| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Healthy volunteers; controlled human malaria infection with PfSPZ |
|
| E.1.1.1 | Medical condition in easily understood language |
| Prophylaxis for controlled malarial infection |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Parasitic Diseases [C03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025494 |
| E.1.2 | Term | Malaria prophylaxis |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the chemoprotective activity of a 400 mg single-dose administration of DSM265, as an early causative and suppressive intervention (no positive blood smear from time of administration to >12 days from PfSPZ inoculation, assessed as a geometric mean of time to parasitemia), on P. falciparum infection in non-immune healthy volunteers after administration of the IV PfSPZ Challenge. |
|
| E.2.2 | Secondary objectives of the trial |
Assess safety & tolerability of DSM265 and atovaquone-proguanil (Malarone®) for causal and suppressive chemoprophylaxis in non-immune healthy volunteers in a PfSPZ challenge.
Assess safety & tolerability of PfSPZ challenge inoculum during DSM265 administration, and atovaquone-proguanil (Malarone®) administration.
Assess DSM265/ DSM450 pharmacokinetics profile from time of DSM265 administration prior to and during the period including Day 28 in non-immune healthy volunteers when administered before the PfSPZ IV Challenge.
Characterize pharmacokinetic-pharmacodynamic relationship of a pre-administration of DSM265 on clearance of Plasmodium falciparum parasites in non-immune healthy volunteers after administration of the PfSPZ IV challenge by Direct Venous Inoculation (DVI).
Characterize potential recrudescence of Parasite kinetics following DSM265 administration, and atovaquone-proguanil (Malarone®) administration.
Exploratory Objectives: see study protocol
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥ 18 and ≤ 45 years healthy volunteers (males or females)
2. Good health based on medical history and on a physical examination without clinically significant findings
3. A body mass index (BMI) >18 and < 30 kg/m2
4. Laboratory results without clinically significant findings within 28 days prior to enrolment
5. Negative urine drug screening test at screening visit (amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, opiates)
6. For female subjects, negative beta-HCG pregnancy test (urine or serum) at screening visit and on the day before first dose of DSM265 and PfSPZ Challenge injection
7. Sexually active male volunteers must agree to use a medically acceptable form of contraception from the day of enrolment in the study and continue it for 120 days after the last dose of study medication
8. Women may only be included if they are either
- Identified as women of non-child bearing potential (WNCBP): surgically sterile (by hysterectomy and/or bilateral oophorectomy and/or bilateral salpingectomy) as documented by an operative report or by ultrasound or postmenopausal ( without use of oral contraceptive for >12 months and either spontaneous amenorrhea for ≥ 12 months or spontaneous amenorrhea for 6-12months and FSH ≥ 40 IU/mL)
or
- Identified as women of child bearing potential (WCBP) and willing and able to practice one of the below listed continuous acceptable methods of contraception (i.e. contraception method used must be one that results in a low failure rate; i.e. 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 prior to the first dose of the study drug + condoms
from the day of screening up to at least 60 days after the last dose of DSM265
9. Agreement to allow the investigators to discuss the volunteer's medical history with their General Practitioner and to sign a request to release medical information concerning contra-indications for participation in the study
10. Able and willing (in the Investigator's opinion) to comply with all study requirements for the duration of the study.
11. Agreement to undergo all study procedures, to attend all study visits and stay overnight for observation if required, up to last follow-up visit
12. Willingness to undergo a CHMI by DVI with PfSPZ Challenge
13. Able and willing to answer all questions on the informed consent quiz correctly demonstrating an understanding of the meaning and of the procedures associated to the study
14. Able and willing to sign the informed consent form for study protocol
15. Reachable (24/7) by mobile phone or electronic mail during the whole study period
16. Agreement to refrain from blood donation during the course of the study and after the end of their involvement in the study according to the local and national blood banking eligibility criteria
17. Willingness to take a curative regimen of artemether-lumefantrine (Riamet®) or another registered antimalarial if necessary
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|
| E.4 | Principal exclusion criteria |
1 Any history of malaria
2. Plans to travel to malaria endemic region during the study period up to last follow-up visit
3. Plans to travel outside of Germany during the challenge period
4. Volunteers unable to be closely followed for social, geographic or psychological reasons
5. Previous participation in any malaria vaccine study vaccine or CHMI study
6. Participation in any other clinical study within 30 days prior to enrolment in the study, or plan to participate in another investigational vaccine/drug research during the study period.
7. Woman who is breast-feeding or planning to become pregnant during the time interval needed to complete the study.
8. Positive HIV, HBV (Seropositive for hepatitis B surface antigen (HBsAg)) or HCV tests
9. Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection, asplenia, recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months before enrolment (inhaled and topical steroids are allowed)
10. 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 five years prior to enrolment, history of a suicide plan or attempt.
11. A history of convulsions or of severe head trauma in volunteer
12. Symptoms, physical signs and laboratory 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 the health of the volunteers
13. History of cancer (except basal cell carcinoma of the skin)
14. History of diabetes mellitus
15. History of arrhythmias or documented prolonged QTF-interval (>450msec)
16. Clinically significant abnormalities in electrocardiogram (ECG) 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)
17. Falling 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
18. Positive family history in 1st and 2nd degree relatives <50 years for cardiac disease
19. A history of psoriasis or porphyria, which may be exacerbated after treatment with chloroquine
20. A history of splenectomy
21. Sickle cell anaemia or other red blood cell disorders
22. A history of allergy or contra-indications to or having contraindications to the use of chloroquine phosphate, atovaquone-proguanil (cohort 1B only), artemether or lumefantrine
23. Use of any prescription drugs (except contraception), herbal supplements (Saint-John’s Wort), or over-the-counter (OTC) medication within 2 weeks prior to initial dosing or 5x half-lives, whichever is longer. [If necessary paracetamol, vitamins and topical treatments are acceptable after approval by the study Sponsor; these treatments will be documented in the case report form (CRF).]
24. Use or anticipated use of medications known to cause drug reactions with rescue medications or atovaquone-proguanil (Malarone) such as cimetidine, metoclopramide, antacids and taken at any point during the study period (Note: During the study, the use of metoclopramide as a rescue medication for nausea / vomiting is considered acceptable if no other treatment can be prescribed. A list of prohibited medication is provided in Attachment 1: PROHIBITED Medication
25. Intake of grapefruit, grapefruit juice, Seville orange or other products containing these ingredients within 7 days of the first drug administration of DSM265.
26. The use of chronic immunosuppressive drugs, or other immune modifying drugs within six months of study enrolment (inhaled and topical corticosteroids and oral anti-histaminic are allowed) and/or during the study period
27. 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
28. Use of immunoglobulins or blood products within 3 months prior to enrolment
29. Suspected or known history or current alcohol abuse as defined by an alcohol intake of greater than 60g (men) or 40g (women) per day per day or a carbohydrate deficient transferrin (CDT) level ≥2.5%
30. Suspected or known injecting drug abuse in the 5 years preceding enrolment
31. Smoking more than 10 cigarettes or equivalent per day
32. Plan for major surgery between enrolment and completion of Study follow-up
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Evaluation of the pre patent period in DSM265/placebo treated subjects in each cohort (i.e., time interval between challenge and the first positive blood smear, given as a geometric mean [days] for a given cohort) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| First positive blood smear or D28 after PfSPZ challenge. |
|
| E.5.2 | Secondary end point(s) |
Safety Endpoints
• Treatment-Emergent Adverse Events (by organ class) during the following study intervals :
- From DSM265/ placebo dose up to initiation of the IV PfSPZ challenge,
- From first Malarone dose up to initiation of the IV PfSPZ challenge,
- From IV PfSPZ challenge up to appearance of parasites in the blood as per the thresholds imposed by the microscopic methodology,
- From IV PfSPZ challenge up to 1st dose of rescue medication,
- From 1st dose of rescue medication up to End of Study Visit (Day60)
• Haematology and blood chemistry laboratory parameters, vital signs and ECG abnormalities will be summarized using the same study intervals.
Pharmacokinetic Endpoints (DSM265 and 450)
• DSM265 pharmacokinetics profile using timepoints described under section 6.3 and inclusive of the period of the PfSPZ Challenge model
• DSM450 pharmacokinetics profile using timepoints described under section 6.3 and inclusive of the period of the PfSPZ Challenge model
Pharmacodynamic Endpoints
• Assessment of observed parasite density over time (assessed by TBS) as a function of DSM265 pharmacokinetics profile: characterization of the DSM26 pharmacokinetic-pharmaco-dynamic relationship on clearance of Plasmodium falciparum parasites in healthy subjects after administration of the PfSPZ I.V. challenge
• Assessment of observed parasite density over time as a function of DSM450 PK profile
• Assessment of the potential recrudescence Parasite kinetics over time as a function of DSM265 pharmacokinetics profile
• Assessment of the potential recrudescence Parasite kinetics over time as a function of DSM450 pharmacokinetics profile
PK/Endpoints
PK/PD investigation will be performed to describe the relationship between DSM265 pharmacokinetics and key pharmacodynamics parameters reflecting parasite load. This will be performed by mean of;
• Direct effect models
• Indirect effect models
• Exploratory models (mechanistic, semi-mechanistic etc)
Endpoints concerning the Malarone antimalarial activity in a PfSPZ Challenge
• Assessment of the observed parasite density over time in Malarone-treated non-immune healthy volunteers after administration of the PfSPZ Challenge.
Endpoints related to the Exploratory Objectives
• Multiplication rate of asexual parasites from Day 7 to time of thick blood smear positivity
• Number of gametocytes as measured by qPCR on the first day of positive TBS or on Day 28. Gametocyte specific qPCR is additionally performed 2 days and 1 day prior of being positive by TBS and on day 3 after rescue.
• AUC of parasitemia from Day 6 to 8 (first cycle) and AUC from first positive qPCR and two subsequent measurements
• Increase from baseline in antibody, B- and T-cell response against plasmodial antigens
• Difference between groups in antibody, B- and T-cell response against plasmodial antigens
• Difference in transcriptional and metabolite pattern to baseline and between groups
• To establish the DSM265/ DSM450 plasma to blood ratio |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| See description of every single endpoint above. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
- Effects on the parasite
- Metabolomics |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Assess the safety of DSM265 within the scope of a parasitic pathogen |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Open with respect to the Malarone treatment arm, double-blind with respect to DSM265 vs. Placebo |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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