A Study to Assess the Safety, Tolerability and PK Profile of FDL176 in Healthy and CF Participants

A Five Part Phase 1 Study to Assess the Safety, Tolerability and Pharmacokinetic (PK) Profile of Single and Repeat Oral Doses of FDL176 in Healthy and Cystic Fibrosis (CF) Participants

This is a 5-part study of FDL176. Part 1 is a double blind, placebo-controlled, dose escalation study in healthy male participants. Part 2 is a single dose, open-label study in healthy male participants. Part 3 is a single dose, double blind, placebo-controlled study in healthy female participants. Part 4 is a randomised, double-blind, placebo-controlled, dose-escalation study in healthy male and female participants.Part 5 is a single dose, open-label study in male and female participants with CF.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: FDL176; Drug: Placebo

Detailed Description

This is a 5-part study. Part 1 is a double blind, placebo-controlled, dose escalation, first-in-human study to assess the safety, tolerability and PK profiles following single oral administration of FDL176 to healthy male participants. Part 2 is a single dose, open-label study in healthy male participants to determine the effect of food on the PK profile of FDL176. Part 3 is a single dose, double blind, placebo-controlled study in healthy female participants to assess the PK, safety and tolerability profiles of FDL176. Part 4 is a randomised, double-blind, placebo-controlled, dose-escalation study to assess the safety, tolerability and PK profiles following multiple oral administrations of FDL176 to healthy male and female participants. Part 5 is a single dose, open-label study in male and female participants with CF to determine the PK profile of FDL176.

• Study Type: Interventional
• Enrollment (Actual): 109
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Queenland
    • Herston, Queenland, Australia, 4006
      • Wayne Hooper Clinic Clive Berghofer Cancer research Center
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
      • Mater Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6009
      • Linear Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria (Part 1 to Part 4):

• If sexually active, must be willing to use two highly effective methods of birth control from Day 1 until 3 months after the last dose of investigational medicinal product (IMP)
• Body mass index (BMI) between 19 and 30 kg/m2 inclusive.
• Healthy as determined by the PI or delegate, based upon a medical evaluation including medical history, physical examination, laboratory tests and ECG.

Inclusion Criteria (Part 5):

• Males and females aged 18 years and older.
• Diagnosis of CF defined as a sweat chloride value ≥60 mmol/L by quantitative pilocarpine iontophoresis or two CF-causing mutations, documented in the participant's medical record.
• History of pancreatic insufficiency, documented in the participant's medical record.
• Stable CF disease as judged by the Investigator (or delegate).
• Forced expiratory volume in one second (FEV1) >40% of predicted normal for age, sex and height at screening.

Exclusion Criteria (Part 1 to 4):

• Prior or ongoing medical condition, medical history, physical findings, ECG findings or laboratory abnormality that, in the Investigator's (or delegate's) opinion, could adversely affect the safety of PK of the participant or would place the participant at increased risk.
• Surgery within the past three months prior to the first study drug administration determined by the PI or delegate to be clinically relevant.
• Alkaline phosphatase (ALP), aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >1.5 x upper limit of normal (ULN) at screening. Repeat testing at screening is acceptable for out of range values following approval by the Sponsor's Medical Monitor.
• Serum creatinine or total bilirubin > 1.5 x ULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%).
• Abnormal renal function at screening, defined as creatinine clearance <60 mL/min using the Modification of Diet in Renal Disease (MDRD) equation
• History of prolonged QT and/or QTcF interval.
• ECG with a single QTcF >450 msec in males, >460 msec in females, at Screening.
• Positive urinary drugs of abuse screen at Screening or Day -1, or positive alcohol screen at Screening or Day -1
• History of human immunodeficiency virus (HIV) or positive HIV, hepatitis B or hepatitis C results at screening.
• Use of any prescription drugs within 14 days or 5 half-lives (whichever is longer) before the first dose of IMP, unless in the opinion of the Investigator (or delegate) and the Sponsor's Medical Monitor the medication will not interfere with the study procedures or compromise participant safety. Hormonal contraceptives are allowed.
• Use of any non-prescription drugs, including vitamins, herbal and dietary supplements within 14 days or 5 half-lives (whichever is longer) before the first dose of IMP, unless in the opinion of the Investigator (or delegate) and the Sponsor's Medical Monitor the medication will not interfere with the study procedures or compromise participant safety.
• Pregnant or nursing females. Female participants of childbearing potential must have a negative pregnancy test at the screening visit. Determination of participant eligibility will be at the discretion of the Investigator (or delegate) following consultation with the Sponsor's Medical Monitor.
• History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >21 units. One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, one glass (125 mL) of wine, or one (25 mL) measure of spirits.
• Current smoking or use of tobacco products or substitutes. Former smokers will be eligible, provided they have not smoked for at least 6 months before Day 1.
• Participation in another clinical trial involving receipt of an IMP within the past 90 days or exposure to more than four new chemical entities with 12 months of the first dosing day.

Exclusion Criteria (Part 5):

• A pulmonary exacerbation, or changes in therapy for pulmonary disease within 4 weeks prior to the Baseline (Day 1) visit.
• Abnormal liver function ≥3 × ULN: AST, ALT, total bilirubin.
• Serum creatinine or total bilirubin > 1.5 x ULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%).
• Abnormal renal function at screening, defined as creatinine clearance <60 mL/min using the MDRD equation.
• Hemoglobin <10 g/dL.
• History of prolonged QT and/or QTcF interval.
• ECG with a single QTcF >450 msec in males, >460 msec in females, at Screening.
• Use of ivacaftor or lumacaftor within 14 days prior to Day 1.
• Any change (initiation, change in type of drug, dose modification, schedule modification, interruption, discontinuation, or re-initiation) in a chronic treatment/prophylaxis regimen for CF or CF related conditions within 4 weeks prior to Day 1.
• Pregnant or nursing females. Female participants of childbearing potential must have a negative pregnancy test at the screening visit. Determination of participant eligibility will be at the discretion of the Investigator (or delegate) following consultation with the Sponsor's Medical Monitor.
• Participation in another clinical trial involving receipt of an IP within the past 90 days or exposure to more than four new chemical entities with 12 months of the first dosing day.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1 SAD FDL176 level 1 to 6; Part 1: Single dose of FDL176 test formulation Level 1 to 6 on healthy males.	Drug: FDL176; CFTR modulator
Placebo Comparator: Part 1 SAD Placebo; Part 1: Single dose of Placebo for FDL176.	Drug: Placebo; Placebo for FDL176
Experimental: Part 2 SAD FDL176 at fasted state; Part 2: single dose of FDL176 test formulation, fasted state.	Drug: FDL176; CFTR modulator
Experimental: Part 2 SAD FDL176 at fed state; Part 2: single dose of FDL176 test formulation, fed state	Drug: FDL176; CFTR modulator
Experimental: Part 3 SAD FDL176 test formulation; Part 3: Single dose of FDL176 test formulation on healthy females.	Drug: FDL176; CFTR modulator
Placebo Comparator: Part 3 SAD placebo; Part 3: Single dose of Placebo for FDL176.	Drug: Placebo; Placebo for FDL176
Experimental: Part 4 MAD FDL176 Level 1 to 3; Part 4: Dose escalation of FDL176 test formulation Level 1 to 3.	Drug: FDL176; CFTR modulator
Placebo Comparator: Part 4 MAD Placebo; Part 4: Dose escalation of Placebo for FDL176 Level 1 to 3.	Drug: Placebo; Placebo for FDL176
Experimental: Part 5 SAD FDL176 test formulation; Part 5: Single dose of FDL176 test formulation.	Drug: FDL176; CFTR modulator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1 and Part 4: Incidence of Treatment-Emergent Adverse Events.	Part 1 and Part 4: Safety and tolerability of FDL176 in healthy male participants as determined by the incidence of adverse events (AE)s and serious adverse events(SAE)s.	Part 1: 4 weeks; Part 4: 6 weeks
Part 2, 3 and 5: Pharmacokinetic parameters, Cmax	The pharmacokinetic parameters of FDL176: maximal plasma concentration	Part 2: 5 weeks, Part 3: 4 weeks and Part 5: 4 weeks
Part 2, 3 and 5: Pharmacokinetic parameters, Tmax	The pharmacokinetic parameters of FDL176: maximal concentration	Part 2: 5 weeks, Part 3: 4 weeks and Part 5: 4 weeks
Part 2, 3 and 5: Pharmacokinetic parameters, AUC	The pharmacokinetic parameters of FDL176: area under the plasma concentration curve	Part 2: 5 weeks, Part 3: 4 weeks and Part 5: 4 weeks
Part 2, 3 and 5: Pharmacokinetic parameters, CL/F	The pharmacokinetic parameters of FDL176: clearance	Part 2: 5 weeks, Part 3: 4 weeks and Part 5: 4 weeks
Part 2, 3 and 5: Pharmacokinetic parameters, V/F	The pharmacokinetic parameters of FDL176: apparent volume of distribution	Part 2: 5 weeks, Part 3: 4 weeks and Part 5: 4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 2, 3, and 5: Incidence of Treatment-Emergent Adverse Events.	Safety and tolerability of FDL176 in healthy male participants as determined by the incidence of adverse events (AE)s and serious adverse events(SAE)s.	Part 2: 5 weeks, Part 3: 4 weeks and Part 5: 4 weeks
Part 1 and 4: Pharmacokinetic parameters, Cmax	The pharmacokinetic parameters of FDL176: maximal plasma concentration	Part 1: 4 weeks; Part 4: 6 weeks
Part 1 and 4: Pharmacokinetic parameters,Tmax	The pharmacokinetic parameters of FDL176: maximal concentration	Part 1: 4 weeks; Part 4: 6 weeks
Part 1 and 4: Pharmacokinetic parameters,AUC	The pharmacokinetic parameters of FDL176: area under the plasma concentration curve	Part 1: 4 weeks; Part 4: 6 weeks
Part 1 and 4: Pharmacokinetic parameters, CL/F	The pharmacokinetic parameters of FDL176: clearance	Part 1: 4 weeks; Part 4: 6 weeks
Part 1 and 4: Pharmacokinetic parameters, V/F	The pharmacokinetic parameters of FDL176: apparent volume of distribution	Part 1: 4 weeks; Part 4: 6 weeks

Collaborators and Investigators

• Sponsor: Flatley Discovery Lab LLC
• Investigators: Study Chair: Claudia Ordonez, MD, Flatley Discovery Lab

Study record dates

Study Major Dates

• Study Start (Actual): June 27, 2017
• Primary Completion (Actual): May 31, 2018
• Study Completion (Actual): May 31, 2018

Study Registration Dates

• First Submitted: May 30, 2017
• First Submitted That Met QC Criteria: May 31, 2017
• First Posted (Actual): June 2, 2017

Study Record Updates

• Last Update Posted (Actual): September 6, 2018
• Last Update Submitted That Met QC Criteria: September 5, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: Cystic Fibrosis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis
• Other Study ID Numbers: FDL176-2016-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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