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

Primary Purpose

Sickle Cell Disease

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Lexiscan
Sponsored by
Dana-Farber Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sickle Cell Disease focused on measuring lexiscan

Eligibility Criteria

10 Years - 70 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Howard University Hospital
  • Johns Hopkins University
  • Brigham and Women's Hospital
  • Childrens Hospital Boston
  • Dana-Farber Cancer Institute
  • Washington University
  • Blood Center of Wisconsin

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Stage 1

Stage 2

Stage 3

Stage 4

Stage 2B

Arm Description

12-hour infusion to adults with SCD who are not having a pain crisis. THIS STAGE IS COMPLETE AND CLOSED TO ACCRUAL.

24-hour infusion to adults with SCD who are not having a pain crisis. THIS STAGE IS COMPLETE AND CLOSED TO ACCRUAL.

24-hour infusion to adults with SCD who are having a pain crisis. THIS STAGE IS COMPLETE AND CLOSED TO ACCRUAL.

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.

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.

Outcomes

Primary Outcome Measures

Dose Limiting Toxicities as a Measure of Whether Infusional Lexiscan is Safe in Individuals With SCD.
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.
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.
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.

Full Information

First Posted
March 10, 2010
Last Updated
February 5, 2014
Sponsor
Dana-Farber Cancer Institute
Collaborators
Brigham and Women's Hospital, Boston Children's Hospital, Washington University School of Medicine, Medical College of Wisconsin, Johns Hopkins University, La Jolla Institute for Allergy & Immunology, National Heart, Lung, and Blood Institute (NHLBI), Astellas Pharma Global Development, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01085201
Brief Title
Adenosine 2A Agonist Lexiscan in Children and Adults With Sickle Cell Disease
Official Title
Safety of Adenosine 2A Agonist Lexiscan in Children and Adults With Sickle Cell Disease
Study Type
Interventional

2. Study Status

Record Verification Date
February 2014
Overall Recruitment Status
Completed
Study Start Date
April 2010 (undefined)
Primary Completion Date
February 2013 (Actual)
Study Completion Date
March 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Dana-Farber Cancer Institute
Collaborators
Brigham and Women's Hospital, Boston Children's Hospital, Washington University School of Medicine, Medical College of Wisconsin, Johns Hopkins University, La Jolla Institute for Allergy & Immunology, National Heart, Lung, and Blood Institute (NHLBI), Astellas Pharma Global Development, Inc.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Disease
Keywords
lexiscan

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
39 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Stage 1
Arm Type
Experimental
Arm Description
12-hour infusion to adults with SCD who are not having a pain crisis. THIS STAGE IS COMPLETE AND CLOSED TO ACCRUAL.
Arm Title
Stage 2
Arm Type
Experimental
Arm Description
24-hour infusion to adults with SCD who are not having a pain crisis. THIS STAGE IS COMPLETE AND CLOSED TO ACCRUAL.
Arm Title
Stage 3
Arm Type
Experimental
Arm Description
24-hour infusion to adults with SCD who are having a pain crisis. THIS STAGE IS COMPLETE AND CLOSED TO ACCRUAL.
Arm Title
Stage 4
Arm Type
Experimental
Arm Description
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.
Arm Title
Stage 2B
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Lexiscan
Intervention Description
Given as an infusion
Primary Outcome Measure Information:
Title
Dose Limiting Toxicities as a Measure of Whether Infusional Lexiscan is Safe in Individuals With SCD.
Description
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.
Time Frame
30 to 54 hours plus 30-day follow-up
Secondary Outcome Measure Information:
Title
Percentage of Activated iNKT Cells and/or Activation Markers on iNKT Cells in Individuals With SCD.
Description
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).
Time Frame
pre-drug to 54 hours
Title
Pain Levels During a Vaso-occlusive Event in Children and Adults With SCD.
Description
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.
Time Frame
pre-drug to 54 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
10 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Nathan, MD
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Howard University Hospital
City
Washington
State/Province
District of Columbia
Country
United States
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
Country
United States
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Childrens Hospital Boston
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Washington University
City
St. Louis
State/Province
Missouri
Country
United States
Facility Name
Blood Center of Wisconsin
City
Milwaukee
State/Province
Wisconsin
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
23377438
Citation
Field JJ, Lin G, Okam MM, Majerus E, Keefer J, Onyekwere O, Ross A, Campigotto F, Neuberg D, Linden J, Nathan DG. Sickle cell vaso-occlusion causes activation of iNKT cells that is decreased by the adenosine A2A receptor agonist regadenoson. Blood. 2013 Apr 25;121(17):3329-34. doi: 10.1182/blood-2012-11-465963. Epub 2013 Feb 1.
Results Reference
derived

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

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