(Stroke. 2000;31:1234.)
© 2000 American Heart Association, Inc.
Original Contributions |
Cervene (Nalmefene) in Acute Ischemic Stroke
Final Results of a Phase III Efficacy Study
From the Oregon Stroke Center (W.M.C.), Portland, Ore; Stanford Stroke Center (D.C.T.), Palo Alto, Calif; and Louisiana State University Medical Center (R.E.K.), Shreveport, La.
Correspondence to Wayne M. Clark, MD, Oregon Stroke Center, UHS 44, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd, Portland, OR 97201. E-mail clarkw{at}ohsu.edu
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionAppendix CERVENEReferences |
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Background and Purpose—The goals of the present study were to assess the efficacy and safety of nalmefene (Cervene) in patients with acute (
6 hours) ischemic
stroke and to investigate the safety of combined recombinant tissue
plasminogen activator and nalmefene in a
separate subset of patients. Nalmefene, an opioid
antagonist with relative 
receptor selectivity, has
shown neuroprotective effects in multiple experimental central nervous
system injury and ischemic models. Results from an earlier
phase II study in patients with acute ischemic stroke suggested
that nalmefene was safe and tolerable and may be effective for patients
<70 years old.
Methods—This investigation was a phase III, placebo-controlled,
double-blind, randomized study of a 24-hour infusion of nalmefene.
Patients with acute ischemic stroke who had an onset of
symptoms within 6 hours and a baseline score of 
4 on the NIH Stroke
Scale were randomized to receive either 60 mg nalmefene administered as
a 10-mg bolus over 15 minutes and then a 50-mg infusion over 23.75
hours or placebo. The primary efficacy outcome was the proportion of
patients achieving a score of 60 on the Barthel Index and a rating of
"moderate disability" or better on the Glasgow Outcome Scale
at 12 weeks. Assessments were performed at baseline (predose), hours 12
and 24, days 2 and 7, and week 12.
Results—A total of 368 patients were randomized at 42 centers, including 32 patients treated with recombinant tissue plasminogen activator and study drug. Nalmefene was well tolerated. Overall, there was no significant difference in 3-month functional outcome for nalmefene treatment compared with placebo on any of the planned analyses. A prospective secondary analysis also failed to find a treatment effect in patients <70 years old.
Conclusions—Although nalmefene appears to be safe and well tolerated, this study failed to find any treatment benefit in stroke patients treated within 6 hours.
Key Words: narcotic antagonists • stroke • therapy
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix CERVENEReferences |
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During central nervous system (CNS) ischemia, the levels of many excitatory neurotransmitters, including excitatory amino acids and endogenous opiates, become elevated.1 2 These increased levels of neurotransmitters overstimulate their respective receptors (N-methyl-D-aspartate [NMDA],
),
which potentiates secondary tissue injury after CNS
ischemia.2 3 4 The therapeutic potential of
NMDA receptor antagonists and agents that decrease
extracellular glutamate has been extensively studied in multicenter
clinical efficacy trials.5 6 7 However, significant CNS
side effects associated with the use of these agents may limit their
widespread clinical application.8 9 10 Another type of
excitatory neurotransmitters, the endogenous opioids, also
appear to play a pathophysiological role in
secondary tissue injury after CNS ischemia.11
Through its actions primarily at the receptor, one of the
endogenous opioids, dynorphin, appears to be important in
the potentiation of CNS ischemia. Studies have found that the
receptor is upregulated after CNS injury,12 that
high doses of dynorphin potentiate traumatic CNS injury,13
that dynorphin immunoreactivity increases at CNS injury
sites,14 and that -opioid receptors have been
demonstrated to increase 1 hour after experimental embolic
stroke.15 The opiate receptor antagonist
naloxone has been extensively studied and has reduced
physiological, histological, and
behavioral changes after focal or global ischemia in many
experimental models.16 17 18 However, several small
double-blind placebo-controlled trials using naloxone for clinical
stroke treatment have produced disappointing results.19 20
The failure of naloxone to demonstrate clinically meaningful
neuroprotection was theorized to be due to the relative nonspecificity
of naloxone for the receptors.
Nalmefene hydrochloride (Cervene) is a relatively pure receptor
opiate antagonist.21 Compared with naloxone,
nalmefene has a substantially longer half-life (8.6 hours) and a
28-fold higher binding affinity for
receptors.22
Nalmefene treatment has been shown to reduce spinal cord ischemia injury23 and has been shown to improve metabolic recovery and limit reperfusion injury after global ischemia in rats.24 In addition, nalmefene has been shown to stereospecifically inhibit glutamate release after global experimental cerebral ischemia25 and to improve the cellular bioenergetic state in traumatic brain injury.26
Nalmefene has previously been tested in 2 randomized trials in the United States. A previous phase IIa stroke trial found that nalmefene (0.1 mg/kg) administered as a bolus infusion followed by a 24-hour infusion starting within 6 hours of symptom onset in patients with acute ischemic cerebral infarction was well tolerated and may have improved 3-month outcomes.27 A larger phase IIb dose-comparison trial found that nalmefene was well tolerated in acute stroke patients up to 60 mg. Although no overall treatment effects were seen, subgroup analysis suggested that nalmefene may be beneficial in patients <70 years old.28
The objectives of the present phase III study were to assess the safety and efficacy of 60 mg nalmefene versus placebo in patients with acute (<6 hours) ischemic stroke.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix CERVENEReferences |
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This was a randomized, double-blind, multicenter, placebo-controlled clinical trial. Patients were randomized 1:1 and treated for 24 hours with either 60 mg nalmefene or placebo within 6 hours of an ischemic stroke. Patients received a bolus dose (50 mL/10 mg) of either nalmefene or placebo (normal saline) during 15 minutes, followed by a 24-hour maintenance infusion (500 mL/50 mg). The 60-mg dose was chosen on the basis of results of the prior dose-finding study,28 in which the 60-mg dose was determined to be safe and appeared to have the greatest potential for efficacy. The objectives of this phase III trial were to assess the efficacy and safety of nalmefene in patients with acute ischemic stroke. The primary efficacy outcome variable was the percentage of patients at 3 months with a Barthel Index (BI)29 of
60 and a moderate disability or better score
on the Glasgow Outcome Score30 (BI+GOS) in the
intent-to-treat (ITT) population. The "success rate" for each group
was the percentage of patients who met these criteria. These functional
end points have been used in other neuroprotective efficacy stroke
trials.8 Secondary planned efficacy outcome measures were
the National Institutes of Health Stroke Scale (NIHSS)31
total score at 3 months; NIHSS success rate (a decrease of 4 points
from baseline) at 3 months, and success rates for BI at 3 months, GOS
at 3 months, and combined BI+GOS at 3 months by patient age (< or 70
years). Sample size was determined with a pooled estimate of the primary efficacy variable from the prior studies (nalmefene 70%, placebo 55%).27 28 With these estimates in a 2-tailed test of equal proportions with a type I error rate of 5% and a power of 80%, the calculated number of patients was 165 per group.
The study was stratified according to whether patients had received recombinant tissue plasminogen activator (rtPA). When rtPA was administered, the patient must have received it within 3 hours to also be eligible for this study. For the purpose of efficacy evaluations, these patients were considered as a separate study population and were excluded from the ITT population.
All personnel at each study site and at Baker Norton who were involved in conducting and monitoring the trial were blinded to the study drug codes. Nalmefene was supplied in 5-mL vials identical in appearance to the placebo (normal saline 5-mL vials). All NIHSS examiners were certified according to NIH guidelines with use of a standard training video tape.32 The blinded members of an independent data safety monitoring board reviewed the adverse experiences in each treatment group on an ongoing basis.
All patients or their legal representatives signed an informed consent approved by the institutional review board of each study site. To be included in the study, patients had to be at least 21 years old with a diagnosis of acute ischemic stroke and an onset of symptoms within 6 hours before dosing. Stroke onset for patients who awoke with symptoms of a stroke was defined as the time when they were last known to be normal. A CT scan that excluded cerebral or subdural hematoma and subarachnoid hemorrhage was requested before randomization, and patients had to be awake or arousable to moderate stimulation.
Patients were excluded if the CT scan was inconsistent with an ischemic stroke, if they had a previous stroke with significant residual paresis on the same side as the current stroke, if they had a seizure between the onset of stroke symptoms and initial dose of study drug, or if they had concurrent life-threatening cardiac illnesses.
Patients with baseline systolic blood pressure <90 mm Hg or baseline diastolic blood pressure >120 mm Hg were excluded. Patients were also excluded if they were known to have hypersensitivity to narcotics or opiate antagonists or if they were currently taking narcotic analgesics on a daily basis. Finally, patients were also excluded if they had any unstable medical condition that the investigator thought would interfere with the conduct of the study.
Patients were monitored closely for the development of any neurological symptoms. An NIHSS and a BI were completed by certified investigators at baseline; 12, 24, 48, and 96 hours; 7 days; and 3 months after the initiation of study drug, and a GOS assessment was performed at days 1 and 7, weeks 4 and 8, and 3 months. Vital signs were obtained hourly for the first 6 hours and every 2 hours for the duration of the study infusion, and then the frequency varied depending on the standard of care for the stroke patient at each institution. General physical examinations were performed before treatment, at 24 and 48 hours, and on day 3 or the day of hospital discharge.
Trial design and data management and analysis were conducted by the sponsor, Baker Norton Pharmaceuticals. STATPROBE Inc contracted with Baker Norton to provide data management, programming, and statistical services for the study. The investigators did not participate in trial methodology planning or statistical analyses. The investigators were able to produce an independent interpretation of the results provided to them by the company in the preparation of the manuscript with the final report reviewed by the company. The primary efficacy assessment was based on an ITT population. The ITT population was defined as all randomized patients who completed the 15-minute initial bolus except those diagnosed initially with a hemorrhagic stroke and patients treated with rtPA. The number of patients responding to drug as determined with success rates was analyzed with the Mantel-Haenszel correlation statistic. The Cochran-Mantel-Haenszel procedure was used to test for a difference in response rates between the placebo group and the nalmefene group. The BI and NIHSS total scores at baseline and at follow-up evaluations were summarized with the use of descriptive statistics (mean, standard, interquartile range, and minimum-maximum). For the differences in NIHSS total scores from baseline to follow-up evaluations, the nalmefene treatment group was compared with placebo using ANOVA with treatment, center, and treatmentxcenter interaction included as factors in the model. The GOS at follow-up evaluations was summarized descriptively with frequency counts and percents.
Safety analyses were carried out on all patients who received treatment. Adverse events were mapped to preferred terms and body system with a COSTART dictionary. The number and proportion of patients who reported adverse events (AEs), as well as the total number of reports of AEs, were determined by preferred term, by body system, and overall. The incidence of frequent AEs was compared between treatment groups with Fisher’s exact test. Based on the prior phase II trials, it was anticipated that nalmefene-treated patients would have a higher incidence of nausea and other digestive system symptoms.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix CERVENEReferences |
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A total of 368 patients (186 nalmefene, 182 placebo) were randomized between May 1, 1996, and January 15, 1998, at 45 centers. Among these, 23 nalmefene-treated patients and 15 placebo patients received rtPA and were excluded from the ITT population, leaving 163 nalmefene-treated and 167 placebo ITT patients (330 total). The percentage of patients who completed the 24-hour infusion were 95% for nalmefene and 96% for placebo (NS). The results of the patient demographics for the ITT population are shown in Table 1
. There were no significant differences
in patient age, stroke severity (NIHSS), history of hypertension, or
presumed stroke type as assessed at hospital discharge. Stroke subtype
was determined by the investigator on the basis of the TOAST
classification.33 Final stroke subtypes were not verified
by an events committee, and no confirmatory imaging studies were
obtained. The time to treatment was significantly longer in the
nalmefene group, whereas diabetes tended to be more common in the
placebo group.
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For all enrolled patients, the overall mortality rates at 3 months in
the treated group was 15.6% (29 of 186) compared with 16.5% (30 of
182) in the placebo group. There were no deaths that were thought to be
related to nalmefene treatment. The proportion of patients with serious
AEs was comparable in the nalmefene (21.5%) and placebo (24.7%)
groups. Table 2 summarizes by body system
the AEs that were considered to be "reasonably attributable" to
study drug administration. Events were classified as "reasonably
attributable" by the local investigator who was blinded to group.
Overall, study drug–related AEs were reported more frequently in
patients in the nalmefene group (21.5%) than in those in the placebo
group (14.8%). Nausea was reported by a greater proportion of patients
in the nalmefene group (9.1%) compared with the placebo group (1.6%).
No other apparent differences were observed between treatment groups in
the distribution of treatment-related AEs. Table 2 reports the
most frequently observed AEs, although within each category, these are
not listed because the incidence of each was <0.5%.
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The efficacy results for ITT patients are shown in Table 3. The primary outcome measure (BI 60
and at least moderate disability on the GOS) at 3 months did not
different for nalmefene treatment (66.9%) compared with placebo
(62.3). There also was no treatment effect seen for all ITT patients on
the secondary outcome variables of BI success, GOS success, NIHSS
success rate, and 3-month NIHSS total score (see Table 3). In
addition, no significant differences were seen in the primary outcome
measure when adjustments were made for baseline NIHSS scores and
time-to-treatment differences.
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A prospective secondary analysis of treatment effect by age (<
or 70 years) was performed. This planned analysis was based
on a significant treatment effect seen in patients <70 years old in
the prior dose-finding study.28 Nalmefene-treated patients
<70 years old had milder baseline strokes (mean 10.7±7.1, median 7.0)
compared with placebo patients (mean 12.2±6.5, median 11.0;
P=0.048). The primary response (BI+GOS) rates for patients
<70 years old were 81.8% for nalmefene and 73% for placebo
(P=0.26). Although a similar trend in favor of nalmefene is
seen on the secondary measures, no significant differences were seen.
There also were no significant treatment effects seen in patients 70
years old with the primary response (BI+GOS) rates being: 56.7% for
nalmefene and 55.8% for placebos.
In an exploratory post hoc analysis, the effect of treatment by gender was evaluated. Male patients treated with nalmefene tended to have milder strokes at baseline (mean 11.7±7.3, median 9.5) than did men in the placebo group (mean 12.9±6.7, median 12.0; P=0.29). A trend in favor of nalmefene was seen for all measures with the primary response being 69.5% for nalmefene and 61.6% for placebo. In contrast, female patients treated with nalmefene tended to have more severe strokes at baseline (mean 12.8±7.8, median 12) than did women in the placebo group (mean 11.7±6.6, median 10; P=0.33). All measures were very similar in female patients (eg, BI+GOS 64.2% for nalmefene and 63.0% for placebo), although mortality rates tended to be higher in the nalmefene group (19.8% versus 12.3%).
There were 23 patients in the nalmefene group and 15 in the placebo group who received rtPA and therefore were a priori excluded from the ITT population. All 38 patients received rtPA within 3 hours and met all approved criteria for treatment. The nalmefene and placebo patients were well matched with baseline demographics similar to the ITT population. The primary outcome measure (BI+GOS) at 3 months were not different for rtPA/nalmefene treatment (73.9%) compared with rtPA/placebo treatment (66.7%) (P=0.85). The secondary outcome variables were also similar (BI: rtPA/nalmefene 78.3%, rtPA/placebo 73.3%; GOS: rtPA/nalmefene 78.3%, rtPA/placebo 66.7%; NIHSS: rtPA/nalmefene 73.9%, rtPA/placebo 66.6%). However, there is a possibility of a type II error with these results given the small patient numbers and high placebo recovery rates.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix CERVENEReferences |
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The results of the present study indicate that the competitive
receptor opiate antagonist nalmefene can be
administered safely to patients with acute stroke in doses up to 60 mg
during 24 hours. There were no serious AEs considered to be related to
treatment. There was a higher incidence of nausea in the
nalmefene-treated patients, but this was easily managed with antiemetic
medications and did not interfere with completion of the infusion.
Patients who received nalmefene did not have an increased incidence of
hallucinations or agitation.
Overall, no treatment effect was seen on functional outcome at 3 months
on any of the outcome measures, with approximately two thirds of both
placebo and nalmefene-treated patients having a successful recovery.
There are several potential reasons for this lack of a treatment
effect; the most likely is that this dose of nalmefene does not provide
significant neuroprotection when administered at 5 hours. A second
possibility is that the trial was underpowered to detect a difference.
This trial was designed to detect a 15% between group difference. It
would have taken >600 patients per group to detect the 5% difference
that was observed. Finally, the high recovery rate in the placebo group
may have caused a type II error by producing a "ceiling effect."
Other acute stroke trials have reported similar difficulties with high
spontaneous recovery rates and potential type II errors when patients
with mild strokes (NIHSS score 4) were allowed to be
enrolled.34 35 For this reason, many current stroke trials
are now targeting patients with moderate to large strokes (NIHSS score
8).34
No significant treatment effects were seen on any of the outcome measures in patients <70 years old. Although a trend favoring nalmefene treatment is seen on all measures, this appears to be secondary to the nalmefene patients having milder strokes at baseline. These results illustrate that potential confounding baseline differences may occur when subgroup analyses are performed in clinical trials. Therefore, the present study did not confirm the positive treatment effects for patients <70 years old seen in our dose-finding study.28 In that study, the pooled BI+GOS success rates in patients <70 years old were 81% for nalmefene and 65% for placebo (P=0.015). Unfortunately, these final results were not known until enrollment in the present study was near completion. For this reason, no prespecified age criterion was used (eg, enrollment limited to patients <70 years old). Therefore, the present study was relatively underpowered to detect treatment differences in patients <70 years old. The study is also underpowered to determine whether treatment within 3 hours of stroke would be beneficial, because <25% of the patients were enrolled before 4 hours. Further exploration in younger patients with ischemic stroke who are treated within a shorter time window is needed before a final determination of the therapeutic efficacy of nalmefene can be determined.
In comparisons of our trial results with those of other studies, it
should be noted that the primary definition of a "successful
recovery" in the present trial is more liberal than that used in
the NINDS TPA trial ("successful recovery" defined as BI
95).36 This in part explains the differences in
spontaneous "good outcomes" seen in the 2 trials: present study
placebo group 62%, NINDS trial placebo group 38%.
Because nalmefene and NMDA receptor antagonists share a similar underlying efficacy mechanism (ie, decreasing excessive neuronal excitation), it is interesting to compare the results of the present study with the results of the trials with NMDA receptor antagonists. Although both nalmefene and NMDA receptor antagonists showed promising preclinical and early phase clinical trial efficacy,37 38 larger NMDA receptor antagonists trials failed to detect treatment benefits, with therapeutic doses limited by significant CNS or cardiovascular side effects.10 39 The present study did not show any significant CNS or cardiovascular events associated with nalmefene, and consequently the dose that was used was not limited by side effects. However, both classes of neuroprotective agents failed to show treatment benefits in patients enrolled up to 6 hours. Whether any of these agents would be beneficial if used within 3 hours of stroke has not been investigated.
In conclusion, these data show that nalmefene at a dose of 60 mg can be administered safely to patients with acute ischemic stroke with relatively few side effects. Unfortunately, no significant benefit was observed with treatment even in a subgroup of patients <70 years old. The present study does not adequately address the therapeutic potential of nalmefene in patients treated concurrently with tPA within 3 hours of symptom onset.
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Acknowledgments |
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This work was supported by Baker Norton Pharmaceuticals, Inc. The authors wish to thank Valerie Roska for her assistance with the manuscript.
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Footnotes |
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Study funded by Baker Norton Pharmaceuticals, Inc.
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Appendix CERVENE |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix CERVENEReferences |
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The following are the study investigators (with number of patients in parentheses), with their affiliation and location. Milton Alter, MD, PhD (9); NeuroTrials, Wynnewood, Pa. Carmel Armon, MD (3); Loma Linda University, Loma Linda, Calif. Richard Atkinson, MD (8); Neurological Consultants Medical Group, Sacramento, Calif. Philip Calanchini, MD (5); California Pacific Medical Center, San Francisco, Calif. J. Robert Clark, MD (6); Future Scripts, Inc, Spokane, Wash. Wayne Clark, MD (64); Oregon Stroke Center, Department of Neurology, Portland, Ore. R. Nelson Cooke, MD (4); Future Scripts, Inc, Spokane, Wash. Bhuvaneswari Dandapani, MD (5); Cleveland Clinic, Department of Neurology, Ft Lauderdale, Fla. Christopher J. Earley, MD, PhD (5); Johns Hopkins Bayview Medical, Baltimore, Md. William Ertag, MD (15); Clinical Pharmacology Investigations, Naples, Fla. Gerald J. Ferencz, MD (10); Community Medical Center, Toms River, NJ. Alex M. Forteza, MD (8); Jackson Memorial Hospital, University of Miami, Miami, Fla. Nancy Futrell, MD (1); Medical College of Ohio, Toledo, Ohio. Adrian Goldzmidt, MD (1); Sinai Hospital, Department of Neurology, Baltimore, Md. Glenn Graham, MD (3); University of New Mexico, Neurology Service, VAMC, Albuquerque, NM. Colby H. Grossman, MD (13); Palmetto Clinic Research, Summerville, SC. Jonathan Harris, MD (10); Neurologic Consultants, Ft Lauderdale, Fla. Mark I. Harris, MD (9); Georgia Neurology Associates, Atlanta, Ga. Barry Hendin, MD (8); Neurology Associates, Phoenix, Ariz. Michael Hodge, MD (3); Florence Neurological Clinic, Florence, SC. Roger Kelley, MD (13); LSU Medical Center, Department of Neurology, Shreveport, La. Louis C. Kirby II, MD (3); Medici Research, Inc, Sun City, Ariz. Marian LaMonte, MD (7); University of Maryland Hospital, Baltimore, Md. Helmi Lutsep, MD (6); Oregon Stroke Center, Department of Neurology, Portland, Ore. Sid Mallenbaum, MD (7); Neurological Consultants Virginia Beach, Virginia Beach, Fla. Lee Marmion, MD (3); Michigan Medical Center, Grand Rapids, Mich. Ken Ng, MD (19); Ocala Neurodiagnostic Center, Ocala, Fla. Edward J. Orecchio, MD (12); The Toledo Hospital, Department of Research, Toledo, Ohio. Jorg J. Pahl, MD, FCP (1); Pahl Brain Associates, PC, Oklahoma City, Okla. Eric Raps, MD
(17); University of Pennsylvania Medical Center,
Philadelphia, Pa. Henry Rothschild, MD (1); LSU Medical
Center–New Orleans, New Orleans, La. Marilyn M. Rymer, MD
(2); Center for Clinical Neurologic Studies, Kansas City, Mo.
Jeffrey L. Saver, MD (4); Reed Neurologic Research
Center/UCLA, Los Angeles, Calif. Jay A. Schecter, MD (16);
Harbin Clinic, Rome, Ga. Lynn Simon, MD (9); Doctors Office
Building, Louisville, Ky. Richard P. Singer, MD (1);
Neurological Associates, Miami, Fla. Richard Smith, MD (9);
Viva Research, Inc, Denver, Colo. Lawrence P. Sullivan, MD
(5); Neurology Associates, Milwaukee, Wis. Dale Terrell, MD
(5); Deaconess Health Systems, St Louis, Mo. Ralph Tieszen,
MD (4); SORRA Research Center, Birmingham, Ala. Gretchen
Tietjen, MD (4); Medical College of Ohio, Department of Neurology,
Toledo, Ohio. Celina Tolge, MD (1); Viva Research, Inc,
Denver, Colo. David Tong, MD (14); Stanford Stroke Center,
Palo Alto, Calif. Frederic Q. Vroom, MD (11); Tallahassee
Memorial Regional Medical Center, Tallahassee, Fla. R. Wityk, MD
(4); Sinai Hospital of Baltimore, Baltimore, Md. Received December 6, 1999; revision received March 2, 2000; accepted March 2, 2000.
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