A phase I, double-blind, placebo-controlled, ascending single intravenous dose, safety, tolerability, pharmacokinetic and pharmacodynamic study in healthy participants and non-cystic fibrosis bronchiectasis patients colonized with pseudomonas aeruginosa administered INFEX702
| ISRCTN | ISRCTN17978477 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN17978477 |
| EudraCT/CTIS number | 2021-005018-32 |
| IRAS number | 1004503 |
| Secondary identifying numbers | IRAS 1004503 |
- Submission date
- 03/02/2022
- Registration date
- 10/05/2022
- Last edited
- 10/01/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Infections and Infestations
Plain English Summary
Background and study aims
There is an unmet medical need to develop effective maintenance treatments for the reduction of exacerbations in patients with Non-Cystic Fibrosis Bronchiectasis (NCFB) colonized with Pa; currently there are no approved drug therapies available in NCFB for reduction of exacerbations. NCFB is a neglected, chronic condition that results in progressive respiratory decline typified by the irreversible permanent dilation of the airways, a chronic cough, overproduction of sputum, recurrent respiratory infections and chronic inflammation resulting in progressive lung damage. Patients have poor quality of life and many patients develop Pa infections which worsen prognosis. Chronic or recurrent infection with Pa is associated with poorer pulmonary function, increased inflammation, higher hospitalization rates, higher healthcare costs, greater morbidity and mortality compared with other NCFB-associated pathogens, such as H. influenzae. Patients with Pa infections can suffer from multiple exacerbations every year; up to 8-12 per annum. The aetiology of NCFB is often unknown but can be the result of previous lung infections.
Who can participate?
Healthy volunteers aged 18 to 55 years and non-cystic fibrosis bronchiectasis patients.
What does the study involve?
Each participant will participate in 1 treatment period only, residing in the CRU from Day -1 (the day before dosing) to Day 5 (96 hours post -dose). All participants will return for 9 out-patient appointments with a final follow up visit on day 106.
Based on the ongoing blinded review of safety, tolerability and pharmacokinetic results, additional non-residential visits may be required. The number of additional non-residential visits will not exceed three per treatment period and will not extend beyond 28 days after the final follow up visit.
What are the possible benefits and risks of participating?
Benefits:
There are no direct benefits to healthy participants taking part in the study. As this is a phase 1 study, it is not known if the trial drug will have a beneficial effect for the patients in Part B. It is hoped that the results of this study will help to inform how patients with Pseudomonas aeruginosa infections are treated in the future.
Risks:
Participants are in-patients during dose administration and closely monitored for signs of anaphylaxis, >96 hrs after. Drugs to treat anaphylaxis and Advanced Life Support equipment available if needed.
Participants will be monitored and encouraged to report any local irritations around the infusion site. If required basic first aid will be administered in addition to anti-histamines and steroids.
Participants will be closely monitored for signs of enhanced inflammatory reaction with frequent observations and monitoring of vital signs. Immediate availability of intravenous fluids, steroids, and Advanced Life Support trained staff and equipment if required.
Collecting blood may cause bruising, fainting, and in rare cases infection. Using a catheter helps in two ways, first it prevents scars or blemishes at the sites of repeat blood samples; and helps in proper administration of medications, fluids, and for collecting a blood sample. If a needle is used, a new needle will be used for each blood sample
The blood pressure cuff used to take your blood pressure may cause discomfort or bruising to your upper arm.
During the collection of nose/throat swabs, you may experience sneezing, retching and eye tearing. People who are susceptible to nose bleeds may experience one.
The ECG procedure may cause discomfort and/or bruising during the attachment and removal of the leads (sticky pads) to and from the skin as well as irritation at the site of the lead application. In some cases, we may have to shave the area of the body where the sticky pads are attached to ensure that the pads stick to your body.
Bronchoscopy and Bronchoalveolar lavage: Minor complications, sore throat, hoarse voice, nose bleeds or irritation, mildly blood-tinged phlegm, fever or flu-like symptoms. Rarely (less than 1%), a chest infection can occur due to a bronchoscopy. More serious complications causing fatality are extremely rare, at less than 0.0002%.
Where is the study run from?
Royal Liverpool Hospital (UK)
When is the study starting and how long is it expected to run for?
January 2022 to September 2025
Who is funding the study?
INFEX Therapeutics (UK)
Who is the main contact?
Cru.contact@liverpoolft.nhs.uk
Contact information
Public, Scientific, Principal Investigator
Prescot Street
Liverpool
L7 8XD
United Kingdom
| Phone | +44 151 706 4863 |
|---|---|
| Cru.contact@liverpoolft.nhs.uk |
Study information
| Study design | Interventional double blind randomized placebo controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Other |
| Study type | Other |
| Scientific title | A phase I, double-blind, placebo-controlled, ascending single intravenous dose, safety, tolerability, pharmacokinetic and pharmacodynamic study in healthy participants and non-cystic fibrosis bronchiectasis patients colonized with pseudomonas aeruginosa administered INFEX702 |
| Study acronym | INFEX-PROTECT 1 |
| Study hypothesis | - To determine the safety and tolerability of ascending single intravenous doses of INFEX702 in healthy adult participants (Part A) and patients with Non-Cystic Fibrosis Bronchiectasis (NCFB) (Part B) - To determine the single intravenous dose pharmacokinetics of INFEX702 in healthy participants (Part A) and NCFB patients (Part B) - To assess immunogenicity of INFEX702 in healthy participants and NCFB patients |
| Ethics approval(s) | Approved 25/03/2022, North West - Greater Manchester Central Research Ethics Committee (3rd Floor Barlow House, 4 Minshull Street, Manchester, M1 3DZ, UK; +44 2071048208; gmcentral.rec@hra.nhs.uk), ref: 22/NW/0048 |
| Condition | Respiratory infection |
| Intervention | The study will be conducted in two parts (Part A: Healthy participants and Part B: patients with non-cystic fibrosis bronchiectasis). Subjects will be randomised to received either active (Infex702) or placebo. Part A Part A will comprise a single dose, sequential cohort study. Healthy participants will be studied in 4 dose cohorts (A1 to A4). Each dose cohort will consist of 8 participants (6 active: 2 placebo per cohort). The planned dose levels in Part A are: A1 – 1 mg/kg A2 – 3 mg/kg A3 – 6 mg/kg A4 – 10 mg/kg Part B, Part B will comprise a single ascending dose, sequential group study. 12 patients with NCFB will be studied in 2 cohorts (Group B1 and B2), each cohort consisting of 6 evaluable participants. In each of cohorts B1 and B2, 5 participants will receive INFEX702 and 1 will receive placebo. Duration of treatment Single intravenous administration of INFEX702 or placebo in all cohorts (Parts A and B). Follow-up Each subject will participate in 1 treatment period only, residing in the CRU from Day -1 (the day before dosing) to Day 5 (96 hours post -dose). In Part B, the residential period post-dose may be reduced from 96 hours to 72 hours post-dose subject to satisfactory review of the safety and tolerability data by the DEC for Part A,. All participants in Parts A and B, will return for appointments on Days 5, 8, 15, 22, 29, 36, 43, 57, 71, 99 and a final follow up visit on day 106. Randomisation process (online tool, sealed envelope) A randomisation code will be produced using a computer-generated pseudo-random permutation procedure. For each participant in the study, an individual sealed envelope (produced by Statistician) containing the randomisation code will be kept in a secure location to enable the Investigator to break the code for safety purposes |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase I |
| Drug / device / biological / vaccine name(s) | INFEX702 |
| Primary outcome measure | Timepoints for the evaluation of this end point for Part A would be the review of all available data per cohort (minimum subjects (6) - 96 hrs post dose) prior to dose escalation committee safety review. For Part B the review of all available safety data and tolerability data up to (and including) a minimum of 7 days (168 hours, D8) for each participant in each cohort prior to dose escalation committee safety review. Safety and tolerability measured by: 1. Incidence and severity of adverse events (AEs) every study day 2. Physical examination findings follow up visit 3. Safety laboratory tests (clinical chemistry, haematology, coagulation, Urinalysis) : Days -1, 1 ,2 ,3 ,5,8,15,22,29,36,43,57,71,99,follow up 4. Vital sign measurements (blood pressure, heart rate, temperature, respiration rate and oxygen saturations) every study day 5. Electrocardiogram (ECG) every study day 6. Local tolerability (number of i.v. site reactions) (study days 1-3) |
| Secondary outcome measures | Timepoints for the evaluation of this end point for Part A would be the review of all available data per cohort (minimum subjects (6) - 96 hrs post dose) prior to dose escalation committee review For Part B the review of all available safety data and tolerability data up to (and including) a minimum of 7 days (168 hours, D8) for each participant in each cohort prior to dose escalation committee review Pharmacokinetics of INFEX702 measured by calculating PK parameters from serum samples taken on every study day. Multiple samples will be taken on Day 1: 1. Area under the serum concentration-time curve from time 0 to infinity (AUC0-∞) 2. Area under the serum concentration-time curve from time 0 to 28 days post dose (AUC0-28d) 3. Area under the serum concentration-time curve from time 0 to the last observed quantifiable concentration (AUC0-t) 4. Serum concentration observed at 28 days post dose (C28d) 5. Maximum observed serum concentration (Cmax) 6. Apparent terminal half-life (t1/2) 7. Time of last quantifiable concentration (tlast) 8. Time of occurrence of Cmax (tmax) |
| Overall study start date | 26/01/2022 |
| Overall study end date | 30/09/2025 |
Eligibility
| Participant type(s) | Mixed |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 55 Years |
| Sex | Both |
| Target number of participants | 44 |
| Participant inclusion criteria | Part A: 1. Provision of signed and dated, written informed consent prior to any study-specific procedures 2. Participants must be willing and able to comply with trial requirements 3. Males and females aged 18 to 55 years inclusive at the time of providing consent 4. BMI between 18 and 32 kg/m² (inclusive) 5. Weight less than or equal to 120 kg 6. In good health as determined by a responsible and qualified physician (including confirmation from GP) and determined by: 6.1. Medical history 6.2. Physical examination 6.3. Vital signs assessment 6.4. 12 lead electrocardiogram (ECG) 6.5. Clinical laboratory evaluations (congenital non haemolytic hyperbilirubinaemia is acceptable). 7. The Over-Volunteering Prevention System (TOPS) registration completed and no conflict found 8. Women of childbearing potential (WOCBP) and fertile male participants who are sexually active with WOCBP must agree to use two methods of contraception and refrain from donating ova or sperm. The duration of contraception will be from the first administration of trial treatment, throughout trial and up to 4 months after dosing. Post-menopausal women defined as no menses for 12 months without an alternative medical cause Part B: 1. Provision of signed and dated, written informed consent prior to any study-specific procedures 2. Participants must be willing and able to comply with trial requirements. 3. Male and female patients of ≥18 years of age at screening 4. BMI between 15 and 40 kg/m² (inclusive) 5. Weight less than or equal to 120kg 6. Proven diagnosis of Non-Cystic Fibrosis bronchiectasis as documented by computed tomography (CT) or high-resolution CT and as assessed by the investigator 7. History of 2 or more exacerbations treated with oral antibiotics OR 1 or more exacerbation requiring parenteral antibiotic treatment within 18 months prior to screening. 8. FEV1 ≥30% predicted at screening 9. A stable regimen of local standard treatment for BE (treatments unchanged for 28 days prior to randomization). 10. Colonised with P. aeruginosa, defined as 2 or more consecutive positive cultures, collected at least 1 month apart within the last 18 months, with last culture collected within the last 12 months. Respiratory samples used can include: expectorated sputum; deep throat cough swab; oro-pharyngeal swab; bronchoalveolar lavage. 11. Able to expectorate sputum on the majority of days 12. Women of childbearing potential (WOCBP defined as all women physiologically capable of becoming pregnant) and fertile male participants who are sexually active with WOCBP must agree to use two methods of contraception and refrain from donating ova or sperm. The duration of contraception will be from the first administration of trial treatment, throughout trial and up to 4 months after the last dose. Post-menopausal women defined as no menses for 12 months without an alternative medical cause |
| Participant exclusion criteria | Part A: 1. Female participants who are pregnant or currently lactating 2. Participants who do not agree, or whose partners of childbearing potential do not agree, to use appropriate contraception or to refrain from donating egg or sperm from the time of dosing until 4 months after the last dose of study drug. 3. Donated blood in the 3 months prior to screening, plasma in the 7 days prior to screening, platelets in the 6 weeks prior to screening (inclusion can be delayed under these circumstances) 4. Consume more than 28 units of alcohol per week or any significant history of alcohol/substance misuse as determined by the investigator 5. Current active smoker or ex-smoker (not stopped smoking within 4 weeks prior to Visit 1) with a history of smoking equivalent to >10 pack years (including vapes) 6. Unwilling to abstain from vigorous exercise for 48 hours prior to any study visit. 7. Unwilling to abstain from alcohol for 48 hours prior to any study visit. 8. Participants who have any clinically significant allergy or allergic condition as determined by the investigator (with the exception of non-active hay fever). 9. Participants who have any abnormality of vital signs prior to the first dose administration that, in the opinion of the investigator, would increase the risk of participating in the study. 10. Participants who have any clinically significant abnormal physical examination finding. 11. Participants who have any clinically significant 12 lead ECG abnormality that, in the opinion of the investigator, would increase the risk of participating in the study. This includes QTcB values >450ms (male) or >470ms (female), confirmed on triplicate ECG recordings from which the mean value will be derived. 12. Participants who have hepatitis B or C or are carriers of HBsAg or are carriers of HCV Ab or are positive for HIV 1/2 antibodies. 13. Any clinically significant abnormal finding on biochemistry, haematology, toxicology or serological blood tests, urinalysis or clinical examination. N.B. In the event of clinically significant abnormal test results, confirmatory repeat tests will be requested 14. Taking concomitant medications (with the exception of up to 2g paracetamol daily or the oral contraceptive pill) 15. Received any medication that has required dose adjustment (with the exception of the OCP or paracetamol) within 14 days prior to the first dose administration. 16. Received any non-prescribed systemic or topical medication, herbal remedy or vitamin/mineral supplementation within 14 days prior to the first dose administration (with the exception of paracetamol) 17. Participants who have a positive alcohol breath test or a positive urine drug screen (a repeat assessment is acceptable). 18. Positive for SARS-CoV-2 (using a polymerase chain reaction test)within 72 hours prior to admission. 19. Participation in another interventional study within 3 months or 5 half-lives, whichever is longer 20. Clinically significant medical history in the opinion of the Investigator. 21. Previously received mAbs, immunoglobulin or any blood products within the last 6 months 22. History of immune complex disease 23. Any other condition or consideration that, in the opinion of the Investigator, would pose a health risk to the participant if they were enrolled in the study, or would otherwise interfere with the evaluation of the study aims 24. Previously enrolled in this study 25. Participants that have any known hypersensitivity to any of the excipients of INFEX702 26. Received any vaccination, including for Covid-19, with 14 days prior to the first dose administration or any planned vaccination 14 days after the last dose of study medication Part B: 1. History of cystic fibrosis. 2. Primary diagnosis of bronchial asthma. 3. Primary diagnosis of COPD associated with at least a 20 pack year smoking history. 4. Current smoker at screening or not stopped smoking within 4 weeks prior to Visit 1. 5. Signs and symptoms of clinically significant acute pulmonary or non-pulmonary conditions with the exception of NCFB. 6. Positive for SARS-CoV-2 within 72 hours prior to admission 7. Any significant medical condition that is either recently diagnosed or was not stable during the last 3 months, other than pulmonary exacerbations, and that in the opinion of the investigator makes participation in the trial against the patients’ best interests. 8. Any patient with lung cancer or a history of lung cancer. 9. Any patient with active cancer or a history of cancer with less than 5 years disease-free survival time (whether or not there is evidence of local recurrence or metastases). Localized basal cell carcinoma (without metastases) of the skin is acceptable. Patients with a history of cancer (excluding lung cancer) and 5 years or more disease-free survival time may be included. 10. Patients requiring long-term oxygen therapy for chronic hypoxemia. This is typically patients requiring oxygen therapy >15 h per day delivered by home oxygen cylinder or concentrator. 11. Patients who have had a pulmonary exacerbation requiring systemic gluco corticosteroid treatment and/or antibiotics in the 4 weeks prior to screening. In the event of an exacerbation occurring during the screening epoch, the patient must discontinue from the study. The patient may be rescreened once the inclusion/exclusion criteria have been met. 12. Patients with active pulmonary tuberculosis (defined by a positive Quanteferon gold test). 13. Patients currently receiving treatment for non-tuberculous mycobacterial (NTM) pulmonary disease. 14. Patients with one or more positive cultures in the last 12 months for Mycobacterium. avium complex, M. abscessus complex, M. kansasii, M. malmoense, M. xenopi, M. simiae or M. chelonae, unless all subsequent NTM cultures (at least two) are negative and in the opinion of the investigator the patient does not meet ATS criteria for NTM-pulmonary disease 15. Haemoptysis of more than 60 mL at any time within 28 days prior to screening 16. Clinically significant laboratory abnormalities (not associated with the study indication) at screening. 17. Primary immunodeficiency receiving immunoglobulin therapy. 18. Patients with History of primary ciliary dyskinesia. 19. Patients with History of or active allergic bronchopulmonary aspergillosis. 20. Diagnosed with an organ and bone marrow transplant/graft versus host disease. 21. Patients with haematological malignancies. 22. Patients with other clinically significant conditions (not associated with the study indication) at screening which might interfere with the assessment of this study. 23. Patients who are receiving inhaled or systemic antibiotic for any indication, other than azithromycin for NCFB, within 28 days prior to study drug administration 24. Receiving any medication that may influence the response to treatment. Prohibited medications: immunomodulators (cyclosporine, tacrolimus, anti-TNF alpha, steroids >15mg/day, alpha 1 antitrypsin, methotrexate, azathioprine, immune globulins (IV or subcutaneous), Prolastin, anti-cytokines). 25. Systemic corticosteroids at >10 mg/day prednisolone equivalent for >14 days or pulse dose corticosteroids (2 -5 days) within 28 days prior to the administration of study drug. Topical corticosteroids are allowed 26. Initiation of treatment with chronic macrolide therapy within 28 days prior to study drug administration (participants may be taking chronic macrolide therapy at the time of enrolment into the study, but they must have initiated treatment more than 28 days prior to Visit study drug administration). 27. Use of any other investigational drug within 30 days prior to screening or 5 half-lives, whichever is longer 28. Previously received mAbs, immunoglobulin or any blood products within the last 6 months 29. Pregnant or nursing (lactating) women where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test. 30. History or current diagnosis of ECG abnormalities or concomitant medication indicating significant risk of safety for patients participating in the study 31. Any known or suspected hypersensitivity to, or known allergy to, or other intolerability to the study medication or placebo. 32. Consume more than 28 units of alcohol per week or any significant history of alcohol / substance misuse as determined by the investigator 33. Unwilling to abstain from vigorous exercise for 48 hours prior to any study visit. 34. Unwilling to abstain from alcohol for 48 hours prior to any study visit 35. Participants that have any known hypersensitivity to any of the excipients of INFEX702 36. Received any vaccination, including for Covid-19, within 14 days prior to the first dose administration or any planned vaccination 14 days after the last dose of study medication |
| Recruitment start date | 10/10/2022 |
| Recruitment end date | 31/03/2025 |
Locations
Countries of recruitment
- United Kingdom
Study participating centre
Ward 4C 4th Floor
Liverpool
L7 8XD
United Kingdom
Sponsor information
Industry
Block 23 Alderley Park
Alderley Edge
SK10 4TG
England
United Kingdom
| derek.lindsay@infextx.com |
Funders
Funder type
Industry
No information available
Results and Publications
| Intention to publish date | 30/11/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Published as a supplement to the results publication |
| Publication and dissemination plan | Peer reviewed scientific journals Internal report Publication on website Submission to regulatory authorities |
| IPD sharing plan | All data generated or analysed during this study will be included in the subsequent results publication |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
10/01/2025: The following changes were made to the study record:
1. The recruitment end date was changed from 31/12/2024 to 31/03/2025.
2. The overall study end date was changed from 30/06/2025 to 30/09/2025.
3. The intention to publish date was changed from 31/08/2025 to 30/11/2025.
03/12/2024: The contacts were changed.
18/09/2024: The following changes were made:
1. The recruitment end date was changed from 30/09/2024 to 31/12/2024.
2. The overall study end date was changed from 31/01/2025 to 31/06/2025.
3. The intention to publish date was changed from 31/03/2025 to 31/08/2025.
06/06/2024: The following changes were made:
1. The recruitment end date was changed from 30/06/2024 to 30/09/2024.
2. The overall study end date was changed from 31/10/2024 to 31/01/2025.
3. The intention to publish date was changed from 31/12/2024 to 31/03/2025.
12/04/2024: The following changes were made to the trial record:
1. The recruitment end date was changed from 30/04/2024 to 30/06/2024.
2. The overall end date was changed from 31/08/2024 to 31/10/2024.
3. The intention to publish date was changed from 31/10/2024 to 31/12/2024.
4. The plain English summary was updated to reflect these changes.
23/10/2023: The following changes were made:
1. The recruitment end date was changed from 31/10/2023 to 30/04/2024.
2. The overall study end date was changed from 31/01/2024 to 31/08/2024.
3. The intention to publish date was changed from 30/03/2024 to 31/10/2024.
04/07/2023: The recruitment end date was changed from 31/07/2023 to 31/10/2023.
08/11/2022: The following changes were made to the trial record:
1. The recruitment start date was changed from 31/05/2022 to 10/10/2022.
2. The recruitment end date was changed from 31/03/2023 to 31/07/2023.
3. The overall end date was changed from 31/10/2023 to 31/01/2024.
4. The intention to publish date was changed from 31/12/2023 to 30/03/2024.
5. The plain English summary was updated to reflect these changes.
06/04/2022: ISRCTN received notification of combined HRA/MHRA approval for this trial on 05/04/2022
03/02/2022: Trial's existence confirmed by NHS HRA.
