Study to Examine the Effects of Oral Fenretinide (PROTECT)

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

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.

Study Overview

• Status: Completed
• Conditions: Dengue
• Intervention / Treatment: Drug: ISLA101; Drug: Dengue 1 Live Virus Human Challenge (DENV-1-LVHC); Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • East Syracuse, New York, United States, 13057
      • SUNY Upstate Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• 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:

  1. History of hysterectomy
  2. 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:

  1. Partners with an intrauterine device (IUD) in place for at least 3 months
  2. Barrier method (condom or diaphragm) for at least 14 days prior to screening
  3. Partners using stable hormonal contraceptive for at least 3 months prior to the study
  4. 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

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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).	Drug: ISLA101; ISLA101 is an oral gelatin capsule containing 100 mg of fenretinide (N-[4-Hydroxyphenyl]retinamide, mw 391.56) dissolved in corn oil and polysorbate 80. ISLA101 capsules will be administered orally as one dose of 300 mg/m2 each 12 hours (q12 +/-1 h).; Other Names: fenretinide; Drug: Dengue 1 Live Virus Human Challenge (DENV-1-LVHC); The DENV-1-LVHC investigational challenge material consists of the dengue-1 virus strain 45AZ5 as a powder, lyophilized for reconstitution. The product is reconstituted with 0.7 mL of water for injection (WFI) and diluted to a concentration of 6.5 x 103 PFU/mL.
Placebo Comparator: 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).	Drug: Dengue 1 Live Virus Human Challenge (DENV-1-LVHC); The DENV-1-LVHC investigational challenge material consists of the dengue-1 virus strain 45AZ5 as a powder, lyophilized for reconstitution. The product is reconstituted with 0.7 mL of water for injection (WFI) and diluted to a concentration of 6.5 x 103 PFU/mL.; Other: Placebo; Placebo capsules will be administered orally as one dose of 300 mg/m2 each 12 hours (q12 +/-1 h).
Experimental: 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.	Drug: ISLA101; ISLA101 is an oral gelatin capsule containing 100 mg of fenretinide (N-[4-Hydroxyphenyl]retinamide, mw 391.56) dissolved in corn oil and polysorbate 80. ISLA101 capsules will be administered orally as one dose of 300 mg/m2 each 12 hours (q12 +/-1 h).; Other Names: fenretinide; Drug: Dengue 1 Live Virus Human Challenge (DENV-1-LVHC); The DENV-1-LVHC investigational challenge material consists of the dengue-1 virus strain 45AZ5 as a powder, lyophilized for reconstitution. The product is reconstituted with 0.7 mL of water for injection (WFI) and diluted to a concentration of 6.5 x 103 PFU/mL.
Placebo Comparator: 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.	Drug: Dengue 1 Live Virus Human Challenge (DENV-1-LVHC); The DENV-1-LVHC investigational challenge material consists of the dengue-1 virus strain 45AZ5 as a powder, lyophilized for reconstitution. The product is reconstituted with 0.7 mL of water for injection (WFI) and diluted to a concentration of 6.5 x 103 PFU/mL.; Other: Placebo; Placebo capsules will be administered orally as one dose of 300 mg/m2 each 12 hours (q12 +/-1 h).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Characterization of DENV viremia following 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	over 29 days from inoculation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate changes from baseline in platelet among the three groups	Number of participants with abnormal platelet counts, observed over 29 days from inoculation, will be summarized overall, by group, by duration and by toxicity grade for each group compared with control. A summary of subjects with shifts from baseline (relative to normal range) in laboratory test results will be provided.	Over 29 days from inoculation
To describe the Cmax of ISLA101 at the tested dose, route, and duration	Concentration-time plots of first and NEXT-TO-LAST dose of ISLA101	from first to next to last dose of ISLA101 (Day 24) for Cohort 1
To describe the Tmax of ISLA101 at the tested dose, route, and duration	Concentration-time plots of first and NEXT-TO-LAST dose of ISLA101	from first to next to last dose of ISLA101 (Day 24) for Cohort 1
To describe the Cmax of ISLA101 at the tested dose, route, and duration	Concentration-time plots of first and NEXT-TO-LAST dose of ISLA101	from first to next to last dose of ISLA101 (Day 21) for Cohort 2
To describe the Tmax of ISLA101 at the tested dose, route, and duration	Concentration-time plots of first and NEXT-TO-LAST dose of ISLA101	from first to next to last dose of ISLA101 (Day 21) for Cohort 2
To further characterize circulating virus in the two interventional groups versus control	Time to positive RNAemia by qRT-PCR	over 29 days from inoculation
To characterize circulating virus in the two interventional groups versus control	Peak level of RNAemia by qRT-PCR	over 29 days from inoculation
To characterize circulating virus in the two interventional groups versus control	Duration of RNAemia by qRT-PCR (Cohort 1)	Over 29 days from inoculation
To characterize circulating virus in the two interventional groups versus control	Area under the curve of RNAemia by qRT-PCR (Cohort 2)	Over 29 days from inoculation
To characterize circulating virus in the two interventional groups versus control	Levels of infectious virus in blood by Plaque Assay	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	The calculated score of solicited signs and symptoms associated with dengue virus infection, including any of the listed events below, will consist of summing the CTCAE grades across all days for all events, where the score will be summarized by number of positive subjects: Fever, nausea, vomiting, fatigue, rash, abdominal pain, eye pain, bone pain, joint pain, muscle pain, headache.	Over 29 days from inoculation
To compare the occurrence of unanticipated signs or symptoms of severe dengue	The proportion of subjects with any of the following: diffuse abdominal pain or tenderness,; persistent vomiting,; clinical fluid accumulation (ascites, pleural effusion),; mucosal bleeding,; lethargy,; restlessness,; liver enlargement >2 cm,; increase in hematocrit concurrent with rapid decrease in platelet count.; severe plasma leakage,; severe hemorrhage,; severe organ impairment.	Over 29 days from inoculation
To compare the need for hospital care between groups	Proportion of subjects hospitalized for dengue symptoms	Over 29 days from inoculation
To compare the need for hospital care between groups	Length of hospitalization stay for dengue symptoms	Over 29 days from inoculation
To compare the need for hospital care between groups	Number of days in the intensive care unit for each hospitalization for dengue symptoms	Over 29 days from inoculation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To identify changes in viral genome	Whole genome DENV nucleotide sequence analyses from all subjects who become DENV infected in both the active and control groups.	over 29 days from inoculation
To examine immune responses to DENV-1-LVHC among the three groups	For each group compared with controls: a. Changes from baseline in anti-DENV-1 antibody levels and biological activity in serum and saliva (isotype specific)	over 29 days from inoculation
To examine subject HLA haplotypes	HLA haplotype determination	over 29 days from inoculation
Number of participants with treatment emergent adverse events of ISLA101 in healthy subjects infected with DENV-1-LVHC	Unsolicited AEs with a focus on SAEs and SUSARs	over 29 days from inoculation
Number of participants with adverse events related to dengue in healthy subjects infected with DENV-1-LVHC	Solicited AEs with a focus on SAEs and SUSARs	over 29 days from inoculation

Collaborators and Investigators

• Sponsor: Island Pharmaceuticals
• Investigators: Study Director: Bert Slade, MD, CCRS

Study record dates

Study Major Dates

• Study Start (Actual): September 5, 2024
• Primary Completion (Actual): May 21, 2025
• Study Completion (Actual): July 21, 2025

Study Registration Dates

• First Submitted: July 15, 2024
• First Submitted That Met QC Criteria: July 25, 2024
• First Posted (Actual): July 30, 2024

Study Record Updates

• Last Update Posted (Estimated): October 24, 2025
• Last Update Submitted That Met QC Criteria: October 23, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: dengue; Dengue with Warning Signs; Dengue Without Warning Signs
• Additional Relevant MeSH Terms: Vector Borne Diseases; Mosquito-Borne Diseases; Infections; RNA Virus Infections; Virus Diseases; Arbovirus Infections; Flavivirus Infections; Flaviviridae Infections; Hemorrhagic Fevers, Viral; Dengue; Organic Chemicals; Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Pigments, Biological; Biological Factors; Fenretinide
• Other Study ID Numbers: ISLA101-P02-CT002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No