Chemoprotective Activity of MMV390048 in PfSPZ Challenge Model

NCT03195387 | Withdrawn Phase 1

• 2 other identifiers: MMV_MMV390048_17_012017-002034-23
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

This study follows a First-In-Human dose-escalation study of MMV390048 (5 to 120 mg MMV390048 powder-in-bottle formulation), a formulation bioavailability study to establish suitable tablet formulation, and a two-part dose-escalation (40 to 120 mg of MMV390048) / induced blood stage malaria (ISBM) challenge study with the new tablet formulation. After identification of the predicted efficacious MMV390048 plasma concentrations in the IBSM model, the current study will evaluate the chemoprotective efficacy of MMV390048 in a standardised and validated controlled human malaria infection (CHMI) model using direct venous inoculation (DVI) of aseptic, purified, cryopreserved, vialed P. falciparum sporozoites (PfSPZ Challenge). Three sequential cohorts of healthy men and women of non-childbearing potential (WONCBP) will be administered the investigational medicinal product (IMP, i.e. MMV390048) under different conditions. This may identify preventative regimens, to be further investigated in a Phase II program. In the first two cohorts, protective administration of the IMP will occur 1 and 7 days before DVI of PfSPZ challenge. The timing of IMP administration and dosage in the last cohort will be determined on the basis of emerging data from the preceding cohorts, but will not exceed 28 days prior to the challenge nor 120 mg MMV390048.

Conditions

Malaria,Falciparum

Keywords

malaria, P. falciparum, chemoprotection, Phase Ib

Outcome Measures

Primary Outcomes (1)

• Cohort-specific geometric mean time to parasitaemia

  Defined by a positive thick blood smear (with 2 qualified microscopists detecting 2 unambiguous parasites each) or qPCR (three positive measurements, each at least 12 hours apart and one with parasitaemia greater 100 parasites per mL), or Day 28 if there is no parasitaemia.

  Up to 28 days

Secondary Outcomes (11)

• Incidence, severity and relationship to MMV390048 of the observed and self-reported treatment-emergent adverse events

  Until Day 29 after IMP administration (cohort-dependent)

• Malaria clinical score and incidence, severity and relationship of the observed and self-reported adverse events after PfSPZ challenge

  From PfSPZ challenge to the day of positive parasitaemia and to Day 28 and Day 60 (EOS visit)

• Area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUClast)

  Duration of the PK study is up to 29 days after IMP administration

• Area under the plasma concentration-time curve from time zero to infinity (AUCinf)

  Duration of the PK study is up to 29 days after IMP administration

• Maximum plasma drug concentration (Cmax)

  Duration of the PK study is up to 29 days after IMP administration

Other Outcomes (1)

• Parasite multiplication rate during early asexual blood stage

  Day 0 to day 60

Study Arms (4)

D-1/120 mg MMV390048

EXPERIMENTAL

Treatment of cohort 1: subjects receive a single oral dose of MMV390048 on Day -1, prior to PfSPZ challenge on Day 0.

Drug: MMV390048

D-7/120 mg MMV390048

EXPERIMENTAL

Treatment of cohort 2: subjects receive a single oral dose of MMV390048 on Day -7, prior to PfSPZ challenge on Day 0.

Drug: MMV390048

D-X/YY mg MMV390048

EXPERIMENTAL

Treatment of cohort 3: subjects receive a single oral dose of MMV390048 (dose to be determined) on a day (to be determined) prior to PfSPZ challenge on Day 0. Dosage and day of administration will be determined on the basis of data emerging from the first two cohorts.

Drug: MMV390048

Placebo

PLACEBO COMPARATOR

MMV390048 placebo

Drug: MMV390048

Interventions

MMV390048 DRUG

Each tablet contains 20 mg MMV390048 and the following excipients: tartaric acid powder, copovidone (Plasdone S-630), hypromellose acetate succinate (AquaSolve HPMC-AS MF), croscaramellose sodium (Solutab), microcrystalline cellulose type 102 (Avicel PH-102), magnesium stearate (Ligamed MF-2-V).

Also known as: MMV-048

D-1/120 mg MMV390048; D-7/120 mg MMV390048; D-X/YY mg MMV390048; Placebo

Eligibility Criteria

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

You may qualify if:

• Completion of written informed consent for study participation by the volunteer
• Able and willing to answer all questions on the informed consent quiz correctly, demonstrating an understanding of the study information and of the procedures associated with the study
• Men or WONCBP aged ≥ 18 and ≤ 45 at screening
• Good health based on the absence of significant medical history and clinically significant findings on physical examination and special investigations at screening and prior to IMP administration
• Body mass index \>18 and \< 30 \[kg/m2\]
• Negative alcohol breath test and urine drug screening test at screening (amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, opiates) and upon admission prior to IMP administration
• Sexually active male volunteers with female partners must agree to use a highly effective, medically acceptable form of contraception from the day of IMP administration until 120 days thereafter (covering a full sperm cycle of 90 days starting after 5 x t½ of the drug). Abstinent male volunteers or male volunteers with same-sex partners must agree to use the above-mentioned contraceptive methods if they commence heterosexual relations during the study, and to continue these methods until 120 days after IMP administration. Acceptable methods of contraception include the following:
• Condom and occlusive cap (diaphragm or cervical/vault caps)
• Surgical sterilization (vasectomy with documentation of azoospermia) plus utilisation of a barrier method (condom or occlusive cap \[diaphragm or cervical/vault caps\])
• The subject's female partner uses contraception known to inhibit ovulation (combined oral oestrogen/progesterone preparation, oral or injectable progesterone, subdermal implants or transdermal contraceptive patch) commenced at least 14 days prior to IMP administration to the male subject plus utilisation of a barrier method (condom or occlusive cap \[diaphragm or cervical/vault caps\]
• The subject's female partner has undergone documented bilateral tubal ligation (female sterilization) plus utilisation of a barrier method (condom or occlusive cap \[diaphragm or cervical/vault caps\]
• The subject's female partner has undergone documented placement of an intrauterine device or intrauterine system plus utilisation of a barrier method (condom or occlusive cap \[diaphragm or cervical/vault caps\]
• Women must be of non-childbearing potential as per one of the following definitions:
• surgically sterile (by hysterectomy and/or bilateral oophorectomy and/or bilateral salpingectomy) as documented by a surgical report or by ultrasound, or
• post-menopausal (spontaneous amenorrhoea for ≥ 12 months, or spontaneous amenorrhoea for 6-12 months and follicle-stimulating hormone (FSH) ≥ 40 IU/mL; either should be together with the absence of oral contraceptive use for \> 12 months)

You may not qualify if:

• Any 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 IMP administration, or spent any time in an endemic area during the 4 weeks prior to IMP administration
• Plans to travel to malaria endemic region during the study period up to last follow-up visit
• Plans to travel outside of Germany during the challenge period
• Volunteer is unable to be closely followed for social, geographic or psychological reasons
• Previous participation in any malaria vaccine or CHMI study
• Previous participation in a trial with MMV390048
• Participation in any other clinical study within 30 days or five half-lives of the investigational compound in that study (whichever is longer) prior to IMP administration in this study, or plans to participate in other investigational vaccine/drug research during the study period
• Participation in any research study involving blood sampling during the 8 weeks prior to IMP administration. (Volunteers from whom blood was last drawn at least 4 weeks prior to IMP administration, and from whom less than 450 ml of blood was taken during the 8 weeks leading up to the last study-related blood draw, may be considered on a case by case basis by the Investigator.)
• Blood product donation to any blood bank during the 8 weeks (whole blood) or 4 weeks (plasma and platelets) prior to IMP administration
• Blood loss of more than 100 ml during the 4 weeks prior to IMP administration
• Male volunteers with a female partner(s) who is (are) pregnant or lactating at the time of the administration of the IMP
• Women of childbearing potential, or nursing (lactating) women
• Positive HIV, HBV (seropositive for hepatitis B surface antigen) or HCV tests
• Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection, asplenia (e.g. post-splenectomy), recurrent, severe infections, or the use of chronic (more than 14 days) immunosuppressant or immune-modifying drugs within the 6 months prior to IMP administration. (The use of oral antihistamines, topical steroids or inhaled steroids at doses less than the equivalent of 800 ug budesonide or 750 ug fluticasone daily are not classified as immunosuppressant or immune-modifying for the purpose of this criterion.)

Sponsors & Collaborators

• Medicines for Malaria Venture: lead
• Datamap: collaborator
• PrimeVigilance Zagreb: collaborator
• ICON Clinical Research: collaborator
• Sanaria Inc.: collaborator
• PTx Solutions Ltd., UK: collaborator
• University of Cape Town: collaborator

Study Sites (1)

Institute of Tropical Medicine / Centre for Clinical Trials, Eberhard Karls University

Tübingen, 72074, Germany

Location

Related Publications (3)

• Sulyok M, Ruckle T, Roth A, Murbeth RE, Chalon S, Kerr N, Samec SS, Gobeau N, Calle CL, Ibanez J, Sulyok Z, Held J, Gebru T, Granados P, Bruckner S, Nguetse C, Mengue J, Lalremruata A, Sim BKL, Hoffman SL, Mohrle JJ, Kremsner PG, Mordmuller B. DSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infection. Lancet Infect Dis. 2017 Jun;17(6):636-644. doi: 10.1016/S1473-3099(17)30139-1. Epub 2017 Mar 28.

  PMID: 28363637 BACKGROUND

• Mordmuller B, Supan C, Sim KL, Gomez-Perez GP, Ospina Salazar CL, Held J, Bolte S, Esen M, Tschan S, Joanny F, Lamsfus Calle C, Lohr SJ, Lalremruata A, Gunasekera A, James ER, Billingsley PF, Richman A, Chakravarty S, Legarda A, Munoz J, Antonijoan RM, Ballester MR, Hoffman SL, Alonso PL, Kremsner PG. Direct venous inoculation of Plasmodium falciparum sporozoites for controlled human malaria infection: a dose-finding trial in two centres. Malar J. 2015 Mar 18;14:117. doi: 10.1186/s12936-015-0628-0.

  PMID: 25889522 BACKGROUND

• World Health Organization. World Malaria Report 2015. World Health. 2015;243

  BACKGROUND

MeSH Terms

Conditions

Malaria, Falciparum; Malaria

Interventions

MMV390048

Condition Hierarchy (Ancestors)

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

Study Officials

• Benjamin Mordmüller, Dr

  Institute of Tropical Medicine / Centre for Clinical Trials, Eberhard Karls University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 15, 2017
• First Posted: June 22, 2017
• Study Start: January 1, 2018
• Primary Completion: September 1, 2018
• Study Completion: December 1, 2018
• Last Updated: February 5, 2018

Record last verified: 2018-02

Locations

DE (1)