DSM265 Chemoprophylaxis of Plasmodium Falciparum Malaria

Study Overview
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Brief Summary
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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
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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.

Official Title
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Evaluation of the Prophylactic Antimalarial Activity of a Single Dose of DSM265 in Non-immune Healthy Adult Volunteers by Controlled Human Malaria Infection With PfSPZ Challenge

Conditions
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Plasmodium Falciparum, Malaria

Intervention / Treatment
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* Drug: DSM265 400mg
* Drug: Placebo to DSM265 400 mg
* Biological: Plasmodium falciparum sporozoite challenge
* Drug: Malarone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1a: DSM265/placebo, sporozoite inoculum<br>DSM265 400mg / placebo Day -1, sporozoite inoculum Day 0 | Drug: DSM265 400mg<br>* DSM265 400mg, single oral administration in a fed state<br>Drug: Placebo to DSM265 400 mg<br>* Placebo to DSM265 400mg, single oral administration in a fed state<br>Biological: Plasmodium falciparum sporozoite challenge<br>* IV Plasmodium falciparum sporozoites (3200) by direct venous inoculation<br>* Other names: Sporozoite inoculum;|
| Active Comparator: Cohort 1b: Malarone, sporozoite inoculum<br>Malarone daily for 9 days from Day -1 to Day 7, sporozoite inoculum Day 0 | Biological: Plasmodium falciparum sporozoite challenge<br>* IV Plasmodium falciparum sporozoites (3200) by direct venous inoculation<br>* Other names: Sporozoite inoculum;Drug: Malarone<br>* 250 mg atovaquone, 100 mg proguanil hydrochloride<br>* Other names: atovaquone / proguanil hydrochloride;|
| Experimental: Cohort 2: DSM265/placebo, sporozoite inoculum<br>DSM265 400mg / placebo Day -7, sporozoite inoculum Day 0 | Drug: DSM265 400mg<br>* DSM265 400mg, single oral administration in a fed state<br>Drug: Placebo to DSM265 400 mg<br>* Placebo to DSM265 400mg, single oral administration in a fed state<br>Biological: Plasmodium falciparum sporozoite challenge<br>* IV Plasmodium falciparum sporozoites (3200) by direct venous inoculation<br>* Other names: Sporozoite inoculum;|
| Experimental: Cohort 3: DSM265 / placebo, sporozoite inoculum (Optional)<br>DSM265 400mg / placebo Day -X, sporozoite inoculum Day 0 | Drug: DSM265 400mg<br>* DSM265 400mg, single oral administration in a fed state<br>Drug: Placebo to DSM265 400 mg<br>* Placebo to DSM265 400mg, single oral administration in a fed state<br>Biological: Plasmodium falciparum sporozoite challenge<br>* IV Plasmodium falciparum sporozoites (3200) by direct venous inoculation<br>* Other names: Sporozoite inoculum;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 0 to Day 28 post-inoculum (daily) | 
| 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. | Day 0 to Day 28 post-inoculum (daily) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From first dose (Day -1 in Cohort 1A and Day -7 in Cohort 2) to Day 60 post-inoculum | 
| 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. | From first dose (Day -1, Cohort 1b) to Day 60 post-inoculum | 
| 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 | Day 0 to Day 60 post-inoculum | 
| DSM265 Pharmacokinetics Profile - T Max | Pre-dose and post-dose during the period including Day 28 | From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum | 
| DSM265 Pharmacokinetics Profile - T 1/2 | Pre-dose and post-dose during the period including Day 28 | From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum | 
| DSM265 Pharmacokinetics Profile - C Max | Pre-dose and post-dose during the period including Day 28 | From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum | 
| 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 | From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum | 
| DSM265 Pharmacokinetics Profile - CL/F | Pre-dose and post-dose during the period including Day 28 | From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum | 
| DSM265 Pharmacokinetics Profile - Vz/F | Pre-dose and post-dose during the period including Day 28 | From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum | 
| DSM450 Pharmacokinetics Profile - T Max | Pre-dose and post-dose during the period including Day 28 | From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum | 
| DSM450 Pharmacokinetics Profile - Cmax | Pre-dose and post-dose during the period including Day 28 | From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum | 
| 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 | From pre-dose of DSM265 (Day -1 in Cohort 1a and Day -7 in Cohort 2) to Day 28 post-inoculum | 
| 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 | 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 | 
| 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 | Day 6 post-inoculum to Day 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, Plasmodium falciparum sporozoite challenge, DSM265