Darusentan Effect on PET Uptake Heterogeneity (Darusentan)
A Phase 2, Investigator-Initiated, Feasibility Study to Evaluate the Mechanisms of Coronary Endothelial Dysfunction Imaged As Resting Myocardial Perfusion Heterogeneity After Endothelin Receptor Blockade With Darusentan
調査の概要
詳細な説明
This 6-week, Phase 2, randomized, double-blind, crossover, investigator-initiated, single-center study will determine the feasibility of detecting the effect of darusentan 100 mg once daily on the extent of myocardial perfusion heterogeneity in subjects with documented CAD, as measured by cardiac PET imaging. Prior to the initiation of any study procedures, an Informed Consent Form and HIPAA Authorization will be reviewed and signed by each subject. Screening assessments and evaluations may be conducted over a period of not more than 4 weeks.
Following a baseline PET scan (PET 1) subjects will be randomized to one of two treatment groups (Group 1 or Group 2), and receive blinded treatment for a total of 4 weeks. The 4-week treatment period will have two phases, Phase 1 and Phase 2. Group 1 will receive darusentan 100 mg for 2 weeks during Phase 1, then placebo for 2 weeks during Phase 2. Group 2 will receive placebo for 2 weeks during Phase 1, then darusentan 100 mg for 2 weeks during Phase 2. Following 4 weeks of treatment with blinded study drug, subjects in both treatment groups will be withdrawn from study drug for an additional 2 weeks. Maximum darusentan exposure in this study will be 2 weeks, and maximum placebo exposure in this study will be 2 weeks. Adjustments to the number or dosage of concomitant medications required for study entry will not be permitted at any time during the study.
A physical exam will be done at baseline and week 6 as well as blood chemistry and hematology samples taken. Vital signs and any adverse events will be monitored at each visit.
Efficacy will be assessed through cardiac PET imaging. In total, four PET scans will be administered: the first at the Randomization Visit (PET 1, Week 0); the second at the conclusion of Phase 1 (PET 2, Week 2); the third at the conclusion of Phase 2 (PET 3, Week 4) and the fourth at the conclusion of the Withdrawal period (PET 4, Week 6).
Subjects will be instructed to take their study drug with or without food once daily at approximately the same time in the morning throughout the course of the study. Subjects will also be instructed to take all concomitant medications consistently and at the same time each day throughout the study.
研究の種類
入学 (実際)
段階
- フェーズ2
連絡先と場所
研究場所
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Texas
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Houston、Texas、アメリカ、77030
- Weatherhead PET Center for Preventing and Reversing Atherosclerosis, UT Medical School, Memorial Hermann Hospital
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参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
Inclusion Criteria:
- Subjects must be competent to provide written informed consent. Subjects must sign an IRB approved ICF and HIPAA Authorization prior to the initiation of any study procedures. All men must be informed of the potential risks of testicular tubular atrophy and infertility associated with taking study drug, and queried regarding their understanding of the potential risks as described in the ICF.
- Subjects must be greater than 18 years of age.
- Female subjects must be surgically sterile or documented as post-menopausal for at least 2 years.
- Subjects must have documented coronary artery disease as evidenced by previous myocardial infarction, interventional procedure, significant stenosis by cardiac catheterization, or an abnormal perfusion study.
- Subjects must have an abnormal PET scan.
Exclusion Criteria:
- Subjects with acute heart failure
- Subjects with sustained or symptomatic hypotension (SBP 90 mmHg)
- Subjects with uncontrolled hypertension (SBP of 170 mmHg or DBP of 100 mmHg) at Screening
- Subjects with unstable angina pectoris
- Subjects with acute myocardial infarction, stroke, transient ischemic attack, or coronary angioplasty within the last 6 months
- Subjects with primary valvular disease
- Subjects with significant vascular aneurysm
- Subjects with a documented history of renal failure
- Subjects with liver disease (total bilirubin 3 mg/dL or serum ALT or AST >2X ULN)
- Subjects with active malignancy
- Subjects with a fatal non-cardiovascular disease that they are expected to succumb to within 1 year
- Female subjects that are pregnant or lactating
- Female subjects with the potential for child-bearing
- Female subjects being treated with hormone therapies
- Subjects with uncontrolled diabetes mellitus
- Subjects with diabetes with gastro paresis or severe neuropathy
- Subjects with a history of substance abuse within the last 2 years
- Subjects who have participated in a clinical study involving another investigational drug or device within 1 month of the Screening Visit
- Subjects with known hypersensitivity or allergy to L-arginine, aminophylline, adenosine, or dipyridamole
- Subjects who have a planned surgical procedure during the course of the study
- Subjects taking herbal food supplements (L-carnitine, L-arginine or Ginko biloba)
- Subjects with known active or dormant type 2 herpes simplex virus infections
- Subjects with a contraindication to treatment with an ERA. Contraindications may include, but are not limited to, evidence of elevated liver function tests (e.g., aminotransferases >2X ULN) or an event defined as a serious adverse event attributed to previous treatment with an ERA
- Subjects who are judged by the investigator to be ineligible for this study for any other reason
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：クロスオーバー割り当て
- マスキング：ダブル
武器と介入
参加者グループ / アーム |
介入・治療 |
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アクティブコンパレータ：Group 1
Group 1 will receive oral darusentan 100mg for 2 weeks during Phase 1 then placebo for 2 weeks during Phase 2.
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All subjects will receive oral darusentan 100 mg for a total of 2 weeks and placebo for 2 weeks.
他の名前：
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アクティブコンパレータ：Group 2
Group 2 will receive placebo for 2 weeks during Phase 1 then oral darusentan 100 mg for two weeks during Phase 2
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All subjects will receive oral darusentan 100 mg for a total of 2 weeks and placebo for 2 weeks.
他の名前：
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Change During Darusentan Treatment in the Markovian Homogeneity Number, a Value That Quantitates Myocardial Perfusion Heterogeneity
時間枠：0, 2, 4, and 6 weeks
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Markovian homogeneity analysis characterizes an image produced by a PET scan by examining the probability that a pixel with a given intensity will have a neighbor with a different intensity.
The homogeneity index ranges from >0 to 1, where a value near 0 represents an image with a high probability that neighboring pixels have intensity values that differ greatly, and a value near 1 represents an image with a high probability that neighboring pixels have similar intensity values.
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0, 2, 4, and 6 weeks
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
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Change During Darusentan Treatment in Absolute Flow at Rest and Hyperemia
時間枠：0, 2, 4, and 6 weeks
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0, 2, 4, and 6 weeks
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Change During Darusentan Treatment in the Coronary Flow Reserve (CFR)
時間枠：0, 2, 4, and 6 weeks
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CFR is calculated as the unitless ratio between hyperemic to resting flow
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0, 2, 4, and 6 weeks
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協力者と研究者
スポンサー
協力者
捜査官
- 主任研究者：K Lance Gould, MD、University of Texas Medical School at Houston
- 主任研究者：Nils Johnson, MD、University of Texas Medical School at Houston
出版物と役立つリンク
一般刊行物
- Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation. 2000 Mar 7;101(9):948-54. doi: 10.1161/01.cir.101.9.948.
- Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, Nour KR, Quyyumi AA. Prognostic value of coronary vascular endothelial dysfunction. Circulation. 2002 Aug 6;106(6):653-8. doi: 10.1161/01.cir.0000025404.78001.d8.
- Verma S, Anderson TJ. Fundamentals of endothelial function for the clinical cardiologist. Circulation. 2002 Feb 5;105(5):546-9. doi: 10.1161/hc0502.104540. No abstract available.
- Clarkson P, Celermajer DS, Powe AJ, Donald AE, Henry RM, Deanfield JE. Endothelium-dependent dilatation is impaired in young healthy subjects with a family history of premature coronary disease. Circulation. 1997 Nov 18;96(10):3378-83. doi: 10.1161/01.cir.96.10.3378.
- Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000 Apr 25;101(16):1899-906. doi: 10.1161/01.cir.101.16.1899.
- Bugiardini R, Manfrini O, Pizzi C, Fontana F, Morgagni G. Endothelial function predicts future development of coronary artery disease: a study of women with chest pain and normal coronary angiograms. Circulation. 2004 Jun 1;109(21):2518-23. doi: 10.1161/01.CIR.0000128208.22378.E3. Epub 2004 May 10.
- Bottcher M, Madsen MM, Refsgaard J, Buus NH, Dorup I, Nielsen TT, Sorensen K. Peripheral flow response to transient arterial forearm occlusion does not reflect myocardial perfusion reserve. Circulation. 2001 Feb 27;103(8):1109-14. doi: 10.1161/01.cir.103.8.1109.
- Nesto RW, Lamas GA, Barry J. Paradoxical elevation of threshold to angina pectoris by cold pressor test in men with significant coronary artery disease. Am J Cardiol. 1989 Mar 15;63(11):656-9. doi: 10.1016/0002-9149(89)90246-4.
- Kjaer A, Meyer C, Nielsen FS, Parving HH, Hesse B. Dipyridamole, cold pressor test, and demonstration of endothelial dysfunction: a PET study of myocardial perfusion in diabetes. J Nucl Med. 2003 Jan;44(1):19-23.
- el-Tamimi H, Mansour M, Wargovich TJ, Hill JA, Kerensky RA, Conti CR, Pepine CJ. Constrictor and dilator responses to intracoronary acetylcholine in adjacent segments of the same coronary artery in patients with coronary artery disease. Endothelial function revisited. Circulation. 1994 Jan;89(1):45-51. doi: 10.1161/01.cir.89.1.45.
- Johnson NP, Gould KL. Physiology of endothelin in producing myocardial perfusion heterogeneity: a mechanistic study using darusentan and positron emission tomography. J Nucl Cardiol. 2013 Oct;20(5):835-44. doi: 10.1007/s12350-013-9756-5. Epub 2013 Jul 11.
研究記録日
主要日程の研究
研究開始
一次修了 (実際)
研究の完了 (実際)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (見積もり)
学習記録の更新
投稿された最後の更新 (見積もり)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
その他の研究ID番号
- HSC-MS-08-0380
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