Review of the HIVNET 012 Perinatal HIV Prevention Study (2005) / Chapter Skim
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3 Study Design, Treatment, Assignment, and Adherence to Study Regimens
3 Study Design, Treatment, Assignment, and Adherence to Study Regimens
Pages 27-47
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From page 27... ...
This chapter also addresses the implementation of the randomization procedure, drug management procedures, and participants' adherence to study regimens. Chapter 4 focuses on issues related to efficacy and safety data, and Chapter 5 focuses on ethical issues related to the design and conduct of the study.
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From page 28... ...
CHOICE OF UGANDA AS STUDY SITE Uganda has been hard hit by the HIV/AIDS epidemic. In 1997 the prevalence of HIV-1 among pregnant women in Kampala was estimated at 15% (USAID, 2005)
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From page 29... ...
On that basis, the HIVNET 012 investigators chose to study an NVP regimen consisting of 200 milligrams taken orally by pregnant women at the onset of labor, followed by 2 milligrams per kilogram of body weight for infants within 72 hours of birth. The impetus for the short-course ZDV regimen used in HIVNET 012 was the belief that a simpler, less expensive version of the ACTG 076 threepart ZDV regimen might retain most or all of its benefits, thereby enabling widespread prevention of mother-to-child transmission in resource-poor settings.
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From page 30... ...
The 7 who had been assigned to a placebo arm were contacted and offered the active regimen corresponding to the placebo arm they had been part of; if they agreed, those previously assigned to ZDV placebo were reassigned to the ZDV arm, and those previously assigned to NVP placebo were reassigned to the NVP arm (SCHARP, 2004a)
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From page 31... ...
The decision to stop the placebo arms of the trial and continue with the originally designed active arms was reviewed and approved appropriately. ELIGIBILITY CRITERIA The investigators sought to develop eligibility criteria that were broadly inclusive, subject to the constraints of the appropriate age and stage of gestation of the mother, her ability to participate in the study, and contraindications to the study regimens.
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From page 32... ...
The resulting patient IDs were then sent to Johns Hopkins University to guide packaging of study drugs.4 The resulting kits were labeled with the ID but did not include any information that would reveal the assigned treatment. The last step in the process was to assign IDs, and hence drug kits, to women enrolled into the study in the chronological order of their enrollment.
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From page 33... ...
The Institutional Review Boards at Johns Hopkins University and in Uganda reviewed and approved the revised study design and in April 1998 the study resumed enrolling patients into the remaining ZDV and NVP arms. At the time when the placebo arms were discontinued, 24 women had been enrolled and assigned to a study regimen but had not yet delivered.
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From page 34... ...
The committee independently verified the randomization procedure and its implementation by reviewing the treatment assignment lists and checking them relative to treatment assignments of individual mothers. A consultant to the committee reviewed the chronological order in which women were enrolled in HIVNET 012 to determine whether kits were assigned in consecutive order.
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From page 35... ...
In April 1998, when enrollment into the ZDV and NVP arms resumed, the investigators considered whether and how the study design should be modified. The intermediate goals of the study became the comparison of the ZDV and NVP arms, in a two-arm open-label Phase IIB screening trial, aimed at selecting one arm to advance to a future phase III trial with an anchor comparison arm.
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From page 36... ...
Thus, for an absolute difference in transmission of 12%, this design realized more than the planned 80% probability of correctly choosing NVP alone as the preferred regimen for further study in a Phase III randomized controlled trial. Finding: The committee finds that the original and revised sample size targets for the HIVNET 012 trial were sufficient to achieve the study goals.
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From page 37... ...
.We review the major components of the drug management system briefly below.7 Drug Packaging and Handling Before Enrollment The study relied on two sets of procedures for packaging and handling of study drugs prior to enrollment. Initially, manufacturers sent the drugs directly to the Johns Hopkins University pharmacy, where active and placebo preparations were packaged into either small white bottles for syrups or single-dose cellophane/foil strips for tablets that were identical in appearance.
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From page 38... ...
Each woman received an identification number after study staff had verified her eligibility and obtained informed consent. When notified that a woman scheduled for enrollment had arrived at the clinic, the study coordinator collected the next sequentially numbered set of source files from the Mulago UniversityJohns Hopkins University data center and corresponding study drug kits from the storage room.
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From page 39... ...
expressed several concerns including that the study site did not use a subject treatment assignment list, several types of dosing errors occurred, and the temperature was not monitored in the rooms where the study products were stored. (Subsequent temperature monitoring under similar conditions by the investigators was in the acceptable range for the study products [Jackson et al., 2003a]
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From page 40... ...
b d f packaging Drug Shipped of for ID Kits University 512-0001 512-0150 512-0151 512-0257 512-0401 512-0801 N/A 512-0799, 512-0802 512-0999 Uganda to Hopkins for JHU)
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From page 41... ...
41 Kit kit time was Patients last it the 512-0011; at The and 512-0401.
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From page 42... ...
They examined study drug treatment assignment, drug kit preparation by the pharmacist, drug distribution, documentation of dispensing procedures, drug return, chain of custody, and destruction of unused drugs. The DAIDS remonitoring team expressed concerns about some inadequate documentation and dosing errors as well.
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From page 43... ...
, 3 of whom had delivered outside of Mulago Hospitals. Of the 244 women in the ZDV arm who delivered at the hospital and who were not redosed, 142 women took a dose prior to arrival, 101 received a dose after arrival at the maternity ward, and for 1 woman, the study database did not state where the dose was taken.
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From page 44... ...
Evidence from cord blood specimens indi cates that participants achieved a high level of adherence to the NVP regimen. Though no direct evidence is available on blood levels of ZDV, the maternal reports of high levels of adherence to the treatment regimen, the fact that hospital personnel administered a substantial fraction of the ZDV regimen, and the absence of detectable levels of NVP in the blood of participants in the ZDV arm suggest that high levels of adherence were also achieved in the ZDV arm.
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From page 45... ...
Re: Verification on drug management procedures. E-mail to Guay L, Gable A on behalf of the IOM's Committee on Reviewing the HIVNET 012 Perinatal HIV Prevention Study.
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From page 46... ...
1997. Protocol HIVNET 012: A Phase III Placebo-Controlled Trial to Determine the Efficacy of Oral AZT and the Efficacy of Oral Nevirapine for the Prevention of Vertical Transmission of HIV-1 Infection in Preg nant Ugandan Women and Their Neonates.
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From page 47... ...
STUDY DESIGN, TREATMENT ASSIGNMENT, AND ADHERENCE 47 UNDP (United Nations Development Programme)
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