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Safety Study of Fenretinide in Adult Patients With Cystic Fibrosis

Primary Purpose

Cystic Fibrosis

Status
Completed
Phase
Phase 1
Locations
Canada
Study Type
Interventional
Intervention
Fenretinide
Placebo
Sponsored by
Elias Matouk
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cystic Fibrosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Signed Informed Consent
  • Males or females
  • 18 years and older
  • Diagnosis: Patients must have a diagnosis of cystic fibrosis (positive sweat chloride test) or confirmation of two genetic mutations, one mutation on each of the two alleles of the Cystic fibrosis transmembrane conductance regulator (CFTR) gene causing Cystic Fibrosis
  • Chronic cystic fibrosis lung disease with baseline Forced Exploratory Volume in one second equal or superior to 40% predicted value for age, gender and height
  • Clinically stable patients will be enrolled in the study, i.e. stable at least one month after successful treatment of pulmonary exacerbation
  • Chronic pulmonary Pseudomonas aeruginosa colonization and/or infection (sustained microbiological evidence from sputum for the past 6 months, prior to enrollment)
  • Pancreatic function: Patient must take pancrelipase supplementation if diagnosed with pancreatic insufficiency as prescribed by a physician. Enzyme supplementation should not be modified during the trial
  • Female patients should be on an effective contraceptive method during the study.

Exclusion Criteria:

  • Pregnancy : due to the potential teratogenic effects of retinoids, pregnant women are NOT eligible
  • Breastfeeding by study patient is NOT allowed
  • Clinically abnormal renal function: Serum Creatinine > 132 micromoles/L
  • Clinically abnormal liver function: Total bilirubin >1.5 x Upper Limit of the Normal range (ULN), Alanine Aminotransferase (ALT) and/or Aspartate AminoTransferase (AST) > 3 x ULN and Alkaline Phosphatase (ALP) > 2 x ULN
  • Known history of a severe allergy or sensitivity to retinoids
  • Presence of a cancerous tumor, active or in remission, treated or not
  • Presence of nyctalopia or hemeralopia at enrolment, or any other serious retinal, ophthalmological condition (eg: retinitis pigmentosa, choroidoretinitis and xerophthalmia), including glaucoma
  • Presence of serious dermatological conditions at entry, including inflammatory or xerotic pathologies such as psoriasis or ichthyosis
  • Prior therapy with Fenretinide. Other retinoids (eg: vitamin A supplements) are allowed, but their dosing regimen should remain constant throughout the study
  • Participation in another drug clinical trial within 30 days prior to the enrollment
  • Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study
  • Patients unable to comply with the study protocol and follow-up schedule for any psychological, familial, sociological or geographical reason.
  • Patients with known allergies to excipients in the oral capsule formulation proposed to be used in the study

Sites / Locations

  • Montreal Chest Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Fenretinide

Placebo

Arm Description

Fenretinide will be administrated orally once per day for 21 consecutive days, in up to three treatment cycles of ascending doses, with a minimum of 7-day drug-free period between cycles. Twelve (12) patients will be on Fenretinide.

Four (4) patients will be on Placebo.

Outcomes

Primary Outcome Measures

Assessment of the safety and tolerability of ascending doses of oral Fenretinide, each dose to be administered to adult cystic fibrosis (CF) patients once-daily (QD) during a 21 days treatment cycle.
Changes in clinical signs and symptoms of safety data during a 21 days treatment cycle, such safety data assessment including physical examinations, ECGs, vital signs, pulmonary function (spirometry), clinical laboratory results, assessment of ophthalmological condition, and adverse events reported. The safety data will be used to authorize dose escalations. Up to three (3) doses of Fenretinide will be assessed in up to three (3) treatment cycles of 21 days.

Secondary Outcome Measures

Pharmacokinetic profile of the drug, measuring Cmax, Tmax, T1/2, AUC (area under the curve) and Css (steady state concentration), for each dose level
Cmax, Tmax, T 1/2, and Css (steady state concentration) with target plasma levels of Fenretinide 1-2 µM as a pharmacokinetic / pharmacodynamic biological activity
Pharmacodynamic lipid markers: plasma Arachidonic Acid (AA) and Docosahexaenoic Acid (DHA)
Arachidonic Acid as omega-6 proinflammatory fatty acid and Docosahexaenoic Acid (DHA) as an omega-3 anti-inflammatory fatty acid.
Pharmacodynamic inflammatory markers: Immunoglobulin G, Interleukin 1β, Interleukin 6, Interleukin 8, Interleukin 10, Macrophage inflammatory protein-1β, Tumor necrosis factors and Vascular endothelial growth factor

Full Information

First Posted
May 13, 2014
Last Updated
July 10, 2016
Sponsor
Elias Matouk
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1. Study Identification

Unique Protocol Identification Number
NCT02141958
Brief Title
Safety Study of Fenretinide in Adult Patients With Cystic Fibrosis
Official Title
An Adaptive Phase I Intra-patient Dose Escalation Study of Fenretinide in Adult Cystic Fibrosis Patients
Study Type
Interventional

2. Study Status

Record Verification Date
July 2016
Overall Recruitment Status
Completed
Study Start Date
April 2014 (undefined)
Primary Completion Date
February 2015 (Actual)
Study Completion Date
February 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Elias Matouk

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to assess the safety and tolerability of ascending doses of a novel oral formulation of Fenretinide to adult cystic fibrosis (CF) patients, once-daily for 21 days (treatment cycle). This study will include up to three (3) dose levels with minimum 7 day breaks in between treatment cycles. For each dose level, blood samples will be collected for exploratory pharmacokinetic (PK) and pharmacodynamic (PD) evaluation.
Detailed Description
Patients with cystic fibrosis have an innate imbalance of essential fatty acids, with increased arachidonic acid (AA) levels, decreased docosahexanoic acid (DHA) levels, and elevated AA/DHA ratio. An increasing amount of evidence suggests that this lipid imbalance is a primary effect in CF, playing a major role in the infection-inflammation vicious cycle that leads to respiratory failure. Fenretinide, a derivative of vitamin A, was shown to correct the AA/DHA imbalance in lungs and blood plasma in specific animal model of CF, resulting in reduced lung inflammation and decrease in the severity of pulmonary infections with Pseudomonas aeruginosa. This is a single center, randomized, double-blinded, placebo-controlled Phase 1 clinical study to evaluate the safety and tolerability of up to 3 increasing oral doses of Fenretinide compared to placebo, and to evaluate the pharmacokinetics of Fenretinide in adult CF patients chronically infected with Pseudomonas aeruginosa. A single cohort of 16 clinically stable adult patients will be randomized to either Fenretinide or placebo, in a 3:1 randomization scheme (12 active, 4 placebo).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cystic Fibrosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Fenretinide
Arm Type
Experimental
Arm Description
Fenretinide will be administrated orally once per day for 21 consecutive days, in up to three treatment cycles of ascending doses, with a minimum of 7-day drug-free period between cycles. Twelve (12) patients will be on Fenretinide.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Four (4) patients will be on Placebo.
Intervention Type
Drug
Intervention Name(s)
Fenretinide
Intervention Description
Fenretinide oral capsules of 100mg, each selected dose being administered once daily for 21 days (treatment cycle). Up to three total daily dose levels will be assessed in the study, as follows: 100mg of Fenretinide (one capsule) for the first treatment cycle, 200mg of Fenretinide (two capsules) in the second treatment cycle, and 300mg or 400mg of Fenretinide (3 or 4 capsules) will be selected for the third treatment cycle, based on safety and PK data collected.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
A matching placebo will be used to keep the study double-blind.
Primary Outcome Measure Information:
Title
Assessment of the safety and tolerability of ascending doses of oral Fenretinide, each dose to be administered to adult cystic fibrosis (CF) patients once-daily (QD) during a 21 days treatment cycle.
Description
Changes in clinical signs and symptoms of safety data during a 21 days treatment cycle, such safety data assessment including physical examinations, ECGs, vital signs, pulmonary function (spirometry), clinical laboratory results, assessment of ophthalmological condition, and adverse events reported. The safety data will be used to authorize dose escalations. Up to three (3) doses of Fenretinide will be assessed in up to three (3) treatment cycles of 21 days.
Time Frame
During a 21 days treatment cycle, from time taking first dose (Day 1) through last day of each treatment cycle (Day 21)
Secondary Outcome Measure Information:
Title
Pharmacokinetic profile of the drug, measuring Cmax, Tmax, T1/2, AUC (area under the curve) and Css (steady state concentration), for each dose level
Description
Cmax, Tmax, T 1/2, and Css (steady state concentration) with target plasma levels of Fenretinide 1-2 µM as a pharmacokinetic / pharmacodynamic biological activity
Time Frame
Day 1 and 21 of each treatment cycle
Title
Pharmacodynamic lipid markers: plasma Arachidonic Acid (AA) and Docosahexaenoic Acid (DHA)
Description
Arachidonic Acid as omega-6 proinflammatory fatty acid and Docosahexaenoic Acid (DHA) as an omega-3 anti-inflammatory fatty acid.
Time Frame
At baseline and Day 21 of each treatment cycle
Title
Pharmacodynamic inflammatory markers: Immunoglobulin G, Interleukin 1β, Interleukin 6, Interleukin 8, Interleukin 10, Macrophage inflammatory protein-1β, Tumor necrosis factors and Vascular endothelial growth factor
Time Frame
At baseline and Day 21 of each treatment t cycle
Other Pre-specified Outcome Measures:
Title
Pre-specified exploratory parameter: pulmonary function using the Forced Expiratory Volume in 1 second test
Description
Forced expired volume in 1 second as percent predicted according to age, gender and height
Time Frame
At baseline and Day 21 of each treatment cycle
Title
Pre-specified exploratory parameter: quality of life using the Cystic Fibrosis Quality of life Questionnaire Revised (CFQ-R)
Description
respiratory symptom score, physical domain and health perception domain
Time Frame
At baseline and Day 21 of each treatment cycle

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Signed Informed Consent Males or females 18 years and older Diagnosis: Patients must have a diagnosis of cystic fibrosis (positive sweat chloride test) or confirmation of two genetic mutations, one mutation on each of the two alleles of the Cystic fibrosis transmembrane conductance regulator (CFTR) gene causing Cystic Fibrosis Chronic cystic fibrosis lung disease with baseline Forced Exploratory Volume in one second equal or superior to 40% predicted value for age, gender and height Clinically stable patients will be enrolled in the study, i.e. stable at least one month after successful treatment of pulmonary exacerbation Chronic pulmonary Pseudomonas aeruginosa colonization and/or infection (sustained microbiological evidence from sputum for the past 6 months, prior to enrollment) Pancreatic function: Patient must take pancrelipase supplementation if diagnosed with pancreatic insufficiency as prescribed by a physician. Enzyme supplementation should not be modified during the trial Female patients should be on an effective contraceptive method during the study. Exclusion Criteria: Pregnancy : due to the potential teratogenic effects of retinoids, pregnant women are NOT eligible Breastfeeding by study patient is NOT allowed Clinically abnormal renal function: Serum Creatinine > 132 micromoles/L Clinically abnormal liver function: Total bilirubin >1.5 x Upper Limit of the Normal range (ULN), Alanine Aminotransferase (ALT) and/or Aspartate AminoTransferase (AST) > 3 x ULN and Alkaline Phosphatase (ALP) > 2 x ULN Known history of a severe allergy or sensitivity to retinoids Presence of a cancerous tumor, active or in remission, treated or not Presence of nyctalopia or hemeralopia at enrolment, or any other serious retinal, ophthalmological condition (eg: retinitis pigmentosa, choroidoretinitis and xerophthalmia), including glaucoma Presence of serious dermatological conditions at entry, including inflammatory or xerotic pathologies such as psoriasis or ichthyosis Prior therapy with Fenretinide. Other retinoids (eg: vitamin A supplements) are allowed, but their dosing regimen should remain constant throughout the study Participation in another drug clinical trial within 30 days prior to the enrollment Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study Patients unable to comply with the study protocol and follow-up schedule for any psychological, familial, sociological or geographical reason. Patients with known allergies to excipients in the oral capsule formulation proposed to be used in the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Elias Matouk, MD
Organizational Affiliation
Montreal Chest Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Montreal Chest Institute
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H2X 2P4
Country
Canada

12. IPD Sharing Statement

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Safety Study of Fenretinide in Adult Patients With Cystic Fibrosis

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