Positive Results for Improved Treatment Against Sleeping Sickness

Pivotal Phase III clinical trial results show Nifurtimox-Eflornithine Combination Therapy (NECT) is well tolerated, effective treatment for advanced stage sleeping sickness

New Orleans, Paris, Geneva; December 9, 2008 – Positive results from a pivotal, multi-center, 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.

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 Doctors Without Borders/Médecins Sans Frontières (MSF) 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 Democratic Republic of Congo (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 randomized 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.”

NECT In A Nutshell

Compared to eflornithine monotherapy as shown in the Phase III study, NECT was shown to be:

• Non-inferior in terms of efficacy: 97% to 98% for NECT (depending on analysis approach)
• Well-tolerated, with low fatality rates in both arms
  • Diarrhea, fever, infection, anorexia, and hypertension more frequent with eflornithine treatment
  • Nausea and/or vomiting more frequent with NECT
• The number of infusions of eflornithine is reduced from 56 to 14:
  • Less burdensome for the health care staff
  • Less risk of infections
  • More convenient for the patient
• The treatment duration is reduced from 14 to 10 days:
  • Less expensive for the severely cost-constrained health system
  • More capacity for the treatment center
  • More convenient for the patient
• The number of infusions per day is reduced from 4 (every 6 hours) to 2 (every 12 hours):
  • Less burdensome for the health care staff: no need for nighttime care
  • More convenient for the patient
• Reduced logistical challenges:
  • Smaller volume/weight (cheaper transportation)
  • A treatment kit can contain 4 instead of 2 full treatments in a ~35 kg package
• Resistance is less likely to develop as the two drugs have different modes of action, thus mutual protection is to be expected.