A Phase 1, 3 Part, Randomized, Placebo Controlled, Ascending Dose Study to Assess Safety, Tolerability, and Pharmacokinetics of Single Intravenous Doses of Meplazumab and to Assess Its Antimalarial Activity Against Plasmodium Falciparum in a Malaria Challenge Model in Healthy Subjects
Overview
- Phase
- Phase 1
- Intervention
- Meplazumab for Injection
- Conditions
- Malaria (Plasmodium Falciparum)
- Sponsor
- Jiangsu Pacific Meinuoke Bio Pharmaceutical Co Ltd
- Primary Endpoint
- Presence of Anti-antibodies
- Status
- Withdrawn
- Last Updated
- 2 years ago
Overview
Brief Summary
This Phase 1 study will be conducted to explore the dose regimen in humans and to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and toxicological effects of meplazumab in healthy subjects, thus providing a new macromolecule antibody drug for the prevention and treatment of P. falciparum infection.
Detailed Description
2.1 Study Rationale. This Phase 1 study will be conducted to explore the dose regimen in humans and to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and toxicological effects of meplazumab in healthy subjects, thus providing a new macromolecule antibody drug for the prevention and treatment of P. falciparum infection. 2.2 Background. Malaria is a mosquito borne infectious disease that manifests as acute fever. Malaria is caused by Plasmodium spp., a parasite which is transmitted to humans by the bite of an infected female Anopheles mosquito (malaria vector).1 When the infected mosquito bites a human, Plasmodium sporozoites in the mosquito's saliva enter the bloodstream and migrate to the liver where they reproduce within hepatocytes. This stage is known as the exoerythrocytic phase.2 Multiplying merozoites reproduce to form schizonts, which contain several thousand merozoites. Mature schizonts rupture to release merozoites into the blood where they invade erythrocytes,3 hence initiating the merozoites reproduction in the erythrocytic phase.2 Malaria may develop into severe or even fatal disease if not treated in time. Five species of Plasmodium infect humans, including Plasmodium falciparum (P. falciparum), P. vivax, P. ovale, P. malariae, and P. knowlesi.4 Among these, P. falciparum and P. vivax are the most common species, with the former as the most dangerous one which has a high morbidity and may result in rapid progression and high mortality. Current methods toward malaria elimination usually involve the combination of prevention and treatment. Early diagnosis and treatment can mitigate disease progression and reduce deaths. Artemisinin based combination therapies are currently recommended by the World Health Organization for treatment of malaria. Antimalarial drugs mainly include drugs to eliminate Plasmodium during the erythrocytic phase or during the exoerythrocytic phase. From the 1950s, falciparum malaria has progressively developed resistance to all antimalarials marketed including chloroquine, sulfadoxine pyrimethamine, etc leading to ineffective malaria control. Plasmodium spp. Have recently developed resistance to the current frontline drugs, artemisinin combination therapy. Therefore, new antimalarial therapies and drugs are urgently needed to combat drug resistance of Plasmodium. 2.2.1 Meplazumab, a Humanized Anti-CD147 IgG2 Monoclonal Antibody Meplazumab (Ketantin®) is a lyophilized powder for injection of small volume. The main active ingredient of the product, meplazumab, is a humanized immunoglobulin (Ig) G2 monoclonal antibody, consisting of the complementary-determining regions of anti CD147 murine antibody and the human framework region. It acts as an erythrocytic stage-macromolecular antibody drug that has the potential to mediate both treatment and prophylaxis of falciparum malaria. 2.2.2 Preclinical Data Preclinical studies and pharmacological studies have indicated that meplazumab for intravenous (IV) injection is safe and effective with well controlled quality. The nonclinical studies of meplazumab include pharmacology, PD, PK, and toxicology studies. Refer to Section 4 of the current IB for meplazumab for further details.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Capable of giving signed informed consent as described in Appendix 2, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol, prior to any study-specific procedures.
- •Men and women aged 18 to 55 years (inclusive), with suitable veins for cannulation or repeated venipuncture.
- •Total body weight ≥50 kg, and a body mass index between 18 to 32 kg/m2, inclusive.
- •Female subjects are eligible to participate if they have a negative pregnancy test at the Screening Visit and on admission to the study center, not lactating
- •Male subjects with female partners of childbearing potential must agree to use contraception as detailed in Appendix 7 of this protocol from the time of informed consent until at least 3 months after dosing with the investigational product. Male subjects with female partners that are surgically sterile, or male subjects who have undergone sterilization and have had testing to confirm the success of the sterilization, may also be included.
- •Male subjects must not donate sperm from the day of dosing until at least 3 months after dosing with the investigational product.
- •Medically healthy with clinically insignificant screening results based on a comprehensive medical history and physical examination as judged by the Principal Investigator.
- •Has to agree to abstain from alcohol intake 48 hours before administration of the study treatment and inoculation with P. falciparum, and during the confinement period of the study.
- •Able to be compliant with the protocol and attend all scheduled visits.
Exclusion Criteria
- •Previously treated with study treatment in the present study.
- •History of any clinically important disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study.
- •Any known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections.
- •Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of investigational product.
- •History of splenectomy.
- •Subjects with history of schizophrenia, bi-polar disease, psychoses, disorders requiring lithium, attempted or planned suicide, or any other severe (disabling) chronic psychiatric diagnosis.
- •Subjects who have been hospitalized within 5 years prior to enrollment for either a psychiatric illness or due to danger to self or others.
- •History of an episode of minor depression that required at least 6 months of pharmacological therapy and/or psychotherapy within the last 5 years; or any episode of major depression.
- •Presence of clinically significant infectious disease or fever (eg, sublingual temperature ≥38.5°C) within 5 days prior to study treatment administration (Parts A and C) or inoculation with the malaria challenge agent (Part B).
- •Hematology, biochemistry, or urinalysis results at Screening or at Day -1 (Parts A and C) or between Day -11 to -9 (Part B) that are outside of Sponsor-approved clinically acceptable laboratory ranges (Appendix 4), or are considered clinically significant by the Investigator. One repeat is permitted at Screening.
Arms & Interventions
Meplazumab
The vial of meplazumab will be reconstituted with 1 mL of water for injection. The required amount of drug solution will be withdrawn and added to 100 mL sterile normal saline (0.9%) for IV infusion. A single dose of meplazumab will be infused over 60 minutes at a constant rate using an infusion pump.
Intervention: Meplazumab for Injection
Placebo
100ml placebo will be infused over 60 minutes at a constant rate using an infusion pump, single time.
Intervention: Sterile normal saline (0.9%)
Outcomes
Primary Outcomes
Presence of Anti-antibodies
Time Frame: Time Frame: 71±3 days (throughout the study period)
collection of blood samples for immunogenicity assessments，using vadiation Anti-body testing assay to test the presence of anti-antibodies
Adverse events / serious adverse events
Time Frame: 43±3 days (from first dose to end of study)
Recording of adverse events / serious adverse events throughout the study period
Secondary Outcomes
- The area under the plasma drug concentration-time curve (AUC)(43±3 days (from first dose to end of study))
- Maximum Plasma Concentration(43±3 days (from first dose to end of study))
- Time to Maximum Plasma Concentration(43±3 days (from first dose to end of study))
- Terminal half-life(43±3 days (from first dose to end of study))
- Systemic clearance(43±3 days (from first dose to end of study))
- Area under the serum concentration-time curve from time zero extrapolated to infinity(43±3 days (from first dose to end of study))
- Area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration(43±3 days (from first dose to end of study))
- Volume of distribution(43±3 days (from first dose to end of study))
- Volume of distribution at steady state(43±3 days (from first dose to end of study))