylactic treatment exposes patients with HAE to significant risk of adverse effects, and the efficacy of prophylactic treatment, although generally good, is far from perfect. Conclusions: No specific treatment is currently available in the United States for acute HAE attacks that will reliably work, resulting in a significant unmet clinical need. The emergence of several promising drugs for the treatment of HAE attacks is, thus, an extraordinarily important development in the management of these patients.

The European respiratory journal, Jan 8, 2015

Efficacy and safety of tiotropium+olodaterol fixed-dose combination (FDC) compared with the mono-... more Efficacy and safety of tiotropium+olodaterol fixed-dose combination (FDC) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in two replicate, randomised, double-blind, parallel-group, multicentre, phase III trials. Patients received tiotropium+olodaterol FDC 2.5/5 μg or 5/5 μg, tiotropium 2.5 μg or 5 μg, or olodaterol 5 μg delivered once-daily via Respimat inhaler over 52 weeks. Primary end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) response, trough FEV1 response and St George's Respiratory Questionnaire (SGRQ) total score at 24 weeks. In total, 5162 patients (2624 in Study 1237.5 and 2538 in Study 1237.6) received treatment. Both FDCs significantly improved FEV1 AUC0-3 and trough FEV1 response versus the mono-components in both studies. Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiot...

SKIN The Journal of Cutaneous Medicine, 2018

Allergy, Asthma & Clinical Immunology, 2010

JAMA

IMPORTANCE There are currently no approved treatments for peanut allergy. OBJECTIVE To assess the... more IMPORTANCE There are currently no approved treatments for peanut allergy. OBJECTIVE To assess the efficacy and adverse events of epicutaneous immunotherapy with a peanut patch among peanut-allergic children. DESIGN, SETTING, AND PARTICIPANTS Phase 3, randomized, double-blind, placebo-controlled trial conducted at 31 sites in 5 countries between January 8, 2016, and August 18, 2017. Participants included peanut-allergic children (aged 4-11 years [n = 356] without a history of a severe anaphylactic reaction) developing objective symptoms during a double-blind, placebo-controlled food challenge at an eliciting dose of 300 mg or less of peanut protein. INTERVENTIONS Daily treatment with peanut patch containing either 250 μg of peanut protein (n = 238) or placebo (n = 118) for 12 months. MAIN OUTCOMES AND MEASURES The primary outcome was the percentage difference in responders between the peanut patch and placebo patch based on eliciting dose (highest dose at which objective signs/symptoms of an immediate hypersensitivity reaction developed) determined by food challenges at baseline and month 12. Participants with baseline eliciting dose of10mgorlesswererespondersiftheposttreatmentelicitingdosewas300mgormore;participants with baseline eliciting dose greater than 10 to 300 mg were responders if the posttreatment eliciting dose was 1000 mg or more. A threshold of 15% or more on the lower bound of a 95% CI around responder rate difference was prespecified to determine a positive trial result. Adverse event evaluation included collection of treatment-emergent adverse events (TEAEs). RESULTS Among 356 participants randomized (median age, 7 years; 61.2% male), 89.9% completed the trial; the mean treatment adherence was 98.5%. The responder rate was 35.3% with peanut-patch treatment vs 13.6% with placebo (difference, 21.7% [95% CI, 12.4%-29.8%; P < .001]). The prespecified lower bound of the CI threshold was not met. TEAEs, primarily patch application site reactions, occurred in 95.4% and 89% of active and placebo groups, respectively. The all-causes rate of discontinuation was 10.5% in the peanut-patch group vs 9.3% in the placebo group. CONCLUSIONS AND RELEVANCE Among peanut-allergic children aged 4 to 11 years, the percentage difference in responders at 12 months with the 250-μg peanut-patch therapy vs placebo was 21.7% and was statistically significant, but did not meet the prespecified lower bound of the confidence interval criterion for a positive trial result. The clinical relevance of not meeting this lower bound of the confidence interval with respect to the treatment of peanut-allergic children with epicutaneous immunotherapy remains to be determined.

JAMA

IMPORTANCE Current treatments for long-term prophylaxis in hereditary angioedema have limitations... more IMPORTANCE Current treatments for long-term prophylaxis in hereditary angioedema have limitations. OBJECTIVE To assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks. DESIGN, SETTING, AND PARTICIPANTS Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow-up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized. INTERVENTIONS Twenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments. MAIN OUTCOME AND MEASURES Primary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period. RESULTS Among 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were −1.

Journal of asthma and allergy, 2018

Patients prefer at-home subcutaneous administration of biologics across different diseases, yet n... more Patients prefer at-home subcutaneous administration of biologics across different diseases, yet no biologic is approved for at-home use for severe, uncontrolled asthma. We assessed at-home functionality, reliability, and performance of an accessorized pre-filled syringe (APFS) for subcutaneous benralizumab administration, an anti-eosinophil monoclonal antibody indicated for add-on maintenance treatment of patients with severe eosinophilic asthma. Patients (N=116) with severe, uncontrolled asthma despite receiving medium- or high-dosage inhaled corticosteroids and long-acting β-agonists received up to 5 APFS-administered subcutaneous doses (Weeks 0, 4, 8, 12, and 16) of benralizumab 30 mg. The first 3 doses were administered at the study sites. The patient/caregiver administered the last 2 doses at home. Endpoints included the percentage of dispensed APFS that were used successfully blood eosinophil counts, Asthma Control Questionnaire 6, and safety. Nearly all dispensed APFS were su...

JAMA, Nov 14, 2017

Epicutaneous immunotherapy may have potential for treating peanut allergy but has been assessed o... more Epicutaneous immunotherapy may have potential for treating peanut allergy but has been assessed only in preclinical and early human trials. To determine the optimal dose, adverse events (AEs), and efficacy of a peanut patch for peanut allergy treatment. Phase 2b double-blind, placebo-controlled, dose-ranging trial of a peanut patch in peanut-allergic patients (6-55 years) from 22 centers, with a 2-year, open-label extension (July 31, 2012-July 31, 2014; extension completed September 29, 2016). Patients (n = 221) had peanut sensitivity and positive double-blind, placebo-controlled food challenges to an eliciting dose of 300 mg or less of peanut protein. Randomly assigned patients (1:1:1:1) received an epicutaneous peanut patch containing 50 μg (n = 53), 100 μg (n = 56), or 250 μg (n = 56) of peanut protein or a placebo patch (n = 56). Following daily patch application for 12 months, patients underwent a double-blind, placebo-controlled food challenge to establish changes in eliciting...

The New England journal of medicine, Mar 23, 2017

Background Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency... more Background Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. Methods We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly follow...

J Allerg Clin Immunol, 1995

Frontiers in Medicine, 2020

International Journal of Emergency Medicine

The Journal of Allergy and Clinical Immunology: In Practice, 2020

Pharmaceuticals, 2020

The Journal of Allergy and Clinical Immunology: In Practice, 2019

PLOS ONE, 2017

Pneumologie, 2015

ABSTRACT

European Respiratory Journal, 2012

Allergy, Asthma & Clinical Immunology, 2010

Allergy, Asthma & Clinical Immunology, 2017

Annals of Allergy, Asthma & Immunology, 2008

The European respiratory journal, Jan 8, 2015

SKIN The Journal of Cutaneous Medicine, 2018

Allergy, Asthma & Clinical Immunology, 2010

JAMA

Journal of asthma and allergy, 2018

JAMA, Nov 14, 2017

The New England journal of medicine, Mar 23, 2017

J Allerg Clin Immunol, 1995