Completed Studies | 10 - Tibetan Autonomous Region - RCT of Zhi Byed 11(ZB11) versus Misoprostol for the prevention of postpartum hemorrhage

Previous research has confirmed that hemorrhage is among the most commonly encountered pregnancy complications in the Tibet Autonomous Region (TAR). Because the majority of hemorrhage-related deaths occur around the time of delivery and because the condition lends itself to preventive intervention (i.e., prevention of uterine atony), we are initiating a clinical trials program to address the problem of postpartum hemorrhage (PPH).

The aims of this project are:

1. to initiate clinically relevant perinatal research, focusing on the prevention of PPH, through a comparison of misoprostol (a prostaglandin E1 analog) and Zhi Byed 11 (ZB11), a Tibetan medicine.
2. to expand the capacity of health care providers and researchers in the TAR to develop and maintain clinical research infrastructure.
3. to encourage scientific collaboration between U.S.- and TAR-based researchers and clinicians, as well as across medical systems (biomedicine and Tibetan medicine), specifically for research that focuses on the leading causes of maternal and perinatal morbidity and mortality in the region.

The clinical research for this project comprises a comparison of ZB11 and misoprostol for the prevention of postpartum hemorrhage (PPH). ZB11 has been used for centuries in traditional Tibetan medicine for the prevention and treatment of postpartum bleeding and uterine atony. According to Tibetan medical texts, ZB11's ingredients are said to promote uterine contractions and help expel the placenta. Misoprostol is a prostaglandin E1 analog that is used for a variety of purposes in obstetrics, such as cervical ripening, induction of labor, and prevention of PPH due to uterine atony. The primary objective of the clinical trial is to determine if ZB11 is as effective as misoprostol for PPH, defined as a measured postpartum blood loss in excess of 500 ml. The study population will be all eligible women with uncomplicated pregnancies delivering during the study period in any of the three major maternity hospitals in Lhasa who give consent (using culturally appropriate informed consent procedures under development) to be involved in the study.

Secondary study objectives include:

• training obstetrical and nursing staff at the maternity hospitals in Lhasa in the principles of clinical research and establishing a self-sustaining clinical research infrastructure
• determining if the Tibetan medicine (ZB11) is acceptable to Chinese- and Western-trained physicians, and if the Western medicine (misoprostol ) is acceptable to the Tibetan-trained physicians
• determining the acceptability of giving Tibetan and Western medicine during third-stage labor to pregnant women delivering at Lhasa maternity hospitals
• determining if the active management of the third stage of labor reduces the incidence of other pregnancy complications.

Because traditional Tibetan medicine is predicated on fundamentally different theories of disease than Western medicine (e.g., balance of humors, pulse diagnosis, spiritual-medical epistemology), Tibetan explanations for mechanisms of effectiveness generally involve concurrent social and/or religious input. Thus, it will be important to monitor the cultural acceptability of the clinical trials. Therefore, we will also evaluate the clinical trial with specific attention to the following issues that arise in cross-cultural scientific research:

• feasibility of the use of Tibetan medicines in randomized clinical trials (RCTs)
• conceptual/theoretical/ methodological issues
• impact of the introduction of Western clinical and scientific models into the Tibetan system.

Throughout the course of this research, we will collaborate with the Data Coordinating Center (DCC) of RTI International (RTI) for central data collection tool development, data management, data analysis, and consultation on all issues related to data.

Highlights of Project Activities: Marcy 2003 - January 2004

• The project PIs, consultants, and Tibet-based collaborators have been engaged in a Feasibility Study (FS), laying the groundwork for an RCT comparing use of the ZB11 with misoprostol for prevention of PPH during the third stage of labor. This has included the establishment of Tibet's first IRB, and the creation of a Research Committee (RC): a group of Tibetan physicians trained in Tibetan medicine and biomedicine with whom we work closely in developing research protocols and implementing clinical research. US collaborators continue to work closely with the RC to refine and develop the study design, and to clarify the objectives, indicators, and methodologies for Phases 1, 2, and 3.
• Travel restrictions set in place by the People's Republic of China in response to the SARS outbreak postponed planned trips in spring 2003 by the PIs until the summer. However, Tibet-based project staff and research coordinators continued to ensure that the RC met regularly during this time, and that the project moved toward initiating the clinical aspects of the FS in 2003.
• Initial qualitative investigation about the traditional and "folk" uses of ZB11 were also undertaken from March - May 2003, as were initial inquiries into the factory production and standardization of this Tibetan medicine at both state-owned and private Tibetan medical factories.
• Between July 2003 and January 2004, more than 60 qualitative patient interviews and more than 20 interviews with providers have been conducted and analyzed, in order to develop a pilot Informed Consent protocol for Phase 2 of the FS. This process, to date, has been conducted as follows:
  
  
  1. information gathering about basic level of knowledge about research, PPH, and perceptions of Tibetan and biomedicine among patients and providers
  2. pilot testing an initial version of an informed consent form with patients at all three Lhasa hospitals, including administering a lengthy questionnaire for comprehension of content in July-August 2003
  3. revising document based on results of interviews and pilot testing the revised informed consent forms in September 2003
  4. revising document a second time, including creation of illustrations, and pilot testing this revised document in December - January

Over the coming months, we will continue to refine the Informed Consent protocol in collaboration with members of the RC, and pilot test the final draft of this protocol with 50-75 patients. These procedures should be completed in spring 2004.

• In August 2003, a 3-day intensive workshop was conducted on research methods and ethics with providers from the 3 Lhasa hospitals where we will conduct the clinical portions of Phase 1, 2, and 3 of the study.
• Baseline labor and delivery data were collected from all 3 Lhasa hospitals, for at least one calendar year. This data is currently being analyzed.
• In October 2003, a week-long, hands-on training was held for Tibet-based providers in the use of the drape and data collection form (DCF). The DCF continues to be revised in collaboration with RC members and other hospital obstetrical service providers. We are in the process of finalizing this tool in preparation for a 2-week pilot data collection period.
• In November 2003, a follow-up workshop on IRB protocols and research methodology was held. The Tibet IRB has approved Phase 1 and Phase 2 protocols for the FS, through November 2004
• In November - December 2003, a 2-week pilot study of Phase 1 data collection was conducted at all 3 maternity hospitals; results were recorded and analyzed in preparation for official start of Phase 1 data collection, which began in Lhasa hospitals on January 1, 2004. Data collection, management, and analysis are ongoing.
• In December, a follow-up workshop on data collection, entry, management, and analysis was conducted with project staff and a Phase 1 data entry and management protocol firmly established.
• Laboratory toxicity testing of ZB11 is ongoing at the University of Utah as one aspect of the FS, and we have shared results of the first two toxicity analyses with members of the RC, as well as the TAR and Lhasa Health Bureaus.