Evaluation of Efficacy, Safety, and Pharmacokinetics of Inhaled ETD001 in Cystic Fibrosis: A Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2023-504092-25-00
- Protocol
- ET-ENAC-03
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and **tolerability** of repeat inhaled doses of ETD001 in individuals with **Cystic Fibrosis** (pwCF), compared to placebo. Additionally, the study aims to assess the effect of these doses on percent predicted forced expiratory volume in 1 second (ppFEV1) in pwCF, compared to placebo. These objectives are clinically relevant as they address the potential therapeutic benefits and risks associated with ETD001, which could inform treatment strategies for managing lung function in Cystic Fibrosis.
Secondary objectives include:
- Characterizing the plasma and urine pharmacokinetics (PK) following repeat inhaled doses of ETD001 in pwCF.
- Assessing the effect of repeat inhaled doses of ETD001 on other lung function assessments, including relative change in ppFEV1, forced vital capacity (FVC), FEV1/FVC ratio, and maximal midexpiratory flow rates (FEF25-75), compared to placebo.
- Evaluating the effect of repeat inhaled doses of ETD001 on safety and tolerability in pwCF, compared to placebo.
- Assessing the effect of repeat inhaled doses of ETD001 on the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain in pwCF, compared to placebo.
- Characterizing the plasma PK via a population PK (Pop PK) approach following repeat inhaled doses of ETD001 in pwCF.
Participants
The clinical trial involves a total of **9 participants** diagnosed with **Cystic Fibrosis**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their ability to use a nebulizer, a body mass index (BMI) between 16 and 30 kg/m², and a confirmed diagnosis of Cystic Fibrosis, characterized by a positive sweat chloride value or genotype with two identifiable mutations consistent with the disease. The trial includes individuals with a forced expiratory volume in 1 second (FEV1) between 40% and 90% of the predicted normal for their age, gender, and height, according to Global Lung Function Initiative standards. Participants are required to have clinically stable CF lung disease, with no significant decrease in FEV1 or acute pulmonary exacerbation symptoms within 28 days prior to the first visit. Routine CF therapy must remain unchanged in dose or medication within the same period. All participants provided written informed consent and demonstrated the ability and willingness to follow study instructions and procedures. The trial does not specify any particular lifestyle considerations such as diet or physical activity.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy, safety, tolerability, and pharmacokinetics of repeat doses of inhaled ETD001 in individuals with **Cystic Fibrosis**. The trial is divided into two parts: Part A focuses on assessing the safety and tolerability of ETD001, while Part B evaluates its effect on percent predicted forced expiratory volume in one second (ppFEV1). The study involves the administration of ETD001 as a **nebuliser solution** using the eFlow® Nebulizer System, which converts the study drug into an aerosol for inhalation. The trial is expected to last until January 20, 2025, with recruitment starting on November 2, 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, ability to use a nebulizer, and a confirmed diagnosis of Cystic Fibrosis. The trial includes follow-up visits to monitor safety and efficacy endpoints, with the primary endpoint being the change in ppFEV1 from baseline to Day 28. Secondary endpoints include derived pharmacokinetic parameters and changes in other lung function measures. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 35 days, corresponding to the maximum treatment period.
Participants may be withdrawn from the study if they experience adverse events (AEs) or serious adverse events (SAEs), including death, or if they withdraw consent. Other conditions for early termination include non-compliance with the study protocol or significant changes in routine Cystic Fibrosis therapy. The trial aims to ensure that all participants are clinically stable and able to perform spirometry maneuvers consistently. The study is conducted under strict adherence to ethical guidelines, with informed consent obtained from all participants prior to enrollment.
Treatment
The clinical trial involves the administration of **ETD001C**, an experimental medication formulated as a **nebuliser solution**. The active substance in ETD001C is **3-amino-N-{[5-[4-[bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]piperidine-1-carbonyl]-1,3-diethyl-benzimidazol-1-ium-2-yl]methyl}-5H-pyrrolo[2,3-b]pyrazine-2-carboxamide dihydrochloride chloride**, which is of chemical origin. The medication is administered via **inhalation** using the eFlow® Nebulizer System (type 678), a quiet, lightweight, battery-operated device that converts the solution into an aerosol for inhalation. The maximum daily dose is 9 mg, with a total maximum dose of 306 mg over a treatment period of 35 days. Participant compliance is monitored through the use of the nebulizer system, ensuring accurate dosing and administration.
The study also includes a **placebo** group, where participants receive a placebo treatment that mimics the experimental medication in appearance but contains no active substance. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know who is receiving the active treatment or the placebo. This allows for an unbiased assessment of the efficacy and safety of ETD001C in individuals with **Cystic Fibrosis**. The placebo is administered in the same manner as the active treatment, using the eFlow® Nebulizer System, to ensure consistency in the administration process across all study participants.
Efficacy
The efficacy of the investigational product ETD001 in the clinical trial will be assessed primarily through the measurement of **percent predicted forced expiratory volume in 1 second (ppFEV1)**. This parameter will be evaluated to determine the change from baseline to Day 28, comparing the results between the treatment group and the placebo group. The primary endpoint for Part B of the study is the change in ppFEV1 from baseline to Day 28.
Secondary efficacy endpoints include the relative change in ppFEV1 from baseline to Day 28, as well as absolute changes in other lung function parameters such as forced vital capacity (FVC), FEV1/FVC ratio, and forced expiratory flow at 25-75% of pulmonary volume (FEF25-75). Additionally, changes in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain from baseline to Day 28 will be assessed. These measurements will be compared to placebo to evaluate the efficacy of ETD001.
The study will utilize spirometry to perform these assessments, ensuring that participants can reproducibly perform the necessary maneuvers. The eFlow® Nebulizer System will be used to administer the study drug, converting it into an aerosol for inhalation. The trial will also collect derived pharmacokinetic parameters in plasma and urine for ETD001 after repeat inhaled dose administration, contributing to the overall assessment of efficacy.
Inclusion and Exclusion Criteria
Inclusion Criteria
- All genders ≥ 18 years of age, who fit one of the following criteria: Women of childbearing potential who are willing and able to use contraception from a minimum of 28 days before receipt of the first dose of study medication until completion of the final follow up visit. Women of non-childbearing potential defined as being amenorrhoeic for >12 months with an appropriate clinical profile (e.g. age appropriate, menopausal symptoms). However, if indicated, this should be confirmed by follicle-stimulating hormone levels consistent with menopause (according to local laboratory ranges). Alternatively, women without a uterus or who have been permanently sterilised (e.g. hysterectomy, bilateral salpingectomy or bilateral oophorectomy, but not tubal ligation). Men who are willing and able to use one of the contraception methods, from the time of the first dose, until completion of the final follow up visit
- Have a confirmed diagnosis of CF [positive sweat chloride value ≥ 60 mEq/L (by quantitative pilocarpine iontophoresis) and/or genotype with two identifiable mutations consistent with CF, accompanied by one or more clinical features consistent with the CF phenotype].
- Have a FEV1 ≥ 40% and ≤ 90% of predicted normal for age, gender, and height using Global Lung Function Initiative (GLI) standards.
- Be able to reproducibly perform spirometry manoeuvres (i.e., able to perform at least three acceptable forced expiratory curves based on the investigator’s assessment).
- Clinically stable CF lung disease, defined as no documented decrease in FEV1 > 10%, or signs and symptoms of acute pulmonary exacerbation such as: increased cough, change in sputum (volume or consistency), change in respiratory examination and respiratory rate, decreased appetite or weight loss, chest pain, hemoptysis, decreased lung function, fever defined as temperature > 38°C (100.4°F) within 28 days prior to Visit 1.
- Routine CF therapy (bronchodilator, anti-inflammatory, inhaled corticosteroid, physiotherapy technique/schedule (including use of vibrating vests etc.) has not changed (in dose or medication) within 28 days prior to Visit 1.
- Provided written informed consent.
- Be able and willing to follow instructions and complete study procedures and be willing to comply with the study protocol and study drug use.
- Females must have a negative serum β human chorionic gonadotropin (β-hCG) at Visit 1
- Be able to use a nebuliser.
- Body mass index (BMI) > 16 and < 30 kg/m2
Exclusion Criteria
- Abnormal liver function defined as any 2 or more of the following: ≥3 × upper limit of normal (ULN) aspartate aminotransferase (AST), ≥3 × ULN alanine aminotransferase (ALT), ≥3 × ULN gamma-glutamyl transpeptidase (GGT), ≥3 × ULN alkaline phosphatase (ALP), or ≥2 × ULN total bilirubin. Abnormal liver function defined as any increase of ≥5 × ULN AST or ALT.
- Using inhaled antibiotics for less than 2 complete cycles and unable to complete the entire study during the off or on cycle.
- Have changes in inhaled or oral antibiotic use within 14 days prior to and inclusive of Visit 1.
- Be taking oral corticosteroids (prednisone equivalents) within 14 days prior to and inclusive of Visit 1, exceeding 10 mg per day or 20 mg every other day.
- Used diuretics, or renin-angiotensin aldosterone system antihypertensive drugs (spironolactone, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARB)), drospirenone, or trimethoprim in the 28 days prior to Visit 1, or an anticipated need for any of these medications during the study.
- Presence of co-morbidities and medical history listed below, or in the opinion of the investigator, may pose additional risk by participating in the study, or may confound the results of the study: - Cirrhosis with portal hypertension (e.g., splenomegaly, oesophageal varices) - Past or present positive sputum culture for organisms that are often associated with a faster decline in pulmonary status (e.g., Mycobacterium abscessus, Burkholderia cenocepacia or B. dolosa, Aspergillus fumigatus infection or allergic bronchopulmonary aspergillosis [ABPA]) is allowed if, in the opinion of the investigator, clinical stability has not been adversely affected. Subjects with these organisms can remain on chronic treatment for them if applicable, as long as the medications are not prohibited in this study. To assure clinical stability, treatment for these organisms should start at least 8 weeks before screening, and the subjects will be expected to continue the treatment through the final study visit. - History of malignancy within past 5 years (except for excised basal cell carcinoma of the skin with no recurrence, or treated carcinoma in situ of the cervix with no recurrence). - Abuse or suspected abuse of alcohol, medications, or illicit drugs within 1 year before Screening, per the investigator. - Psychiatric condition that makes it unlikely that the course of treatment or follow-up will be completed. - Smoking or vaping tobacco or cannabis products within 1 year before Screening. - Need for supplemental oxygen while awake, or > 2 L/minute while sleeping. - Recent significant weight loss, defined as 2 kg loss within the 4 weeks prior to screening. - Severe CF related diabetes mellitus with poor glucose control, microvascular complications or microalbuminuria. - History or current evidence of any clinically significant cardiac (eg, heart failure, left ventricular hypertrophy, myocardial infarction, and unstable arrhythmia) or prolonged QTcF >450 msec at screening.
- Serum potassium > ULN in non-haemolysed sample, at Visit 1.
- History of significant intolerance to inhaled hypertonic saline (HS) or dornase alfa
- Is pregnant, breast-feeding or intending to become pregnant before or during the study, or before completing the final follow up visit.
- Received an investigational drug or used an investigational medical device within 30 days or within a period less than five times the drug’s half-life, whichever is longer, before the first dose of the study drug is scheduled.
- Abnormal renal function defined as glomerular filtration rate ≤50 mL/min/1.73 m2 (calculated by the Modification of Diet in Renal Disease Study Equation.
- Participant is mentally or legally incapacitated or legally institutionalised.
- Participant is an employee of the Sponsor or contract research organisation (CRO), or a relative of an employee of the Sponsor or CRO.
- A positive test for HIV-1 & -2 antibodies or positive hepatitis C antibody result or a positive hepatitis B surface antigen at Visit 1 or anytime
- People with a history of any solid organ transplantation.
- Have a historical chest x-ray (anterior/posterior view) within the past 12 months with abnormalities suggesting unstable pulmonary disease other than CF.
- Received CFTR modulator therapy ( TRIKAFTA®, SYMDEKO®, KALYDECO®, ORKAMBI®) in the 60 days before Visit 1.
- Have changes in bronchodilator, corticosteroid or other anti-inflammatory medications 14 days prior to and inclusive of Visit 1.
- Be unable to withhold use of long-acting bronchodilators (i.e., Salmeterol, Advair, Formoterol, Indacaterol) 24 hours prior to spirometry or unable to withhold short-acting bronchodilator within 6 hours prior to spirometry.
- Be unable to withhold use of anti-cholinergics within 24 hours of spirometry.
- Have started using dornase alfa, hypertonic saline, or other airway clearing therapy less than 28 days prior to Visit 1.
- A positive test for HIV-1 & -2 antibodies or positive hepatitis C antibody result or a positive hepatitis B surface antigen at Visit 1 or anytime
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 02 Nov 2023 | 13 |
 Germany | Not Recruiting | 02 Nov 2023 | 15 |
 Italy | Not Recruiting | 02 Nov 2023 | 22 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
ETD001 Placebo | Placebo | N/A | — | — | — | N/A |
ETD001C | Test | NEBULISER SOLUTION | INHALATION | 9 | 35 | PRD10472357 |