A study to investigate the effect of inhaled and intranasal pathogens on pro-infammatory markers using (existing) techniques in order to acquire experience with these techniques.|
|- candidate number||13251|
|- NTR Number||NTR3590|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd.|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||23-aug-2012|
|- Secondary IDs||NL41617.056.12 METC|
|- Public Title||A study to investigate the effect of inhaled and intranasal pathogens on pro-infammatory markers using (existing) techniques in order to acquire experience with these techniques.|
|- Scientific Title||A phase 0 study to investigate the effects of inhaled and intranasal lipopolysaccharide (LPS) on pro-inflammatory markers sampled by hypertonic saline-induced sputum (SI) and nasal lavage (NAL) in healthy subjects. Part 1 with 0,9% NaCl.|
|- hypothesis||To acquire experience with sputum induction and LPS challenge techniques. |
|- Healt Condition(s) or Problem(s) studied||Asthma, Chronic Obstructive Pulmonary Disease (COPD)|
|- Inclusion criteria||1. Healthy Male/Female subjects, aged 18-55 yrs (inclusive);|
2. FVC, FEV1 80% ; FEV1/FVC ratio 0.75;
3. Oxygen saturation 94% (pulsoximetry);
4. Normal blood pressure (SBP 90-150, DBP 60-90 mmHg, inclusive) and pulse (45-100 bpm, inclusive);
5. ECG without clinically relevant abnormalities;
6. Normal body temperature (<37.5 °C);
7. Normal blood leukocyte count;
8. Normal CRP;
9. Adequate contraception (from screening to follow-up);
10. Must be able to return <10 days after LPS challenge, for follow up.
|- Exclusion criteria||1. History of upper and lower airway infection <4 wks;|
2. Relevant atopy;
3. Current smokers (ex-smoker >1 yr, <10 packyrs, inclusive);
4. Positive metacholine inhalation test with a post challenge FEV1 decrease <20% (PC20), <16 mg/ml;
5. Any relevant upper airway condition (e.g. serious septal deviation, status post
any upper airway surgery, chronic sinusitis or polyposis, at the discretion of the
6. History of clinically relevant pulmonary or cardiovascular disease;
7. Any inhaler or intranasal medications – other medications, at the dis-cretion of
8. Positive pregnancy test or lactation;
9. Unable to perform any of the study-related tests.
|- mec approval received||yes|
|- multicenter trial||no|
|- Type||Single arm|
|- planned startdate ||27-aug-2012|
|- planned closingdate||31-jul-2013|
|- Target number of participants||10|
|- Interventions||Primary objectives Part 1:|
1. To set up the SI and LPS (in part 1 substituted by Normal Saline) challenge techniques;
2. To evaluate the sampling success (i.e., the percentage of analysable sputum and NAL samples), pre- and post-LPS challenge; in terms of non-squamous cell counts (total cell numbers and differentials);
3. To identify “LPS-responders”, defined as those subjects with an absolute increase (pre- vs. post challenge) in sputum neutrophil count of >=10%.
Primary objectives part 2:
1. To investigate the pro-inflammatory effects of inhaled LPS (at a previously applied dose of 60 μg) within the lower airways of healthy subjects, by hypertonic saline-induced (NaCl 4.5%) sputum;
2. To investigate the pro-inflammatory effects of low-dose intranasal LPS (at a previously applied dose using the split nose method) within the upper airways of healthy subjects, using NAL;
3. To evaluate the repeatability of the LPS inflammatory response, all procedures need to be repeated with the same subjects in a second identical study period;
4. Additional subjects need to be tested, to validate the techniques used.
Intervention Part 1:
On day 1, after baseline spirometry, sputum will be induced by inhalation of hypertonic saline (NaCl 4.5% aerosol generated by ultrasonic nebulization), during 3 times 5 min (at approximately 15 min intervals). Sputum samples will be collected in a clean plastic container on melting ice and processed within 2 hrs. This will serve as the baseline sputum sample. On day 2, an inhaled LPS* challenge will be performed (approx. 24 hrs after baseline SI) followed by SI 6 hrs later (approx. 30 hrs after baseline SI); to assess the acute LPS effects in the lower airways. On day 3, an intranasal LPS challenge will be performed, using the split-nose method, followed by a NAL 6 hrs post challenge.
Intervention Part 2:
Part One study participants (those actually exposed to SI and LPS challenge, will also be invited to participate in a second study period (washout >=3 weeks), identical to the first study period (to test SI and LPS challenge repeatability). Only those will be invited again, from whom an analysable sputum sample could be obtained during Part One. To validate the techniques used, additional subjects will be included, each of them will participate in two identical study periods as well. For individual subjects, all study related measurements will be performed in similar within-day time frames (±3 hrs).
|- Primary outcome||1. Cellular fraction endpoints, for evaluation of total and differential cell count (analyzable sputum);|
2. Sputum inflammatory cell response (i.e., number of neutrophils; responders
versus non-responders; response defined as an absolute rise in sputum neutrophil counts of at least 10% from pre-challenge evaluation;
3. Soluble fraction (supernatant) endpoints, to be frozen pending analysis. Used
analyses technique examples are: ELISA, RIA, Luminax for the detection of
soluble inflammatory biomarkers including cytokines and mediators Including, but
not limited to e.g. interleukin (IL)-8, TNF-alpha, leakage markers (e.g., alpha2-
|- Secondary outcome||1. FEV1, to assess bronchoconstriction;|
2. Pulsoximetry to assess peripheral oxygen saturation;
3. Vital signs (blood pressure, heart rate, body temperature), and adverse events (in case they occur).
|- Timepoints||After spututum induction challenges, after LPS challenges and during the course of the study (safety endpoints).|
|- Trial web site||N/A|
|- status||open: patient inclusion|
|- CONTACT FOR PUBLIC QUERIES|| M.C.E. Beukers-Reuvers|
|- CONTACT for SCIENTIFIC QUERIES||MD. PhD. T. Mensinga|
|- Sponsor/Initiator ||QPS Netherlands BV|
(Source(s) of Monetary or Material Support)
|QPS Netherlands B.V.|
|- Brief summary||This is a phase 0 study to investigate the effects of inhaled and intranasal lipopolysaccharide (LPS) on pro-inflammatory markers sampled by hypertonic saline-induced sputum (SI)
and nasal lavage (NAL) in healthy subjects. The main objectives are to set up the SI and LPS challenge techniques, to evaluate the sampling success, to investigate the pro-inflammatory effects of inhaled and intranasal LPS, and to evaluate the repeatability of the LPS inflammatory response. In part 1 of the study LPS will be substituted by normal saline.
This study contributes to further development of medicine of obstructive airway diseases.
Subjects will be recruited in the Netherlands.
|- Main changes (audit trail)|
|- RECORD||23-aug-2012 - 6-okt-2012|
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