A Two-Part Study to Assess the Effectiveness, Safety, and Blood Levels of Repeat Doses of Inhaled ETD001 in People with Cystic Fibrosis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Enterprise Therapeutics Limited

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

4 Jun 2024 → 15 Nov 2025

Decision date (initial)

2024-01-15

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Enterprise Therapeutics Ltd

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Others, Efficacy

Part A: To assess the safety and tolerability of repeat inhaled doses of ETD001 in people with Cystic Fibrosis (pwCF), compared to
placebo
Part B: To assess the effect of repeat inhaled doses of ETD001 on percent predicted forced expiratory
volume in 1 second (ppFEV1) in pwCF, compared to placebo

Secondary objectives 1

1. Part A • To characterise the plasma and urine PK following repeat inhaled doses of ETD001 in pwCF Part B • To assess 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 • To assess the effect of repeat inhaled doses of ETD001 on safety and tolerability in pwCF, compared to placebo • To assess the effect of repeat inhaled doses of ETD001 on CFQ-R (respiratory domain) in pwCF, compared to placebo • To characterise the plasma PK via a population PK (Pop PK) approach following repeat inhaled doses of ETD001 in pwcF

Conditions and MedDRA coding

Cystic Fibrosis

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 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
2. 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].
3. Have a FEV1 ≥ 40% and ≤ 90% of predicted normal for age, gender, and height using Global Lung Function Initiative (GLI) standards.
4. 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).
5. 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.
6. 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.
7. Provided written informed consent.
8. Be able and willing to follow instructions and complete study procedures and be willing to comply with the study protocol and study drug use.
9. Females must have a negative serum β human chorionic gonadotropin (β-hCG) at Visit 1
10. Be able to use a nebuliser.
11. Body mass index (BMI) > 16 and < 30 kg/m2

Exclusion criteria 22

1. 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.
2. Using inhaled antibiotics for less than 2 complete cycles and unable to complete the entire study during the off or on cycle.
3. Have changes in inhaled or oral antibiotic use within 14 days prior to and inclusive of Visit 1.
4. 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.
5. 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.
6. 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.
7. Serum potassium > ULN in non-haemolysed sample, at Visit 1.
8. History of significant intolerance to inhaled hypertonic saline (HS) or dornase alfa
9. Is pregnant, breast-feeding or intending to become pregnant before or during the study, or before completing the final follow up visit.
10. 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.
11. 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.
12. Participant is mentally or legally incapacitated or legally institutionalised.
13. Participant is an employee of the Sponsor or contract research organisation (CRO), or a relative of an employee of the Sponsor or CRO.
14. 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
15. People with a history of any solid organ transplantation.
16. Have a historical chest x-ray (anterior/posterior view) within the past 12 months with abnormalities suggesting unstable pulmonary disease other than CF.
17. Received CFTR modulator therapy ( TRIKAFTA®, SYMDEKO®, KALYDECO®, ORKAMBI®) in the 60 days before Visit 1.
18. Have changes in bronchodilator, corticosteroid or other anti-inflammatory medications 14 days prior to and inclusive of Visit 1.
19. 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.
20. Be unable to withhold use of anti-cholinergics within 24 hours of spirometry.
21. Have started using dornase alfa, hypertonic saline, or other airway clearing therapy less than 28 days prior to Visit 1.
22. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Part A: Incidence of AE, SAE (including death), withdrawals due to AE Part A: Change from baseline in safety assessments (ECG, vital signs, spirometry, clinical laboratory results and physical examination) Part B: Change in ppFEV1 from baseline to Day 28 (for either Treatment Period 1 or Treatment Period 2), compared to placebo

Secondary endpoints 2

1. Part A: Derived PK parameters in plasma and urine for ETD001 after repeat inhaled dose administration
2. Relative change in ppFEV1 from baseline to D28, compared to placebo. Absolute change in other lung function endpoints including FVC, FEV1/FVC ratio and FEF25-75 from baseline to D28, compared to placebo.Incidence of AE, SAE (including death), withdrawals due to AE.Change in safety assessments from baseline to D28, compared to placebo.Change in CFQ-R (respiratory domain) from baseline to D28, compared to placebo. Population PK characteristics and model generated individual PK Parameters

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Enterprise Therapeutics Limited

Sponsor organisation

Enterprise Therapeutics Limited

Address

Science Park Square, Falmer Falmer

City

Brighton

Postcode

BN1 9SB

Country

United Kingdom

Scientific contact point

Organisation

Enterprise Therapeutics Limited

Contact name

Paul Russell

Public contact point

Organisation

Enterprise Therapeutics Limited

Contact name

Kathy Woodward

Third parties 10

Locations

3 EU/EEA countries · 18 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 76 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications