Rivipansel (B5201002)

Principal Investigator: Anupam Verma
Keywords: Pfizer , Sickle , Sickle cell , Rivipansel , GMI-1070 Department: Pediatric Administration
IRB Number: 00076374 Co Investigator:  
Specialty: Pediatric Hematology and Oncology
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

Tiffanie Hales
tiffanie.hales@hsc.utah.edu
8012133367

Brief Summary

Primary Objective
 
To demonstrate the efficacy of rivipansel in treating a single episode of VOC in hospitalized subjects with SCD.
 
Secondary Objective
To evaluate the safety of rivipansel when used to treat a single episode of VOC in hospitalized subjects with SCD.
 
Exploratory Objectives
To evaluate biomarkers of cell adhesion, coagulation pathway activation, white blood cell
mobilization, and inflammation/markers of acute chest syndrome (ACS) for subjects with
SCD hospitalized for VOC.
 
To provide information that describes the medical resource use and cost of VOC episodes
treated in a hospital setting.
 
Efficacy Endpoints
Primary
Time to readiness-for-discharge, defined as the difference between the
readiness-for-discharge date and time (see Section 7.1.1) and the start date and time of
the first infusion of study drug (in hours).
 
Secondary
Time to discharge, defined as the difference in hours between the time and date of the
hospital discharge order by a qualified healthcare provider and the time and date of the
initiation of the first infusion of study drug.
 
Cumulative IV opioid consumption (standardized using morphine equivalents) from the
time of the loading dose of study drug to discharge.
 
Time to discontinuation of IV opioids.
 
Other secondary
Cumulative IV opioid consumption (standardized using morphine equivalents) within the
first 24 hours post-loading dose of study drug.
 
Percent of subjects re-hospitalized for VOC within 3 days of discharge.
 
Safety
Incidence and severity of adverse events during study.
 
Incidence of clinical laboratory abnormalities and change from baseline in clinical
laboratory values at end of treatment.
 
Incidence of clinically significant changes in physical examination.
 
Change from baseline in vital signs over the study.
 
Incidence of adjudicated ACS.
 
Incidence of adjudicated severe and/or generalized cutaneous manifestations.
 
Percent of subjects re-hospitalized for VOC within 7, 14 and 30 days of discharge.
 
Exploratory Endpoints
Hourly IV opioid use (standardized using morphine equivalents) every 4 hours for first
48 hours post-loading dose of study drug.
 
Daily IV opioid use (standardized using morphine equivalents).
 
Daily non-opioid IV pain medication use (yes/no).
 
Time to first clinically meaningful reduction in VOC pain from baseline. Pain will be
measured by an 11-point (0-10) Numeric Rating Scale (NRS) in subjects >/=12 years of age
and a 6-point Faces scale in subjects aged 6 – 11. A clinically meaningful reduction on
the NRS is defined as an absolute score reduction >/=2 points from baseline, or a relative
score reduction >/=30% from baseline; a clinically meaningful reduction on the Faces scale
is defined as an absolute reduction of one point from baseline. Results will be reported
for all subjects, and for those subjects with a baseline score >/=5 on the NRS (>/=3 on the
Faces scale).
 
Time to first confirmed clinically meaningful reduction in VOC pain from baseline. Pain
will be measured by an 11-point (0-10) NRS in subjects >/=12 years of age and a 6-point
Faces scale in subjects aged 6 – 11. A clinically meaningful reduction on the NRS is
defined as an absolute score reduction >/=2 points from baseline, or a relative score
reduction >/=30% from baseline; a clinically meaningful reduction on the Faces scale is
defined as an absolute reduction of one point from baseline. Reduction will be
considered confirmed when at least 2 consecutive pain measurements both reflect
clinically meaningful reduction. Results will be reported for all subjects and for those
subjects with a baseline score >/=5 on the NRS (>/=3 on the Faces scale).
 
Change from baseline of NRS/Faces every 4 (+/-1) hours for the first 48 hours post-loading
dose (while awake) and twice daily for all subjects and those subjects with baseline score
>/=5 on the NRS (>/=3 on the Faces scale).
 
Change from baseline in the Pain Interference index score on the Brief Pain Inventory
(BPI) at 8 hours after loading dose administration and daily.
 
Scores on the four questions in the Return to Normal Activity Questionnaire (RNAQ)
daily for up to a maximum of 10 days post-discharge.
 
Biomarkers:
 
Measures of cell adhesion: sE-selectin, sP-selectin, sL-selectin, sICAM-1,
sICAM-3, sVCAM;
 
Measures of coagulation pathway activation: Tissue Factor (TF) Total,
Thrombin-Antithrombin (TAT), D-dimer, Prothrombin Fragment 1.2 (F1.2);
 
Measures of white blood cell mobilization: WBC count, absolute neutrophil
count;
 
Measures of acute inflammation and ACS: high sensitivity C Reactive Protein
(hsCRP), Serum secretory phospholipase A2 (sPLA2).
 
Plasma concentrations of rivipansel.
 
Resource use and cost of VOC episodes as described by billing data.

 

Inclusion Criteria

Subject eligibility should be reviewed and documented by an appropriate member of the
investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the
study:
1. >/=6 years of age.
2. Documented diagnosis of sickle cell disease (HbSS, HbS-Bthalassemia [HbSB0 and
Hb SB+thalassemia], HbSC or HbS-Variant, including HbSD and HbSE).
3. Diagnosis of VOC at the time of enrollment; necessitating admission to the hospital with
treatment including IV opioids. This applies to the VOC/Treatment-Ready Screening
entry point.
4. Able to receive the first dose of study drug within 24 hours from the administration of the
first dose of IV opioids (Subjects treated as an outpatient within the past 48 hours for the
same VOC episode may be enrolled if dosing with study drug is expected within 24 hours
from the administration of the first dose of IV opioids for this admitting presentation).
5. Evidence of a personally signed and dated informed consent (and assent, where
applicable) document indicating that the subject (or a legally acceptable
representative/parent(s)/legal guardian) has been informed of all pertinent aspects of the
study. This applies to consent/assent at the time of Pre-VOC/Study Entry Screening or
VOC/Treatment-Ready Screening.
6. Subjects who are willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures.
7. Male subjects able to father children and female subjects of childbearing potential and at
risk for pregnancy must agree to use a highly effective method of contraception
throughout the duration of the active treatment period (starting at VOC/Treatment-Ready
Screening) and for at least 28 days after the last dose of assigned treatment.
Female subjects who are not of childbearing potential (ie, meet at least one of the
following criteria):
  • Have undergone a documented hysterectomy and/or bilateral oophorectomy;
  • Have medically confirmed ovarian failure;
  • Have achieved post-menopausal status, defined as cessation of regular menses for
at least 12 consecutive months with no alternative pathological or physiological
cause and a serum follicle-stimulating hormone (FSH) level confirming the
post-menopausal state. If FSH result is not available by the end of the screening
period the decision will be based on the investigator’s judgment and subject’s
medical history.

All other female subjects (including females with tubal ligations and females that do
NOT have a documented hysterectomy, bilateral oophorectomy and/or ovarian
failure) will be considered to be of childbearing potential.
 
 

Exclusion Criteria

Subjects presenting with any of the following will not be included in the study:
 
1. Serious systemic infection, evidenced by clinical signs and symptoms, and/or
microbiological investigations, consistent with this diagnosis. Subjects with fever < 39°C
(102.2°F) may be considered for enrollment if in the opinion of the investigator there is
no evidence of any serious systemic infection.
 
2. Subjects presenting with clinical risk factors of acute chest syndrome:
  • Hypoxia – defined as O2 saturation of <90% (by pulse oximetry) on room air on 2 separate readings 15 minutes apart, or single value of PaO2 <60 mmHg on arterial blood gas, 

and/or

  • Hemoglobin <5 gm/dL.
3. Acute chest syndrome, at the time of presentation, as defined by the National Institutes of
Health (NIH) treatment guidelines:24,25
 
New pulmonary infiltrate involving at least one complete lung segment consistent with
the presence of alveolar consolidation, (excluding atelectasis) AND one or more of the following: 
 
  • Chest Pain;
  • Temperature > 38.5 degrees C;
  • Tachypnea
  • Wheezing or rales;
  • Cough
4. SCD pain atypical of VOC, including hepatic or splenic sequestration, cholecystitis, or
pneumonia.
5. At the time of presentation, acute stroke or severe avascular necrosis of the hip/shoulder
when the presenting pain is only in the affected hip/shoulder.
6. Estimated glomerular filtration rate (eGFR) </=60 mL/min/1.73 m2 
7. History consistent with rapidly progressive decrease or decrement in renal function, in
the opinion of the investigator.
8. Alanine transaminase (ALT/SGPT) >3 times the upper limit of normal (X ULN) (based
on clinic laboratory normal range).
9. Platelets <50,000/mm3.
10. Recent (within the past 30 days) major surgery (see definition in Section 4.3.2),
hospitalization for reasons other than VOC, documented serious infection requiring IV
antibiotic treatment, or significant bleeding.
11. Hospitalization for uncomplicated VOC, or treatment with parenteral pain medications in
other medical settings such as the emergency department or day hospital for
uncomplicated VOC, from 48 hours to 14 days prior to admitting presentation.
  • Subjects may be included if treated as an outpatient within the past 48 hours for the same VOC episode.
12. Recent (within the past 14 days) diagnosis of cerebrovascular accident, or transient
ischemic attack.
13. Greater than 5 episodes of hospitalization for VOC in the past 6 months (180 days).
14. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality
that may increase the risk associated with study participation or study drug administration
or may interfere with the interpretation of study results and, in the judgment of the
investigator, would make the subject inappropriate for entry into this study.
15. Any condition(s) that compromises the subject’s ability to comply with and/or perform
study-related activities or that poses a clinical contraindication to study participation
(these conditions include, but are not limited to, inadequate medical history to assure
study eligibility; inadequate venous access).
16. Participation in other studies involving investigational drug(s) (Phases 1-4) within
4 weeks before the current study begins and/or during study participation.
17. Expectation that the subject will not be able to be followed for the duration of the study.
18. Pregnant female subjects; breastfeeding female subjects and male and female subjects of
childbearing potential who are unwilling or unable to use a highly effective method of
contraception as outlined in this protocol for the duration of the active treatment period
(starting at VOC/Treatment-Ready Screening) and for at least 28 days after last dose of
study drug.
19. Subjects who are investigational site staff members directly involved in the conduct of
the study and their family members, site staff members otherwise supervised by the
Investigator, or subjects who are Pfizer employees directly involved in the conduct of the
study.
20. Active use of illicit drugs and/or alcohol dependence, as determined by the investigator.
21. Male subjects able to father children and female subjects of childbearing potential who
are unwilling or unable to use a highly effective method of contraception as outlined in
this protocol for the duration of the active treatment period (starting at
VOC/Treatment-Ready Screening) and for at least 28 days after last dose of study drug.
22. Subjects who are investigational site staff members directly involved in the conduct of
the study and their family members, site staff members otherwise supervised by the
Investigator, or subjects who are Pfizer employees directly involved in the conduct of the
study.
23. Active use of illicit drugs and/or alcohol dependence, as determined by the investigator.