Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT00293735 |
| Other study ID # |
H-28505 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
Phase 2/Phase 3
|
| First received |
February 16, 2006 |
| Last updated |
January 12, 2017 |
| Start date |
June 2015 |
| Est. completion date |
January 2017 |
Study information
| Verified date |
January 2017 |
| Source |
Baylor College of Medicine |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Eclampsia is a major cause of perinatal morbidity and mortality. The pathophysiology is not
known but magnetic resonance imaging (MRI) and Doppler data suggest that overperfusion of
the cerebral tissues is a major etiologic factor. Hypertensive encephalopathy from
overperfusion, and vascular damage from excessive arterial pressure (cerebral barotrauma)
are believed to lead to vasogenic and cytotoxic cerebral edema, with resultant neuronal
anomalies, seizure activity and cerebral bleeding if left unchecked. Doppler data have shown
that cerebral perfusion pressure (CPP) is abnormally increased in severe preeclampsia and
that autoregulation of the middle cerebral artery is affected by this condition leading to
increased CPP. Magnesium sulfate (MgSO4) is the most widely accepted eclampsia treatment and
prophylactic agent, and it has been used in the USA since the 1950's. Despite widespread
use, its mechanism of action is unknown. MgSO4 is given intravenously or intramuscularly and
requires specialized nursing training and monitoring to minimize toxicity from respiratory
and cardiac depression. Labetalol, a combined alpha and beta blocker, has been used for many
years to safely treat hypertension in preeclamptic women, and is now known to reduce CPP in
women with preeclampsia. In the United Kingdom labetalol was for many years used as the sole
agent in treating preeclampsia, and the rate of seizure was no different to that reported in
the USA with MgSO4. Since labetalol can be administered orally, is economical, has low
toxicity potential, does not require specialized training to administer or monitor, and
decreases CPP, it may be an ideal agent for controlling blood pressure (BP) and decreasing
the incidence of eclampsia in women with preeclampsia. The current study is a multicenter,
randomized, controlled trial to compare the anti-seizure effect of parenteral MgSO4 versus
oral labetalol in hypertensive pregnant women who are eligible for MgSO4 therapy. The
primary outcome measure is eclampsia, and the secondary outcome measures include blood
pressure control, and relevant antenatal, intrapartum, and postnatal maternal and
fetal/neonatal parameters including adverse effects and complications. Inclusion criteria
are deliberately broad in order to make the study clinically relevant. Hypertensive pregnant
women, in whom the decision for delivery has been made, will be enrolled after written,
informed consent. Patients will be randomized to receive MgSO4 therapy as given in their
institution, versus oral labetalol (200mg/q6 hours), from enrollment in the study until 24
hours post delivery. There will be 4000 patients in each arm of the study and analysis will
be by intention-to-treat. The study is powered to show both therapeutic superiority as well
as clinical equivalence. This study has the potential to change the way preeclampsia is
managed, and will represent a major advance in terms of the availability and safety of
prophylactic therapy, especially in developing nations where MgSO4 is underutilized due to
cost constraints.
Description:
Research Design and Methods:
The study will be a multicenter, randomized, controlled, clinical trial comparing the
anti-seizure effect of parenteral and/or oral labetalol (n = 4000) versus parenteral
(intravenous or intramuscular) magnesium sulfate (n = 4000) with mild or severe preeclampsia
who are deemed to be at sufficient risk to warrant seizure prophylaxis with magnesium
sulfate. This allows for a 2% lost to follow-up rate. Patients receiving labetalol will
either be given a 20 mg intravenous loading dose IV followed by a 200 mg oral dose every 6
hours from the time of inclusion in the study until 24 hours postpartum, or will receive
only the 200 mg oral dose every 6 hours from inclusion. Whether or not an IV dose is
necessary will be decided by the clinician in charge. Only patients thought to be at
sufficient risk to warrant immediate anti-hypertensive therapy will receive the initial IV
dose. Patients randomized to the magnesium sulfate group will receive intravenous magnesium
sulfate as a 4 or 6 gram loading dose over 20 minutes followed by a 1 or 2 g/h continuous
infusion until 24 hours postpartum. The exact MgSO4 protocol used will be determined by the
protocol in use at each institution. We have previously shown in the Nimodipine study (as
have others with the MAGPIE study) that there is no difference in seizure rate between the
1g/hr and 2g/hr protocols. Patients on the labetalol arm of the study who convulse will be
treated with magnesium sulfate. Patients on the magnesium sulfate arm will continue to
receive magnesium sulfate. All patients who convulse will be managed per the unit's standard
protocol for eclampsia treatment.
Principal Outcome Measure:
Occurrence of eclamptic seizure(s) after enrollment in the study.
Secondary Outcome Measures
1. Maternal:
- Blood pressure, pulse pressure and heart rate changes
- Need for additional antihypertensive medication (defined by need to control BP >
160 mmHg systolic and/or 110 mmHg)
- Subjective assessment of side effects by the patient
- Objective assessment of new onset complications and/or side effects by the
treating clinicians
- Labor and delivery parameters including; induction to delivery interval, rate of
cervical dilatation, oxytocin dosages, length of labor, delivery route, blood loss
at delivery, and postpartum course
- Type of anesthesia administered (none, local infiltration for delivery only,
epidural for labor, epidural for delivery, spinal for delivery, combined/spinal
epidural for labor and delivery, general anesthesia for delivery).
2. Fetal and Neonatal:
- Occurrence of newly diagnosed fetal distress during labor necessitating emergent
delivery
- Umbilical cord gases at delivery (if available in institution);
- Apgar scores
- Neonatal outcome as defined by NICU admission, hospital survival to discharge,
length of hospital survival, days in NICU, need for blood transfusion, need for
pressor agents, need for mechanical ventilation, neonatal cardiac dysrhythmias,
neonatal cardiac failure, necrotizing enterocolitis, sudden infant death, neonatal
sepsis, neonatal hypoglycemia, and there will be an other block for recording any
other identified complications not mentioned.
Institutional Review and Informed Consent Procedures:
The protocol for this study will be approved by the Institutional Review Board of each
participating institution and copies of the approval will be on file with the principal
investigator prior to dispensing of the drug. All patients will give written informed
consent, and will have the protocol described to them in their native language if they do
not understand English.
Study Procedures
Informed Consent:
The final protocol will first be approved by the appropriate IRBs of the US and foreign
institutions as well as the data coordinating center. All women must participate in an
informed consent dialogue and must give their written informed consent prior to enrollment
and participation in the study.
Eligible patients that fit the required criteria for being entered into the study, but do
not wish to enter into the study or their primary physician doesn't wish them to participate
will be recorded. This will allow us to determine the percentage of patients who are
eligible but are not enrolled.
Enrollment:
Once delivery is planned, and inclusion criteria have been satisfied, the patient will
either be approached and counseled by an investigator or co-investigator (who may be the
patient's primary care physician) and informed written consent will be taken, or she will be
informed of the study and given a consent document by the nurse to read and then
telephonically consented by an investigator at that site. The nurse will then document on
the consent form that the patient was consented by the physician. If the patient is
telephonically consented, a site investigator will co-sign the consent document at a later
time.
Entry into this study will not in any way influence the obstetric management of the patient,
and the patient will be informed of her freedom to withdraw at any time without compromise
to the standard of her treatment. All routine patient care and routine observations will be
carried out by the labor and delivery staff.
Each institution in the USA will be cross-referenced to the IND number of the US Principal
Investigator (#63,966). This IND number is only necessary for grant funding. The FDA has
assessed this study and does not feel that it required an IND number for clinical reasons
since labetalol is already an approved antihypertensive medication. The only reason that an
IND number was requested was to allow us to satisfy the requirements for various Federal
Funding agencies. The foreign institutions will not require an IND number but will all
require an active approval from their Institutional Review Board.
Study Interventions
Interventions:
Patients will be assigned to one of two treatment groups with a randomization sequence
prepared and maintained centrally by the database. The random permuted block method of
randomization will be used because it guarantees that at no time during randomization will
the imbalance be large and at certain points the number of patients in each group will be
equal. Because the study is unblinded, random block sizes will be used. Randomization will
be stratified by clinical center, parity, and age to assure balance between the two
treatment groups with respect to anticipated differences in the patient population and
possible differences in patient management.
Sufficient stocks of the study drugs are kept in the labor and delivery areas of the study
sites to ensure no undue delay in beginning the therapy. This will reduce the chance of a
seizure occurring after randomization but before drug administration. Since this study will
have an intent-to-treat analysis, such patients will still be included in the analysis in
the group to which they were assigned.
The study drugs will be kept in appropriately secure areas in the labor and delivery suite
of each site. This system will allow for the most efficient administration of drug after
randomization and will limit the rate of drop out because of seizure prior to getting the
intended drug. In this intent-to-treat analysis, each patient will be analyzed in the group
she was originally assigned to regardless of whether or not she received the drug or not.
All patient data will be recorded in an internet-based interactive computer database. The
URL is www.labetalol.org. The database has been designed by MedSciNet
(http://www.medscinet.se/msn/home.htm) who have extensive experience in designing,
maintaining and managing large multicenter internet based studies for national and
international organizations (WHO, Government of Sweden). The database satisfies all HCA,
HIPPA, FDA CRF 21 Part 11, and NIH security protocols. Each study site will have a computer
available to the research team for this study. The database is set up to ensure that correct
and complete data are entered. The program determines eligibility and will only allow
enrollment once the specific inclusion and exclusion criteria are satisfied. If eligible a
consent form will be offered to the patient. Once she has signed the consent form she will
be formally enrolled following the prompts on the screen. The computer will then randomize
her to a treatment group. There will be prompts that will guide the research team through
the data collection sheets. There are reminders built in to ensure that essential
demographic and primary outcome data are entered. In addition certain fields will not allow
data entry if other essential fields are not completed or have incorrect data entered. The
program will query any impossible numbers that may be entered in error. This will hopefully
reduce errors from data transcription and will ensure that the protocol is adhered to.
Adverse event datasheets will be automatically displayed and will require completion prior
to continuation of the study once any reportable events are noted. These and all other data
will always be available to the (Data Safety and Monitoring Board) DSMB for analysis as
outlined elsewhere in this proposal.
Each PI will be responsible for ensuring the integrity of the data from their site. Prior to
the data being stored in the main database a sign-off will be required by each site PI. In
addition, the Study Coordinator and Study PI will be responsible for checking all data for
quality issues and reliability on a regular basis. The main database will be monitored for
accuracy and quality of data by the Principal Investigator at the St. Mark's Hospital site
in Salt Lake City, Utah. All investigators will be kept current on any/all adverse event
reports and interim analyses.
Patients randomized to labetalol will receive two 100 mg tablets orally. The labetalol
tablets (200 mg) will be repeated every 6 hours, unless the patient is hypotensive (BP < 90
mmHg systolic and/or 60 mmHg diastolic). The tablets will be swallowed with a maximum of
10cc of water. In those patients where the clinical team desires a more rapid intravenous
dosing, a single 20mg of labetalol will be given before the oral dose is taken. Labetalol
therapy will be continued for 24 hours post delivery.
If the blood pressure is not controlled (reduction in BP to < 160 systolic and < 110 mmHg
diastolic) within 40 minutes of beginning labetalol therapy, the patient will receive an
intravenous dose of 20mg labetalol, which can be increased in an escalating dose to a
maximum of 80mg (20 mg, 40 mg, 80 mg) every 20 minutes as necessary to control the blood
pressure until a cumulative maximum of 240 mg has been given. It is extremely important that
the blood pressure is controlled as outlined in this protocol and any deviation from these
instructions will be deemed a protocol violation.
Even if repeated labetalol is required for blood pressure control, the patient will continue
to receive 200mg labetalol orally every 6 hours unless she has bradycardia or hypotension
(as defined by a blood pressure of < 90 mmHg systolic and/or < 60 mmHg diastolic). If blood
pressure is not controlled with labetalol the patient will have her blood pressure
controlled by the delivery team using whatever other agent they choose. In those
institutions where intravenous labetalol is unavailable the patient will receive an
intravenous dose of 5mg hydralazine, which can be repeated every 20 minutes as necessary to
control the blood pressure.
Patients randomized to the magnesium sulfate arm of the study will receive a 4-6 gram
intravenous loading dose per institution protocol over at least 20 minutes, and this will be
followed by a continuous infusion of 1-2 grams per hour. Magnesium sulfate levels will be
recorded as per the usual protocol of the participating hospital only in those hospitals
where this is the protocol. Magnesium sulfate levels are not mandatory as long as there is
an active protocol for determining the presence or absence of magnesium sulfate toxicity.
Magnesium sulfate therapy will be discontinued 24 hours after delivery. If the blood
pressure is not controlled (reduction in BP to below 160 mmHg systolic and 110 mmHg
diastolic) within 40 minutes of beginning magnesium sulfate therapy, the patient will be
given an intravenous dose of 5mg hydralazine, which can be repeated every 20 minutes as
necessary to control the blood pressure. If the patient still needs further BP control she
should be given anything EXCEPT labetalol for BP control, i.e. nifedipine, hydralazine, etc.
Persistent blood pressure readings above 160 systolic and/or 110 diastolic are a protocol
violation.
Following randomization, patients will be managed as per the standard labor and delivery
protocol for preeclampsia in that institution. The only restrictions will be that no other
anti-seizure medications (apart from the study agents) will be given unless the patient is
removed from the study. Use of non seizure-related drugs used will be recorded on the case
report. The enrollment of patients in the study will not, other than in the choice of the
anti-seizure agent, influence the obstetrical management of the patient. Routine hourly
vital signs and fetal heart rate monitoring will be employed. A standardized case report
form will be used for all study patients.
Patients who experience a seizure prior to receiving their study drug, but after being
randomized to the study, will be removed from active participation in the study and treated
according to routine practice in that institution. Those patients randomized to labetalol
and who have a seizure on the drug will be started on magnesium sulfate per institutional
protocol. Patients on the magnesium sulfate arm of the study who convulse will be continued
on magnesium sulfate per institutional protocol. Since all of the above mentioned patients
will have been randomized they will be included in the intent to treat analysis. Outcome
data will be obtained on all randomized patients, regardless of whether they receive study
drug or have to stop study drug.
Data Collection and Storage:
All patient data will be recorded in an internet-based interactive computer database. The
URL is www.labetalol.org and for the purposes of this grant application a testing/training
program can be accessed by reviewers using the URL http://www.medscinet.com/labetaloltest/
the login name: training and the password: training will allow reviewers to review the
training web site. The database has been designed by MedSciNet
(http://www.medscinet.se/msn/home.htm) who have extensive experience in designing,
maintaining and managing large multicenter internet based studies for national and
international organizations (WHO, Government of Sweden). The database satisfies all HCA,
HIPPA, FDA CRF 21 Part 11, and NIH security protocols. Each study site will have a computer
available to the research team for this study. The database is set up to ensure that correct
and complete data are entered. The program determines eligibility and will only allow
enrollment once the specific inclusion and exclusion criteria are satisfied. If eligible a
consent form will be offered to the patient. Once she has signed the consent form she will
be formally enrolled following the prompts on the screen. The computer will then randomize
her to a treatment group. There will be prompts that will guide the research team through
the data collection sheets. There are reminders built in to ensure that essential
demographic and primary outcome data are entered. In addition certain fields will not allow
data entry if other essential fields are not completed or have incorrect data entered. The
program will query any impossible numbers that may be entered in error. This will hopefully
reduce errors from data transcription and will ensure that the protocol is adhered to.
Adverse event datasheets will be automatically displayed and will require completion prior
to continuation of the study once any reportable events are noted. These and all other data
will always be available to the DSMB for analysis as outlined elsewhere in this proposal.
Each PI will be responsible for ensuring the integrity of the data from their site. Prior to
the data being stored in the main database a sign-off will be required by each site PI. In
addition, the Study Coordinator and Study PI will be responsible for checking all data for
quality issues and reliability on a regular basis. The main database will be monitored for
accuracy and quality of data by the Principal Investigator at the St. Mark's Hospital site
in Salt Lake City, Utah. All investigators will be kept current on any/all adverse event
reports and interim analyses. The Principal Investigator of the study, Dr. Michael A.
Belfort, MD, PhD or a designated study co-investigator will be in contact with each of the
institutions on a regular basis during the 5 years of the study to monitor the trial. The
Trial Coordinator will ensure that all personnel are trained on the system. She will monitor
enrollment on a daily basis and will be responsible for ensuring that all data are
transmitted to the central database in a timely manner and that data integrity is
maintained.
Study Timetable
Patient Recruitment:
One of the major stumbling blocks in any research into the pathophysiology of eclampsia is
the enrollment of sufficient patients to achieve statistical significance. No single center
is capable of completing a study of the scope and nature of that proposed in a reasonable
time period. For this reason it is essential that multicenter networks such as the one that
we have established be used to their full capacity and supported adequately to allow this to
happen. All of the participating institutions in our network deliver in excess of 1500
patients per year. We have shown at the St. Marks and University of Utah sites that
enrollment of 2 patients per week is easily attainable with on-site presence and
encouragement. We have asked each site to enroll a minimum of 2 patients per week and we
expect more from the larger sites (Texas Women's Hospital - 8000 deliveries per annum,
University of Minnesota Medical Center Hospitals 10 000 patients per annum, Utah HCA
facilities 8000 deliveries per annum). Given an enrollment of 2 patients per week from 20
sites we anticipate annual enrollment of at least 2000 patients and that this study can be
realistically performed within 5 years. In addition, we expect that as the LAMPET Study
gains impetus and information is disseminated within the HCA network of obstetric
institutions we will have more sites joining the study. There is an active program within
the HCA Perinatal Safety Initiative that rewards facilities for Quality Programs. HCA has
started a grading system within its obstetric hospitals that has as its acme "Center of
Excellence" status. This status within the HCA organization confers significant advantages
to the facility and is as such a highly sought after designation. One of the components for
attaining Center of Excellence status is an active obstetric research program, and we expect
that the LAMPET study will be established and ongoing, it will represent an attractive
option for centers wishing to gain the Center of Excellence goal. As outlined above there
are already a number of the larger HCA facilities that have committed a 0.5 nursing FTE to
this project and have been included in the grant application. There are more facilities that
have pledged support and committed nursing support but are not eligible for grant funding
because of their smaller size and lower potential for enrolling the required 2 patients per
week. Despite the fact that they will not be paid anything, their CEO's have committed up to
a 0.5 nursing FTE to help these smaller facilities participate. We anticipate that more and
more of the smaller hospitals will also join the study as we disseminate the project
throughout the company at divisional meetings and national conferences. These particular
sites are prepared to participate in this study without any support and we anticipate that
as the study progresses and the protocol is disseminated further HCA facilities will sign up
simply for the Center of Excellence designation. This will further ensure success of this
project. HCA has a Letter of Agreement program that allows any hospital within the system to
accept the IRB approval from the St. Marks site, and thus circumvents time-consuming and
costly bureaucracy. This will allow individual physicians and groups of practitioners who
wish to participate in research to play an active role in a major RCT. Potential Principal
Investigators will be able to download the protocol and a template consent from the Study
Website for their own use. All consent form and protocol changes that may be made will be
vetted by Dr. Belfort to ensure that these are only cosmetic to satisfy the particular needs
of that institution. No substantive changes to the protocol or consent form will be allowed.
Timetable:
5 years will be a realistic amount of time to successfully complete the study.
Statistical Analysis:
One of the most widely used procedures for interim analysis of a clinical trial is the
spending function approach of Lan and DeMets. This method uses a function of time to specify
the rate at which the total Type I error probability is to be spent during the trial so that
this quantity does not exceed the desired alpha level. For this study, the spending function
corresponding to an O'Brien and Fleming boundary will be used. With this method, the rate at
which the type I error is spent is a function of the fraction of total information available
at the time of the interim analysis (i.e., information time). The information time is
determined by the type of statistical test employed. For the analysis of seizure rate, the
information time is the proportion of the total patients randomized. The table below
provides the Z score at each time point required for considering terminating the study early
and for final analysis to show statistical significance at the alpha=0.05 level:
The Lan-DeMets procedure is flexible in that the total number and timing of the sequential
analyses need not be specified in advance. Also, there is no requirement that looks be
equally spaced. In some clinical trials, however, a surprising development may lead to extra
"looks" or even continuous monitoring of data. The Lan-DeMets procedure is flexible, in that
it can switch from occasional to continuous monitoring of the data with negligible effect on
the Type I error level.
Data Monitoring Committee:
An independent data monitoring committee has been established to review the progress of the
study. The data monitoring committee will meet periodically to review trial results, monitor
patient safety and study progress. The data monitoring committee will meet when
approximately 25%, 50% and 75% of the patients have been enrolled and delivered. However,
this committee will be responsible for deciding whether more or less frequent meetings are
necessary. The data monitoring committee will be completely independent of the study group
and will not include any member of the research team or any individual with a conflict of
interest.
