DSM265 Phase IIa Investigation Treating Plasmodium Falciparum or Vivax

NCT02123290 | Completed Phase 2 DMC

• 1 other identifier: MMV_DSM265_13_02
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

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).

Conditions

Plasmodium Falciparum Malaria; Plasmodium Vivax Malaria

Keywords

Plasmodium; falciparum; malaria; vivax; DSM265; pharmacokinetics; adult

Outcome Measures

Primary Outcomes (9)

• Adequate Clinical and Parasitological Response rate at Day 14

  Day 14 clinical and parasitological response rate for Plasmodium falciparum and Plasmodium vivax cohorts

  Day 14

• Pharmacokinetic parameter for exposure up to 168 hours

  Area under the plasma concentration vs time curve from time zero up to and including Day 7 (AUC 0-168)

  Day 0 to 168 hours post-dose

• Pharmacokinetic parameter for exposure AUC (0-t)

  Area under the plasma concentration vs time curve from time zero to the time of the last measurable concentration post-dose

  Day 0 to Day 28

• Area under the plasma concentration vs time curve from time zero to infinity

  Area under the plasma concentration vs time curve from time zero to the infinity. Participants will be followed for 28 days, data will be extrapolated.

  To Day 28

• Maximum plasma concentration (Cmax)

  Pharmacokinetic parameter maximum plasma concentration

  Day 0 to Day 28

• Time to reach maximum plasma concentration (tmax)

  Pharmacokinetic parameter: Time to reach maximum plasma concentration (tmax)

  Day 0 to Day 28

• Terminal half-life (t½)

  Pharmacokinetic parameter: Terminal half-life

  Day 0 to Day 28

• The plasma concentration at 168hours post-dose (C168h)

  Pharmacokinetic parameter C168 hours

  Day 7

• The terminal elimination rate constant

  Pharmacokinetic parameter: The terminal elimination rate constant (Lambda z)

  Day 0 to 28

Secondary Outcomes (5)

• Parasite Clearance kinetics

  Day 0 to 28

• Endpoints concerning Safety and tolerability of DSM265 in patients

  Day 0 to 28

• Endpoints concerning gametocytemia

  Days 0 to 28

• The effect of DSM265 on signs and symptoms of malaria

  Day 0 to Day 28

• Antimalarial pharmacodynamics - minimum parasiticidal concentration, Minimum Inhibitory Concentration, Time and concentration of parasitemia nadir

  Day 0 to Day 28

Study Arms (2)

Plasmodium falciparum

EXPERIMENTAL

Patients with Plasmodium falciparum malaria

Drug: DSM265 400mg; Drug: DSM265 xmg; Drug: DSM265 ymg

Plasmodium vivax

EXPERIMENTAL

Patients with Plasmodium vivax malaria

Drug: DSM265 400mg; Drug: DSM265 xmg; Drug: DSM265 ymg

Interventions

DSM265 400mg DRUG

Plasmodium falciparum; Plasmodium vivax

DSM265 xmg DRUG

Dose of DSM265 to be determined based on the results of the first cohort

Plasmodium falciparum; Plasmodium vivax

DSM265 ymg DRUG

Dose of DSM265 to be determined based on the results of the second cohort

Plasmodium falciparum; Plasmodium vivax

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Body weight between 45kg and 90kg
• Mono-infection of P. falciparum or P. vivax confirmed by:
• Fever, or history of fever in the previous 24 hours and,
• 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

You may not qualify if:

• Signs and symptoms of severe / complicated malaria according to the World Health Organisation Criteria 2010
• Mixed Plasmodium infection
• 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

Sponsors & Collaborators

• Medicines for Malaria Venture: lead
• Asociacion Civil Selva Amazonica: collaborator

Study Sites (1)

Clínica de la Asociación Civil Selva Amazónica

Iquitos, Departamento de Loreto (Amazonía Peruana), Peru

Location

Related Publications (1)

• 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.

  PMID: 29909069 DERIVED

MeSH Terms

Conditions

Malaria, Falciparum; Malaria, Vivax; Malaria

Interventions

DSM265

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Study Officials

• Alejandro Llanos, Professor

  Clínica de la Asociación Civil Selva Amazónica

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 15, 2014
• First Posted: April 25, 2014
• Study Start: January 1, 2016
• Primary Completion: January 1, 2016
• Study Completion: January 1, 2016
• Last Updated: June 22, 2016

Record last verified: 2016-06

Locations

PE (1)