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The Role of Endothelin-1 in Sickle Cell Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02712346
Recruitment Status : Active, not recruiting
First Posted : March 18, 2016
Last Update Posted : July 17, 2019
Sponsor:
Collaborators:
Gilead Sciences
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Abdullah Kutlar, Augusta University

Tracking Information
First Submitted Date  ICMJE October 2, 2015
First Posted Date  ICMJE March 18, 2016
Last Update Posted Date July 17, 2019
Study Start Date  ICMJE September 2015
Actual Primary Completion Date May 30, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 14, 2016)
Safety and Tolerability of ambrisentan in patients with sickle cell disease measured by physical exam, vital signs, blood and urine testing, ECG (specified visits), concomitant medication review, adverse events review [ Time Frame: Day 1 (Baseline) through Day 113 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02712346 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 28, 2017)
  • Efficacy of ambrisentan in improving kidney function in patients with sickle cell disease measured by blood [ Time Frame: Day 1 (Baseline), Day 15, Day 29, Day 57, Day 85, and Day 113 ]
    measured by blood
  • Efficacy of ambrisentan in decreasing TRJ velocity [ Time Frame: Day 1 (Baseline) and at the end of the 12 week treatment period ]
    measured by echocardiogram
  • Efficacy of ambrisentan in decreasing inflammation [ Time Frame: Day 1 (Baseline) through Day 113 ]
    measurement of inflammatory markers in blood
  • Efficacy of ambrisentan in improving micro-circulation [ Time Frame: Day 1 (Baseline) and at the end of the 12 week treatment period ]
    measured by forearm and skin blood flow measurements
  • Efficacy of ambrisentan in improving macro-circulation [ Time Frame: Day 1 (Baseline), and at the end of the 12 week treatment period ]
    measured by Transcranial Doppler (TCD)
  • Efficacy of ambrisentan in improving nociception/pain [ Time Frame: Day 1 (Baseline), and at the end of the 12 week treatment period ]
    performance of quantitative sensory testing
  • Efficacy of ambrisentan in improving kidney function in patients with sickle cell disease measured by urine testing for microalbuminuria/proteinuria [ Time Frame: Day 1 (Baseline), Day 15, Day 29, Day 43, Day 57, Day 71, Day 85, and Day 113 ]
    measured by urine testing for microalbuminuria/proteinuria
  • Efficacy of ambrisentan in improving nociception/pain [ Time Frame: Day 1 (Baseline) through the 12 week treatment period ]
    assessment of pain diaries/questionnaires
  • Efficacy of ambrisentan in improving nociception/pain [ Time Frame: Day 1 (Baseline) through the 12 week treatment period ]
    assessment of adverse events
Original Secondary Outcome Measures  ICMJE
 (submitted: March 14, 2016)
  • Efficacy of ambrisentan in improving kidney function in patients with sickle cell disease measured by blood [ Time Frame: Day 1 (Baseline), Day 15, Day 29, Day 57, Day 85, and Day 113 ]
    measured by blood
  • Efficacy of ambrisentan in decreasing TRJ velocity [ Time Frame: Day 1 (Baseline) and at the end of the 12 week treatment period ]
    measured by echocardiogram
  • Efficacy of ambrisentan in decreasing inflammation [ Time Frame: Day 1 (Baseline) through Day 113 ]
    measurement of inflammatory markers in blood
  • Efficacy of ambrisentan in improving micro-circulation [ Time Frame: Day 1 (Baseline) and at the end of the 12 week treatment period ]
    measured by forearm and skin blood flow measurements
  • Efficacy of ambrisentan in improving macro-circulation [ Time Frame: Day 1 (Baseline), and at the end of the 12 week treatment period ]
    measured by Transcranial Doppler (TCD)
  • Efficacy of ambrisentan in improving nociception/pain [ Time Frame: Day 1 (Baseline), and at the end of the 12 week treatment period ]
    performance of quantitative sensory testing
  • Efficacy of ambrisentan in improving kidney function in patients with sickle cell disease measured by urine testing for microalbuminuria/proteinuria [ Time Frame: Day 1 (Baseline), Day 15, Day 29, Day 43, Day 57, Day 71, Day 85, and Day 113 ]
    measured by urine testing for microalbuminuria/proteinuria
  • Efficacy of ambrisentan in improving nociception/pain [ Time Frame: Day 1 (Baseline), and at the end of the 12 week treatment period ]
    assessment of pain diaries/questionnaires
  • Efficacy of ambrisentan in improving nociception/pain [ Time Frame: Day 1 (Baseline) through the 12 week treatment period ]
    assessment of adverse events
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Role of Endothelin-1 in Sickle Cell Disease
Official Title  ICMJE The Role of Endothelin-1 in Sickle Cell Disease
Brief Summary The primary goal of the study is to determine the safety and tolerability of ambrisentan. It is also expected that ambrisentan will improve blood flow in the lungs, decrease inflammation, and reduce pain in sickle cell patients. An additional goal is to evaluate the use of select biomarkers in evaluating sickle nephropathy.
Detailed Description

The purpose of this study is to test the hypothesis that endothelin antagonist (ETA) receptor blockade using ambrisentan is safe, tolerable, and improves kidney function/albuminuria in patients with sickle cell disease (SCD). The investigators anticipate a reduction in proteinuria, a decrease in tricuspid regurgitation jet (TRJ) velocity, reduction in inflammatory markers, improvement in forearm blood flow, and improvement in nociception/pain.

The primary efficacy endpoint was chosen as the effect of ETA receptor blockade on the reduction of microalbuminuria based upon findings in diabetic nephropathy, which has a similar pathogenesis to sickle nephropathy. A 30% reduction in proteinuria is rather conservative and realistic based upon the results of studies of ETA receptor blockade in diabetic nephropathy that consistently resulted in 40-45% reduction in proteinuria. Pre-clinical data has shown that changes can be detected in urinary nephrin excretion before overt proteinuria is observed in a model of chronic ET-1 elevation. Furthermore, tubular injury that can occur as a result of an intrarenal vaso-occlusive crisis (VOC) should be expected to increase the level of renal tubular injury markers, neutrophil gelantinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and netrin. Treatment with ambrisentan would be expected to attenuate these changes. Dr. Jennifer Pollock, has extensive experience with all of the biomarker assays including ET-1. Dr. Pollock runs bio-analytical core labs for two PO1s and has published extensively on these and similar methods in human and animal samples.

Additional rationale for this project is based on recent 24-hour urine results for creatinine clearance and total protein excretion from 97 patients with sickle cell anemia (Hb SS) and sickle beta zero thalassemia (SB0-thalassemia) followed in the Augusta Sickle Cell Clinic. These patients ranged in age from 19-63 years (52 females, 45 males). Of these, 17 (18%) had microalbuminuria as defined by a 24-hour albumin excretion of 150-300 mg, 34 (36%) had macroalbuminuria (>300 mg albumin excretion/24-hours), thus 54% of the patients had microalbuminuria or macroalbuminuria and only 46% were normo albuminuric. 58 patients (58%) were on chronic hydroxyurea therapy. 9 patients were on angiotensin converting enzyme inhibitors (ACEi) and 20 were on angiotensin receptor blockers (ARBs) (total 30%). 55 patients (57%) had glomerular hyperfiltration (creatinine clearance of >120 ml/min). There was an age related decline in the glomerular filtration rate (GFR) observed. The number of patients with normo albuminuria shows a sharp decline by age indicative of the progression of sickle nephropathy. Recent studies of pain in SCD have led to a change in perception. Approximately 50% of the patients reported experiencing daily, chronic pain. In addition, issues related to centralization and neuropathic pain in this patient population has begun to gain increasing attention. A large body of evidence suggests that endothelin-1 plays an important role in enhancing pain stimuli and nociception in various conditions. This is mediated by ETA receptor. Berkeley SCD transgenic mice do have hyperalgesia as shown in the rationale preliminary data section of Aim 2 and ETA receptor blockade reverses this hyperalgesia towards normal. As part of an ongoing National Institute on Minority Health and Health Disparities (NIMHD) funded study of pain and its genetic correlates (study reference: 1 P20 MD003383-01), the investigators have found that SCD patients display significant hyperalgesia as measured by pressure pain algometer testing. The testing was done at three different anatomic sites in patients (n=38) and controls (n=20) and showed that SCD patients perceived pain at significantly lower pressures compared to controls (masseter: 157.7 kilopascal (kPa) for patients, 214.4 kPa for controls, p=0.017; ulna: 299.1 kPa for patients, 477.5 kPa for controls, p=0.0018; and trapezius: 290.1 kPa for patients, 462.8 kPa for controls, p=0.02). These data suggest that hyperalgesia is present in the vast majority of SCD patients and will constitute an objective parameter to monitor during the study.

Protocol-required assessments performed at every study visit include: physical exam, vital signs, con medication review, study drug accountability, adverse events review, pain diary completion, and pregnancy testing if applicable.

Protocol-required assessments performed at specified study visits include: collection of blood and urine for safety and efficacy testing; electrocardiogram (ECG); echocardiogram (echo); Quantitative Sensory Testing (pressure pain threshold via algometer, cutaneous mechanical pain via monofilament, and thermal testing via Q-Sense Small Fiber Test); transcranial Doppler (TCD); forearm blood flow measurement; skin blood flow measurement; and completion of quality of life questionnaires.

Description of Procedures:

Sensory Testing: Patients will also undergo sensory testing at baseline and at the end of the study period. Sensory testing will include: 1) Pressure pain threshold will be measured by a hand-held, digital algometer as described by Fillingim et al at three different anatomical sites: center of right upper trapezius, right masseter, and the right ulna; 2) Cutaneous mechanical pain testing- Assessment of temporal summation of mechanical pain will be done using nylon monofilaments tested on the dorsum of the hand.; and 3) Thermal sensory testing will be performed using Q-Sense Small Fiber Test, which offers a scientifically validated measure of warm, cool and heat-pain thermal sensory thresholds.

Pain Diaries/Questionnaires: Patients will be asked to complete a daily pain diary as described in the PISCES study. The evaluation of pain diaries will be performed by Dr. Robert Gibson and the research staff. In addition, investigators will also incorporate two pre/post measures that will examine the effects of pain on functional performance and quality of life. The Assessment of Motor and Process Skills (AMPS) is a well-established functional assessment. This assessment has demonstrated the ability to discriminate between healthy controls and those with wide spread chronic pain. It also demonstrates the ability to measure change following intervention. The investigators will also measure patient's quality of life with the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me). This quality of life assessment has been specifically developed for sickle cell populations. Dr. Robert Gibson has training and experience with the ASCQ-Me and is certified to administer the AMPS.

Echocardiogram for tricuspid regurgitation jet (TRJ) Velocity Measurement: A transthoracic echocardiogram for the measurement of TRJ velocity and pulmonary artery systolic pressure will be performed at baseline (unless obtained clinically within 6 months of Day 1) and at the end of the study.

Electrocardiogram: An electrocardiogram (ECG) is a test that measures the electrical activity of the heart. An ECG will be done as a safety measure at baseline, Day 8 visit, and end of study, although ambrisentan is not known to prolong corrected QT interval (QTc).

Forearm Blood Flow Measurement: Brachial artery flow-mediated dilation (FMD) will be performed in accordance to the recent tutorial for ultrasound assessment of FMD. Patients will be tested under fasting conditions in a controlled environment at baseline and at the end of the study period.

Skin Blood Flow Measurement: Skin blood flow will be measured non-invasively using a low frequency laser imaging camera and/or a small skin probe. Ring-shaped probes that are about 1.5 inches wide will be placed on the forearm with sticky tape. One ring will be filled with approximately 2 ml (about 1/2 teaspoon) of water for local heat and the others will be used for iontophoresis. For local heat, investigators will heat the water in the ring to between 42°C (107°F) and 44°C (111°F) and wait approximately 30 minutes for the increase in skin blood flow to become stable. Iontophoresis is a technique that delivers a vasoactive drug about 1 mm deep into the skin using a low level electrical current. The advantage of this technique is that it is non-invasive and the drug does not go into the body, it just remains at the surface of the skin. We will use a 1-2% solution of either acetylcholine, sodium nitroprusside, or N-nitro-L-arginine methyl ester (L-NAME) (vasoactive substances) to increase or decrease skin blood flow. Multiple short currents (10-180 seconds) will be performed approximately 1 minute apart. Investigators will monitor skin blood flow through the ring during the forearm arterial blood flow test described above as well as during local heat and iontophoresis.

Blood and Urine Measurement: Lab tests to be performed for safety/ efficacy assessments at specified study visits include complete blood count (CBC), complete metabolic panel (CMP), spot urine for albumin-creatinine ratio, 24-hour urine, pregnancy testing, biomarkers, and inflammatory markers.

Transcranial Doppler (TCD): Pre- and post-treatment TCD will be performed to assess velocity of cerebral blood flow. This non-invasive test is performed while the subject is lying down and involves use of sound waves to assess macro-circulation in the head. A transducer is used to hear and record the results.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Sickle Cell Anemia
Intervention  ICMJE
  • Drug: Ambrisentan
    Ambrisentan 5 milligrams a day or a placebo (sugar pill) for twelve weeks
    Other Name: Letairis
  • Drug: Placebo
    One inactive pill daily for twelve weeks
    Other Name: "Sugar Pill"
Study Arms  ICMJE
  • Experimental: Treatment
    Ambrisentan 5 mg PO daily
    Intervention: Drug: Ambrisentan
  • Placebo Comparator: Placebo
    One inactive pill PO daily
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 15, 2019)
26
Original Estimated Enrollment  ICMJE
 (submitted: March 14, 2016)
30
Estimated Study Completion Date  ICMJE November 30, 2019
Actual Primary Completion Date May 30, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. SS or Sβo-thalassemia
  2. Age 18-65 years
  3. Microalbuminuria (24-hour albumin 150-300 mg) or macroalbuminuria (24-hour albumin >300 mq) OR random urine albumin-creatinine ratio (MA Random) ≥ 30 µg/ mg creatinine
  4. Subjects can have Stage 1, II, or III chronic kidney disease (CKD)
  5. Subjects can be on hydroxyurea, ACE inhibitors (ACEi), or angiotensin receptor blockers (ARBs) for a period of 3 months or greater
  6. Females of child bearing potential must agree to use two forms of birth control with one being a barrier method; abstinence is an acceptable form of birth control

Exclusion Criteria:

  1. Other genotypes of SCD
  2. History of renal transplant
  3. Chronic kidney disease (Stage IV and V including patients on hemo dialysis or peritoneal dialysis)
  4. Patients on chronic transfusion therapy
  5. Uncontrolled/poorly controlled hypertension or history of hypertension pre-dating proteinuria or
  6. Known history of HIV, Hepatitis C, and/or diabetes
  7. Peripheral edema
  8. History of congestive heart failure or pulmonary edema
  9. Recent history of coronary artery disease
  10. Pregnant or breast feeding
  11. Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) >3-fold upper limit of normal
  12. Albumin <2.5 gm/dl
  13. Hemoglobin < 6 gm/dL
  14. History of non-compliance with medications and clinic visits; or Inability to give informed consent; or Patient deemed ineligible or unsuitable in the judgment of investigators
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02712346
Other Study ID Numbers  ICMJE Endothelin
5U01HL117684 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Abdullah Kutlar, Augusta University
Study Sponsor  ICMJE Augusta University
Collaborators  ICMJE
  • Gilead Sciences
  • National Heart, Lung, and Blood Institute (NHLBI)
Investigators  ICMJE
Principal Investigator: Abdullah Kutlar, MD Augusta University
PRS Account Augusta University
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP