Randomized Controlled Trial

. 2024 Apr 27;403(10437):1635-1648.

doi: 10.1016/S0140-6736(24)00469-0. Epub 2024 Apr 7.

Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials

Javed Butler¹, Sanjiv J Shah², Mark C Petrie³, Barry A Borlaug⁴, Steen Z Abildstrøm⁵, Melanie J Davies⁶, G Kees Hovingh⁵, Dalane W Kitzman⁷, Daniél Vega Møller⁵, Subodh Verma⁸, Mette Nygaard Einfeldt⁵, Marie L Lindegaard⁵, Søren Rasmussen⁵, Walter Abhayaratna⁹, Fozia Z Ahmed¹⁰, Tuvia Ben-Gal¹¹, Vijay Chopra¹², Justin A Ezekowitz¹³, Michael Fu¹⁴, Hiroshi Ito¹⁵, Małgorzata Lelonek¹⁶, Vojtěch Melenovský¹⁷, Bela Merkely¹⁸, Julio Núñez¹⁹, Eduardo Perna²⁰, Morten Schou²¹, Michele Senni²², Kavita Sharma²³, Peter van der Meer²⁴, Dirk Von Lewinski²⁵, Dennis Wolf²⁶, Mikhail N Kosiborod²⁷; STEP-HFpEF Trial Committees and Investigators

Affiliations

¹ Baylor Scott & White Research Institute, Dallas, TX, USA; Department of Medicine, University of Mississippi, Jackson, MS, USA.
² Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
³ School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK.
⁴ Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
⁵ Novo Nordisk, Søborg, Denmark.
⁶ Diabetes Research Centre, University of Leicester, Leicester, UK; National Institute for Health and Care Research Leicester Biomedical Research Centre, Leicester, UK.
⁷ Department of Cardiovascular Medicine and Section on Geriatrics and Gerontology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁸ Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada.
⁹ College of Health and Medicine, Australian National University, Canberra, ACT, Australia.
¹⁰ Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
¹¹ Heart Failure Unit, Department of Cardiology, Rabin Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
¹² Max Super Speciality Hospital, Saket, New Delhi, India.
¹³ Canadian VIGOUR Centre, University of Alberta, Edmonton, AB, Canada.
¹⁴ Section of Cardiology, Department of Medicine, Sahlgrenska University Hospital-Ostra, Gothenburg, Sweden.
¹⁵ Department of General Internal Medicine 3, Kawasaki Medical School, Okayama, Japan.
¹⁶ Department of Noninvasive Cardiology, Medical University of Lodz, Lodz, Poland.
¹⁷ Institute for Clinical and Experimental Medicine-IKEM, Prague, Czech Republic.
¹⁸ Heart and Vascular Centre, Semmelweis University, Budapest, Hungary.
¹⁹ Hospital Clínico Universitario de Valencia, INCLIVA, Universidad de Valencia, Valencia, Spain; Centro de Investigación Biomédica en Red Cardiovascular, Valencia, Spain.
²⁰ Instituto de Cardiologia J F Cabral, Corrientes, Argentina.
²¹ Department of Cardiology, Herlev-Gentofte Hospital, Hellerup, Denmark; Department of Clinical Medicine, University of Copenhagen, Herlev, Denmark.
²² Azienda Socio Sanitaria Territorial Papa Giovanni XXIII, Bergamo, Italy.
²³ Heart Failure & Cardiac Transplantation, Johns Hopkins University Heart Failure with Preserved Ejection Fraction Program, Johns Hopkins Hospital, Baltimore, MD, USA.
²⁴ Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
²⁵ Medical University of Graz, Graz, Austria.
²⁶ Cardiology and Angiology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²⁷ Department of Cardiovascular Disease, Saint Luke's Mid America Heart Institute, Kansas City, MO, USA; University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA. Electronic address: mkosiborod@saint-lukes.org.

PMID: 38599221
PMCID: PMC11317105
DOI: 10.1016/S0140-6736(24)00469-0

Randomized Controlled Trial

Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials

Javed Butler et al. Lancet. 2024.

. 2024 Apr 27;403(10437):1635-1648.

doi: 10.1016/S0140-6736(24)00469-0. Epub 2024 Apr 7.

Authors

Affiliations

¹ Baylor Scott & White Research Institute, Dallas, TX, USA; Department of Medicine, University of Mississippi, Jackson, MS, USA.
² Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
³ School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK.
⁴ Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
⁵ Novo Nordisk, Søborg, Denmark.
⁶ Diabetes Research Centre, University of Leicester, Leicester, UK; National Institute for Health and Care Research Leicester Biomedical Research Centre, Leicester, UK.
⁷ Department of Cardiovascular Medicine and Section on Geriatrics and Gerontology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁸ Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada.
⁹ College of Health and Medicine, Australian National University, Canberra, ACT, Australia.
¹⁰ Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
¹¹ Heart Failure Unit, Department of Cardiology, Rabin Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
¹² Max Super Speciality Hospital, Saket, New Delhi, India.
¹³ Canadian VIGOUR Centre, University of Alberta, Edmonton, AB, Canada.
¹⁴ Section of Cardiology, Department of Medicine, Sahlgrenska University Hospital-Ostra, Gothenburg, Sweden.
¹⁵ Department of General Internal Medicine 3, Kawasaki Medical School, Okayama, Japan.
¹⁶ Department of Noninvasive Cardiology, Medical University of Lodz, Lodz, Poland.
¹⁷ Institute for Clinical and Experimental Medicine-IKEM, Prague, Czech Republic.
¹⁸ Heart and Vascular Centre, Semmelweis University, Budapest, Hungary.
¹⁹ Hospital Clínico Universitario de Valencia, INCLIVA, Universidad de Valencia, Valencia, Spain; Centro de Investigación Biomédica en Red Cardiovascular, Valencia, Spain.
²⁰ Instituto de Cardiologia J F Cabral, Corrientes, Argentina.
²¹ Department of Cardiology, Herlev-Gentofte Hospital, Hellerup, Denmark; Department of Clinical Medicine, University of Copenhagen, Herlev, Denmark.
²² Azienda Socio Sanitaria Territorial Papa Giovanni XXIII, Bergamo, Italy.
²³ Heart Failure & Cardiac Transplantation, Johns Hopkins University Heart Failure with Preserved Ejection Fraction Program, Johns Hopkins Hospital, Baltimore, MD, USA.
²⁴ Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
²⁵ Medical University of Graz, Graz, Austria.
²⁶ Cardiology and Angiology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²⁷ Department of Cardiovascular Disease, Saint Luke's Mid America Heart Institute, Kansas City, MO, USA; University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA. Electronic address: mkosiborod@saint-lukes.org.

PMID: 38599221
PMCID: PMC11317105
DOI: 10.1016/S0140-6736(24)00469-0

Abstract

Background: In the STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials, the GLP-1 receptor agonist semaglutide improved symptoms, physical limitations, bodyweight, and exercise function in people with obesity-related heart failure with preserved ejection fraction. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, we aimed to provide a more definitive assessment of the effects of semaglutide across a range of outcomes and to test whether these effects were consistent across key patient subgroups.

Methods: We conducted a prespecified pooled analysis of individual patient data from STEP-HFpEF and STEP-HFpEF DM, randomised, double-blind, placebo-controlled trials at 129 clinical research sites in 18 countries. In both trials, eligible participants were aged 18 years or older, had heart failure with a left ventricular ejection fraction of at least 45%, a BMI of at least 30 kg/m², New York Heart Association class II-IV symptoms, and a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; a measure of heart failure-related symptoms and physical limitations) of less than 90 points. In STEP-HFpEF, people with diabetes or glycated haemoglobin A_1c concentrations of at least 6·5% were excluded, whereas for inclusion in STEP-HFpEF DM participants had to have been diagnosed with type 2 diabetes at least 90 days before screening and to have an HbA_1c of 10% or lower. In both trials, participants were randomly assigned to either 2·4 mg semaglutide once weekly or matched placebo for 52 weeks. The dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and bodyweight in all randomly assigned participants. Confirmatory secondary endpoints included change from baseline to week 52 in 6-min walk distance, a hierarchical composite endpoint (all-cause death, heart failure events, and differences in changes in KCCQ-CSS and 6-min walk distance); and C-reactive protein (CRP) concentrations. Heterogeneity in treatment effects was assessed across subgroups of interest. We assessed safety in all participants who received at least one dose of study drug.

Findings: Between March 19, 2021 and March 9, 2022, 529 people were randomly assigned in STEP-HFpEF, and between June 27, 2021 and Sept 2, 2022, 616 were randomly assigned in STEP-HFpEF DM. Overall, 1145 were included in our pooled analysis, 573 in the semaglutide group and 572 in the placebo group. Improvements in KCCQ-CSS and reductions in bodyweight between baseline and week 52 were significantly greater in the semaglutide group than in the placebo group (mean between-group difference for the change from baseline to week 52 in KCCQ-CSS 7·5 points [95% CI 5·3 to 9·8]; p<0·0001; mean between-group difference in bodyweight at week 52 -8·4% [-9·2 to -7·5]; p<0·0001). For the confirmatory secondary endpoints, 6-min walk distance (mean between-group difference at week 52 17·1 metres [9·2 to 25·0]) and the hierarchical composite endpoint (win ratio 1·65 [1·42 to 1·91]) were significantly improved, and CRP concentrations (treatment ratio 0·64 [0·56 to 0·72]) were significantly reduced, in the semaglutide group compared with the placebo group (p<0·0001 for all comparisons). For the dual primary endpoints, the efficacy of semaglutide was largely consistent across multiple subgroups, including those defined by age, race, sex, BMI, systolic blood pressure, baseline CRP, and left ventricular ejection fraction. 161 serious adverse events were reported in the semaglutide group compared with 301 in the placebo group.

Interpretation: In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide was superior to placebo in improving heart failure-related symptoms and physical limitations, and reducing bodyweight in participants with obesity-related heart failure with preserved ejection fraction. These effects were largely consistent across patient demographic and clinical characteristics. Semaglutide was well tolerated.

Funding: Novo Nordisk.

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Conflict of interest statement

Declaration of interests JB is a paid consultant to Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Daxor Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Roche, Secretome, Sequana, SQ Innovation, Tenex, and Vifor. SJS has received research grants from AstraZeneca, Corvia, and Pfizer, and consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, ReCor, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. MCP has received research funding from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novo Nordisk, Novartis, Pharmacosmos, Roche, and SQ Innovations, and has served on committees or consulted for AbbVie, Akero, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Cardiorentis, Corvia, Eli Lilly, Horizon Therapeutics, LIB Therapeutics, Moderna, New Amsterdam, Novartis, Novo Nordisk, Pharmacosmos, Siemens, SQ Innovations, Takeda, Teikoku, and Vifor. BAB has received research funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics, has served as a paid consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, NGM, Novo Nordisk, NXT, and VADovations, and is named inventor (US patent number 10 307 179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. SZA, GKH, DVM, MNE, MLL, and SR are employees of, and shareholders in, Novo Nordisk. MJD has acted as paid consultant, advisory board member, and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi, a paid advisory board member and speaker for AstraZeneca, a paid advisory board member for Medtronic, Pfizer, and ShouTi Pharma, and a paid speaker for Amgen, Novartis, and Sanofi, and has received grants as an investigator in support of investigator-initiated trials from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi-Aventis. DWK reports receiving honoraria as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Corvia Medical, Ketyo, Novartis, Novo Nordisk, Pfizer, and Rivus, has received grant funding from AstraZeneca, Bayer, Novartis, Novo Nordisk, Pfizer, and Rivus, and owns stock in Gilead. SV reports speaking honoraria or consulting fees from Abbott, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, and TIMI. WA reports honoraria or consulting fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk. FZA reports honoraria or consulting fees from Abbott, AstraZeneca, Medtronic, Novo Nordisk, Occlutech, Pharmacosmos, and Vifor. VC reports speaker fees from AstraZeneca, Boehringer Ingelheim, Cipla, Dr Reddy's, Lupin, Novartis, Novo Nordisk, Mankind, Pfizer, Sanofi, Sun Pharma, and Torrent. JAE reports research support for trial leadership from American Regent, Applied Therapeutics, Bayer, Cytokinetics, Merck, and Novo Nordisk, reports honoraria for consultancy from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, and Otsuka, and serves as an advisor to US2.ai. HI reports honoraria or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Mochida, Novartis, and Novo Nordisk. ML reports honoraria or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Ewopharma, Gedeon Richter, Novartis, Novo Nordisk, Roche, and Servier. VM reports consulting fees from Bayer, Merck Sharp & Dohme, and Novo Nordisk and research grants from Regeneron. BM reports speaker fees or research payments from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, CSL Behring, Daiichi-Sankyo, DUKE Clinical Institute, Medtronic, and Novartis, and institutional grants from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo, DUKE Clinical Institute, Eli Lilly, Medtronic, Novartis, Terumo, and Vifor. JN reports honoraria or consulting fees from Alleviant, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Pfizer, Novartis, Novo Nordisk, Rovi, and Vifor. EP reports honoraria from Novo Nordisk. MSc reports speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Novo Nordisk. MSe reports honoraria or consulting fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Merck Sharp & Dohme, Novartis, Novo Nordisk, and Vifor. KS received honoraria for serving as an advisory board member and consultant for Alleviant, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Janssen, Novartis, Novo Nordisk, and Rivus. PvdM reports institutional payments for consultancy fees or grants from AstraZeneca, Boehringer Ingelheim, BridgeBio, Ionis, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharma Nord, and Vifor. DVL reports honoraria or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Novo Nordisk, Recardio, Sanofi, Sanova, and Vaxxinity. DW reports consultancy fees from Novo Nordisk. MNK served as a paid consultant or advisory board member for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor, and Youngene Therapeutics, has received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer, holds stocks in Artera Health and Saghmos Therapeutics, has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk, and has received other research support from AstraZeneca. TB-G and MF report no competing interests.

Figures

**Figure 1:. Change in KCCQ-CSS (A) and percentage reduction in bodyweight (B) from baseline to week 52 in the pooled STEP-HFpEF and STEP-HFpEF DM population**
Analyses of between-group treatment differences were by ANCOVA and based on the treatment policy estimand, with missing data imputed. Data are observed (ie, as measured) mean changes. Error bars represent SEs. The fluctuating numbers of participants at risk is a result of variations in participants attending study visits. KCCQ-CSS=Kansas City Cardiomyopathy Questionnaire Clinical Summary Score. *The between-group comparisons at week 52 are for all participants in the full analysis set (n=573 in the semaglutide group and n=572 in the placebo group); missing data were imputed for these analyses.

**Figure 2:. Change from baseline to week 52 in KCCQ-CSS across prespecified subgroups in the pooled STEP-HFpEF and STEP-HFpEF DM population, by treatment group**
Analyses were by ANCOVA and based on the treatment policy estimand in the full analysis set for the in-trial period, with missing data imputed. KCCQ-CSS=Kansas City Cardiomyopathy Questionnaire Clinical Summary Score. NYHA=New York Heart Association. RAAS=renin–angiotensin–aldosterone system inhibitors. *Subgroups defined on the basis of pooled median values.

**Figure 3:. Time to first heart failure event (A) and time to first heart failure event or cardiovascular death (B) in the pooled STEP-HFpEF and STEP-HFpEF DM population**
The adjusted cumulative incidence rate was calculated using the Aalen-Johansen method for first event, with all-cause death (A) and non-cardiovascular death (B) as a competing risks. Analyses were done in the full analysis set. Hazard ratios and 95% CIs were calculated using a Cox proportional hazards model, with treatment and BMI stratum (<35 kg/m^² vs ≥35 kg/m^²) as fixed factors and stratified by study.

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Comment in

Semaglutide-a new treatment for obesity-related heart failure with preserved ejection fraction?
Donal E, L'Official G, Istratoaie S. Donal E, et al. Lancet. 2024 Apr 27;403(10437):1604-1606. doi: 10.1016/S0140-6736(24)00653-6. Epub 2024 Apr 7. Lancet. 2024. PMID: 38599218 No abstract available.

References

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1. Pandey A, LaMonte M, Klein L, et al. Relationship between physical activity, body mass index, and risk of heart failure. J Am Coll Cardiol 2017; 69: 1129–42. - PMC - PubMed
1. Shah SJ. BNP: biomarker not perfect in heart failure with preserved ejection fraction. Eur Heart J 2022; 43: 1952–54. - PubMed
1. Lindman BR, Davila-Roman VG, Mann DL, et al. Cardiovascular phenotype in HFpEF patients with or without diabetes: a RELAX trial ancillary study. J Am Coll Cardiol 2014; 64: 541–49. - PMC - PubMed
1. McHugh K, DeVore AD, Wu J, et al. Heart failure with preserved ejection fraction and diabetes: JACC state-of-the-art review. J Am Coll Cardiol 2019; 73: 602–11. - PubMed

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Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials

Affiliations

Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

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Publication types

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