Study to Determine How Cialis Effects the Renal Function in Response to Volume Expansion in Preclinical Systolic Cardiomyopathy (Aim2)
Condition: Cardiomyopathy; Renal Impairment
MeSH terms: Renal Insufficiency; Cardiomyopathies
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      To determine the effect of 12 weeks of chronic PDEV inhibition with Tadalafil versus placebo
      on basal cardiorenal and humoral function and on the integrated cardiorenal and humoral
      response to acute sodium loading in subjects with preclinical systolic dysfunction (PSD) and
      renal (kidney) dysfunction.
    

Detailed description: 
      At the consent visit a blood draw will be done also a the 6 minute walk will be done to
      determine eligibility and a physical exam along with vital signs, height and weight will be
      done. Twenty-four hour urine collection will be obtained one day prior to the active study
      day.

      Prior to initiation of the study, subjects will be stabilized for at least one week on a no
      added salt diet (120 milliequivalents of sodium/salt per day (mEq Na/day) which will be
      maintained throughout the study period.

      Subjects will be admitted to the Clinical Research Unit (CRU)on the evening before the active
      study day. They will be able to order a no-added salt meal and will not have anything to eat
      after midnight until the last renal clearance blood draw the next day. Bladder scan will be
      carried out to assess for urine retention. On the active study day, subjects take their
      medications upon awakening, however, diabetics will hold their diabetic medications until
      after the last renal clearance test then they will be able to order a regular diet meal and
      take their diabetic medications. Subjects will be asked to drink 5ml/Kg (milliliters per
      kilogram of body weight) of water to insure sufficient urinary flow. A priming dose
      (calculated according to body size) of Iothalamate, to measure glomerular filtration rate
      (GFR) and para-amino-hippurate (PAH) to measure effective renal plasma flow (ERPF) is
      infused, followed by a constant rate IV sustaining dose (calculated according to estimated
      kidney function) of Iothalamate or PAH. The subjects will be asked to empty their bladder
      spontaneously every thirty minutes. Throughout the study, at the end of each 30-minute
      clearance period, subjects will be asked to drink an amount of water equivalent to the sum of
      the blood losses and the urinary flow. After an equilibration period of 45 minutes, a
      30-minute baseline renal clearance will be carried out.

      Blood pressure will be measured at 20-minute intervals by using automatic blood pressure
      cuff, and heart rate will be continuously monitored by electrocardiography. Echocardiography
      will be performed during these baseline clearances to determine left atrial (LA) and Left
      Ventricular (LV)volumes and systolic and diastolic function.

      After the baseline clearance the acute saline load will be administered (normal saline 0.9%
      0.25 ml/kg/min for 1 hour). During the 1 hour saline load, one 30-minute clearance (as
      outlined above) will be repeated with the subjects in supine position after which a second
      30-minute clearance will be repeated with the subject sitting or the head of the bed up. As
      above, blood samples are collected midway during each clearance and urine samples are
      obtained every 30 minutes. Echocardiography will be repeated immediately after the end of the
      saline infusion.

      At the completion of the baseline renal clearance periods and response to acute sodium load,
      subjects will be randomized to Tadalafil or placebo. Subjects will be randomized in a 2:1
      fashion.

      All subjects will take oral Tadalafil (5 mg) or placebo once a day. The blood pressure will
      be checked prior to administering the drug.Thereafter, both blood pressure and heart rate
      will continue to be monitored for the next 4 hours. If after the first dose of study drug if
      patient's systolic blood pressure is < 85 mmHg systolic and has symptoms of hypotension e.g.
      lightheadedness, dizziness, feeling faint, blurred vision, the study drug will be stopped
      however the subject will continue in the study. After 2 hours if blood pressure is >95
      systolic then give 1 more (5 mg) of Tadalafil or placebo and monitor blood pressure for 2
      hours. If blood pressure is >95 then dismiss subject on 2 (5 mg) tabs of tadalafil or
      placebo. If blood pressure is between 90 - 95 mmHg systolic, then dismiss on 1 (5 mg) tab of
      Tadalafil or placebo.

      Patients will then be dismissed. Subjects will also have access to a 24-hour phone number
      should they have any questions or develop any side effects. Subjects will return after one
      week (+ or - 4 days) for electrolyte check. They will also receive a weekly phone call to
      review status.

      At 2 weeks (± 5 days) from dismissal if blood pressure is> 100 than add 1 (5 mg) tab of
      Tadalafil or placebo to make a total of 3 (5mg) tabs of Tadalafil or placebo.

      At 4 weeks(± 5 days) if blood pressure is > 100 add 1 (5 mg) tab to make a total of 4 (5 mg)
      Tadalafil or placebo.

      After six weeks( + or - 5 days) , subjects will repeat blood draw for safety labs (total
      blood count and electrolytes). For patients who do not live more than 25 miles away we will
      try to arrange this visit with the patient's local physician.

      At the end of the twelve-week study period (+ or - 8 days), subjects will be admitted to the
      Clinical Research Unit the afternoon prior to the renal clearance study. Echocardiography,
      renal clearance, humoral determination and acute saline load will be performed in the same
      manner as the baseline study. Subjects will also perform a 24-hour urine collection the day
      prior to their return visit for determination of sodium excretion and creatinine clearance.
      Subjects will be dismissed after the renal clearance study.
    

Intervention name(s): Tadalafil; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Tadalafil 5 mg tablet. Daily. Tadalafil dose varies from 5 mg to 20 mg for 12 weeks. If blood pressure is >95 then subject dismissed from the Clinical Research Unit (CRU) on 2 (5 mg) tabs of tadalafil or placebo. If blood pressure is between 90 - 95 mmHg systolic, then dismiss on 1 (5 mg) tab of Tadalafil. At 2 weeks (± 5 days) if blood pressure is> 100 than add 1 (5 mg) tab of Tadalafil to make a total of 3 (5mg) tabs of Tadalafil. At 4 weeks(± 5 days) if blood pressure is > 100 add 1 (5 mg) tab to make a total of 4 (5 mg) tablets of Tadalafil.; Placebo tablet. Daily. Placebo tablets made to match appearance of 5mg Tadalafil tablets. Placebo dose varies from 5 mg to 20 mg (1 to 4 tablets) for 12 weeks. If blood pressure is >95 then subject dismissed from CRU on 2 tabs of placebo. If blood pressure is between 90 - 95 mmHg systolic, then dismiss on 1 (5 mg) tablet of placebo. At 2 weeks (± 5 days) if blood pressure is> 100 than add 1 tab of placebo to make a total of 3 tablets of placebo. At 4 weeks(± 5 days) if blood pressure is > 100 add 1 (5 mg) tab to make a total of 4 tablets of placebo.
Other intervention name(s): Tadalafil 5mg tablet; Placebo tablet
Intervention MeSH terms: Tadalafil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science