Sickle Cell Disease
Conditions
Keywords
lexiscan
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).
Interventions
DRUGLexiscan
Given as an infusion
Sponsors
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.
Dana-Farber Cancer Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
10 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicities as a Measure of Whether Infusional Lexiscan is Safe in Individuals With SCD. | 30 to 54 hours plus 30-day follow-up | 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
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Activated iNKT Cells and/or Activation Markers on iNKT Cells in Individuals With SCD. | pre-drug to 54 hours | 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. | pre-drug to 54 hours | 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. |
Countries
United States
Participant flow
Recruitment details
Recruitment began on 4/19/10 and ceased completely on 3/26/13. In Stages 1, 2 and 2b, patients were recruited from the medical clinic. For Stages 3 and 4, in which subjects were treated during a pain crisis hospitalization, patients were first informed about the study in clinic, and reminded about the study after being admitted.
Pre-assignment details
Patients who were assigned to Stages 1, 2 or 2b, in which subjects were studied at baseline (i.e. not in pain crisis), could be excluded if they experienced a pain crisis in the interim period between enrollment and their scheduled study date.
Participants by arm
| Arm | Count |
|---|---|
| Stage 1 12-hour infusion to adults with SCD who are not having a pain crisis. THIS STAGE IS COMPLETE AND CLOSED TO ACCRUAL.
Lexiscan : Given as an infusion | 15 |
| Stage 2 24-hour infusion to adults with SCD who are not having a pain crisis. THIS STAGE IS COMPLETE AND CLOSED TO ACCRUAL.
Lexiscan : Given as an infusion | 6 |
| 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.
Lexiscan : Given as an infusion | 3 |
| Stage 3 24-hour infusion to adults with SCD who are having a pain crisis. THIS STAGE IS COMPLETE AND CLOSED TO ACCRUAL.
Lexiscan : Given as an infusion | 6 |
| 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.
Lexiscan : Given as an infusion | 3 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Fond ineligible after consent | 0 | 1 | 1 | 0 | 0 |
| Overall Study | Scheduling conflict | 1 | 0 | 1 | 0 | 0 |
| Overall Study | Unknown- no study drug | 2 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Stage 2 | Stage 2B | Stage 3 | Stage 1 | Stage 4 | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 3 Participants | 6 Participants | 15 Participants | 0 Participants | 30 Participants |
| Age, Continuous | 33.84 years STANDARD_DEVIATION 8.75 | 23.68 years STANDARD_DEVIATION 5.05 | 31.61 years STANDARD_DEVIATION 6.42 | 33.71 years STANDARD_DEVIATION 10.49 | 16.77 years STANDARD_DEVIATION 0.89 | 30.9 years STANDARD_DEVIATION 9.86 |
| Region of Enrollment United States | 6 participants | 3 participants | 6 participants | 15 participants | 3 participants | 33 participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 3 Participants | 8 Participants | 3 Participants | 18 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 3 Participants | 7 Participants | 0 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 15 | 0 / 6 | 0 / 3 | 0 / 6 | 0 / 3 |
| serious Total, serious adverse events | 0 / 15 | 2 / 6 | 0 / 3 | 1 / 6 | 0 / 3 |
Outcome results
Primary
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.
Time frame: 30 to 54 hours plus 30-day follow-up
Population: The number of participants was determined per protocol following a 3+3 design. In Stages 2b and 4, we received permission from the FDA, IRB, and DSMB to study only 3 subjects because we did not observe any prior DLT. One patient enrolled in Stage 2b withdrew consent during the infusion due to an unrelated toothache, and was excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1 - Dose Levels 0, 1 and 2 | Dose Limiting Toxicities as a Measure of Whether Infusional Lexiscan is Safe in Individuals With SCD. | 1 number of DLT |
| Stage 2 - Dose Level 2 | Dose Limiting Toxicities as a Measure of Whether Infusional Lexiscan is Safe in Individuals With SCD. | 0 number of DLT |
| Stage 2B - Dose Level 2 | Dose Limiting Toxicities as a Measure of Whether Infusional Lexiscan is Safe in Individuals With SCD. | 0 number of DLT |
| Stage 3 - Dose Level 2 | Dose Limiting Toxicities as a Measure of Whether Infusional Lexiscan is Safe in Individuals With SCD. | 0 number of DLT |
| Stage 4 - Dose Level 2 | Dose Limiting Toxicities as a Measure of Whether Infusional Lexiscan is Safe in Individuals With SCD. | 0 number of DLT |
Secondary
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.
Time frame: pre-drug to 54 hours
Population: The number of participants was determined per protocol following a 3+3 design. Stages 1, 2 and 2b were excluded because this outcome measure is specific to the experience of a vaso-occlusive event, which was studied in Stages 3 and 4.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Stage 3 - Dose Level 2 | Pain Levels During a Vaso-occlusive Event in Children and Adults With SCD. | 5.8 units on a scale | Standard Deviation 0.8 |
| Stage 4 - Dose Level 2 | Pain Levels During a Vaso-occlusive Event in Children and Adults With SCD. | 7.8 units on a scale | Standard Deviation 1.1 |
Secondary
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).
Time frame: pre-drug to 54 hours
Population: The number of subjects was determined per protocol. Stage 1 was excluded as the goal was to determine the optimal markers for iNKT cells. Only 4 subjects were analyzed in Stage 2 because 24-hour samples were not obtained for 2 subjects. Stages 2b and 4 were not completely analyzed because these stages were completed early after studying 3 subjects.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Stage 2 - Dose Level 2 | Percentage of Activated iNKT Cells and/or Activation Markers on iNKT Cells in Individuals With SCD. | -3 percentage of change in activation | Standard Deviation 0.3 |
| Stage 3 - Dose Level 2 | Percentage of Activated iNKT Cells and/or Activation Markers on iNKT Cells in Individuals With SCD. | -48 percentage of change in activation | Standard Deviation 0.3 |