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Author contributions
K.P.W., N.R., and C.M.D. designed the experiments; C.M.D., S.J.M, and K.P.W. collected data; all authors analyzed data and edited the paper; M.G., C.M.D., and K.P.W. wrote the manuscript; K.P.W., N.R., and C.M.D. obtained funding and supervised the research.
PMC10689438
Funding
This research was supported by National Institutes of Health Grants: HL109706, HL145099, DK111161, TR001082, DK048520, HL132150, and Sleep Research Society Foundation 011-JP-16. K.P.W. reports during the conduct of the study being an advisory bmoard member and receiving personal fees from the NIH; being a scientific ad...
PMC10689438
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
PMC10689438
Competing interests
The authors declare no competing interests.
PMC10689438
References
PMC10689438
Abstract
Cemi, cHL anti‐PD‐1/programmed, toxicities, PTCL, DLBCL, cHL, lymphoma, peripheral T‐cell lymphoma
LYMPHOMA, CLASSIC HODGKIN LYMPHOMA, CHL
Patients with relapsed or refractory lymphoma have limited treatment options, requiring newer regimens. In this Phase 1/2 study (NCT03769181), we assessed the safety, efficacy, and pharmacokinetics of isatuximab (Isa, anti‐CD38 antibody) in combination with cemiplimab (Cemi, anti‐programmed death‐1 [PD‐1] receptor anti...
PMC10092787
INTRODUCTION
PD‐L1, death, tumor, cancers, HL, hematological cancers, leukemia, hematological malignancies, Cemi, PTCL, DLBCL, Hodgkin lymphoma, NHL
TUMOR, CANCERS, LEUKEMIA, MULTIPLE MYELOMA (MM), HEMATOLOGICAL MALIGNANCIES, HODGKIN LYMPHOMA, NHL, LYMPHOMA
Immune checkpoint blockade has contributed to the efficacy of targeted anti‐programmed death 1 (PD‐1)/anti‐programmed death‐ligand 1 (PD‐L1) agents in many tumor types, with clinical responses observed in a small proportion of patients with Hodgkin lymphoma (HL) and rare non‐HL (NHL) subtypes.The expression of the tran...
PMC10092787
PATIENTS AND METHODS
PMC10092787
Study design and participants
tumor, death, immune‐related disease/conditions, HL, toxicity, Cemi, PTCL, DLBCL, cHL, anti‐PD‐L2, peripheral T‐cell lymphoma
TUMOR, LYMPHOMA, DISEASE, CHL, ONCOLOGY, CLASSIC HODGKIN LYMPHOMA
This was a Phase 1/2 multicenter, non‐comparative, open‐label study. Patients were enrolled at 23 study sites in seven countries (France, Italy, Republic of Korea, Netherlands, Portugal, Spain, and Taiwan).Eligible patients were ≥12 years old and had disease location amenable to tumor biopsy at baseline, measurable dis...
PMC10092787
Procedures
INFUSION REACTION
In Phase 1, patients received a starting dose of Isa (10 mg/kg) every week in Cycle 1, every 2 weeks in Cycles 2–6, and every 3 weeks thereafter. Cemi was given at 250 mg every 2 weeks in Cycles 1–6, and at 350 mg every 3 weeks thereafter. The cycle duration was 28 days for Cycles 1–6, then 21 days in subsequent cycles...
PMC10092787
Outcomes
DLTs, TEAEs, Cancer
ADVERSE EVENTS, ADVERSE EVENT, SECONDARY, CANCER
In Phase 1, safety and tolerability were assessed based on DLTs in Cycle 1, treatment‐emergent adverse events (TEAEs) or serious TEAEs, and laboratory abnormalities. TEAEs and laboratory abnormalities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.Disease resp...
PMC10092787
Pharmacokinetics
BLOOD
Blood samples were collected at selected time points during Cycle 1 (predose, end of infusion [EOI], EOI+4h, start of infusion [SOI]+72h, SOI+144h) to perform Isa pharmacokinetics by non‐compartmental analysis using Phoenix WinNonlin® version 8.2 (Pharsight). Gyrolab Platform, a quantitative Sandwich immunoassay using ...
PMC10092787
Statistical analysis
MAY
The sample size was determined based on the primary efficacy endpoint. An interim efficacy analysis was performed when the first 18 (Cohort A1), 12 (Cohort A2), 17 (Cohort B), and 11 (Cohort C) patients in Phase 2 had been treated and the last patient in Phase 2 had been followed up for 24 weeks (data cutoff: 5 May 202...
PMC10092787
RESULTS
PMC10092787
Patients
Cemi, PTCL, DLBCL, cHL, ≥15,000/mmExposure, leukocytosis
ALEUKOCYTOSIS, S; HEMOGLOBIN, CHL
In cohorts A1, A2, B, and C, 18, 12, 17, and 11 patients were enrolled, respectively. Patient baseline characteristics are shown in Table Patient baseline characteristics Abbreviations: Different risk factors are used to calculate the International Prognostic Score for cHL, DLBCL, and PTCL. For cHL cohorts, 1 point is ...
PMC10092787
Safety
death, DLTs, overdose, toxicity, immune‐related TEAEs, thrombocytopenia, TEAEs, PTCL, DLBCL, anemia, lymphopenia, cHL, deaths, peripheral T‐cell lymphoma
DISEASE, THROMBOCYTOPENIA, ANEMIA, LYMPHOPENIA, ADVERSE EVENT, CHL, INFUSION REACTION, LYMPHOMA, INTESTINAL PERFORATION, URINARY TRACT INFECTION, HODGKIN'S LYMPHOMA
TEAEs were reported in 83.3% of the patients in the cHL anti‐PD‐1/PD‐L1 naïve cohort and in all patients in the remaining cohorts (Table Safety summary by cohort, all‐treated population Abbreviations: AE, adverse event; AESI, adverse event of special interest; cHL, classic Hodgkin's lymphoma; DLT, dose‐limiting toxicit...
PMC10092787
Efficacy
death, HL, Cemi, PTCL, DLBCL, cHL, peripheral T‐cell lymphoma
LYMPHOMA, CLASSIC HODGKIN LYMPHOMA, CHL, HODGKIN'S LYMPHOMA
Among the all‐treated population, response rate was 55.6%, 33.3%, 5.9%, and 9.1% in cHL anti‐PD‐1/PD‐L1 naïve, cHL anti‐PD‐1/PD‐L1 progressor, DLBCL, and PTCL cohorts, respectively (Table Summary of response rate per Lugano 2014 criteria, all‐treated population Abbreviations: cHL, classic Hodgkin's lymphoma; CR, comple...
PMC10092787
Pharmacokinetics
cHL
CHL, HODGKIN'S LYMPHOMA
Mean Isa maximum plasma concentration (Isa pharmacokinetic parametersMedian.Min–max. Abbreviations: AUC, area under curve; cHL, classic Hodgkin's lymphoma;
PMC10092787
DISCUSSION
relapsed/refractory lymphoma, DLTs, Cemi, PTCL, DLBCL, + lymphoma, cHL, lymphoma, prostate cancer, NHL
LUNG CANCER, CHL, NHL, LYMPHOMA, EVENTS, CYTOTOXICITY, PROSTATE CANCER
In patients with relapsed/refractory lymphoma, treatment beyond the first line remains challenging and represents a significant unmet need.The expression of CD38 in lymphoma, together with preclinical evidence for anti‐CD38 antibodies against CD38+ lymphoma, suggests potential utility for these agents in patients with ...
PMC10092787
CONCLUSION
Cemi, cHL, PTCL, DLBCL
CHL
Isa + Cemi had a manageable safety profile. Limited clinical efficacy was observed in patients with cHL who had prior anti‐PD‐1/PD‐L1 exposure, as well as in those who did not. However, we did not observe a synergistic effect of Isa in combination with Cemi in patients with cHL, DLBCL, or PTCL.
PMC10092787
AUTHOR CONTRIBUTIONS
cHL, PTCL, DLBCL
DER, CHL
Rao Saleem was responsible for study oversight. Carmelo Carlo‐Stella, Pier Luigi Zinzani, Anna Sureda, Luis Araújo, Olivier Casasnovas, Cecilia Carpio, Su‐Peng Yeh, Krimo Bouabdallah, Guillaume Cartron, Won Seog Kim, Raul Cordoba, Youngil Koh, Alessandro Re, Daniela Alves, Martine Chamuleau, Steven Le Gouill, Armando L...
PMC10092787
CONFLICT OF INTEREST
CC‐S:
PMC10092787
PEER REVIEW
The peer review history for this article is available at
PMC10092787
ETHICS STATEMENT
The study was conducted in accordance with the Declaration of Helsinki, Council for International Organizations of Medical Sciences International Ethical Guidelines, and the International Conference on Harmonization Good Clinical Practice Guidelines. The relevant independent ethics committees and institutional review b...
PMC10092787
ACKNOWLEDGMENTS
This study was sponsored by Sanofi. The authors thank the participating patients and their families, and the study centers and investigators for their contributions to the study. Medical writing support was provided by Smitha Reddy, PhD, of Elevate Scientific Solutions, contracted by Sanofi for publication support serv...
PMC10092787
DATA AVAILABILITY STATEMENT
Qualified researchers can request access to patient‐level data and related study documents including the clinical study report, study protocol with any amendments, blank case report forms, statistical analysis plan, and dataset specifications. Patient‐level data will be anonymized, and study documents will be redacted ...
PMC10092787
REFERENCES
PMC10092787
Methods
diabetes
DIABETES
A three-armed randomized controlled trial was conducted online in Singapore between September and October 2021. A total of 1000 undergraduate students were recruited through campus advertisements to complete a 30- to 45-minute online survey, which randomly exposed participants to one of three informational brochures on...
PMC10619829
Results
Exposure to age-related fertility information resulted in significant reductions in the ideal age at first childbirth, significant increases in the expected probability of marriage before age 30, and (among female participants) significant increases in the expected likelihood of undergoing social egg-freezing. No diffe...
PMC10619829
Conclusions
Information on age-related fertility decline brought forward university students’ expected timing of childbearing and marriage without reducing their educational and career expectations. The provision of fertility information at early ages, such as during university, can help correct widespread inaccurate beliefs about...
PMC10619829
Data Availability
All relevant data are within the paper and its
PMC10619829
Introduction
infertility
Delayed childbearing has increased in prevalence in developed countries despite the risks of infertility and adverse reproductive outcomes associated with advanced maternal and paternal age [Past studies suggest that informational interventions can help to address these knowledge gaps [Moreover, although existing resea...
PMC10619829
The present study
diabetes, ARF
ARF, DIABETES
The primary aim of the present study was to examine the effects of providing fertility information and objective fertility policy information on university students’ family formation and career expectations. A total of 1,000 university students were randomly assigned to one of three treatment arms receiving information...
PMC10619829
Materials and methods
PMC10619829
Ethical approval
The study protocol was approved by the Institutional Review Board of the National University of Singapore (NUS-IRB-2020-362) prior to commencement. Study participants were presented with the Participant Information Sheet and Informed Consent Form at the beginning of the online survey. Participants provided consent by c...
PMC10619829
Participants
RECRUITMENT
Participants were undergraduate students at the National University of Singapore. Inclusion criteria were: full-time undergraduate student, aged between 20 and 24, unmarried, childless and not currently expecting, self-identifies as heterosexual, and Singaporean citizen. Participants were recruited in September and Oct...
PMC10619829
CONSORT flow diagram.
PMC10619829
Procedure
ARF
ARF
Participants who met the inclusion criteria completed an online survey that took 30–45 minutes. The online survey consisted of a pretest questionnaire, a one-page information sheet with the intervention material, and a posttest questionnaire. The survey and intervention material were presented online using Qualtrics. P...
PMC10619829
Intervention
diabetes, ARF
ARF, DIABETES
The ARF treatment arm was exposed to a six-item (164 words) informational sheet on age-related fertility decline and IVF effectiveness developed by the authors. In particular, the intervention material included information on IVF success rates for different age groups and statements such as “age is a more important pre...
PMC10619829
Measures
The pre- and posttest surveys consisted of 72 items that covered five domains developed to examine factors related to participants’ family and career expectations. Those questions relevant to the analyses presented in this paper are described here.
PMC10619829
Data collected pretest only
Background characteristics of participants were collected pretest, including age, year of study, area of study, gender, ethnicity, mother’s and father’s highest level of education, number of siblings, current relationship status (single, in a relationship), number of past relationships, plans to have children (yes, no,...
PMC10619829
Data collected both pre- and posttest
Family formation and career expectations were collected both pre- and posttest. Questions on family formation expectations included ideal age at first birth, probability of having at least one child by age 30 (0 to 100), ideal number of children, ideal age at marriage, probability of getting married by age 30 (0 to 100...
PMC10619829
Data collected posttest only
anxiety
Information evaluation and psychological measurement was taken once immediately after exposure to the information brochure. We used a single item to evaluate the usefulness of the information brochure (rated on a 5-point Likert scale): ‘How do you feel about the information just presented?’ ‘I found the information use...
PMC10619829
Statistical analysis
Pretest demographic characteristics were summarized overall and by treatment arm. Differences across treatment arms were compared using ANOVA tests (for continuous variables) and
PMC10619829
Results
PMC10619829
Participant characteristics and group equivalence
In total, 1,000 students were recruited, randomized into the treatment arms, and completed the study.
PMC10619829
Effect of the intervention on outcomes
PMC10619829
Child-timing and child-number expectations
ARF
ARF
The mean ideal age at first childbirth was 30.3 years at pretest (median = 30 years; interquartile range, 29 to 32; range, 21 to 40). Exposure to age-related fertility information significantly reduced the ideal age at first childbirth. At posttest, the average ideal age was lower in the ARF group than in the control g...
PMC10619829
Box plot of pre- and posttest measures of ideal age at first childbirth by treatment group.
ARF
ARF
Within each box, horizontal black lines denote median values. Boxes extend from the 25The mean expected probability of having a child by age 30 was 47.8 percent at pretest (median = 50; interquartile range, 25 to 70; range, 0 to 100). The age-related fertility information significantly increased participants’ expected ...
PMC10619829
Marriage-timing expectations
ARF
ARF
At pretest, the mean ideal age at marriage was 28.2 years (median = 28 years; interquartile range, 27 to 30; range, 20 to 40). Neither age-related fertility information nor fertility policy information had any statistically significant impact on the ideal age at marriage. The within-group change in ideal age at marriag...
PMC10619829
Expected probability of social egg-freezing
ARF
ARF
We analyzed the effects of the interventions on female participants’ expected chances of undergoing social egg-freezing by age 25 and age 30. At pretest, female participants’ mean expected probability of egg-freezing by age 25 is 20.2 percent (median = 0 percent; interquartile range, 0 to 30; range, 0 to 100); the mean...
PMC10619829
Expected educational attainment and future income
For all three outcome variables measuring expected educational attainment and future income, the change over time was small and statistically nonsignificant in all three groups. At posttest, there were no differences between groups in any of the three outcome variables (
PMC10619829
Information evaluation and post-intervention anxiety
anxiety, ARF
ARF
On average, participants rated both the age-related fertility and the fertility policy information significantly more useful than the control information (both P < 0.001). Participants also rated the age-related fertility information marginally more useful than the fertility policy information (P = 0.060). The average ...
PMC10619829
Subgroup analysis
ARF
ARF
We conducted post hoc analyses to explore whether the effects of the age-related fertility information on the primary outcome, the ideal age at first childbirth, were heterogeneous by participants’ gender. At pretest, the average ideal age at first childbirth was significantly lower among female participants (mean = 29...
PMC10619829
Discussion
Findings show that information on age-related fertility decline brought forward university students’ expected timing of family formation without reducing their educational and career expectations. The findings on child-timing ideals are consistent with previous studies that show fertility information reduces desired ag...
PMC10619829
Limitations
ARF
ARF
We acknowledge several limitations to the present study. One, there was a violation of randomization (i.e., the ARF group comprises a higher share of female students than the other two groups), which happened by chance. However, we presented results using analysis of covariance that adjusted for participant’s gender. T...
PMC10619829
Conclusion
A short informational brochure with accurate information on age-related fertility decline and IVF success rates could effectively reduce university students’ ideal ages of childbearing. Moreover, at least in the short run, such interventions do not seem to bear any negative consequences on participants’ educational and...
PMC10619829
Supporting information
PMC10619829
Appendix: Intervention material.
(DOC)Click here for additional data file.(ZIP)Click here for additional data file.Thanks to ALSET, Provost’s Office, NUS for help with data collection, and to Rais Kamis, Daryl Joel Si-Xuan Lee, Jing Yi Ooi, and Zhi Xing Tan for excellent research assistance.
PMC10619829
References
PMC10619829
Background
STABLE ANGINA
Percutaneous coronary intervention (PCI) is frequently performed to improve symptoms of stable angina. Whether PCI without background antianginal medication relieves angina beyond placebo remains unknown.
PMC7615400
Methods
death, intolerable angina, angina
ACUTE CORONARY SYNDROME, STABLE ANGINA
We conducted a randomized, double-blind, placebo-controlled trial of PCI in patients with stable angina. Patients stopped all antianginal medications and underwent a 2-week pre-randomization symptom assessment. Patients were randomized 1:1 to PCI or placebo and were followed for 12-weeks. The primary end point was the ...
PMC7615400
Results
intolerable angina, angina, Ischemia
ACUTE CORONARY SYNDROME, ISCHEMIA
A total of 301 patients were randomized, with 151 patients assigned to receive PCI and 150 to placebo. The mean age of patients was 64±9 years and 79% were male. Ischemia was present in one cardiac territory in 242 patients (80%), two territories in 52 patients (17%) and three territories in 7 patients (2%). The median...
PMC7615400
Conclusions
ischemia, angina
ISCHEMIA, HEART, STABLE ANGINA
Among patients with stable angina on little or no antianginal medication and objective evidence of ischemia, PCI improved the angina symptom score compared to placebo. (Funded by NIHR Imperial Biomedical Research Centre, Medical Research Council, NIHR, British Heart Foundation, Philips, Coronary Flow Trust; ORBITA-2 Cl...
PMC7615400
Introduction
Angina, Angioplasty, coronary artery disease
CORONARY ARTERY DISEASE, STABLE ANGINA
Angina relief is the primary reason that patients with stable coronary artery disease undergo percutaneous coronary intervention (PCI).ORBITA (Objective Randomized Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina), a placebo-controlled trial of PCI that mandated the use of guideline-di...
PMC7615400
Methods
PMC7615400
Trial Design And Oversight
The ORBITA-2 trial was an investigator-initiated multicenter, double-blind, randomized, placebo-controlled trial performed at 14 sites in the United Kingdom. The full protocol
PMC7615400
Patients
coronary stenosis, ischemia, angina
CORONARY STENOSIS, ISCHEMIA
Patients were eligible if they were considered clinically suitable for PCI by the referring heart team, had angina or an anginal equivalent, anatomical evidence of at least one severe coronary stenosis identified by invasive diagnostic coronary angiography or computed tomography coronary angiography and non-invasive or...
PMC7615400
Study Procedures And Randomization
angina, visual stenosis, ischemia, atrial fibrillation, heart failure
ATRIAL FIBRILLATION, ISCHEMIA, HEART FAILURE
At enrollment, patients ceased antianginal medication. Antihypertensive medications with antianginal properties were replaced with alternatives with no antianginal effects. Medications with antianginal properties required for other clinical indications such as heart failure or atrial fibrillation rate control were cont...
PMC7615400
Blinding And Interventions
multivessel coronary-artery disease
For the PCI group, angiographic and physiological complete revascularization of target vessels was mandated, and intravascular imaging encouraged. For multivessel coronary-artery disease, all vessels were treated during the index procedure. The placebo group remained sedated, without any further intervention, for at le...
PMC7615400
Follow-Up
On the day of randomization, all antianginal medications initiated in the pre-randomization period were stopped. Patients entered the 12-week blinded follow-up phase, with continued daily smartphone application symptom reporting. During this period, antianginal medication initiation and uptitration was triggered by pat...
PMC7615400
End Points
angina
The primary end point is the angina symptom score: an ordinal clinical outcome scale calculated daily from the number of angina episodes and the units of antianginal medication (Secondary end points included self-reported angina frequency (smartphone application); antianginal medication initiation and uptitration; trea...
PMC7615400
Statistical Analysis
angina
EVENT
The sample size was determined by assuming a standard deviation of 6 angina symptom score units; 284 patients would give 80% power with an alpha of 0.05 to detect a difference of 2 angina symptom score units between the PCI and placebo groups, using a 2-sample t-test. Based on prior experience, the study planned to enr...
PMC7615400
Results
PMC7615400
Patients
Between 12th November 2018 and 17th June 2023, 923 patients were assessed for eligibility. Of these, 439 were enrolled into the pre-randomization symptom assessment phase, and 301 were randomized to PCI or placebo (
PMC7615400
Procedural characteristics
Procedural characteristics are described in Images of qualifying coronary lesions from all randomized patients are shown in
PMC7615400
Primary end point
angina
Data were available for 99.7% of the 22,823 patient days in the trial. Two participants in the placebo group had missing data. For these participants, the last angina symptom score was carried forward for the primary end point. At 12-week follow-up, the angina symptom score was 2.9 for patients assigned to PCI and 5.6 ...
PMC7615400
Secondary end points
The treadmill exercise time (
PMC7615400
Serious Adverse Events
deaths, intolerable angina
ACUTE CORONARY SYNDROME
Unblinding for intolerable angina occurred in 0 patients in the PCI group and 1 patient in the placebo group. Acute coronary syndromes occurred in 4 patients in the PCI group and 6 patients in the placebo group. There were no deaths (
PMC7615400
Blinding Index
The principal assessment of blinding was performed prior to discharge after PCI or placebo. The blinding index for the PCI group was 0.01 (95% CI, -0.05 to 0.06) and the placebo group was -0.09 (95% CI, -0.15 to -0.03) demonstrating effective blinding. The index for blinded staff for patients in the PCI group was 0.01 ...
PMC7615400
Discussion
ischemia, Angioplasty, angina, angioplasty
STABLE ANGINA, ISCHEMIA, DISEASE, STENOSES, EVENTS
In this placebo-controlled trial in patients with stable angina on little or no antianginal medication, with coronary-artery stenoses causing ischemia, PCI improved the angina symptom score. Reduction in the angina symptom score appeared to result from reduction in daily angina episodes. Assignment to the PCI group was...
PMC7615400
Supplementary Material
PMC7615400
Funding
HEART
“Funded by NIHR Imperial Biomedical Research Centre, Medical Research Council, NIHR, British Heart Foundation, Philips, Coronary Flow Trust.”Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
PMC7615400
Primary end point of angina symptom score and its constituents.
angina
Panel A shows the individual patient data composition of the primary end point (angina symptom score) stratified by treatment allocation. The method for derivation of the score is depicted below and the overall calculated score is shown next to the colored box. Panel B shows individual patient data of daily angina epis...
PMC7615400
Secondary end points.
Panel A shows treadmill exercise at follow-up stratified by baseline performance, with 95% confidence intervals. ETT denotes exercise treadmill time. Panel B shows the distribution of CCS class according to treatment group at pre-randomization and follow-up. CCS denotes Canadian Cardiovascular Society class. The widths...
PMC7615400
Baseline Patient Characteristics
Left ventricular systolic function
Plus–minus values are means ±SD. Results may not total to 100% due to rounding.PCI denotes percutaneous coronary intervention.Left ventricular systolic function was defined as normal (≥55%), mildly impaired (45-54%) or moderately impaired (35-44%).
PMC7615400
Procedural Characteristics
Plus–minus values are means ±SD.PCI denotes percutaneous coronary intervention, FFR fractional flow reserve, iFR instantaneous wave-free ratio.Where iFR was not available, an alternative non-hyperemic pressure ratio was utilized.
PMC7615400
Primary and Secondary End Points
Angina, SAQ angina, angina
ANGINA AT REST
PCI denotes percutaneous coronary intervention, SAQ denotes Seattle Angina Questionnaire, EQ-5D denotes EuroQOL 5 dimensions, and EQ-VAS denotes EuroQOL visual analogue scale.Treadmill exercise time and stress echocardiography score are presented for the patients who had both pre-randomization and follow-up scores.The ...
PMC7615400
Background
CORONAVIRUS DISEASE 2019
Edited by: Chuanxi Fu, Zhejiang Chinese Medical University, ChinaReviewed by: Ning Jiang, Peking University, ChinaDaniel Leung, The University of Hong Kong, Hong Kong SAR, China†These authors have contributed equally to this work and share first authorshipCoronaVac has been authorized worldwide for preventing coronavir...
PMC10796506
Methods
-11
In this randomized, double-blind, phase IV clinical trial in healthy children and adolescents aged 3-17 years, we aimed to assess the lot-to-lot and workshop-to-workshop consistency, as well as immunogenicity and safety of seven lots of commercial-scale CoronaVac from three workshops. Eligible participants were enrolle...
PMC10796506
Results
Between July 27
PMC10796506
Conclusion
CoronaVac is well-tolerated and can elicit a good immune response among children and adolescents. Lot-to-lot consistency results indicate stable manufacturing of commercial-scale CoronaVac.
PMC10796506
Introduction
respiratory disease
CORONAVIRUS, RESPIRATORY DISEASE, CORONAVIRUS DISEASE 2019, SEVERE ACUTE RESPIRATORY SYNDROME
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a highly contagious respiratory disease that has radically impacted the world since its emergence in December 2019 (The development of COVID-19 vaccine has been a top priority since the beginning of the pande...
PMC10796506
Materials and methods
PMC10796506
Study design and participants
DISEASE
This study was a single-center, randomized, double-blind, phase IV clinical trial, which was conducted in Yanliang District, Xian City, Shaanxi Province, China, from July 27This trial was approved by the ethics committee of Shaanxi Provincial Centre for Disease Control and Prevention. Written informed consents were obt...
PMC10796506
Randomization and blinding
-11, BLIND
Eligible participants were enrolled into three different age cohorts (3-5, 6-11 and 12-17 years old). Within each cohort, participants were randomly assigned, in a ratio of 1:1:1:1:1:1:1, to receive two doses of CoronaVac from one of the seven lots from three workshops on a commercial scale, with four weeks apart. Rand...
PMC10796506
Study vaccines
The manufacturing process and facilities for CoronaVac have been described previously (CoronaVac used in this trial was packed in prefilled syringes and stored at 2-8°C. It was administered intramuscularly into the lateral deltoid muscle of upper arm, at a dose of 600SU/0.5ml (3μg antigen). In this trial, the schedule ...
PMC10796506
Immunogenicity assessment
For all participants, each time 3 ml of blood samples were collected before the first dose vaccination (Day 0) and at 28 days after the second dose vaccination (Day 56). Neutralizing antibody titers against the ancestral strain were then tested using a micro-cytopathogenic effect assay, which was done by Sinovac (The i...
PMC10796506
Safety assessment
myalgia, swelling, fever, diarrhea, fatigue, erythema, rash, pain, appetite, vomiting, nausea, cough, pruritus, headache, mucocutaneous disorder, acute hypersensitive reaction
ADVERSE EVENTS, ADVERSE REACTIONS, ERYTHEMA, INDURATION
Participants stayed in the trial center for at least 30 minutes after each vaccination for immediate adverse events (AE) observation. Within28 days after each vaccination, participants and their legal guardians were required to record any local AEs (at the injection site) and systemic AEs on the electronic diary cards ...
PMC10796506
Sample size determination and statistical analysis
ADVERSE REACTIONS, -11
For the consistency assessment, equivalence is considered to be fulfilled when the 95% confidence interval (CI) for the inter-group GMT ratio were between 0.67 and 1.5, which was equivalent to the GMT difference after logGenerally, Pearson’s chi-squared test, Fisher’s exact test or one-way ordered Cochran–Mantel–Haensz...
PMC10796506