Clinical trial NCT03173573: A Study to Assess the Safety, Tolerability and PK Profile of FDL176 in Healthy and CF Participants
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cystic Fibrosis
Keywords: Cystic Fibrosis
Lead sponsor: Flatley Discovery Lab LLC
Sponsor class: OTHER
First posted: 2017-06-02
Enrollment: 109
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 5-part study. Part 1,3,4: parallel assignment; Part 2: cross over assignment; Part 5: single assignment
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Part 1 and Part 4: Incidence of Treatment-Emergent Adverse Events.
timeFrame: Part 1: 4 weeks; Part 4: 6 weeks
measure: Part 2, 3 and 5: Pharmacokinetic parameters, Cmax
timeFrame: Part 2: 5 weeks, Part 3: 4 weeks and Part 5: 4 weeks
measure: Part 2, 3 and 5: Pharmacokinetic parameters, Tmax
timeFrame: Part 2: 5 weeks, Part 3: 4 weeks and Part 5: 4 weeks
measure: Part 2, 3 and 5: Pharmacokinetic parameters, AUC
timeFrame: Part 2: 5 weeks, Part 3: 4 weeks and Part 5: 4 weeks
measure: Part 2, 3 and 5: Pharmacokinetic parameters, CL/F
timeFrame: Part 2: 5 weeks, Part 3: 4 weeks and Part 5: 4 weeks
measure: Part 2, 3 and 5: Pharmacokinetic parameters, V/F
timeFrame: Part 2: 5 weeks, Part 3: 4 weeks and Part 5: 4 weeks
Secondary outcomes:
measure: Part 2, 3, and 5: Incidence of Treatment-Emergent Adverse Events.
timeFrame: Part 2: 5 weeks, Part 3: 4 weeks and Part 5: 4 weeks
measure: Part 1 and 4: Pharmacokinetic parameters, Cmax
timeFrame: Part 1: 4 weeks; Part 4: 6 weeks
measure: Part 1 and 4: Pharmacokinetic parameters,Tmax
timeFrame: Part 1: 4 weeks; Part 4: 6 weeks
measure: Part 1 and 4: Pharmacokinetic parameters,AUC
timeFrame: Part 1: 4 weeks; Part 4: 6 weeks
measure: Part 1 and 4: Pharmacokinetic parameters, CL/F
timeFrame: Part 1: 4 weeks; Part 4: 6 weeks
measure: Part 1 and 4: Pharmacokinetic parameters, V/F
timeFrame: Part 1: 4 weeks; Part 4: 6 weeks
Other outcomes:
Locations:
city: Herston
country: Australia
facility: Wayne Hooper Clinic Clive Berghofer Cancer research Center
state: Queenland
city: South Brisbane
country: Australia
facility: Mater Hospital
state: Queensland
city: Perth
country: Australia
facility: Linear Clinical Research
state: Western Australia
Study officials:
affiliation: Flatley Discovery Lab
name: Claudia Ordonez, MD
role: STUDY_CHAIR
References: