Adenosine 2A Agonist Lexiscan in Children and Adults With Sickle Cell Disease

This study has been completed.
Sponsor:
Collaborators:
Brigham and Women's Hospital
Children's Hospital Boston
Washington University School of Medicine
Medical College of Wisconsin
Johns Hopkins University
La Jolla Institute for Allergy & Immunology
Astellas Pharma Global Development, Inc.
Information provided by (Responsible Party):
David G. Nathan, MD, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:
NCT01085201
First received: March 10, 2010
Last updated: February 5, 2014
Last verified: February 2014
  Purpose

Sickle cell disease (SCD) is an inherited blood disorder that causes the red blood cells to change their shape from a round shape to a half-moon/crescent or sickled shape. People who have SCD have a different type of protein that carries oxygen in their blood (hemoglobin) then people without SCD. This different type of hemoglobin makes the red blood cells change into a crescent shape under certain conditions. Sickle-shaped cells are a problem because they often get stuck in blood vessels blocking the flow of blood, and cause inflammation and injury to the important areas in the body. Lexiscan is drug that may prevent this inflammation and injury caused by the sickle shaped cells. This drug is approved by the FDA to be used as a fast infusion during a heart stress test in people who are unable to exercise enough to put stress on their heart by making it beat faster. Lexiscan has never been studied in patients with SCD and has never been given as a long infusion.


Condition Intervention Phase
Sickle Cell Disease
Drug: Lexiscan
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Safety of Adenosine 2A Agonist Lexiscan in Children and Adults With Sickle Cell Disease

Resource links provided by NLM:


Further study details as provided by Dana-Farber Cancer Institute:

Primary Outcome Measures:
  • Dose Limiting Toxicities as a Measure of Whether Infusional Lexiscan is Safe in Individuals With SCD. [ Time Frame: 30 to 54 hours plus 30-day follow-up ] [ Designated as safety issue: Yes ]
    Per protocol, Lexiscan was considered "safe" if well tolerated based on number of DLTs reported. Stage 1 of the study was a 3+3 dose escalation study. Three doses were tested: 0.24 mcg/kg/hr (dose level 0), 0.6 mcg/kg/hr (dose level 1), and 1.44 mcg/kg/hr (dose level 2). Dose escalation continued until 6 participants were treated at the maximum planned dose (dose level 2). We studied a total of 15 patients in Stage 1. In Stages 2 and 3, if at least 2/3 participants tolerated the dose, an additional 3 participants were studied. We studied 6 participants in each of stages 2 and 3. In stage 2b, Lexiscan was studied for a longer (48 hr) duration in 3 participants. In stage 4, Lexiscan was studied in 3 pediatric participants.


Secondary Outcome Measures:
  • Percentage of Activated iNKT Cells and/or Activation Markers on iNKT Cells in Individuals With SCD. [ Time Frame: pre-drug to 54 hours ] [ Designated as safety issue: No ]
    Percentage of activated iNKT cells after receiving a 24-hour infusion of Lexiscan was compared to pre-drug. iNKT cell activation was evaluated using antibodies targeting the p65 subunit of nuclear factor-kappa B (phospho-NF-kB p65). Measures are given as percentage of change in phospho-NF-kB p65 activation in iNKT cells compared to pre-drug after a 24-hour infusion. iNKT cell activation in Stages 1, 2b, and 4 was not analyzed (see analysis population description).

  • Pain Levels During a Vaso-occlusive Event in Children and Adults With SCD. [ Time Frame: pre-drug to 54 hours ] [ Designated as safety issue: No ]
    Pain was measured using a standardized pain scale. The scale is a 10-cm visual analogue scale (10 cm-long line printed on white paper), where 0 is no pain and 10 is maximum pain. Participants were asked to indicate their pain level by marking on the line prior to each blood draw.


Enrollment: 39
Study Start Date: April 2010
Study Completion Date: March 2013
Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Stage 1
12-hour infusion to adults with SCD who are not having a pain crisis. THIS STAGE IS COMPLETE AND CLOSED TO ACCRUAL.
Drug: Lexiscan
Given as an infusion
Experimental: Stage 2
24-hour infusion to adults with SCD who are not having a pain crisis. THIS STAGE IS COMPLETE AND CLOSED TO ACCRUAL.
Drug: Lexiscan
Given as an infusion
Experimental: Stage 3
24-hour infusion to adults with SCD who are having a pain crisis. THIS STAGE IS COMPLETE AND CLOSED TO ACCRUAL.
Drug: Lexiscan
Given as an infusion
Experimental: Stage 4
24-hour infusion to children with SCD who are having a pain crisis. THIS STAGE IS COMPLETE AFTER STUDYING 3 PATIENTS BY AGREEMENT FROM THE FDA, IRB, AND DSMB. THIS STAGE IS CLOSED TO ACCRUAL.
Drug: Lexiscan
Given as an infusion
Experimental: Stage 2B
48-hour infusion to adults with SCD who are not having a pain crisis. THIS STAGE IS COMPLETE AFTER STUDYING 3 PATIENTS BY AGREEMENT FROM THE FDA, IRB, AND DSMB. THIS STAGE IS CLOSED TO ACCRUAL.
Drug: Lexiscan
Given as an infusion

Detailed Description:
  • In this research study we are looking for the highest dose of Lexiscan that can be given safely to patients with SCD. There are 4 stages to this study. Each stage will look for the highest dose that can be given safely in the following situations: Stage 1: Lexiscan will be given through a 12 hours infusion to adults with SCD who are not having a pain crisis. Stage 2: Lexiscan will be given through a 24 hour infusion to adults with SCD who are not having a pain crisis. Stage 2b: Lexiscan will be given through a 48 hour infusion to adults with SCD who are not having a pain crisis. Stage 3: Lexiscan will be given through a 24 hour infusion to adults with SCD who are having a pain crisis. Stage 4: Lexiscan will be given through a 24 hour infusion to children with SCD who are having a pain crisis. Stages 1-3 are now complete and closed to accrual. The study is now open to children ages 10-17 with SCD pain crisis (stage 4) only.
  • When participants sign the consent form, they will be told what stage they will join.
  • Participants in Stages 1, 2, and 2b will be given an infusion of the study drug at the time when they do not have a pain crisis. The infusion for Stage 1 participants will be 12 hours long, followed by a 6-hour observation period. The infusion for Stage 2 will be 24 hours long, followed by a 6-hour observation period. The infusion for Stage 2b will be 48 hours long, followed by a 6-hour observation period.
  • Participants in Stages 3 and 4 will be given one infusion of the study drug when they are admitted to the hospital for a pain crisis. The infusion will be 24 hours long, followed by a 6-hour observation period. During the infusion, they will receive standard treatment for their pain crisis.
  • Before the infusion the following procedures will be performed: Pulmonary function test (optional, Stage 1 only), blood test and vital signs.
  • During the infusion the following procedures will be performed: heart rate and amount of oxygen in the blood will be monitored continuously, blood tests and blood pressure.
  • During the observation period immediately following the infusion the following procedures will be performed: heart rate and amount of oxygen in the blood will be monitored continuously, blood tests, blood pressure and Pulmonary Function test (optional, Stage 1 only).
  Eligibility

Ages Eligible for Study:   10 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria Stage I/II/IIb: (COMPLETE AND CLOSED TO ACCRUAL)

  • Participants must have sickle cell anemia confirmed by hemoglobin analysis
  • Participants must report that their pain is at baseline. Additionally, they cannot report an increase in dose or frequency of opioid use in the last 2 weeks prior to drug administration
  • Age 21-70 years
  • Participants must have the laboratory indices as outlined in the protocol
  • Participants must have reliable IV access as determined by the investigator
  • Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of the study.

Inclusion Criteria Stage III: (COMPLETE AND CLOSED TO ACCRUAL)

  • Participants must have sickle cell anemia confirmed by hemoglobin analysis
  • Participant is admitted to the hospital for a pain episode
  • Age 21-70 years
  • Participants must have the laboratory indices as outlined in the protocol
  • Participants must have reliable IV access as determined by the investigator
  • Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation

Inclusion Criteria Stage IV: (open, still accruing volunteers)

  • Participants must have sickle cell disease confirmed by hemoglobin analysis
  • Participant is admitted to the hospital for a pain episode
  • Ages of assent (10 to 17 years at DFCI, but different depending on institution)
  • Participants must have the laboratory indices as outlined in the protocol
  • Participants must have reliable IV access as determined by the investigator
  • Participants and parents must have the ability to understand and the willingness to sign a written informed consent and assent document
  • Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation

Exclusion Criteria Stage I/II/IIb: (COMPLETE AND CLOSED TO ACCRUAL)

  • Participants with a current physician diagnosis of asthma (within last 12 months), require continuous supplemental oxygen, or predicted or current use of some asthma medications.
  • Participants with second- or third-degree AV block or sinus node dysfunction
  • Have a history of bleeding diathesis
  • Have a history of clinically overt stroke
  • Have a history of severe hypertension not adequately controlled with anti-hypertensive medications
  • Participants who are receiving chronic anti-coagulation or anti-platelet therapy
  • Participants with a history of metastatic cancer
  • Participants who have had a hospitalization or emergency room visit for any reason in the past 2 weeks
  • Participants may not be receiving any other study agents or have received a study agent in the past 30 days
  • Uncontrolled intercurrent illness
  • Pregnant or breastfeeding women
  • Participants with HIV
  • Participants who have previously enrolled and received the investigational agent as part of this study
  • Participants who are taking medications that may interact with the investigational agent

Exclusion Criteria Stage III: (COMPLETE AND CLOSED TO ACCRUAL)

  • Participants with a current physician diagnosis of asthma (within last 12 months), require continuous supplemental oxygen, or predicted or current use of some asthma medications.
  • Participants with second- or third-degree AV block or sinus node dysfunction
  • Have a history of bleeding diathesis
  • Have a history of clinically overt stroke
  • Have a history of severe hypertension not adequately controlled with anti-hypertensive medications
  • Participants who are receiving chronic anti-coagulation or anti-platelet therapy
  • Participants with a history of metastatic cancer
  • Participants may not be receiving any other study agents or have received a study agent in the past 30 days

Exclusion Criteria Stage IV: (open, still accruing volunteers)

  • Participants with a current physician diagnosis of asthma (within last 12 months), require continuous supplemental oxygen, or predicted or current use of some asthma medications.
  • Participants with second- or third-degree AV block or sinus node dysfunction
  • Have a history of bleeding diathesis
  • Have a history of clinically overt stroke
  • Have a history of hypertension not adequately controlled with anti-hypertensive medications
  • Participants who are receiving chronic anti-coagulation or anti-platelet therapy
  • Participants with a history of metastatic cancer
  • Participants may not be receiving any other study agents or have received a study agent in the past 30 days
  • Participants with HIV
  • Participants who have previously enrolled and received the investigational agent as part of this study
  • Participants who are taking medications that may interact with the investigational agent
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01085201

Locations
United States, District of Columbia
Howard University Hospital
Washington, District of Columbia, United States
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Childrens Hospital Boston
Boston, Massachusetts, United States, 02115
United States, Missouri
Washington University
St. Louis, Missouri, United States
United States, Wisconsin
Blood Center of Wisconsin
Milwaukee, Wisconsin, United States
Sponsors and Collaborators
Dana-Farber Cancer Institute
Brigham and Women's Hospital
Children's Hospital Boston
Washington University School of Medicine
Medical College of Wisconsin
Johns Hopkins University
La Jolla Institute for Allergy & Immunology
Astellas Pharma Global Development, Inc.
Investigators
Principal Investigator: David Nathan, MD Dana-Farber Cancer Institute
  More Information

No publications provided by Dana-Farber Cancer Institute

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: David G. Nathan, MD, Professor of Pediatrics, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT01085201     History of Changes
Other Study ID Numbers: 09-308, 1RC2HL101367-01
Study First Received: March 10, 2010
Results First Received: May 2, 2013
Last Updated: February 5, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Dana-Farber Cancer Institute:
lexiscan

Additional relevant MeSH terms:
Hematologic Diseases
Genetic Diseases, Inborn
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hemoglobinopathies
Adenosine
Regadenoson
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Anti-Arrhythmia Agents
Cardiovascular Agents
Vasodilator Agents
Adenosine A2 Receptor Antagonists
Purinergic P1 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 20, 2014