scholarly journals A Cluster-randomised, Non-inferiority Trial of the Impact of a Two-dose Compared to Three-dose Schedule of Pneumococcal Conjugate Vaccination in Rural Gambia: the PVS Trial

2021 ◽  
Author(s):  
Grant Austin Mackenzie ◽  
Isaac Osei ◽  
Rasheed Salaudeen ◽  
Ilias Hossain ◽  
Benjamin Young ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Field Trial ◽  
Pneumococcal Disease ◽  
Population Level ◽  
Dose Schedule ◽  
Reduced Dose ◽  
Pneumococcal Carriage ◽  
Cluster Randomised ◽  
Vaccine Type ◽  
Secondary Endpoints

Abstract Background:Pneumococcal conjugate vaccines (PCV) effectively prevent pneumococcal disease but the global impact of pneumococcal vaccination is hampered by the cost of PCV. The relevance and feasibility of trials of reduced dose schedules is greatest in middle- and low-income countries, such as The Gambia, where PCV has been introduced with good disease control but where transmission of vaccine-type pneumococci persists. We are conducting a large cluster-randomised, non-inferiority, field trial of an alternative reduced dose schedule of PCV compared to the standard schedule, the PVS trial.Methods:PVS is prospective, cluster-randomised, non-inferiority, real-world field trial of an alternative schedule of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months (i.e. the alternative ‘1+1’ schedule) compared to the standard schedule of three primary doses scheduled at 6, 10, and 14 weeks weeks of age (i.e. the stardard ‘3+0’ schedule). The intervention will be delivered for 4 years. The primary endpoint is the population-level prevalence of nasopharyngeal vaccine-type pneumococcal carriage in children aged 2 weeks to 59 months with clinical pneumonia in Year 4 of the trial. Participants and field staff are not masked to group allocation while measurement of the laboratory endpoint will be masked. Sixty-eight geographic population clusters have been randomly allocated, in a 1:1 ratio, to each schedule and all resident infants are eligible for enrolment. All resident children less than 5 years of age are under continuous surveillance for clinical safety endpoints measured at 11 health facilities; invasive pneumococcal disease, radiological pneumonia, clinical pneumonia, and hospitalisations. Secondary endpoints include the population-level prevalence of nasopharyngeal vaccine-type pneumococcal carriage in Year 2 and 4 and vaccine-type carriage prevalence in unimmunised infants aged 6-12 weeks in Year 4. The trial includes components of mathematical modeling, health economics, and health systems research.Discussion:Analysis will account for potential non-independence of measurements by cluster, comparing the population-level impact of the two schedules with interpretation at the individual level. The non-inferiority margin is informed by the ‘acceptable loss of effect’ of the alternative compared to standard schedule. The secondary endpoints will provide substantial evidence to support the interpretation of the primary endpoint. PVS will evaluate the effect of transition from a standard 3+0 schedule to an alternative 1+1 schedule in a setting of high pneumococcal transmission. The results of PVS will inform global decision-making concerning the use of reduced-dose PCV schedules.Trial registration: International Standard Randomised Controlled Trial Number – 15056916.

scholarly journals Pneumococcal Conjugate Vaccination Schedules Acquisition, Immunogenicity and Pneumococcal Conjugate and Yellow Fever Vaccine Co-Administration Study

2021 ◽  
Author(s):  
Grant Austin Mackenzie ◽  
Isaac Osei ◽  
Rasheed Salaudeen ◽  
Ousman Secka ◽  
Umberto D’Alessandro ◽  
...  
Keyword(s):  
Yellow Fever ◽  
Field Trial ◽  
Yellow Fever Vaccine ◽  
Large Field ◽  
Individual Level ◽  
Reduced Dose ◽  
Cluster Randomised ◽  
Vaccine Type ◽  
Alternative Schedule ◽  
The Individual

Abstract Background:Pneumococcal conjugate vaccines (PCV) effectively prevent pneumococcal disease but the global impact of pneumococcal vaccination is hampered by its cost. The evaluation of reduced dose schedules of PCV includes measurement of effects on immunogenicity and carriage acquisition compared to standard schedules. The relevance and feasibility of trials of reduced dose schedules is greatest in middle- and low-income countries, such as The Gambia, where the introduction of PCV resulted in good disease control but where transmission of vaccine-type pneumococci persists. We designed a large cluster-randomised field trial of an alternative reduced dose schedule of PCV compared to the standard schedule, the PVS trial. We will also conduct a sub-study to evaluate the individual-level effect of the two schedules on carriage acquisition, immunogenicity, and co-administration of PCV with yellow fever vaccine, the PVS-AcqImm trial.Methods:PVS-AcqImm is prospective, cluster-randomised trial of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months (i.e. alternative ‘1+1’ schedule) compared to three primary doses scheduled at 6, 10, and 14 weeks weeks of age (i.e. stardard ‘3+0’ schedule). Sub-groups within the alternative schedule group will receive yellow fever vaccine separately or co-administered with PCV at 9 months of age. The primary endpoints are: a) rate of nasopharyngeal vaccine-type pneumococcal acquisition from 9-14 months of age, b) geometric mean concentration of vaccine-type pneumococcal IgG at 18 months of age, and c) proportions with yellow fever neutralizing antibody titre ≥8 four weeks after administration of yellow fever vaccine. Participants and field staff will not be masked to group allocation while the measurement of laboratory endpoints will be masked. Approximately equal numbers of participants will be resident in each of 28 geographic clusters (14 clusters in alternative and standard schedule groups); 784 enrolled for acquisition measurements and 336 for immunogenicity measurements. Discussion:Analysis will account for potential non-independence of measurements by cluster and so interpretation of effects will be at the individual level (i.e. a population of individuals). PVS-AcqImm will evaluate whether acquisition of vaccine-type pneumococci is reduced by the alternative compared to standard schedule, which is required if the alternative schedule is to be effective. Likewise, evidence of superior immune response at 18 months of age and safety of PCV co-administration with yellow fever vaccine will support decision-making regarding the use of the alternative 1+1 schedule. Acquisition and immunogenicity outcomes will be essential for interpretation of the results of the large field trial comparing the two schedules.Trial registration: International Standard Randomised Controlled Trial Number – 72821613.

scholarly journals Pneumococcal conjugate vaccination schedules in infants—acquisition, immunogenicity, and pneumococcal conjugate and yellow fever vaccine co-administration study

Trials ◽  
2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Grant A. Mackenzie ◽  
Isaac Osei ◽  
Rasheed Salaudeen ◽  
Ousman Secka ◽  
Umberto D’Alessandro ◽  
...  
Keyword(s):  
Yellow Fever ◽  
Field Trial ◽  
Yellow Fever Vaccine ◽  
Large Field ◽  
Individual Level ◽  
Reduced Dose ◽  
Cluster Randomised ◽  
Vaccine Type ◽  
Alternative Schedule ◽  
The Individual

Abstract Background Pneumococcal conjugate vaccines (PCVs) effectively prevent pneumococcal disease, but the global impact of pneumococcal vaccination is hampered by its cost. The evaluation of reduced dose schedules of PCV includes measurement of effects on immunogenicity and carriage acquisition compared to standard schedules. The relevance and feasibility of trials of reduced dose schedules is greatest in middle- and low-income countries, such as The Gambia, where the introduction of PCV resulted in good disease control but where transmission of vaccine-type pneumococci persists. We designed a large cluster-randomised field trial of an alternative reduced dose schedule of PCV compared to the standard schedule, the PVS trial. We will also conduct a sub-study to evaluate the individual-level effect of the two schedules on carriage acquisition, immunogenicity, and co-administration of PCV with yellow fever vaccine, the PVS-AcqImm trial. Methods PVS-AcqImm is a prospective, cluster-randomised trial of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months (i.e. alternative ‘1+1’ schedule) compared to three primary doses scheduled at 6, 10, and 14 weeks of age (i.e. standard ‘3+0’ schedule). Sub-groups within the alternative schedule group will receive yellow fever vaccine separately or co-administered with PCV at 9 months of age. The primary endpoints are (a) rate of nasopharyngeal vaccine-type pneumococcal acquisition from 9 to 14 months of age, (b) geometric mean concentration of vaccine-type pneumococcal IgG at 18 months of age, and (c) proportions with yellow fever neutralising antibody titre ≥8 four weeks after administration of yellow fever vaccine. Participants and field staff will not be masked to group allocation while the measurement of laboratory endpoints will be masked. Approximately equal numbers of participants will be resident in each of 28 geographic clusters (14 clusters in alternative and standard schedule groups); 784 enrolled for acquisition measurements and 336 for immunogenicity measurements. Discussion Analysis will account for potential non-independence of measurements by cluster and so interpretation of effects will be at the individual level (i.e. a population of individuals). PVS-AcqImm will evaluate whether acquisition of vaccine-type pneumococci is reduced by the alternative compared to the standard schedule, which is required if the alternative schedule is to be effective. Likewise, evidence of superior immune response at 18 months of age and safety of PCV co-administration with yellow fever vaccine will support decision-making regarding the use of the alternative 1+1 schedule. Acquisition and immunogenicity outcomes will be essential for the interpretation of the results of the large field trial comparing the two schedules. Trial registration International Standard Randomised Controlled Trial Number 72821613.

scholarly journals 1181. Serotype Distribution by Age of Remaining Invasive Pneumococcal Disease After Long-Term PCV10/13 Use: The PSERENADE Project

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S683-S684
Author(s):  
Maria Garcia Quesada ◽  
Marissa Hetrich ◽  
Maria Deloria Knoll
Keyword(s):  
Invasive Pneumococcal Disease ◽  
Pneumococcal Disease ◽  
Age Groups ◽  
Dose Schedule ◽  
Cross Protection ◽  
Distribution Data ◽  
Middle Income ◽  
Specific Distribution ◽  
Vaccine Type ◽  
Research Grant

Abstract Background Pneumococcal conjugate vaccines (PCV) have reduced invasive pneumococcal disease (IPD) (see other PSERENADE abstract), of which > 70% was vaccine-type pre-PCV. We described the serotype (ST) distribution of remaining IPD in countries with mature infant PCV10/13 programs. Methods IPD ST distribution data were obtained directly from surveillance sites, supplemented with published literature. Mature programs were defined as exclusive use of PCV10 or PCV13 for at least 5-7 years (depended on if prior PCV7 use and/or PCV10/13 catch-up) with primary series uptake > 70%. The distribution was estimated using a multinomial Dirichlet regression, stratified by PCV product and age (< 5 years, ≥ 50 years). Results Serotyped IPD cases from 42 PCV13- (n=78,912) and 12 PCV10-using sites (n=8,429) in 41 countries were analyzed. Most sites were from high-income countries (67%) and used a booster dose schedule (81%). For low- and middle-income countries, only 5 and 7 sites had more than 20 eligible cases for children and adults, respectively. In PCV10 sites, 10.0% (95% CI: 6.3-12.9%) and 15.5% (95% CI: 13.4-19.3%) of the remaining IPD during the mature period was PCV10-type among children and adults, respectively (Figure 1). For PCV13 sites, PCV13-type was 26.4% (95% CI: 21.3-30.0%) among children and 29.5% (95% CI: 27.5-33.0%) among adults. PCV20-, PCV24-, and PPV23-type cases ranged from 62-72% across all age and PCV-use groups. ST 19A was the leading ST at PCV10 sites, though more so for children (30.6%, 95% CI: 18.2-43.1%) than adults (14.8%, 95% CI: 11.9-17.8%; Figure 2). ST 3 was a top ST in both PCV10 and PCV13 sites, causing about 9% of cases in children and 14% in adults. ST 6C was the third most common ST in PCV10 sites, causing 6% of cases in both age groups. Some top non-PCV13 STs are included in higher-valent investigational PCVs (15BC, 12F, 22F, 8, 9N) but others are not (24F, 23B, 23A, 15A). Figure 1. Percentage of IPD cases in the mature PCV10/13 period due to serotypes included in current and upcoming products. Serotype (ST) 3 is illustrated separately in lighter purple in the bars corresponding to products that include ST3 due to the uncertain effectiveness against ST3 in current products. ST6C is illustrated in grey above the bars where ST6A is included. Although ST6C is not included in PCV10 or PCV13, PCV13 offers cross-protection through ST6A. ST6A also benefits from cross-protection with ST6B, included in both PCV10 and PCV13. Therefore, ST6A causes a very small fraction of disease in both settings and age groups, and it is not shown. Confidence intervals do not include ST6C, as this serotype is not included in PCV10/13. PCV13 is Pfizer’s Prevnar13/Prevenar13; PCV10 is GSK’s Synflorix. Figure 2. Serotype-specific distribution of IPD in the mature PCV10/13 period. Serotypes are colored by the lowest valency PCV product they are included in. The “x” in the PCV legend represents the extra serotypes included in that product relative to the next lower product (i.e., PCV13x includes serotypes 3, 6A, and 19A not in PCV10). Serotype (ST) 6C is colored separately because, although it is not included in any product, it is covered through cross-protection with PCV13-type serotype 6A. PCV13 is Pfizer’s Prevnar13/Prevenar13; PCV10 is GSK’s Synflorix. Conclusion IPD due to vaccine STs was low for both children and adults in countries with mature PCV programs. ST distribution of remaining IPD differed between PCV10 and PCV13 sites and between age groups. Higher-valency PCVs under evaluation target over half of remaining IPD cases, but some prevalent STs are not included in known investigational products. Disclosures Maria Deloria Knoll, PhD, Merck (Research Grant or Support)Pfizer (Research Grant or Support)

scholarly journals 2711. Effectiveness of 13-Valent Pneumococcal Conjugate Vaccine Against Invasive Pneumococcal Disease in Older Adults

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S953-S954
Author(s):  
Ned Lewis ◽  
Amber Hsiao ◽  
John Hansen ◽  
Arnold Yee ◽  
Charlie Chao ◽  
...  
Keyword(s):  
Conjugate Vaccine ◽  
Invasive Pneumococcal Disease ◽  
Pneumococcal Conjugate Vaccine ◽  
Pneumococcal Disease ◽  
Vaccine Coverage ◽  
Conditional Logistic Regression ◽  
Population Level ◽  
P Value ◽  
Kaiser Permanente ◽  
Vaccine Type

Abstract Background Routine use of 13-valent pneumococcal conjugate vaccine (PCV13) has been recommended for infants since early 2010 and for adults ≥65 years since 2014 when KPNC began routine use of PCV13 in adults. PCV13 vaccine effectiveness (VE) against vaccine-type invasive pneumococcal disease (IPD) has been demonstrated; however, recent surveillance data have been interpreted as showing limited population-level impact of PCV13 on serotype 3 IPD. We estimated PCV13 VE against IPD due to vaccine serotypes at Kaiser Permanente Northern California (KPNC). Methods The study period spanned September 2014 through September 2018. The cohort included KPNC members who were aged ≥65 years with no record of pneumococcal polysaccharide vaccine (PPV23) receipt before age 65 years. We compared IPD cases with KPNC members who were the same age on the date of the positive pneumococcal culture using conditional logistic regression, conditioned on age and date, and controlled for sex, race, KPNC service area and membership history, prior season influenza vaccine receipt, PPV23 receipt after age 65 years, risk factors for IPD, and healthcare utilization. Results From September 2014 to September 2018, PCV13 vaccine coverage among persons ≥65 years old increased from < 1% to 77%. During the same period, there was a total of 245 IPD cases. For a variety of reasons, we did not have serotype results for 57 (23%) IPD cases, which were excluded from the analysis. There were 61 (25%) PCV13-type IPD cases included in the analysis, of which 33 (14%) were serotype 3. PCV13 VE against PCV13-type serotypes was 68.0% (95% CI: 37.7%, 83.6%; P-value < 0.01), and 53.4% (95% CI: −10.0%, 80.3%; P = 0.08) against serotype 3. Conclusion During the first 4 years of PCV13 vaccination implementation in adults ≥65 years of age at KPNC, PCV13 provided significant protection against PCV13-type IPD. Further surveillance will allow for more precise estimation of PCV13 VE on overall and serotype 3 IPD over time. Disclosures All authors: No reported disclosures.

scholarly journals Randomised, controlled trial of erenumab for the prevention of episodic migraine in patients from Asia, the Middle East, and Latin America: The EMPOwER study

Cephalalgia ◽  
2021 ◽  
pp. 033310242110241
Author(s):  
Shuu-Jiun Wang ◽  
Artemio A Roxas ◽  
Bibiana Saravia ◽  
Byung-Kun Kim ◽  
Debashish Chowdhury ◽  
...  
Keyword(s):  
Latin America ◽  
Middle East ◽  
Primary Endpoint ◽  
Episodic Migraine ◽  
Acute Migraine ◽  
Efficacy And Safety ◽  
Medication Treatment ◽  
Significant Difference ◽  
Specific Medication ◽  
Secondary Endpoints

Objective EMPOwER, a double-blind, randomised, phase 3 study, evaluated the efficacy and safety of erenumab in adults with episodic migraine from Asia, the Middle East, and Latin America. Methods Randomised patients (N = 900) received monthly subcutaneous injections of placebo, erenumab 70 mg, or 140 mg (3:3:2) for 3 months. Primary endpoint was change from baseline in monthly migraine days at Month 3. Other endpoints included achievement of ≥50%, ≥75%, and 100% reduction in monthly migraine days, change in monthly acute migraine-specific medication treatment days, patient-reported outcomes, and safety assessment. Results At baseline, mean (standard deviation) age was 37.5 (9.9) years, 81.9% were women, and monthly migraine days was 8.2 (2.8). At Month 3, change from baseline in monthly migraine days (primary endpoint) was −3.1, −4.2, and −4.8 days for placebo, erenumab 70 mg, and erenumab 140 mg, respectively, with a statistically significant difference for erenumab versus placebo (P = 0.002 [70 mg], P < 0.001 [140 mg]). Both erenumab doses were also significantly superior to placebo on all secondary endpoints, including the proportion of patients achieving ≥50% reduction from baseline in monthly migraine days, change from baseline in monthly acute migraine-specific medication treatment days and change from baseline in the Headache Impact Test-6™ scores. The safety profile of erenumab was comparable with placebo; no new safety signals were observed. Conclusions This study of erenumab in patients with episodic migraine from Asia, the Middle East, and Latin America met all primary and secondary endpoints. A consistent numerical benefit was observed with erenumab 140 mg versus erenumab 70 mg across all efficacy endpoints. These findings extend evidence of erenumab’s efficacy and safety to patients under-represented in previous trials. ClinicalTrials.gov identifier: NCT03333109

scholarly journals Mortality in patients with atrial fibrillation with or without heart failure following hospital discharge

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Kartas ◽  
A Samaras ◽  
D Vasdeki ◽  
G Dividis ◽  
G Fotos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Primary Endpoint ◽  
Cox Regression ◽  
Cross Sectional ◽  
Tertiary Center ◽  
All Cause Mortality ◽  
Endpoint Event ◽  
Secondary Endpoints ◽  
Sectional Analysis

Abstract Background The association of heart failure (HF) with the prognosis of atrial fibrillation (AF) remains unclear. OBJECTIVES To assess all-cause mortality in patients following hospitalization with comorbid AF in relation to the presence of HF. Methods We performed a cross-sectional analysis of data from 977 patients discharged from the cardiology ward of a single tertiary center between 2015 and 2018 and followed for a median of 2 years. The association between HF and the primary endpoint of death from any cause was assessed using multivariable Cox regression. Results HF was documented in 505 (51.7%) of AF cases at discharge, including HFrEF (17.9%), HFmrEF (16.5%) and HFpEF (25.2%). A primary endpoint event occurred in 212 patients (42%) in the AF-HF group and in 86 patients (18.2%) in the AF-no HF group (adjusted hazard ratio [aHR] 2.27; 95% confidence interval [CI], 1.65 to 3.13; P&lt;0.001). HF was associated with a higher risk of the composite secondary endpoint of death from any cause, AF or HF-specific hospitalization (aHR 1.69; 95% CI 1.32 to 2.16 p&lt;0.001). The associations of HF with the primary and secondary endpoints were significant and similar for AF-HFrEF, AF-HFmrEF, AF-HFpEF. Conclusions HF was present in half of the patients discharged from the hospital with comorbid AF. The presence of HF on top of AF was independently associated with a significantly higher risk of all-cause mortality than did absence of HF, irrespective of HF subtype. Funding Acknowledgement Type of funding source: None

scholarly journals Nurse-based secondary preventive follow-up by telephone reduced recurrence of cardiovascular events: a randomised controlled trial

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anna-Lotta Irewall ◽  
Anders Ulvenstam ◽  
Anna Graipe ◽  
Joachim Ögren ◽  
Thomas Mooe
Keyword(s):  
Randomised Controlled Trial ◽  
Primary Endpoint ◽  
Cardiovascular Events ◽  
Controlled Trial ◽  
Control Group ◽  
Coronary Syndrome ◽  
Secondary Endpoints ◽  
Randomised Controlled

AbstractEnhanced follow-up is needed to improve the results of secondary preventive care in patients with established cardiovascular disease. We examined the effect of long-term, nurse-based, secondary preventive follow-up by telephone on the recurrence of cardiovascular events. Open, randomised, controlled trial with two parallel groups. Between 1 January 2010 and 31 December 2014, consecutive patients (n = 1890) admitted to hospital due to stroke, transient ischaemic attack (TIA), or acute coronary syndrome (ACS) were included. Participants were randomised (1:1) to nurse-based telephone follow-up (intervention, n = 944) or usual care (control, n = 946) and followed until 31 December 2017. The primary endpoint was a composite of stroke, myocardial infarction, cardiac revascularisation, and cardiovascular death. The individual components of the primary endpoint, TIA, and all-cause mortality were analysed as secondary endpoints. The assessment of outcome events was blinded to study group assignment. After a mean follow-up of 4.5 years, 22.7% (n = 214) of patients in the intervention group and 27.1% (n = 256) in the control group reached the primary composite endpoint (HR 0.81, 95% CI 0.68–0.97; ARR 4.4%, 95% CI 0.5–8.3). Secondary endpoints did not differ significantly between groups. Nurse-based secondary preventive follow-up by telephone reduced the recurrence of cardiovascular events during long-term follow-up.

scholarly journals Sensitivity analysis of the primary endpoint from the N-MOmentum study of inebilizumab in NMOSD

2021 ◽  
pp. 135245852198892
Author(s):  
Bruce AC Cree ◽  
Jeffrey L Bennett ◽  
Ho Jin Kim ◽  
Brian G Weinshenker ◽  
Sean J Pittock ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Evaluation Method ◽  
Demographic Groups ◽  
Patient Demographics ◽  
Treatment History ◽  
Previous Therapy ◽  
Hazard Ratios ◽  
Secondary Endpoints ◽  
Post Hoc ◽  
Attack Type

Background: In the N-MOmentum trial, the risk of an adjudicated neuromyelitis optica spectrum disorder (NMOSD) attack was significantly reduced with inebilizumab compared with placebo. Objective: To demonstrate the robustness of this finding, using pre-specified sensitivity and subgroup analyses. Methods: N-MOmentum is a prospective, randomized, placebo-controlled, double-masked trial of inebilizumab, an anti-CD19 monoclonal B-cell-depleting antibody, in patients with NMOSD. Pre-planned and post hoc analyses were performed to evaluate the primary endpoint across a range of attack definitions and demographic groups, as well as key secondary endpoints. Results: In the N-MOmentum trial (ClinicalTrials.gov: NCT02200770), 174 participants received inebilizumab and 56 received placebo. Attack risk for inebilizumab versus placebo was consistently and significantly reduced, regardless of attack definition, type of attack, baseline disability, ethnicity, treatment history, or disease course (all with hazard ratios < 0.4 favoring inebilizumab, p < 0.05). Analyses of secondary endpoints showed similar trends. Conclusion: N-MOmentum demonstrated that inebilizumab provides a robust reduction in the risk of NMOSD attacks regardless of attack evaluation method, attack type, patient demographics, or previous therapy. The N-MOmentum study is registered at ClinicalTrials.gov: NCT2200770.

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