Pivotal Phase III clinical trial results conclusively show that Nifurtimox-Eflornithine Combination Therapy (NECT) is well tolerated and effective against the advanced stage of T. b. gambiense sleeping sickness, a fatal disease that threatens 60 million people in sub-Saharan Africa.
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Positive results from a pivotal, multi-centre, multi-country Phase III trial investigating an improved treatment for the advanced stage of sleeping sickness were presented yesterday at the 57th Annual Meeting of the American Society of Tropical Medicine & Hygiene held in New Orleans, Louisiana, USA. This trial shows conclusively that NECT is a safe, effective, and practical treatment.
Treatment Against Sleeping Sickness
Fatal if untreated, sleeping sickness (human African trypanosomiasis, or HAT) threatens 60 million people in 36 countries and has devastated many communities in sub-Saharan Africa over the past century. Because the first stage of sleeping sickness often goes undiagnosed, most patients are not treated until they reach the deadly second stage. Current treatment options for stage 2 sleeping sickness are either toxic or difficult to use in the rural, remote, and extremely poor areas where the disease persists. The potential increase in resistance to the two available drugs is also of great concern.
The clinical trial enrolled 280 patients and was completed in five years. It compared the safety and efficacy of NECT, a coadministration of the oral drug nifurtimox and the intravenous drug eflornithine, with eflornithine monotherapy, the current first-line treatment for stage 2 T. b. gambiense sleeping sickness. As is requisite to establish efficacy in this disease, patients were actively followed up for 18 months after treatment.
The trial conclusively demonstrated that NECT is as well-tolerated and efficacious as eflornithine monotherapy. NECT is a far more practical treatment than eflornithine monotherapy (which requires 56 round-the-clock injections over 14 days) because the number of injections is reduced to 14, the frequency of injections is halved, and the treatment duration is reduced to 10 days. This schedule better fits the routine of health care centers because infusions are reduced to twice a day, without nighttime infusions.
Epicentre and Médecins Sans Frontières (MSF/Doctors Without Borders) initiated the study in 2003 at Nkayi, the Republic of the Congo (RoC) along with the national HAT control program. The trial, which was conducted at international Good Clinical Research Practice (GCP) standards, was extended to additional sites in the DRC by Drugs for Neglected Diseases initiative (DNDi) as of 2004: Epicentre, MSF, the Swiss Tropical Institute (STI) and the national HAT control program contributed to the study’s conduct in the DRC.
“The trial results demonstrate that NECT can deliver immediate benefits to both patients and healthcare workers in the field,” remarked Emmanuel Baron, Director of Epicentre. “New combinations of existing drugs offer an important avenue of improvement for patients suffering from this disease while new drugs are undergoing the lengthy process of development.”
Undertaking clinical trials for sleeping sickness is very difficult due to the remote location of patients, where infrastructure and research capacity are lacking, and civil disruption and war are frequent. Despite these considerable challenges, the NECT trial is among the few randomised controlled studies to be successfully completed and achieved greater than 90% follow-up of the patients at 18 months after treatment.
“NECT, which will provide patients with a new and improved treatment of stage 2 sleeping sickness will reduce the use of melarsoprol, a toxic drug which kills 1 in 20 patients,” remarked Bernard Pécoul, Executive Director of DNDi. “However, it is still a far-from-ideal treatment because it requires infusions and trained health care staff; DNDi remains committed to further research efforts into delivering innovation that will best meet the needs of the most neglected patients.”
We have made considerable progress in controlling sleeping sickness and in ensuring access to drugs, donated to the World Health Organization by sanofi-aventis and Bayer Healthcare. However, the increasing risk of resistance and the complexity in administering these drugs may hamper the sustainability of ongoing control measures. The WHO Department of Neglected Tropical Diseases is firmly committed to do all it can for the timely inclusion of the NECT in the WHO List of Essential Medicines (EML) and also provide appropriate recommendations for the use of this combination of drugs. Once these recommendations are issued, distribution and implementation will be ensured by WHO. We have partnered with DNDi since their foundation and this new combination of drugs is a great achievement to patients. It sends out a strong message to partners to continue research and development of new and safer drugs, said Dr. Lorenzo Savioli, Director of WHO Department of Neglected Tropical Diseases.
“The results of the NECT study instill hope in practitioners and patients across sub-Saharan Africa,” remarked Dr. Constantin Miaka Bilenge, the Special Advisor to the HAT National Control Program of the DRC. “We are looking for an easy-to-use treatment that can improve case management in the field, and NECT provides us this practical improvement.”
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About sleeping sickness (human African trypanosomiasis; HAT)
Commonly known as sleeping sickness, human African trypanosomiasis (HAT), is a life-threatening illness from which 60 million people in 36 countries, primarily in sub-Saharan Africa, are at risk . HAT mainly affects working adults, which means it has an immense social and economic impact on local communities in HAT-endemic countries, many of which already have to contend with poverty and armed conflict as well as other major diseases such as malaria. Transmitted by tsetse flies, HAT exists in two forms, Trypanosoma brucei gambiense (T.b. gambiense) or Trypanosoma brucei rhodesiense (T.b. rhodesiense) disease. T.b. gambiense HAT accounts for ~97% of reported cases and is endemic in 24 countries; the disease is more chronic than its rhodesiense counterpart. The initial haemolymphatic stage disease (stage 1) often goes undiagnosed as there are few differential clinical symptoms. If left untreated, the disease will progress into the advanced meningo-encephalitic stage (stage 2) when the parasites cross over the blood-brain barrier and invade the patient’s central nervous system (CNS). This stage 2 disease causes neuropsychiatric problems, convulsions, and serious sleep disturbance; eventually these symptoms lead to coma. Without appropriate treatment, the disease is invariably fatal. HAT places a large burden on communities and individual households. In 2002, WHO estimated that approximately 1.5 million disability-adjusted life years (DALYs) were lost due to HAT. A more recent study in the DRC showed that the cost to each household following a HAT outbreak was equivalent to 5 months’ income for that household . No new treatments for stage 2 HAT are expected in next 5 years, so there is an urgent need to develop new regimens based on currently available drugs.
About Epicentre
Epicentre is a non-profit organisation created in 1987 by Médecins Sans Frontières, which groups health professionals specialised in public health and epidemiology. In 1996, Epicentre became a World Health Organization Collaborating Center for Research in Epidemiology and Response to Emerging Diseases. Epicentre’s team carries out operational and clinical research from its offices in Paris (headquarters), Geneva, and Brussels, and a permanent research base in Mbarara, Uganda. Epicentre also offers its expertise to organisations requesting short-term field epidemiology studies in developing countries. Epicentre designs and organises training sessions for Médecins Sans Frontières and other partners in public health and epidemiology. Epidemiologists from Epicentre also give guest lectures and organise training modules in the field of applied epidemiology as part of university or diploma courses. Lastly, Epicentre has developed an expertise in the development and field installation of software applications for the management of health information. For more information, please consult: www.epicentre.msf.org.
About DNDi
The Drugs for Neglected Diseases initiative (DNDi) is an independent, not-for-profit product development partnership working to research and develop new and improved treatments for neglected diseases such as malaria, leishmaniasis, human African trypanosomiasis, and Chagas disease. With the objective to address unmet patient needs for these diseases, DNDi was established in 2003 by Institut Pasteur and Médecins Sans Frontières along with four publicly-funded research organizations in neglected disease-endemic countries. Working in partnership with industry and academia, DNDi has the largest ever R&D portfolio for the kinetoplastid diseases and currently has 6 clinical and 4 preclinical projects. DNDi delivered its first product, a fixed-dose antimalarial “ASAQ”, in partnership with sanofi-aventis in 2007. In April 2008, DNDi delivered its second product, fixed-dose “ASMQ”, with Farmanguinhos as first-line treatment for children and adults suffering from uncomplicated P. falciparum malaria cases in Latin America and Asia. For further information, please consult www.dndi.org.
About MSF
Doctors Without Borders/Médecins Sans Frontières (MSF) is an international medical humanitarian organization created in 1971. Today, MSF provides aid in nearly 60 countries to people whose survival is threatened by violence, neglect, or catastrophe, primarily due to armed conflict, epidemics, malnutrition, exclusion from health care, or natural disasters. MSF provides independent, impartial assistance to those most in need. MSF reserves the right to speak out to bring attention to neglected crises, to challenge inadequacies or abuse of the aid system, and to advocate for improved medical treatments and protocols. For more information, please consult http://www.msf.org.
Media Contacts
Epicentre
Caroline Livio, MSF/Paris, +33 (0)1 40 21 29 29
DNDi
Sadia Kaenzig, DNDi Geneva, +41 (0)79 819 99 71 skaenzig@dndi.org
Michelle French, DNDi North America, (212) 298-3743 or (646) 552-4600 mfrench@dndi.org
Ann-Marie Sevcsik, DNDi Geneva, (646) 258-8131 or +41 (0)79 814 9147 amsevcsik@dndi.org
MSF
Koert Ritmeijer, Head, Public Health Department a.i., MSF Holland, +31 (0) 20 520 8767 koert.ritmeijer@amsterdam.msf.org
