Ignite Creation Date:
2024-05-05 @ 5:13 PM
Last Modification Date:
2024-10-26 @ 9:29 AM
Study NCT ID:
NCT00418392
Status:
UNKNOWN
Last Update Posted:
2012-12-17
First Post:
2006-12-31
Brief Title:
Intrapleural Minocycline After Simple Aspiration for the Prevention of Primary Spontaneous Pneumothorax
Sponsor:
National Taiwan University Hospital
Organization:
National Taiwan University Hospital
Study Overview
Official Title:
Intrapleural Minocycline After Simple Aspiration for the Prevention of Primary Spontaneous Pneumothorax A Randomized Trial
Status:
UNKNOWN
Status Verified Date:
2012-11
Last Known Status:
RECRUITING
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:
The estimated recurrence rate of primary spontaneous pneumothorax is 23-50 after the first episode and the optimal treatment remains unknown In the recently published British Thoracic Society BTS guidelines simple aspiration is recommended as first line treatment for all primary pneumothoraces requiring intervention However the 1 year recurrence rate of this procedure was as high as 25-30 making it inappropriate as a standard of care
Intrapleural instillation of a chemical irritant chemical pleurodesis is an effective way to shorten the duration of air leaks and reduce the rates of recurrent spontaneous pneumothorax in surgical and non-surgical patients Many chemical irritants tetracycline talc and minocycline have been used to decrease the rate of recurrence in spontaneous pneumothorax Tetracycline which was the most commonly used irritant is no longer available Talc insufflation of the pleural cavity is safe and effective for primary spontaneous pneumothorax However it should be applied either with surgical or medical thoracoscopy Minocycline a derivative of tetracycline is as effective as tetracycline in inducing pleural fibrosis in rabbits In the previous studies we have shown that additional minocycline pleurodesis is a safe and convenient procedure to decrease the rates of ipsilateral recurrence after thoracoscopic treatment of primary spontaneous pneumothorax In the present study additional minocycline pleurodesis will be randomly administered in patients with first episode of primary spontaneous pneumothorax after simple aspiration to test if it can reduce the rate of recurrence
Intrapleural instillation of a chemical irritant chemical pleurodesis is an effective way to shorten the duration of air leaks and reduce the rates of recurrent spontaneous pneumothorax in surgical and non-surgical patients Many chemical irritants tetracycline talc and minocycline have been used to decrease the rate of recurrence in spontaneous pneumothorax Tetracycline which was the most commonly used irritant is no longer available Talc insufflation of the pleural cavity is safe and effective for primary spontaneous pneumothorax However it should be applied either with surgical or medical thoracoscopy Minocycline a derivative of tetracycline is as effective as tetracycline in inducing pleural fibrosis in rabbits In the previous studies we have shown that additional minocycline pleurodesis is a safe and convenient procedure to decrease the rates of ipsilateral recurrence after thoracoscopic treatment of primary spontaneous pneumothorax In the present study additional minocycline pleurodesis will be randomly administered in patients with first episode of primary spontaneous pneumothorax after simple aspiration to test if it can reduce the rate of recurrence
Detailed Description:
Background
Primary spontaneous pneumothorax most commonly occurs in young tall lean males 1 2 The estimated recurrence rate is 23-50 after the first episode 3 Optimal treatment of patients presenting with a first episode of primary spontaneous pneumothorax remains unknown In the recently published British Thoracic Society BTS guidelines 4 simple aspiration is recommended as first line treatment for all primary pneumothoraces requiring intervention However the 1 year recurrence rate of this procedure was as high as 26-30 5 making it inappropriate as a standard of care
Intrapleural instillation of a chemical irritant chemical pleurodesis is an effective way to shorten the duration of air leaks and reduce the rates of recurrent spontaneous pneumothorax in surgical and non-surgical patients 6 7 Light et al has shown that intrapleural tetracycline is effective in reducing the rate of ipsilateral recurrence for patients with spontaneous pneumothorax 7 However the recently published guidelines recommended that chemical pleurodesis should only be attempted if the patient is either unwilling or unable to undergo surgery because the rates of recurrence of pneumothoraces after surgical intervention either by thoracotomy or VATS with or without surgical pleurodesis is far less than after chemical pleurodesis 4 8 As a result chemical pleurodesis has rarely been used in primary spontaneous pneumothorax and the effect of additional chemical pleurodesis after simple aspiration in preventing recurrence of pneumothoraces has never been evaluated
Tetracycline which was the most commonly used irritant is no longer available Minocycline a derivative of tetracycline is as effective as tetracycline in inducing pleural fibrosis in rabbits 9 In the previous studies we have shown that additional minocycline pleurodesis is a safe and convenient procedure that associates with lower rates of prolonged air leaks and ipsilateral recurrence after thoracoscopic treatment of primary spontaneous pneumothorax 10 11
In the present study additional minocycline pleurodesis will be randomly administered in patients with first episode of primary spontaneous pneumothorax after simple aspiration to test if it can reduce the rate of recurrence This study will comply with the protocol GCP and applicable requirement of the Institutional Review Boards IRB of the NTUH and Far Eastern Memorial Hospital
Patients and Methods
Study design This study is a prospective randomized controlled trial to evaluate if additional minocycline pleurodesis after simple aspiration will be effective in preventing recurrence of primary spontaneous pneumothorax
Primary Objective The primary end point is to compare the rates of ipsilateral recurrence between the minocycline and observation groups after simple aspiration of the pneumothorax
Secondary Objectives
1 Safety profile of minocycline pleurodesis
2 Early results including immediate success rates one-week success rates complication rates rates of hospitalization duration of hospitalization and the degrees of chest pain
3 Long-term effects of minocycline pleurodesis including degrees of residual chest pain and pulmonary function test
Eligibility criteria
Patients must meet ALL of the inclusion criteria for the entry of this study
1 Male or female
2 Age between 15 and 40 years old
3 First episode of spontaneous pneumothorax
4 Symptomatic dyspnea or chest pain or the rim of air is 2cm on CXR requiring simple aspiration
5 Complete or nearly complete and persistent lung expansion immediately following manual aspiration
6 Organ Function Requirements
1 Adequate hematological function Hb 10 gdl ANC 15 x 109L platelets 100 x 109L
2 Normal renal and hepatic functions serum creatinine 1 x ULN SGPT and SGOT 25 x ULN alkaline phosphatase 5 x ULN
7 Written inform consent
The exclusion criteria are
1 With underlying pulmonary disease asthma chronic obstructive pulmonary disease bronchiectasis etc
2 With hemothorax or tension pneumothorax requiring chest tube insertion or operation
3 A history of previous pneumothorax
4 A history of previous ipsilateral thoracic operation
5 Allergy to tetracycline or minocycline
6 Pregnant or lactating patients
7 Other serious concomitant illness or medical conditions
1 Congestive heart failure or unstable angina pectoris
2 History of myocardial infarction within 1 year prior to the study entry
3 Uncontrolled hypertension or arrhythmia
4 History of significant neurologic or psychiatric disorders including dementia or seizure
5 Active infection requiring iv antibiotics Subjects who are unwilling to undergo randomization treatment or follow-up procedures will be removed from the study Subjects can also withdraw from the trial at any time point by their will
Randomization
Patients will be randomized at each center with separate random number lists into one of the two treatment groups using a computer-generated table numerically corresponding with the treatment group The trial treatment randomization codes will be maintained until the end of the study and will be broken by investigators who were blind to the randomization procedure
Manual aspiration Manual aspiration will be performed as follows patients were seated in semi-supine position After skin disinfection and field preparation a small-caliber pig-tail catheter 6-10 French will be introduced after local anesthesia with 2 lidocaine in the second intercostal space at the midclavicular line After the catheter enters the pleural space the catheter will be fixed to the skin using sterile adhesive tape and connected via a three-way valve to a 50-ml syringe Air will be manually aspirated until a resistance was felt and air was no longer aspirated Thereafter a chest X-ray will be performed with the catheter in place
Minocycline pleurodesis In the minocycline group 30 mL of 1 lidocaine hydrochloride 300mg followed by a solution of 30 mL of normal saline containing 300 mg of minocycline Mirosin Taiwan Panbiotic Laboratories Kaohsiung Taiwan will be instilled into the pleural cavity through the pig-tail catheter or chest tube In the observation group nothing will be administered Administration of other chemical pleurodesis agents is prohibited during the study period Intramuscular meperidine hydrochloride Demerol 50mgampule will be administered every 4 to 6 hours according to the patients request if the pain became intolerable could not be relieved by oral analgesics and visual analogue scale was greater than 7 Chest radiography will be performed immediate postoperatively or the next morning VAS will be evaluated immediately 6 hours later after minocycline administration
Study Endpoints
The primary end point will be rate of ipsilateral recurrence after the procedure Secondary end points include safety early results and long-term effects of minocycline pleurodesis
Immediate success rates defined as complete or nearly complete and persistent lung expansion immediately following manual aspiration Immediate success for chest tube drainage is defined as complete lung expansion absence of air leakage and chest drain removal within 24 hours after catheter placement
One weeks success rates are defined as complete and persistent lung expansion at one weeks after the first attempt of aspiration or tube insertion
One-year success absence of recurrent pneumothorax during a 1-year follow-up period
Safety assessments
Safety assessments will consist of monitoring and recording all toxicity adverse events safety laboratory examination vital signs physical examination The adverse events which are not reported will be graded as mild moderate severe and life-threatening Adverse event will be tabulated and the incidence rates will be calculated
Sample size estimation
A sample size of 300 patients 150 in each group will be needed to reach clinical significance at the 05 level with a power of 09 if minocycline reduced the recurrence rate from 30 to 15 and the drop out rate is 10 A planned interim analysis will be conducted after enrollment of 150 patients with at least 12 months of follow-up Statistical analysis will be performed on an intent-to-treat basis rather than in an actual treatment basis
Follow-up After discharge from the hospital patients will be followed at the outpatient clinics at 1 week 1 month 3 months and 6 months where chest radiography will be performed Follow-ups will then be conducted every 6 months by a registered nurse who is blinded to the group allocation by telephone conversation according to a standard questionnaire that included when the patient returns to work or school whether a recurrence occurred when it happened and how it is treated Residual postoperative chest pain will be evaluated on a pain score from 0 to 5 where 0 is pain free 1 is occasional discomfort 2 is occasional use of analgesics 3 is using nonopiate analgesics 4 is regular pain using opiates 5 is severe and intractable pain All patients will be followed for at least 12 months Patients can come back to the clinic or visit emergency department whenever they have chest pain dyspnea or any signs related to the recurrence of pneumothorax
Pulmonary function analysis Pulmonary function tests will be performed for patients able to attend a hospital outpatient appointment at least 6 months after surgery Forced vital capacity FVC and forced expiratory volume in 1 second FEV10 will be measured using a spirometer of Microspiro HI-298 Chest Corporation Tokyo Japan with the patients seated A minimum of three acceptable forced expiratory maneuvers will be performed and the best one will be selected for analysis
Data collection and statistical analysis The clinical data duration of chest drainage length of hospital stay complications requested doses of meperidine and data of VAS will be collected Continuous variables such as age or weight will be expressed as the mean standard deviation and analyzed by the two sample t-test Categorical variables such as gender or smoking status will be presented by frequency and analyzed by the Fishers exact test Intensity of postoperative pain measured by VAS from 0 to 10 were summarized by mean 95 percent confidence interval and compared by Wilcoxon rank-sum test Scores of residual chest pain will be analyzed by the Wilcoxon rank-sum test Freedom from recurrence will be analyzed by the Kaplan-Meier method and comparisons will be made by the log-rank test
Reference
1 Gobbel WG Jr Rhea WG Nelson IA Daniel RA Jr Spontaneous pneumothorax J Thorac Cardiovasc Surg 196346331-345
2 Lichter J Gwynne JF Spontaneous pneumothorax in young subjects Thorax 197125409-417
3 Light RW Management of spontaneous pneumothorax Am Rev Respir Dis 1993148245-258
4 Henry M Arnold T Harvey J Pleural Diseases Group Standards of Care Committee British Thoracic Society BTS guidelines for the management of spontaneous pneumothorax Thorax 200358Supple 239-52
5 Noppen M AJRCCM 2003
6 Hatta T Tsubota N Yoshimura M Yanagawa M Intrapleural minocycline for postoperative air leakage and control of malignant pleural effusion Kyobu Geka 199043283-286
7 Light RW OHara VS Moritz TE McElhinney AJ Butz R Haakenson CM Read RC Sassoon CS Eastridge CE Berger R et al Intrapleural tetracycline for the prevention of recurrent spontaneous pneumothorax JAMA 19902642224-2230
8 Baumann MH Strange C Heffner JE Light R Kirby TJ Klein J Luketich JD Panacek EA Sahn SA AACP Pneumothorax Consensus Group Management of spontaneous pneumothorax an American College of Chest Physicians Delphi consensus statement Chest 2001119590-602
9 Light RW Wang NS Sassoon CSH Gruer SE Vargas FS Comparison of the effectiveness of tetracycline and minocycline as pleural sclerosing agents in rabbits Chest 1994106577-582
10 Chen JS Hsu HH Kuo SW Tsai PR Chen RJ Lee JM Lee YC Effects of additional minocycline pleurodesis after thoracoscopic procedures for primary spontaneous pneumothorax Chest 200412550-55
11 Chen JS Hsu HH Chen RJ Kuo SW Huang PM Tsai PR Lee JM Lee YC Additional minocycline pleurodesis after thoracoscopic surgery for primary spontaneous pneumothorax Am J Respir Crit Care Med 2006173 548-554
Primary spontaneous pneumothorax most commonly occurs in young tall lean males 1 2 The estimated recurrence rate is 23-50 after the first episode 3 Optimal treatment of patients presenting with a first episode of primary spontaneous pneumothorax remains unknown In the recently published British Thoracic Society BTS guidelines 4 simple aspiration is recommended as first line treatment for all primary pneumothoraces requiring intervention However the 1 year recurrence rate of this procedure was as high as 26-30 5 making it inappropriate as a standard of care
Intrapleural instillation of a chemical irritant chemical pleurodesis is an effective way to shorten the duration of air leaks and reduce the rates of recurrent spontaneous pneumothorax in surgical and non-surgical patients 6 7 Light et al has shown that intrapleural tetracycline is effective in reducing the rate of ipsilateral recurrence for patients with spontaneous pneumothorax 7 However the recently published guidelines recommended that chemical pleurodesis should only be attempted if the patient is either unwilling or unable to undergo surgery because the rates of recurrence of pneumothoraces after surgical intervention either by thoracotomy or VATS with or without surgical pleurodesis is far less than after chemical pleurodesis 4 8 As a result chemical pleurodesis has rarely been used in primary spontaneous pneumothorax and the effect of additional chemical pleurodesis after simple aspiration in preventing recurrence of pneumothoraces has never been evaluated
Tetracycline which was the most commonly used irritant is no longer available Minocycline a derivative of tetracycline is as effective as tetracycline in inducing pleural fibrosis in rabbits 9 In the previous studies we have shown that additional minocycline pleurodesis is a safe and convenient procedure that associates with lower rates of prolonged air leaks and ipsilateral recurrence after thoracoscopic treatment of primary spontaneous pneumothorax 10 11
In the present study additional minocycline pleurodesis will be randomly administered in patients with first episode of primary spontaneous pneumothorax after simple aspiration to test if it can reduce the rate of recurrence This study will comply with the protocol GCP and applicable requirement of the Institutional Review Boards IRB of the NTUH and Far Eastern Memorial Hospital
Patients and Methods
Study design This study is a prospective randomized controlled trial to evaluate if additional minocycline pleurodesis after simple aspiration will be effective in preventing recurrence of primary spontaneous pneumothorax
Primary Objective The primary end point is to compare the rates of ipsilateral recurrence between the minocycline and observation groups after simple aspiration of the pneumothorax
Secondary Objectives
1 Safety profile of minocycline pleurodesis
2 Early results including immediate success rates one-week success rates complication rates rates of hospitalization duration of hospitalization and the degrees of chest pain
3 Long-term effects of minocycline pleurodesis including degrees of residual chest pain and pulmonary function test
Eligibility criteria
Patients must meet ALL of the inclusion criteria for the entry of this study
1 Male or female
2 Age between 15 and 40 years old
3 First episode of spontaneous pneumothorax
4 Symptomatic dyspnea or chest pain or the rim of air is 2cm on CXR requiring simple aspiration
5 Complete or nearly complete and persistent lung expansion immediately following manual aspiration
6 Organ Function Requirements
1 Adequate hematological function Hb 10 gdl ANC 15 x 109L platelets 100 x 109L
2 Normal renal and hepatic functions serum creatinine 1 x ULN SGPT and SGOT 25 x ULN alkaline phosphatase 5 x ULN
7 Written inform consent
The exclusion criteria are
1 With underlying pulmonary disease asthma chronic obstructive pulmonary disease bronchiectasis etc
2 With hemothorax or tension pneumothorax requiring chest tube insertion or operation
3 A history of previous pneumothorax
4 A history of previous ipsilateral thoracic operation
5 Allergy to tetracycline or minocycline
6 Pregnant or lactating patients
7 Other serious concomitant illness or medical conditions
1 Congestive heart failure or unstable angina pectoris
2 History of myocardial infarction within 1 year prior to the study entry
3 Uncontrolled hypertension or arrhythmia
4 History of significant neurologic or psychiatric disorders including dementia or seizure
5 Active infection requiring iv antibiotics Subjects who are unwilling to undergo randomization treatment or follow-up procedures will be removed from the study Subjects can also withdraw from the trial at any time point by their will
Randomization
Patients will be randomized at each center with separate random number lists into one of the two treatment groups using a computer-generated table numerically corresponding with the treatment group The trial treatment randomization codes will be maintained until the end of the study and will be broken by investigators who were blind to the randomization procedure
Manual aspiration Manual aspiration will be performed as follows patients were seated in semi-supine position After skin disinfection and field preparation a small-caliber pig-tail catheter 6-10 French will be introduced after local anesthesia with 2 lidocaine in the second intercostal space at the midclavicular line After the catheter enters the pleural space the catheter will be fixed to the skin using sterile adhesive tape and connected via a three-way valve to a 50-ml syringe Air will be manually aspirated until a resistance was felt and air was no longer aspirated Thereafter a chest X-ray will be performed with the catheter in place
Minocycline pleurodesis In the minocycline group 30 mL of 1 lidocaine hydrochloride 300mg followed by a solution of 30 mL of normal saline containing 300 mg of minocycline Mirosin Taiwan Panbiotic Laboratories Kaohsiung Taiwan will be instilled into the pleural cavity through the pig-tail catheter or chest tube In the observation group nothing will be administered Administration of other chemical pleurodesis agents is prohibited during the study period Intramuscular meperidine hydrochloride Demerol 50mgampule will be administered every 4 to 6 hours according to the patients request if the pain became intolerable could not be relieved by oral analgesics and visual analogue scale was greater than 7 Chest radiography will be performed immediate postoperatively or the next morning VAS will be evaluated immediately 6 hours later after minocycline administration
Study Endpoints
The primary end point will be rate of ipsilateral recurrence after the procedure Secondary end points include safety early results and long-term effects of minocycline pleurodesis
Immediate success rates defined as complete or nearly complete and persistent lung expansion immediately following manual aspiration Immediate success for chest tube drainage is defined as complete lung expansion absence of air leakage and chest drain removal within 24 hours after catheter placement
One weeks success rates are defined as complete and persistent lung expansion at one weeks after the first attempt of aspiration or tube insertion
One-year success absence of recurrent pneumothorax during a 1-year follow-up period
Safety assessments
Safety assessments will consist of monitoring and recording all toxicity adverse events safety laboratory examination vital signs physical examination The adverse events which are not reported will be graded as mild moderate severe and life-threatening Adverse event will be tabulated and the incidence rates will be calculated
Sample size estimation
A sample size of 300 patients 150 in each group will be needed to reach clinical significance at the 05 level with a power of 09 if minocycline reduced the recurrence rate from 30 to 15 and the drop out rate is 10 A planned interim analysis will be conducted after enrollment of 150 patients with at least 12 months of follow-up Statistical analysis will be performed on an intent-to-treat basis rather than in an actual treatment basis
Follow-up After discharge from the hospital patients will be followed at the outpatient clinics at 1 week 1 month 3 months and 6 months where chest radiography will be performed Follow-ups will then be conducted every 6 months by a registered nurse who is blinded to the group allocation by telephone conversation according to a standard questionnaire that included when the patient returns to work or school whether a recurrence occurred when it happened and how it is treated Residual postoperative chest pain will be evaluated on a pain score from 0 to 5 where 0 is pain free 1 is occasional discomfort 2 is occasional use of analgesics 3 is using nonopiate analgesics 4 is regular pain using opiates 5 is severe and intractable pain All patients will be followed for at least 12 months Patients can come back to the clinic or visit emergency department whenever they have chest pain dyspnea or any signs related to the recurrence of pneumothorax
Pulmonary function analysis Pulmonary function tests will be performed for patients able to attend a hospital outpatient appointment at least 6 months after surgery Forced vital capacity FVC and forced expiratory volume in 1 second FEV10 will be measured using a spirometer of Microspiro HI-298 Chest Corporation Tokyo Japan with the patients seated A minimum of three acceptable forced expiratory maneuvers will be performed and the best one will be selected for analysis
Data collection and statistical analysis The clinical data duration of chest drainage length of hospital stay complications requested doses of meperidine and data of VAS will be collected Continuous variables such as age or weight will be expressed as the mean standard deviation and analyzed by the two sample t-test Categorical variables such as gender or smoking status will be presented by frequency and analyzed by the Fishers exact test Intensity of postoperative pain measured by VAS from 0 to 10 were summarized by mean 95 percent confidence interval and compared by Wilcoxon rank-sum test Scores of residual chest pain will be analyzed by the Wilcoxon rank-sum test Freedom from recurrence will be analyzed by the Kaplan-Meier method and comparisons will be made by the log-rank test
Reference
1 Gobbel WG Jr Rhea WG Nelson IA Daniel RA Jr Spontaneous pneumothorax J Thorac Cardiovasc Surg 196346331-345
2 Lichter J Gwynne JF Spontaneous pneumothorax in young subjects Thorax 197125409-417
3 Light RW Management of spontaneous pneumothorax Am Rev Respir Dis 1993148245-258
4 Henry M Arnold T Harvey J Pleural Diseases Group Standards of Care Committee British Thoracic Society BTS guidelines for the management of spontaneous pneumothorax Thorax 200358Supple 239-52
5 Noppen M AJRCCM 2003
6 Hatta T Tsubota N Yoshimura M Yanagawa M Intrapleural minocycline for postoperative air leakage and control of malignant pleural effusion Kyobu Geka 199043283-286
7 Light RW OHara VS Moritz TE McElhinney AJ Butz R Haakenson CM Read RC Sassoon CS Eastridge CE Berger R et al Intrapleural tetracycline for the prevention of recurrent spontaneous pneumothorax JAMA 19902642224-2230
8 Baumann MH Strange C Heffner JE Light R Kirby TJ Klein J Luketich JD Panacek EA Sahn SA AACP Pneumothorax Consensus Group Management of spontaneous pneumothorax an American College of Chest Physicians Delphi consensus statement Chest 2001119590-602
9 Light RW Wang NS Sassoon CSH Gruer SE Vargas FS Comparison of the effectiveness of tetracycline and minocycline as pleural sclerosing agents in rabbits Chest 1994106577-582
10 Chen JS Hsu HH Kuo SW Tsai PR Chen RJ Lee JM Lee YC Effects of additional minocycline pleurodesis after thoracoscopic procedures for primary spontaneous pneumothorax Chest 200412550-55
11 Chen JS Hsu HH Chen RJ Kuo SW Huang PM Tsai PR Lee JM Lee YC Additional minocycline pleurodesis after thoracoscopic surgery for primary spontaneous pneumothorax Am J Respir Crit Care Med 2006173 548-554
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| DOH95-TD-I-111-012 | None | None | None |