Iloprost in Preventing Lung Cancer in Patients at High Risk for This Disease

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT00084409
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 152
• Locations: 6
• Arms: 2
• Duration (Months): 86
• Patients Per Site: 25.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

RATIONALE: Chemoprevention therapy is the use of certain drugs to try to prevent the development or recurrence of cancer. Iloprost may be effective in preventing lung cancer.

PURPOSE: This randomized phase II trial is studying how well iloprost works in preventing lung cancer in patients who are at high risk for this disease.

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer; Precancerous Condition	Drug: iloprost; Other: placebo	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Compare the reversal of premalignant histological changes in the bronchial epithelium of patients at high risk for lung cancer (defined by > 20 pack years of smoking and sputum atypia) treated with iloprost vs placebo.

• Determine whether this drug modulates Ki-67 proliferation index (Antigen Ki-67) in these patients.

• Determine whether this drug affects prostaglandin metabolism in these patients.

• Determine the toxicity profile of this drug in these patients.

Secondary

• Determine whether this drug modulates a panel of biomarkers, including MCM-2(Minichromosome maintenance protein: forms DNA helicase), EGFR (Epidermal growth factor receptor: cell surface receptor for the epidermal growth factor family of proteins. Mutations in EGFR expression or activity can result in cancer.) , HER2/neu (Human epidermal growth factor receptor 2 HER2 is a member of the EGFR family), RARβ (Retinoic Acic Receptor Beta is a nuclear transcription regulator and a member of the thyroid-steroid hormone receptor superfamily), p53, FHIT (Fragile histidine triad protein is an enzyme involved in purine metabolism and had been demonstrated to be a tumor suppressor), apoptotic index, and microvessel density, in these patients.

• Determine the genes whose expression is altered by this drug in these patients.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to smoking status (current vs former) and participating center. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral iloprost twice daily.

• Arm II: Patients receive oral placebo twice daily. In both arms, treatment continues for 6 months in the absence of unacceptable toxicity.

Patients are followed at 1 month and then annually thereafter.

PROJECTED ACCRUAL: A total of 152 patients (76 [38 current smokers and 38 former smokers] per treatment arm) will be accrued for this study within 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 152 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• Official Title: A Randomized Phase II Chemoprevention Study of Iloprost Versus Placebo in Patients at High Risk for Lung Cancer
• Study Start Date: Nov 1, 2001
• Actual Primary Completion Date: Jan 1, 2009
• Actual Study Completion Date: Jan 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Patients receive oral iloprost twice daily for 6 months in the absence of unacceptable toxicity.	Drug: iloprost; Given orally
Placebo Comparator: Arm II Patients receive oral placebo twice daily for 6 months in the absence of unacceptable toxicity.	Other: placebo; Given orally

Outcome Measures

Primary Outcome Measures

1. Change in Average (Follow-up - Baseline) From All Biopsies [Nine years]

   This outcome measure is created for each subject as follows: From all biopsies scored at the baseline bronchoscopy, the mean WHO score is calculated. From all biopsies scored at the follow-up bronchoscopy, the mean WHO score is calculated.Histology on bronchial biopsies pre-treatment and post-treatment will be compared. All biopsies will be graded according to the WHO classification for bronchial epithelium for this outcome, and all the following outcomes. WHO Classification Grade Normal 1.0 Reserve Cell Hyperplasia 2.0 Metaplasia 3.0 Mild Dysplasia 4.0 Moderate Dysplasia 5.0 Severe Dysplasia 6.0 Carcinoma in Situ 7.0 Carcinoma 8.0 The difference (follow-up mean - baseline mean) is used as the outcome measure for each subject.

Secondary Outcome Measures

1. Change in Dysplasia Index (Follow-up - Baseline) Using All Biopsies [9 Years]

   This outcome measure is created for each subject as follows: From all biopsies scored at the baseline bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated (this is the definition of Dysplasia Index (DI)). From all biopsies scored at the follow-up bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated. The difference (follow-up DI - baseline DI) is used as the outcome measure for each subject.

2. Change in Average (Follow-up - Baseline) Using Reference Sites [9 Years]

   This outcome measure is created for each subject as follows: The biopsies used in this analysis are those from the following 6 anatomical sites pre-specified in the protocol to be biopsied: RUL (Right upper lobe: the superior region of the right lung), RML (Right middle lobe: an anatomic portion of the right lung), RB6 (The carina in the right lower lobe at the entrance to the superior segment), LUL (Left upper lobe: the superior portion of the lung), LUDB (Left upper division bronchus: the carina between the lingular orifice and the left upper lobe), and LB6 (The carina in the left lower lobe at the entrance to the superior segment). From these biopsies scored at the baseline bronchoscopy, the mean WHO score is calculated. From these biopsies scored at the follow-up bronchoscopy, the mean WHO score is calculated. The difference (follow-up mean - baseline mean) is used as the outcome measure for each subject.

3. Change in Maximum (Follow-up - Baseline) Using Reference Sites [9 Years]

   This outcome measure is created for each subject as follows: The biopsies used in this analysis are those from the following 6 anatomical sites pre-specified in the protocol to be biopsied: RUL, RML, RB6, LUL, LUDB, and LB6. From these biopsies scored at the baseline bronchoscopy, the maximum WHO score is used. From these biopsies scored at the follow-up bronchoscopy, the maximum WHO score is used. The difference (follow-up maximum - baseline maximum) is used as the outcome measure for each subject.

4. Change in Dysplasia Index (Follow-up - Baseline) Using Reference Sites [9 Years]

   This outcome measure is created for each subject as follows: The biopsies used in this analysis are those from the following 6 anatomical sites pre-specified in the protocol to be biopsied: RUL, RML, RB6, LUL, LUDB, and LB6. From these biopsies scored at the baseline bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated (this is the definition of Dysplasia Index (DI)). From these biopsies scored at the follow-up bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated. The difference (follow-up DI - baseline DI) is used as the outcome measure for each subject.

5. Change in Average (Follow-up - Baseline) Using Matched Sites [9 Years]

   This outcome measure is created for each subject as follows: The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies, thus creating "pairs" of biopsies. From these biopsies scored at the baseline bronchoscopy, the mean WHO score is calculated. From these biopsies scored at the follow-up bronchoscopy, the mean WHO score is calculated. The difference (follow-up mean - baseline mean) is used as the outcome measure for each subject.

6. Change in Maximum (Follow-up - Baseline) Using Matched Sites [9 Years]

   This outcome measure is created for each subject as follows: The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies. From these biopsies scored at the baseline bronchoscopy, the maximum WHO score is used. From these biopsies scored at the follow-up bronchoscopy, the maximum WHO score is used. The difference (follow-up maximum - baseline maximum) is used as the outcome measure for each subject.

7. Change in Dysplasia Index (Follow-up - Baseline) Using Matched Sites [9 Years]

   This outcome measure is created for each subject as follows: The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies. From these biopsies scored at the baseline bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated (this is the definition of Dysplasia Index (DI)). From these biopsies scored at the follow-up bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated. The difference (follow-up DI - baseline DI) is used as the outcome measure for each subject.

8. Change in Average (Follow-up - Baseline) Using Baseline Non-Normal Pairs [9 Years]

   This outcome measure is created for each subject as follows: The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies, thus creating "pairs" of biopsies. Any "pair" for which the baseline WHO score was 1 (i.e. normal tissue) was excluded from the analysis. From these biopsies scored at the baseline bronchoscopy, the mean WHO score is calculated. From these biopsies scored at the follow-up bronchoscopy, the mean WHO score is calculated. The difference (follow-up mean - baseline mean) is used as the outcome measure for each subject.

9. Change in Maximum (Follow-up - Baseline) Using Baseline Non-Normal Pairs [9 Years]

   This outcome measure is created for each subject as follows: The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies, thus creating "pairs" of biopsies. Any "pair" for which the baseline WHO score was 1 (i.e. normal tissue) was excluded from the analysis. From these biopsies scored at the baseline bronchoscopy, the maximum WHO score is used. From these biopsies scored at the follow-up bronchoscopy, the maximum WHO score is used. The difference (follow-up maximum - baseline maximum) is used as the outcome measure for each subject.

10. Change in Dysplasia Index (Follow-up - Baseline) Using Baseline Non-Normal Pairs [9 Years]

    This outcome measure is created for each subject as follows: The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies, thus creating "pairs" of biopsies. Any "pair" for which the baseline WHO score was 1 (i.e. normal tissue) was excluded from the analysis. From these biopsies scored at the baseline bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated (this is the definition of Dysplasia Index (DI)). From these biopsies scored at the follow-up bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated. The difference (follow-up DI - baseline DI) is used as the outcome measure for each subject.

Other Outcome Measures

1. To Determine if Iloprost Can Modulate K-67 Proliferation Index in Patients at High Risk to Develop Lung Cancer [nine years]

2. To Determine Whether Iloprost Affects Prostaglandin Metabolism by Examining 4 Markers, PGIS, COX-2, PPAR and PPAR. [Nine years]

   PGIS (Prostacyclin synthase: an enzyme in the eicosanoid pathway that catalyzes the conversion of prostaglandin H2 to prostaglandin I2 (prostacyclin). PPAR (Peroxisome proliferator-activated receptor: a group of nuclear receptor proteins that act as transcription factors regulating gene expression),

3. To Determine the Toxicity Profile of Iloprost in Patients at High Risk to Develop Lung Cancer. [Nine Years]

4. Define the Genes Whose Expression is Altered by Iloprost Treatment by Gene Expression Arrays and Quantitative PCR. [Nine Years]

5. To Determine Whether Iloprost Can Modulate a Panel of Biomarkes. [9 years]

   To determine if Iloprost can modulate a panel of biomarkers including MCM-2, EGFR, Her-2/neu, RARβ, p53, FHIT, apoptotic index, and microvessel density.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Current or former smoker with ≥ 20 pack-year history of smoking with no tobacco use within the past 6 months

• Mild atypia or worse on sputum cytology, or

• Bronchial biopsy with mild or worse dysplasia within the past 12 months

• Age 18 and over

• SWOG (Southwest Oncology Group)0-2

• Life expectancy at least 6 months

• Granulocyte count > 1,500/mm^3

• Platelet count > 100,000/mm^3

• Alkaline phosphatase ≤ 2.5 times upper limit of normal (ULN)

• Transaminases ≤ 2.5 times ULN

• Bilirubin ≤ 2.0 mg/dL

• Albumin ≥ 2.5 g/dL

• Creatinine ≤ 1.5 mg/dL

• Well-controlled atrial fibrillation OR rare (< 2 minutes) premature ventricular contractions allowed

• Negative pregnancy test

• Fertile patients must use effective contraception

• Able and willing to undergo bronchoscopy

Exclusion Criteria

• Clinically apparent bleeding diathesis

• Ventricular tachycardia

• Multifocal premature ventricular contractions or supraventricular tachycardias with rapid ventricular response

• Pneumonia or acute bronchitis within the past 2 weeks

• Hypoxemia (< 90% saturation with supplemental oxygen)

• Pregnant or nursing

• Malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix

• Serious medical condition that would preclude bronchoscopy or study participation

• Clinically active coronary artery disease

• Myocardial infarction within the past 6 weeks

• Chest pain

• Congestive heart failure

• Cardiac dysrhythmia that is potentially life-threatening

Exclusion for PRIOR CONCURRENT THERAPY:

• Biologic therapy (Not specified)

• More than 5 years since prior chemotherapy

• More than 6 weeks since prior inhaled steroids

• More than 5 years since prior thoracic radiotherapy

• Surgery (Not specified)

• No prior prostacyclin

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Cancer Center at UC Health Sciences Center	Aurora	Colorado	United States	80045
2	Veterans Affairs Medical Center - Denver	Denver	Colorado	United States	80220
3	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21231-2410
4	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
5	UPMC Cancer Centers	Pittsburgh	Pennsylvania	United States	15232
6	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232-6838

Sponsors and Collaborators

• University of Colorado, Denver
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Robert Keith, MD, University of Colorado, Denver

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• ClinicalTrials.Gov

Publications

None provided.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT00084409
• Other Study ID Numbers: 01-279.cc; National Cancer Institute; 01-279
• First Posted: Jun 11, 2004
• Last Update Posted: May 14, 2020
• Last Verified: May 1, 2020

• Keywords provided by University of Colorado, Denver: non-small cell lung cancer; squamous lung dysplasia
• Additional relevant MeSH terms: Lung Neoplasms; Precancerous Conditions; Iloprost

Study Results

Participant Flow

Recruitment Details	The majority of patients were recruited between November 2002 and July 2008 from from pulmonary medicine clinics.
Pre-assignment Detail	Patients were excluded from randomization according to the exclusion criteria which included prior history of cancer, significant comorbid disease or inability to undergo 2 bronchoscopies, hypoxemia with the required use of supplemental oxygen, use of inhaled steroids within 6 weeks of enrollment, and carcinoma in situ or invasive cancer on bronch.

Arm/Group Title	Iloprost	Placebo
Arm/Group Description	Patients receive oral iloprost twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.	Patients receive oral placebo twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.
Period Title: Overall Study
STARTED	75	77
COMPLETED	60	65
NOT COMPLETED	15	12

Baseline Characteristics

Arm/Group Title	Iloprost	Placebo	Total
Arm/Group Description	Patients receive oral iloprost twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.	Patients receive oral placebo twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.	Total of all reporting groups
Overall Participants	75	77	152
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	57 76%	62 80.5%	119 78.3%
>=65 years	18 24%	15 19.5%	33 21.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58 (11)	58 (9)	58 (10)
Sex: Female, Male (Count of Participants)
Female	23 30.7%	19 24.7%	42 27.6%
Male	52 69.3%	58 75.3%	110 72.4%
Region of Enrollment (participants) [Number]
United States	75 100%	77 100%	152 100%

Outcome Measures

1. Primary Outcome

Title	Change in Average (Follow-up - Baseline) From All Biopsies
Description	This outcome measure is created for each subject as follows: From all biopsies scored at the baseline bronchoscopy, the mean WHO score is calculated. From all biopsies scored at the follow-up bronchoscopy, the mean WHO score is calculated.Histology on bronchial biopsies pre-treatment and post-treatment will be compared. All biopsies will be graded according to the WHO classification for bronchial epithelium for this outcome, and all the following outcomes. WHO Classification Grade Normal 1.0 Reserve Cell Hyperplasia 2.0 Metaplasia 3.0 Mild Dysplasia 4.0 Moderate Dysplasia 5.0 Severe Dysplasia 6.0 Carcinoma in Situ 7.0 Carcinoma 8.0 The difference (follow-up mean - baseline mean) is used as the outcome measure for each subject.
Time Frame	Nine years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Iloprost	Placebo
Arm/Group Description
Measure Participants	60	65
Mean (Standard Deviation) [WHO Units]	-0.23 (0.77)	-0.02 (0.79)

2. Secondary Outcome

Title	Change in Dysplasia Index (Follow-up - Baseline) Using All Biopsies
Description	This outcome measure is created for each subject as follows: From all biopsies scored at the baseline bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated (this is the definition of Dysplasia Index (DI)). From all biopsies scored at the follow-up bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated. The difference (follow-up DI - baseline DI) is used as the outcome measure for each subject.
Time Frame	9 Years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Iloprost	Placebo
Arm/Group Description	Patients receive oral iloprost twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.	Patients receive oral placebo twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.
Measure Participants	60	65
Mean (Standard Deviation) [Percentage points]	-7.70 (21.76)	-0.92 (25.23)

3. Secondary Outcome

Title	Change in Average (Follow-up - Baseline) Using Reference Sites
Description	This outcome measure is created for each subject as follows: The biopsies used in this analysis are those from the following 6 anatomical sites pre-specified in the protocol to be biopsied: RUL (Right upper lobe: the superior region of the right lung), RML (Right middle lobe: an anatomic portion of the right lung), RB6 (The carina in the right lower lobe at the entrance to the superior segment), LUL (Left upper lobe: the superior portion of the lung), LUDB (Left upper division bronchus: the carina between the lingular orifice and the left upper lobe), and LB6 (The carina in the left lower lobe at the entrance to the superior segment). From these biopsies scored at the baseline bronchoscopy, the mean WHO score is calculated. From these biopsies scored at the follow-up bronchoscopy, the mean WHO score is calculated. The difference (follow-up mean - baseline mean) is used as the outcome measure for each subject.
Time Frame	9 Years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Iloprost	Placebo
Arm/Group Description	Patients receive oral iloprost twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.	Patients receive oral placebo twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.
Measure Participants	60	65
Mean (Standard Deviation) [WHO Units]	-0.23 (0.82)	-0.01 (0.82)

4. Secondary Outcome

Title	Change in Maximum (Follow-up - Baseline) Using Reference Sites
Description	This outcome measure is created for each subject as follows: The biopsies used in this analysis are those from the following 6 anatomical sites pre-specified in the protocol to be biopsied: RUL, RML, RB6, LUL, LUDB, and LB6. From these biopsies scored at the baseline bronchoscopy, the maximum WHO score is used. From these biopsies scored at the follow-up bronchoscopy, the maximum WHO score is used. The difference (follow-up maximum - baseline maximum) is used as the outcome measure for each subject.
Time Frame	9 Years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Iloprost	Placebo
Arm/Group Description	Patients receive oral iloprost twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.	Patients receive oral placebo twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.
Measure Participants	60	65
Mean (Standard Deviation) [WHO Units]	-0.35 (1.58)	0.11 (1.30)

5. Secondary Outcome

Title	Change in Dysplasia Index (Follow-up - Baseline) Using Reference Sites
Description	This outcome measure is created for each subject as follows: The biopsies used in this analysis are those from the following 6 anatomical sites pre-specified in the protocol to be biopsied: RUL, RML, RB6, LUL, LUDB, and LB6. From these biopsies scored at the baseline bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated (this is the definition of Dysplasia Index (DI)). From these biopsies scored at the follow-up bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated. The difference (follow-up DI - baseline DI) is used as the outcome measure for each subject.
Time Frame	9 Years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Iloprost	Placebo
Arm/Group Description	Patients receive oral iloprost twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.	Patients receive oral placebo twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.
Measure Participants	60	65
Mean (Standard Deviation) [Percentage points]	-7.61 (23.43)	0.15 (26.41)

6. Secondary Outcome

Title	Change in Average (Follow-up - Baseline) Using Matched Sites
Description	This outcome measure is created for each subject as follows: The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies, thus creating "pairs" of biopsies. From these biopsies scored at the baseline bronchoscopy, the mean WHO score is calculated. From these biopsies scored at the follow-up bronchoscopy, the mean WHO score is calculated. The difference (follow-up mean - baseline mean) is used as the outcome measure for each subject.
Time Frame	9 Years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Iloprost	Placebo
Arm/Group Description	Patients receive oral iloprost twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.	Patients receive oral placebo twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.
Measure Participants	60	65
Mean (Standard Deviation) [WHO Units]	-0.24 (0.78)	-0.06 (0.86)

7. Secondary Outcome

Title	Change in Maximum (Follow-up - Baseline) Using Matched Sites
Description	This outcome measure is created for each subject as follows: The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies. From these biopsies scored at the baseline bronchoscopy, the maximum WHO score is used. From these biopsies scored at the follow-up bronchoscopy, the maximum WHO score is used. The difference (follow-up maximum - baseline maximum) is used as the outcome measure for each subject.
Time Frame	9 Years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Iloprost	Placebo
Arm/Group Description	Patients receive oral iloprost twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.	Patients receive oral placebo twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.
Measure Participants	60	65
Mean (Standard Deviation) [WHO Units]	-0.53 (1.46)	0.11 (1.26)

8. Secondary Outcome

Title	Change in Dysplasia Index (Follow-up - Baseline) Using Matched Sites
Description	This outcome measure is created for each subject as follows: The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies. From these biopsies scored at the baseline bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated (this is the definition of Dysplasia Index (DI)). From these biopsies scored at the follow-up bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated. The difference (follow-up DI - baseline DI) is used as the outcome measure for each subject.
Time Frame	9 Years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Iloprost	Placebo
Arm/Group Description	Patients receive oral iloprost twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.	Patients receive oral placebo twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.
Measure Participants	60	65
Mean (Standard Deviation) [Percentage points]	-7.97 (22.13)	-2.34 (25.49)

9. Secondary Outcome

Title	Change in Average (Follow-up - Baseline) Using Baseline Non-Normal Pairs
Description	This outcome measure is created for each subject as follows: The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies, thus creating "pairs" of biopsies. Any "pair" for which the baseline WHO score was 1 (i.e. normal tissue) was excluded from the analysis. From these biopsies scored at the baseline bronchoscopy, the mean WHO score is calculated. From these biopsies scored at the follow-up bronchoscopy, the mean WHO score is calculated. The difference (follow-up mean - baseline mean) is used as the outcome measure for each subject.
Time Frame	9 Years

Outcome Measure Data

Analysis Population Description

The analysis was restricted to the 107 subjects (52 in the iloprost group, 55 in the placebo group) with at least 1 non-normal biopsy at baseline, thereby excluding the 18 subjects (8 in the iloprost group and 10 in the placebo group) who had only normal biopsy tissue at baseline.

Arm/Group Title	Iloprost	Placebo
Arm/Group Description	Patients receive oral iloprost twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.	Patients receive oral placebo twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.
Measure Participants	52	55
Mean (Standard Deviation) [WHO Units]	-0.71 (0.93)	-0.38 (0.99)

10. Secondary Outcome

Title	Change in Maximum (Follow-up - Baseline) Using Baseline Non-Normal Pairs
Description	This outcome measure is created for each subject as follows: The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies, thus creating "pairs" of biopsies. Any "pair" for which the baseline WHO score was 1 (i.e. normal tissue) was excluded from the analysis. From these biopsies scored at the baseline bronchoscopy, the maximum WHO score is used. From these biopsies scored at the follow-up bronchoscopy, the maximum WHO score is used. The difference (follow-up maximum - baseline maximum) is used as the outcome measure for each subject.
Time Frame	9 Years

Outcome Measure Data

Analysis Population Description

The analysis was restricted to the 107 subjects (52 in the iloprost group, 55 in the placebo group) with at least 1 non-normal biopsy at baseline, thereby excluding the 18 subjects (8 in the iloprost group and 10 in the placebo group) who had only normal biopsy tissue at baseline.

Arm/Group Title	Iloprost	Placebo
Arm/Group Description	Patients receive oral iloprost twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.	Patients receive oral placebo twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.
Measure Participants	52	55
Mean (Standard Deviation) [WHO Units]	-0.81 (1.46)	-0.13 (1.26)

11. Secondary Outcome

Title	Change in Dysplasia Index (Follow-up - Baseline) Using Baseline Non-Normal Pairs
Description	This outcome measure is created for each subject as follows: The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies, thus creating "pairs" of biopsies. Any "pair" for which the baseline WHO score was 1 (i.e. normal tissue) was excluded from the analysis. From these biopsies scored at the baseline bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated (this is the definition of Dysplasia Index (DI)). From these biopsies scored at the follow-up bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated. The difference (follow-up DI - baseline DI) is used as the outcome measure for each subject.
Time Frame	9 Years

Outcome Measure Data

Analysis Population Description

The analysis was restricted to the 107 subjects (52 in the iloprost group, 55 in the placebo group) with at least 1 non-normal biopsy at baseline, thereby excluding the 18 subjects (8 in the iloprost group and 10 in the placebo group) who had only normal biopsy tissue at baseline.

Arm/Group Title	Iloprost	Placebo
Arm/Group Description	Patients receive oral iloprost twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.	Patients receive oral placebo twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.
Measure Participants	52	55
Mean (Standard Deviation) [Percentage points]	-14.32 (31.39)	-6.48 (34.26)

12. Other Pre-specified Outcome

Title	To Determine if Iloprost Can Modulate K-67 Proliferation Index in Patients at High Risk to Develop Lung Cancer
Time Frame	nine years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Other Pre-specified Outcome

Title	To Determine Whether Iloprost Affects Prostaglandin Metabolism by Examining 4 Markers, PGIS, COX-2, PPAR and PPAR.
Description	PGIS (Prostacyclin synthase: an enzyme in the eicosanoid pathway that catalyzes the conversion of prostaglandin H2 to prostaglandin I2 (prostacyclin). PPAR (Peroxisome proliferator-activated receptor: a group of nuclear receptor proteins that act as transcription factors regulating gene expression),
Time Frame	Nine years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Other Pre-specified Outcome

Title	To Determine the Toxicity Profile of Iloprost in Patients at High Risk to Develop Lung Cancer.
Time Frame	Nine Years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Other Pre-specified Outcome

Title	Define the Genes Whose Expression is Altered by Iloprost Treatment by Gene Expression Arrays and Quantitative PCR.
Time Frame	Nine Years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Other Pre-specified Outcome

Title	To Determine Whether Iloprost Can Modulate a Panel of Biomarkes.
Description	To determine if Iloprost can modulate a panel of biomarkers including MCM-2, EGFR, Her-2/neu, RARβ, p53, FHIT, apoptotic index, and microvessel density.
Time Frame	9 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	6 Years
Adverse Event Reporting Description	Adverse event collection was obtained at monthly visits on all randomized participants according to the NCI CommonToxicity criteria version 2.0, entered in case report forms, and in the NCI Oracle Clinical Database
Arm/Group Title	Iloprost		Placebo
Arm/Group Description	Patients receive oral iloprost twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.		Patients receive oral placebo twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.
All Cause Mortality
	Iloprost		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Iloprost		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/75 (4%)		6/77 (7.8%)
General disorders
Hospitalization	3/75 (4%)		4/77 (5.2%)
Death	0/75 (0%)		1/77 (1.3%)
Nervous system disorders
CVA - Stroke	0/75 (0%)		1/77 (1.3%)
Other (Not Including Serious) Adverse Events
	Iloprost		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	52/75 (69.3%)		32/77 (41.6%)
Gastrointestinal disorders
Nausea	12/75 (16%)		6/77 (7.8%)
General disorders
Pain - Other	12/75 (16%)		6/77 (7.8%)
Fatigue	8/75 (10.7%)		2/77 (2.6%)
Investigations
Metabolic/Laboratory - Other	3/75 (4%)		6/77 (7.8%)
Musculoskeletal and connective tissue disorders
Myalgia (muscle pain)	13/75 (17.3%)		1/77 (1.3%)
Nervous system disorders
Headache	40/75 (53.3%)		17/77 (22.1%)
Neuropathic pain	7/75 (9.3%)		1/77 (1.3%)
Vascular disorders
Flushing	18/75 (24%)		6/77 (7.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.