A Phase 2, Randomized, Double Blind, Placebo-Controlled Study to Examine the Prophylactic and Treatment Effects of a Single Dose Level of Oral Fenretinide in a Dengue Virus Challenge Model
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- Characterization of DENV viremia following inoculation
研究概览
简要总结
This randomized, placebo controlled single center study examines the extent to which 600 mg/m2/day of orally administered ISLA101 (fenretinide), given prophylactically or therapeutically, may reduce or eliminate signs and symptoms of dengue virus (DENV) infection over 29 days following subcutaneous challenge of healthy subjects with 'Dengue 1 Live Virus Human Challenge' (DENV-1-LVHC). Humoral and cellular immune responses, both innate and adaptive, circulating virus, and changes in clinical laboratory measures will also be examined.
详细描述
Pharmacology studies have identified the potential for fenretinide to inhibit the binding of the DENV nonstructural protein 5 (NS5) to host nuclear importins (IMPs) IMP-α and IMP-β1, thereby impairing infection and replication. This Phase 2 study is to evaluate the effectiveness of fenretinide in an encapsulated oral formulation (ISLA101) against challenge with Dengue 1 Live Virus Human Challenge (DENV-1-LVHC) product, both prophylactically and therapeutically. Oral doses will be taken with a high fat meal to improve absorption, as fenretinide is known to have poor gut permeability attributed to its accumulation in lipophilic cell membranes.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy male and female subjects not of childbearing potential who are 18 years to 55 years of age (inclusive) at the time of consent
- •Females not of childbearing potential as defined in the following criteria:
- •History of hysterectomy
- •Post-menopausal:
- •i. Natural post-menopausal females with at least 12 months from natural spontaneous amenorrhea and a serum follicle-stimulating hormone (FSH) concentration ≥ 40 IU/L ii. Post-surgical females must have undergone bilateral oophorectomy at least 6 weeks prior to study
- •Male subjects with female partners of childbearing potential must agree to practice abstinence or use a combination of 2 of the following acceptable birth control methods during the study and for at least 90 days after dosing:
- •Partners with an intrauterine device (IUD) in place for at least 3 months
- •Barrier method (condom or diaphragm) for at least 14 days prior to screening
- •Partners using stable hormonal contraceptive for at least 3 months prior to the study
- •History of vasectomy at least 3 months prior to signing the Informed Consent Form
- •Ability and willingness to sign informed consent
- •Passing score on comprehension test of at least 75%, with up to 3 attempts
- •Available for the study period
- •Provide consent for release of medical records from primary care physician, college or university, urgent care or emergency room visit
排除标准
- •Known or suspected pregnancy (confirmed via a positive serum human chorionic gonadotropin (hCG) pregnancy test at screening), planned pregnancy during the study period, nursing, or lactation
- •Men who intend to father a child or donate sperm during the study period, and for 90 days after dosing with study drug
- •Any disorders of coagulation
- •Any current malignancy other than non-melanoma skin cancer
- •Men who intend to father a child during the study period (approximately 120 days)
- •Blood tests confirming infection with human immunodeficiency virus- 1 (HIV-1), hepatitis C, hepatitis B (assessed by HBsAg) virus, or suspicion of active influenza virus infection
- •Positive antibodies to dengue virus
- •Any history of dengue infection or dengue vaccination (licensed or experimental); or planned dengue vaccination during the study period
- •Recent (in the past 4 weeks) travel to any dengue endemic area or travel to a country with risk of Yellow Fever or Japanese encephalitis transmission
- •Positive urine screen for cocaine, amphetamines, opiates or methadone
- •Currently taking anti-coagulant medication, aspirin or non-steroidal anti-inflammatory drugs (NSAIDs)
- •Active diabetes, active peptic ulcer disease (PUD), chronic obstructive pulmonary disease (COPD), coronary artery disease (CAD)
- •Known or suspected congenital or acquired immunodeficiency; or receipt of immunomodulation therapy such as anti-cancer chemotherapy or radiation therapy; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months)
- •Use of drugs listed in §6.6 that inhibit or induce Cytochrome P450 3A4 (CYP 3A4) enzymes within 30 days prior to administration of study drug and for the duration of Subject participation
- •Current, or a history of, auto-immune disease other than well controlled Hashimoto's thyroiditis
- •History of Guillain-Barré syndrome
- •Diagnosis with Bipolar Disorder or Schizophrenia, hospitalization in the past year for a mental health disorder, or any other psychiatric condition, which in the opinion of the investigator prevents the Subject from participating in the study
- •Hives, shortness of breath, swelling of the lips or throat, or hospitalization related to a previous vaccination or an allergy to specific medications/animals for which antigens may be in the virus preparations to include: shellfish allergy, fetal bovine serum, L-glutamine, neomycin and streptomycin
- •Chronic migraine headaches, defined as more than 15 headache days per month over a 3-month period of which more than 8 are migraines, in the absence of medication over use
- •Planning to donate blood in the 1 year following inoculation with dengue
- •Recent blood donation within prior 14 days of inoculation
- •Receipt of blood products or antibodies within 56 days of inoculation or during the study period
- •Planned travel during the study period (~120 days) which would interfere with the ability to complete all study visits
- •Any laboratory abnormalities prior to inoculation for the tests specified in the protocol, that are considered by the investigator to be clinically significant except those listed in exclusion criteria #25
- •subjects with the following grade 2 or greater lab abnormalities: Creatinine; Liver Function Tests - alanine transaminase (ALT), aspartate aminotransferase (AST); Hemoglobin (females and males); white blood count (WBC) decrease; Platelets decreased; prothrombin time (PT); partial thromboplastin time (PTT); Fibrinogen decrease
- •Significant screening physical examination abnormalities at the discretion of the investigator
- •Participation (active or follow-up phase) or planned participation in another vaccine, drug, medical device, or medical procedure clinical trial in the 4 weeks prior to this trial or during the trial.
- •Recent or scheduled receipt of any vaccine 4 weeks prior to or after virus inoculation
- •Beliefs that restrict the administration of blood products or transfusions
- •Chronic medical condition that, in the opinion of the investigator, impacts Subject safety
- •Physician discretion
研究组 & 干预措施
Cohort A
The first cohort (Cohort A) allows examination of prophylaxis as well as treatment, as ISLA101 will be taken prior to inoculation and for 21 days thereafter. Subjects will be randomized 3:1 (active:control), enrolling in a single group three days prior to inoculation. Following the morning dose on the 4th day of dosing, all subjects will be administered 0.5 mL DENV-1-LVHC (6.5 x 103 PFU/mL).
干预措施: Dengue 1 Live Virus Human Challenge (DENV-1-LVHC) (Drug)
Cohort A
The first cohort (Cohort A) allows examination of prophylaxis as well as treatment, as ISLA101 will be taken prior to inoculation and for 21 days thereafter. Subjects will be randomized 3:1 (active:control), enrolling in a single group three days prior to inoculation. Following the morning dose on the 4th day of dosing, all subjects will be administered 0.5 mL DENV-1-LVHC (6.5 x 103 PFU/mL).
干预措施: ISLA101 (Drug)
Cohort B
The first cohort (Cohort B) allows examination of prophylaxis as well as treatment, as placebo will be taken prior to inoculation and for 21 days thereafter. Subjects will be randomized 3:1 (active:control), enrolling in a single group three days prior to inoculation. Following the morning dose on the 4th day of dosing, all subjects will be administered 0.5 mL DENV-1-LVHC (6.5 x 103 PFU/mL).
干预措施: Dengue 1 Live Virus Human Challenge (DENV-1-LVHC) (Drug)
Cohort B
The first cohort (Cohort B) allows examination of prophylaxis as well as treatment, as placebo will be taken prior to inoculation and for 21 days thereafter. Subjects will be randomized 3:1 (active:control), enrolling in a single group three days prior to inoculation. Following the morning dose on the 4th day of dosing, all subjects will be administered 0.5 mL DENV-1-LVHC (6.5 x 103 PFU/mL).
干预措施: Placebo (Other)
Cohort C
The second cohort (Cohort C) is planned to enroll in two groups of five subjects each, using 4:1 randomization (active:control). All subjects will be administered 0.5 mL DENV-1-LVHC (6.5 x 103 PFU/mL) on Day 1. After the inoculation, subjects will be evaluated in the clinic daily through day 18 (eighteen consecutive daily clinic visits). Dosing with ISLA101 will commence on the morning of Day 8 and continue with a total of 28 doses taken twice daily through Day 21.
干预措施: ISLA101 (Drug)
Cohort C
The second cohort (Cohort C) is planned to enroll in two groups of five subjects each, using 4:1 randomization (active:control). All subjects will be administered 0.5 mL DENV-1-LVHC (6.5 x 103 PFU/mL) on Day 1. After the inoculation, subjects will be evaluated in the clinic daily through day 18 (eighteen consecutive daily clinic visits). Dosing with ISLA101 will commence on the morning of Day 8 and continue with a total of 28 doses taken twice daily through Day 21.
干预措施: Dengue 1 Live Virus Human Challenge (DENV-1-LVHC) (Drug)
Cohort D
The second cohort (Cohort D) is planned to enroll in two groups of five subjects each, using 4:1 randomization (active:control). All subjects will be administered 0.5 mL DENV-1-LVHC (6.5 x 103 PFU/mL) on Day 1. After the inoculation, subjects will be evaluated in the clinic daily through day 18 (eighteen consecutive daily clinic visits). Dosing with placebo will commence on the morning of Day 8 and continue with a total of 28 doses taken twice daily through Day 21.
干预措施: Dengue 1 Live Virus Human Challenge (DENV-1-LVHC) (Drug)
Cohort D
The second cohort (Cohort D) is planned to enroll in two groups of five subjects each, using 4:1 randomization (active:control). All subjects will be administered 0.5 mL DENV-1-LVHC (6.5 x 103 PFU/mL) on Day 1. After the inoculation, subjects will be evaluated in the clinic daily through day 18 (eighteen consecutive daily clinic visits). Dosing with placebo will commence on the morning of Day 8 and continue with a total of 28 doses taken twice daily through Day 21.
干预措施: Placebo (Other)
结局指标
主要结局
Characterization of DENV viremia following inoculation
时间窗: over 29 days from inoculation
Area under the curve of RNAemia by qRT-PCR for Cohort 1 Time to loss of detection of dengue virus RNAemia for Cohort 2
次要结局
- To further characterize circulating virus in the two interventional groups versus control(over 29 days from inoculation)
- To compare the need for hospital care between groups(Over 29 days from inoculation)
- To describe the Cmax of ISLA101 at the tested dose, route, and duration(from first to next to last dose of ISLA101 (Day 21) for Cohort 2)
- To characterize circulating virus in the two interventional groups versus control(Over 29 days from inoculation)
- To determine the effect of ISLA101 on solicited signs and symptoms of DENV when given prophylactically and through Day 21 post-inoculation, or only as delayed therapy(Over 29 days from inoculation)
- To evaluate changes from baseline in platelet among the three groups(Over 29 days from inoculation)
- To describe the Tmax of ISLA101 at the tested dose, route, and duration(from first to next to last dose of ISLA101 (Day 21) for Cohort 2)
- To compare the occurrence of unanticipated signs or symptoms of severe dengue(Over 29 days from inoculation)