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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: FDL176
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 5-part study. Part 1,3,4: parallel assignment; Part 2: cross over assignment; Part 5: single assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystic Fibrosis