Pharmacokinetic, Efficacy, Safety and Tolerability Study of a Single Dose of Acoziborole in g-HAT Paediatric Patients

Brief Title

Pharmacokinetic, Efficacy, Safety and Tolerability Study of a Single Dose of Acoziborole in g-HAT Paediatric Patients

Official Title

Pharmacokinetic, Efficacy, Safety, and Tolerability Study of a Single Dose of Acoziborole Under Fasting Conditions in Paediatric Patients From 1 to 14 Years of Age and With g-HAT: a Multicentre, Open-label Study

Brief Summary

      Acoziborole has been studied in an open-label pivotal Phase II/III trial (DNDi-OXA-02-HAT) in
      the DRC and Guinea. As the numbers of reported cases diminish, resources for surveillance and
      specialised screening will also taper. This decrease, coupled with the loss of diagnostic
      skills and disease management expertise, will lead to a weak and less specialised HAT
      technical environment. The history of g-HAT has shown that outbreaks or re-emergence of the
      disease have already happened under different circumstances when surveillance was relaxed or
      simply because the populations at risk live in areas of political instability, limiting
      access to specialised care. Even with a steady decrease of reported incidence, no model can
      currently predict that HAT could not re-emerge.

      Although g-HAT is predominantly a disease of adults, children are also affected at diverse
      rates depending on the geographical and behavioural characteristics in the different areas of
      disease transmission. Hence efforts are needed to develop a paediatric formulation from a new
      generation of oral HAT treatments.
    

Detailed Description

      Human African trypanosomiasis (HAT), or sleeping sickness, is a life-threatening disease
      transmitted by tsetse flies and caused by a single-celled extracellular parasite that lives
      free in the bloodstream and other body fluids, including lymph and cerebrospinal fluid (CSF).
      There are many species of African trypanosomes; however, only two subspecies of the
      Trypanosoma brucei (T.b.) species are causative of HAT. T.b. gambiense is endemic in West and
      Central Africa and causes over 98% of current cases. It progresses at a more indolent pace
      than that of T.b. rhodesiense.

      Approximately 5 million people live in areas, mainly in rural parts of 24 disease endemic
      countries in West and Central Africa, where HAT due to T.b. gambiense (g-HAT) is still
      considered a public health problem; whereas, 51 million people are estimated to be at risk of
      infection on the African continent. With 864 cases of g-HAT reported in 2019, the global goal
      of sustainable disease elimination by 2030, including the interruption of the transmission of
      g-HAT, is foreseeable. Consistently falling numbers of cases are thanks to efforts from
      national control programmes, supported by the World Health Organization (WHO),
      non-governmental organisations, bilateral cooperation, the private sector (including
      pharmaceutical companies), and philanthropic organisations.

      As the numbers of reported cases diminish, resources for surveillance and specialised
      screening will also taper. This decrease, coupled with the loss of diagnostic skills and
      disease management expertise, will lead to a weak and less specialised HAT technical
      environment. The history of g-HAT has shown that outbreaks or re-emergence of the disease
      have already happened under different circumstances when surveillance was relaxed, e.g. South
      Sudan and the Democratic Republic of the Congo (DRC) or simply because the populations at
      risk live in areas of political instability, limiting access to specialised care. Even with a
      steady decrease of reported incidence, no model can currently predict that HAT could not
      re-emerge.

      Although g-HAT is predominantly a disease of adults, children are also affected at diverse
      rates depending on the geographical and behavioural characteristics in the different areas of
      disease transmission. Globally, the WHO Expert Committee on control and surveillance report
      states: "rates in children are usually less than half of those in adults, reflecting less
      exposure to flies during daily activities". In data from the Médecins Sans Frontières
      Database on HAT control projects, out of 684 second stage HAT patients included, 17.5% were
      children under the age of 15 hence efforts are needed to develop a paediatric formulation
      from a new generation of oral HAT treatments. The majority of signs and symptoms associated
      with HAT occur at similar frequencies in paediatric patients with first and second stage
      disease compared with adults, including sleep disturbances. The presence of trypanosomes in
      cervical lymph nodes is less frequent in preschool children than in older children and
      adults. More infants are seen at the second stage, most likely due to delayed diagnosis and
      the immaturity of the blood-brain barrier. In some studies, fever, hepatomegaly, splenomegaly
      and facial oedema were observed more frequently in children aged 2 to 15 years than in
      adults.

      As per the WHO 2019 interim guidelines for the treatment of HAT, the choice treatment is
      determined by a two-step assessment. The first step is the clinical assessment and the second
      step is the CSF examination (lumbar puncture), which is required only for patients with
      clinical symptoms and signs suggestive of the severe meningo-encephalitic stage.

      For children <6 years old and <20 kg body weight who are second stage g-HAT, a 7-day, twice a
      day intravenous course of NECT or eflornithine is the sole treatment option. Treatment in
      first stage g-Hat involves intramuscular injections of pentamidine for 7 days. Both
      treatments require pre-treatment lumbar puncture and hospitalisation with a specialised
      health care environment that is not always possible in remote rural African areas where g-HAT
      is prevalent.

      The aim of the current study is to validate the weight-based exposure based on the population
      pharmacokinetic (pop-PK) modelling, efficacy, and safety of acoziborole in first and second
      stage g-HAT paediatric patients from 1 to 14 years of age enabling a paradigm shift in the
      management of paediatric g-HAT patients reducing the subsequent burden on families (i.e.
      mothers and the entire family will spend less time providing care). Furthermore, if the
      clinical status permits, administering a single-dose oral drug at the point of diagnosis will
      avoid the need for costly hospitalisation in specialised health centres, lumbar puncture and
      parenteral treatments. Compliance and adherence of children to treatment will be more
      straightforward and will shorten the delay between diagnosis and effective treatment, which
      will contribute to stopping disease progression and the avoidance of neurological sequelae in
      this population.

      Achieving the challenging objective of g-HAT elimination by 2030 requires a safe, effective,
      and easy-to-use tool that enables treatment at the point-of-diagnosis for all individuals,
      including children. As a single administration oral drug, acoziborole would facilitate
      treatment access for children.
    

Study Phase

Phase 2/Phase 3

Study Type

Interventional


Primary Outcome

Maximum concentration (Cmax)

Secondary Outcome

 Success or failure

Condition

Trypanosomiasis, African

Intervention

Acoziborole

Study Arms / Comparison Groups

 Acoziborole
Description:  Single dose administration
Two different formulations will be used depending on the body weight and on the step of the study:
Tablets of 320 mg dose for paediatric patients weighing 30 to 40 kg in step 1.
Granules in bottle for paediatric patients weighing 10 to 40 kg in step 2. Granules will be packed in bottles of 160 mg dose.
Initially, recruitment will be limited to paediatric patients weighing 30 to 40 kg who will receive the 320 mg tablet formulation.
Once the PK data from the first six patients have been analysed and the dosing regimen confirmed or adapted, inclusion will resume and be extended to allow enrolment of paediatric patients weighing >10 kg with the granule formulation (including for paediatric patients weighing 30 to 40 kg).

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

35

Start Date

July 15, 2022

Completion Date

June 30, 2024

Primary Completion Date

June 30, 2024

Eligibility Criteria

        Inclusion Criteria:

          -  Signed informed consent from one parent or from the legal representative

          -  Assent from the paediatric patient (for paediatric patients >6 years of age) to
             participate in the study, collected in the presence of an impartial witness

          -  Between 1 and 14 years of age and between 10 and ≤40 kg (as per the requirements of
             step 1 and step 2)

          -  Male or female

          -  Evidence of trypanosomes in any body fluid (blood or lymph or CSF)

          -  Having a permanent address and able to comply with the schedule of follow-up visits

          -  Agreement to not take part in any other clinical trials during the participation in
             this study

          -  For pubescent girls of childbearing potential must agree to have protected sexual
             relations to avoid becoming pregnant from enrolment up to 3 months after dosing
             (contraceptive protection will be advised and offered at no cost)

        Exclusion Criteria:

          -  Previous treatment for g-HAT

          -  Refusal to participate in the study, expressed by the paediatric patient and/or parent
             or legal representative

          -  Complicated severe acute malnutrition as defined by weight for height (-3 SDs Z score)

          -  Unable to take medication by the oral route

          -  Clinically significant medical condition (other than HAT) that could, in the opinion
             of the Investigator, jeopardise the patient's safety or interfere with participation
             in the study

          -  Any condition (excluding HAT-specific symptoms) that affects the patient's and/or
             parent's ability to communicate with the Investigator as required to complete the
             study

          -  Prior enrolment in the study or prior intake of acoziborole

          -  Foreseeable difficulty complying with follow-up, including family of migrant workers,
             refugee status, itinerant trader, etc.

          -  Clinically significant laboratory test abnormality, with:

               -  Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) more than
                  twice the upper limit of normal (ULN)

               -  Total bilirubin more than 1.5 x ULN

               -  Severe leukopenia at <2000/mm3

               -  Potassium <3.5 mmol/L

               -  Any other clinically significant laboratory test abnormality

          -  Pregnancy confirmed by a positive urine pregnancy test (during the screening period
             and/or within 24 hours prior to the start of treatment) for pubescent girls of
             childbearing potential

          -  Not tested for malaria and/or not having received appropriate treatment for malaria

          -  Not having received appropriate treatment for soil-transmitted helminthiasis
      

Gender

All

Ages

1 Year - 14 Years

Accepts Healthy Volunteers

No

Contacts

Victor Kande Betu Ku Mesu, Dr, +41 22 906 92 60, [email protected]

Location Countries

Congo, The Democratic Republic of the

Location Countries

Congo, The Democratic Republic of the

Administrative Informations


NCT ID

NCT05433350

Organization ID

DNDi-OXA-05-HAT

Secondary IDs

ACOZI-KIDS

Responsible Party

Sponsor

Study Sponsor

Drugs for Neglected Diseases


Study Sponsor

Victor Kande Betu Ku Mesu, Dr, Principal Investigator, Ministry of Public Health, Hygiene and Prevention, Kinshasa


Verification Date

July 2022