Review of the HIVNET 012 Perinatal HIV Prevention Study (2005) / Chapter Skim
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4 Efficacy and Safety
4 Efficacy and Safety
Pages 48-72
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From page 48... ...
4 Efficacy and Safety This chapter evaluates the HIVNET 012 trial efficacy endpoints (HIV1 positivity and HIV-1-free survival1 of infants) and safety endpoints-their design, their implementation, and the committee's analysis.
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From page 49... ...
and serious adverse events (SAEs) were recorded on case report forms (CRFs)
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The HIVNET 012 protocol, version 1.0, defined an SAE as follows: A serious adverse event is defined as any experience that is fatal or life threatening, permanently disabling, requires in-patient hospitalization, is a congenital anomaly, cancer or overdose or is otherwise judged to be serious by the onsite clinician (HIVNET Group, 1997)
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From page 51... ...
Adverse event information was generally recorded on source documents that were transcribed to CRFs and regularly transmitted to SCHARP for entry into the study database and analysis (Guay, 2004; SCHARP, 2004)
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From page 52... ...
Westat site visit staff expressed their concern that the protocol definition seemed in practice to make hospitalization the primary threshold for SAEs, which if true, would mean that other serious conditions that were not considered "hospitalizable" might potentially be missing. (As noted earlier in this chapter, the committee finds that the interpretation of SAE used by the HIVNET 012 investigators was reasonable under the circumstances.)
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From page 53... ...
. TABLE 4.2 Serious Adverse Events in HIVNET 012 Mothers Type of SAE Number Total reported 121 Fatal or life-threatening (including 4 stillbirth deliveries)
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Recording Serious Adverse Events HIVNET 012 study staff documented clinical and laboratory findings in the source documents and transcribed these to CRFs for each participant. Westat and remonitoring teams reported that some AEs and SAEs were not consistently noted on the proper forms, including CRFs.
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From page 55... ...
. Record Keeping at the HIVNET 012 Site The Westat site visit team conducted a limited assessment of the quality of record keeping and the conditions of record storage (Chamberlin et al., 2002)
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. A small number of infants from both the active arms and the early placebo arms of HIVNET 012 were enrolled in the vitamin A study, including 33 HIV-positive infants from the ZDV arm and 23 infants from the NVP arm.
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From page 57... ...
Impact of Flooding and Other Natural Phenomena on Study Records In its report, the Westat site visit team stated that it found that one of the health visitors' log books, containing notes about follow-up visits to participants' homes, appeared to be a recent transcription. Upon asking study staff about that, Westat team members were informed that the origi
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From page 58... ...
There is no evidence that flooding or any other natural phenomenon signifi cantly impacted the completeness of study records. COMMITTEE'S REVIEW OF THE COMPLETENESS AND ACCURACY OF EFFICACY AND SAFETY ENDPOINTS Because of the various and somewhat inconsistent reports about the quality and completeness of the HIVNET 012 study data, the committee undertook its own evaluation of HIVNET 012 for the purpose of assessing the quality and completeness of source documents, the consistency between information in source documents and the CRFs, the information captured in the SCHARP data sets, and the timeliness and accuracy with which information was transferred from the source documents/CRFs to the SCHARP database.
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From page 59... ...
Copies of the source documents were transferred from the study site in Uganda to Baylor College of Medicine in Houston, Texas, for processing and review. Approval for copying and review of study documents was obtained from Human Subjects committees at Mulago Hospital/Makerere University and Johns Hopkins University.
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From page 60... ...
Infant adverse events were recorded through 6 weeks of life; serious adverse events were recorded through 18 months of life. Survival Status The committee evaluated the records of the sample of 49 infants to assess the completeness of ascertainment and verification of survival status in the source documents, the timeliness by the site in ascertaining infant deaths, the degree to which survival status information in source documents was accurately transferred to the SCHARP database, and the timeliness in reporting survival status to the SCHARP database.
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From page 61... ...
was assessed by determining each infant's last study visit prior to the June 1999 and April 2001 data freeze dates for the main study publications. Missed visits immediately prior to the freeze dates could, in theory, reflect unrecognized infant deaths.
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Finding: Source document information regarding survival status was accurately transferred to the SCHARP database in a timely manner. HIV-1 Status For the assessment of infant HIV-1 infection in the 49 sampled infants, we examined the degree to which scheduled PCR/EIA assessments were completed by the site, and whether the information about PCR/EIA positivity/negativity in the source documents/site CRFs was verified by inclusion of laboratory slips.
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From page 63... ...
Finding: The committee finds that in the subset of 49 infants whose charts it reviewed, PCR and EIA information in the source documents used to assess HIV-1 infection status was accurately transferred to the SCHARP database, and done so in a timely manner so that all results available at the time of the data freeze for study publications were included in the analyses. Capture of Adverse Events, Serious Adverse Events, and Hospitalizations The committee's review of AEs, SAEs, and hospitalizations for the subset of 49 infants began with a review of source documents, followed by review of corresponding CRFs and database information.
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From page 64... ...
The 17 SAEs that were found in the source documents but not in the corresponding CRFs are shown in Table 4.4. Only 2 of the 23 infant deaths identified in the source documents were recorded in the CRFs as serious adverse events.
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From page 65... ...
13 NVP Malaria week 15 Pneumonia at week Pneumonia month 9 15 Gastroenteritis, dehydrated, malaria at month 9 34 NVP Cardiohypertrophy, Febrile septicemia, urinary tract convulsions, infection at week 6 bronchopneumonia week 6 36 NVP Pneumonia at month 15 Diarrhea, failure to thrive, dehydration, poor nutrition, death at month 15 53 ZDV Paralytic ileus at week 11 Malaria, septicemia, diarrhea, electrolyte imbalance 78 ZDV Oral thrush at month 7 Diarrhea, anemia, death at month 7
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From page 66... ...
of the comparisons of AEs between the NVP and ZDV arms in HIVNET 012, though it could have decreased the power to detect a real difference. Finding: The committee finds that infant deaths, hospitalizations, and visits where an infant experienced an SAE were accurately reported to the SCHARP database, although, in some instances, not all concomi tant SAEs were reported.
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From page 67... ...
. Study infant bilirubin levels were then assigned a grade of severity based on DAIDS tables grading serious adverse events as multiples of the ULN.
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From page 68... ...
Finding: The committee concurs with the HIVNET 012 investigators' determination that 1.2 mg/dL, as suggested in the April 8, 2003, IND Safety Report, was not an appropriate upper limit of normal value for bilirubin in newborns, whose bilirubin levels change rapidly over the first few days after birth and are normally substantially higher than those in adults. The committee also concurs with DAIDS' decision to withdraw its initial IND safety report finding of excess hyperbilirubine mia because it was derived from the application of an incorrect crite rion to study data.
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From page 69... ...
Hence, the intrapartum plus early postpartum transmission rates from this study are not directly comparable to those of HIVNET 012 or the other four studies. The ZDV-only arm of the HIVNET 012 trial was less directly comparable to other randomized controlled trials for prevention of MTCT that included ZDV.
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From page 70... ...
Additionally, the observed rates of serious adverse events were similar to those observed in randomized controlled trials that tested similar NVP regimens, randomized controlled trials that used NVP plus other antiretrovirals, a randomized postnatal prophylaxis trial, HIVNET-023 (Shetty et al., 2003) , and observational studies.
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From page 71... ...
A Phase III Placebo-Controlled Trial to Determine the Efficacy of Oral AZT and the Efficacy of Oral Nevirapine for the Preven tion of Vertical Transmission of HIV-1 Infection in Pregnant Ugandan Women and Their Neonates. Jackson JB, Musoke P, Fleming T, Guay LA, Bagenda D, Allen M, Nakabiito C, Sherman J, Bakaki P, Owor M, Ducar C, Deseyve M, Mwatha A, Emel L, Duefield C, Mirochnick M, Fowler MG, Mofenson L, Miotti P, Gigliotti M, Bray D, Mmiro F
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From page 72... ...
1997. HIVNET 012 Study-Specific Procedures: Phase III Efficacy Trial of Oral AZT vs Oral Nevirapine in Pregnant Ugandan Women and Their Neonates for the Prevention of Vertical Transmission of HIV-1 Infection.
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