TITLE:  CREATE, Summary Budget for Year 2

DATES:  September 1, 2005 through August 31, 2006

Awarded Amount:  $ 10,214,205

Subgrantee/Subcontractors	Total Amount $U.S.	Duration From/to dates	Grant or contract
London School of Hygiene & Tropical Medicine - ZAMSTAR	$ 2,685,502	09/01/2005-08/31/2006	Contract
London School of Hygiene & Tropical Medicine – Biostatistics Core	$    388,767	09/01/2005-08/31/2006	Contract
Aurum Institute	$ 4,496,022	09/01/2005-08/31/2006	Contract
Rio de Janeiro Secretariat of Health	$    671,522	09/01/2005-08/31/2006	Contract
World Health Organization – PAC	$    327,072	09/01/2005-08/31/2006	Contract

Public Project Description:                                                

 is a global research and implementation project targeting tuberculosis (TB) control in areas with severe HIV/AIDS epidemics. CREATE’s purpose is to evaluate novel strategies to reduce TB morbidity and mortality in populations with high rates of HIV and TB co-infection. TB is the leading killer of people with HIV infection worldwide, and the HIV epidemic has seriously undermined TB control efforts globally. New strategies using currently existing tools will enhance TB control and will facilitate future interventions designed to reduce the incidence of morbidity and mortality from HIV-related TB.

CREATE is conducting three large, community level studies evaluating alternative strategies for control of TB in Brazil, South Africa and Zambia.  The Thibela TB project is assessing the impact of community-wide isoniazid preventive therapy (IPT) in South African miners.  The THRio study is evaluating extensive use of IPT in HIV-infected patients with access to antiretroviral therapy in Rio de Janeiro.  The ZAMSTAR study is a community-randomized trial of enhanced TB case finding and household interventions to reduce risks among contacts of TB patients in Zambia and South Africa.

CREATE has a Biostatistics Core at the Johns Hopkins Bloomberg School of Public Health and the London School of Hygiene and Tropical Medicine.  The CREATE Policy and Advocacy Core at the World Health Organization maintains communication with the TB/HIV global community, and advocates policies to improve TB/HIV control.  An Education and Training Core provides support to study sites for training a new generation of public health researchers who will have an enduring impact on health improvement in the years to come.

Financial Report

Amount received from the foundation during the reporting period:	$10,693,,205
Amount of interest earned on received grant funds in your last fiscal year:	$     337,000

Other Sources of Project Support: Did the project receive any additional unreported monetary support from outside donors during the last reporting period?  Y                                                               

Are any new sources of additional monetary support expected in the next funding period? N   

Donor	Amount In $U.S.	% of project	Committed or Potential	Expected Receipt date
FIND - Thibela TB FIND – THRio FIND – ZAMSTAR	$  97,731       $  71,140       $203,000	2.1% 6.0% 5.5%	Committed Committed Committed	Received Received Received
SIMRAC – Thibela TB	$198, 698	4.1%	Committed	Received
NIH – THRio	$45,000	3.9%	Committed	Received
DFID – ZAMSTAR	$100,000	2.8%	Committed	Received

FIND: 

   Thibela:   Donated MGIT machine and funds for supplies for culture of specimens during study

   THRio:      Donated MGIT machine and funds for supplies for culture of specimens during study

   ZAMSTAR: Donated 3 MGIT machines and funds for supplies for culture of specimens during pilot study

SIMRAC:  South African Safety in Mines Research Advisory Committee is providing support for pilot studies and latent TB prevalence study in Year 2

NIH:  KO1 award for Jonathan Golub to work on THRio study

DFID: Tuberculosis Knowledge Program is supporting evaluation of pilot studies in Lusaka

 

I.  Introduction

The Consortium to Respond Effectively to the AIDS/TB Epidemic (CREATE) is a global health consortium of investigators, clinicians, public health practitioners, and health agencies with the goal of identifying and evaluating novel strategies to reduce tuberculosis incidence in populations with high rates of HIV and tuberculosis co-infection.  CREATE is coordinated by the Johns Hopkins Center for Tuberculosis Research and has multiple international partners.  Phase II is the implementation phase and was initiated in June 2004.  This report provides a summary of Phase II activities for year 2, from 1 September 2005 through 31 August 2006.

 

Overall goal:  To develop, evaluate, and promote new public health strategies to reduce the incidence of tuberculosis in settings of high HIV prevalence.

 

Primary Objectives Phase II: 

Objective 1.  Design, implement and evaluate a portfolio of community–level trials of new strategies designed to reduce TB incidence in communities with high HIV prevalence.

 

• The Administrative Core accomplished its projected activities for the year.  Subcontracts for partners were maintained, and supplemental funds to cover currency exchange losses were negotiated with the Foundation.  The Consortium held its second annual meeting in Paarl, South Africa, featuring a speech by Nobel Laureate Archbishop Desmond Tutu, who lauded the CREATE mission.  Administrative and protocol monitoring site visits were carried out by the Administrative Core throughout the year.  All three studies have been registered at public access clinical trial registration sites.  The CREATE DSMB held its second meeting in June 2006. 

• The Biostatistics Core had another successful although somewhat stressful year.  ZAMSTAR implemented a successful public randomization with a ceremony in December 2005.  Data base design decisions and implementation, including case report form design, were exceedingly challenging, but completed for all three CREATE studies.  For all studies, initial data have been entered into study data bases and some preliminary analyses are being conducted on baseline data.  In Year 3 additional baseline and pilot data analyses will be completed.  The Biostats Core designed a template for reporting to its DSMB which was reviewed and approved by the DSMB at its annual meeting in June.  The use of a standardized format was strongly supported by the DSMB.

• Education and Training Core accomplished its projected activities for the year.  Training needs and training effectiveness were assessed on-site throughout the year.  Education and training resources were identified and were developed if not already available.  Study sites were provided international training opportunities in which they could participate, in some cases with negotiated reduced fees.  An Internet Training program for research coordinators was initiated through the Johns Hopkins School of Nursing, and a DVD version of the course is in development.  Technical support continued and evaluation data forms were enhanced to facilitate ease of completion.  In Year 3 we anticipate producing a new training series on ethics in community-based research in conjunction with Dr. Nancy Kass.

• Policy and Advocacy Core accomplished its projected activities for the year.  Three staff are employed to work part-time on CREATE; a medical officer who focuses on the technical aspects of policy development, a technical officer who focuses on the advocacy and communication elements of CREATE activities and an administrative officer.  PAC visited all four project sites during Year 2, contributing to a full understanding of project implementation, advocacy challenges and needs, and the barriers to implementation of IPT and other collaborative TB/HIV activities.  The attendance of PAC at the ZAMSTAR launch has resulted in Archbishop Desmond Tutu becoming engaged in Stop TB Partnership activities.  In Year 3 the policy officer and advocacy officers are leaving and will be replaced.  Two papers on IPT will be published in addition to lessons learned from CREATE study implementation to date.  Site visits, and professional meetings will continue to strengthen advocacy and prepare the TB control community for policy changes. 

• Study implementation:   CREATE’s 3 community-based trials are underway.    

o   Thibela TB

1. Year 2 was focused primarily on identifying and responding to challenges posed by delays to implementation.  Year 3 will focus on recruitment, with implementation of a concurrent enrollment process to ensure project completion on schedule.
2. Data management system 100% established.
3. Thibela TB was launched nationally on October 31, 2005 and regionally at Tau Tona (the first intervention shaft) on November 1, 2005. 
4. TB baseline case notification data collection was completed.
5. A public randomization event was held.
6. Two pilot studies were completed; a third will be fully enrolled as of the end of Year 2 and the fourth pilot will commence in first two regions concurrently with the parent study:

• Pilot study A: Qualitative research with focus groups of miners to learn perceptions of TB and preventive therapy – completed.
• Pilot study B:  422 participants enrolled to evaluate prevalence of latent TB – enrolled – completed.
• Pilot study C:  60 participants enrolled in control arm and 121/138 enrolled in INH arm to assess utility of urine INH metabolite testing for measuring adherence – preliminary data submitted to DSMB 2006.
• Pilot study D - estimation of new TB case notification collected on ongoing basis for enrolled clusters – underway

7. Community Mobilization Programme launched in November 2005, followed by extensive community outreach with education material, recruitment pamphlets, Community and Peer Educator Activities, Study awareness (Road) Shows, Community Advisory Groups, Shaft Advisory Group. 

8. Recruitment initiated at TauTona and Great Noligwa mines.

 

o   THRio

1. The study was initiated on schedule on 1 September 2005 and the intervention is implemented in 20 of 29 study clinics, as planned.
2. Process measurements are being made and used to provide feedback to intervention sites.  To date, 82% of eligible individuals have started INH preventive therapy.
3. All baseline data have been collected and entered into the study database.  Over 10,000 abstractions of clinic records have been recorded, documenting all patients attending the clinics at least once between the dates of September 1, 2003 and September 1, 2005. These data provide the baseline denominators of patients to be followed to measure the impact of the intervention on TB incidence. 
4. The procedure to match the THRio database with the other external databases to ensure completion of outcomes is underway.  Initial algorithms for ensuring matches have been constructed and tested, and we intend to have the process completed in Year 3. 
5. Cost measurements have been recorded for various study activities to be incorporated into the prospective cost effectiveness analysis for THRio.  Documentation of training costs, detailing personnel and equipment costs, in addition to time motion studies of patient flow in intervention clinics, have begun.  THRio staff members have been trained to conduct more time motion studies as the intervention begins in more study clinics.
6. Increased interaction between HIV and TB services in Rio de Janeiro has been observed in the clinics where training has been conducted in addition to the improvement of patient care in the areas of HIV and TB as a specific beneficial outcome to the development of eligibility and lists and improvements in the feedback system for physicians.
7. The MGIT substudy supported by FIND has been implemented and is evaluating specimens from intervention clinics.
8. An analysis of baseline data has been completed and will be presented at the International AIDS Conference in Toronto in August 2006.  The results show that the combination of IPT and ARVs is associated with greater reductions in TB incidence than either treatment alone.

o   ZAMSTAR

1. Year 2 has been an exciting mixture of frantic word, rapid growth and consolidation of the research teams.  Despite many challenges progress has been maintained. 
2. The full protocol for interventions, randomization, data analysis and monitoring and evaluation is completed and approved. 
3. A successful public randomization procedure and ceremony was carried out in Lusaka with broad participation from both South Africa and Zambia.
4. New office building completed in Lusaka and team moved in with high speed internet network being established between all sites and central office (will be complete by end of year two). Central office space in Cape Town expanded.
5. Field offices established and functional in all 24 sites, usually within district health management offices. New office space has had to be built or converted in all South African sites and several Zambian sites

• More than 250 staff now recruited and working in three countries.  Site teams functional with respect to transport, finance, office space.  All staff trained in GCP.
• Senior public health physician appointed to support Prof. Beyers in clinical aspects of study in Cape Town.

6. TST Surveys completed – 22,500 skin tests read.

• Data cleaning and analysis ongoing – 12% of children have >15mm induration

7. Prevalence primary sample collection completed in all 4 sites with a high consent rate and people in communities liked the study

• Data cleaning and analysis ongoing – surprisingly large number of atypical mycobacteria isolated necessitates additional mycobacteriological work

8. Social Science baseline data collected and data analysis ongoing

9. “Combined TB and HIV activities at the clinic” intervention started in all sites so that all teams are trained and ready to start interventions.

10. Quality assurance team recruited and the tools for quality assurance under development

 

Objective 2.    Transform global policies for HIV-related TB through evidence-based advocacy. 

Although transformation of policies will depend on study results, a number of steps have been taken to prepare and advocate for new approaches to TB/HIV control.  In particular, advocacy related to INH preventive therapy has been extensive, with acceptance for publication of several reviews on this topic, a symposium planned at the World AIDS Conference, and a planned global consultation on IPT to be held in early 2007.  A policy on smear negative TB in HIV-infected individuals was developed by the PAC in collaboration with many international partners, and approved by the WHO TB Scientific and Technical Advisory Group in June 2006.  This policy not only advocates for improved case finding and more empiric therapy for HIV-related TB, but also endorses broad access to culture as a case-finding strategy.  Policy and Advocacy Core and CREATE investigators continue the global dialogue about HIV-related tuberculosis in professional, advocacy and program-oriented venues. 

• CREATE has enhanced its advocacy for TB/HIV control and research globally and locally through a variety of activities:
• Participating in the launch of the new Stop TB Strategy which places collaborative TB/HIV activities firmly within global TB control strategies for the future.
• Maintaining CREATE profile in TB/HIV Working Group newsletters and website and promoting CREATE in the forthcoming Expert Committee meeting.
• PAC’s attendance at the ZAMSTAR launch contributed to Archbishop Desmond Tutu’s decision to engage in Stop TB Partnership activities, adding a high profile advocate who supports TB/HIV collaboration. 
• In addition, although obliquely related, Dr Kenneth Kaunda, the First President of Zambia has become engaged with the work of the Stop TB Partnership.  As keynote speaker for the African launch of the Global Plan to Stop TB 2006-2015 in Nairobi in January 2006, Dr. Kaunda’s advocacy has drawn attention to collaborative TB/HIV activities in CREATE study countries, raising the profile of HIV related TB as a problem and facilitating the smooth running of studies and timely uptake of results by policymakers and partners.
• Presentations of baseline data from CREATE studies at the International AIDS Conference, Toronto, Canada in August 2006 will contribute to policy evolution.

Additional specific steps being taken can be seen under VII. Progress in Achieving a Global Access Strategy. 

 

II.         Accomplishments: 

Accomplishments are included above in the Project and Core reports.

 

III.       Changes: 

• Collaborative TB/HIV activities have become more established and mainstreamed into international policy and planning with the launch of the Global Plan and the Stop TB strategy which will facilitate the smooth running of the CREATE projects and the uptake of results into global policy.

• At the recommendation of the CREATE DSMB, THRio will begin an adherence survey which was not part of the original proposal requiring the addition of 2-3 new staff.

• Thibela TB has implemented a contingency plan for concurrent enrollment to ensure project completion on schedule

• In ZAMSTAR, the protocols for follow-up of tuberculin-negative children in Zambia have been reviewed and children are now followed to their homes, rather than relying on chaotic school class systems that are not robust enough to ensure that the protocol is followed correctly.

• Personnel changes will occur in Year 3 in both Policy and Advocacy and Administrative Cores, necessitating smooth transitions to new personnel to facilitate continuity of procedures and communication throughout the consortium.

 

IV.       Challenges:

• The Kwacha has appreciated from 4850 to <3000 to the US dollar and the Rand has fluctuated from 7 to 6 during the study. This has put significant strain on project funding, which was already the bare minimum necessary. Additional funding has been requested and approved.
• Foreign exchange rates will continue to pressure funds in Year 3.  As a result, we are requesting a supplemental budget – drawn from the CREATE mortgage – of $1,378,000 in Year 3 to support the Thibela and ZAMSTAR projects at their originally budgeted levels.  The revised budget request is amended separately to this report.
• The considerable variability between study sites continues to be a challenge when attempting to present data in a standard format or to compare data between study sites. 
• Biostatistics Core:  Standardization of routine reporting, especially to the DSMB, will continue to remain difficult, due to the highly varied nature of the projects, and to the changing needs over time within each project.  This will continue to be a priority at our next Biostatistics Core meeting, scheduled for the day after the full CREATE meeting in South Africa, September 2006.
• Education and Training Core:  Coordination among three project sites with unique training needs and various venues for training presents some challenges.  However, the ETC coordinators at each site continue to be responsive in apprising the ETC of what is useful and what cannot be adapted to their specific setting.
• Communication within the consortium and communicating CREATE’s progress to local and global stakeholders presents a challenge. 
• Administrative Core and Policy and Advocacy Core must balance the need to give and receive information without drawing attention too far from the work of the studies.
• PAC will need to maintain contact with, educate and support the main political stakeholders in each country that will most rapidly influence policy-making and implementation of CREATE findings as they become available.
• In 2006, PAC needs to maintain and expand the various forums in which CREATE findings can be presented to the broadest cross section of the HIV/AIDS and TB communities.  PAC will need to build the base of stakeholders that receive CREATE information through the TB/HIV Working Group listserv, newsletter and website.
• Continued support of other stakeholders requires ongoing attention in all the studies.

o   Thibela TB: Mining health services are becoming more alert and aware of the potential burden the study may place on them.  This burden may arise from increased identification of TB suspects for further investigation and treatment, as well as the diagnosis of potentially study related adverse events. Aurum will have to manage both the perceptions and realities of the situation as it develops.

• Regular feedback to communities is challenging and takes an enormous amount of time.  This is essential in order to keep the CAB members enthusiastic about their tasks and to maintain the support for the study teams.
• Life of mine - the operating lives of the participating shafts are being followed on an ongoing basis.  One shaft has been identified as high risk for earlier closure than originally anticipated and a contingency plan is under discussion by the investigator team.
• Unions - No new challenges have arisen. However, since this is a high risk area, monitoring activity and close liaison is essential.

o   THRio:  Several health units that had been under the administration of the city health department at the time of planning and starting the study have returned to administration by the federal government.  Because of this, these units have required a disproportionate amount of time to arrange for access by the THRio team in order to begin baseline data collection, and to arrange for scheduling for training for the intervention.  We also expect that these units will be continue to provide challenges as we implement the intervention in them, as our direct influence will be more limited.

o   ZAMSTAR:  Working in poorly resourced setting, especially the health sector which is devastated by human and financial resource constraints.  In addition there are sometimes strained relationships between the clinic staff, politicians and community health workers.

• Training and coordinating staff to ensure proper implementation of interventions using Good Clinical Practice requires ongoing diligence and oversight.

o   THRio:   It is a challenge is to assure that the intervention is implemented properly.  The training sessions for the clinics are quite involved.  At first, several clinics were not as successful at placing and reading TSTs as we had hoped.  After seeing preliminary data, the training needs were reassessed and new training sessions were conducted.  The results have been positive since the retraining. These initial issues have now been incorporated into our standard training practices and we do not anticipate similar problems in the future.

o   ZAMSTAR:  It is a huge challenge to do a study of this size in 2 different countries and to try and keep all the activities and timelines the same in the 2 countries.  Within Zambia, the geographical separation of the sites increases this challenge. The MOH specifically requested that we work in an underdeveloped province, Luapula, which is some 900km from Lusaka. The Zambian sites are therefore 1400km from north to south.

• Uptake of isoniazid preventive therapy has been recognized by both Thibela TB and THRio as an ongoing challenge. 

o   Thibela TB:  A Community Mobilisation Program, including recruitment and retention aspects, has been rolled out.

o   THRio:  At this time we have very few people who have been receiving IPT for a significant period of time, so measurements of adherence are not possible.  We are developing an adherence survey to be used on a sample of patients at all clinics.  Patients will be randomly sampled, consented, and asked a few adherence questions.  In addition, patients will be asked to submit a urine specimen which will be measured for the presence of isoniazid metabolites.  The adherence protocol is currently under review at the Rio de Janeiro IRB after receiving IRB approval from Johns Hopkins University.

• And finally, there are unforeseen challenges, such as ZAMSTAR’s experience in which one of the prevalence sites (Site B) had houses demolished in some of the enumerator areas and thus no-one in those areas could be enrolled. The team went on to enroll in the next enumeration area.

 

V.        Lessons Learned:

• Comprehensive planning, budgeting, training and supervision are worth the initial time and effort. 

o   Thibela TB:  Data management is a significant portion of any project and should receive priority during start up.

o   THRio:  All the efforts in supervision, training and retraining, especially in PPD placement and reading, are giving us good returns in better operational indicators, such as higher PPD positivity and IPT inclusion.

o   ZAMSTAR:  The TST protocol for obtaining consent via the schools was not adequate in Zambia. This allowed violations of the protocol such that some children were injected without consent, and we could not be certain that the person who actually signed the consent form was the parent or guardian of the child. This has had consequences for the rest of the study and will need us to change the way we conduct the final TST survey. More time and staff will be needed to ensure such problems do not reoccur.

• Investment in ongoing communication with the community is vital. 

o   Thibela TB: Informal communication channels in communities should be utilised in combination with formal channels of communication. This requires involvement of all role players on various levels of representation.

• Stakeholder management is key to the success of a project of this nature. It is costly in terms of time invested to establish a network for communication.

o   THRio:  Engaging all stakeholders:  It is important to ensure full engagement in the study of all stakeholders at all levels. Developing good stakeholder relationships has been one of the most time-consuming elements in setting up the study but vital for its smooth running.

o   ZAMSTAR:  We elected to use existing structures (Health Centre Committees) for the Community Advisory Boards which works well if these are functional. In areas where the health centre committees are not functional and already subject to suspicion within the community, it is extremely difficult to establish a functional body.

• Policy and Advocacy Core:  From the site visits it is clear that there is a wealth of information and experience at all levels of the CREATE studies that is relevant for policy development, beyond the scientific outcome data. PAC is considering the most efficient ways to collate and disseminate these lessons and hopes to hold a discussion on this in the CREATE Investigators meeting in September. 

• Education and Training Core:  Distance-based internet courses provide an excellent opportunity for in-country training, but not all of the CREATE project sites have the internet accessibility to participate in this type of training.  We plan to produce videos/DVD’s as enduring products to enhance training activities.

• It is difficult to work in townships in South Africa during elections and during strikes.  Training of local field workers from townships took longer than anticipated.

 

VI.       Publications and Data Sharing: 

See appendix.

 

VII.     Progress in Achieving a Global Access Strategy: 

CREATE’s long-term goal is to transform global TB/HIV control strategies through evidence-based advocacy.  Our target, therefore, is people living in countries with a high burden of TB and HIV, and our activities are directed toward reaching this population.  Thus, in terms of global access, the major challenge is to generalize the outcomes of CREATE to affect policy for all regions suffering from an HIV/TB co-epidemic.  Our Policy and Advocacy Core is specifically tasked with addressing this objective, and all CREATE partners are committed to achieving it.  Specific activities toward this end during the past year are listed below.

• Participating in the Bill and Melinda Gates Foundations’ advocacy efforts to build political and financial commitment to TB, including TB/HIV activities
• Ongoing collaboration between PAC and Gabrielle Fitzgerald, TB advocacy officer of the Bill and Melinda Gates Foundation how PAC may position itself to fill the advocacy space between CREATE and the Stop TB Partnership and Stop TB department proposal to Build Political and Financial Commitment to the Global Plan to Stop TB 2006-2015.
• CREATE Principal Investigator Dr. Richard Chaisson participated in a press briefing on the Global Plan to Stop TB January 27, 2006 with representatives of other Bill and Melinda Gates Foundation TB research initiative.
• Presentation of CREATE activities to the STOP TB Partnership via the TB/HIV Working Group and during the Scientific and Technical Advisory Group meeting of the STOP TB Department.

• THRio:  The Rio de Janeiro Health Department continues to support the TB NGO forum and other community partners to promote IPT, and increase community involvement in THRio and in collaborative TB/HIV activities in general. PAC is actively engaged in linking the TB NGO with other national/international TB community groups.

• Enhancing communication between CREATE and the TB/HIV community.

• CREATE has featured in regular TB/HIV newsletters (distributed to more than 500 TB/HIV working group and HIV community partners) and on the Stop TB Partnership website and regular communiqué.

o   Meetings: 

• Facilitated the attendance of CREATE investigators, stakeholders and partners at the Stop TB Partnership Joint Working Group meeting Versailles and the TB/HIV Working Group and Core Group meetings in 2005.
• PAC will support the attendance of CREATE staff and stakeholders at the forthcoming TB/HIV Working Group meeting, and a TB/HIV satellite symposium and skills building workshop on TB screening at the International AIDS Society (IAS) AIDS 2006 conference in Toronto in August 2006 which is attended by approximately 20,000 participants from all sectors of the AIDS community.
• The TB/HIV Working Group meeting will be an open consultation on 'HIV And TB in the Context Of Universal Access: What Is Working And What Is Not?', and will provide CREATE investigators an opportunity to share their experiences with approximately 400 participants.
• Stephen Lewis, the United Nations Special Envoy on HIV/AIDS has agreed to open the satellite symposium entitled 'HIV and Tuberculosis: overcoming the fatal interaction'.  This symposium has the potential to attract 900 participants and will include CREATE investigators in the panel.
• The skills building workshop, entitled 'Screen for TB:  A simple questionnaire can save the lives of PLWHA' will enable CREATE investigators to share their experiences on community based TB screening with up to 400 participants.
• These meetings will raise the visibility and profile of the CREATE activities through formal presentations to at least 1,700 conference participants and through informal meetings, discussions and information sharing. Attendance at these meetings will also ensure that CREATE researchers and stakeholders are kept up to date on global progress and experiences in reducing the impact of HIV related TB.   The expectation is that these presentations will motivate the HIV community to address TB as an important HIV care issue and work with the TB community to reduce the burden of HIV related TB.

Isoniazid Preventive Therapy

Globally

• Two manuscripts, one reviewing the role of IPT and another describing the policy development cycle for INH preventive therapy (IPT) and the constraints to widespread implementation of IPT in high TB/HIV settings, are being cleared for submission to peer-reviewed journals.    
• There is continued resistance to uptake of IPT for PLHIV in many settings. Existing global policy is not convincing enough to persuade countries to implement IPT routinely. PAC is proposing to hold an expert consultation meeting early in 2007 to define ways to overcome the barriers to IPT policy implementation and revise international IPT policy in the light of new evidence. PAC will be seeking strong representation from the CREATE researchers in the meeting and where available will use the evidence to date from the studies to inform the policy revision.
• In preparation for a proposed PAC-led Expert Consultation on the use of IPT in 2007, PAC will provide the opportunity for CREATE investigators to discuss the use of IPT with a broad segment of the TB community at the 37^th Union World Conference on TB in Paris from 31 October to 4 November, 2006.

Locally

• The South African Mine Health and Safety Council have provided support for Thibela TB.  If the study results show a clear benefit, we anticipate the Council’s support in adopting the use of mass IPT in mines.  However, it is not clear what level of benefit (and at what cost) the study will have to show in order for the MHSC to adopt mass IPT as standard policy.
• Plan to continue dialogue with MHSC about their response to various possible research outcome scenarios in order to facilitate the rapid uptake of results when available.
• Challenge of transforming policy in the private sector.  The experiences and results from Thibela and other Aurum research studies are likely to have relevance for other private sector industries outside the mining industry, where TB and HIV are likely to have a major impact on productivity.
• Plan to partner with PAC to build relationships with local and international private sector organizations such as the World Economic Forum, the South African Business Council on AIDS (SABCOA) and the Business Unit in South Africa (BUSA). Engagement of these stakeholders early in the study may increase the likelihood of IPT and other workplace TB/HIV activities being adopted into company policies.
• Challenge of transforming national health policy and ensuring government support.  Despite the existence of national policy on the use of IPT for PLHIV, PAC and Aurum staff have encountered institutionalized skepticism to its use because of concerns about adherence, inability to exclude active TB, and promoting isoniazid resistance. To ensure uptake of research findings in South Africa it is essential to secure support from the Ministry of Health and provincial health departments. 
• Plan to partner with PAC to continue discussions with the Director of TB Services, Department of Health, to present the Thibela study promote implementation of the IPT policy in South Africa and uptake of study results when completed. The Principal Investigator, the national TB Director and a high level delegation from WHO could jointly meet with the Minister and provincial Members of the Executive Councils of Health to support wider IPT.

 

IP & Regulatory Assurances Checklists

If nothing has changed from your previous submission, check here:  __X_No change  

1. Project has/will involve collaboration with for-profit companies	YES     NO
2. Project will involve use, further development or creation of technology that is or will be subject to intellectual property	YES     NO
3. Report contains proprietary information	YES     NO
4. If you checked “yes” for any of the above 3 statements, have any facts and circumstances changed from your last report/proposal submission?	YES     NO
5. Project has/will involve research using vertebrate animals	YES     NO
6. Project has/will involve research using human subjects	YES     NO
7. Project will involve clinical trials	YES     NO
8. Project will involve use of  any of the following substances: recombinant DNA pathogens/toxins identified as “select agents” by U.S. law: (http://www.aphis.usda.gov/vs/ncie/pdf/agent_toxin_list.pdf) biohazards or genetically modified organisms	YES     NO

 

Annual Progress Report Form Section B

II. Regulatory Assurances – Checklist Questions 5-8

Research Assurances

A. Assurances Update

Assurance Type	Date of original approval	Date of latest approval	Comments
Thibela TB Recruitment materials UKZN London School Protocol UKZN   London School Pilots UKZN London School	11/24/05  10/24/05      07/11/05  12/02/05      05/05/05  11/25/04	02/22/06      10/24/05          04/21/06     12/02/05          05/05/05     11/25/04

THRio Protocol Rio de Janeiro Hopkins	08/08/04  03/04/05	11/23/05  01/23/06
ZAMSTAR Capetown (Stellenbosch) Lusaka (Zambia)   (London School)	01/18/05    11/22/04    03/14/05	07/15/05    06/16/05    05/16/06

 
Types of assurances include:

2. Research on Human Subjects

Thibela TB:

            University of Kwazulu-Natal Biomedical Research Ethics Committee

            London School of Hygiene and Tropical Medicine Ethics Committee

THRio:

            Sauza Aguir Municipal Hospital (original)

            Comite de Etica em Pesquisa (current)

            Johns Hopkins Medicine Institutional Review Board

ZAMSTAR:

            Committee for Human Research, Stellenbosch University

            The University of Zambia Research Ethics Committee

            London School of Hygiene and Tropical Medicine Ethics Committee

 

3.  Clinical Trials (If you checked yes to item 7, Section A.IV.)

            (1) – (5) Thibela TB:   There have been no changes in this study.  The clinical trial has not started.

             (6) Date of the most recent meeting of the Data Safety and Monitoring Board: June 9, 2006

•  interim analyses: N/A

• Are any previously unreported disciplinary actions by a regulatory agency pending against any of the principals in the trial?       Yes     No  

If yes, please elaborate below.

 

B. Other Sensitive or Regulated Research

Have any changes occurred in the project involving other areas that are subject to regulation or involve risk in the areas indicated below? No 

Examples include: hazardous materials, “select agents” as defined under U.S. law, recombinant DNA, and release of modified insect vectors or genetically altered plants or other organisms into the environment.  If yes, describe how you addressed the regulatory or other requirements, and on what timeframes any remaining pending required approvals/permits will be acquired.   Topics in this area include:

• Biosafety and protection of the environment.  (For example: hazardous materials, recombinant DNA, release of modified insect vectors, genetically altered plants, or other genetically modified organisms into the environment; or use of “select agents” for entities with components in the United States). N/A

• Assuring privacy of data linked to personal identifiers. For entities with components in the United States, indicate if the grantee or organization is considered to be a “covered entity” under the Health Insurance Portability and Accountability Act of 1996 (HIPAA). N/A http://privacyruleandresearch.nih.gov/pr_02.asp

• At risk populations. For projects involving reproductive health, sexually transmitted infections, or other work that might involve studies in exploited populations (such as commercial sex workers), please reaffirm your assurance that no funds have been used to support, sponsor or engage in trafficking of persons. http://www.unodc.org/unodc/en/trafficking_links.html  N/A

 

Appendix.  Publications and Data Sharing.

Dowdy DW, Chaisson RE, Moulton LH, Dorman SE. The Potential Impact of Enhanced Diagnostic Techniques for Tuberculosis Driven by HIV: A Mathematical Model. AIDS 20: 751-762, 2006.

Corbett EL, Marston B, Churchyard GJ, De Cock KM. Tuberculosis in Sub-Saharan Africa: Opportunities, Challenges and Change in the Era of Antiretroviral Therapy. Lancet. 2006;367:926-37.

Chaudhary MA, Moulton LH: A SAS Macro for Constrained Randomization of Group- Randomized Designs.  Computer Methods and Programs in Biomedicine. (accepted)

Moulton LH, Golub JE, Durovni B, Cavalcante SC, Pacheco AG, Saraceni V, King B, Chaisson RE.  Statistical design of THRio: A phased-implementation clinic-randomized study of a tuberculosis preventive therapy intervention. (submitted)

Hanifa Y, Molefe P, Chikwava S, Opperman L, Fielding K, Lewis J, Grant AD, Churchyard GJ. Prevalence of latent TB infection, radiological TB disease and silicosis among gold miners in South Africa. IUATLD Congress, 2006. (submitted)

Hanifa Y, Mngadi K, Sefuthi C, Tautesile G, Mafube E, Mahlatsi N, Mantsoe I, Opperman L, Fielding K,  Lewis J, Churchyard GJ, Grant AED. Evaluation of Arkansas method of urine testing for Isoniazid in a South African population. IUATLD Congress, 2006. (submitted)

Highly Constrained Randomization of a Clinic-Randomized Study with a Stepped Wedge Design. L. H. Moulton; APHA Annual Meetings, Philadelphia, 2005. (invited talk)

 Is spatial dependency a problem in community-randomized trials? W. K. Pan; APHA Annual Meetings, Philadelphia, 2005. (invited talk)

Estimating Incremental Cost Effectiveness Ratios from Group Randomized Intervention Trials. M. A. Chaudhary, M. Shoukri; APHA Annual Meetings, Philadelphia, 2005. (invited talk)

Design and Analysis of Cluster Randomized Phased Implementation Studies. L. H. Moulton; ENAR, Tampa, 2006. (invited talk)

 Applying Project Management in Health Research.  L. Opperman, G.J. Churchyard: PMI Conference, Midrand, South Africa, 2006. (invited talk)  

The effect of HAART and isoniazid preventive therapy in reducing tuberculosis incidence in HIV-infected patients.  Golub, J.E., Saraceni, V., Cavalcante, S., Pacheco, A.G., Moulton, L.H., King, B., Moore, R.D., Chaisson R.E., Durovni, B.  International AIDS Conference, Toronto, 2006. (abstract)