The Effects of Renin Inhibition on Fibrinolytic Balance and Endothelial Function
Condition: High Blood Pressure
MeSH terms: Hypertension
Study type: Interventional
Phase: Phase 4

Summary: 
      Aliskiren (also called TekturnaTM) is a new drug for high blood pressure. Aliskiren works by
      blocking the actions of a substance called renin. Renin is a natural substance in the body
      that raises blood pressure. Renin is believed to contribute to the production of blood clots
      by increasing the amount of a substance known as Plasminogen Activator Inhibitor or PAI-1.
      This study will measure how aliskiren changes the amount of PAI-1 in the blood depending on
      the time of dosing. The purpose of this study is to find out if it is better to take
      aliskiren in the morning or at night.
    

Detailed description: 
      Qualifying subjects will be withdrawn from RAAS blockers in a stepwise fashion over one to
      two weeks. All other blood pressure medications will be continued. If the subject's blood
      pressure rises above SBP > 170 or DBP > 120 at any time during the study, they will be
      excluded and the subject will restart their home medication(s).

      Week Two - Visit 2 - Post-taper visit: will be issued hydrochlorothiazide (25mg po, qd x 18
      weeks, open label). All study medications will be taken daily between 7 and 10 AM. PAI-1
      blood sample will be drawn. Pre-menopausal women will schedule this visit for when they have
      began their cycle.

      Week Four- Visit 3 - If their BP (> 120/60 mmHg), potassium (≤ 5.5 meq/dl) and renal function
      permit (Cr ≤ 1.5 mg/dl), they will be randomized to aliskiren (150 mg po, qd x 2 weeks) or
      placebo. If applicable, a urine pregnancy test will be done for child bearing age females.

      Week Six - Visit 4 - Titration visit: Subjects will return to the GCRC for an interval
      history, pill count, blood pressure check, and basic metabolic panel. If their BP, potassium
      and renal function permit, the medication will be increased to aliskiren (300 mg po, qd x 4
      weeks) or placebo (double dose). If applicable, a urine pregnancy test will be done for child
      bearing age females.

      Week Eight - Visit 5 - Post-Titration visit: Subjects will return to the GCRC for an interval
      history, pill count, blood pressure check and basic metabolic panel. If their BP, potassium
      and renal function permit, they will remain on the current dose of aliskiren.

      Week 10 - Visit 6 - Study Day 1 - Patients will be admitted to the GCRC as an inpatient. They
      will be asked to lie supine for 24 hours with the head of their bed no higher than 10
      degrees. They will have an interval history and physical. An IV catheter will be placed.
      After an initial void, they will begin a 24 hour urine creatinine, sodium and aldosterone.
      They will have a baseline BMP, high sensitivity C-Reactive Protein (hsCRP) and CBC. They will
      have blood drawn every 3 hours for PAI-1 antigen levels, plasma renin activity, plasma ACE
      activity, plasma aldosterone levels, plasma cortisol and melatonin. White blood cells will be
      harvested in PaxGene tubes for future extraction of white blood cell mRNA. They will be on a
      eucaloric, low sodium diet. At the end of the study day they will remain on their home
      medications, HCTZ (25mg po, qd), however they will stop their current blinded study
      medication (aliskiren or placebo). Subjects will have DNA banked from unused blood buffy
      coats. If applicable, UA pregnancy test will be performed by CRC nurses on admission.

      Washout Period - The reason for the washout period is four-fold. The washout period insures
      that drug is completely washed out of the system before initiation of placebo in the arm that
      received aliskiren first. This will allow the study to observe a placebo effect on blood
      pressure in the "aliskiren first" arm, in the event that there is one. It would also insure
      that that sufficient time has passed between SD1 and SD 2 to see the effect of placebo on
      hsCRP in the "aliskerin first" arm. From a safety standpoint, it insures that subjects have
      more than 8 weeks to recover their blood counts between study days, as a significant amount
      of blood is drawn on each study day. Fourth, as there is a menstrual variation in Pai-1
      levels, it insures that pre-menopausal women participating in the study will be the same
      phase of their cycle on SD1 and SD2.

      Week 12 - Visit 7 - Mid-Washout visit: Subjects will return to the GCRC for an interval
      history, pill count, blood pressure check. If their BP permits (<170/120 mmHg) they will
      remain off study medication. If they are anemic (Hgb < 11) they will be started on iron
      supplementation.

      Week 16 - Visit 8 - Post-Washout visit: Subjects will return to the GCRC for an interval
      history, pill count, blood pressure check, BMP and CBC, if indicated. If BP and renal
      function permit, the patient will receive their crossover medication (placebo x 2 weeks or
      aliskiren 150mg po, qd x 2 weeks). If applicable, a urine pregnancy test will be done for
      child bearing age females.

      Week 18 - Visit 9 - Titration visit 2: Subjects will return to the GCRC for an interval
      history, pill count, blood pressure check, and basic metabolic panel, and CBC if indicated.
      If their BP, potassium and renal function permit, the medication will be increased to
      aliskiren (300 mg po, qd x 4 weeks) or placebo (double dose).

      Week 20 - Visit 10 - Post-Titration visit 2: Subjects will return to the GCRC for an interval
      history, pill count, blood pressure check and basic metabolic pane, and CBC if indicated. If
      their BP, potassium and renal function permit, they will remain on the current dose of
      aliskiren. If their Hgb ≥ 11 mg/dl, they will be able to participate in the final study day.

      Week 22 - Visit 11 - Study Day 2: Patients will be admitted to the GCRC as an inpatient. They
      will be asked to lie supine for 24 hours with the head of their bed no higher than 10
      degrees. They will have an interval history and physical. An IV catheter will be placed.
      After an initial void, they will begin a 24 hour urine creatinine, sodium and aldosterone.
      They will have a baseline BMP, hsCRP, and CBC. They will have blood drawn every 3 hours for
      PAI-1 antigen levels, plasma renin activity, plasma ACE activity, plasma aldosterone levels,
      plasma cortisol and melatonin. White blood cells will be harvested in PaxGene tubes for
      future extraction of white blood cell mRNA. They will be on a eucaloric, low sodium diet. At
      the end of the study day they will remain on their home medications, and resume home
      medications that were previously stopped for study purposes. If applicable, UA pregnancy test
      will be performed by CRC nurses on admission.
    

Intervention name(s): Aliskiren 150 mg; Placebo; HCTZ; Aliskiren 300 mg
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Aliskiren 150 mg daily for 2 weeks; Placebo tablet for Aliskerin; HCTZ 25mg every day for 18 weeks; Aliskiren 300 mg for 4 weeks
Other intervention name(s): Tekturna
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Diagnostic