Shorter TB drug treatment trial

Patient enrolment target is met

TDR news item
19 December 2008

A pivotal Phase III trial of a shorter, 4-month course for tuberculosis (TB) treatment has taken a significant step forward after the enrolment quota of 1836 volunteer patients was reached in African study sites. The trial is testing a 4-month course of TB multidrug treatment including gatifloxacin, against the standard 6-month multidrug TB course.

The trial, launched in 2005, aims to show that the new regimen is safe and is not inferior in efficacy in comparison with the standard 6-month regimen. The achievement of the target recruitment of 1836 patients in October 2008 means that the final patients needed for the study will now complete treatment in the second quarter of 2009.

TB centres of the National Control Programme in Senegal and Benin together with clinical and research institutions in Guinea, Kenya and South Africa are all partners in the study, which is conducted in collaboration with institutions in Europe (France, United Kingdom and Belgium) federated in the European Commission (EC)-funded Oflotub Consortium. The study is cosponsored through technical oversight by TDR, the Special Programme for Research and Training in Tropical Diseases, and the Institut de Recherche pour le Développement (IRD), France, with funding provided by TDR.

Despite widespread success in implementing the internationally recommended strategy for TB control called DOTS, many patients in developing countries still fail to adhere to the entire 6-month regimen. These treatment failures in individuals have, in turn, contributed to the worldwide spread of resistant forms of TB, which are even more difficult to treat and pose a serious long-term public health threat.

Gatifloxacin is an oral fluoroquinolone antibiotic with activity against Mycobacterium tuberculosis. In 2003, TDR began a programme to develop and register a gatifloxacin-containing treatment of pulmonary TB, in collaboration with the EC-funded Oflotub Consortium. A series of non-clinical toxicology studies were followed by a Phase I and a Phase II study in South Africa. The Phase II trial was conducted in 217 people with TB, equally distributed between four treatment arms where either gatifloxacin, moxifloxacin, or ofloxacin replaced ethambutol in the standard regimen, which acted as a control treatment. The results suggested that inclusion of gatifloxacin in multidrug therapy could facilitate the overall reduction of treatment from 4 to 6 months.

In the Phase III trial, patients are randomly allocated to receive either the standard treatment (rifampicin + isoniazid + pyrazinamide + ethambuthol for 2 months, followed by rifampicin + isoniazid for 4 months) or the shortened tested treatment (rifampicin + isoniazid + pyrazinamide + gatifloxacin for 2 months, followed by rifampicin + isoniazid + gatifloxacin for 2 months).

The study involves only adults under the age of 65. Because gatifloxacin has been associated with the problem of hypo- and hyperglycaemia, patients with a history of diabetes or abnormal blood glucose levels have been excluded from the trial. The study is conducted according to international standards of Good Clinical and Laboratory Practice (GCLP) and is supervised by an independent Data Safety Monitoring Board.

It is expected that the initial analysis of safety and efficacy will be conducted after 1 year post-treatment, i.e. in mid-2010, followed by a final 2-year analysis. Should the initial 1-year analysis be positive, it is anticipated that a formal file for registration of a gatifloxacin-containing TB drug combination will be submitted to the United States Food and Drug Administration and other regulatory authorities in late 2010 or early 2011.

For more information:

TDR contact
Dr Piero Olliaro

IRD contact
Dr Christian Lienhardt, Christian.Lienhardt@ird.fr

European Commission contact
Hannu Laang, Scientific Officer for TB, Hannu.laang@cec.eu.int

About TDR
The Special Programme for Research and Training in Tropical Diseases (TDR) is a global programme of scientific collaboration established in 1975, sponsored by the United Nations Children's Fund, United Nations Development Programme, World Bank, and World Health Organization and based in Geneva, Switzerland. Its focus is research into neglected diseases of the poor, with a two-pronged mission of improving existing approaches and developing new ways to prevent, diagnose, treat and control the diseases, while building research capacity and leadership in the countries where the diseases are prevalent.

About IRD
Founded in 1944, the Institut de Recherche pour le Développement (IRD) is a public science and technology research institute, reporting to the French ministries of research and development cooperation. IRD's research mission focuses on the relationship between man and the environment in tropical and Mediterranean countries, with a view to contributing to their sustainable development, particularly in the area of societies, health, environment and living resources.

About the Oflotub Consortium
Oflotub is a consortium of 10 partners from Europe and Africa that was initiated in 2002 to undertake Phase II and Phase III trials to test the safety and efficacy of a gatifloxacin-containing 4-month treatment regimen for the treatment of TB. It was established under the auspices of the European Commission and is coordinated by the Institut de Recherche pour le Développement (IRD) in Paris, France. The objective of the Consortium is to contribute to the development of research capacities and the reinforcement of structures to conduct clinical trials respecting international standards of care in Africa.

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