Download Leading European and African clinicians commence a new trial that

Leading European and African clinicians commence a new trial that may
lead to shorter tuberculosis treatment.
The PanACEA consortium (Pan African Consortium for the Evaluation of Antituberculosis agents) have started recruiting patients to an innovative new
clinical trial of tuberculosis (TB) treatments. The aim of this trial is to identify
new treatment regimens that could significantly shorten the length of therapy
from six months to three months. The trial is being conducted in Tanzania and
South Africa and uses a new approach that could reduce the time taken to bring
the treatment to market. The MAMS-TB trial (Multi-arm-multi-stage -TB) uses a
combination of established drugs and novel drugs and is funded by the European
Developing Country Clinical Trials Partnership (EDCTP).
The MAMS adaptive trial design was developed for assessment of new cancer
regimens at the UK Medical Research Council (MRC) Clinical Trials Unit (CTU).
The MAMS-TB trial is the first trial to use this approach in the selection of TB
regimens. The MAMS design enables regimens with unsatisfactory outcomes to
be dropped rapidly. It allows the researchers to test multiple potential
treatments quickly to select the best regiment to be used in a trial that would
allow a new treatment to be approved by licensing authorities. The methodology
is more fully described in a recent publication.1
The Chief Investigator Martin Boeree from the University of Nijmegen said “The
MAMS-TB trial is a unique opportunity to develop a novel TB treatment rapidly
that will substantially shorten treatment”. Michael Hoelscher from LudwigMaximilians-University of Munich, who represents the University who sponsors
the study said “in the MAMS-TB study we are developing better methods to treat
TB for the most disadvantaged in the world community”. Stephen Gillespie from
the University of St Andrews noted that this new development has only been
able to occur because of the work of our many collaborators in Africa and the
work that the consortium has been doing to develop capacity to test new
regimens in an African setting. One of the Principle Investigators, Gibson Kibiki,
is excited to start this trial, which is innovative in terms of design, collaboration
and the use of a complete electronic source system. Nyanda Ntinginya, the
Principle Investigator from the NIMR-Mbeya Medical Research Center is
delighted to see that Tanzania together with South Africa is taking a leading role
in the global effort to control tuberculosis. Lilian Tina Minja, Principal
Investigator at the Ifakara Health Institute, points out that the PanACEA
consortium is an excellent example for bilateral and dynamic collaborations
between Southern and Northern partners in TB drug development and
evaluation.
Background information
Tuberculosis is a major public health emergency with approximately 8 million
new cases a year and more than a million deaths. It causes a chronic lung
infection that tends to affect the poorest members of society. Conventional
market solutions to tuberculosis drug development cannot be expected to
provide a solution. The PanACEA consortium has been brought together under
the auspices of the EDCTP to be the main vehicle of European – African
collaboration to build a research network that can tackle this problem that is
causing so much death in individuals in the most productive years of their life.
The consortium has been able to develop capacity of African centres to tackle
tuberculosis through building infrastructure and supporting the professional
development of African and European scientists. We have 11 collaborating
centres in sub-Saharan Africa and a growing group of European collaborators.
Additional information about the PanACEA consortium
In 2003 the European and Developing Countries Clinical Trial Partnership
(EDCTP) was founded as a European Economic Interest Group by the European
member states and the European Commission. Its target was poverty-related
disease (HIV/AIDS, malaria and tuberculosis) and focusing on phase II and III
clinical trials. It was also recognised that successful clinical trials required a true
partnership between the countries where the drug/vaccine is invented and
where it is to be tested. EDCTP was intended to be a platform where countries
from the South and the North could receive funding and where research agendas
and priorities were set jointly. The EDCTP has become a catalyst for innovative
trials and for successful scientific capacity development programmes and is now
supporting approximately 200 projects.
An expert consultation was held in Dublin in 2007 under the aegis of the
partnership and concluded that, since the funds for clinical trials were small and
the number of options limited, a brokered call would be the most efficient
approach to form a consortium that could achieve more than “just another
clinical trial”. The aims were to develop a product portfolio free of
political/commercial constraints, to develop a network of African trial centres
that would be large enough to host pivotal phase III trials, and to attract future
product development projects. This was the first time that competing scientists
working on development of different anti-TB drugs agreed to work together for a
uniform approach. This will also facilitate future trials where drugs can cross
over from one project to another to improve the efficacy of combined TB
treatment regimens. It is also useful to funders who can jointly evaluate the
performance of their drugs of interest within the common research platform.
The selected research groups met with external advisors from the Gates
Foundation and the Global Alliance to decide the optimum use of the research
funding. The most pressing trials goals were to take the moxifloxacin
development programme to completion, to study the optimal dosage of
rifampicin, and to take a new compound SQ 109 through its early phase clinical
trials providing a balanced portfolio.
Creating enhanced trials capacity in high burden countries to perform regulatory
trials and empowering African research groups to be able to compete
internationally for research funds is a major priority. A grant request was
written to the EDCTP by the partners and reviewed externally in the usual way.
Co-funding was achieved through generous grants from the participating
European Union member states, the European Commission, Gates Foundation,
the Global Alliance, and pharmaceutical companies.
The network
The PanACEA network includes 11 African institutions in six countries and four
European Institutions with current capacity ranging from basic patient care to
full ICH-GCP compliance. Physical structure and equipment upgrades are
planned for seven of the sites and five sites will conduct observational /
epidemiological studies. All sites will participate in the core PanACEA training
and capacity development as described below. Specific activities at each site are
shown in figure 1.
Previous trials activities
REMoxTB is a randomised placebo-controlled double blind phase III trial,
comparing two months moxifloxacin, isoniazid, rifampicin and pyrazinamide
followed by two months moxifloxacin, isoniazid and rifampicin, and two months
ethambutol, moxifloxacin, rifampicin and pyrazinamide followed by two months
moxifloxacin and rifampicin compared with the standard for the treatment of
adults with smear positive pulmonary tuberculosis. This has now completed
recruitment and will report in early 2014.
The first HIGHRIF trial consists of a dose-escalating study to explore the
maximum safe and tolerable dose in TB patients. The study started in Cape
Town, South Africa, and has recruited patients from 10mg/kg (the standard
dose), 20 mg/kg 25mg/kg, 30 mg/kg and 35mg/kg of rifampicin without
evidence of toxicity. There was a suggestion of increasing bactericidal activity
with dose and higher doses of rifampicin are therefore being evaluated with
standard and novel drugs in the MAMS-TB trial. Another HIGHRIF trial in Moshi
and Bagamoyo, Tanzania compared for a two month period 10 mg/kg, 15 mg/kg
and 20 mg/kg. No serious toxicity was observed.
The first SQ109 trial is a phase IIa “early bactericidal activity” study that started
in December 2010 in Cape Town South Africa and has now completed enrolment.
SQ109 is being evaluated in the MAMS-TB trial in combination other novel drugs.
Panacea was one of the five daughters of Asclepius and Epione each of whom
received one aspect of Aesclepius’ powers. Panacea’s gift was that of universal
cure. There is no doubt that the tuberculosis emergency needs, if not a universal
cure then a much more effective one. The PanACEA consortium hopes to play its
part in bringing this about.
Stephen H. Gillespie
Martin Boeree
Michael Hoelscher
Chief Investigators for the PanACEA consortium
Reference
1.
Phillips PPJ, Gillespie SH, Boeree M, Heinrich N, Aarnoutse R, McHugh T,
et al. Innovative trial designs are practical solutions for improving the treatment
of tuberculosis. Journal of Infectious Diseases. 2012; 205(suppl 2): S250-S7.