Context Sickle cell disease (SCD) can cause severe painful episodes that are
often thought to be caused by vaso-occlusion. The current therapy for these
uncomplicated painful episodes includes hydration, oxygen, and analgesics.
Purified poloxamer 188 may increase tissue oxygenation and thereby reduce
inflammation, pain, and the overall duration of such painful episodes in patients
with SCD.
Objective To compare the duration of painful episodes in patients with SCD treated
with purified poloxamer 188 to that of similar episodes experienced by patients
who receive a placebo.
Design and Setting Randomized, double-blind, placebo-controlled, intention-to-treat trial
conducted between March 1998 and October 1999 in 40 medical centers in the
United States.
Participants Two hundred fifty-five patients with SCD (aged 9-53 years) who had a
painful episode sufficiently severe to require hospitalization and narcotic
analgesics.
Intervention Patients were randomly assigned to receive an intravenous infusion of
purified poloxamer 188, 100 mg/kg for 1 hour followed by 30 mg/kg per hour
for 47 hours (n = 127), or a matching volume of saline placebo (n = 128).
Main Outcome Measure Duration of the painful episode, from randomization to crisis resolution.
Results Mean (SD) duration of the painful episodes was 141 (42) hours in the
placebo group compared with 133 (41) hours in those treated with purified
poloxamer 188, a 9-hour reduction (P = .04). Subset
analyses indicated an even more pronounced purified poloxamer 188 effect in
children aged 15 years or younger (21 hours; P =
.01) and in patients who were receiving hydroxyurea (16 hours; P = .02). Finally, the proportion of patients achieving crisis resolution
was increased by purified poloxamer 188 (65/126 [52%] vs 45/123 [37%]; P = .02). Similar results were observed in children aged
15 years or younger (22/37 [60%] vs 10/36 [28%]; P
= .009) and in patients who were also receiving hydroxyurea (12/26 [46%] vs
4/28 [14%]; P = .02).
Conclusions A decrease in the duration of painful episodes and an increase in the
proportion of patients who achieved resolution of the symptoms were observed
when the purified poloxamer 188–treated patients were compared with
the patients receiving placebo. However, the difference between these groups
was significant but relatively small. In subgroup analysis, a more significant
effect on both parameters was observed in children and in patients who were
receiving concomitant hydroxyurea. It is important to confirm both of these
observations in further prospective trials.
Sickle cell disease (SCD) refers to homozygous sickle cell anemia (SS)
as well as mixed heterozygous states, such as SC, SD, and S-β thalassemia.
This entire group of genetic illnesses is characterized by a variety of vaso-occlusive
complications, the most common of which is the acute painful episode, or vaso-occlusive
crisis.
It has been estimated that approximately 90% of hospital admissions
among patients with SCD are for treatment of acute pain.1
Current treatment of an uncomplicated painful crisis includes analgesics,
oxygen, and gentle hydration.2-4
It is generally accepted that the painful episodes and organ damage associated
with SCD are caused by microvascular occlusion and tissue ischemia resulting
from complex interactions among the sickle erythrocytes, endothelium and subendothelial
matrix proteins, platelets, plasma clotting factors, and certain inflammatory
mediators.5-10
Accordingly, an agent that alters these interactions and restores blood flow
is likely to be beneficial.
Purified poloxamer 188 (PP188) is a nonionic block copolymer surfactant
with hemorheologic and antithrombotic properties. Purified poloxamer 188 improves
microvascular blood flow by reducing blood viscosity, especially in low shear
conditions, and by reducing adhesive frictional forces. The mechanism of action
of PP188 is not fully understood, but it is hypothesized that the polyoxypropylene
core of the molecule binds to hydrophobic portions of cells, leaving the hydrophilic
polyoxyethylene chains free to interact with the surrounding aqueous environment.11,12 Consequently, PP188 provides a hydrated,
relatively noncompressible barrier that appears to block hydrophobic adhesive
interactions (eg, cell-cell, cell-protein, protein-protein) in the blood.
As a result, there is a reduction in whole blood viscosity, erythrocyte aggregation,
and adhesion to the vascular endothelium under both static and flow conditions13,14 and an improvement in microvascular
blood flow.15-18
Purified poloxamer 188 has been studied in more than 300 patients with SCD.
Tolerability and pilot efficacy studies have been completed in patients experiencing
a painful crisis19 and in patients with acute
chest syndrome.20 Purified poloxamer 188 has
been shown to be safe and well tolerated at doses as high as 200 mg/kg as
a 1-hour bolus infusion followed by 120 mg/kg per hour as a continuous infusion
for an additional 23 hours.21
We hypothesized that an agent with the properties of PP188 would increase
tissue oxygenation, reduce inflammation and pain, and thereby shorten the
overall duration of the painful episode. We therefore conducted a randomized,
placebo-controlled, double-blind study of PP188 in patients with SCD.22
Between March 1998 and October 1999, 255 patients with SCD were enrolled
in the study at 40 different medical centers in the United States. Patients
were enrolled in the study within 12 hours of presentation to the hospital
if they satisfied the inclusion and exclusion criteria (Table 1). Each patient remained in the study until a final follow-up
visit that occurred between days 28 and 35. The study received approval from
the institutional review board at each medical center, and all patients provided
written informed consent after the details of the study had been carefully
presented.
The study was a randomized, multicenter, double-blind, placebo-controlled
phase 3 study designed to assess the efficacy of PP188 in reducing the duration
of painful episodes in patients with SCD. Patients were randomized at a 1:1
ratio to receive either PP188 or placebo. Patients randomized to active therapy
were given PP188 as a loading dose of 100 mg/kg for 1 hour followed by a maintenance
dose of 30 mg/kg per hour for 47 hours. The selection of this dosage was based
on a previous successful pilot study of PP188.19
Patients randomized to the placebo arm received a saline solution delivered
at a volume and duration identical to that of the active drug. Parenteral
analgesics were given intramuscularly or intravenously. Nonsteroidal anti-inflammatory
drug use was not allowed during infusion of the study drug or for 12 hours
following its discontinuation. Concurrent therapy with hydroxyurea was allowed.
Parenteral analgesic use was limited to morphine, hydromorphone, and meperidine.
Oral analgesic use was restricted to codeine, morphine, hydromorphone, oxycodone,
acetaminophen, and appropriate combinations of each. One intravenous line
was reserved exclusively for infusion of the study drug (ie, PP188 or placebo),
and no other medications (eg, analgesics, antiemetics, antibiotics) were given
through this line.
Visual analog scale (VAS) pain assessments were obtained every 4 hours
during treatment and through resolution of crisis or 5 days after infusion,
whichever occurred first. This VAS scale (range, 0-100, with higher scores
indicating more pain) has been used effectively and validated in SCD.23-25 Patient safety was
also assessed throughout the study. Blood was collected from patients for
pharmacokinetic assessments at baseline and 24, 48, 51, 54, and 60 hours after
initiation of study drug infusion. Follow-up safety assessments were conducted
between days 7 and 14 and days 28 and 35 after discontinuation of study drug
infusion.
The primary end point of the study was duration of the painful episode.
Secondary end points included proportion of patients achieving crisis resolution,
time to discharge, VAS pain assessment area under the curve, and analgesic
consumption (oral, parenteral, and total). Pharmacoeconomic data were also
collected. The duration of each crisis was measured from randomization until
all of the following had been simultaneously achieved: (1) pain relief (pain
scores ≤40 maintained during 2 consecutive readings obtained 4 hours apart);
(2) freedom from parenteral analgesic use (no parenteral analgesic use in
preceding 12 hours); (3) ability to walk without difficulty (unless the patient
was not able to walk for any reason other than acute vaso-occlusive crisis
prior to onset of crisis); and (4) patient's belief that the painful episode
was over (defined as readiness for discharge with or without oral analgesic
use). Specific covariates that were identified a priori included investigational
site, age, sex, genotype, and concurrent use of hydroxyurea.
The study was powered to detect a 25% (26-hour) reduction in the duration
of crisis with 80% power at α = .05 based on a mean crisis duration
for the control group of 103 hours and a pooled SD of 60 hours based on the
earlier pilot study.19 In addition, the following
clinical parameters were evaluated: duration and intensity of pain, total
analgesic use, length of hospitalization, and pharmacoeconomic impact. Safety
monitoring included assessment of adverse events, disease-related events,
clinical laboratory test results, vital signs, and physical examinations.
Finally, all aspects of the study were carefully monitored by an independent
data and safety monitoring board composed of nationally recognized experts
in the fields of SCD, nephrology, hepatology, and statistics.
Using simple descriptive statistics, the groups were compared at baseline
with respect to demographic and other clinical variables (Table 2 and Table 3).
No substantial differences among the groups were identified for any of these
parameters, and the modest differences observed were simply a consequence
of the finite sizes of the 2 groups as well as the overall randomization process
itself.
When duration of crisis was defined using the worst possible score algorithm,
differences between treatments were analyzed using the Wilcoxon rank sum test.
When duration of crisis was defined as a censored time-to-event variable,
differences between treatments in the distribution of time to event were estimated
using the Kaplan-Meier method and analyzed using the log-rank test. Differences
between treatments in the reduction of pain intensity were tested using the
Wilcoxon rank sum test. The proportion of patients achieving crisis resolution,
the proportion of patients with adverse events, markedly abnormal laboratory
values, and markedly abnormal vital sign measurements were evaluated using
the Fisher exact test.
All inferential analyses that were performed and reported herein include
testing of (1) a priori hypotheses regarding the primary end point (crisis
duration); (2) exploratory analyses of other end points that were also identified
a priori (eg, the various secondary efficacy end points and the subgroup analyses
involving children (aged ≤15 years) and patients receiving concomitant
hydroxyurea); and (3) the supportive post hoc test and analysis presented
in Table 4, ie, the proportion
of patients achieving crisis resolution within 168 hours.
Two interim analyses were conducted for the data and safety monitoring
board. The first was a safety assessment after enrollment of 50 patients.
The second was a complete safety and efficacy analysis after enrollment of
112 patients. Since the multiple tests associated with such interim analyses
are known to affect the overall type I error rate, the protocol specified
a statistically appropriate sequential monitoring procedure that maintained
the overall significance level at .05 for the tests of efficacy. The sequential
monitoring procedure used was that of Lan and DeMets using the O'Brien and
Fleming spending functions.26 Specifically,
by setting the P value needed to achieve statistical
significance of efficacy at the time of the interim analysis at .0035, the P value required for statistical significance of efficacy
at the time of the final analysis decreased from .05 to .0488. The P values for tests of safety were not adjusted. Statistical analyses
were carried out using SAS/STAT (SAS Institute Inc, Cary, NC).
All reported adverse events were converted to preferred terms using
a modified COSTART (Coding Symbols for a Thesaurus of Adverse Reaction Terms)
translation dictionary,27 which allowed standard
terms, categorized into body systems, to be used for all similar events regardless
of the terms used by the investigator. For purposes of summarization by preferred
term, a patient was only counted once regardless of the number of occurrences
of the preferred term. Similarly, for body system totals, a patient was only
counted once regardless of the number of preferred terms reported in that
body system.
Patients were randomized 1:1 to each treatment group by a central procedure
using the dynamic randomization method of Pocock and Simon,28
stratifying by site, genotype, and use of hydroxyurea. This approach ensured
balance across sites for genotype and hydroxyurea use. The treatment assignment
was used to select a treatment kit of the appropriate type that was known
to be available on site, and the package number on that kit was given to the
investigator and the site pharmacist. The package numbers had been randomly
generated to prevent detection of a pattern that might indicate contents.
Numbered kits containing eleven 100-mL vials were provided to each site. The
vials in each kit were numbered using a double-panel tear-off label. After
assignment of a kit number, the pharmacist prepared the infusion bottles and
covered each with aluminum foil to minimize the possibility of treatment identification.
These bottles were labeled 1, 2, or 3 for loading infusion, day 1 maintenance
infusion, and day 2 maintenance infusion, respectively.
Of the 255 patients enrolled, 127 were randomized to PP188 and 128 to
placebo. Six of the patients who had been randomized (1 to PP188 and 5 to
placebo) did not receive the study drug (Figure 1). The 2 treatment groups were similar in terms of sex,
race, age, weight, number of pain locations, baseline VAS pain score, current
use of hydroxyurea, and genotype distribution (Table 2). The groups were also comparable with regard to time from
onset of pain to randomization, time from hospital presentation to randomization,
time from randomization to start of infusion, and duration of infusion (Table 3).
The primary end point of this study was the total duration (in hours)
of each individual painful episode or crisis, measured from randomization
to achievement of the criteria for crisis resolution. The duration of each
episode was analyzed in 2 different ways. The first analysis, on which the
study results are based, assigned the worst possible outcome score for length
of crisis (168 hours) to patients who did not achieve resolution of the crisis
within 168 hours of randomization or for whom documentation of crisis resolution
was not available. For patients who met the resolution criteria, the total
duration was calculated as number of hours elapsed from randomization to crisis
resolution. These data were evaluated primarily using the Wilcoxon rank sum
test. The results are presented in Table
5. When all randomized patients (n = 255) were assessed, the 9-hour
difference was statistically significant (P = .04).
However, when only the treated patients were evaluated (n = 249), the results
were no longer statistically significant (P = .07).
In the subset evaluation of patients receiving concurrent hydroxyurea (n =
54), a 16-hour decrease in duration of crisis was observed, which was significant
(P = .02). In children, the observed 21-hour decrease
in crisis duration reached even greater statistical significance (P = .01).
The second approach assigned a duration of crisis to patients who met
the criteria for crisis resolution as hours from randomization to achievement
of resolution. For patients who were discharged prior to 168 hours without
crisis resolution, duration was calculated from randomization to hospital
discharge. For patients discharged at more than 168 hours after randomization,
duration of crisis was treated as a censored value. The data were analyzed
in a time-to-event manner using the Kaplan-Meier log-rank method, and the
results are presented in Figure 2.
In this group, the differences failed to achieve statistical significance
(P = .09). When the 2 subgroups were assessed by
the latter method, the rate of crisis resolution in the patients receiving
hydroxyurea was significant (P = .01), as were the
responses for children (P = .007).
In PP188-treated patients, 65 (52%) of 126 achieved crisis resolution
per the protocol definition compared with 45 (37%) of the 123 placebo-treated
patients. This difference was statistically significant (P = .02). For patients receiving concurrent hydroxyurea, 12 (46.1%)
of 26 treated with PP188 achieved crisis resolution. This was also significantly
higher than the 4 (14.3%) of 12 placebo-treated patients (P = .02). Finally, the proportion of children who achieved crisis resolution
was markedly higher in the PP188-treated group (22 [59.5%] of 37) than in
those who received placebo (10 [27.8%] of 36; P =
.009).
The secondary efficacy end points of time to discharge, pain, total
analgesic use, and pharmacoeconomic costs were not statistically different
between the 2 treatment groups (Table 6). The occurrences of secondary complications of SCD such as acute
chest syndrome (PP188 group, 12/126 vs placebo group, 11/123; P = .82) and recurrent vaso-occlusive crisis (PP188 group, 32/126 vs
placebo group, 36/123; P = .72) during the study
period (35 days) were not significantly different between the groups. For
both children and hydroxyurea-treated patients receiving PP188, the incidence
of acute chest syndrome during hospitalization was somewhat lower (PP188 group,
3/37 and 0/26 vs placebo group, 6/36 and 3/28 for children and hydroxyurea-treated
patients, respectively). However, these results were not statistically significant
(P = .31 and .24, respectively).
Blood samples for PP188 pharmacokinetics were collected from 167 patients
enrolled in the study. Of these, 81 patients were treated with PP188 and 86
received placebo. The number of blood samples that could be obtained was severely
restricted by poor venous access. The mean (SD) PP188 concentration at steady
state was 420 (420) µg/mL between 28 and 48 hours. These concentrations
are within the expected therapeutic range for the rheological and antiadhesive
effects of PP188.24,25
Of the 255 patients enrolled, 249 patients were actually treated. There
were no differences between the 2 treatment groups in the overall incidence
of adverse events, for adverse events defined as serious, or for adverse events
involving any body system for the groups as a whole. There was no evidence
of increased risk of bleeding during PP188 treatment. There was 1 death due
to pulmonary fat embolism in a patient in the PP188 group; the patient had
not received study drug infusion for 3 days prior to death. The underlying
cause of death was judged by the investigator to be SCD and not study drug
treatment.
Renal function was not influenced by PP188 treatment. However, the group
randomized to PP188 did exhibit a modest but statistically significant increase
in levels of alanine aminotransferase and direct bilirubin, each of which
returned to its respective baseline level by the 35-day follow-up visit.
Painful episodes are the most common medical complication of SCD. Patients
experiencing such episodes frequently require hospitalization for adequate
management. The course of these crises can be further complicated by life-threatening
conditions such as acute chest syndrome. The 2 primary approaches to the management
of sickle cell crisis are prevention and intervention. Hydroxyurea, the only
preventive agent approved by the US Food and Drug Administration for this
specific indication, has been shown to decrease the severity of SCD by reducing
the frequency of acute painful episodes.29-31
Another modality, bone marrow transplantation, can cure SCD. However, transplantation
is limited in SCD by a lack of HLA-matched donors and by a 9% mortality rate.32,33
Although hydroxyurea was found to be effective in reducing the frequency
of painful episodes in adults with SCD, it is not useful as a treatment for
patients who are experiencing an acute painful episode. During the past 25
years, a number of pharmacological agents (eg, cetiedil citrate, urea sodium,
cyanate) have been evaluated as potential intervention strategies that might
be capable of shortening or reducing the severity of painful episodes. However,
each of these therapies was found to be either too toxic or only marginally
effective.34-37
In a more recent study, Griffin et al38 observed
that treatment with methylprednisolone significantly shortened the duration
of acute painful episodes in children with SCD. However, the overall effectiveness
of methylprednisolone was limited by a rebound in pain that occurred soon
after the drug had been discontinued. It is important to emphasize that studies
with preventive agents such as hydroxyurea involve end points that are relatively
easy to quantify (eg, number of emergency department visits, number of hospitalizations).
In contrast, all of the studies involving interventional agents, including
this study, used end points, such as crisis duration, that inevitably rely
on subjective pain severity assessments rather than on the much more easily
quantifiable end points that are used in studies with preventive agents.
This report represents the first large-scale, rigorously controlled,
multicenter, double-blind acute intervention study conducted in both children
and adults with SCD. In this study, PP188 was found to be safe and well tolerated
and demonstrated a modest treatment benefit in patients with SCD. The beneficial
effects of PP188 were especially apparent in children and in those receiving
concurrent hydroxyurea therapy. In these 2 subsets, PP188 reduced the overall
duration of the crisis by 21 hours and 16 hours, respectively, and the proportion
of patients achieving crisis resolution within 168 hours was increased by
30% and 32%, respectively.
It is important to emphasize that in an earlier phase 2 study, even
greater benefits with PP188 had been observed.19
This disparity may be explained at least in part by the assumptions used in
our definition of crisis duration, the primary end point in this study. Specifically,
we observed that fewer patients achieved crisis resolution within 168 hours
than patients in the earlier pilot study had led us to anticipate.19 The current study used a very stringent definition
of crisis resolution, one that required repeated assessments of pain throughout
the entire hospitalization, including the period following discontinuation
of parenteral analgesics. In a number of instances, patients were discharged
from the hospital before pain relief had been confirmed by a second pain assessment.
In still other instances, study patients were discharged before the criteria
for crisis resolution had been met. In either case, the analysis plan required
that these patients be considered as treatment failures and that the worst-case
duration of crisis (ie, 168 hours) be imputed for them.
Use of an extremely stringent definition of crisis resolution represented
a very conservative approach to the analysis of the data. Because the proportion
of patients achieving crisis resolution within 168 hours was lower than anticipated,
the ability of this study to detect differences in the length of crisis was
correspondingly smaller than expected.39 The
work reported here also differed from the earlier phase 2 study in that treatment
assignment was made according to the stratified dynamic randomization method
of Pocock and Simon.28 For these reasons, the
statistical analysis methods used in this study were conservative. While less
conservative methods might have shown substantially greater differences between
the study populations, such an analysis plan would have required taking into
account the use of the randomization method.
Nevertheless, the decrease in the duration of vaso-occlusive crisis
and increase in the proportion of patients able to achieve crisis resolution,
particularly in children, are very encouraging. It is possible that children
exhibit a better response to PP188 because they have less overall tissue and
organ damage due to previous crises and experience less chronic pain, thereby
making more evident the rheologic and anti-inflammatory effects of PP188.
A beneficial effect was also observed in patients who received hydroxyurea
along with PP188. This could be due to a cooperative or even a synergistic
effect between these 2 agents, one that might be a result of decreased adhesion
of sickle erythrocytes to the microvascular endothelium or to some other less
well-defined mechanism. Future studies of PP188 in sickle cell crisis would
be useful to confirm the efficacy observed in children and to determine the
nature of the interaction between PP188 and hydroxyurea.
1.Ballas SK. Sickle Cell Pain: Progress in Pain Research and Management,
Volume 11. Seattle, Wash: IASP Press; 1998:51-89.
2.Shapiro BS, Ballas SK. The acute painful episode. In: Embury SH, Hebbel RP, Mohandas N, Steinberg MG, eds. Sickle Cell Disease: Basic Principles and Clinical Practice. New York,
NY: Raven Press; 1994:531-543.
3.Ballas SK. Sickle Cell Pain: Progress in Pain Research and Management,
Volume 11. Seattle, Wash: IASP Press; 1998:201-254.
4.Benjamin LJ, Dampier CD, Jacox A.
et al. Guideline for the Management of Acute and Chronic
Pain in Sickle Cell Disease. Glenview, Ill: American Pain Society; 1999. APS Clinical Practice
Guidelines Series, No. 1.
5.Hebbel RP, Boogaerts MA, Eaton JW, Steinberg MH. Erythrocyte adherence to endothelium in sickle cell anemia: a possible
determinant of disease severity.
N Engl J Med.1980;302:992-995.Google Scholar 6.Sugihara K, Sugihara T, Mohandas N, Hebbel RP. Thrombospondin mediates adherence of CD36
+ sickle reticulocytes
to endothelial cells.
Blood.1992;80:2634-2642.Google Scholar 7.Wick TM, Moake JL, Udden MM, McIntire LV. Unusually large von Willebrand factor multimers preferentially promote
young sickle and non-sickle erythrocyte adhesion to endothelial cells.
Am J Hematol.1993;42:284-292.Google Scholar 8.Swerlick RA, Eckman JR, Kumar A, Jeitler M, Wick TM. α4β1-Integrin expression on sickle reticulocytes: vascular
cell adhesion molecule-1-dependent binding to endothelium.
Blood.1993;82:1891-1899.Google Scholar 9.Gee BE, Platt OS. Sickle reticulocytes adhere to VCAM-1.
Blood.1995;85:268-274.Google Scholar 10.Joneckis CC, Ackley RL, Orringer EP, Wayner EA, Parise LV. Integrin α4β1 and glycoprotein IV (CD36) are expressed on
circulating reticulocytes in sickle cell anemia.
Blood.1993;82:3548-3555.Google Scholar 11.Carr ME, Powers PL, Jones MR. Effects of poloxamer 188 on the assembly, structure and dissolution
of fibrin clots.
Thromb Haemost.1991;66:565-568.Google Scholar 12.Carter C, Fisher TC, Hamai H.
et al. Haemorheological effects of a nonionic copolymer surfactant (poloxamer
188).
Clin Hemorheol.1992;12:109-120.Google Scholar 13.Smith CM, Hebbel RP, Tukey DP, Clawson CC, White JG, Vercellotti GM. Pluronic F-68 reduces the endothelial adherence and improves the rheology
of liganded sickle erythrocytes.
Blood.1987;69:1631-1636.Google Scholar 14.Hsu LL, Liu XW, Pierangeli S.
et al. Microcirculatory effects of blocking cell adhesion molecules in transgenic
sickle cell mice [abstract].
Blood.2000;96:528a.Google Scholar 15.McKenna R, Cole E, MacLeod C, Emanuele M, Hunter R. The effects of RheothRx on platelet function and coagulation in man
[abstract].
Blood.1989;74:411a.Google Scholar 16.Grover FL, Kahn RS, Heron MW, Paton BC. A nonionic surfactant and blood viscosity.
Arch Surg.1973;106:307-310.Google Scholar 17.Toth K, Bogar L, Juricskay I.
et al. The effect of RheothRx injection on the hemorheological parameters
in patients with acute myocardial infarction.
Clin Hemorheol Microcirc.1997;17:117-125.Google Scholar 18.Armstrong JK, Meiselman HJ, Fisher TC. Inhibition of red blood cell-induced platelet aggregation in whole
blood by a nonionic surfactant, poloxamer 188 (RheothRx injection).
Thromb Res.1995;79:437-450.Google Scholar 19.Adams-Graves P, Kedar A, Koshy M.
et al. RheothRx (poloxamer 188) injection for the acute painful episode of
sickle cell disease: a pilot study.
Blood.1997;90:2041-2046.Google Scholar 20.Files BA, Ballas SK, Benjamin LJ, Wojtowicz-Praga S, Grindel JM. Multicenter trial of FLOCOR in patients with sickle cell disease and
acute chest syndrome [abstract].
Blood.1998;92:30b.Google Scholar 21.Luchtman-Jones L, Files B, Ballas SK.
et al. Phase I study of FLOCOR in patients with acute chest syndrome of sickle
cell disease [abstract].
Blood.1999;94:25b.Google Scholar 22.Casella JF, Wojtowicz-Praga S, Grindel JM. A phase III, multicenter, randomized, double-blind, placebo-controlled
study of FLOCOR (purified poloxamer 188) in patients with sickle cell disease
in acute vaso-occlusive crisis. Presented at: 24th annual meeting of the National Sickle Cell Disease
Program; April 12, 2000; Philadelphia, Pa.
23.Gonzalez ER, Bahal N, Hansen LA.
et al. Intermittent injection vs patient-controlled analgesia for sickle cell
crisis pain: comparison in patients in the emergency department.
Arch Intern Med.1991;151:1373-1378.Google Scholar 24.Ballas SK, Delengowski A. Pain measurement in hospitalized adults with sickle cell painful episodes.
Ann Clin Lab Sci.1993;23:358-361.Google Scholar 25.Hardwick WE, Givens TG, Monroe KW, King WD, Lawley D. Effect of ketorolac in pediatric sickle cell vaso-occlusive pain crisis.
Pediatr Emerg Care.1999;15:179-182.Google Scholar 26.Fleming TR, Harrington DP, O'Brien PC. Designs for group sequential tests.
Control Clin Trials.1984;5:348-361.Google Scholar 27.Spilker B. Multinational Drug Companies: Issues in Drug Discovery
and Development. New York, NY: Raven Press; 1989:361-397.
28.Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors
in the controlled clinical trial.
Biometrics.1975;31:103-115.Google Scholar 29.Charache S, Dover GJ, Moore RD.
et al. Hydroxyurea effects on hemoglobin F production in patients with sickle
cell anemia.
Blood.1992;79:2555-2565.Google Scholar 30.Ballas SK, Dover GJ, Charache S. Effects of hydroxyurea on the rheological properties of sickle erythrocytes
in vivo.
Am J Hematol.1989;32:104-111.Google Scholar 31.Charache S, Terrin ML, Moore RD.
et al. Multicenter study of hydroxyurea in sickle cell anemia: effect of hydroxyurea
on the frequency of painful crises in sickle cell anemia.
N Engl J Med.1995;332:1317-1322.Google Scholar 32.Walters MC, Patience M, Leisenring W.
et al. Bone marrow transplantation for sickle cell disease.
N Engl J Med.1996;335:369-376.Google Scholar 33.Platt OS, Guinan EC. Bone marrow transplantation in sickle cell anemia—the dilemma
of choice.
N Engl J Med.1996;335:426-428.Google Scholar 34.Benjamin LJ, Berkowitz LR, Orringer E.
et al. A collaborative, double-blind, randomized study of cetiedil citrate
in sickle cell crisis.
Blood.1986;67:1442-1447.Google Scholar 35.Cooperative Urea Trials Group. Clinical trials of therapy for sickle cell vaso-occlusive crises.
JAMA.1974;228:1120-1124.Google Scholar 36.Harkness DR, Roth S. Clinical evaluation of cyanate in sickle cell anemia.
Prog Hematol.1975;9:157-184.Google Scholar 37.Peterson CM, Tsairis P, Ohnishi A, Lu YS, Grady R. Sodium cyanate induced polyneuropathy in patients with sickle cell
disease.
Ann Intern Med.1974;81:152-158.Google Scholar 38.Griffin TC, McIntire D, Buchanan GR. High-dose intravenous methylprednisolone therapy for pain in children
and adolescents with sickle cell disease.
N Engl J Med.1994;330:733-737.Google Scholar 39.Lee ET. Statistical Methods for Survival Data Analysis. Belmont, Calif: Lifetime Learning Publications; 1980:366-391.