MM-0100 RCT205
Research type
Research Study
Full title
A Randomised, Double-Blind, Placebo-Controlled, Two-Way Crossover Study in Healthy Smokers to Investigate the Effect of Inhaled Dosing with MMI-0100 on Airway Inflammation as Assessed in Induced Sputum after Challenge with Inhaled Lipopolysaccharide (LPS)
IRAS ID
177775
Contact name
Brian Leaker
Contact email
Sponsor organisation
Moerae Matrix Incorporated
Eudract number
2015-001497-17
Duration of Study in the UK
0 years, 7 months, 31 days
Research summary
MMI-0100 RCT205 is a randomised, double-blinded, placebo-controlled, two-way crossover study. The purpose of this study is to see whether MMI-0100 can prevent inflammation in the lung and therefore, potentially treat diseases of the lung caused by inflammation including smoker’s lung (chronic obstructive pulmonary disease or COPD) and also Pulmonary Fibrosis. These are chronic, progressive diseases that affect an increasing number of people each year.
For this study, participants will be healthy male and female smokers aged 18 to 70 years inclusive. This is because the disease being studied most commonly occurs in persons who have a history of cigarette smoking.
This study aims to include 20 eligible subjects with a minimum of 16 subjects completing the study.
This study will be conducted at one site and randomised subjects will be involved in the study for approximately three months from screening visit to study completion. Within these three months, there are 12 scheduled trial visits which will involve the subject attending the Centre on 12 occasions. These 12 visits include a screening visit (Visit 0) and two treatment periods, each consisting of 5 days (Visit 1 to Visit 5; Visit 6 to Visit 10), following by a follow-up visit (Visit 11).
A potential extra visit may be required between screening visit (Visit 0) and Visit 1 if any of the screening assessments need to be repeated, to ensure subject safety and eligibility.
During each Treatment Period, the subject will be asked to attend the Centre daily for five days where they will receive either MMI-0100 or a placebo. For the duration of these five days, inflammation will be measured by obtaining sputum and blood samples to observe cells and chemicals (biomarkers of inflammation). Appropriate safety measures will be performed throughout both treatment periods as outlined in the protocol to ensure subject safety at all times.
On day 5 of each treatment period (Visit 5 and Visit 10), subjects will be challenged with Lipopolysaccharides (LPS), which is a substance that stimulates an inflammatory response. This will be done in order to measure the effect of MMI-0100 or placebo.
There will be a wash out period of 21-42 days between these treatment periods to ensure that subjects are at baseline as at screening visit prior to commencing the second treatment period.
A mandatory safety assessment visit will be conducted for all subjects participating in this study.Lay Summary of Results
Objectives: Primary objectives:
To assess safety and tolerability data for MMI-0100 following repeat administration.
To investigate the effect of inhaled MMI-0100 compared to placebo treatment on inflammatory markers (including but not limited to interleukin [IL]-6, IL-1β, CXCL8/IL-8, tumour necrosis factor alpha [TNFα]) in induced sputum after challenge with inhaled LPS.
Secondary objectives:
To investigate the effect of inhaled MMI-0100 compared to placebo treatment on cell counts (total cell count; total neutrophil count and differential [%]; total macrophage count, and differential [%]) in induced sputum after challenge with inhaled LPS.
To investigate the effect of inhaled MMI-0100 compared to placebo treatment on phosphorylation of MK2 protein in sputum leucocytes using a proprietary assay system developed by Respiratory Clinical Trials (RCT) in induced sputum after challenge with inhaled LPS.
To measure the concentration of MMI-0100 in blood and induced sputum following inhaled administration and after challenge with inhaled LPS.
To investigate the effect of MMI-0100 compared to placebo treatment on additional biomarkers, which included those of inflammation in blood and induced sputum (including but not limited to surfactant protein-D [SP-D], Krebs von den Lungen-6 [KL-6] and C reactive protein [CRP]).The study was a randomised, double-blind, placebo-controlled, two-way crossover study of MMI-0100 and placebo, conducted at 1 study centre.
The study began with a Screening Visit (Visit 0) to evaluate and confirm eligibility of the subject for inclusion into this study, followed by 2 treatment periods: Treatment Period 1 (TP1) and Treatment Period 2 (TP2), both lasting 5 days. Subjects received a once daily dose of either MMI-0100 (2.25 mg) or placebo, administered by inhalation via a nebuliser, in the morning for 5 consecutive days for both TP1 (Visits 1 to 5) and TP2 (Visits 6b to 10). Subjects remained under medical supervision until up to 5 hours post-dose, depending on the assessments planned. Treatment in this study only occurred (and was monitored) at the study centre. Following the end of TP1 and prior to start of TP2, a wash-out period of 21-42 days took place.
At Visits 3, 8, and 10, subjects underwent sputum induction post-dosing. At the end of each treatment period (Visit 5 and Visit 10), subjects were challenged with inhaled LPS 1 hour post-dosing and a lung function test and sputum induction took place 6 hours later. In addition, pharmacokinetic (PK) blood samples were collected at Visits 1, 2, 3, 4, 5, 6b, 7, 8, 9, and 10 to measure levels of MMI-0100 in the bloodstream. Blood samples were also obtained at Visits 1, 3, 5, 6b, 8, and 10 to measure additional biomarkers of inflammation. Blood sampling for clinical chemistry and haematology was required a maximum of 72 hours prior to Visit 6b (i.e. Visit 6a). A follow-up visit (Visit 11) was performed 7 to 14 days after completion of TP2.Number of subjects (planned and analysed): 20 subjects were planned to ensure a minimum of 16 subjects completed the study.
24 subjects randomised (12 MMI-0100 – placebo; 12 placebo – MMI-0100)
22 subjects treated and included in safety population (10 MMI-0100 – placebo; 12 placebo – MMI-0100)
20 subjects in primary analysis (evaluable population) (10 MMI-0100 – placebo; 10 placebo – MMI-0100)
Diagnosis and main criteria for inclusion: Male or female subjects who were current smokers with history of ≥10 cigarettes per day for more than 10 years, aged 18 to 70 years, inclusive. Subjects had to have a body mass index (BMI) between 18 and 35 kg/m2 inclusive and minimum body weight of 50 kg. At screening (Visit 0) subjects had to have a forced expired volume in one second (FEV1) >80% predicted value and FEV1/forced vital capacity (FVC) ratio ≥0.7 at post-bronchodilator spirometry, be able to produce a minimum of 0.1g sputum after induction with inhaled hypertonic saline, have a sputum eosinophilia count of ≤3%, and have a total leucocyte count per gram sputum of less than 20 x106 cells.
Test products, dose and mode of administration, batch number: MMI-0100, 2.25 mg once daily in the morning, inhaled via an eFlow® nebuliser
Batch number: MOR062/08JUL2015
Duration of treatment: Two 5-day treatment periods (TP1 and TP2) with a washout period of 21 42 days between treatment periods in this crossover study
Reference therapy, dose and mode of administration, batch number: Placebo, once daily in the morning, inhaled via an eFlow® nebuliser
Batch numbers: 1501439, 1500057, 1500058, 1502481
LPS batch number: 025M4088V
Criteria for evaluation:
Efficacy: Pharmacodynamic assessments, including inflammatory mediators IL-6, IL-1β, CXCL8/IL-8 and TNFα in sputum, total cell count, total neutrophil count, neutrophil % differential, total macrophage count, and macrophage % differential in sputum, phosphorylation of MK2 protein, and additional inflammatory biomarkers measured in blood and induced sputum (including, but not limited to, SP-D, KL-6/MUC-1 and CRP). To assess pharmacokinetics, MMI-0100 was measured in the cellular component of blood (white blood cells and platelets) and in sputum using a buffy coat assay.
Safety: 12 lead electrocardiogram (ECG), laboratory blood tests for safety analysis, urinalysis and urine pregnancy test (where applicable), vital signs (blood pressure [BP], blood oxygen saturation [SpO2], pulse rate and body temperature), lung function test and adverse events (AEs)
Statistical methods: This was an exploratory study with no inferential statistical testing. If data were non-normally distributed, a log transformation was performed prior to analysis. Comparisons between treatments were carried out using an analysis of variance (ANOVA) for a crossover design with subject (sequence and subject within sequence), period, and treatment as factors in the model, if no significant sequence effect was shown. The geometric least square (LS) treatment means along with 95% confidence intervals (CIs) (following a back transformation) and % ratio of the LS treatment means were presented. If data were normally distributed, then arithmetic LS treatment means along with 95% CI and difference of the LS treatment means were to be shown. The absolute difference between treatments, the percentage difference between treatments, and the percentage ratio were calculated for all parameters as appropriate, and timepoints, and summarised with descriptive statistics including the 95% CI.
SUMMARY OF RESULTS
DEMOGRAPHICS: 95.5% of the subjects were male, 63.6% were Caucasian of European descent, and the mean age of all subjects was 40 years. The demographic details were generally similar in the 2 treatment sequences. All subjects were current smokers and had a smoking history of ≥10 cigarettes per day for more than 10 years. Approximately half of the subjects (54.5%) had at least one medical or surgical condition. Depression was the most common condition (reported in 3 subjects), followed by eczema (reported in 2 subjects). All subjects had an FEV1 >80% of the predicted value and an FEV1/FVC ratio ≥0.7, as required by the protocol inclusion criteria. The spirometry results were comparable in the 2 treatment sequences.
EFFICACY RESULTS: The primary biomarkers of IL 1β, IL-6, CXCL8/IL-8 and TNFα were analysed in induced sputum and blood. Although changes were seen from baseline to Day 3 and Day 5 (post-LPS challenge) in both treatment groups, the treatment difference between the 2 treatment groups was not statistically significant for any of the primary biomarkers. However, it is of note that there was a consistently lower increase in the inflammatory markers at Day 5 post-LPS challenge in blood the MMI-0100 group compared to the placebo group for IL-6, CXCL8/IL-8 and less notably for IL-1β.
Although changes were seen in cell counts in induced sputum from baseline to Day 3 and Day 5 in both treatment groups, the treatment difference between the 2 treatment groups was not statistically significant for all of the cell count results. Only small changes were seen at Day 3 for phosphorylation of MK2 protein in both blood and induced sputum following MMI-0100 and placebo treatment, with none of the treatment difference being statistically significant. Similar results were seen for phosphorylation of MK2 protein using weighted mean fluorescence intensity.
A range of exploratory biomarkers were evaluated in induced sputum and blood. The treatment difference between the 2 treatment groups was not statistically significant for most of the biomarker results, although SP-D, MMP13, and HSP27 phosphorylation all showed changes in sputum that reached statistical significance at some time points. In blood, MMP2, CCL5, CXCL1 and CXXL5 all showed a statistically significant decrease in the MMI-0100 group compared to an increase in the placebo group from pre-dose to post-dose on Day 5. It is also of note that there was a consistently lower increase in the inflammatory markers at Day 5 post-LPS challenge in the MMI-0100 group compared to the placebo group for MMP8, IL 1ra, IL-18 BPa, CCL2, ICAM-1, VCAM-1, lipocalin, periostin, and MUC-1.
Post-hoc analyses showed that total cell counts, total neutrophil counts and the primary endpoint cytokines increased in the majority of subjects following LPS challenge, indicating that the LPS challenge was successfully performed. The majority of biomarkers showed no correlation with MUC-1 levels either in the placebo treatment period or after administration of MMI 0100. All subjects classed as a responder had evidence of a drug effect in greater than half the selected biomarkers.
SAFETY RESULTS: A total of 209 doses of study treatments were administered, the mean number of inhalations was 9.5 and the mean duration of each dose was 2.7 minutes. There was no noteworthy difference in exposure to study medication for subjects who were treated with the MMI-0100 – placebo sequence compared with those randomised to placebo – MMI-0100.
A total of 12 subjects (54.5%) experienced a TEAE during this study. The most common TEAE was headache, which was reported 9 times by 5 subjects (22.7%) during the MMI 0100 treatment period and 6 times by 3 subjects (13.6%) during the placebo treatment period. There was no notable difference seen in the type or frequency of TEAEs reported during the MMI-0100 treatment period compared to during the placebo treatment period. The majority of TEAEs were considered mild or moderate, with only 1 TEAE considered severe (a single episode of severe lower respiratory tract infection) during the placebo treatment period. The majority of TEAEs were not considered related to the study treatments with only the single episode of severe lower respiratory tract infection considered possibly related to the study treatment.
One subject experienced a SAE: the subject was involved in a road traffic accident and experienced joint dislocation and concussion on Day 15 of Treatment Period 2 during placebo treatment. No subjects had a TEAE leading to drug or study discontinuation and no subjects had a fatal TEAE.
Small changes were seen in laboratory values during the study, but there were no notable differences following treatment with MMI-0100 compared to treatment with placebo.
Between 30 minutes and 5 hours post-LPS, treatment with MMI-010 resulted in a decrease in FEV1 of approximately 0.5 L. By 6 hours post-LPS the values were almost back to pre-treatment levels. A decrease in blood pressure was also seen, with a decrease of approximately 15 mmHg in systolic blood pressure and 8 mmHg in diastolic blood pressure being seen between 15 and 30 minutes post-LPS with MMI-0100 treatment compared to a decrease of approximately 5 mmHg in systolic blood pressure and 4 mmHg in diastolic blood pressure being seen between 15 and 30 minutes post-LPS with placebo treatment. However, in Treatment Period 2 the reverse was seen, with a greater decrease in blood pressure being seen following placebo treatment compared to MMI-0100 treatment (a maximum decrease of approximately 5 mmHg in systolic blood pressure and 2 mmHg in diastolic blood pressure being seen between 15 and 30 minutes post-LPS with MMI-0100 treatment compared to a decrease of approximately 12 mmHg in systolic blood pressure and 7 mmHg in diastolic blood pressure being seen between 15 and 30 minutes post-LPS with MMI-0100 treatment.
Only small changes were seen in pulse rate, body temperature and SpO2 during the study, with no notable differences being seen with MMI-0100 treatment compared to placebo treatment. No ECG changes indicative of an adverse effect were seen.
CONCLUSION: In conclusion, although no statistically significant differences were seen between MMI-0100 treatment and placebo treatment for the primary biomarkers of IL 1β, IL-6, CXCL8/IL-8 and TNFα when analysed in induced sputum and blood, trends in the data indicated that IL-6 and CXCL8/IL-8 might be useful biomarkers to evaluate response to MMI 0100 in future studies. Additional exploratory biomarkers of SP D, MMP13, HSP27 phosphorylation, MMP2, CCL5, CXCL1, CXCL5, MMP8, IL 1ra, IL-18 BPa, CCL2, ICAM-1, VCAM-1, lipocalin, periostin, and MUC-1 all showed changes of interest that might also warrant further investigation. The safety of MMI-0100 was good, although treatment with MMI-0100 caused transient decreases in FEV1 and blood pressure which lasted approximately 5 hours.
Date of the report: xxx May 2016REC name
London - Surrey Borders Research Ethics Committee
REC reference
15/LO/0846
Date of REC Opinion
24 Jun 2015
REC opinion
Further Information Favourable Opinion