Study of TelmisartanFor the Prevention of Acute GVHD Post Allogeneic Hematopoietic Stem Cell Transplantation

GVHD Clinical Trial

Official title:

Pilot Study of Telmisartan (Micardis) For the Prevention of Acute Graft vs. Host Disease Post Allogeneic Hematopoietic Stem Cell Transplantation

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02338232
• Other study ID #: Pro5465
• Status: Terminated
• Phase: N/A
• Start date: July 7, 2015
• Est. completion date: January 5, 2023

Study information

• Verified date: April 2024
• Source: Hackensack Meridian Health
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is single-center, open-label, prospective study of telmisartan for the prevention of acute GVHD in approximately 60 subjects undergoing allogeneic HCT for treatment of a hematologic malignancy.

Description:

This is single-center, open-label, prospective study of telmisartan for the prevention of acute GVHD in approximately 60 subjects undergoing allogeneic HCT for treatment of a hematologic malignancy. Subjects will receive 160 mg Micardis brand telmisartan once daily, starting 2 days prior to HCT (day -2). Once the patient is discharged post-HCT, treatment will continue through Day +98 post-HCT for a total of 101 days. After treatment discontinuation on or before day +98 post-HCT, subjects will be followed for up to 6 months for primary and secondary endpoints.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 32
• Est. completion date: January 5, 2023
• Est. primary completion date: January 5, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria:

• Diagnosis of:

• Acute myeloid or lymphoid leukemia in remission,

• Myelodysplastic syndrome,

• Chronic lymphoid leukemia,

• Non-Hodgkin lymphoma,

• Hodgkin lymphoma,

• Chronic myeloid leukemia in chronic or accelerated phase,

• Myeloproliferative disorder, or

• Multiple myeloma

• Undergoing allogeneic HSC transplantation from a related or unrelated donor matched at least at 7 of 8 of the HLA-A, -B, -C, and DR loci ("8/8" or "7/8" match)

• Undergoing allogeneic HSC transplantation after a myeloablative TBI-, busulfan-, or (non-myeloablative) melphalan-based pre-transplant conditioning regimen. Regimens for transplantation will include at one of the following agents, given in conjunction with fludarabine or cyclophosphamide:

• Busulfan 130 mg/m2 iv daily x 2 (reduced intensity) or 4 days

• TBI 150 cGy bid x8 doses (1200 Gy)

• Melphalan 140 mg/m2. (Although melphalan is not a myeloablative regimen, it results in clinically significant mucositis and patients receiving this medication will be of considerable interest in the analysis of these data.)

• Male or female patient age 18 years or older

• Karnofsky performance status > 70% at time of initiation of pre-transplant conditioning

• Transplantation-specific co-morbidity score of <5 at time of initiation of pre-transplant conditioning

• Patients taking antihypertensive medications (including telmisartan) are eligible but the patient must discontinue treatment at least 48 hours prior to first dose of study medication

• Capable of giving informed consent and having signed the informed consent form

Exclusion Criteria:

• Inability to provide informed consent

• Subjects with known heart failure, advanced renal impairment requiring renal replacement therapy, or liver failure although these patients would most likely not be eligible for HCT.

• Subjects taking ACE inhibitors, potassium supplements, or spironolactone (or any other potassium-sparing diuretics) who cannot discontinue use prior to initiation of study treatment OR who require a high-potassium diet

• Patient unable to discontinue current hypertension medication for medical or other reasons for two days prior to starting telmisartan

• Chronic symptomatic hypotension, volume depletion.

Related Conditions & MeSH terms

• GVHD

Intervention

Drug:
• Telmisartan

Locations

Country	Name	City	State
United States	Hackensack University Medical Center	Hackensack	New Jersey

Sponsors (1)

Lead Sponsor	Collaborator
Hackensack Meridian Health

Country where clinical trial is conducted

United States, 

References & Publications (111)

Alevriadou BR. CAMs and Rho small GTPases: gatekeepers for leukocyte transendothelial migration. Focus on "VCAM-1-mediated Rac signaling controls endothelial cell-cell contacts and leukocyte transmigration". Am J Physiol Cell Physiol. 2003 Aug;285(2):C250-2. doi: 10.1152/ajpcell.00189.2003. No abstract available. — View Citation

Arab HH, Al-Shorbagy MY, Abdallah DM, Nassar NN. Telmisartan attenuates colon inflammation, oxidative perturbations and apoptosis in a rat model of experimental inflammatory bowel disease. PLoS One. 2014 May 15;9(5):e97193. doi: 10.1371/journal.pone.0097193. eCollection 2014. — View Citation

Arck P, Handjiski B, Hagen E, Pincus M, Bruenahl C, Bienenstock J, Paus R. Is there a 'gut-brain-skin axis'? Exp Dermatol. 2010 May;19(5):401-5. doi: 10.1111/j.1600-0625.2009.01060.x. Epub 2010 Jan 25. — View Citation

Bahr IN, Tretter P, Kruger J, Stark RG, Schimkus J, Unger T, Kappert K, Scholze J, Parhofer KG, Kintscher U. High-dose treatment with telmisartan induces monocytic peroxisome proliferator-activated receptor-gamma target genes in patients with the metabolic syndrome. Hypertension. 2011 Oct;58(4):725-32. doi: 10.1161/HYPERTENSIONAHA.111.173542. Epub 2011 Aug 29. — View Citation

Bardi G, Niggli V, Loetscher P. Rho kinase is required for CCR7-mediated polarization and chemotaxis of T lymphocytes. FEBS Lett. 2003 May 8;542(1-3):79-83. doi: 10.1016/s0014-5793(03)00351-x. — View Citation

Barreiro O, Yanez-Mo M, Serrador JM, Montoya MC, Vicente-Manzanares M, Tejedor R, Furthmayr H, Sanchez-Madrid F. Dynamic interaction of VCAM-1 and ICAM-1 with moesin and ezrin in a novel endothelial docking structure for adherent leukocytes. J Cell Biol. 2002 Jun 24;157(7):1233-45. doi: 10.1083/jcb.200112126. Epub 2002 Jun 24. — View Citation

Benais-Pont G, Punn A, Flores-Maldonado C, Eckert J, Raposo G, Fleming TP, Cereijido M, Balda MS, Matter K. Identification of a tight junction-associated guanine nucleotide exchange factor that activates Rho and regulates paracellular permeability. J Cell Biol. 2003 Mar 3;160(5):729-40. doi: 10.1083/jcb.200211047. Epub 2003 Feb 25. — View Citation

Bivalacqua TJ, Champion HC, Usta MF, Cellek S, Chitaley K, Webb RC, Lewis RL, Mills TM, Hellstrom WJ, Kadowitz PJ. RhoA/Rho-kinase suppresses endothelial nitric oxide synthase in the penis: a mechanism for diabetes-associated erectile dysfunction. Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9121-6. doi: 10.1073/pnas.0400520101. Epub 2004 Jun 7. — View Citation

Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol. 2012 May 11;12(6):443-58. doi: 10.1038/nri3212. — View Citation

Bourguignon LY, Zhu H, Shao L, Zhu D, Chen YW. Rho-kinase (ROK) promotes CD44v(3,8-10)-ankyrin interaction and tumor cell migration in metastatic breast cancer cells. Cell Motil Cytoskeleton. 1999;43(4):269-87. doi: 10.1002/(SICI)1097-0169(1999)43:43.0.CO;2-5. — View Citation

Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, Defor T, Levine BL, June CH, Rubinstein P, McGlave PB, Blazar BR, Wagner JE. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood. 2011 Jan 20;117(3):1061-70. doi: 10.1182/blood-2010-07-293795. Epub 2010 Oct 15. — View Citation

Chen X, Dodge J, Komorowski R, Drobyski WR. A critical role for the retinoic acid signaling pathway in the pathophysiology of gastrointestinal graft-versus-host disease. Blood. 2013 May 9;121(19):3970-80. doi: 10.1182/blood-2012-08-445130. Epub 2013 Mar 25. — View Citation

Cheng CI, Lin YC, Tsai TH, Lin HS, Liou CW, Chang WN, Lu CH, Yuen CM, Yip HK. The prognostic values of leukocyte Rho kinase activity in acute ischemic stroke. Biomed Res Int. 2014;2014:214587. doi: 10.1155/2014/214587. Epub 2014 Feb 27. — View Citation

Chetty VT, Damjanovic S, Gerstein H, Singh N, Yusuf S, Anand SS, Sharma AM. Metabolic effects of telmisartan in subjects with abdominal obesity: a prospective randomized controlled trial. Blood Press. 2014 Feb;23(1):54-60. doi: 10.3109/08037051.2013.791411. Epub 2013 Jun 3. — View Citation

Choi S, Reddy P. Graft-versus-host disease. Panminerva Med. 2010 Jun;52(2):111-24. — View Citation

Cianchetti S, Del Fiorentino A, Colognato R, Di Stefano R, Franzoni F, Pedrinelli R. Anti-inflammatory and anti-oxidant properties of telmisartan in cultured human umbilical vein endothelial cells. Atherosclerosis. 2008 May;198(1):22-8. doi: 10.1016/j.atherosclerosis.2007.09.013. Epub 2007 Oct 22. — View Citation

Cooke KR, Gerbitz A, Crawford JM, Teshima T, Hill GR, Tesolin A, Rossignol DP, Ferrara JL. LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation. J Clin Invest. 2001 Jun;107(12):1581-9. doi: 10.1172/JCI12156. — View Citation

Croft DR, Sahai E, Mavria G, Li S, Tsai J, Lee WM, Marshall CJ, Olson MF. Conditional ROCK activation in vivo induces tumor cell dissemination and angiogenesis. Cancer Res. 2004 Dec 15;64(24):8994-9001. doi: 10.1158/0008-5472.CAN-04-2052. — View Citation

Engelhardt BG, Jagasia M, Savani BN, Bratcher NL, Greer JP, Jiang A, Kassim AA, Lu P, Schuening F, Yoder SM, Rock MT, Crowe JE Jr. Regulatory T cell expression of CLA or alpha(4)beta(7) and skin or gut acute GVHD outcomes. Bone Marrow Transplant. 2011 Mar;46(3):436-42. doi: 10.1038/bmt.2010.127. Epub 2010 May 31. — View Citation

Engelhardt BG, Sengsayadeth SM, Jagasia M, Savani BN, Kassim AA, Lu P, Shyr Y, Yoder SM, Rock MT, Crowe JE Jr. Tissue-specific regulatory T cells: biomarker for acute graft-vs-host disease and survival. Exp Hematol. 2012 Dec;40(12):974-982.e1. doi: 10.1016/j.exphem.2012.08.002. Epub 2012 Aug 10. — View Citation

Eriguchi Y, Takashima S, Oka H, Shimoji S, Nakamura K, Uryu H, Shimoda S, Iwasaki H, Shimono N, Ayabe T, Akashi K, Teshima T. Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of alpha-defensins. Blood. 2012 Jul 5;120(1):223-31. doi: 10.1182/blood-2011-12-401166. Epub 2012 Apr 24. Erratum In: Blood. 2014 Aug 14;124(7):1201. — View Citation

Etienne S, Adamson P, Greenwood J, Strosberg AD, Cazaubon S, Couraud PO. ICAM-1 signaling pathways associated with Rho activation in microvascular brain endothelial cells. J Immunol. 1998 Nov 15;161(10):5755-61. — View Citation

Fanning SL, Zilberberg J, Stein J, Vazzana K, Berger SA, Korngold R, Friedman TM. Unraveling graft-versus-host disease and graft-versus-leukemia responses using TCR Vbeta spectratype analysis in a murine bone marrow transplantation model. J Immunol. 2013 Jan 1;190(1):447-57. doi: 10.4049/jimmunol.1201641. Epub 2012 Nov 30. — View Citation

Ferrara JL, Harris AC, Greenson JK, Braun TM, Holler E, Teshima T, Levine JE, Choi SW, Huber E, Landfried K, Akashi K, Vander Lugt M, Reddy P, Chin A, Zhang Q, Hanash S, Paczesny S. Regenerating islet-derived 3-alpha is a biomarker of gastrointestinal graft-versus-host disease. Blood. 2011 Dec 15;118(25):6702-8. doi: 10.1182/blood-2011-08-375006. Epub 2011 Oct 6. — View Citation

Forclaz A, Maillard M, Nussberger J, Brunner HR, Burnier M. Angiotensin II receptor blockade: is there truly a benefit of adding an ACE inhibitor? Hypertension. 2003 Jan;41(1):31-6. doi: 10.1161/01.hyp.0000047512.58862.a9. — View Citation

Fricke WF, Maddox C, Song Y, Bromberg JS. Human microbiota characterization in the course of renal transplantation. Am J Transplant. 2014 Feb;14(2):416-27. doi: 10.1111/ajt.12588. Epub 2013 Dec 26. — View Citation

Fukumoto Y, Mohri M, Inokuchi K, Ito A, Hirakawa Y, Masumoto A, Hirooka Y, Takeshita A, Shimokawa H. Anti-ischemic effects of fasudil, a specific Rho-kinase inhibitor, in patients with stable effort angina. J Cardiovasc Pharmacol. 2007 Mar;49(3):117-21. doi: 10.1097/FJC.0b013e31802ef532. — View Citation

Gomez A, Hammer S, Braun T, Hanash S, Ferrara J, Greenson J, Wang H, Zhang Q, Vander Lugt M, Pongtornpipat P, Lamiman K, Colon M, Chang L, Choi S, Levine J, Harris A, Couriel D, Reddy P, Paczesny S. A novel CD4+CD146+CCR5+ T-cell population is a biomarker of intestinal graft-versus-host disease. 39th meeting of the European Group for Blood and Marrow Transplantation Wednesday, April 10, 2013, 09:30 - 09:42

Hata Y, Miura M, Nakao S, Kawahara S, Kita T, Ishibashi T. Antiangiogenic properties of fasudil, a potent Rho-Kinase inhibitor. Jpn J Ophthalmol. 2008 Jan-Feb;52(1):16-23. doi: 10.1007/s10384-007-0487-5. Epub 2008 Mar 28. — View Citation

Hill GR, Ferrara JL. The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood. 2000 May 1;95(9):2754-9. — View Citation

Hilmi I, Kellum J, Planinsic R, Foster D, Abdullah A, Damian D, Gligor S, Klein D, Abu-elmagd K. Endotoxemia is common following abdominal organ transplantation and is associated with reperfusion and rejection.Journal of Organ Dysfunction. Dec 2009, Vol. 5 Issue 4, p254-260.

Holler E, Landfried K, Meier J, Hausmann M, Rogler G. The role of bacteria and pattern recognition receptors in GVHD. Int J Inflam. 2010 Oct 31;2010:814326. doi: 10.4061/2010/814326. — View Citation

Ikeda T, Ikeda K, Suda S, Ueno T. Usefulness of the endotoxin activity assay as a biomarker to assess the severity of endotoxemia in critically ill patients. Innate Immun. 2014 Nov;20(8):881-7. doi: 10.1177/1753425913516885. Epub 2014 Jan 7. — View Citation

Inokuchi K, Ito A, Fukumoto Y, Matoba T, Shiose A, Nishida T, Masuda M, Morita S, Shimokawa H. Usefulness of fasudil, a Rho-kinase inhibitor, to treat intractable severe coronary spasm after coronary artery bypass surgery. J Cardiovasc Pharmacol. 2004 Sep;44(3):275-7. doi: 10.1097/01.fjc.0000134775.76636.3f. — View Citation

Iyengar S, Zhan C, Lu J, Korngold R, Schwartz DH. Treatment with a rho kinase inhibitor improves survival from graft-versus-host disease in mice after MHC-haploidentical hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2014 Aug;20(8):1104-11. doi: 10.1016/j.bbmt.2014.04.029. Epub 2014 May 2. — View Citation

Jenq RR, Ubeda C, Taur Y, Menezes CC, Khanin R, Dudakov JA, Liu C, West ML, Singer NV, Equinda MJ, Gobourne A, Lipuma L, Young LF, Smith OM, Ghosh A, Hanash AM, Goldberg JD, Aoyama K, Blazar BR, Pamer EG, van den Brink MR. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J Exp Med. 2012 May 7;209(5):903-11. doi: 10.1084/jem.20112408. Epub 2012 Apr 30. — View Citation

Kamai T, Tsujii T, Arai K, Takagi K, Asami H, Ito Y, Oshima H. Significant association of Rho/ROCK pathway with invasion and metastasis of bladder cancer. Clin Cancer Res. 2003 Jul;9(7):2632-41. — View Citation

Kishi T, Hirooka Y, Masumoto A, Ito K, Kimura Y, Inokuchi K, Tagawa T, Shimokawa H, Takeshita A, Sunagawa K. Rho-kinase inhibitor improves increased vascular resistance and impaired vasodilation of the forearm in patients with heart failure. Circulation. 2005 May 31;111(21):2741-7. doi: 10.1161/CIRCULATIONAHA.104.510248. — View Citation

Kobayashi N, Ohno T, Yoshida K, Fukushima H, Mamada Y, Nomura M, Hirata H, Machida Y, Shinoda M, Suzuki N, Matsuoka H. Cardioprotective mechanism of telmisartan via PPAR-gamma-eNOS pathway in dahl salt-sensitive hypertensive rats. Am J Hypertens. 2008 May;21(5):576-81. doi: 10.1038/ajh.2008.27. Epub 2008 Mar 20. — View Citation

Komanduri KV. Targeting neovascularization in GVHD. Blood. 2013 Apr 25;121(17):3303-4. doi: 10.1182/blood-2013-01-480483. — View Citation

Kuno M, Takai S, Matsushima-Nishiwaki R, Minamitani C, Mizutani J, Otsuka T, Harada A, Adachi S, Kozawa O, Tokuda H. Rho-kinase inhibitors decrease TGF-beta-stimulated VEGF synthesis through stress-activated protein kinase/c-Jun N-terminal kinase in osteoblasts. Biochem Pharmacol. 2009 Jan 15;77(2):196-203. doi: 10.1016/j.bcp.2008.10.014. Epub 2008 Oct 19. — View Citation

Lammermann T, Bader BL, Monkley SJ, Worbs T, Wedlich-Soldner R, Hirsch K, Keller M, Forster R, Critchley DR, Fassler R, Sixt M. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature. 2008 May 1;453(7191):51-5. doi: 10.1038/nature06887. — View Citation

Lee JH, Katakai T, Hara T, Gonda H, Sugai M, Shimizu A. Roles of p-ERM and Rho-ROCK signaling in lymphocyte polarity and uropod formation. J Cell Biol. 2004 Oct 25;167(2):327-37. doi: 10.1083/jcb.200403091. — View Citation

Lee SJ, Klein JP, Barrett AJ, Ringden O, Antin JH, Cahn JY, Carabasi MH, Gale RP, Giralt S, Hale GA, Ilhan O, McCarthy PL, Socie G, Verdonck LF, Weisdorf DJ, Horowitz MM. Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse. Blood. 2002 Jul 15;100(2):406-14. doi: 10.1182/blood.v100.2.406. — View Citation

Leonhardt F, Grundmann S, Behe M, Bluhm F, Dumont RA, Braun F, Fani M, Riesner K, Prinz G, Hechinger AK, Gerlach UV, Dierbach H, Penack O, Schmitt-Graff A, Finke J, Weber WA, Zeiser R. Inflammatory neovascularization during graft-versus-host disease is regulated by alphav integrin and miR-100. Blood. 2013 Apr 25;121(17):3307-18. doi: 10.1182/blood-2012-07-442665. Epub 2013 Jan 17. — View Citation

Levine JE, Logan BR, Wu J, Alousi AM, Bolanos-Meade J, Ferrara JL, Ho VT, Weisdorf DJ, Paczesny S. Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a Blood and Marrow Transplant Clinical Trials Network study. Blood. 2012 Apr 19;119(16):3854-60. doi: 10.1182/blood-2012-01-403063. Epub 2012 Mar 1. — View Citation

Levine JE, Paczesny S, Sarantopoulos S. Clinical applications for biomarkers of acute and chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2012 Jan;18(1 Suppl):S116-24. doi: 10.1016/j.bbmt.2011.10.019. — View Citation

Li B, Zhao WD, Tan ZM, Fang WG, Zhu L, Chen YH. Involvement of Rho/ROCK signalling in small cell lung cancer migration through human brain microvascular endothelial cells. FEBS Lett. 2006 Jul 24;580(17):4252-60. doi: 10.1016/j.febslet.2006.06.056. Epub 2006 Jun 30. — View Citation

Liu C, Li Y, Yu J, Feng L, Hou S, Liu Y, Guo M, Xie Y, Meng J, Zhang H, Xiao B, Ma C. Targeting the shift from M1 to M2 macrophages in experimental autoimmune encephalomyelitis mice treated with fasudil. PLoS One. 2013;8(2):e54841. doi: 10.1371/journal.pone.0054841. Epub 2013 Feb 13. — View Citation

Liu Z, Zhao Y, Wei F, Ye L, Lu F, Zhang H, Diao Y, Song H, Qi Z. Treatment with telmisartan/rosuvastatin combination has a beneficial synergistic effect on ameliorating Th17/Treg functional imbalance in hypertensive patients with carotid atherosclerosis. Atherosclerosis. 2014 Mar;233(1):291-9. doi: 10.1016/j.atherosclerosis.2013.12.004. Epub 2014 Jan 10. — View Citation

Lv M, Ye HG, Zhao XS, Zhao XY, Chang YJ, Liu DH, Xu LP, Huang XJ. Ceruloplasmin is a potential biomarker for aGvHD following allogeneic hematopoietic stem cell transplantation. PLoS One. 2013;8(3):e58735. doi: 10.1371/journal.pone.0058735. Epub 2013 Mar 7. — View Citation

Marshall JC, Foster D, Vincent JL, Cook DJ, Cohen J, Dellinger RP, Opal S, Abraham E, Brett SJ, Smith T, Mehta S, Derzko A, Romaschin A; MEDIC study. Diagnostic and prognostic implications of endotoxemia in critical illness: results of the MEDIC study. J Infect Dis. 2004 Aug 1;190(3):527-34. doi: 10.1086/422254. Epub 2004 Jul 2. — View Citation

Masumoto A, Mohri M, Shimokawa H, Urakami L, Usui M, Takeshita A. Suppression of coronary artery spasm by the Rho-kinase inhibitor fasudil in patients with vasospastic angina. Circulation. 2002 Apr 2;105(13):1545-7. doi: 10.1161/hc1002.105938. — View Citation

Michel MC, Bohner H, Koster J, Schafers R, Heemann U. Safety of telmisartan in patients with arterial hypertension : an open-label observational study. Drug Saf. 2004;27(5):335-44. doi: 10.2165/00002018-200427050-00005. — View Citation

Mihaescu A, Santen S, Jeppsson B, Thorlacius H. Rho kinase signalling mediates radiation-induced inflammation and intestinal barrier dysfunction. Br J Surg. 2011 Jan;98(1):124-31. doi: 10.1002/bjs.7279. Epub 2010 Sep 29. — View Citation

Ming XF, Viswambharan H, Barandier C, Ruffieux J, Kaibuchi K, Rusconi S, Yang Z. Rho GTPase/Rho kinase negatively regulates endothelial nitric oxide synthase phosphorylation through the inhibition of protein kinase B/Akt in human endothelial cells. Mol Cell Biol. 2002 Dec;22(24):8467-77. doi: 10.1128/MCB.22.24.8467-8477.2002. — View Citation

Mizukami Y, Fujiki K, Duerr EM, Gala M, Jo WS, Zhang X, Chung DC. Hypoxic regulation of vascular endothelial growth factor through the induction of phosphatidylinositol 3-kinase/Rho/ROCK and c-Myc. J Biol Chem. 2006 May 19;281(20):13957-63. doi: 10.1074/jbc.M511763200. Epub 2006 Mar 16. — View Citation

Mohri M, Shimokawa H, Hirakawa Y, Masumoto A, Takeshita A. Rho-kinase inhibition with intracoronary fasudil prevents myocardial ischemia in patients with coronary microvascular spasm. J Am Coll Cardiol. 2003 Jan 1;41(1):15-9. doi: 10.1016/s0735-1097(02)02632-3. — View Citation

Mueller T, Dieplinger B. The Presage((R)) ST2 Assay: analytical considerations and clinical applications for a high-sensitivity assay for measurement of soluble ST2. Expert Rev Mol Diagn. 2013 Jan;13(1):13-30. doi: 10.1586/erm.12.128. — View Citation

Nagai N, Noda K, Urano T, Kubota Y, Shinoda H, Koto T, Shinoda K, Inoue M, Shiomi T, Ikeda E, Tsubota K, Suda T, Oike Y, Ishida S. Selective suppression of pathologic, but not physiologic, retinal neovascularization by blocking the angiotensin II type 1 receptor. Invest Ophthalmol Vis Sci. 2005 Mar;46(3):1078-84. doi: 10.1167/iovs.04-1101. — View Citation

Nakabayashi H, Shimizu K. HA1077, a Rho kinase inhibitor, suppresses glioma-induced angiogenesis by targeting the Rho-ROCK and the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signal pathways. Cancer Sci. 2011 Feb;102(2):393-9. doi: 10.1111/j.1349-7006.2010.01794.x. Epub 2010 Dec 19. — View Citation

Nohria A, Grunert ME, Rikitake Y, Noma K, Prsic A, Ganz P, Liao JK, Creager MA. Rho kinase inhibition improves endothelial function in human subjects with coronary artery disease. Circ Res. 2006 Dec 8;99(12):1426-32. doi: 10.1161/01.RES.0000251668.39526.c7. Epub 2006 Nov 9. — View Citation

Noma K, Rikitake Y, Oyama N, Yan G, Alcaide P, Liu PY, Wang H, Ahl D, Sawada N, Okamoto R, Hiroi Y, Shimizu K, Luscinskas FW, Sun J, Liao JK. ROCK1 mediates leukocyte recruitment and neointima formation following vascular injury. J Clin Invest. 2008 May;118(5):1632-44. doi: 10.1172/JCI29226. — View Citation

Ogawa T, Tashiro H, Miyata Y, Ushitora Y, Fudaba Y, Kobayashi T, Arihiro K, Okajima M, Asahara T. Rho-associated kinase inhibitor reduces tumor recurrence after liver transplantation in a rat hepatoma model. Am J Transplant. 2007 Feb;7(2):347-55. doi: 10.1111/j.1600-6143.2006.01647.x. Epub 2007 Jan 4. — View Citation

Otsuka T, Ibuki C, Suzuki T, Ishii K, Kodani E, Atarashi H, Kishida H, Takano T. Vasodilatory effect of subsequent administration of fasudil, a rho-kinase inhibitor, surpasses that of nitroglycerin at the concentric coronary stenosis in patients with stable angina pectoris. Circ J. 2006 Apr;70(4):402-8. doi: 10.1253/circj.70.402. — View Citation

Ozeki K, Tanida S, Morimoto C, Inoue Y, Mizoshita T, Tsukamoto H, Shimura T, Kataoka H, Kamiya T, Nishiwaki E, Ishiguro H, Higashiyama S, Joh T. Telmisartan inhibits cell proliferation by blocking nuclear translocation of ProHB-EGF C-terminal fragment in colon cancer cells. PLoS One. 2013;8(2):e56770. doi: 10.1371/journal.pone.0056770. Epub 2013 Feb 22. — View Citation

Paczesny S. Discovery and validation of graft-versus-host disease biomarkers. Blood. 2013 Jan 24;121(4):585-94. doi: 10.1182/blood-2012-08-355990. Epub 2012 Nov 19. — View Citation

Patel PA, Patravale VB, Commercial Telmisartan Tablets: A Comparative Evaluation with Innovator Brand Micardis, International Journal of Pharma Sciences and Research (IJPSR) 2010, 1(8): 282-292.

Patterson AE, Korngold R. Infusion of select leukemia-reactive TCR Vbeta+ T cells provides graft-versus-leukemia responses with minimization of graft-versus-host disease following murine hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2001;7(4):187-96. doi: 10.1053/bbmt.2001.v7.pm11349805. — View Citation

Penack O, Henke E, Suh D, King CG, Smith OM, Na IK, Holland AM, Ghosh A, Lu SX, Jenq RR, Liu C, Murphy GF, Lu TT, May C, Scheinberg DA, Gao DC, Mittal V, Heller G, Benezra R, van den Brink MR. Inhibition of neovascularization to simultaneously ameliorate graft-vs-host disease and decrease tumor growth. J Natl Cancer Inst. 2010 Jun 16;102(12):894-908. doi: 10.1093/jnci/djq172. Epub 2010 May 12. — View Citation

Penack O, Holler E, van den Brink MR. Graft-versus-host disease: regulation by microbe-associated molecules and innate immune receptors. Blood. 2010 Mar 11;115(10):1865-72. doi: 10.1182/blood-2009-09-242784. Epub 2009 Dec 30. — View Citation

Penack O, Socie G, van den Brink MR. The importance of neovascularization and its inhibition for allogeneic hematopoietic stem cell transplantation. Blood. 2011 Apr 21;117(16):4181-9. doi: 10.1182/blood-2010-10-312934. Epub 2011 Jan 21. — View Citation

Petrovic A, Alpdogan O, Willis LM, Eng JM, Greenberg AS, Kappel BJ, Liu C, Murphy GJ, Heller G, van den Brink MR. LPAM (alpha 4 beta 7 integrin) is an important homing integrin on alloreactive T cells in the development of intestinal graft-versus-host disease. Blood. 2004 Feb 15;103(4):1542-7. doi: 10.1182/blood-2003-03-0957. Epub 2003 Oct 16. — View Citation

Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995 Jun;15(6):825-8. — View Citation

Reshef R, Luger SM, Hexner EO, Loren AW, Frey NV, Nasta SD, Goldstein SC, Stadtmauer EA, Smith J, Bailey S, Mick R, Heitjan DF, Emerson SG, Hoxie JA, Vonderheide RH, Porter DL. Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. N Engl J Med. 2012 Jul 12;367(2):135-45. doi: 10.1056/NEJMoa1201248. — View Citation

Riento K, Ridley AJ. Rocks: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol. 2003 Jun;4(6):446-56. doi: 10.1038/nrm1128. — View Citation

Ringden O, Shrestha S, da Silva GT, Zhang MJ, Dispenzieri A, Remberger M, Kamble R, Freytes CO, Gale RP, Gibson J, Gupta V, Holmberg L, Lazarus H, McCarthy P, Meehan K, Schouten H, Milone GA, Lonial S, Hari PN. Effect of acute and chronic GVHD on relapse and survival after reduced-intensity conditioning allogeneic transplantation for myeloma. Bone Marrow Transplant. 2012 Jun;47(6):831-7. doi: 10.1038/bmt.2011.192. Epub 2011 Sep 26. — View Citation

Romaschin AD, Klein DJ, Marshall JC. Bench-to-bedside review: Clinical experience with the endotoxin activity assay. Crit Care. 2012 Dec 3;16(6):248. doi: 10.1186/cc11495. — View Citation

Sahai E, Marshall CJ. ROCK and Dia have opposing effects on adherens junctions downstream of Rho. Nat Cell Biol. 2002 Jun;4(6):408-15. doi: 10.1038/ncb796. — View Citation

Sanada Y, Mizuta K, Urahashi T, Ihara Y, Wakiya T, Okada N, Yamada N, Ushijima K, Otomo S, Sakamoto K, Yasuda Y, Kawarasaki H. Impact of endotoxin measured by an endotoxin activity assay during liver transplantation. J Surg Res. 2013 Apr;180(2):349-55. doi: 10.1016/j.jss.2012.05.004. Epub 2012 May 24. — View Citation

Sanchez-Madrid F, del Pozo MA. Leukocyte polarization in cell migration and immune interactions. EMBO J. 1999 Feb 1;18(3):501-11. doi: 10.1093/emboj/18.3.501. — View Citation

Schumacher H, Mancia G. The safety profile of telmisartan as monotherapy or combined with hydrochlorothiazide: a retrospective analysis of 50 studies. Blood Press Suppl. 2008 Jun;1:32-40. doi: 10.1080/08038020802144383. — View Citation

Sharpe M, Jarvis B, Goa KL. Telmisartan: a review of its use in hypertension. Drugs. 2001;61(10):1501-29. doi: 10.2165/00003495-200161100-00009. — View Citation

Shimokawa H, Hiramori K, Iinuma H, Hosoda S, Kishida H, Osada H, Katagiri T, Yamauchi K, Yui Y, Minamino T, Nakashima M, Kato K. Anti-anginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina: a multicenter study. J Cardiovasc Pharmacol. 2002 Nov;40(5):751-61. doi: 10.1097/00005344-200211000-00013. — View Citation

Signori A, Crocchiolo R, Oneto R, Sacchi N, Sormani MP, Fagioli F, Rambaldi A, Ciceri F, Bacigalupo A. Chronic GVHD is associated with lower relapse risk irrespective of stem cell source among patients receiving transplantation from unrelated donors. Bone Marrow Transplant. 2012 Nov;47(11):1474-8. doi: 10.1038/bmt.2012.58. Epub 2012 Apr 2. — View Citation

Siragusa M, Sessa WC. Telmisartan exerts pleiotropic effects in endothelial cells and promotes endothelial cell quiescence and survival. Arterioscler Thromb Vasc Biol. 2013 Aug;33(8):1852-60. doi: 10.1161/ATVBAHA.112.300985. Epub 2013 May 23. — View Citation

Smith A, Bracke M, Leitinger B, Porter JC, Hogg N. LFA-1-induced T cell migration on ICAM-1 involves regulation of MLCK-mediated attachment and ROCK-dependent detachment. J Cell Sci. 2003 Aug 1;116(Pt 15):3123-33. doi: 10.1242/jcs.00606. Epub 2003 Jun 10. — View Citation

Smith DH, Matzek KM, Kempthorne-Rawson J. Dose response and safety of telmisartan in patients with mild to moderate hypertension. J Clin Pharmacol. 2000 Dec;40(12 Pt 1):1380-90. — View Citation

Somlyo AV, Bradshaw D, Ramos S, Murphy C, Myers CE, Somlyo AP. Rho-kinase inhibitor retards migration and in vivo dissemination of human prostate cancer cells. Biochem Biophys Res Commun. 2000 Mar 24;269(3):652-9. doi: 10.1006/bbrc.2000.2343. — View Citation

Somlyo AV, Phelps C, Dipierro C, Eto M, Read P, Barrett M, Gibson JJ, Burnitz MC, Myers C, Somlyo AP. Rho kinase and matrix metalloproteinase inhibitors cooperate to inhibit angiogenesis and growth of human prostate cancer xenotransplants. FASEB J. 2003 Feb;17(2):223-34. doi: 10.1096/fj.02-0655com. — View Citation

Song EK, Yim JM, Yim JY, Song MY, Rho HW, Yim SK, Jeon SY, Kim HS, Yhim HY, Lee NR, Kwak JY, Sohn MH, Park HS, Jang KY, Yim CY. Rosiglitazone prevents graft-versus-host disease (GVHD). Transpl Immunol. 2012 Oct;27(2-3):128-37. doi: 10.1016/j.trim.2012.09.001. Epub 2012 Sep 13. — View Citation

Stangier J, Su CA, Roth W. Pharmacokinetics of orally and intravenously administered telmisartan in healthy young and elderly volunteers and in hypertensive patients. J Int Med Res. 2000 Jul-Aug;28(4):149-67. doi: 10.1177/147323000002800401. — View Citation

Takata K, Morishige K, Takahashi T, Hashimoto K, Tsutsumi S, Yin L, Ohta T, Kawagoe J, Takahashi K, Kurachi H. Fasudil-induced hypoxia-inducible factor-1alpha degradation disrupts a hypoxia-driven vascular endothelial growth factor autocrine mechanism in endothelial cells. Mol Cancer Ther. 2008 Jun;7(6):1551-61. doi: 10.1158/1535-7163.MCT-07-0428. — View Citation

Tominaga T, Sugie K, Hirata M, Morii N, Fukata J, Uchida A, Imura H, Narumiya S. Inhibition of PMA-induced, LFA-1-dependent lymphocyte aggregation by ADP ribosylation of the small molecular weight GTP binding protein, rho. J Cell Biol. 1993 Mar;120(6):1529-37. doi: 10.1083/jcb.120.6.1529. — View Citation

Usui T, Sugisaki K, Iriyama A, Yokoo S, Yamagami S, Nagai N, Ishida S, Amano S. Inhibition of corneal neovascularization by blocking the angiotensin II type 1 receptor. Invest Ophthalmol Vis Sci. 2008 Oct;49(10):4370-6. doi: 10.1167/iovs.07-0964. — View Citation

van Buul JD, Hordijk PL. Signaling in leukocyte transendothelial migration. Arterioscler Thromb Vasc Biol. 2004 May;24(5):824-33. doi: 10.1161/01.ATV.0000122854.76267.5c. Epub 2004 Feb 19. — View Citation

Vander Lugt MT, Braun TM, Hanash S, Ritz J, Ho VT, Antin JH, Zhang Q, Wong CH, Wang H, Chin A, Gomez A, Harris AC, Levine JE, Choi SW, Couriel D, Reddy P, Ferrara JL, Paczesny S. ST2 as a marker for risk of therapy-resistant graft-versus-host disease and death. N Engl J Med. 2013 Aug 8;369(6):529-39. doi: 10.1056/NEJMoa1213299. — View Citation

Vicari RM, Chaitman B, Keefe D, Smith WB, Chrysant SG, Tonkon MJ, Bittar N, Weiss RJ, Morales-Ballejo H, Thadani U; Fasudil Study Group. Efficacy and safety of fasudil in patients with stable angina: a double-blind, placebo-controlled, phase 2 trial. J Am Coll Cardiol. 2005 Nov 15;46(10):1803-11. doi: 10.1016/j.jacc.2005.07.047. Epub 2005 Oct 19. — View Citation

Vishnubhotla R, Sun S, Huq J, Bulic M, Ramesh A, Guzman G, Cho M, Glover SC. ROCK-II mediates colon cancer invasion via regulation of MMP-2 and MMP-13 at the site of invadopodia as revealed by multiphoton imaging. Lab Invest. 2007 Nov;87(11):1149-58. doi: 10.1038/labinvest.3700674. Epub 2007 Sep 17. — View Citation

Walcher D, Hess K, Heinz P, Petscher K, Vasic D, Kintscher U, Clemenz M, Hartge M, Raps K, Hombach V, Marx N. Telmisartan inhibits CD4-positive lymphocyte migration independent of the angiotensin type 1 receptor via peroxisome proliferator-activated receptor-gamma. Hypertension. 2008 Feb;51(2):259-66. doi: 10.1161/HYPERTENSIONAHA.107.099028. Epub 2007 Dec 24. — View Citation

Wang DS, Dou KF, Li KZ, Song ZS. Enhancement of migration and invasion of hepatoma cells via a Rho GTPase signaling pathway. World J Gastroenterol. 2004 Jan 15;10(2):299-302. doi: 10.3748/wjg.v10.i2.299. — View Citation

Wang Y, Zheng XR, Riddick N, Bryden M, Baur W, Zhang X, Surks HK. ROCK isoform regulation of myosin phosphatase and contractility in vascular smooth muscle cells. Circ Res. 2009 Feb 27;104(4):531-40. doi: 10.1161/CIRCRESAHA.108.188524. Epub 2009 Jan 8. — View Citation

Washida N, Wakino S, Tonozuka Y, Homma K, Tokuyama H, Hara Y, Hasegawa K, Minakuchi H, Fujimura K, Hosoya K, Hayashi K, Itoh H. Rho-kinase inhibition ameliorates peritoneal fibrosis and angiogenesis in a rat model of peritoneal sclerosis. Nephrol Dial Transplant. 2011 Sep;26(9):2770-9. doi: 10.1093/ndt/gfr012. Epub 2011 Mar 4. — View Citation

White WB. Comparative effects of telmisartan in the treatment of hypertension. J Clin Hypertens (Greenwich). 2002 Jul-Aug;4(4 Suppl 1):20-5. doi: 10.1111/j.1524-6175.2002.01585.x. — View Citation

Witzenrath M, Ahrens B, Schmeck B, Kube SM, Hippenstiel S, Rosseau S, Hamelmann E, Suttorp N, Schutte H. Rho-kinase and contractile apparatus proteins in murine airway hyperresponsiveness. Exp Toxicol Pathol. 2008 Jun;60(1):9-15. doi: 10.1016/j.etp.2008.03.002. Epub 2008 Apr 22. — View Citation

Wolf D, von Lilienfeld-Toal M, Wolf AM, Schleuning M, von Bergwelt-Baildon M, Held SA, Brossart P. Novel treatment concepts for graft-versus-host disease. Blood. 2012 Jan 5;119(1):16-25. doi: 10.1182/blood-2011-08-339465. Epub 2011 Sep 26. — View Citation

Wong CC, Wong CM, Ko FC, Chan LK, Ching YP, Yam JW, Ng IO. Deleted in liver cancer 1 (DLC1) negatively regulates Rho/ROCK/MLC pathway in hepatocellular carcinoma. PLoS One. 2008 Jul 23;3(7):e2779. doi: 10.1371/journal.pone.0002779. — View Citation

Xue F, Takahara T, Yata Y, Xia Q, Nonome K, Shinno E, Kanayama M, Takahara S, Sugiyama T. Blockade of Rho/Rho-associated coiled coil-forming kinase signaling can prevent progression of hepatocellular carcinoma in matrix metalloproteinase-dependent manner. Hepatol Res. 2008 Aug;38(8):810-7. doi: 10.1111/j.1872-034X.2008.00333.x. Epub 2008 May 27. — View Citation

Ying H, Biroc SL, Li WW, Alicke B, Xuan JA, Pagila R, Ohashi Y, Okada T, Kamata Y, Dinter H. The Rho kinase inhibitor fasudil inhibits tumor progression in human and rat tumor models. Mol Cancer Ther. 2006 Sep;5(9):2158-64. doi: 10.1158/1535-7163.MCT-05-0440. — View Citation

Yoneda A, Multhaupt HA, Couchman JR. The Rho kinases I and II regulate different aspects of myosin II activity. J Cell Biol. 2005 Aug 1;170(3):443-53. doi: 10.1083/jcb.200412043. Epub 2005 Jul 25. — View Citation

Zhu F, Zhang Z, Wu G, Li Z, Zhang R, Ren J, Nong L. Rho kinase inhibitor fasudil suppresses migration and invasion though down-regulating the expression of VEGF in lung cancer cell line A549. Med Oncol. 2011 Jun;28(2):565-71. doi: 10.1007/s12032-010-9468-5. Epub 2010 Mar 19. — View Citation

* Note: There are 111 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Subjects With Grade 3 or Greater Acute Graft vs. Host Disease (GVHD) in Patients Receiving Allogeneic HCT.		100 days post-transplant
Secondary	Number of Subjects With Grade III-IV Hypotension as Per the National Cancer Institute's Common Terminology		180 days post- transplant