Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Safety, Tolerability and Chemoprotective Activity of P218 in PfSPZ Challenge Model

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03707041
Recruitment Status : Completed
First Posted : October 16, 2018
Last Update Posted : June 5, 2019
Sponsor:
Collaborators:
SGS Life Sciences, a division of SGS Belgium NV
Institute of Tropical Medicine, Belgium
Washington University School of Medicine
Swiss BioQuant A.G., Switzerland
PrimeVigilance Ltd., UK
Biologic LLP, UK
Sanaria Inc.
FGK Representative Service B.V., The Netherlands
Information provided by (Responsible Party):
Medicines for Malaria Venture

Brief Summary:

This is a single centre, randomised, double-blind, placebo-controlled Phase Ib study, to evaluate the safety, tolerability and chemoprotective activity of P218 in a controlled P. falciparum sporozoite infection model.

Healthy men and women, aged 18 to 45 years will be enrolled in 3 study cohorts and will be administered either P218 or placebo twice, 48 hours apart. Subjects in cohorts 2 and 3 will be inoculated with P. falciparum sporozoites. Enrolment in cohorts will proceed sequentially, to facilitate review of data by a Safety Review Team (SRT) before proceeding with a subsequent cohort.

In cohort 1, safety and tolerability of P218 will be assessed. In cohorts 2 and 3, chemoprotective activity of P218 against malaria infection will be assessed, as well as the Influence of time of initiation of the P218 treatment on the protective effect.


Condition or disease Intervention/treatment Phase
Malaria Drug: P218 (1000 mg) Oral Capsules Drug: Placebo Oral Capsules Drug: P218 (100 mg) Oral Capsules Biological: PfSPZ Challenge Phase 1

Show Show detailed description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 32 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: In each of the three treatment cohorts, subjects will be randomly allocated to receive either P218 or placebo.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Placebo capsules matched to the drug product with regard to appearance and taste
Primary Purpose: Prevention
Official Title: A Single Centre, Randomised, Double-blind, Placebo-controlled, Phase Ib Study to Evaluate the Safety, Tolerability and Chemoprotective Antimalarial Activity of P218 Against Controlled Human Malaria Infection With Plasmodium Falciparum Sporozoite Challenge in Non-immune Healthy Adult Volunteers
Actual Study Start Date : December 11, 2018
Actual Primary Completion Date : May 27, 2019
Actual Study Completion Date : May 27, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

Arm Intervention/treatment
Experimental: P218 1000 mg (Oral Capsules) - Cohort 1
Two administrations of 1000 mg P218 (capsules p.o.), 48 hours apart
Drug: P218 (1000 mg) Oral Capsules
1000 mg P218 (4 x 250 mg capsules)

Placebo Comparator: P218 Placebo Oral Capsules - Cohort 1
Two administrations of P218 placebo (capsules p.o.), 48 hours apart
Drug: Placebo Oral Capsules
Placebo capsules matched to the P218 capsules with regard to appearance and taste

Experimental: P218 1000 mg (Oral Capsules) - Cohort 2
One administration of 1000 mg P218 (capsules p.o.), 2 hours after PfSPZ Challenge and one administration of 1000 mg P218 (capsules p.o.), 48 hours after first administration.
Drug: P218 (1000 mg) Oral Capsules
1000 mg P218 (4 x 250 mg capsules)

Biological: PfSPZ Challenge
3200 P. falciparum Sporozoites by direct venous inoculation (DVI)

Placebo Comparator: P218 Placebo Oral Capsules - Cohort 2
One administration of P218 placebo (capsules p.o.), 2 hours after PfSPZ Challenge and one administration of P218 placebo (capsules p.o.,) 48 hours after first administration.
Drug: Placebo Oral Capsules
Placebo capsules matched to the P218 capsules with regard to appearance and taste

Biological: PfSPZ Challenge
3200 P. falciparum Sporozoites by direct venous inoculation (DVI)

Experimental: P218 100 mg (Oral Capsules) - Cohort 3
One administration of 100 mg P218 (capsules p.o.), 2 hours after PfSPZ Challenge and one administration of 100 mg P218 (capsules p.o.), 48 hours after first administration.
Drug: P218 (100 mg) Oral Capsules
100 mg P218 (2 x 50 mg capsules)

Biological: PfSPZ Challenge
3200 P. falciparum Sporozoites by direct venous inoculation (DVI)

Active Comparator: P218 Placebo Oral Capsule - Cohort 3
One administration of P218 placebo (capsules p.o.), 2 hours after PfSPZ Challenge and one administration of P218 placebo (capsules p.o.), 48 hours after first administration.
Drug: Placebo Oral Capsules
Placebo capsules matched to the P218 capsules with regard to appearance and taste

Biological: PfSPZ Challenge
3200 P. falciparum Sporozoites by direct venous inoculation (DVI)




Primary Outcome Measures :
  1. Cohort 1: Number of TEAEs [ Time Frame: 9 days ]
    Incidence, severity and relationship to the treatment of observed or self-reported treatment emergent adverse events (TEAEs) after two single doses of 1000 mg P218 administered 48 hours apart in healthy adult volunteers.

  2. Cohort 2: Geometric mean time from PfSPZ Challenge to first quantitative polymerase chain reaction (qPCR) outcome equal or greater than 250 asexual parasites per mL of blood [ Time Frame: Number of days from PfSPZ Challenge DVI to positive parasitaemia, or 28 days ]
    Chemoprotective activity of two single doses of 1000 mg P218 administered 2 hours after PfSPZ Challenge and 48 hours later in healthy adult volunteers

  3. Cohort 3: Geometric mean time from PfSPZ Challenge DVI to first qPCR outcome equal or greater than 250 asexual parasites per mL of blood [ Time Frame: Number of days from PfSPZ Challenge to positive parasitaemia, or 28 days ]
    Chemoprotective activity of two single doses of 100 mg P218 administered 2 hours after PfSPZ Challenge and 48 hours later in healthy adult volunteers


Secondary Outcome Measures :
  1. Cohorts 2 and 3: Number of P218 TEAEs [ Time Frame: 35 days ]
    Incidence, severity and relationship to the P218 treatment of observed or self-reported treatment emergent adverse events in non-immune healthy adult volunteers after two single doses of 1000 mg P218 administered 48 hours apart in a controlled human malaria infection (PfSPZ Challenge)

  2. Cohorts 2 and 3: Number of PfSPZ Challenge TEAEs [ Time Frame: 35 days ]
    Incidence, severity and relationship to the PfSPZ Challenge of observed or self-reported treatment emergent adverse events in non-immune healthy adult volunteers before and after P218 administration

  3. Cohorts 2 and 3: Malaria clinical score [ Time Frame: On the day of positive parasitaemia or on Day 28 ]
    Malaria clinical score at the time of introduction of rescue therapy.

  4. Cohorts 1, 2 and 3: P218 AUC[0-48h] [ Time Frame: 9 days ]
    Area under the P218 plasma concentration-time curve from first administration to 48 hours after first administration

  5. Cohorts 1, 2 and 3: P218 AUC[48-96h] [ Time Frame: 9 days ]
    Area under the P218 plasma concentration-time curve from 48 hours after first administration to 96 hours after first administration

  6. Cohort 1: P218-OH AUC[0-48h] [ Time Frame: 9 days ]
    Area under the P218-OH plasma concentration-time curve from first P218 administration to 48 hours after first P218 administration

  7. Cohort 1: P218-OH AUC[48-96h] [ Time Frame: 9 days ]
    Area under the P218-OH plasma concentration-time curve from 48 hours after first P218 administration to 96 hours after first P218 administration.

  8. Cohort 1: P218-beta-acyl-glucuronide AUC[0-48h] [ Time Frame: 9 days ]
    Area under the P218-beta-acyl-glucuronide plasma concentration-time curve from first P218 administration to 48 hours after first P218 administration

  9. Cohort 1: P218-beta-acyl-glucuronide AUC[48-96h] [ Time Frame: 9 days ]
    Area under the P218-beta-acyl-glucuronide plasma concentration-time curve from 48 hours after first P218 administration to 96 hours after first P218 administration

  10. Cohort 1: P218-beta-acyl-glucuronide-OH AUC[0-48h] [ Time Frame: 9 days ]
    Area under the P218-beta-acyl-glucuronide-OH plasma concentration-time curve from first P218 administration to 48 hours after first P218 administration

  11. Cohort 1: P218-beta-acyl-glucuronide-OH AUC[48-96h] [ Time Frame: 9 days ]
    Area under the P218-beta-acyl-glucuronide-OH plasma concentration-time .curve from 48 hours after first P218 administration to 96 hours after first P218 administration

  12. Cohorts 1, 2 and 3: P218 Cmax [ Time Frame: 9 days ]
    Maximum observed P218 plasma concentration after each P218 administration

  13. Cohorts 1, 2 and 3: P218 Tmax [ Time Frame: 9 days ]
    Time to P218 Cmax after each P218 administration

  14. Cohort 1: P218-OH Cmax [ Time Frame: 9 days ]
    Maximum observed P218-OH plasma concentration after each P218 administration

  15. Cohort 1: P218-OH Tmax [ Time Frame: 9 days ]
    Time to P218-OH Cmax after each P218 administration

  16. Cohort 1: P218-beta-acyl-glucuronide Cmax [ Time Frame: 9 days ]
    Maximum observed P218-OH plasma concentration after each P218 .administration

  17. Cohort 1: P218-beta-acyl-glucuronide Tmax [ Time Frame: 9 days ]
    Time to P218-beta-acyl-glucuronide Cmax after each P218 administration

  18. Cohort 1: P218-beta-acyl-glucuronide-OH Cmax [ Time Frame: 9 days ]
    Maximum observed P218-beta-acyl-glucuronide-OH plasma concentration after each P218 administration

  19. Cohort 1: P218-beta-acyl-glucuronide-OH Tmax [ Time Frame: 9 days ]
    Time to P218-beta-acyl-glucuronide-OH Cmax after each P218 administration



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Subjects meeting all of the following criteria are eligible to participate in this study:

  1. Informed Consent Form signed voluntarily before any study-related procedure is performed, indicating that the subject understands the purpose of and procedures required for the study and is willing to participate in the study, including administration of rescue treatment.
  2. Male or female, between 18 and 45 years old (extremes included) at screening.
  3. Body weight of at least 50 kg and a body mass index (BMI) of 19 to 30 kg/m2 (extremes included).
  4. Good general health without clinically relevant medical illness, physical exam findings including vital signs, and laboratory abnormalities as determined by the investigator.
  5. Willing to adhere to the prohibitions and restrictions (see Section 4.3) specified in this protocol, including willingness to stay confined to the inpatient unit for required duration and willingness to avoid to travel outside of Benelux during the study period.
  6. Female subjects should fulfil one of the following criteria:

    1. At least 1 year post-menopausal (amenorrhea >12 months and follicle-stimulating hormone (FSH) >30 mIU/mL) prior to screening;
    2. Surgically sterile (bilateral oophorectomy, hysterectomy or tubal ligation);
    3. Will use contraceptives as outlined in inclusion criteria 7 and 8.
  7. Female subjects of childbearing potential must agree to the use of a highly effective method of birth control from screening visit to until 40 days after the last dose of IMP (covering a full menstrual cycle of 30 days starting after 5 half-lives of last dose of IMP).

    Note: Highly effective birth control methods include: combined (estrogen and progestogen containing) oral/intravaginal/transdermal hormonal contraception associated with inhibition of ovulation, progestogen-only oral/injectable/implantable hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner or sexual abstinence.

  8. Male subjects who are sexually active with a female partner of childbearing potential must agree to the use of an effective method of birth control from the day of the first IMP dose until 100 days thereafter (covering a full sperm cycle of 90 days starting after 5 half-lives of last dose of IMP).

    Note: Medically acceptable methods of contraception that may be used by the subject and/or partner include sterilization and vasectomy or a double barrier option combining oral contraceptive, contraceptive vaginal ring, contraceptive injection, intrauterine device or etonogestrel implant.

  9. Female subject has a negative pregnancy test at screening and upon admission in the clinical unit.

    Note: Pregnancy testing will consist of a serum β-human chorionic gonadotropin (β-HCG) test at screening and urine β-HCG tests at other visits, in all women.

    Inclusion Criteria - CHMI (controlled human malaria infection) specific:

  10. Different ways of being reachable 24/7 (e.g. by mobile phone, regular phone or electronic mail) during the whole study period.

Subjects meeting any of the following criteria are excluded from participation in this study:

  1. Nursing (lactating) women.
  2. Participation in any other clinical drug or vaccine study within 30 days (or five half-lives for drugs) preceding the first dose of IMP (whichever is longer), or plans to participate in other investigational drug or vaccine research during the study period.
  3. Blood product donation to any blood bank during the 8 weeks (whole blood) or 4 weeks (plasma and platelets) prior to admission in the clinical unit.
  4. ECG outside normal range and deemed clinically relevant by the investigator. Examples of clinically significant ECG abnormalities for this study include:

    1. PR-interval >220 ms;
    2. QRS-complex >120 ms;
    3. QT interval corrected according to Bazett's formula (QTcB) or QT interval corrected according to Fridericia's formula [3] (QTcF) >450 ms;
    4. Pathologic Q wave;
    5. Significant ST-T wave changes;
    6. Left or right ventricular hypertrophy;
    7. Non-sinus rhythm except isolated premature atrial contractions and ventricular extrasystole <2 per 10 s ECG lead;
    8. Incomplete left bundle branch block, or complete or intermittent right or left bundle branch block;
    9. Second or third degree A-V heart block.
  5. Seropositive human immunodeficiency virus (HIV) (antibody and antigen), hepatitis B virus (HBV) (hepatitis B surface antigen [HBsAg]) or hepatitis C virus (HCV) (antibody) tests.
  6. 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, see Section 5.2), or history of anaphylaxis or other severe allergic reactions.

    Note: Subjects with seasonal allergies/hay fever, house dust mite or allergy to animals that are untreated and asymptomatic at the time of dosing can be enrolled in the study.

  7. History of convulsion or severe head trauma.

    Note: A medical history of a single febrile convulsion during childhood is not an exclusion criteria.

  8. History of serious psychiatric condition that may affect participation in the study or preclude compliance with the protocol, including but not limited to past or present psychoses, disorders requiring lithium, a history of attempted or planned suicide, more than one previous episode of major depression, any previous single episode of major depression lasting for or requiring treatment for more than 6 months, or any episode of major depression during the 5 years preceding screening.

    Note: The Beck Depression Inventory (Attachment 2) will be used as an objective tool for the assessment of depression at screening. In addition to the conditions listed above, subjects with a score of 20 or more on the Beck Depression Inventory and/or a response of 1, 2 or 3 for item 9 of this inventory (related to suicidal ideation) will not be eligible for participation. Subjects with a Beck score of 17 to 19 may be enrolled at the discretion of the Investigator if they do not have a history of the psychiatric conditions mentioned in this criterion and their mental state is not considered to pose additional risk to the health of the volunteer or to the execution of the study and interpretation of the data gathered.

  9. A medical, occupational or family problem as a result of alcohol or illicit drug abuse during the past 12 months or current alcohol or illicit drug abuse or addiction (positive alcohol breath test or positive drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine or opiates at screening or upon check-in at the clinical unit).

    Note: Excessive use of alcohol is an intake of >21 units per week for males and >14 units per week for females where one alcohol unit is defined as 10 mL or 8 g of pure alcohol. A single unit is equal to one 25-mL (single) measure of whisky (alcohol by volume [ABV] 40%), or a third of a pint of beer (190 mL; ABV 5-6%) or half a standard (175 mL) glass of wine (ABV 12%).

  10. Subjects are non-smokers or ex-smokers for more than 90 days prior to screening or smoke no more than 5 cigarettes per day. If users of nicotine products (i.e. spray, patch, e-cigarette, etc.) they should use the equivalent of no more than 5 cigarettes per day. Subjects must agree to abstain from smoking while in the unit.
  11. 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 IMP administration, or an anticipated requirement for the use of these during the course of the study (See Section 6.2).

    Note: If necessary, the incidental use of non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol (2g/day, 10 gr/week), vitamins and topical treatments may be acceptable after approval by the study Sponsor 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 subject safety nor 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.

  12. Any surgical or medical condition possibly affecting drug absorption (e.g. cholecystectomy, gastrectomy, bowel disease), distribution, metabolism or excretion.
  13. Any history of gallbladder disease, including cholecystitis and/or cholelithiasis.
  14. History of megaloblastic anaemia or folate deficiency.
  15. 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.
  16. Any condition that in the opinion of the investigator would jeopardize the safety or rights of a person participating in the trial or would render the person unable to comply with the protocol.

    Exclusion Criteria - CHMI specific:

  17. Glucose-6-phosphate dehydrogenase (G6PD) deficiency (due to possible hemolysis induced by primaquine treatment at study end in G6PD deficient subjects).
  18. Personal history of malaria.
  19. Volunteer has travelled to or lived in a malaria-endemic area for more than 4 weeks during the 12 months prior to first IMP administration, or spent any time in an endemic area during the 4 weeks prior to first IMP administration.
  20. Plans to travel to malaria-endemic region during the study period up to last follow-up visit.
  21. Previous participation in any malaria vaccine or CHMI study.
  22. Falling in moderate or higher risk category for a fatal or non-fatal cardiovascular event within 10 years (≥5%) determined by a validated risk estimation system e.g. SCORE [13].
  23. Use of medications known to interact with atovaquone-proguanil (Malarone®), artemether-lumefantrine (Riamet®) or primaquine (Primaquine®) such as cimetidine, metoclopramide or antacids, or an anticipated requirement for the use of these at any point during the study period (see Section 6.2).
  24. Use of systemic antibiotics with known antimalarial activity within 30 days (or 5 half-lives whichever is longer) of first IMP 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 (see Section 6.2).
  25. Receipt of blood or blood-derived products (including immunoglobulin) within 3 months prior to screening. Receipt of packed red blood cells given for an emergent indication in an otherwise healthy person, and not required as ongoing treatment is not exclusionary (for example packed red blood cells emergently given during an elective surgery).

Note: In case of an out-of-range clinical laboratory test, vital sign or ECG value that will determine a subject's eligibility, or in case of a positive drug screen, a retest or expert evaluation can be requested. Results of any retest must be available prior to inoculation. The result of the retest will be considered for subject eligibility at the investigator's discretion. Subjects can be rescreened at the discretion of the investigator.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03707041


Locations
Layout table for location information
Belgium
SGS Belgium NV Clinical Pharmacology Unit
Antwerpen, Belgium, 2060
Sponsors and Collaborators
Medicines for Malaria Venture
SGS Life Sciences, a division of SGS Belgium NV
Institute of Tropical Medicine, Belgium
Washington University School of Medicine
Swiss BioQuant A.G., Switzerland
PrimeVigilance Ltd., UK
Biologic LLP, UK
Sanaria Inc.
FGK Representative Service B.V., The Netherlands
Investigators
Layout table for investigator information
Study Director: Cristina Donini, PhD MMV
Principal Investigator: Pieter-Jan Berghmans, MD SGS Belgium NV
Layout table for additonal information
Responsible Party: Medicines for Malaria Venture
ClinicalTrials.gov Identifier: NCT03707041    
Other Study ID Numbers: MMV_P218_17_01
2018-003004-39 ( EudraCT Number )
First Posted: October 16, 2018    Key Record Dates
Last Update Posted: June 5, 2019
Last Verified: May 2019

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Medicines for Malaria Venture:
malaria
PfSPZ Challenge
chemoprotection
Additional relevant MeSH terms:
Layout table for MeSH terms
Malaria
Protozoan Infections
Parasitic Diseases