A Study of MRx-4DP0004 in Asthma

• ClinicalTrials.gov Identifier: NCT03851250
• Recruitment Status: Active, not recruiting
• First Posted: February 22, 2019
• Last Update Posted: July 6, 2022
• Sponsor: 4D pharma plc
• Information provided by (Responsible Party): 4D pharma plc

Study Description

Brief Summary:

This is a multicentre, phase I/II, double-blind, placebo-controlled study of MRx-4DP0004 in participants taking long-term medication for asthma. Participants will take two capsules of MRx-4DP0004 twice daily in addition to their existing asthma medication for 12 weeks. Safety and tolerability and immune modulatory effects of MRx-4DP0004 will be assessed throughout the study.

Condition or disease	Intervention/treatment	Phase
Asthma	Drug: MRx-4DP0004; Drug: Placebo	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A First in Human, Double-blind, Placebo-controlled, Multicentre Phase I/II Study to Evaluate the Safety, Tolerability and Immune Modulatory Effects of MRx-4DP0004 in Participants Taking Long-term Control Medication for Their Asthma
• Actual Study Start Date: July 4, 2019
• Estimated Primary Completion Date: September 2022
• Estimated Study Completion Date: September 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: MRx-4DP0004; MRx-4DP0004 is a Live Biotherapeutic Product containing 10^9 to 10^10 Colony Forming Units. Participants randomised to this arm will take 2 capsules twice daily at approximately 12 hour intervals for 12 weeks.	Drug: MRx-4DP0004; Participants randomised to receive MRx-4DP0004 will take it in addition to their regular asthma medication.
Placebo Comparator: Placebo; Participants randomised to this arm will take 2 capsules of placebo twice daily at approximately 12 hour intervals for 12 weeks. All participants will receive placebo in a single blind manner for two weeks in addition to the 12 weeks of double blind treatment.	Drug: Placebo; Participants randomised to receive placebo will take it in addition to their regular asthma medication.

Outcome Measures

Primary Outcome Measures :

1. Number of participants in each treatment arm experiencing adverse events [ Time Frame: Baseline to Day 127 ]
   Adverse events will be considered alongside other primary outcome measures for assessment of safety and tolerability.
2. Number of clinically relevant adverse changes in clinical laboratory tests in each treatment arm [ Time Frame: Baseline to Day 127 ]
   Clinically relevant adverse changes clinical laboratory tests will be considered alongside other primary outcome measures for assessment of safety and tolerability. Clinical laboratory tests will include clinical chemistry, haematology and urinalysis.
3. Number of clinically relevant adverse changes in vital signs in each treatment arm [ Time Frame: Baseline to Day 127 ]
   Clinically relevant adverse changes in vital signs will be considered alongside other primary outcome measures for assessment of safety and tolerability. Vital signs assessments will include measurement of systolic blood pressure, diastolic blood pressure, oral body temperature and pulse rate.
4. Number of clinically relevant adverse changes in 12-lead ECGs in each treatment arm [ Time Frame: Baseline to Day 127 ]
   The number of participants experiencing clinically relevant adverse changes in Clinically relevant adverse changes in vital signs will be considered alongside other primary outcome measures for assessment of safety and tolerability. ECG assessments will include measurement of PR, QRS, QT and QTcF.

Secondary Outcome Measures :

1. Difference in the mean change in the Asthma Control Questionnaire (ACQ-6) between treatment arms [ Time Frame: Baseline to Day 99 ]
   The ACQ-6 consists of 6 questions relating to control of asthma symptoms answered on a 7 point scale. The overall score is the mean of the 6 questions and is rated from 0 (totally controlled) to 6 (severely uncontrolled).
2. Difference in the number of subjects achieving good asthma control (as defined by an ACQ-6 score <1.0) between treatment arms. [ Time Frame: Baseline to Day 99 ]
   The ACQ-6 consists of 6 questions relating to control of asthma symptoms answered on a 7 point scale. The overall score is the mean of the 6 questions and is rated from 0 (totally controlled) to 6 (severely uncontrolled).
3. Difference in the number of asthma exacerbations between treatment arms [ Time Frame: Baseline to Day 99 ]
   To determine if MRx-4DP0004 can reduce the number of asthma exacerbations, the number of participants experiencing an exacerbation will be assessed.
4. Difference in the number of hospitalisations due to asthma exacerbation between treatment arms [ Time Frame: Baseline to Day 99 ]
   To determine if MRx-4DP0004 can reduce the number of hospitalisations due to exacerbation of asthma symptoms, the number of participants who are hospitalised due to an exacerbation will be assessed.
5. Difference in the change from baseline in Forced Expiratory Volume in 1 second (FEV1) between treatment arms [ Time Frame: Baseline to Day 99 ]
   To assess the response to MRx-4DP0004 in respect of changes to FEV1, the change from baseline in FEV1 will be assessed.
6. Difference in the change from baseline in Peak Expiratory Flow (PEF) between treatment arms [ Time Frame: Baseline to Day 99 ]
   To assess the response to MRx-4DP0004 in respect of changes to PEF, the change from baseline in PEF will be assessed.
7. Difference in the change from baseline in Forced Vital Capacity (FVC) between treatment arms [ Time Frame: Baseline to Day 99 ]
   To assess the response to MRx-4DP0004 in respect of changes to FVC, the change from baseline in FVC will be assessed.
8. Difference in the change from baseline in blood eosinophils between treatment arms [ Time Frame: Baseline to Day 99 ]
   To assess the effect of MRx-4DP0004 on levels of eosinophils in blood, the change from baseline in percentage and absolute eosinophil counts will be assessed.
9. Difference in the change from baseline in blood neutrophils between treatment arms [ Time Frame: Baseline to Day 99 ]
   To assess the effect of MRx-4DP0004 on levels of neutrophils in blood, the change from baseline in percentage and absolute neutrophil counts will be assessed.
10. Difference in the change from baseline in use of short-acting beta agonists (SABAs) between treatment arms [ Time Frame: 7 period prior to baseline to 7 day period prior to Day 99 ]
    To assess the effect of MRx-4DP0004 on the use of SABAs, the change from baseline in SABA use will be assessed.
11. Difference in the mean change from baseline in the Asthma Quality of Life Questionnaire (standardised version) (AQLQ(S)) between treatment arms [ Time Frame: Baseline to Day 99 ]
    The AQLQ(S) consists of 32 questions relating to quality of life in relation to asthma answered on a 7 point scale. The overall score is the mean of the 32 questions and is rated from 7 (not impaired at all) to 1 (severely impaired).

Other Outcome Measures:

1. Difference in the change from baseline in faecal microbiota profile between treatment arms [ Time Frame: Baseline to Day 99 ]
   Faecal samples will be analysed using the MicroDx (R) platform.
2. Difference in the change from baseline in Fraction exhaled nitric oxide (FeNO) between treatment arms [ Time Frame: Baseline to Day 99 ]
   Changes in participants FeNO concentrations will be assessed over the course of the study.
3. Difference in the change from baseline in Immunoglobulin E (IgE) between treatment arms [ Time Frame: Baseline to Day 99 ]
   Changes in participants serum IgE levels will be assessed over the course of the study.
4. Difference in the change from baseline in leukotriene E4 between treatment arms [ Time Frame: Baseline to Day 99 ]
   Changes in participants urinary leukotriene E4 levels will be assessed over the course of the study.
5. Difference in the change from baseline in peripheral blood mononuclear cells (PBMCs) between treatment arms [ Time Frame: Baseline to Day 99 ]
   To assess the effect of MRx-4DP0004 on PBMCs, changes from baseline in lymphocytes and monocytes will be assessed through measurement of CD3, CD16+56, CD45, CD4, CD19, CD8, CD14, CD15, CD16 and CD64.
6. Difference in the change from baseline in serum cytokines between treatment arms [ Time Frame: Baseline to Day 99 ]
   To assess the effect of MRx-4DP0004 on serum cytokines, changes from baseline in IL-1a, IL-1b, CXCL1, CXCL2, IL-6, IL-8, IL-17A, IL-5, IL-4, IL-13, CCL11/eotaxin and TSLP will be assessed
7. Difference in the change from baseline in sputum eosinophils (percentage count) between treatment arms [ Time Frame: Baseline to Day 99 ]
   To assess the effect of MRx-4DP0004 on levels of eosinophils in induced sputum, changes form baseline in percentage eosinophil count will be assessed for participants in the UK only.
8. Difference in the change from baseline in sputum eosinophils (absolute count) between treatment arms [ Time Frame: Baseline to Day 99 ]
   To assess the effect of MRx-4DP0004 on levels of eosinophils in induced sputum, changes form baseline in absolute eosinophil count will be assessed for participants in the UK only.
9. Difference in the change from baseline in sputum neutrophils (percentage count) between treatment arms [ Time Frame: Baseline to Day 99 ]
   To assess the effect of MRx-4DP0004 on levels of neutrophils in induced sputum, changes form baseline in percentage neutrophil count will be assessed for participants in the UK only.
10. Difference in the change from baseline in sputum neutrophils (absolute count) between treatment arms [ Time Frame: Baseline to Day 99 ]
    To assess the effect of MRx-4DP0004 on levels of neutrophils in induced sputum, changes form baseline in absolute neutrophil count will be assessed for participants in the UK only.
11. Difference in the change from baseline in sputum microbiota profile between treatment groups [ Time Frame: Baseline to Day 99 ]
    To assess the effect of MRx-4DP0004 on induced sputum microbiota, changes from baseline in sputum microbiota will be assessed. Sputum samples will be analysed using the MicroDx (R) platform.
12. Difference in the change from baseline in sputum cytokine profile between treatment arms [ Time Frame: Baseline to Day 99 ]
    To assess the effect of MRx-4DP0004 on induced sputum cytokines, changes from baseline in sputum cytokines will be assessed
13. Difference in the change from baseline in urine metabolomics profile between treatment arms [ Time Frame: Baseline to Day 99 ]
    To assess the effect of MRx-4DP0004 on urine metabolomics, the change from baseline in urine metabolomics will be assessed. Urine samples will be analysed using the MicroDx (R) platform

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Documented history and diagnosis of asthma at least 6 months prior to Visit 1.
• Stable current asthma treatment as per GINA steps 2-4 (ICS with or without LABA) for at least 2 months prior to Visit 1.
• ACQ-6 score >1.5 and <=4
• FEV1 >50% of predicted normal
• Following protocol specified contraception requirements.

Exclusion Criteria:

• Non-compliant with prescribed asthma maintenance treatment.
• At significant risk of exposure to a change in environmental sensitising substances during the study.
• Co-morbidities not optimally controlled for the last 3 months or any co-morbidity that may put the subject at risk or influence the outcome of the study.
• Hepatitis B or C or HIV.
• GI fistula, feeding tubes or inflammatory bowel disease.
• GI disease resulting in inability for oral intake, malabsorption syndrome, surgical procedures affecting absorption, uncontrolled inflammatory bowel disease.
• History of life-threatening asthma.
• Systemic corticosteroids within 6 weeks of first dose.
• Allergy to all of ampicillin, clindamycin and imipenem.
• Probiotic supplements.
• Immunosuppression or immunosuppressant medication.
• Use of ICS and LABA as Maintenance and Reliever Therapy.
• Smokers or nicotine users within 3 months of screening.
• Former smokers >15 pack years.
• Systemic antibiotics within 6 weeks of first dose.
• Clinically significant haematology and serum biochemistry.
• Sensitivity to any constituent of IMP.
• Diastolic blood pressure <45 or >90, systolic blood pressure <95 or >155mmHg, Pulse rate <40 or >100 bpm.
• Clinically significant ECGs or structural cardiac abnormalities.
• Any other condition that may interfere with primary objective.
• Receipt of a positive COVID-19 test result within 4 weeks of first dose of IMP

Contacts and Locations

Locations

United States, Oregon

OHSU Allergy and Clinical Immunology Clinic

Portland, Oregon, United States, 97239

United Kingdom

Bradford Teaching Hospital

Bradford, West Yorkshire, United Kingdom

4D Site Leicester

Leicester, United Kingdom

4D Site Manchester

Manchester, United Kingdom

Sponsors and Collaborators

4D pharma plc

Investigators

• Principal Investigator: Christopher Brightling, Professor; University of Leicester

More Information

• Responsible Party: 4D pharma plc
• ClinicalTrials.gov Identifier: NCT03851250
• Other Study ID Numbers: MRx-4DP0004-I-001
• First Posted: February 22, 2019
• Last Update Posted: July 6, 2022
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by 4D pharma plc:

MRx-4DP0004; Asthma; Live Biotherapeutic Product

Additional relevant MeSH terms:

Asthma; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases