Assessment and Impact of Age on the Safety and Efficacy of Etrasimod in Patients With Ulcerative Colitis: A Post Hoc Analysis of Data From the ELEVATE UC Clinical Program

Abstract

Background

Patient age can impact the safety and efficacy of ulcerative colitis (UC) treatments. Etrasimod is an oral, once daily (QD), selective sphingosine 1-phosphate_1,4,5 receptor modulator for the treatment of moderately to severely active UC. Here, we evaluate the impact of age on etrasimod safety and efficacy in patients with UC in the phase 3 ELEVATE UC clinical program.

Methods

Data were pooled from ELEVATE UC 52 and ELEVATE UC 12 in patients receiving etrasimod 2 mg QD or placebo. Proportions and incidence rates (IRs) per 100 patient-years of treatment-emergent adverse events (AEs) were stratified by age (<40, 40-59, and ≥60 years). With the same age stratifications, efficacy was evaluated in patients with baseline Modified Mayo scores of 5-9 and 4-9 for the primary efficacy endpoint (clinical remission) and secondary efficacy endpoints.

Results

Overall, 787 patients were enrolled (<40 years, n = 420 [53.4%]; 40-59 years, n = 276 [35.1%]; and ≥60 years, n = 91 [11.6%]). Arthralgia, fatigue, and hypertension IRs were higher in older patients, irrespective of treatment. Serious AEs and AEs leading to treatment discontinuation were low and consistent across age groups. Significantly more patients receiving etrasimod 2 mg QD vs placebo achieved efficacy endpoints, regardless of age.

Conclusions

The safety profile of etrasimod 2 mg QD in the ELEVATE UC population was consistent across age groups, with no change in the incidence of AEs. Patients receiving etrasimod vs placebo showed significant clinical benefit, regardless of age.

ClinicalTrials.gov

NCT03945188; NCT03996369.

Introduction

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by episodes of inflammation that remit and relapse.¹ New UC diagnosis among older people is becoming more frequent, possibly due in part to improvements in disease awareness, and together with existing aging patients who have longstanding UC,² the elderly consequently represent a considerable proportion of the current UC population.^3-6 Despite this upward trend in prevalence, IBD management in elderly patients is understudied, and older patients are often underrepresented in clinical trials and treatment algorithms.^4,5 As current estimates suggest that 24% of Americans will be 65 and older by 2060,⁷ with similar trends observed globally, there is a need for further study into this patient population.

Although it has been observed that late-onset UC can present with a milder disease course than that of earlier onset disease,¹ older patients with UC are at greater risk of mortality owing to comorbidities, polypharmacy, and the associated risk of drug–drug interactions, and increased susceptibility to various stressors.^5,8 Population-based studies have identified an increased likelihood of serious infections, herpes zoster, opportunistic infections, and malignancies among older patients with IBD compared with younger patients.^9,10 An age-related predisposition to these complications is further compounded by the findings that some currently available treatments for UC (including tumor necrosis factor inhibitors [TNFi] and Janus kinase inhibitors [JAKi]) are associated with a higher risk of infections and malignancies, which may be more pronounced in older patients vs younger patients.^5,11,12

Etrasimod is an oral, once daily (QD), selective, sphingosine 1-phosphate (S1P)_1,4,5 receptor modulator for the treatment of moderately to severely active UC. The efficacy and safety of etrasimod 2 mg QD have been demonstrated in patients with moderately to severely active UC in the phase 3 ELEVATE UC clinical program (comprising ELEVATE UC 52 [NCT03945188] and ELEVATE UC 12 [NCT03996369]).¹³ In this analysis, we examined outcomes in 3 separate cohorts of patients (<40 years of age; 40-59 years of age; and ≥60 years of age) in order to evaluate the impact of age on etrasimod safety and efficacy in patients with UC in the phase 3 ELEVATE UC clinical program.

Materials and Methods

Study Design and Patients

Patient enrollment and trial design have been described previously.¹³ Briefly, ELEVATE UC 52 and ELEVATE UC 12 were phase 3, multicenter, randomized, double-blind, placebo-controlled trials. ELEVATE UC 52 was a 52-week trial, comprising a 12-week induction period followed by a 40-week maintenance period with a treat-through design; ELEVATE UC 12 was a 12-week trial (induction period only). Eligible patients were adults (16-80 years of age) with moderately to severely active UC (defined by a modified Mayo score [MMS] of 4-9 [endoscopic subscore of ≥2 and a rectal bleeding subscore of ≥1]). Patients were randomized (2:1) to receive etrasimod 2 mg QD or placebo and were stratified by disease activity at baseline (MMS; 4-6 vs 7-9), baseline corticosteroids (yes vs no), and prior exposure to biologic or JAKi therapy (yes vs no).

All studies were registered with ClinicalTrials.gov and were performed in compliance with the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice Guidelines. The trials were approved by the Institutional Review Boards and/or Independent Ethics Committees at each participating investigational center, or at a central Institutional Review Board. All patients provided written, informed consent. An external independent data monitoring committee was employed to supervise the safety of participants and to enhance the integrity and credibility of the study.

In this post hoc analysis, patients were further stratified into 3 age groups according to their age at the trial baseline (<40, 40-59, and ≥60 years). Age categories were selected on the basis of studies that have suggested that earlier diagnosis of UC (at age <40 years) is associated with a poorer prognosis,¹⁴ and to align with similar analyses conducted for other UC therapies.¹⁵

Safety Assessments

Treatment-emergent adverse events (TEAEs) which occurred in >5% of patients in any treatment group, and selected adverse events (AEs) based on system-organ class (SOC) and preferred term (PT) from the Medical Dictionary for Regulatory Activities were reported by age group and assessed up to week 52.

The selected AEs of interest reported are those that have been associated with the treatment of UC by advanced therapies.^16-18 The ELEVATE UC clinical program further evaluated a number of specific AEs to assess if they met the criteria for identification as an adverse event of special interest (AESI). Assessment of potential AESIs involved the review of a subset of reported TEAEs designated “Targeted Medical Events and relevant laboratory parameters”; from this additional medical review it was determined if an event qualified as AESI based upon specific AESI criteria.¹³

Efficacy Assessments

Efficacy was assessed at week 12 (pooled data from ELEVATE UC 52 and ELEVATE UC 12) and/or week 52 (ELEVATE UC 52 only) (see Supplementary Table S1, which summarizes efficacy endpoints in the trials). In both trials, the primary efficacy outcome was the proportion of patients in clinical remission at the end of the 12-week induction period and at week 52 (ELEVATE UC 52 only).

Statistical Analysis

Safety was assessed in all randomized patients who received ≥1 dose of the study treatment (the safety analysis set) in the Pivotal UC cohort, which comprised pooled data from the ELEVATE UC 52 and ELEVATE UC 12 trials. Safety outcomes, baseline disease characteristics, and demographics were summarized descriptively in the overall population of patients with baseline MMS 4-9, stratified by age. Proportions and incidence rates (IRs) per 100 patient-years (PY) for TEAEs and events of interest were stratified by age. Exposure-adjusted IRs were calculated as the number of patients with an AE divided by the total exposure in PY, adjusted to per 100 PY, with exposure defined as the sum of the patient’s time from baseline to first AE episode or time in the study if the patient was event-free.

Efficacy outcomes in patients with an MMS of 5-9 at baseline were assessed, comprising randomly assigned patients who received ≥1 dose of etrasimod 2 mg QD or placebo (full analysis set [FAS]). Primary and select secondary efficacy endpoints, including clinical response, endoscopic improvement, and corticosteroid-free clinical remission, were analyzed in patients with baseline MMS 4-9. Comparisons between treatment groups, as well as 2-sided P values, were obtained using a Cochran–Mantel–Haenszel method, adjusted to reported randomization stratification of naivety to biologic/JAKi therapy at study entry, baseline disease activity (MMS 4-6 or 7-9), and study identifier (pooled data only). Missing responses were considered as nonresponses. All P values are reported without adjustment for multiple comparisons; P < .05 was considered statistically significant.

Results

Patients

Out of the enrolled 787 patients, 420 (53.4%) were <40 years of age, 276 (35.1%) were 40-59 years of age, and 91 (11.6%) were ≥60 years of age (Table 1). Consistent with the previously reported demographics and baseline disease characteristics,¹³ demographics and baseline disease characteristics of patients were generally comparable between the etrasimod and placebo groups, irrespective of age (Table 1). Of note, patients receiving a placebo in the ≥60 years subgroup had higher rates of proctosigmoiditis than any other subgroup. Additionally, patients ≥60 years of age receiving placebo had lower disease duration, and lower proportions of endoscopic subscore of 3, pancolitis, prior biologic/JAKi treatment, and prior failure of TNFi therapy compared with those ≥60 years of age who received etrasimod, although the relatively small size of the cohort should be taken into consideration (Table 1).

Safety Outcomes

The proportion of etrasimod patients who reported SAEs or TEAEs leading to discontinuation did not exceed 5.5% in any age group (Figure 1). Overall, proportions and IRs of SAEs, and proportions of TEAEs leading to study treatment discontinuation, were similar between ages and treatment arms, though slightly more patients treated with etrasimod vs placebo experienced a TEAE leading to discontinuation in the 40-59 subgroup (Figure 1A and B). Proportions of SAEs were slightly higher in patients receiving etrasimod 2 mg QD vs placebo in those patients aged 40-59 years and ≥60 years (Figure 1A). In patients aged <40 and ≥60 years, gastrointestinal disorders (placebo: colitis ulcerative [n = 1], abdominal pain upper [n = 1], and large intestine perforation [n = 1]; etrasimod 2 mg QD: colitis ulcerative [n = 8]; and placebo: colitis ulcerative [n = 1]; etrasimod 2 mg QD: diarrhea [n = 1], respectively) were the most common TEAEs leading to study treatment discontinuation. Additionally, cardiac disorders (sinus bradycardia) in the ≥60 years subgroup were slightly higher in the etrasimod treatment group (n = 1) vs placebo (n = 0). In patients aged 40-59 years, the most common TEAEs that led to discontinuation of etrasimod 2 mg QD were cardiac related, including atrioventricular block second degree (n = 1), bradycardia (n = 1), and sinus bradycardia (n = 1), though this was not the case in the placebo group; 1 patient experienced 1 TEAE of malaise leading to study treatment discontinuation.

Between age groups and treatment arms, the proportions and IRs of TEAEs and events of interest were generally similar (Table 2). Of the most common TEAEs (reported in >5% of patients), IRs for arthralgia, fatigue, and hypertension were generally higher in patients aged ≥60 years vs patients aged <40 years, and higher in patients treated with etrasimod than placebo (Table 2). Incidence rates for hypertension were highest in patients aged ≥60 years (11.3 and 9.5 for etrasimod and placebo groups, respectively) vs those aged <40 years (0.7 and 1.6 for etrasimod and placebo groups, respectively). Of the total 13 hypertension events (PT) reported, none led to treatment discontinuation, 10 resolved/were resolving at the final visit, 1 had an unknown outcome, and 2 were unresolved at the time of study completion. The proportions of patients and IRs for headache were higher for etrasimod vs placebo, regardless of age (Table 2).

The proportions of patients and IRs for serious infections and infection events of interest (cytomegalovirus, tuberculosis, and herpes zoster) were low and generally balanced across treatment groups (Table 2); none of these events met reporting criteria for seriousness. No malignancies or deaths were reported in any age or treatment group.

After medical review based upon specific AESI criteria, the following events (PT) were deemed AESI for patients receiving etrasimod aged <40 years: bradycardia (n = 1), hypertension (n = 1), atrioventricular block first degree (n = 1), and oral herpes (n = 2). Among patients receiving a placebo aged <40 years, there were 3 events of severe infection (PT: campylobacter infection, cellulitis, peritonitis) and single events of tuberculosis (narrow opportunistic infection), herpes zoster, and oral herpes. Of the patients receiving etrasimod aged 40-59 years, the following were deemed AESI: 6 hypertension events, 2 herpes zoster events, and single events of blood pressure increased, bradycardia, sinus bradycardia, atrioventricular block first degree, atrioventricular block second degree (Mobitz type 1), macular edema, oral herpes, severe infections (PT: pneumonia bacterial) and hypertensive crisis. The hypertensive crisis event occurred in a 51- to 60-year-old male who received etrasimod 2 mg QD in ELEVATE UC 52 and was self-reported and the patient self-administered 1 dose of captopril. No changes were made to the study treatment and the event was resolved on the same day without intervention from the investigator. This was confirmed by the investigator as not a “hypertensive crisis” event based on the objective blood pressure measurements and accepted diagnostic definitions. Among patients receiving a placebo aged 40-59 years, there were 2 reported severe infections (PT: coronavirus disease 2019 [COVID-19] and COVID-19 pneumonia), and a single event of essential hypertension, meeting AESI criteria. In patients receiving etrasimod aged ≥60 years, the AESI were 4 events of hypertension, 3 severe infections (in 2 patients) (PT: COVID-19, COVID-19 pneumonia, and pneumonia viral), and single events of cytomegalovirus infection (narrow opportunistic infection), herpes simplex, and sinus bradycardia. In patients receiving placebo aged ≥60 years, there were single events of hypertension and herpes zoster.

Efficacy Outcomes

In the FAS of patients with baseline MMS 5-9, a significantly greater proportion of patients achieved clinical remission (the primary efficacy endpoint) at weeks 12 and 52 when treated with etrasimod 2 mg QD vs placebo, regardless of age (P < .05; Figure 2). The key secondary efficacy outcomes of clinical response, symptomatic remission, endoscopic improvement, endoscopic improvement–histologic remission, histologic–endoscopic mucosal improvement, and corticosteroid-free remission at week 52, generally followed a similar trend (Figure 3A–C and Table 3). Differences between age groups were less discernible at week 12 compared with week 52, and no clear trend was observed. Variations in efficacy between treatment arms in the age ≥60 years group compared with the other age groups at week 52 were a result of the limited sample size (Figure 3C). Similar trends to those in the FAS of patients with baseline MMS 5-9 were observed across efficacy endpoints in the FAS of patients with baseline MMS 4-9 (see Supplementary Figures S1 and S2, which shows proportions of patients achieving each of the above efficacy endpoints, stratified by age, across both trials).

Discussion

Given the growing population of older patients with UC,^3-6 this post hoc analysis of data from the ELEVATE UC clinical program provides an important contribution to the current knowledge around the safety and efficacy of etrasimod across the age strata, including those patients ≥60 years of age. Similarly, the armamentarium of options and mechanisms of action in the management of moderately to severely active UC is expanding, which makes understanding the impact of factors such as age on treatment effectiveness a critical part of the treatment choice.

In the ELEVATE UC clinical program, baseline demographics and disease characteristics of patients were balanced across treatment and age groups, and the extent of disease generally did not vary with age. The lower usage of oral corticosteroids observed in older patients in the placebo arm of this analysis is consistent with previous research, which has reported on the risk of steroid dependency and steroid-related toxicity in the elderly, including the risk of osteoporosis and serious infections.¹⁹ It was also observed that patients in the age ≥60 years cohort who received a placebo were less likely to have been treated previously with a biologic or JAKi. This could reflect a reticence of physicians to prescribe such therapies to elderly patients given a deficit of clinical evidence from controlled trials, regulatory guidance recommending the use of alternative treatments (if available), a perception of greater risk, and an overall hesitancy to prescribe advanced therapies to a patient population often beset by higher rates of comorbidity and a predisposition to adverse effects.^20-23

Safety was comparable with that reported in the overall populations of the ELEVATE UC 52 and ELEVATE UC 12 trials,¹³ with safety outcomes generally similar across etrasimod and placebo treatment groups, irrespective of patient age. Overall, aside from IRs of AEs established as being associated with increasing age, the safety profile of etrasimod 2 mg QD was consistent with that reported in the overall populations of the ELEVATE UC 52 and ELEVATE UC 12 trials.¹³ While rates of SAEs were numerically greater in older patients who received etrasimod vs placebo, there was no discernible trend for SAEs or study discontinuations due to TEAEs overall. Arthralgia, fatigue, and hypertension were reported more frequently for older patients, in particular among those receiving etrasimod. Elevated IRs for cardiovascular events, the most common of which was hypertension, were also observed in older vs younger patients; however, there were no study discontinuations due to hypertension. That TEAEs of this nature were more common in older patients is unsurprising, given the “comorbid load” typically experienced by the elderly, and the relative ubiquity of these symptoms in particular.^24,25 While the relatively short follow-up of ELEVATE UC 52 and ELEVATE UC 12 must be taken into consideration, it is noteworthy that no malignancies or deaths were reported in the current analyses. Further information will be generated from the ELEVATE ongoing open-label extension and post-authorization safety studies.²⁶

An elevated risk of infections among older patients compared with younger patients is well established in UC.^9,10 However, the current analyses did not reveal any clear trend in the occurrence of infections. A post hoc analysis of infection risk in the phase 3 ELEVATE program has shown that patients with UC receiving etrasimod exhibited no increased risk of infection, and that patient age (<50 vs ≥50 years) was not linked with an increased risk of infections.²⁷

These results are in contrast to the greater risk of infections observed in older patients treated with some TNFi or JAKi compared with younger patients or patients of the same age not treated with these therapeutics.^11,12 However, an analysis of the True North study of the S1P receptor modulator ozanimod, which included double-blind, placebo-controlled, and open-label patient UC cohorts, also showed low and comparable rates of infection among patients aged over and under 60 years.¹⁵

The efficacy outcomes observed in this post hoc analysis were consistent with those reported in the overall study population.¹³ Etrasimod was associated with significantly greater improvements in rates of clinical remission, clinical response, symptomatic remission, endoscopic improvement, endoscopic improvement–histologic remission, histologic–endoscopic mucosal improvement, and corticosteroid-free remission than placebo, regardless of the age of the patient. These data are consistent with recent studies of ozanimod and tofacitinib in older patients with UC, which have reported a uniformity of efficacy across age groups.^11,15

Noted limitations of these analyses include their post hoc nature and insufficient power to assess potential differences between age groups. Furthermore, the 12- and 52-week duration of the trials limits the timeframe for the emergence of some AEs, in particular malignancies. The small size of some of the groups, particularly that of the ≥60 years of age group, limits the overall interpretability and generalizability of these findings, highlighting a need for further analyses of the ELEVATE OLE program and real-world UC cohorts.

In conclusion, the safety profile of etrasimod 2 mg QD in the UC population was consistent across age groups, with no change in incidences of AEs. Patients treated with etrasimod in the ELEVATE UC clinical program showed significant clinical benefit as assessed by clinical remission, symptomatic remission, and endoscopic improvement compared with placebo, irrespective of their age.

Acknowledgments

The authors would like to thank the patients, investigators, and study teams involved in the etrasimod ELEVATE UC clinical program. This study was sponsored by Pfizer. Medical writing support, under the direction of the authors, was provided by Eleanor Finn, PhD, on behalf of CMC Connect, a division of IPG Health Medical Communications, and was funded by Pfizer, New York, NY, USA, in accordance with Good Publication Practice (GPP 2022) guidelines (Ann Intern Med. 2022;175:1298-304).

Author Contributions

Concept and methodology: M.K., K.L., E.B., and G.L. Project administration: J.C.W. and E.B. Supervision: M.K., K.L., A.M., and E.B. Data curation: A.B.D. and M.K. Investigation: A.B.D. and M.K. Validation: A.B.D., A.M., and K.L. Formal analysis, writing, reviewing, and editing of the manuscript: All authors.

Funding

This work was supported by Pfizer. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this study was sponsored by Pfizer. Funding for medical writing support was provided by Pfizer.

Conflicts of Interest

G.R.L. has received consulting, advisory board and/or speaking honoraria (relating to Continuing Medical Education activities) from AbbVie, Allergan, American Gastroenterological Association, American Regent, Annenberg Center for Health Sciences at Eisenhower, Bristol Meyers Squibb, Celgene, Celltrion, Eli Lilly, Endo Pharmaceuticals, Ferring, Focus Medical Communications, Fresenius Kabi, Gilead, Ironwood, Johnson and Johnson, Med Ed Consultants, Pharmacosmos, Pfizer Inc, Professional Educational Resources, Prometheus, Sandoz, and Vindico. Research support from Bristol Myers Squibb, and Johnson and Johnson. Support of the University of Pennsylvania IBD fellowship, Janssen Orthobiotech, Pfizer Inc, and AbbVie. Editorship of Gastroenterology and Hepatology (Gastro-Hep Communications), Professional Communications Inc, SLACK Inc, Walters Kluwer, Springer Science, and Business Media. He has received grants/research support from Bristol Myers Squibb, Celgene, Janssen Ortho Biotech, Pfizer Inc, Takeda, and UCB. J.R.A. has received consulting fees from AbbVie, Adiso, Bristol Myers Squibb, Ferring, Finch Therapeutics, GSK, Janssen, Merck, Pfizer, Seres Therapeutics, and Roivant; grants/research support from Janssen, Merck, and Pfizer; and speaker fees from AbbVie, Bristol Myers Squibb, and Janssen. E.V.L. has received consulting fees from AbbVie, Amgen, Astellas, Avalo Therapeutics, Biocon, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GSK, Gossamer Bio, Iota Biosciences, Iterative Health, Janssen, Morphic Therapeutic, Ono Pharma, Protagonist, Surrozen, Takeda, TR1X Bio, and UCB Pharma; grants/research support from AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene/Receptos, Genentech, Gilead, Gossamer Bio, Janssen, Takeda, and UCB Pharma; and is a stockholder of Exact Sciences and Moderna. P.M.I. has received grants/research support from Celltrion, Galapagos, Janssen, MSD, and Takeda; speaker fees from AbbVie, Bristol Myers Squibb, Celgene, Celltrion, Falk Pharma, Ferring, Galapagos, Gilead, MSD, Janssen, Pfizer, Sandoz, Sapphire Medical, Shire, Takeda, Tillotts, and Warner Chilcott; and advisory board fees from AbbVie, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Genentech, Gilead, Hospira, Janssen, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VH2, Vifor Pharma, and Warner Chilcott. R.B. has received grants/research support from the Asian Healthcare Foundation, DBT India, the Indian Council of Medical Research (ICMR), and the Leona M and Harry B Helmsley Charitable Trust; and advisory board fees from Abbott, AstraZeneca, Cadila, Cipla, Celltrion, Dr Reddy Labs, Emcure, Ferring Pharmaceuticals, Hetero Drugs, Janssen, La Renon, MSN Labs, Mankind Pharma, Menarini, Micro Labs, Nestle, Pfizer, RPG Lifesciences, Sun Pharmaceuticals, Systopic, Takeda Pharmaceuticals, Torrent, Waterley, and Zydus. A.C. has received consulting fees from AbbVie, Boehringer Ingelheim, Eli Lilly, Janssen, Pfizer, and Takeda. T.K. has received lecture and consulting fees from AbbVie, Almirall, Amgen, Arena, Bristol Myers Squibb, Braun, Celgene, Celltrion, Eli Lilly, Ferring, Falk, Gastro Today, Gilead, Galapagos, Janssen, Medtronic, MSD, Mundipharma, Immunowissen, Pfizer, Roche, Takeda, Tillotts, and Vifor. E.B., J.C.W., and M.K. are employees and stockholders of Pfizer Inc. A.B.D. is an employee of Pfizer Inc. K.L. is an employee of Pfizer AG and a stockholder of Pfizer Inc. A.M. is an employee of Pfizer Ltd and a stockholder of Pfizer Inc. S.D. has received speaker fees from AbbVie, Amgen, Ferring Pharmaceuticals Inc, Gilead, Janssen, Mylan, Pfizer, and Takeda; consulting/advisory board fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead, Hospira, Janssen, Johnson & Johnson, MSD, Mundipharma, Pfizer Inc, Roche, Sandoz, Takeda, TiGenix, UCB, and Vifor; and holds directorship/ownership of Gastroenterology and Endoscopy.

Ethical Considerations

All studies were registered with ClinicalTrials.gov and were conducted in compliance with the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice Guidelines, and were approved by the Institutional Review Boards and/or Independent Ethics Committees at each investigational center participating in the studies, or at a central Institutional Review Board. All patients provided written, informed consent. An external independent data monitoring committee was used to monitor the safety of participants and to enhance the integrity and credibility of the study.

Data Availability

Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.

References