Clinical trial NCT02123290: DSM265 Phase IIa Investigation Treating Plasmodium Falciparum or Vivax
Official title: A Proof-of-Concept, Open Label Study to Assess the Efficacy, Safety, Tolerability and Pharmacokinetics of Single Doses of DSM265 in Adult Patients With Acute, Uncomplicated Plasmodium Falciparum or Vivax Malaria Mono-Infection Over a 35-Day-Extended Observation Period
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Plasmodium Falciparum Malaria
Plasmodium Vivax Malaria
Keywords: Plasmodium
falciparum
malaria
vivax
DSM265
pharmacokinetics
adult
Lead sponsor: Medicines for Malaria Venture
Sponsor class: OTHER
Collaborators: name: Asociacion Civil Selva Amazonica
First posted: 2014-04-25
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This will be a Proof-of-concept / Phase IIa, open label study to examine the efficacy of DSM265 in uncomplicated Plasmodium vivax and Plasmodium falciparum blood-stage malaria in adult patients. A minimum of two cohorts (20 patients) and a maximum of 6 cohorts (60 patients, 3 dose levels) will be tested. The starting dose of DSM265 for the first P. vivax and P. falciparum cohorts will be 400 mg. This dose is expected to show complete clearance of parasites by microscopy by Day 7 and a decrease in recrudescence rate assessed at Day 14 (success criteria for dose de-escalation and continuation of the study).


Eligibility criteria: Inclusion Criteria:

* Body weight between 45kg and 90kg
* Mono-infection of P. falciparum or P. vivax confirmed by:

  1. Fever, or history of fever in the previous 24 hours and,
  2. Microscopically confirmed parasite infection: 1,000 to 35,000 asexual parasite count/µL blood
* Written informed consent
* Able to swallow oral medication
* Able and willing to participate and to comply with the study requirements
* Agree to hospitalisation for at least 72 hours and until malarial parasites are not detected by microscopy on 2 consecutive occasions
* Agree to return to clinic on Day 5 (in addition to the other study days), if by Day 3 malarial parasites have not fallen below level of detection on at least two consecutive occasions. If there are no longer any signs or symptoms of malaria then to be available every 3-4 days for blood sampling for microscopy and Quantitative Polymerase Chain Reaction, and re-hospitalisation for standard treatment in the event of levels being detectable

Exclusion Criteria:

* Signs and symptoms of severe / complicated malaria according to the World Health Organisation Criteria 2010
* Mixed Plasmodium infection
* Severe vomiting, (more than three times in the 24 hours prior to inclusion) or inability to tolerate oral treatment, or severe diarrhoea
* Presence of other serious or chronic clinical condition requiring hospitalisation
* Severe malnutrition
* Known history or evidence of clinically significant disorders such as cardiovascular (including arrhythmia, QTcB or QTcF interval greater than or equal to 450 msec, personal or family history of long QT syndrome, PR interval \>200msec; any degree of heart block), respiratory (including active tuberculosis), history of jaundice, hepatic, renal, gastrointestinal, immunological, neurological (including auditory), endocrine including any type of diabetes mellitus (controlled or not), diabetes insipidus, uncontrolled hypo- or hyperthyroidism, endocrine reproductive disorders not requiring concurrent medication, disorders of adrenal function, infectious conditions other than minor skin or soft tissue infections or confirmed lower urinary tract infection, malignancy, psychiatric, history of convulsions or other neurological or psychiatric abnormality; any other disorder or condition that may render the patient unfit for participation or place him/her at increased risk
* Known active Hepatitis A, Hepatitis B or Hepatitis C antibody
* Any antimalarial treatment in the past:

  * a piperaquine-based compound, mefloquine, naphthoquine or sulphadoxine / pyrimethamine in the previous 6 weeks
  * amodiaquine or chloroquine in the previous 4 weeks
  * quinine, halofantrine, lumefantrine-based compounds and any other anti-malarial treatment or antibiotics with antimalarial activity (including cotrimoxazole, tetracyclines, quinolones and fluoroquinolones, and azithromycin) in the past 14 days
  * any herbal products or traditional medicines, in the past 7 days
* Have received antibacterial treatment with known antimalarial activity in the preceding 14 days
* Have received an investigational drug in the 4 weeks prior to screening
* (a) Aspartate Aminotransferase / Alanine Aminotransferase at least twice the upper limit of normal range and total bilirubin is normal (b) Aspartate Aminotransferase / Alanine Aminotransferase more than 1.5 times the upper limit of normal range and total bilirubin is greater than 1 and less than or equal to 1.5 times the upper limit of normal range
* Hemoglobin level less than or equal to 8g/dL
* Total bilirubin greater than 1.5 times the upper limit of normal range
* Serum creatinine levels more than twice the upper limit of normal range
* Female patients must be neither lactating nor pregnant as demonstrated by a negative pregnancy test at screening and pre-dose and must be willing to take measures not to become pregnant during the study period and safety follow-up period (abstinence or oral contraceptives or double barrier contraception, such as male condom, female condom or diaphragm)
* Any prohibited medication

Primary outcomes:
measure: Adequate Clinical and Parasitological Response rate at Day 14
timeFrame: Day 14
measure: Pharmacokinetic parameter for exposure up to 168 hours
timeFrame: Day 0 to 168 hours post-dose
measure: Pharmacokinetic parameter for exposure AUC (0-t)
timeFrame: Day 0 to Day 28
measure: Area under the plasma concentration vs time curve from time zero to infinity
timeFrame: To Day 28
measure: Maximum plasma concentration (Cmax)
timeFrame: Day 0 to Day 28
measure: Time to reach maximum plasma concentration (tmax)
timeFrame: Day 0 to Day 28
measure: Terminal half-life (t½)
timeFrame: Day 0 to Day 28
measure: The plasma concentration at 168hours post-dose (C168h)
timeFrame: Day 7
measure: The terminal elimination rate constant
timeFrame: Day 0 to 28
Secondary outcomes:
measure: Parasite Clearance kinetics
timeFrame: Day 0 to 28
measure: Endpoints concerning Safety and tolerability of DSM265 in patients
timeFrame: Day 0 to 28
measure: Endpoints concerning gametocytemia
timeFrame: Days 0 to 28
measure: The effect of DSM265 on signs and symptoms of malaria
timeFrame: Day 0 to Day 28
measure: Antimalarial pharmacodynamics - minimum parasiticidal concentration, Minimum Inhibitory Concentration, Time and concentration of parasitemia nadir
timeFrame: Day 0 to Day 28
Other outcomes:
Locations:
city: Iquitos
country: Peru
facility: Clínica de la Asociación Civil Selva Amazónica
state: Departamento de Loreto (Amazonía Peruana)
Study officials:
affiliation: Clínica de la Asociación Civil Selva Amazónica
name: Alejandro Llanos, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Llanos-Cuentas A, Casapia M, Chuquiyauri R, Hinojosa JC, Kerr N, Rosario M, Toovey S, Arch RH, Phillips MA, Rozenberg FD, Bath J, Ng CL, Cowell AN, Winzeler EA, Fidock DA, Baker M, Mohrle JJ, Hooft van Huijsduijnen R, Gobeau N, Araeipour N, Andenmatten N, Ruckle T, Duparc S. Antimalarial activity of single-dose DSM265, a novel plasmodium dihydroorotate dehydrogenase inhibitor, in patients with uncomplicated Plasmodium falciparum or Plasmodium vivax malaria infection: a proof-of-concept, open-label, phase 2a study. Lancet Infect Dis. 2018 Aug;18(8):874-883. doi: 10.1016/S1473-3099(18)30309-8. Epub 2018 Jun 13.