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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT02123290
Other study ID # MMV_DSM265_13_02
Secondary ID
Status Completed
Phase Phase 2
First received April 15, 2014
Last updated June 21, 2016
Start date January 2016
Est. completion date January 2016

Study information

Verified date June 2016
Source Medicines for Malaria Venture
Contact n/a
Is FDA regulated No
Health authority Peru: Instituto Nacional de Salud
Study type Interventional

Clinical Trial 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).


Recruitment information / eligibility

Status Completed
Enrollment 45
Est. completion date January 2016
Est. primary completion date January 2016
Accepts healthy volunteers No
Gender Both
Age group 18 Years to 60 Years
Eligibility 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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment


Intervention

Drug:
DSM265 400mg

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

Locations

Country Name City State
Peru Clínica de la Asociación Civil Selva Amazónica Iquitos Departamento de Loreto (Amazonía Peruana)

Sponsors (2)

Lead Sponsor Collaborator
Medicines for Malaria Venture Asociacion Civil Selva Amazonica

Country where clinical trial is conducted

Peru, 

Outcome

Type Measure Description Time frame Safety issue
Primary 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 Yes
Primary 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 No
Primary 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 No
Primary 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 No
Primary Maximum plasma concentration (Cmax) Pharmacokinetic parameter maximum plasma concentration Day 0 to Day 28 No
Primary Time to reach maximum plasma concentration (tmax) Pharmacokinetic parameter: Time to reach maximum plasma concentration (tmax) Day 0 to Day 28 No
Primary Terminal half-life (t½) Pharmacokinetic parameter: Terminal half-life Day 0 to Day 28 No
Primary The plasma concentration at 168hours post-dose (C168h) Pharmacokinetic parameter C168 hours Day 7 No
Primary The terminal elimination rate constant Pharmacokinetic parameter: The terminal elimination rate constant (Lambda z) Day 0 to 28 No
Secondary Parasite Clearance kinetics Parasite clearance time
PRR (Parasite reduction rate) and parasitemia half life
Times to microscopic clearance of asexual parasites
Total reduction
99% reduction
90% reduction
50% reduction
Percent reduction in asexual parasites from baseline (microscopically measured) at 24, 48 and 72 hours post-dose
Proportion of aparasitemic patients at 24, 48 and 72 hours post-dose
Day 0 to 28 Yes
Secondary Endpoints concerning Safety and tolerability of DSM265 in patients For P. falciparum and for P. vivax:
Incidence, severity, drug-relatedness, seriousness of adverse events
Laboratory values (biochemistry and haematology)
Vital signs
ECG findings, including heart rate, ECG intervals (PR, QTcB, QTcF), conduction changes or abnormalities
Day 0 to 28 Yes
Secondary Endpoints concerning gametocytemia Percent microscopic reduction in gametocytes (stratified by gametocyte status at inclusion) from baseline at
24 hours after administration of study drug
72 hours after administration of study drug
Proportion of subjects with gametocytes (stratified by gametocyte status at inclusion)
Area under the curve (AUC) over 14 and 28 days for gametocyte density (stratified by gametocyte status at inclusion)
Days 0 to 28 Yes
Secondary The effect of DSM265 on signs and symptoms of malaria 28 day Adequate Clinical and Parasitological Response (for P. vivax and P. falciparum)
Kaplan Meier survival analysis for rate of recurrence, recrudescence and new infection over 28 days in comparison to historical controls
Day 0 to Day 28 Yes
Secondary Antimalarial pharmacodynamics - minimum parasiticidal concentration, Minimum Inhibitory Concentration, Time and concentration of parasitemia nadir Minimum Parasiticidal Concentration
Minimum Inhibitory Concentration
Time and concentration of parasitemia nadir (if observed)
A model based link between observed pharmacokinetics and observed parasite density over time
Day 0 to Day 28 No
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