Please select the eligibility criteria that correspond to the clinical trial below.
Title: Double-blind, Placebo-controlled Cross-over Study to Investigate the Effects of the Phosphodiesterase 5-inhibitor Vardenafil on Periphery Blood Flow and Clinical Symptoms of Patients With Raynaud's Syndrome
Brief Summary: The purpose of this study is to determine whether vardenafil is effective in improving clinical symptoms and peripheral blood flow in patients with primary and secondary Raynaud phenomenon.


Options:
A: Inclusion Criteria:

* Male or female subjects between the ages of 18 years and 60 years will be selected for the study if they have a clinical diagnosis of Raynaud's phenomenon secondary to systemic sclerosis (scleroderma). Raynaud's phenomenon is defined as a history of cold sensitivity associated with colour changes of cyanosis or pallor, as well as a history of at least 4 attacks per week during two pre-trial period even with treatment with other vasodilators. The diagnosis of scleroderma is defined by the American College of Rheumatology (ACR) criteria or by the presence of at least 3 of the 5 features of the CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias).

Exclusion Criteria:

Patients will be excluded if they have:

* Symptomatic orthostatic hypotension
* Evidence of current malignancy
* History of sympathectomy
* Upper extremity deep vein thrombosis or lymphedema within 3 months
* Recent surgical procedure requiring general anesthesia
* AMI, unstable angina, strokes and TIA within the past three months
* Smoking
* Use of any investigational drug within 30 days of the study sessions
* Use of medications that might interfere with tadalafil like nitrates and alpha adrenergic blockers that have vasoactive effects, and patients taking potent inhibitors of CYP3A4 such as ritonavir, ketoconazole, and itraconazole, erythromycin, itraconazole, and grapefruit juice
* Patients taking alcohol
* Patients with bleeding disorders
* Significant active peptic ulceration
* Current pregnancy
* Current breast-feeding
B: Inclusion Criteria:

* raynaud-syndrome (primary or secondary) \> 1 year duration
* age ≥ 18 years; ≤ 80 years
* informed consent
* a negative pregnancy test in women of child-bearing age

Exclusion Criteria:

* any unstable organic, psychiatric or addictive disease, which - in the opinion of the investigators - might result in an unsuccessful / unreliable participation or premature termination of the trial
* known contraindications against PDE 5-inhibitors (such as intolerance, therapy with nitrates or inhibitors of CYP3A4, etc.)
* extensive necrosis of the finger tips
* pigmentary retinopathy
* verification as a HbsAg or hepatitis C carrier
* unstable angina
* heart failure (NYHA III or IV)
* valve defects of higher degree (particularly aortic stenosis and hypertrophic obstructive cardiomyopathy)
* myocardial infarction, stroke or life-threatening cardiac arrhythmias within the last 6 months
* uncontrolled atrial fibrillation / -flutter with a heart rate \> 100 bpm
* prolonged QTc-interval (\> 450 msec)
* congenital long-QT-syndrome
* hypokalemia
* severe acute or chronic liver disease, which might lead to priapism (sickle cell anemia, leucemia)
* hemophilia
* active peptic ulcers
* arterial hypotension (systolic blood pressure at rest \<90 mmHg) or
* arterial hypertension(systolic blood pressure at rest \>170 mmHg or diastolic blood pressure at rest \>110 mmHg)
* malignancy within the last 5 years (except squamous or basal cell skin cancer)
* patients with injuries of the spinal cord or central nervous system
* patients with severe chronic kidney disease (creatinin clearance \< 30 ml)
* patients with mild to severe liver disease (Child-Pugh A-C)
* Age below 18 or above 80
* prohibited concomitant medication during the study:

  * nitrates or other NO-donators (including amylnitrit)
  * anticoagulative drugs except inhibitors of thrombocyte function
  * androgens (such as testosterone) or anti-androgens
  * strong inhibitors of cytochrome P4503A4:
* very potent HIV-Protease-inhibitors (ritonavir, indinavir)
* anti-mycotic like itraconazole and ketoconazole (topical applications are allowed)
* erythromycin
* grapefruit-juice or products containing grapefruit-juice

  * other study medications (including placebo) up to 30 days before study inclusion
  * therapy of erectile dysfunction(including sildenafil, sublingual apomorphin, MUSE®, intracavernous injections or vacuum pumps) or other therapies of erectile dysfunction within 4 weeks and during the trial period
  * nebivolol
  * alpha-blockers
  * Calcium antagonists
  * medications prolonging the QT-interval
  * abnormal lab tests like:
* serum-creatinine \> 3 mg/dl at visit 1
* GOT and GPT \> 3 x reference limit set
* diabetes mellitus with a HbA1c \> 9%
* patients who are not willing to disclaim a therapy of their erectile dysfunction with vacuum pumps, intravenous injections, sildenafil or other therapies during the trial
* severe migraine (more than once a moth during the last 6 months)
* intolerance to the study medication
* patients who are not able to understand the information and informed consent due to a mental disorder or linguistic barriers
* persons who are living in a institution directly under federal government control due to a court order
* patients who refuse to renounce drinking grapefruit juice during the trial
* women who are pregnant or lactating
* women who are not protected from a pregnancy (intake of oral contraceptives alone in insufficient; highly effective methods of birth control have to be used with a failure rate \<1%; barriers: implants, intrauterine-devices (IUD´s),diaphragm, condoms, abstinence, partner is vasectomized, spermicides)
* patients who participated in other interventional studies within 30 days of study inclusion
C: Inclusion Criteria:

* Active Raynaud's Phenomenon characterized by a clinical history of primary or secondary Raynaud's Phenomenon
* At least 7 RP attacks per week on 5 or more days per week (assessed over the 2 weeks preceding inclusion)
* Patients who have dated and signed the informed consent form
* Contraception for women

Exclusion Criteria:

* Recently diagnosed RP (less than 2 months).
* Uncontrolled hypertension, diabetes mellitus, angina
* Haemodynamic instability
* Nonarteritic ischemic optic neuropathy
* Pulmonary hypertension
* Subjects currently taking sildenafil, tadalafil or vardenafil
* Subjects currently taking nitrates
* Subjects currently taking strong CYP3A inhibitors
* Pregnancy (or considering pregnancy in the next 4 months)
* Breast feeding
* Participation in another clinical trial
D: Inclusion Criteria:

* secondary Raynaud's phenomenon

Exclusion Criteria:

* primary raynaud phenomenon
* active infection
* hypersensitivity to PDE5 inhibitor or Calcium Chanel Blocker (CCB)
* elevated AST/ALT (3 times above the upper normal limit)
* severe renal failure
* patients on nitrite or nitric oxide (NO) donor treatment
* recent history of cerebrovascular accidents, acute myocardial infarction, or coronary artery bypass surgery
* hypotension (less than 90/50 mmHg) or uncontrolled hypertension

Answer: B