Ignite Creation Date:
2024-05-06 @ 1:47 PM
Last Modification Date:
2024-10-26 @ 1:20 PM
Study NCT ID:
NCT04125563
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-04-24
First Post:
2019-09-02
Brief Title:
Influence on Cough and Airway Symptoms by Oral Capsaicin
Sponsor:
Vastra Gotaland Region
Organization:
Vastra Gotaland Region
Study Overview
Official Title:
Influence on Cough and Airway Symptoms by Oral Capsaicin - a Phase 2 Randomised Placebo-controlled Clinical Study in Patients With Chronic Idiopathic Cough
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Study objectives
To establish whether an oral intake of Capsicum oleoresin capsaicinoids expressed as 04 mg capsaicin C18H27N03 Mw 3054 in each capsule from chili extract can desensitise the cough reflex and improve unexplained coughing
Study period
Estimated Start date first patient enrolled June 2019
Estimated End date last patient completed follow up June 2020
First data available for presentation September 2020
Investigational productcomparator
The formulation is prepared from Capsicum oleoresin Each capsule will contend a dose corresponding to 04 mg capsaicin All test methods are as per the European Pharmacopoeia for Capsicum oleoresin refined and standardised
The formulation is developed by Research Institutes of Sweden RISE Sodertalje Sweden
Supplier of raw material for the Capsicum oleoresin productIMP RANSOM Ltd London UK
Producer of capsules with Capsicum oleoresin and placebo by Catalent Pharma Solutions St Petersburg Florida USA
Packing bottles of capsules with the investigational medical product IMP and placebo by Apotek Produktion Laboratorier AB APL Stockholm Sweden
Study design
Capsules taken orally with standardised doses of Capsicum oleoresin corresponding to 04 mg pure capsaicin from chili extract in each capsule in comparison to matched capsules with placebo sorbitol and colorant all capsules looking the same Four weeks of active treatment is compared to four weeks of placebo In between there is a wash out period of two weeks
The time frame is 24 hours 10 weeks During the first 24 hours the patients carry a cough recorder Leicester Cough Monitor - LCM and then start with 4 weeks of active treatment or placebo This is followed by 2 weeks of wash out and then the patients start with another 4 weeks of active treatment or placebo After this the study ends
Collaboration
Professor Alyn Morice MD PhD chief physician at Hull York Medical School University of Hull UK Professor Surinder Birring MD Senior Lecturer specialist in respiratory medicine Imperial College London UK Associate professor Alastair RossPhD Chalmers University of Technology Gothenburg Sweden
Study center and number of subjects planned
All clinical trials take place at the asthma and allergy clinic Sahlgrenska University Hospital Gothenburg Sweden from where 60 patients with chronic idiopathic cough CIC are recruited
To establish whether an oral intake of Capsicum oleoresin capsaicinoids expressed as 04 mg capsaicin C18H27N03 Mw 3054 in each capsule from chili extract can desensitise the cough reflex and improve unexplained coughing
Study period
Estimated Start date first patient enrolled June 2019
Estimated End date last patient completed follow up June 2020
First data available for presentation September 2020
Investigational productcomparator
The formulation is prepared from Capsicum oleoresin Each capsule will contend a dose corresponding to 04 mg capsaicin All test methods are as per the European Pharmacopoeia for Capsicum oleoresin refined and standardised
The formulation is developed by Research Institutes of Sweden RISE Sodertalje Sweden
Supplier of raw material for the Capsicum oleoresin productIMP RANSOM Ltd London UK
Producer of capsules with Capsicum oleoresin and placebo by Catalent Pharma Solutions St Petersburg Florida USA
Packing bottles of capsules with the investigational medical product IMP and placebo by Apotek Produktion Laboratorier AB APL Stockholm Sweden
Study design
Capsules taken orally with standardised doses of Capsicum oleoresin corresponding to 04 mg pure capsaicin from chili extract in each capsule in comparison to matched capsules with placebo sorbitol and colorant all capsules looking the same Four weeks of active treatment is compared to four weeks of placebo In between there is a wash out period of two weeks
The time frame is 24 hours 10 weeks During the first 24 hours the patients carry a cough recorder Leicester Cough Monitor - LCM and then start with 4 weeks of active treatment or placebo This is followed by 2 weeks of wash out and then the patients start with another 4 weeks of active treatment or placebo After this the study ends
Collaboration
Professor Alyn Morice MD PhD chief physician at Hull York Medical School University of Hull UK Professor Surinder Birring MD Senior Lecturer specialist in respiratory medicine Imperial College London UK Associate professor Alastair RossPhD Chalmers University of Technology Gothenburg Sweden
Study center and number of subjects planned
All clinical trials take place at the asthma and allergy clinic Sahlgrenska University Hospital Gothenburg Sweden from where 60 patients with chronic idiopathic cough CIC are recruited
Detailed Description:
This is a phase 2 clinical study in humans for therapeutic use of Capsicum oleoresin - capsaicin in chronic idiopathic cough CIC The study has a randomised double-blind and cross-over design During 4 weeks the participants take either active capsules Capsicum oleoresin or matching placebo capsules This period follows by 2 weeks of wash out and then another 4 weeks with active capsules or placebo
The IMP
The soft gel capsules used in the study are easily digested in the stomach and contain standardised doses of Capsicum oleoresin with the main component capsaicin 8-methyl-N-vanillyl-6-nonenamide from chili extract The placebo capsules are filled with sorbitol and colorant
Capsicum oleoresin and capsaicin is found naturally in a variety of chili fruits and the use of chili peppers in food varies greatly between different parts of the world The maximum daily intake of capsaicin from Capsicum oleoresin in the current study could be exceeded many times in countries such as Mexico and Thailand but it does not reach that level in most Western countries
In concordance with the known effect of topical capsaicin for neuropathic pain the expected effect of orally taken capsaicin is desensitisation Capsaicin desensitise the cough-sensitive transient receptor potential vanilloids one receptors TRPV1 and other TRP receptors followed by decreased cough reflex sensitivity and coughing in patients with CIC Capsaicin causes depletion of neuropeptides leading to exhausting of the receptor with ameliorated symptoms in the patients
In the application to the Swedish Medical Products Agency the capsules the active product ingredient API and the formulation are extensively described in the investigational medical product dossier IMPD
In summary
Supplier of raw material for the Capsicum oleoresin productIMP RANSOM Ltd London UK
The IMP is developed by RISE Sodertalje Sweden
Filling of capsules with Capsicum oleoresin and placebo Catalent Pharma Solutions St Petersburg Florida USA
Packing in bottles of capsules with IMP and placebo by Apotek Produktion Laboratorier AB APL Stockholm Sweden
Labelling Tamro Gothenburg Sweden an independent pharmaceuticals logistics service provider Each package will be labelled with study code randomisation number dosage form quantity dosage instructions name of investigator expiry date storage instruction
Storage in room temperature at the allergy clinic at Sahlgrenska University Hospital and at Tamro Gothenburg Sweden
Independent monitoring of the clinical study by qualified staff from Gothia Forum Sahlgrenska University Hospital Gothenburg Sweden
A safety report will be completed after the study end and sent to the relevant Competent Authority and the Ethics Committee
Study population
60 patients with CIC from the outpatient clinic at the asthma and allergy clinic Sahlgrenska University Hospital Gothenburg Sweden are included
Study design
The total study time for each patient is 24 hours 10 weeks and includes 6 visits At the first visit tests and questionnaires are assessed as described below outcome measures and the patients collect a cough monitor to record cough during 24 hours After returning the cough monitor the patients start with 4 weeks of active treatment or placebo This is followed by 2 weeks of wash out and then the patients start with another 4 weeks of active treatment or placebo After this the study ends Estimated time for each visit is 2 hours
During the first 2 weeks of each arm active or placebo of 4 weeks the patients take one capsule morning and evening During the following 2 weeks they take 2 capsules morning and evening
At each visit
The patients answer the questionnaires LCQ-S the HARQ-S and also score their cough severity during the past two weeks using a VAS-scale 0-100 mm
A cough sensitivity test is performed with a standardised capsaicin inhalation test assessing concentration of inhaled capsaicin causing 2 coughs C2 5 coughs C5 and 10 coughs C10
Lung function measured with spirometry and impulse oscillometry IOS
Pain sensitivity is assessed with pressure algometry at 4 pre-defined points
Levels of capsaicindihydrocapsaicin in sera are measured
At 4 opportunities
1 24 hours before any treatment 2 at the end of 4 weeks of active treatment or placebo respectively 3 at the end of 2 weeks wash out 4 at the end of 4 weeks of active treatment or placebo respectively
Fraction of exhaled nitric oxide FeNO is measured
Particles in exhaled air PExA are measured
The cough frequency during 24h is assessed using the LCM cough monitor
Statistical Analysis Plan SAP
All detailed statistical analyses will be specified in a separate study SAP that is developed and finalized
Sample size calculation
The sample size calculations for the primary variables LogC2 and LogC5 given the results obtained in an earlier pilot study are described in the following
In order to reach the power of 080 with mean difference in LogC2 between the Active-Placebo treatment of 0590 and standard deviation for the difference of 0885 with two-tailed Fishers non-parametric permutation test alpha 0025 24 patients are needed to be included in the study
In order to reach the power of 080 with mean difference between in LogC5 the Active-Placebo treatment of 0425 and standard deviation for mean difference of 0911 with two-tailed Fishers non-parametric permutation test alpha 0025 47 patients are needed to be included in the study
In order to adjust for drop-outs 60 patients will be included in this study Statistical methodology The main analyses will be on the ITT population and complementary analyses will be performed on the PP population In this cross over study all main analysis will be adjusted for period effects
For non-normal continuous variables ordered categorical variables and dichotomous variables the following non-parametric analyses of cross-over design for test between Capsaicin and Placebo will be used adjusting for period effects The difference between period 2 and period 1 values will be calculated and this difference will be tested between the treatment sequences For continuous variables this difference will be continuous and analysed with Fishers non-parametric permutation test For ordered categorical variables and dichotomous variables this difference will be an ordered categorical variable and analysed with Mantel-Haenszel chi-square test
The test regarding the effect of Capsaicin vs Placebo on normally distributed efficacy variables will be performed by using generalised linear models for cross-over design with sequence period and treatment group as fixed effects SAS code for the analysis of normally distributed data
PROC MIXED CLASS SEQ PATIENT PERIOD TRT MODEL YSEQ PERIOD TRT REPEATED TYPECS SUBPATIENTSEQ RUN The most appropriate variance-covariance structure will be used that might by other than Compound Symmetry CS specified in the code above
For continuous variables the distribution of the variables will be given at baseline visit 2 and visit 4 and change from baseline to visit 2 and 4 by Capsaicin treatment and placebo
95 confidence interval for the mean difference between Capsaicin and placebo treatment adjusted for period effect will be given The results will be presented in both tables and figures
All categorical variables will be described by number and percentage and all continuous variables by mean standard deviation median minimum and maximum
The carry-over effect for the primary variables will be analysed by testing the mean of period 1 and period 2 values between the two treatment sequences
For test of change within groups Sign test will be used for ordered categorical variables and dichotomous variables and Fishers non-parametric permutation test for paired observations for continuous variables
The missing values will be imputed by using stochastic imputation seed99786 using all available baseline and relevant follow-up data for all efficacy analyses
The main analyses will be performed on stochastic imputed values and sensitivity analyses on complete case and on last observation carried forward for primary efficacy variable Baseline and demographic variables will be described for the total sample
The study will be considered positive in case any of the two primary variables reach the significance level below 0025 For all other tests the significance level of 005 will be applied All significance tests will be two-tailed and all analyses will be performed by using SAS v94 or later SAS Institute Inc Cary NC USA
The IMP
The soft gel capsules used in the study are easily digested in the stomach and contain standardised doses of Capsicum oleoresin with the main component capsaicin 8-methyl-N-vanillyl-6-nonenamide from chili extract The placebo capsules are filled with sorbitol and colorant
Capsicum oleoresin and capsaicin is found naturally in a variety of chili fruits and the use of chili peppers in food varies greatly between different parts of the world The maximum daily intake of capsaicin from Capsicum oleoresin in the current study could be exceeded many times in countries such as Mexico and Thailand but it does not reach that level in most Western countries
In concordance with the known effect of topical capsaicin for neuropathic pain the expected effect of orally taken capsaicin is desensitisation Capsaicin desensitise the cough-sensitive transient receptor potential vanilloids one receptors TRPV1 and other TRP receptors followed by decreased cough reflex sensitivity and coughing in patients with CIC Capsaicin causes depletion of neuropeptides leading to exhausting of the receptor with ameliorated symptoms in the patients
In the application to the Swedish Medical Products Agency the capsules the active product ingredient API and the formulation are extensively described in the investigational medical product dossier IMPD
In summary
Supplier of raw material for the Capsicum oleoresin productIMP RANSOM Ltd London UK
The IMP is developed by RISE Sodertalje Sweden
Filling of capsules with Capsicum oleoresin and placebo Catalent Pharma Solutions St Petersburg Florida USA
Packing in bottles of capsules with IMP and placebo by Apotek Produktion Laboratorier AB APL Stockholm Sweden
Labelling Tamro Gothenburg Sweden an independent pharmaceuticals logistics service provider Each package will be labelled with study code randomisation number dosage form quantity dosage instructions name of investigator expiry date storage instruction
Storage in room temperature at the allergy clinic at Sahlgrenska University Hospital and at Tamro Gothenburg Sweden
Independent monitoring of the clinical study by qualified staff from Gothia Forum Sahlgrenska University Hospital Gothenburg Sweden
A safety report will be completed after the study end and sent to the relevant Competent Authority and the Ethics Committee
Study population
60 patients with CIC from the outpatient clinic at the asthma and allergy clinic Sahlgrenska University Hospital Gothenburg Sweden are included
Study design
The total study time for each patient is 24 hours 10 weeks and includes 6 visits At the first visit tests and questionnaires are assessed as described below outcome measures and the patients collect a cough monitor to record cough during 24 hours After returning the cough monitor the patients start with 4 weeks of active treatment or placebo This is followed by 2 weeks of wash out and then the patients start with another 4 weeks of active treatment or placebo After this the study ends Estimated time for each visit is 2 hours
During the first 2 weeks of each arm active or placebo of 4 weeks the patients take one capsule morning and evening During the following 2 weeks they take 2 capsules morning and evening
At each visit
The patients answer the questionnaires LCQ-S the HARQ-S and also score their cough severity during the past two weeks using a VAS-scale 0-100 mm
A cough sensitivity test is performed with a standardised capsaicin inhalation test assessing concentration of inhaled capsaicin causing 2 coughs C2 5 coughs C5 and 10 coughs C10
Lung function measured with spirometry and impulse oscillometry IOS
Pain sensitivity is assessed with pressure algometry at 4 pre-defined points
Levels of capsaicindihydrocapsaicin in sera are measured
At 4 opportunities
1 24 hours before any treatment 2 at the end of 4 weeks of active treatment or placebo respectively 3 at the end of 2 weeks wash out 4 at the end of 4 weeks of active treatment or placebo respectively
Fraction of exhaled nitric oxide FeNO is measured
Particles in exhaled air PExA are measured
The cough frequency during 24h is assessed using the LCM cough monitor
Statistical Analysis Plan SAP
All detailed statistical analyses will be specified in a separate study SAP that is developed and finalized
Sample size calculation
The sample size calculations for the primary variables LogC2 and LogC5 given the results obtained in an earlier pilot study are described in the following
In order to reach the power of 080 with mean difference in LogC2 between the Active-Placebo treatment of 0590 and standard deviation for the difference of 0885 with two-tailed Fishers non-parametric permutation test alpha 0025 24 patients are needed to be included in the study
In order to reach the power of 080 with mean difference between in LogC5 the Active-Placebo treatment of 0425 and standard deviation for mean difference of 0911 with two-tailed Fishers non-parametric permutation test alpha 0025 47 patients are needed to be included in the study
In order to adjust for drop-outs 60 patients will be included in this study Statistical methodology The main analyses will be on the ITT population and complementary analyses will be performed on the PP population In this cross over study all main analysis will be adjusted for period effects
For non-normal continuous variables ordered categorical variables and dichotomous variables the following non-parametric analyses of cross-over design for test between Capsaicin and Placebo will be used adjusting for period effects The difference between period 2 and period 1 values will be calculated and this difference will be tested between the treatment sequences For continuous variables this difference will be continuous and analysed with Fishers non-parametric permutation test For ordered categorical variables and dichotomous variables this difference will be an ordered categorical variable and analysed with Mantel-Haenszel chi-square test
The test regarding the effect of Capsaicin vs Placebo on normally distributed efficacy variables will be performed by using generalised linear models for cross-over design with sequence period and treatment group as fixed effects SAS code for the analysis of normally distributed data
PROC MIXED CLASS SEQ PATIENT PERIOD TRT MODEL YSEQ PERIOD TRT REPEATED TYPECS SUBPATIENTSEQ RUN The most appropriate variance-covariance structure will be used that might by other than Compound Symmetry CS specified in the code above
For continuous variables the distribution of the variables will be given at baseline visit 2 and visit 4 and change from baseline to visit 2 and 4 by Capsaicin treatment and placebo
95 confidence interval for the mean difference between Capsaicin and placebo treatment adjusted for period effect will be given The results will be presented in both tables and figures
All categorical variables will be described by number and percentage and all continuous variables by mean standard deviation median minimum and maximum
The carry-over effect for the primary variables will be analysed by testing the mean of period 1 and period 2 values between the two treatment sequences
For test of change within groups Sign test will be used for ordered categorical variables and dichotomous variables and Fishers non-parametric permutation test for paired observations for continuous variables
The missing values will be imputed by using stochastic imputation seed99786 using all available baseline and relevant follow-up data for all efficacy analyses
The main analyses will be performed on stochastic imputed values and sensitivity analyses on complete case and on last observation carried forward for primary efficacy variable Baseline and demographic variables will be described for the total sample
The study will be considered positive in case any of the two primary variables reach the significance level below 0025 For all other tests the significance level of 005 will be applied All significance tests will be two-tailed and all analyses will be performed by using SAS v94 or later SAS Institute Inc Cary NC USA
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None