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

NCT03707041 | Completed Phase 1 Results

• 2 other identifiers: MMV_P218_17_012018-003004-39
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

This was 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 were to be enrolled in 3 study cohorts and to be administered either P218 or placebo twice, 48 hours apart. Subjects in cohorts 2 and 3 were to be inoculated with P. falciparum sporozoites. Enrolment in cohorts was to 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 was assessed. In cohorts 2 and 3, chemoprotective activity of P218 against malaria infection was assessed, as well as the Influence of time of initiation of the P218 treatment on the protective effect.

Conditions

Malaria

Keywords

malaria; PfSPZ Challenge; chemoprotection

Outcome Measures

Primary Outcomes (2)

• Cohort 1: Number of TEAEs

  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.

  9 days

• Cohorts 2 and 3: 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

  Chemoprotective activity of two single doses of 1000 mg P218 administered 2 hours after PfSPZ Challenge and 48 hours later in healthy adult volunteers

  Number of days from PfSPZ Challenge DVI to positive parasitaemia, or 28 days

Secondary Outcomes (7)

• Cohorts 2 and 3: Number of P218 TEAEs

  35 days

• Cohorts 2 and 3: Number of PfSPZ Challenge TEAEs

  35 days

• Cohorts 2 and 3: Malaria Clinical Score at the Time of Introduction of Rescue Therapy

  On the day of positive parasitaemia or on Day 28

• Cohorts 1, 2 and 3: P218 AUC[0-48h] - Day 1

  9 days

• Cohort 1: P218-beta-acyl-glucuronide-OH AUC[48-96h]

  9 days

Study Arms (6)

P218 1000 mg (Oral Capsules) - Cohort 1

EXPERIMENTAL

Two administrations of 1000 mg P218 (capsules p.o.), 48 hours apart

Drug: P218 (1000 mg) Oral Capsules

P218 Placebo Oral Capsules - Cohort 1

PLACEBO COMPARATOR

Two administrations of P218 placebo (capsules p.o.), 48 hours apart

Drug: Placebo Oral Capsules

P218 1000 mg (Oral Capsules) - Cohort 2

EXPERIMENTAL

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; Biological: PfSPZ Challenge

P218 Placebo Oral Capsules - Cohort 2

PLACEBO COMPARATOR

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; Biological: PfSPZ Challenge

P218 100 mg (Oral Capsules) - Cohort 3

EXPERIMENTAL

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; Biological: PfSPZ Challenge

P218 Placebo Oral Capsule - Cohort 3

ACTIVE COMPARATOR

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; Biological: PfSPZ Challenge

Interventions

P218 (1000 mg) Oral Capsules DRUG

1000 mg P218 (4 x 250 mg capsules)

P218 1000 mg (Oral Capsules) - Cohort 1; P218 1000 mg (Oral Capsules) - Cohort 2

Placebo Oral Capsules DRUG

Placebo capsules matched to the P218 capsules with regard to appearance and taste

P218 Placebo Oral Capsule - Cohort 3; P218 Placebo Oral Capsules - Cohort 1; P218 Placebo Oral Capsules - Cohort 2

P218 (100 mg) Oral Capsules DRUG

100 mg P218 (2 x 50 mg capsules)

P218 100 mg (Oral Capsules) - Cohort 3

PfSPZ Challenge BIOLOGICAL

3200 P. falciparum Sporozoites by direct venous inoculation (DVI)

P218 100 mg (Oral Capsules) - Cohort 3; P218 1000 mg (Oral Capsules) - Cohort 2; P218 Placebo Oral Capsule - Cohort 3; P218 Placebo Oral Capsules - Cohort 2

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• 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.
• 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.
• 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:
• Nursing (lactating) women.
• 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.
• 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.
• ECG outside normal range and deemed clinically relevant by the investigator. Examples of clinically significant ECG abnormalities for this study include:
• PR-interval \>220 ms;
• QRS-complex \>120 ms;
• QT interval corrected according to Bazett's formula (QTcB) or QT interval corrected according to Fridericia's formula \[3\] (QTcF) \>450 ms;

You may not qualify if:

• 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.
• 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%).
• 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.
• 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.
• Any surgical or medical condition possibly affecting drug absorption (e.g. cholecystectomy, gastrectomy, bowel disease), distribution, metabolism or excretion.
• Any history of gallbladder disease, including cholecystitis and/or cholelithiasis.
• History of megaloblastic anaemia or folate deficiency.
• 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.
• 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.
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency (due to possible hemolysis induced by primaquine treatment at study end in G6PD deficient subjects).
• Personal history of malaria.
• 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.

Sponsors & Collaborators

• Medicines for Malaria Venture: lead
• SGS Life Sciences, a division of SGS Belgium NV: collaborator
• Institute of Tropical Medicine, Belgium: collaborator
• Washington University School of Medicine: collaborator
• Swiss BioQuant: collaborator
• PrimeVigilance Ltd., UK: collaborator
• Biologic LLP, UK: collaborator
• Sanaria Inc.: collaborator
• FGK Representative Service B.V., The Netherlands: collaborator

Study Sites (1)

SGS Belgium NV Clinical Pharmacology Unit

Antwerp, 2060, Belgium

Location

MeSH Terms

Conditions

Malaria

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Results Point of Contact

• Title: Andrew Slade
• Organization: Medicines for Malaria Venture

sladea@mmv.org

+41 22 555 0415

Study Officials

• Cristina Donini, PhD

  MMV

  STUDY DIRECTOR

• Pieter-Jan Berghmans, MD

  SGS Belgium NV

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Placebo capsules matched to the drug product with regard to appearance and taste
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: In each of the three treatment cohorts, subjects will be randomly allocated to receive either P218 or placebo.

Study Record Dates

• First Submitted: October 9, 2018
• First Posted: October 16, 2018
• Study Start: November 16, 2018
• Primary Completion: May 27, 2019
• Study Completion: June 3, 2019
• Last Updated: April 9, 2021
• Results First Posted: April 9, 2021

Record last verified: 2021-03

Locations

BE (1)