Primary Objectives:- To assess chemoprophylactic activity of single oral doses of M5717 administered after DVI of Plasmodium falciparum sporozoites (PfSPZ) challenge in healthy participants. - To explore the dose-exposure-response relationship of a…
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Brief title
Condition
- Ectoparasitic disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Response endpoints:
- Number of participants over time with positive parasitemia defined as first
positive qPCR outcome equal or greater than 100 asexual parasites per mL of
blood within 28 days of PfSPZ challenge
- Time to parasitemia, defined as time from PfSPZ DVI to the first qPCR outcome
equal or greater than 100 asexual parasites per mL of blood (time frame: number
of days from PfSPZ DVI challenge to positive parasitemia, or 28 days)
- Number of participants with documented blood stage parasite growth, defined
as an increase of qPCR measured asexual parasites per mL compared to the first
parasitemia measurement, within 28 days of PfSPZ DVI
- Clinical symptoms of malaria using the Malaria Clinical Score.
Dose-exposure-response relationship:
- Selected pharmacokinetic (PK) endpoints/concentrations (e.g. AUC0-24,
AUC0-144, C24, C144) and pharmacodynamic (PD) endpoints (cured/not-cured) will
be used for PK/PD modeling approaches.
Secondary outcome
- Nature, incidence, frequency, severity of adverse events (AEs)/ serious
adverse events (SAEs), and relationship to the study intervention
- Incidence of clinically significant changes and abnormalities in safety
laboratory parameters (hematology, coagulation, biochemistry [specifically
alanine aminotransferase (ALT) and aspartate aminotransferase (AST), alkaline
phosphatase (ALP), bilirubin (total)], and urinalysis)
- Incidence of clinically significant changes and abnormalities in vital signs
and 12 lead electrocardiogram (ECG).
Exposure endpoints:
- Concentration-time curve for M5717 after single-dose administration
- Pharmacokinetic parameters of M5717 such as AUC0-*, AUC0-t, AUC0-24,
AUC0-144, Cmax, C24, C144, tmax, t1/2, *Z, CL/f and Vz/f to be specified in the
Integrated Analysis Plan.
Background summary
Human malaria is an acute febrile illness caused by five Plasmodium parasite
species (P falciparum, P vivax, P malariae, P ovale and P knowlesi). According
to the latest estimates, released on 19 November 2018 by the World Health
Organization (WHO), there were about 219 million cases of malaria and an
estimated 435,000 deaths due to malaria worldwide in 2017 (WHO Malaria report ,
2018). Most deaths (60%) occur among children below 5 years of age, most of
whom live in Africa. In a non-immune individual, symptoms appear about 7 days
after the infective mosquito bite and the subsequent asymptomatic liver stages.
Although atovaquone-proguanil (Malarone®) and recently tafenoquine (ArakodaTM,
60 Degrees Pharmaceuticals, Washington, DC, USA) have been registered for
chemoprophylaxis in the traveler population, there are limited preventive
chemotherapy options available for extended use by the populations in endemic
areas and migrants. Chemoprophylactic agents are mainly based on the
repurposing of drugs used for treatment and all of these agents are facing
emerging or established resistance.
The development of new treatments in malaria targeting prophylaxis and
transmission is becoming increasingly important. Target Product Profiles have
been defined in the malaria drug development field to address future cure and
chemoprophylaxis compound profiles, consistent with the strong recommendation
from WHO to develop only combination therapies, to minimize the risk of
emerging resistance (Burrows JN et al., 2013).
M5717 is a first-in-class compound with a new mode of action (i.e., inhibition
of plasmodial protein synthesis by targeting the Plasmodium eukaryotic
translation Elongation Factor 2 [PeEF2]) and shows excellent activity against
malaria blood-stages (including clinical isolates and drug-resistant strains),
liver-stages, and in transmission blocking assays in preclinical
investigations. M5717 displayed a long half-life and an effective exposure with
high potency against all forms of the parasite. This allows for administration
of a single oral dose and maintaining protection over an extended period of
time.
In the view of accelerating the development of new antimalarial medications,
CHMI studies have been established, involving infection of participants with
low numbers of malaria parasites, either through injection of sporozoites and
allowing the development of pre-erythrocytic stages, or injection of
malaria-infected erythrocytes (blood stage). These models are well-accepted,
their safety profile is well understood, and their overall benefit was
demonstrated in terms of reduction of development times and limiting the number
of participants in Phase II dose-finding studies.
The DVI of P falciparum sporozoites (PfSPZ) is a validated and standardized
model for 100% induction of malaria infection in healthy participants
(Mordmüller et al., 2015). DVI of 3200 PfSPZ has been implemented for testing
efficacy of malaria vaccines (Jongo et al., 2018; Mordmüller et al., 2017) and
more recently for evaluating efficacy of antimalarial drugs (Murphy et al.,
2018; Sulyok et al., 2017).
The aim of this study is to assess the chemoprophylactic activity and to
explore the dose-exposure-response relationship of single oral doses of M5717
administered immediately (early liver stage) or few days after (late liver
stage) DVI of PfSPZ Challenge in malaria-naïve, healthy participants in the
CHMI model.
Study objective
Primary Objectives:
- To assess chemoprophylactic activity of single oral doses of M5717
administered after DVI of Plasmodium falciparum sporozoites (PfSPZ) challenge
in healthy participants.
- To explore the dose-exposure-response relationship of a single oral dose of
M5717 administered after DVI of PfSPZ challenge in healthy participants.
Secondary Objectives:
- To evaluate the safety and tolerability of single, oral doses of M5717 in
healthy participants following infection with PfSPZ challenge.
- To investigate the PK of M5717 after administration of single, oral doses in
healthy participants following infection with PfSPZ.
Exploratory Objectives:
- To determine the incidence of resistance generation following M5717
administration.
- To explore the effect of pharmacogenetics (PGx) and variations of associated
genes on the PK profile of M5717 (optional).
Study design
Double-blind, randomized, placebo-controlled study.
Intervention
4 to 5 cohorts are planned with different doses. The number of participants
will be 4 to 12 participants per cohort with an active to placebo ratio of 3:1.
This means that of every 4 participants, 3 will receive an active treatment
with M5717 and 1 will receive a placebo.
Participants will receive M5717 or placebo capsules dissolved in water once.
The starting dose of M5717 of the first cohort is 200 mg.
The dosage of consecutive cohorts depends on the assessment of safety and PK /
PD by the Safety Monitoring Committee (SMC).
This study targets the early stage since for prophylaxis this will give an
indication about the concentrations that are needed to have an effect on the
parasite in the liver. This is the concentration that needs to be attained over
a certain period of e.g.7 days (if dosing is weekly) to be able to prevent the
parasite to develop in a human as the human can be infected at all days in this
time period. By investigating the effect on the early stage it is thought that
this concentration can then be extrapolated to a dose that will ensure high
enough blood concentrations needed for prophylaxis for a certain time period
(e.g 7 days in our example). It will also help to determine whether dosing
every 2 or 3 weeks for prophylaxis is feasible (i.e. if the effective dose
needed to sustain certain levels over a certain period does not give safety
concerns).
It might be possible that a subject starts with malaria prophylaxis in the
clinical situation when already being infected with the parasite but not yet
having progressed to the erythrocyte stage. Thus the malaria infection cannot
be detected in the blood of the subject. The second part of the study would
like to investigate whether the concentrations that have been established to be
effective on the early liver stage, are still effective when the parasite has
already multiplied and progressed to the late liver stage.
The concentrations and doses that will be identified in the current study will
substantially reduce the number of doses to be investigated in a clinical study
in the target population.
Study burden and risks
Burden:
- Admission to the hospital / study site:
- Visits to the doctor / researcher: max 30;
- Daily contact (on site or by telephone / by email) with the doctor /
researcher;
- Intravenous injection (inoculation): once;
- Blood tests: 26 times, 12 ml per time;
- Urine examination: 15 times;
- Alcohol breath test: 3 times;
- Physical examination: 4 times;
- Vital signs: 13 times;
- ECG measurement: 5 times;
- Diary: daily from the time of discharge;
- Fasting: from 8 hours prior to 4 hours after dosing. Water is allowed up to 2
hours before the dose and again after 2 hours after the dose.
- Nutritional restrictions: starting 14 days prior to the study until the end
of the study.
- Restrictions in the use of medication: see In / Exclusion criteria for
details regarding duration.
- Use of contraception: during the study intervention period up to a minimum of
120 days for male and 62 days for female after receiving study medication.
- Travel restrictions: for the entire duration of the study.
- Smoking restrictions: the use of tobacco products is not permitted for the
entire duration of participation in the study.
- Alcohol restrictions: abstention from alcohol consumption for 1 week prior to
study treatment. After the end of the admission to the research location, no
more than 1 drink (2 units) of alcohol per day until the end of the study visit.
- Exercise restrictions: abstain from strenuous exercise for 48 hours before
each blood collection for clinical laboratory tests. Refrain from taking up any
new unaccustomed exercise from Screening until the End of Study visit.
- Availability of contact person with whom test subject cohabits: daily during
the entire study.
Risks:
- Possible side effects of the study medication: headache, tachycardia, upper
respiratory tract infection, sunburn, lymphopenia, myalgia, dizziness,
contusion, oropharyngeal pain, rhinorrhea, abdominal discomfort, arthralgia,
blurred vision, abdominal distension, increased ALT, increased AST, diarrhea,
increased creatine phosphokinase in the blood, oral hypoaesthesia, neutropenia,
pyrexia and flushing.
- Possibility of malaria infection.
- Possible side effects of Malarone or Riamet rescue medication.
- Possibility of a positive HIV or Hepatis test result.
- Possibility of a positive pregnancy test.
- Possible damage to an unborn child.
- Possible abrasions in places where electrodes are placed for the ECG metig.
- Possible discomfort and side effects associated with blood sampling:
bruising, infection of the puncture site, dizziness, nausea and fainting.
Justification for research:
The risk for the subjects in this study has been minimized by adequate
inclusion and exclusion criteria, extensive medical monitoring, and a
well-considered dosing schedule. All this makes the risk acceptable to the
subjects in light of the "unmet need" of medication against malaria.
Frankfurter Strasse 250
Darmstadt 64293
DE
Frankfurter Strasse 250
Darmstadt 64293
DE
Listed location countries
Age
Inclusion criteria
Age
1. Are between 18 and 45 years of age at the time of signing the informed
consent.
Type of Participant and Disease Characteristics
2. Are overtly healthy as determined by medical evaluation, including no
clinically significant abnormality identified on physical examination or
laboratory evaluation and no active clinically significant disorder, condition,
infection or disease that would pose a risk to participant safety or interfere
with the study evaluation, procedures or completion.
Weight
3. Have a body weight within 50 to 100 kg and body mass index within the range
19.0 to 29.9 kg/m2 (inclusive).
Sex
4. Are male or female
Contraceptive use by males or females will be consistent with local regulations
on contraception methods for those participating in clinical studies.
* Male Participants:
Agree to the following during the study intervention period and for at least
120 days after the day of the study intervention dose (covering a full sperm
cycle of 90 days starting after 5 half-lives of last dose of study intervention:
* Refrain from donating sperm
PLUS, either:
* Abstain from intercourse with a woman of childbearing potential
OR
* Use a male condom:
* When having sexual intercourse with a woman of childbearing potential, who is
not currently pregnant, and advise her to use a highly effective contraceptive
method with a failure rate of < 1% per year, as described in Appendix 3
Contraception, since a condom may break or leak.
* Female Participants:
* Have a negative serum test at Screening and a highly sensitive urine
pregnancy test within 24 hours before the first study intervention (DVI) and
within 24 hours before the second study intervention (M5717) administration, as
required by local regulations. [If a urine test cannot be confirmed as negative
(e.g., an ambiguous result), a serum pregnancy test is required. In such cases,
the participant must be excluded from participation if the serum pregnancy
result is positive].
* Are not pregnant or breastfeeding, and at least one of the following
conditions applies:
* Not a woman of childbearing potential
* At least 1 year post-menopausal (amenorrhea * 12 months and
follicle-stimulating hormone (FSH) * 40 mIU/mL) at Screening;
* Surgically sterile (bilateral oophorectomy, hysterectomy or bilateral
salpingectomy; tubal ligation alone is not sufficient).
OR
* If a woman of childbearing potential, use a highly effective contraceptive
method (i.e., with a failure rate of < 1% per year), preferably with low user
dependency, as described in Appendix 3 for the following time periods:
* Before the first dose of the study intervention(s), if using hormonal
contraception:
* Has completed at least one 4-week cycle of an oral contraception pill and
either had or has begun her menses
OR
* Has used a depot contraceptive or extended-cycle oral contraceptive for at
least 28 days and has a documented negative pregnancy test using a highly
sensitive assay.
* During the intervention period
* After the study intervention period (i.e., after the last dose of study
intervention is administered) for at least 62 days, corresponding to the time
needed to eliminate any study intervention(s) (5 times terminal half-live of
155 hours) plus 30 days (a menstrual cycle) after the last dose of study
intervention (and agree not to donate eggs (ova, oocytes) for reproduction
during this period).
* Additional requirements for pregnancy testing during and after study
intervention are in Section 8.2.4.
* The investigator reviews the medical history, menstrual history, and recent
sexual activity to decrease the risk for inclusion of a female with an early
undetected pregnancy.
Informed Consent
5. Capable of giving signed informed consent, as indicated in Appendix 2 Study
Governance, which includes compliance with the requirements (including
mandatory intake of rescue medication to participants who have been
administered the investigational P. falciparum sporozoite challenge) and
restrictions listed in the informed consent form (ICF) and this protocol.
Other Inclusions
6. A non-smoker or ex-smoker for more than 90 days prior to Screening, or a
smoker of no more than 5 cigarettes per day or nicotine products (spray, patch,
e-cigarette, etc.) equivalent of no more than 5 cigarettes per day.
Participants must agree to abstain from smoking while in the study.
7. Willing to adhere to the prohibitions and restrictions (see Section 6.5.3)
specified in this protocol, including willingness to stay confined to the
inpatient unit for the required duration and willingness to avoid extensive
travelling during the study period.
8. Different ways of being reachable 24 hours per day, 7 days per week (e.g.,
by mobile phone, regular phone or electronic mail) during the whole study
period.
9. Does not live alone (from start of DVI with malaria sporozoites until at
least the end of the antimalarial drug treatment), willing to provide contact
details of a person living with him/her who is contactable and available for
the duration of the study.
Exclusion criteria
Medical Conditions
1. 12-Lead electrocardiogram (ECG) outside normal range (QTcF > 450 ms, PR
interval > 215 ms, or QRS > 120 ms) and deemed clinically relevant by the
Investigator.
2. Supine systolic blood pressure > 140 or < 90 mmHg, diastolic blood pressure
> 90 or < 50 mmHg, and pulse rate > 90 or < 50 beats per minute (min) at
Screening and at Admission on Day -1 (Any abnormal blood pressure or pulse rate
results may be repeated once and if the repeat result is within the normal
range, it is not considered to have met the exclusion criterion).
3. Seropositive for human immunodeficiency virus (HIV) I and II antibody or
antigen), hepatitis B virus (HBV; hepatitis B surface antigen [HBsAg]), or
hepatitis C virus (HCV; antibody) tests.
4. Liver function tests (see Appendix 5 Liver Safety: Suggested Actions and
Follow-up Assessments) above the upper limit of normal (ULN) (> 3xULN) (as
specified in the Laboratory Manual) the day before DVI / study intervention
administration (Day -1).
5. History or presence of diagnosed food or known drug allergies (including but
not limited to allergy to any of the antimalarial rescue medications to be used
in the study), or history of anaphylaxis or other severe allergic reactions.
Note: Participants with seasonal allergies/hay fever, house dust mite allergy,
or allergy to animals that are untreated and asymptomatic at the time of dosing
can be enrolled in the study.
6. History of a serious psychiatric condition that may affect participation in
the study or preclude compliance with the protocol.
7. Any surgical or medical condition possibly affecting drug absorption (e.g.
cholecystectomy, gastrectomy, bowel disease), distribution, metabolism or
excretion.
8. Any history of gallbladder disease, including cholecystitis and/or
cholelithiasis.
9. Any condition that in the opinion of the investigator would jeopardize the
safety or rights of a person participating in the study or would render the
person unable to comply with the protocol.
10. Frequent headaches of clinical relevance and/or migraine, recurrent nausea,
and/or vomiting (> 2 times per month).
11. Ingestion of any poppy seeds within 24 hours prior to each Drug Abuse
Screening.
12. Personal history of malaria or medical history of possible exposure to
malaria.
13. Presence of acute infectious disease or fever (i.e., sublingual temperature
* 38.0°C) within the 5 days prior to DVI with malaria sporozoites.
Prior/Concomitant Therapy
14. Use of medications known to interact with atovaquone-proguanil (Malarone)
or artemether-lumefantrine (Riamet) such as cimetidine, metoclopramide or
antacids, or an anticipated requirement for the use of these at any point
during the study period (see also Section 5.1).
15. Use of systemic antibiotics with known antimalarial activity within 30 days
(or 5 half-lives whichever is longer) of first study intervention
administration (e.g. trimethoprim-sulfamethoxazole, doxycycline, tetracycline,
clindamycin, erythromycin, fluoroquinolones or azithromycin) or an anticipated
requirement for the use of these during the study period.
16. Use of any prescription drugs, herbal supplements (e.g., St John's Wort) or
over-the-counter medication within 7 days or five half-lives (whichever is
longer) prior to the first study intervention administration, or an anticipated
requirement for the use of these during the course of the study.
Note: If necessary, the incidental use of non-steroidal anti-inflammatory drugs
(NSAIDs), paracetamol (2 g/day, 10 g/week), vitamins and topical treatments may
be acceptable after approval by the Investigator and will be documented in the
eSource system. The use of nutritional supplements during this time that are
not believed to have the potential to affect participant safety or the overall
results of the study, may be permitted on a case-by-case basis, following
approval by the Sponsor in consultation with the Investigator.
Prior/Concurrent Clinical Study Experience
17. Participation in an investigational drug or device study within 3 months
prior to first dosing or more than 4 times a year or plans to participate in
other investigational drug or vaccine research during the study period.
Diagnostic Assessments
None.
Other Exclusions
18. Personnel (e.g. investigator, sub-investigator, research assistant,
pharmacist, study coordinator or anyone mentioned in the delegation log)
directly involved in the conduct of the study or students of the departments
involved.
19. Intake of grapefruit, Seville oranges, cranberries, star fruit or juices of
these fruits, as well as quinine-containing food/beverages (e.g., tonic water,
bitter lemon), within 14 days prior to study intervention administration until
the end of the ambulatory period.
20. Participant has travelled to or lived in a malaria-endemic area for more
than 4 weeks during the 12 months prior to first study intervention
administration or spent any time in an endemic area during the 4 weeks prior to
first study intervention administration.
21. Plans to travel to a malaria-endemic region during the study period up to
last Follow-Up (FU) visit.
22. Previous participation in any malaria vaccine or CHMI study.
23. Participant with a whole blood donation or loss of > 450 mL within 60 days
before administration of study drug or unwilling to defer blood donations for 6
months.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-003414-14-NL |
| CCMO | NL71266.056.19 |