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| Clinical study comparing the nifurtimox-eflornithine combination with the standard eflornithine regimen for the treatment of Trypanosoma brucei gambiense human African trypanosomiasis in the meningo-encephalitic phase |
| ISRCTN | ISRCTN03148609 |
| ClinicalTrials.gov identifier | |
| Public title | Clinical study comparing the nifurtimox-eflornithine combination with the standard eflornithine regimen for the treatment of Trypanosoma brucei gambiense human African trypanosomiasis in the meningo-encephalitic phase |
| Scientific title | |
| Acronym | N/A |
| Serial number at source | WHO ref: A50402 and A60444; NFE0105; NFE0206 |
| Study hypothesis |
Melarsoprol is the most commonly used product for the treatment of patients suffering from human African trypanosomiasis (HAT) in the meningo-encephalitic (second, late) phase. This treatment is frequently complicated by fatal reactive encephalopathy, and at the same time resistance is beginning to appear in various countries. Eflornithine is effective and better tolerated, but it is more difficult to use. Nifurtimox, registered in several South American countries for treatment of Chagas' disease but used off label since the 1970's in series of cases of meningo-encephalitic HAT, is at present the only other potential alternative for the treatment of late-stage HAT.
The very limited number of compounds available, the lack of prospects for the development of new products and the emergence of resistance are arguments for the use of therapeutic combinations. Ideally, drug combinations should allow for reductions in the dosages of the drugs used in a way that, in particular in the case of toxic drugs such as those used for second stage HAT, the toxicity of the combination does not exceed that of either monotherapy. Of the three drug combinations nowadays possible: melarsoprol-nifurtimox, melarsoprol-eflornithine and eflornithine-nifurtimox, the last one has (in two different dosing regimens) shown the least treatment-associated toxicity and mortality in the 69 patients treated in one previous and this clinical trial to date. Good tolerability was also observed in a case series of 31 patients. The efficacy data to date suggest that efficacy is comparable to that of eflornithine and that of melarsoprol (in areas without high melarsoprol failure rates). The main objective of the study is to compare the therapeutic combination of intravenous (IV) eflornithine and oral nifurtimox to the standard IV eflornithine regimen in terms of therapeutic efficacy and clinical safety, in patients suffering from Trypanosoma brucei gambiense (Tbg) HAT in the meningo-encephalitic phase. If therapeutic non-inferiority is shown, the combination regimen will represent an alternative therapy with simpler and shorter administration regimen, shorter hospitalisation, lower cost and some level of protection against the emergence of resistance. |
| Ethics approval |
Ethics approval received from:
1. Ethical Clearance Committee (Uganda) on the 8th May 2005 and 8th May 2006 (ref: VCD/UNCT/06) 2. World Health Organization (WHO) Ethics Review Committee (ERC) on the 30th May 2005, and was reviewed on the 26th April 2006 and 27th February 2007 |
| Study design | Randomised, open label, clinical non-inferiority trial |
| Countries of recruitment | Uganda |
| Disease/condition/study domain | Human African trypanosomiasis |
| Participants - inclusion criteria |
1. Confirmed second-stage Tb gambiense infection: presence of the parasite in blood, lymph node fluid or cerebrospinal fluid (CSF) and greater than 20 white blood cells/µL in CSF
2. Age 15 years or older, either sex 3. Resident in a radius of 50 km from Omugo Sleeping Sickness Treatment Centre 4. Written informed consent of the patient or of a legally acceptable representative if the patient is a minor (less than 18 years for both genders in Uganda) or unable to communicate |
| Participants - exclusion criteria |
1. Pregnant woman (systematic testing (urine human chorionic gonadotropin [HCG]) of women of childbearing potential)
2. Treated for late-stage HAT during the last 36 months. Patients previously treated for first-stage (pentamidine) can be included. 3. Unlikely to have access to the treatment centre or be accessible at their place of residence for 18 months after treatment 4. Unable to take oral medication 5. Suffering from conditions other than second stage HAT that seriously limit the chances of survival over 18 months time 6. Severe anaemia (haemoglobin [Hb] less than 5 g/dl) 7. Severe underlying diseases upon admission (e.g. active tuberculosis and/or being treated for TB; bacterial or cryptoccocal meningitis; stages 3 or 4 human immunodeficiency virus [HIV]/acquired immune deficiency syndrome [AIDS] according to the WHO clinical definition) (WHO, 1986) 8. Renal failure based on clinical examination combined with biochemistry. Calculated creatinine clearance less than 20 mL/min (Cockcroft's equation). 8.1. Males: creatinine clearance (mL/min) = (Wt [kg] x 140 - age [years]) ÷ (72 x serum creatinine [mg/dL]) 8.2. Females: 0.85 x the above value 9. Hepatic failure based on clinical examination combined with biochemistry total bilirubin greater than 50 µmol/L, alanine aminotransferase (ALAT)/glutamate pyruvate transaminase [GPT] greater than 70 UI/L |
| Anticipated start date | 01/11/2005 |
| Anticipated end date | 13/06/2009 |
| Status of trial | Ongoing |
| Patient information material | |
| Target number of participants | 280 |
| Interventions |
1. Eflornithine IV 7 days 400 mg/kg/day 12 hourly and nifurtimox orally 10 days 15 mg/kg/day 8 hourly
2. Eflornithine IV 14 days 400 mg/kg/day 6 hourly The total duration of follow up is 18 months for both arms. Contact details for Principal Investigators: 1. Moyo site: Dr Seraphine Adibaku District Director of Health Services Moyo District Local Government P.O. Box 1 Moyo, Uganda 2. Omugo site: Dr Freddie Kagwisagi Kansiime Deputy Director Coordinating Office for Control of Trypanosomiasis in Uganda (COCTU) P.O. Box 16345 Kampala, Uganda |
| Primary outcome measure(s) | The cure rate assessed via the number of alive subjects 18 months after treatment without laboratory signs of infection, i.e. absence of trypanosome(s) in the CSF, blood or lymph node fluid and CSF leukocytes count less than 20/µl. |
| Secondary outcome measure(s) |
1. The duration of survival without laboratory signs of infection up to 18 months after treatment
2. Proportion of serious adverse events and of major (grade 3 and 4) adverse events related to the treatment (adverse occurring in each treatment arm) |
| Sources of funding | United Nations Children's Fund (UNICEF)/United Nations Development Programme (UNDP)/World Bank/World Health Organization (WHO) - Special Programme for Research and Training in Tropical Diseases (TDR) |
| Trial website | |
| Publications | |
| Contact name | Dr D. Kioy |
| Address |
World Health Organization (WHO)
20 Avenue Appia |
| City/town | Geneva-27 |
| Zip/Postcode | CH-1211 |
| Country | Switzerland |
| Sponsor | UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) |
| Address | 20 Avenue Appia |
| City/town | Geneva-27 |
| Zip/Postcode | CH-1211 |
| Country | Switzerland |
| Fax | +41 (0)22 791 4854 |
| tdr@who.int | |
| Sponsor website: | http://www.who.int/tdr |
| Date applied | 12/09/2005 |
| Last edited | 18/04/2008 |
| Date ISRCTN assigned | 18/04/2008 |
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