Project 5 of the APRIORI programme

Project details
Title: Development of drug regimens to shorten treatment for tuberculosis
Project coordinator: R. Aarnoutse (UMCN)
Researcher(s): to be determined
Running time: 2006-2010

Project summary
Background / problem statement
Tuberculosis (TB) is one of the major infectious diseases that cause immense morbidity and mortality in sub-Saharan Africa. Available treatment regimens are lengthy and complex, inviting problems of nonadherence, inadequate response and resistance development. Therefore, a long-term goal for TB control has been to shorten the duration of treatment. Unfortunately, shorter regimens with currently available TB drugs in usual dosages have not
ensured acceptable rates of cure and relapse. Therefore, alternative strategies to shorten treatment are urgently needed. Such strategies are (1) optimizing the use/dosing of available TB-drugs, (2) use of new antimicrobials with added activity against M. tuberculosis and a combination of (1) and (2).
Unfortunately, sub-Saharan countries have only limited capacity to investigate such interventions that could relieve the burden of TB.
Therefore this project was developed as a cooperative initiative of African and Dutch researchers, with both scientific/medical as well as capacity building aims.

Overall aims
The overall aims of this project are

• to perform in-depth farmacological studies to provide the scientific background for shorter treatment regimens for TB.
• to build capacity, contributing to the establishment of a site for drug trials (phase II) at
  KCMC / Kibong’oto National TB Hospital, Tanzania.

Development of new regimens and interventions to shorten TB-treatment (first aim)
Two innovative strategies to shorten TB treatment are explored in this project, each corresponding to one of the abovementioned strategies to shorten TB treatment:
(1) a higher dose of rifampicin will be evaluated and
(2) two treatment regimens incorporating the new fluoroquinolone moxifloxacin plus high dose rifampicin will be investigated.
To assess the pharmacokinetics, safety/tolerability and bacteriological response of these regimens and interventions, two phase II studies will be set up (see figure). The most important bacteriological parameters indicative for the propensity of an intervention to shorten treatment (to be assessed in both studies) are the time to sputum culture conversion and the percentage of patients with sputum culture conversion after 2 months.

Study 1.
Study 1 will be a two-arm phase II study among 100 pulmonary TB patients, evaluating differences in pharmacokinetics, safety/tolerability and bacteriological response between regimens that incorporate a standard (600 mg) or high (900 mg) daily dose of rifampicin in the intensive phase.

Study 2.
Study 2 is a three-arm phase II study (150 patients) that focuses on moxifloxacin as a promising drug to shorten TB treatment. This study builds on the anticipated results of study 1. In a control arm, patients will take isoniazid, pyrazinamide, ethambutol and high-dose rifampicin during the intensive phase. Participants in arms 2 and 3 will take the same regimen, but with moxifloxacin instead of either ethambutol (arm 2) or isoniazid (arm 3).

Capacity development (second aim)
Conductance of this project will build capacity for the actual establishment of a phase II clinical trial site at KCMC/Kibong’oto.
In terms of human resources, one African PhD student, a local post-doc, research nurses, lab technicians and administrators will be recruited and trained in pharmacokinertic and safty assessments, bacteriological evaluations, adherence measurements, data recording, statistics and scientific writing.
In terms of upgrading of infrastructure, standard operating procedures will be developed, GCP and GLP practices will be implemented, and data recording and management systems will be optimized. A facility for pharmacokinetic assessments (PK unit) will be built.
Specific microbiological tools will be introduced/optimized and new surrogate (bio-)markers of TB treatment outcome will be explored. This project and the project "Concurrent treatment in TB and HIV co-infection" collectively contribute to and simultaneously profit from several developments in TB capacity building. Therefore these joint projects represent an efficient means of capacity building at the research sites.
In the end, the Kilimanjaro region and Tanzania will be provided with well evaluated alternative treatment regimens , to be tested in larger phase III studies with a long follow-up to assess relapse rates. These phase III trials will enable new capacity building.