Plasmodium Falciparum, Malaria
Conditions
Keywords
Malaria, Plasmodium falciparum sporozoite challenge, DSM265
Brief summary
Study to evaluate the efficacy of DSM265 as a causal prophylactic in a standardized and validated Human Challenge model using direct venous inoculation of aseptic, purified, cryopreserved, vialed Plasmodium falciparum sporozoites.
Detailed description
This study follows the First In Human dose-escalation study of DSM265 (25 - 800 mg of DSM265) and an Induced-Blood Stage Malaria Challenge study (150 mg of DSM265) conducted in healthy adult volunteers in Australia. After identification of efficacious DSM265 plasma concentrations in the Induced-Blood Stage Malaria model, the current study will evaluate the efficacy of DSM265 as a causal prophylactic in a standardized and validated Human Challenge model using direct venous inoculation of aseptic, purified, cryopreserved, vialed Plasmodium falciparum sporozoites (Challenge). Three sequential cohorts of healthy male and women volunteers, of non-childbearing potential or of childbearing potential with predefined accepted methods of contraception, are planned in order to investigate three preventive conditions with regard to administration of DSM265. Preventive administration of the study drug will occur 1 and 7 days before inoculum of Plasmodium falciparum sporozoite Challenge, with a last cohort administered at a time point to be determined from the 2 previous cohorts but which will not exceed 28 days before the challenge. The study will also include a cohort where subjects will be treated with atovaquone-proguanil (Malarone®) using the approved regimen for chemoprophylaxis.
Interventions
DRUGDSM265 400mg
DSM265 400mg, single oral administration in a fed state
DRUGPlacebo to DSM265 400 mg
Placebo to DSM265 400mg, single oral administration in a fed state
BIOLOGICALPlasmodium falciparum sporozoite challenge
IV Plasmodium falciparum sporozoites (3200) by direct venous inoculation
DRUGMalarone
250 mg atovaquone, 100 mg proguanil hydrochloride
Sponsors
Institute of Tropical Medicine, University of Tuebingen
Medicines for Malaria Venture
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Good health based on medical history and physical examination- Body mass index \>18 and \<30 kg/m2 * Lab results without clinically significant findings in 28 days prior to enrolment * Negative drug screening test * Females: negative pregnancy test at screening and on the day before first dose of DSM265 and sporozoite challenge injection * Sexually active males must agree to use a medically acceptable form of contraception from enrolment and continue for 12 weeks after the dose of DSM265 * Women may only be included if they are either Identified as not of child bearing potential, or if of child bearing potential and willing and able to practice one of the continuous acceptable methods of contraception (must be one with failure rate less than 1% per year) with double barrier protection: * Intrauterine device+condoms, * Diaphragms+spermicidal gel/foam+condoms, * Hormonal contraceptives (oral, depot, patch, injectable or vaginal ring) stabilized for at least 30 days before the study drug + condoms from screening to at least 60 days after dose of DSM265 * Agree to allow the investigators to discuss the medical history with General Practitioner and to sign a request to release medical information concerning contra-indications for participation in the study * Able and willing to comply with all study requirements for the duration of the study * Agree to undergo all study procedures, to attend all study visits and stay overnight for observation if required, up to last follow up visit * Willing to undergo a sporozoite challenge * Able and willing to answer all questions on the informed consent quiz correctly demonstrating an understanding of the meaning and of the study procedures * Able and willing to sign the informed consent form * Reachable (24/7) by mobile phone or email during the whole study period * Agree to refrain from blood donation during the course of the study and after the end of involvement in the study according to the local and national blood banking eligibility criteria (currently 4 years in Germany) * Willing to take a curative regimen of Riamet or another registered antimalarial if necessary
Exclusion criteria
* Any history of malaria * Plans to travel to malaria endemic region during the study period up to last follow up visit or plans to travel outside of Germany during the challenge period * unable to be closely followed for social, geographic or psychological reasons * Previous participation in any malaria vaccine study or controlled human malaria infection study * Participation in any other clinical study within 30 days before enrolment in the study, or plan to participate in another investigational vaccine/drug research during the study period. * Woman who is breast-feeding or planning to become pregnant during the study * Positive human immunodeficiency virus, seropositive for hepatitis B surface antigen or Hepatitis C virus tests * Any confirmed/suspected immunosuppressive or immunodeficient state, including human immunodeficiency virus infection, asplenia, recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the 6 months before enrolment (inhaled and topical steroids are allowed) * History of serious psychiatric condition that may affect participation in the study, precludes compliance with the protocol; past or present psychoses; disorder requiring lithium; or within 5 years prior to enrolment, history of a suicide plan or attempt. * History of convulsions or severe head trauma * Symptoms, physical signs and lab values suggestive of systemic disorders including renal, hepatic, cardiovascular, pulmonary, skin, immunodeficiency, and other conditions which could interfere with the interpretation of the study results or compromise health * History of cancer (except basal cell carcinoma of the skin), or diabetes mellitus or of arrhythmias or documented prolonged QTF-interval (\>450msec) * Clinically significant abnormalities in electrocardiogram at screening: pathologic Q wave, prolonged QT interval, and significant ST-T wave changes, left ventricular hypertrophy, non-sinus rhythm except isolated premature atrial contractions, right or left bundle branch block, advanced A-V heart block (type 2 or type 3) * In moderate risk or higher categories for fatal or non-fatal cardiovascular event within 5 years (\>10%) determined by non-invasive criteria for cardiac risk * Positive family history in relatives \<50 years for cardiac disease * History of psoriasis or porphyria, which may be exacerbated by chloroquine * History of splenectomy * Sickle cell anaemia or other red blood cell disorders * History of allergy or contra-indications to or having contraindications to the use of chloroquine phosphate, atovaquone-proguanil (cohort 1B), artemether or lumefantrine * Use of any prescription drugs (except contraception), herbal supplements or over-the-counter medication in 4 weeks before dosing or 5x half-lives, whichever is longer * Use or anticipated use of medications known to cause drug reactions with rescue medications or Malarone, such as cimetidine, metoclopramide, antacids and taken at any point during the study period. * Intake of grapefruit, grapefruit juice, Seville orange or other products containing these ingredients within 7 days of the first drug administration * Use of chronic immunosuppressive drugs, or other immune modifying drugs within 6 months of enrolment (inhaled and topical corticosteroids and oral anti-histaminic are allowed) and/or during the study period * Use of systemic antibiotics with known antimalarial activity within 30 days of study enrolment (e.g. trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones, or azithromycin ) and/or during the study period * Use of immunoglobulins or blood products in 3 months prior to enrolment * Suspected/known injecting drug abuse in 5 years preceding enrolment * Current smoking more than 10 cigarettes or equivalent per day * Plan for major surgery between enrolment and follow up
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Infection Rate | Day 0 to Day 28 post-inoculum (daily) | The infection rate is the number (percentage) of subjects in a cohort who became positive for parasitemia. Complete protection = Subjects with pre-patent period equal to 28 days. |
| Pre-patent Period | Day 0 to Day 28 post-inoculum (daily) | The pre-patent period is defined as the time (days) from inoculation with PfSPZ to first occurrence of a positive TBS. If no positive TBS is seen by Day 28, this variable is set to 28 days. Complete protection = Subjects showing with pre-patent period equal to 28 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Plasmodium Falciparum Sporozoite Challenge Inoculum | Day 0 to Day 60 post-inoculum | Safety & tolerability of Plasmodium falciparum sporozoite challenge inoculum during DSM265 administration, and Malarone administration. Measured by adverse events, laboratory data |
| DSM265 Pharmacokinetics Profile - T Max | From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum | Pre-dose and post-dose during the period including Day 28 |
| DSM265 Pharmacokinetics Profile - T 1/2 | From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum | Pre-dose and post-dose during the period including Day 28 |
| DSM265 Pharmacokinetics Profile - C Max | From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum | Pre-dose and post-dose during the period including Day 28 |
| DSM265 Pharmacokinetics Profile - AUC 0-∞, AUC 0-168h, and AUC 0-480h | From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum | Pre-dose and post-dose during the period including Day 28 for AUC 0-∞, AUC 0-168h, and AUC 0-480h |
| DSM265 Pharmacokinetics Profile - CL/F | From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum | Pre-dose and post-dose during the period including Day 28 |
| Number of Participants With Adverse Events as a Measure of Safety & Tolerability of DSM265 | From first dose (Day -1 in Cohort 1A and Day -7 in Cohort 2) to Day 60 post-inoculum | Safety & tolerability of DSM265 for causal and suppressive chemoprophylaxis in non-immune healthy volunteers in a non-immune healthy volunteers in CHMI with PfSPZ challenge. |
| DSM450 Pharmacokinetics Profile - T Max | From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum | Pre-dose and post-dose during the period including Day 28 |
| DSM450 Pharmacokinetics Profile - Cmax | From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum | Pre-dose and post-dose during the period including Day 28 |
| DSM450 Pharmacokinetics Profile - AUC 0-t, AUC 0-168h, and AUC 0-480h | From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum | Pre-dose and post-dose during the period including Day 28 for AUC 0-t, AUC 0-168h, and AUC 0-480h |
| The Pharmacokinetic-pharmacodynamic Profile of Pre-administration of DSM265 on Clearance of Plasmodium Falciparum Parasites After Administration of the Sporozoite Challenge | From first dose of DSM265 (Day -1 in Cohort 1a, Day -7 in Cohort 2 and Day -X in Cohort 3) to 480 hours post-dose | The profile of plasma concentrations and pharmacokinetic parameters (AUC, Cmax, Tmax, T0-inf, AUC0-t, t1/2) will be reviewed on a background of the safety profile (adverse events, laboratory and ECG data) and the clearance of Plasmodium falciparum parasites (efficacy) after administration of the sporozoite challenge |
| Recrudescence of Parasite Kinetics Following DSM265 Administration. | Day 6 post-inoculum to Day 60 | On any re-appearance of parasites, thick smears and PCR samples will be examined to determine whether the parasite is a different variant(recrudescence) or has the same genetic profile as the original infection (re-infection) post-dose |
| DSM265 Pharmacokinetics Profile - Vz/F | From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum | Pre-dose and post-dose during the period including Day 28 |
| Number of Participants With Treatment Emergent Adverse Events (TEAE) as a Measure of Safety & Tolerability of Malarone | From first dose (Day -1, Cohort 1b) to Day 60 post-inoculum | Safety & tolerability of Malarone for causal and suppressive chemoprophylaxis in non-immune healthy volunteers in a Plasmodium falciparum sporozoite challenge. Measured by adverse events, laboratory data. Malarone® was administered as a single daily dose over a period of 9 days from Day -1 to Day 7. |
Countries
Germany
Participant flow
Recruitment details
A total of 40 subjects were screened. Of these 22 (55.0%) were enrolled to participate in the study
Pre-assignment details
One subject was allocated to treatment but did not receive any study medication due to an ECG abnormality discovered after randomization and, therefore, 21 out of 22 subjects received at least one dose of the study medications. In agreement with the Safety Review Team, the Sponsor decided to close the study without progressing to conduct Cohort 3.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1A: 400 mg DSM265, Sporozoite Challenge DSM265 400 mg on Day -1, sporozoite challenge on Day 0
DSM265 400 mg: single oral administration in a fed state
Plasmodium falciparum sporozoite challenge: Plasmodium falciparum sporozoites (3200) by direct venous inoculation | 5 |
| Cohort 1B: Malarone, Sporozoite Challenge Malarone daily for 9 days from Day -1 to Day 7, sporozoite challenge Day 0
Malarone: 250 mg atovaquone, 100 mg proguanil hydrochloride
Plasmodium falciparum sporozoite challenge: Plasmodium falciparum sporozoites (3200) by direct venous inoculation | 6 |
| Cohort 2: 400 mg DSM265, Sporozoite Challenge DSM265 400 mg on Day -7, sporozoite challenge on Day 0
DSM265 400 mg: single oral administration in a fed state
Plasmodium falciparum sporozoite challenge: Plasmodium falciparum sporozoites (3200) by direct venous inoculation | 6 |
| Placebo Cohorts 1A and 2 Placebo to DSM265 400 mg on Day -7, sporozoite challenge on Day 0
Placebo to DSM265 400 mg: single oral administration in a fed state
Plasmodium falciparum sporozoite challenge: Plasmodium falciparum sporozoites (3200) by direct venous inoculation | 4 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | ECG abnormality so not treated | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Cohort 1A: 400 mg DSM265, Sporozoite Challenge | Cohort 1B: Malarone, Sporozoite Challenge | Cohort 2: 400 mg DSM265, Sporozoite Challenge | Placebo Cohorts 1A and 2 |
|---|---|---|---|---|---|
| Age, Customized Age (years) | 26.00 years STANDARD_DEVIATION 4.24 | 24.20 years STANDARD_DEVIATION 4.02 | 26.67 years STANDARD_DEVIATION 4.93 | 25.33 years STANDARD_DEVIATION 4.18 | 24.82 years STANDARD_DEVIATION 3.95 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 21 Participants | 5 Participants | 6 Participants | 6 Participants | 4 Participants |
| Region of Enrollment Germany | 21 participants | 5 participants | 6 participants | 6 participants | 4 participants |
| Sex: Female, Male Female | 8 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 13 Participants | 3 Participants | 4 Participants | 4 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 6 | 0 / 6 | 0 / 4 |
| other Total, other adverse events | 5 / 5 | 5 / 6 | 6 / 6 | 4 / 4 |
| serious Total, serious adverse events | 1 / 5 | 0 / 6 | 0 / 6 | 0 / 4 |
Outcome results
Primary
Infection Rate
The infection rate is the number (percentage) of subjects in a cohort who became positive for parasitemia. Complete protection = Subjects with pre-patent period equal to 28 days.
Time frame: Day 0 to Day 28 post-inoculum (daily)
Population: All subjects who received both at least one dose of study medication and the PfSPZ challenge
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | Infection Rate | Complete Protection | 5 Participants |
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | Infection Rate | Parasitemic | 0 Participants |
| Cohort 1B: Malarone, Sporozoite Challenge | Infection Rate | Parasitemic | 0 Participants |
| Cohort 1B: Malarone, Sporozoite Challenge | Infection Rate | Complete Protection | 6 Participants |
| Cohort 2: 400 mg DSM265 (Day-7), Sporozoite Challenge (Day0) | Infection Rate | Complete Protection | 3 Participants |
| Cohort 2: 400 mg DSM265 (Day-7), Sporozoite Challenge (Day0) | Infection Rate | Parasitemic | 3 Participants |
| Placebo Cohorts 1A and 2 | Infection Rate | Complete Protection | 0 Participants |
| Placebo Cohorts 1A and 2 | Infection Rate | Parasitemic | 4 Participants |
Primary
Pre-patent Period
The pre-patent period is defined as the time (days) from inoculation with PfSPZ to first occurrence of a positive TBS. If no positive TBS is seen by Day 28, this variable is set to 28 days. Complete protection = Subjects showing with pre-patent period equal to 28 days.
Time frame: Day 0 to Day 28 post-inoculum (daily)
Population: All subjects who received both at least one dose of study medication and the PfSPZ challenge
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | Pre-patent Period | 28.0 Days | Geometric Coefficient of Variation 0 |
| Cohort 1B: Malarone, Sporozoite Challenge | Pre-patent Period | 28.0 Days | Geometric Coefficient of Variation 0 |
| Cohort 2: 400 mg DSM265 (Day-7), Sporozoite Challenge (Day0) | Pre-patent Period | 20.6 Days | Geometric Coefficient of Variation 2.78 |
| Placebo Cohorts 1A and 2 | Pre-patent Period | 11.7 Days | Geometric Coefficient of Variation 7.93 |
Secondary
DSM265 Pharmacokinetics Profile - AUC 0-∞, AUC 0-168h, and AUC 0-480h
Pre-dose and post-dose during the period including Day 28 for AUC 0-∞, AUC 0-168h, and AUC 0-480h
Time frame: From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum
Population: All subjects who received study drug and provided they had sufficient DSM265 and/or DSM450 concentration data for the non-compartmental analysis were included in the pharmacokinetic analysis (all-treated set).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM265 Pharmacokinetics Profile - AUC 0-∞, AUC 0-168h, and AUC 0-480h | AUC 0-∞ DBS | 979000 ng*h/mL | Geometric Coefficient of Variation 25.8 |
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM265 Pharmacokinetics Profile - AUC 0-∞, AUC 0-168h, and AUC 0-480h | AUC 0-∞ Plasma | 1870000 ng*h/mL | Geometric Coefficient of Variation 23.4 |
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM265 Pharmacokinetics Profile - AUC 0-∞, AUC 0-168h, and AUC 0-480h | AUC 0-168h DBS | 582000 ng*h/mL | Geometric Coefficient of Variation 22.8 |
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM265 Pharmacokinetics Profile - AUC 0-∞, AUC 0-168h, and AUC 0-480h | AUC 0-168h Plasma | 1100000 ng*h/mL | Geometric Coefficient of Variation 22.3 |
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM265 Pharmacokinetics Profile - AUC 0-∞, AUC 0-168h, and AUC 0-480h | AUC 0-480h DBS | 863000 ng*h/mL | Geometric Coefficient of Variation 22 |
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM265 Pharmacokinetics Profile - AUC 0-∞, AUC 0-168h, and AUC 0-480h | AUC 0-480h Plasma | 1680000 ng*h/mL | Geometric Coefficient of Variation 19.5 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM265 Pharmacokinetics Profile - AUC 0-∞, AUC 0-168h, and AUC 0-480h | AUC 0-480h DBS | 847000 ng*h/mL | Geometric Coefficient of Variation 25.4 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM265 Pharmacokinetics Profile - AUC 0-∞, AUC 0-168h, and AUC 0-480h | AUC 0-∞ DBS | 906000 ng*h/mL | Geometric Coefficient of Variation 29.8 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM265 Pharmacokinetics Profile - AUC 0-∞, AUC 0-168h, and AUC 0-480h | AUC 0-168h Plasma | 949000 ng*h/mL | Geometric Coefficient of Variation 14 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM265 Pharmacokinetics Profile - AUC 0-∞, AUC 0-168h, and AUC 0-480h | AUC 0-∞ Plasma | 1540000 ng*h/mL | Geometric Coefficient of Variation 30.4 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM265 Pharmacokinetics Profile - AUC 0-∞, AUC 0-168h, and AUC 0-480h | AUC 0-480h Plasma | 1430000 ng*h/mL | Geometric Coefficient of Variation 25.9 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM265 Pharmacokinetics Profile - AUC 0-∞, AUC 0-168h, and AUC 0-480h | AUC 0-168h DBS | 568000 ng*h/mL | Geometric Coefficient of Variation 13.3 |
Secondary
DSM265 Pharmacokinetics Profile - CL/F
Pre-dose and post-dose during the period including Day 28
Time frame: From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum
Population: All subjects who received study drug and provided they had sufficient DSM265 and/or DSM450 concentration data for the non-compartmental analysis were included in the pharmacokinetic analysis (all-treated set).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM265 Pharmacokinetics Profile - CL/F | CL/F DBS | 409 mL/h | Geometric Coefficient of Variation 25.8 |
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM265 Pharmacokinetics Profile - CL/F | CL/F Plasma | 214 mL/h | Geometric Coefficient of Variation 23.4 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM265 Pharmacokinetics Profile - CL/F | CL/F DBS | 441 mL/h | Geometric Coefficient of Variation 29.8 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM265 Pharmacokinetics Profile - CL/F | CL/F Plasma | 260 mL/h | Geometric Coefficient of Variation 30.4 |
Secondary
DSM265 Pharmacokinetics Profile - C Max
Pre-dose and post-dose during the period including Day 28
Time frame: From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum
Population: All subjects who received study drug and provided they had sufficient DSM265 and/or DSM450 concentration data for the non-compartmental analysis were included in the pharmacokinetic analysis (all-treated set).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM265 Pharmacokinetics Profile - C Max | C max DBS | 6860 ng/mL | Geometric Coefficient of Variation 28.2 |
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM265 Pharmacokinetics Profile - C Max | C max Plasma | 13300 ng/mL | Geometric Coefficient of Variation 34.3 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM265 Pharmacokinetics Profile - C Max | C max DBS | 6990 ng/mL | Geometric Coefficient of Variation 15 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM265 Pharmacokinetics Profile - C Max | C max Plasma | 11200 ng/mL | Geometric Coefficient of Variation 18 |
Secondary
DSM265 Pharmacokinetics Profile - T 1/2
Pre-dose and post-dose during the period including Day 28
Time frame: From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum
Population: All subjects who received study drug and provided they had sufficient DSM265 and/or DSM450 concentration data for the non-compartmental analysis were included in the pharmacokinetic analysis (all-treated set).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM265 Pharmacokinetics Profile - T 1/2 | t 1/2 DBS | 132 hours | Geometric Coefficient of Variation 31.4 |
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM265 Pharmacokinetics Profile - T 1/2 | t 1/2 Plasma | 134 hours | Geometric Coefficient of Variation 34.8 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM265 Pharmacokinetics Profile - T 1/2 | t 1/2 DBS | 113 hours | Geometric Coefficient of Variation 39 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM265 Pharmacokinetics Profile - T 1/2 | t 1/2 Plasma | 116 hours | Geometric Coefficient of Variation 40.4 |
Secondary
DSM265 Pharmacokinetics Profile - T Max
Pre-dose and post-dose during the period including Day 28
Time frame: From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum
Population: All subjects who received study drug and provided they had sufficient DSM265 and/or DSM450 concentration data for the non-compartmental analysis were included in the pharmacokinetic analysis (all-treated set).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM265 Pharmacokinetics Profile - T Max | T max DBS | 2.02 hours |
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM265 Pharmacokinetics Profile - T Max | T max Plasma | 2.00 hours |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM265 Pharmacokinetics Profile - T Max | T max DBS | 8.48 hours |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM265 Pharmacokinetics Profile - T Max | T max Plasma | 8.48 hours |
Secondary
DSM265 Pharmacokinetics Profile - Vz/F
Pre-dose and post-dose during the period including Day 28
Time frame: From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum
Population: All subjects who received study drug and provided they had sufficient DSM265 and/or DSM450 concentration data for the non-compartmental analysis were included in the pharmacokinetic analysis (all-treated set).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM265 Pharmacokinetics Profile - Vz/F | Vz/F DBS | 77900 mL | Geometric Coefficient of Variation 29 |
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM265 Pharmacokinetics Profile - Vz/F | Vz/F Plasma | 41400 mL | Geometric Coefficient of Variation 31.8 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM265 Pharmacokinetics Profile - Vz/F | Vz/F DBS | 71700 mL | Geometric Coefficient of Variation 18.7 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM265 Pharmacokinetics Profile - Vz/F | Vz/F Plasma | 43600 mL | Geometric Coefficient of Variation 18.9 |
Secondary
DSM450 Pharmacokinetics Profile - AUC 0-t, AUC 0-168h, and AUC 0-480h
Pre-dose and post-dose during the period including Day 28 for AUC 0-t, AUC 0-168h, and AUC 0-480h
Time frame: From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum
Population: All subjects who received study drug and provided they had sufficient DSM265 and/or DSM450 concentration data for the non-compartmental analysis were included in the pharmacokinetic analysis (all-treated set).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM450 Pharmacokinetics Profile - AUC 0-t, AUC 0-168h, and AUC 0-480h | AUC 0-∞ DBS | 185000 ng*h/mL | Geometric Coefficient of Variation 34.9 |
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM450 Pharmacokinetics Profile - AUC 0-t, AUC 0-168h, and AUC 0-480h | AUC 0-∞ Plasma | 326000 ng*h/mL | Geometric Coefficient of Variation 32.1 |
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM450 Pharmacokinetics Profile - AUC 0-t, AUC 0-168h, and AUC 0-480h | AUC 0-168h DBS | 63800 ng*h/mL | Geometric Coefficient of Variation 44.9 |
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM450 Pharmacokinetics Profile - AUC 0-t, AUC 0-168h, and AUC 0-480h | AUC 0-168h Plasma | 115000 ng*h/mL | Geometric Coefficient of Variation 45.9 |
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM450 Pharmacokinetics Profile - AUC 0-t, AUC 0-168h, and AUC 0-480h | AUC 0-480h DBS | 185000 ng*h/mL | Geometric Coefficient of Variation 34.9 |
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM450 Pharmacokinetics Profile - AUC 0-t, AUC 0-168h, and AUC 0-480h | AUC 0-480h Plasma | 326000 ng*h/mL | Geometric Coefficient of Variation 32.1 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM450 Pharmacokinetics Profile - AUC 0-t, AUC 0-168h, and AUC 0-480h | AUC 0-480h DBS | 234000 ng*h/mL | Geometric Coefficient of Variation 46.5 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM450 Pharmacokinetics Profile - AUC 0-t, AUC 0-168h, and AUC 0-480h | AUC 0-∞ DBS | 225000 ng*h/mL | Geometric Coefficient of Variation 42.5 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM450 Pharmacokinetics Profile - AUC 0-t, AUC 0-168h, and AUC 0-480h | AUC 0-168h Plasma | 142000 ng*h/mL | Geometric Coefficient of Variation 40.4 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM450 Pharmacokinetics Profile - AUC 0-t, AUC 0-168h, and AUC 0-480h | AUC 0-∞ Plasma | 367000 ng*h/mL | Geometric Coefficient of Variation 39.7 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM450 Pharmacokinetics Profile - AUC 0-t, AUC 0-168h, and AUC 0-480h | AUC 0-480h Plasma | 375000 ng*h/mL | Geometric Coefficient of Variation 44.1 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM450 Pharmacokinetics Profile - AUC 0-t, AUC 0-168h, and AUC 0-480h | AUC 0-168h DBS | 85300 ng*h/mL | Geometric Coefficient of Variation 45.1 |
Secondary
DSM450 Pharmacokinetics Profile - Cmax
Pre-dose and post-dose during the period including Day 28
Time frame: From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum
Population: All subjects who received study drug and provided they had sufficient DSM265 and/or DSM450 concentration data for the non-compartmental analysis were included in the pharmacokinetic analysis (all-treated set).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM450 Pharmacokinetics Profile - Cmax | Cmax DBS | 545 ng/mL | Geometric Coefficient of Variation 35.3 |
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM450 Pharmacokinetics Profile - Cmax | Cmax Plasma | 999 ng/mL | Geometric Coefficient of Variation 31 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM450 Pharmacokinetics Profile - Cmax | Cmax DBS | 714 ng/mL | Geometric Coefficient of Variation 37.1 |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM450 Pharmacokinetics Profile - Cmax | Cmax Plasma | 1170 ng/mL | Geometric Coefficient of Variation 36.7 |
Secondary
DSM450 Pharmacokinetics Profile - T Max
Pre-dose and post-dose during the period including Day 28
Time frame: From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum
Population: All subjects who received study drug and provided they had sufficient DSM265 and/or DSM450 concentration data for the non-compartmental analysis were included in the pharmacokinetic analysis (all-treated set).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM450 Pharmacokinetics Profile - T Max | t max Plasma | 169 hours |
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | DSM450 Pharmacokinetics Profile - T Max | t max DBS | 169 hours |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM450 Pharmacokinetics Profile - T Max | t max DBS | 216 hours |
| Cohort 1B: Malarone, Sporozoite Challenge | DSM450 Pharmacokinetics Profile - T Max | t max Plasma | 169 hours |
Secondary
Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Plasmodium Falciparum Sporozoite Challenge Inoculum
Safety & tolerability of Plasmodium falciparum sporozoite challenge inoculum during DSM265 administration, and Malarone administration. Measured by adverse events, laboratory data
Time frame: Day 0 to Day 60 post-inoculum
Population: All the subjects included in the safety population were administered the study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Plasmodium Falciparum Sporozoite Challenge Inoculum | 3 Participants |
| Cohort 1B: Malarone, Sporozoite Challenge | Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Plasmodium Falciparum Sporozoite Challenge Inoculum | 5 Participants |
| Cohort 2: 400 mg DSM265 (Day-7), Sporozoite Challenge (Day0) | Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Plasmodium Falciparum Sporozoite Challenge Inoculum | 5 Participants |
| Placebo Cohorts 1A and 2 | Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Plasmodium Falciparum Sporozoite Challenge Inoculum | 4 Participants |
Secondary
Number of Participants With Adverse Events as a Measure of Safety & Tolerability of DSM265
Safety & tolerability of DSM265 for causal and suppressive chemoprophylaxis in non-immune healthy volunteers in a non-immune healthy volunteers in CHMI with PfSPZ challenge.
Time frame: From first dose (Day -1 in Cohort 1A and Day -7 in Cohort 2) to Day 60 post-inoculum
Population: All the subjects included in the safety population were administered the study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | Number of Participants With Adverse Events as a Measure of Safety & Tolerability of DSM265 | 5 Participants |
| Cohort 1B: Malarone, Sporozoite Challenge | Number of Participants With Adverse Events as a Measure of Safety & Tolerability of DSM265 | 6 Participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAE) as a Measure of Safety & Tolerability of Malarone
Safety & tolerability of Malarone for causal and suppressive chemoprophylaxis in non-immune healthy volunteers in a Plasmodium falciparum sporozoite challenge. Measured by adverse events, laboratory data. Malarone® was administered as a single daily dose over a period of 9 days from Day -1 to Day 7.
Time frame: From first dose (Day -1, Cohort 1b) to Day 60 post-inoculum
Population: All the subjects included in the safety population were administered the study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1A: 400 mg DSM265 (Day-1), Sporozoite Challenge (Day0) | Number of Participants With Treatment Emergent Adverse Events (TEAE) as a Measure of Safety & Tolerability of Malarone | 5 Participants |
Secondary
Recrudescence of Parasite Kinetics Following DSM265 Administration.
On any re-appearance of parasites, thick smears and PCR samples will be examined to determine whether the parasite is a different variant(recrudescence) or has the same genetic profile as the original infection (re-infection) post-dose
Time frame: Day 6 post-inoculum to Day 60
Population: Recrudescence was not observed in this study.
Secondary
The Pharmacokinetic-pharmacodynamic Profile of Pre-administration of DSM265 on Clearance of Plasmodium Falciparum Parasites After Administration of the Sporozoite Challenge
The profile of plasma concentrations and pharmacokinetic parameters (AUC, Cmax, Tmax, T0-inf, AUC0-t, t1/2) will be reviewed on a background of the safety profile (adverse events, laboratory and ECG data) and the clearance of Plasmodium falciparum parasites (efficacy) after administration of the sporozoite challenge
Time frame: From first dose of DSM265 (Day -1 in Cohort 1a, Day -7 in Cohort 2 and Day -X in Cohort 3) to 480 hours post-dose
Population: Data were not collected. Analysis was not done because, because all subjects were administered with the same dose of 400mg DSM; so not enough variability for the DSM concentration parameter.