Pivotal Study of Fexinidazole for Human African Trypanosomiasis in Stage 2

• ClinicalTrials.gov Identifier: NCT01685827
• Recruitment Status: Completed
• First Posted: September 14, 2012
• Last Update Posted: February 20, 2018
• Sponsor: Drugs for Neglected Diseases
• Information provided by (Responsible Party): Drugs for Neglected Diseases

Study Description

Brief Summary:

This clinical trial is designed to prove the efficacy and safety of Fexinidazole as an oral treatment for human african trypanosomiasis in advanced stage. The Fexinidazole is compared to reference treatment NECT. The trial will try to demonstrate that Fexinidazole is not inferior to NECT treatment.

Condition or disease	Intervention/treatment	Phase
Human African Trypanosomiasis (HAT); Sleeping Sickness	Drug: Fexinidazole; Drug: Nifurtimox; Drug: Eflornithine	Phase 2; Phase 3

Detailed Description:

Human African Trypanosomiasis (HAT) is a life-threatening and neglected disease.

Few treatment options are currently available for stage 2 (meningo-encephalitic stage) HAT, with NECT being the most commonly used one since 2010. Though NECT represents a significant improvement over current therapies, it is still far from ideal given the environment in which HAT patients live (remote, poor areas with little health infrastructure, if any, and difficult logistics). There is an urgent need for less toxic and more easily manageable compounds to treat this fatal disease.

Fexinidazole is a 2-5-nitroimidazole, formulated for oral administration, which has been shown to possess in vitro and in vivo activity against both T. b. rhodesiense and T. b. gambiense parasites.

Predicted CSF concentrations reached target levels after repeated dosing. Its efficacy and safety must now be tested in patients with stage 2 HAT.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 394 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Fexinidazole Compared to Nifurtimox-Eflornithine Combination Therapy (NECT) in Patients With Late-stage Human African Trypanosomiasis (HAT) Due to T.b. Gambiense: Pivotal, Non-inferiority, Multicentre, Randomised, Open-label Study
• Study Start Date: October 2012
• Actual Primary Completion Date: November 11, 2016
• Actual Study Completion Date: April 26, 2017

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: NECT (Nifurtimox Eflornithine Combination Therapy); Nifurtimox tablets will be given orally three times a day, at the daily dose of 15 mg/kg/day, for 10 days.; Eflornithine (400 mg/kg/day) will be given twice daily for 7 days, as a 2-hour IV infusion.	Drug: Nifurtimox; Other Name: Lampit; Drug: Eflornithine; Other Name: Ornidyl
Experimental: Fexinidazole; Fexinidazole, 600 mg tablets given by oral route, after the main daily meal (within 30 minutes from the start of the meal), at the daily dose of: 1 800 mg (3 tablets) once a day for 4 days,; Followed by 1 200 mg (2 tablets) once a day for 6 days. Total duration of treatment will be 10 days.	Drug: Fexinidazole

Outcome Measures

Primary Outcome Measures :

1. success or failure at 18 months FU visit [ Time Frame: 18 months after treatment ]

   The primary endpoint is the outcome (success or failure) at the test of cure (ToC) visit 18 months after the end of treatment (EOT) adapted from WHO criteria.

   Success at 18 months is:

   • Either cure:

     • patient alive,
     • AND with no evidence of trypanosomes in any body fluid,
     • AND 20 or less WBC/µl CSF

   • Or Probable cure:

     • Patient with no parasitological evidence of relapse in blood and lymph
     • AND who refuses lumbar puncture OR whose CSF sample is haemorrhagic without trypanosomes
     • AND whose clinical condition is satisfactory (without clinical symptom or signs) OR whose clinical status is unlikely to be due to HAT

Secondary Outcome Measures :

1. Safety endpoint [ Time Frame: 18 days - observation period ]

   Occurrence of any grade (all grades combined) adverse events during the observation period (D1-18) including:

   • any worsening of clinical symptoms listed in the inclusion checklist of symptoms and signs,
   • laboratory abnormalities of grade ≥ 2
   • Occurrence of grade ≥ 3 adverse events during the observation period
   • Occurrence of drug-related adverse events (grade ≥ 3 and any grade) during the observation period
2. Safety endpoint [ Time Frame: 24 months ]
   Occurrence of any serious adverse events from first drug intake to the end of follow-up period (18 months), and from M18 to M24.
3. Pharmacokinetics endpoint [ Time Frame: from D8 to D12 after first dosing ]
   Whole blood and CSF concentrations of fexinidazole, M1, M2 and PK parameters derived from a model of population PK data.
4. QT evaluation [ Time Frame: D0 - D4 - D10 ]
   recording of triplicates ECG

Eligibility Criteria

• Ages Eligible for Study: 15 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 15 years old or more
• Male or female
• Able to ingest at least one complete meal per day (or at least one Plumpy'Nut® sachet)
• Karnofsky index>50 (see Appendix 2 - Karnofsky Scale; p81)
• Parasitologically confirmed late-stage African trypanosomiasis infection with T. b. gambiense in the blood and/or lymph and/or CSF, attested by mobile team report (with detail of exams performed and values of WBC measured in CSF) or done at the study centre. If parasitologically negative in CSF, WBC >20/µl detected in the CSF to document stage 2 infection.
• Having a permanent address and able to comply with follow-up visit schedule
• Signed Informed Consent Form

Exclusion Criteria:

• Severely malnourished patients, defined as having a BMI < 16.
• Patients unable to take oral medication.*
• Pregnancy or lactation
• Active clinically relevant medical conditions that, in the Investigator's opinion, may jeopardize subject safety or interfere with participation in the study, including but not limited to significant liver or cardiovascular disease, active documented or suspected infection, CNS trauma or seizure disorders, coma or altered consciousness.
• Severely deteriorated general condition, such as cardiovascular shock, respiratory distress, or terminal illness.
• Any condition which compromises ability to communicate with the Investigator as required for the completion of this study.
• Any contraindication to imidazole products (known hypersensitivity to imidazoles) and NECT (known hypersensitivity to eflornithine).
• Patients previously treated for HAT.
• Patients previously enrolled in the study.
• Follow-up expectable difficulties (migrants, refugees, traders, etc.).
• History of alcohol abuse or any drug addiction.
• Clinically significant abnormal laboratory value
• Pregnancy
• Unstable ECG abnormalities
• QTcF≥ 450 msec in resting position (confirmed by 2 measurement).
• Patients not tested for malaria and/or treated adequately for this infection
• Patients not treated adequately for soil transmitted helminthic diseases

Contacts and Locations

Locations

Central African Republic

Batangafo

Batangafo, Central African Republic

Congo, The Democratic Republic of the

Bagata Hospital

Bagata, Bandundu, Congo, The Democratic Republic of the

Congo

Masi Manimba Hospital

Masi Manimba, Bandundu - DRC, Congo

Vanga Hospital

Vanga, Bandundu - DRC, Congo

HGR Mushie hospital

Mushie, Bandundu, Congo

CRT (Centre de Réference et de Traitement) Dipumba, Dipumba general hospital

Mbuji Mayi, East Kasai, Congo

HS Katanda hospital

Katanda, Kasaï Oriental, Congo

HGR ISANGI hospital

Isangi, Province Orientale, Congo

HGR (General Reference Hospital) Bandundu

Bandundu, Congo

Dingila

Dingila, Congo

Sponsors and Collaborators

Drugs for Neglected Diseases

Investigators

• Principal Investigator: Victor KANDE, MD; HAT National Control Program in DRC

More Information

Additional Information:

Sponsor Website 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Mesu VKBK, Kalonji WM, Bardonneau C, Mordt OV, Blesson S, Simon F, Delhomme S, Bernhard S, Kuziena W, Lubaki JF, Vuvu SL, Ngima PN, Mbembo HM, Ilunga M, Bonama AK, Heradi JA, Solomo JLL, Mandula G, Badibabi LK, Dama FR, Lukula PK, Tete DN, Lumbala C, Scherrer B, Strub-Wourgaft N, Tarral A. Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial. Lancet. 2018 Jan 13;391(10116):144-154. doi: 10.1016/S0140-6736(17)32758-7. Epub 2017 Nov 4. Erratum in: Lancet. 2018 Jan 13;391(10116):124.

• Responsible Party: Drugs for Neglected Diseases
• ClinicalTrials.gov Identifier: NCT01685827
• Other Study ID Numbers: DNDiFEX004
• First Posted: September 14, 2012
• Last Update Posted: February 20, 2018
• Last Verified: February 2018

Additional relevant MeSH terms:

Trypanosomiasis; Trypanosomiasis, African; Euglenozoa Infections; Protozoan Infections; Parasitic Diseases; Eflornithine; Nifurtimox; Antineoplastic Agents; Trypanocidal Agents; Antiprotozoal Agents; Antiparasitic Agents; Anti-Infective Agents; Ornithine Decarboxylase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action