DSM265 Phase IIa Investigation Treating Plasmodium Falciparum or Vivax

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified August 2014 by Medicines for Malaria Venture
Sponsor:
Collaborator:
Asociacion Civil Selva Amazonica
Information provided by (Responsible Party):
Medicines for Malaria Venture
ClinicalTrials.gov Identifier:
NCT02123290
First received: April 15, 2014
Last updated: August 27, 2014
Last verified: August 2014
  Purpose

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).


Condition Intervention Phase
Plasmodium Falciparum Malaria
Plasmodium Vivax Malaria
Drug: DSM265 400mg
Drug: DSM265 xmg
Drug: DSM265 ymg
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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 28-Day-Extended Observation Period

Resource links provided by NLM:


Further study details as provided by Medicines for Malaria Venture:

Primary Outcome Measures:
  • Adequate Clinical and Parasitological Response rate at Day 14 [ Time Frame: Day 14 ] [ Designated as safety issue: Yes ]
    Day 14 clinical and parasitological response rate for Plasmodium falciparum and Plasmodium vivax cohorts

  • Pharmacokinetic parameter for exposure up to 168 hours [ Time Frame: Day 0 to 168 hours post-dose ] [ Designated as safety issue: No ]
    Area under the plasma concentration vs time curve from time zero up to and including Day 7 (AUC 0-168)

  • Pharmacokinetic parameter for exposure AUC (0-t) [ Time Frame: Day 0 to Day 28 ] [ Designated as safety issue: No ]
    Area under the plasma concentration vs time curve from time zero to the time of the last measurable concentration post-dose

  • Area under the plasma concentration vs time curve from time zero to infinity [ Time Frame: To Day 28 ] [ Designated as safety issue: No ]
    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.

  • Maximum plasma concentration (Cmax) [ Time Frame: Day 0 to Day 28 ] [ Designated as safety issue: No ]
    Pharmacokinetic parameter maximum plasma concentration

  • Time to reach maximum plasma concentration (tmax) [ Time Frame: Day 0 to Day 28 ] [ Designated as safety issue: No ]
    Pharmacokinetic parameter: Time to reach maximum plasma concentration (tmax)

  • Terminal half-life (t½) [ Time Frame: Day 0 to Day 28 ] [ Designated as safety issue: No ]
    Pharmacokinetic parameter: Terminal half-life

  • The plasma concentration at 168hours post-dose (C168h) [ Time Frame: Day 7 ] [ Designated as safety issue: No ]
    Pharmacokinetic parameter C168 hours

  • The terminal elimination rate constant [ Time Frame: Day 0 to 28 ] [ Designated as safety issue: No ]
    Pharmacokinetic parameter: The terminal elimination rate constant (Lambda z)


Secondary Outcome Measures:
  • Parasite Clearance kinetics [ Time Frame: Day 0 to 28 ] [ Designated as safety issue: Yes ]
    1. Parasite clearance time
    2. PRR (Parasite reduction rate) and parasitemia half life
    3. Times to microscopic clearance of asexual parasites

      1. Total reduction
      2. 99% reduction
      3. 90% reduction
      4. 50% reduction
    4. Percent reduction in asexual parasites from baseline (microscopically measured) at 24, 48 and 72 hours post-dose
    5. Proportion of aparasitemic patients at 24, 48 and 72 hours post-dose

  • Endpoints concerning Safety and tolerability of DSM265 in patients [ Time Frame: Day 0 to 28 ] [ Designated as safety issue: Yes ]

    For P. falciparum and for P. vivax:

    1. Incidence, severity, drug-relatedness, seriousness of adverse events
    2. Laboratory values (biochemistry and haematology)
    3. Vital signs
    4. ECG findings, including heart rate, ECG intervals (PR, QTcB, QTcF), conduction changes or abnormalities

  • Endpoints concerning gametocytemia [ Time Frame: Days 0 to 28 ] [ Designated as safety issue: Yes ]
    1. Percent microscopic reduction in gametocytes (stratified by gametocyte status at inclusion) from baseline at

      1. 24 hours after administration of study drug
      2. 72 hours after administration of study drug
    2. Proportion of subjects with gametocytes (stratified by gametocyte status at inclusion)
    3. Area under the curve (AUC) over 14 and 28 days for gametocyte density (stratified by gametocyte status at inclusion)

  • The effect of DSM265 on signs and symptoms of malaria [ Time Frame: Day 0 to Day 28 ] [ Designated as safety issue: Yes ]
    1. 28 day Adequate Clinical and Parasitological Response (for P. vivax and P. falciparum)
    2. Kaplan Meier survival analysis for rate of recurrence, recrudescence and new infection over 28 days in comparison to historical controls

  • Antimalarial pharmacodynamics - minimum parasiticidal concentration, Minimum Inhibitory Concentration, Time and concentration of parasitemia nadir [ Time Frame: Day 0 to Day 28 ] [ Designated as safety issue: No ]
    1. Minimum Parasiticidal Concentration
    2. Minimum Inhibitory Concentration
    3. Time and concentration of parasitemia nadir (if observed)
    4. A model based link between observed pharmacokinetics and observed parasite density over time


Estimated Enrollment: 60
Study Start Date: November 2014
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Plasmodium falciparum
Patients with Plasmodium falciparum malaria
Drug: DSM265 400mg Drug: DSM265 xmg
Dose of DSM265 to be determined based on the results of the first cohort
Drug: DSM265 ymg
Dose of DSM265 to be determined based on the results of the second cohort
Experimental: Plasmodium vivax
Patients with Plasmodium vivax malaria
Drug: DSM265 400mg Drug: DSM265 xmg
Dose of DSM265 to be determined based on the results of the first cohort
Drug: DSM265 ymg
Dose of DSM265 to be determined based on the results of the second cohort

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02123290

Contacts
Contact: Alejandro Llanos, Professor alejandro.llanos.c@upch.pe

Locations
Peru
Clínica de la Asociación Civil Selva Amazónica Not yet recruiting
Iquitos, Departamento de Loreto (Amazonía Peruana), Peru
Principal Investigator: Alejandro Llanos, Professor         
Sub-Investigator: Martin Casapia, MPH         
Sponsors and Collaborators
Medicines for Malaria Venture
Asociacion Civil Selva Amazonica
Investigators
Principal Investigator: Alejandro Llanos, Professor Clínica de la Asociación Civil Selva Amazónica
  More Information

No publications provided

Responsible Party: Medicines for Malaria Venture
ClinicalTrials.gov Identifier: NCT02123290     History of Changes
Other Study ID Numbers: MMV_DSM265_13_02
Study First Received: April 15, 2014
Last Updated: August 27, 2014
Health Authority: Peru: Instituto Nacional de Salud

Keywords provided by Medicines for Malaria Venture:
Plasmodium
falciparum
malaria
vivax
DSM265
pharmacokinetics
adult

Additional relevant MeSH terms:
Malaria
Malaria, Falciparum
Malaria, Vivax
Protozoan Infections
Parasitic Diseases

ClinicalTrials.gov processed this record on September 14, 2014