Title

Adenosine 2A Agonist Lexiscan in Children and Adults With Sickle Cell Disease
Safety of Adenosine 2A Agonist Lexiscan in Children and Adults With Sickle Cell Disease
  • Phase

    Phase 1
  • Study Type

    Interventional
  • Study Participants

    39
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.
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).
Study Started
Apr 30
2010
Primary Completion
Feb 28
2013
Study Completion
Mar 31
2013
Results Posted
Mar 07
2014
Estimate
Last Update
Mar 07
2014
Estimate

Drug Lexiscan

Given as an infusion

Stage 1 Experimental

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

Stage 2 Experimental

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

Stage 3 Experimental

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

Stage 4 Experimental

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.

Stage 2B Experimental

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.

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

Summary

Stage 2B - Dose Level 2

Stage 1 - Dose Levels 0, 1 and 2

Stage 2 - Dose Level 2

Stage 3 - Dose Level 2

Stage 4 - Dose Level 2

All Events

Event Type Organ System Event Term Stage 1 - Dose Levels 0, 1 and 2 Stage 2 - Dose Level 2 Stage 2B - Dose Level 2 Stage 3 - Dose Level 2 Stage 4 - Dose Level 2

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.

Stage 1 - Dose Levels 0, 1 and 2

1.0
number of DLT

Stage 2 - Dose Level 2

Stage 2B - Dose Level 2

Stage 3 - Dose Level 2

Stage 4 - Dose Level 2

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).

Stage 1 - Dose Levels 0, 1 and 2

Stage 2 - Dose Level 2

-3.0
percentage of change in activation (Median)
Standard Deviation: 0.30

Stage 2B - Dose Level 2

Stage 3 - Dose Level 2

-48.0
percentage of change in activation (Median)
Standard Deviation: 0.30

Stage 4 - Dose Level 2

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.

Stage 1

Stage 2

Stage 2B

Stage 3

5.8
units on a scale (Median)
Standard Deviation: 0.8

Stage 4

7.8
units on a scale (Median)
Standard Deviation: 1.1

Total

33
Participants

Age, Continuous

30.9
years (Mean)
Standard Deviation: 9.86

Age, Categorical

Region of Enrollment

Sex: Female, Male

Overall Study

Stage 1

Stage 2

Stage 2B

Stage 3

Stage 4

Drop/Withdrawal Reasons

Stage 1

Stage 2

Stage 2B