Experiences and challenges in data monitoring for clinical trials within an international tropical disease research network.

BACKGROUND: Models for the structure and procedures of data and safety monitoring boards (DSMBs) continue to evolve in response to issues of new and of old concern. Some authors have called for an open dialogue on these questions through publication of the experiences of DSMBs in addressing them. PURPOSE: The goal of this paper is to add to the current discussion about acceptable models for establishing, serving on, and reporting to monitoring committees, particularly those that oversee multiple studies in less developed countries. The paper seeks to do so by describing the establishment and subsequent operation of one such multi-trial DSMB over a five-year period. This DSMB was formed to monitor trials conducted by members of the International Centers for Tropical Disease Research (ICTDR) network of the National Institute of Allergy and Infectious Diseases (NIAID). METHODS: The operational model and experiences are summarized by the authors, who had immediate responsibilities for directing the DSMB's activities. RESULTS: The board played an active, traditional role in assuring that patient safety was maintained and that current standards for clinical research were met. In addition, both NIAID and the board members viewed education of investigators to be an important role for the board to play in this particular setting. This affected the threshold for identifying which trials would be monitored, and it impacted several procedures adopted by the board. LIMITATIONS: This report reflects the observations of those involved in managing the DSMB, including comments offered by the DSMB and by investigators, but not data gathered in a systematic way. CONCLUSIONS: The operational model described here has allowed the DSMB to fulfill its role in the oversight of the trials. We hope that the ideas we present may help others facing similar situations and may stimulate further critical thinking about DSMB structure and function.

Adolescent pregnancy 1 year later: the effects of abortion vs. motherhood in Northeast Brazil.

PURPOSE: To determine social and behavioral consequences of pregnancy and how these differed according to the pregnancy outcome (live birth or abortion) 1 year after the event. METHODS: This was a prospective study of two groups of young women aged 12-18 years, one attending prenatal services and the other admitted for abortion complications at the same hospital in northeast Brazil. Adolescents who gave birth were subsequently classified as having intended or unintended pregnancies, and those who aborted were divided between those who terminated their pregnancies and those who miscarried. Baseline data were collected between 1995 and 1997 from all teens who met the eligibility criteria. Information was collected through one-on-one interviews using a questionnaire that was structured and precoded. Multiple logistic regression was used to identify characteristics that predicted outcomes at 1 year. RESULTS: Teens who terminated their pregnancies were the most likely to be in school or working 1 year later. They also showed the greatest increase in self-esteem. The young mothers, however, had the highest self-esteem but perceived the impact of pregnancy on their lives as being more negative than they did initially. Group affiliation was not associated with the quality of partner relationships, which tended to deteriorate over time. The young mothers used contraception at 1 year at higher rates and had experienced fewer subsequent pregnancies than the two abortion groups. CONCLUSIONS: The experience of adolescent pregnancy for this group of teens produced mixed findings, some more negative than others. Interventions to decrease the adolescent's desire to have a baby will have to be tailored differently from those designed to prevent an unintended pregnancy, but both are needed.

Effect of the Yuzpe regimen of emergency contraception on markers of endometrial receptivity.

This exploratory study was designed to determine whether treatment with the Yuzpe regimen of emergency contraception altered endometrial integrin expression or other markers of uterine receptivity. Nineteen parous women were followed for two menstrual cycles. In the second cycle, each participant took 100 mg ethinyl oestradiol and 1 mg norgestrel on the day of the urinary luteinizing hormone (LH) surge and repeated the dose 12 h later. In both cycles, endometrial biopsy, phlebotomy and vaginal sonogram were performed 8-10 days after the urinary LH surge. No significant difference was found between untreated and treated cycles in most measures of endometrial histology or in endometrial expression of beta3 integrin subunit, leukaemia inhibitory factor, glycodelin, or progesterone receptors assessed by immunohistochemical techniques. Five statistically significant changes were noted in treated cycles: a reduction in endometrial MUC-1 expression, an increase in endometrial oestrogen receptor, lower luteal phase serum oestrogen concentration, reduced endometrial thickness, and greater proportion of glandular supranuclear vacuoles. The relationship of these findings to the contraceptive action of the Yuzpe regimen is unclear.

The female condom and STDs: design of a community intervention trial.

OBJECTIVES: The main purpose of this study is to compare sexually transmitted disease (STD) prevalence in cohorts of women with and without access to female condoms. METHODS: Six matched pairs of communities were identified from Kenya tea, coffee and flower plantations. One community within each pair was randomly selected to receive the female condom intervention. Approximately 160 eligible women were enrolled at each site. Female condom communities underwent an education program on use of female and male condoms and STDs, comprising group meetings, puppetry and other folk media, and training of clinic service providers and community outreach workers. Control communities received similar information on use of male condoms (freely available at all sites). At baseline, participants were tested for cervical gonorrhea and chlamydia and vaginal trichomoniasis, to be repeated at 6 and 12 months. The study has 80% power to detect a 10% prevalence difference, assuming an aggregate STD prevalence of 20% with 25% loss to follow-up and intracluster correlation of 0.03. RESULTS: Among 1929 women at baseline, the mean age was 33.1 years; 78% had never used a male condom. The prevalences of gonorrhea, chlamydia and trichomoniasis were 2.6%, 3. 2% and 20.4%, respectively (23.9% overall). The intracluster correlation based on these data was near zero. CONCLUSIONS: Comparable pairs of study sites have been selected. STD prevalence is sufficiently high, and the variation between sites is acceptably low. The study is feasible as designed.

The effect of one injection of Depo-Provera on the human vaginal epithelium and cervical ectopy.

Two studies in rhesus monkeys have shown that progesterone implants, Depo-Provera and Norplant, were associated with vaginal thinning. Progesterone implants have also been associated with an increased risk of simian immunodeficiency virus (SIV) acquisition. This study in 16 women was done to assess vaginal epithelial thickness and number of cell layers from biopsies taken in the untreated follicular and luteal phases, and at 1 month and 3 months after administration of Depo-Provera. There was no significant change over time in either parameter from biopsies obtained in the luteal phase compared with those at either time after Depo-Provera administration. There was also no change in the mean number of Langerhans cells in vaginal wall specimens and no change in cervical ectopy. It appears that women do not respond to exogenous progestins with the dramatic vaginal thinning seen in rhesus monkeys.

PIP: This study assesses vaginal epithelial thickness and number of cell layers from biopsies taken in the untreated follicular and luteal phases and at 1 month and 3 months after administration of Depo-Provera. Subjects were seen at the CONRAD Clinical Research Center at the Eastern Virginia Medical School, Norfolk, Virginia. Findings showed that there was no significant change over time in either parameter from biopsies obtained in the luteal phase compared with those at either time after Depo-Provera administration. There was also no change in the mean number of Langerhans cells in vaginal wall specimens and no change in cervical ectopy. The dramatic vaginal thinning seen in rhesus monkeys was not observed among these subjects.

Intracluster correlation of STD prevalence in a community intervention trial in Kenya.

This study is a cluster-randomised, community intervention trial to measure the impact of female condom introduction on STD prevalence among Kenyan agricultural workers. The intracluster correlation coefficient of baseline STD prevalences at the 12 sites was 0.0011.

PIP: A cluster-randomized, community intervention trial to measure the impact of female condom introduction on sexually transmitted disease (STD) prevalence was conducted among Kenyan agricultural workers. The intracluster correlation coefficient (ICC) was used to measure the degree of homogeneity within clusters in comparison to total variability. The women in the sample population received condoms and were exposed to an STD prevention program through group meetings, video presentations, puppetry, and other folk media. They were also screened and tested for gonorrhea, chlamydia, and vaginal trichomoniasis. Tests were repeated after 6 and 12 months. The ICC of baseline STD prevalence at the 12 sites was 0.0011, and the proportion of women with STDs was higher at the control sites, which indicates a negligible clustering effect.

Analysis of client characteristics that may affect early discontinuation of the TCu-380A IUD.

The purpose of this study was to analyze the reasons for early discontinuation of the TCu-380A IUD in women participating in a large multicenter trial. The study relates specific characteristics of the women at the time of TCu-380A insertion with specific 1-year reasons for discontinuation. A secondary analysis was performed on data obtained from 2748 women from sites in Africa, Asia, and Latin America. By the end of the year, 321 discontinuations were observed. The gross cumulative 12-month life table rates of reasons for discontinuation were 13.3 for all reasons and 3.1, 4.5, and 4.3 for expulsion, removals for bleeding/pain, and personal reasons, respectively. Study site, age, and religion had a significant effect on early discontinuation. Women who had IUD insertions in the African centers had significantly higher expulsion rates than women from other centers. Women < 20 years old had significantly higher expulsion rates than older women. Muslim women had significantly higher rates of removal for bleeding and pain than women of other religions. This information may guide the counseling and follow-up process of women with such characteristics and result in a more satisfactory use and improved continuation rates of the TCu 380A.

PIP: This article presents a secondary analysis of the relationship between client characteristics and reasons for TCu-380A IUD discontinuation. The information gathered in this study served as a guide in the counseling process to ensure better user satisfaction and continuation rates. Data from the international multicenter trial among 2748 women from Africa, Asia, and Latin America were used to assess the continuation/discontinuation status 1 year after device insertion. The 12-month life table rates of reasons for discontinuation were used in the assessment of data. Participants were 18-40 years old, sexually active, with application of the contraceptive device 42 or more days after the last pregnancy. After a year, the rate of discontinuation was 13.3% for all reasons, 4.5% for bleeding/pain, 4.3% for personal reasons, and 3.1% for expulsion. Specific characteristics related to age, parity, religion and study site had significant effects on the discontinuation of IUD use. Women under age 20 were reported to have had a higher expulsion rate than older women, particularly those living in Africa. Removal due to bleeding and pain was found significantly higher among Muslim women compared to women from other religions.

Intervention to improve physician documentation and knowledge of child sexual abuse: a randomized, controlled trial.

OBJECTIVE: To determine if written feedback improves the chart documentation and knowledge of physicians doing evaluations for child sexual abuse and to learn what other factors are associated with better documentation and knowledge. DESIGN: Randomized, controlled trial. SETTING: A statewide network of physicians performing child abuse evaluations. PARTICIPANTS: All physicians who performed evaluations for sexual abuse during 1991 to 1992. One hundred forty-seven physicians were randomized to control (n = 75) and intervention (n = 72) groups, 122 (83%) remained at follow-up, and 87 of the 122 (71%) had done evaluations for child sexual abuse. INTERVENTIONS: Tailored written feedback based on chart reviews and relevant articles were sent to a randomly selected one-half of the physicians during a 3-month period. MAIN OUTCOME MEASURES: The quality of documentation and physician knowledge before and after the intervention. RESULTS: Documentation by chart review of up to five randomly chosen records per physician (preintervention, n = 552; postintervention, n = 259) by reviewers blinded to intervention status and physician knowledge was assessed by survey (78% completion). Change in documentation and knowledge for physicians in the intervention group was not statistically significant compared with the control group. The risk ratio for a mean overall history rating of excellent/good was 0.89 (0.63, 1.25) and for a mean overall physical examination rating of excellent/good was 1.03 (0.73, 1.45). Both groups improved significantly during the time period. The largest improvements in the time period were in documenting the history of where abuse occurred, in the physical examination position, hymenal description, penile findings, and knowing that chlamydia infection should be assessed by culture. A structured medical record, female physicians, and credits in continuing medical education were associated with better documentation. CONCLUSIONS: Tailored feedback to the physician with directed educational materials did not seem to improve most aspects of documentation and knowledge of child sexual abuse, although notable improvement was seen during the time period studied. This study suggests that chart audits may not be the best use of resources for trying to improve physician behavior; credits in continuing medical education and use of structured records may be more likely to be beneficial.

Spirometric nomograms for normal children and adolescents in Puerto Rico.

OBJECTIVE: The use of spirometric reference values specific to the population being tested is preferable. A study carried out in Puerto Rico is used here to develop nomograms for normal children and adolescents based on age and height, two variables that have been found to be good predictors of pulmonary function. MATERIAL AND METHODS: The data for healthy individuals aged 5 to 18 were extracted (108 girls and 107 boys) from a larger study of spirometric measurements collected on 4527 individuals attending medical services in Puerto Rico. Several models were tested for the prediction of FEV1, FVC and the ratio FEV1/FVC. The best models were selected for each gender, and nomograms were developed showing the fifth, twenty-fifth, fiftieth, seventy-fifth, and ninety-fifth percentile of the predicted values according to age and height separately. RESULTS: The best models were those using the logarithm of the pulmonary function and the cube of height (R2 = 0.79-0.81), and age without transformation (R2 = 0.73-0.77). Corresponding nomograms were developed based on these models. The ratio showed little variation for different ages and heights. CONCLUSIONS: Pulmonary function can be efficiently predicted by age and height. Nomograms provide a simple way to use spirometric references that can be incorporated to clinical practice.