Inositol in Preventing Lung Cancer in Current or Former Smokers With Bronchial Dysplasia

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00783705
• Collaborator: (none)
• Enrollment: 85
• Locations: 4
• Arms: 2
• Duration (Months): 65.9
• Patients Per Site: 21.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This randomized phase II trial is studying inositol to see how well it works compared with a placebo in preventing lung cancer in current or former smokers with bronchial dysplasia. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of inositol may prevent lung cancer. It is not yet known whether inositol is more effective than a placebo in preventing lung cancer in smokers with bronchial dysplasia.

Condition or Disease	Intervention/Treatment	Phase
Non-small Cell Lung Cancer; Squamous Lung Dysplasia	Other: placebo; Drug: inositol	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To evaluate the efficacy of myo-inositol (inositol) 9 grams by mouth twice a day for 6 months versus placebo to revert bronchial dysplasia in current/former smokers with or without curatively treated Stage 0/I non-small cell lung cancer.

SECONDARY OBJECTIVES:

1. To further define the mechanism(s) of action of pharmacological doses of myo-inositol as a lung cancer chemopreventive agent by evaluating changes in: the number of dysplastic lesions, Ki-67, caspase-3, peroxisome proliferator-activated receptor (PPAR) gamma, cyclin D1, cyclin E and vascular endothelial growth factor (VEGF) immunostaining in bronchial biopsies; gene expression analysis of ribonucleic acid (RNA) from bronchial brush cells; and changes in inflammatory biomarkers (C-reactive protein [CRP], monocyte chemotactic protein-1 [MCP-1], myeloid progenitor inhibitory factor-1 [MPIF-1] and L-Selectin) levels in bronchoalveolar lavage (BAL) and plasma before and after treatment.

2. To collect additional safety and adverse event profiles of participants enrolled in both intervention arms. III. To establish a biospecimen repository archive for future correlative studies.

OUTLINE: Patients are stratified according to smoking status (current vs former), prior lung cancer (yes vs no), and number of dysplastic lesions at baseline (1 vs > 1). Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.

ARM II: Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.

Patients undergo white light and autofluorescence bronchoscopy with bronchoalveolar lavage, bronchial brushings, and biopsies as well as optical coherence tomography imaging and blood sample collection at baseline and after completion of study treatment. Samples are analyzed for tissue biomarkers (e.g., PPAR gamma, Ki-67, caspase-3, cyclin D1, cyclin E, and VEGF) by immunohistochemistry (IHC); cytokine levels (e.g., CRP, MCP-1, MPIF-1, and L-selectin) by ELISA; and gene expression profiles of RNA by microarray.

After completion of study treatment, patients are followed within 30 days.

Study Design

• Study Type: Interventional
• Actual Enrollment: 85 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: Phase IIb Randomized Comparative Study of the Efficacy and Safety of Myo-inositol Versus Placebo in Smokers With Bronchial Dysplasia
• Study Start Date: Nov 1, 2008
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (inositol) Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Drug: inositol; Given orally; Other Names: myo-inositol
Experimental: Arm II (placebo) Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Other: placebo; Given orally; Other Names: PLCB

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Response Determined by Change in the Histologic Grade of Bronchial Dysplasia as Measured by Mucosal Biopsy Samples on Participant-specific Analysis. [From baseline up to 6 months]

   The definitions of responses are: Complete response: regression of all dysplastic lesion (DL) found at baseline to lesions that were no worse than hyperplasia and no new DL that were mild dysplasia or worse; Partial response: regression of some but not all of the DL with no new lesions that are mild dysplasia or worse; Progressive disease: progression of one or more sites by two or more grades or new DL that were mild dysplasia or worse; Stable disease: no complete response, partial response or progression.

2. Percentage of Participants With Response Determined by Change in the Histologic Grade of Bronchial Dysplasia as Measured by Mucosal Biopsy Samples on Lesion-specific Analysis. [From baseline up to 6 months]

   The definitions of responses are: Complete response: the regression of a dysplastic lesion (DL) of any grade to one classified as being hyperplastic/normal; Progressive disease: appearance of lesions that were classified as mild dysplasia or worse; Stable disease: lesions that are not classified as complete response or progressive disease

Secondary Outcome Measures

1. Percent Change in the Number of Bronchial Dysplastic Lesions Before and After Treatment [From baseline up to 6 months]

   The change in the number of bronchial dysplastic lesions is defined as disappearance or appearance of lesions.

2. Mean Percent Change in Ki-67 Expression Level in the Bronchial Biopsies With Dysplasia [From baseline up to 6 months]

3. Change in Gene Expression Profiles of RNA in Bronchial Brush Cell Samples as Assessed by Microarray [From baseline up to 6 months]

4. Change in Inflammatory Biomarkers Levels (CC-16) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) [From baseline up to 6 months]

   The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).

5. Change in Inflammatory Biomarkers Levels (IL-6) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) [From baseline up to 6 months]

   The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).

6. Change in Inflammatory Biomarkers Levels (CCL-2) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) [From baseline up to 6 months]

   The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).

7. Change in Inflammatory Biomarkers Levels (MPO) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) [From baseline up to 6 months]

   The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).

8. Change in Inflammatory Biomarkers Levels (CC18) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) [From baseline up to 6 months]

   The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).

9. Change in Inflammatory Biomarkers Levels (SFTPD) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) [From baseline up to 6 months]

   The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).

10. Change in Inflammatory Biomarkers Levels (Total Glutathione) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) [From baseline up to 6 months]

    The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).

11. Change in Inflammatory Biomarkers Levels (CC-16) in Plasma Samples as Assessed by ELISA [From baseline up to 6 months]

    The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).

12. Change in Inflammatory Biomarkers Levels (CRP) in Plasma Samples as Assessed by ELISA [From baseline up to 6 months]

    The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).

13. Change in Inflammatory Biomarkers Levels (IL-6) in Plasma Samples as Assessed by ELISA [From baseline up to 6 months]

    The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).

14. Change in Inflammatory Biomarkers Levels (CCL-2) in Plasma Samples as Assessed by ELISA [From baseline up to 6 months]

    The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).

15. Change in Inflammatory Biomarkers Levels (MPO) in Plasma Samples as Assessed by ELISA [From baseline up to 6 months]

    The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).

16. Change in Inflammatory Biomarkers Levels (Nitrotyrosine) in Plasma Samples as Assessed by ELISA [From baseline up to 6 months]

    The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).

17. Change in Inflammatory Biomarkers Levels (CC18) in Plasma Samples as Assessed by ELISA [From baseline up to 6 months]

    The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).

18. Change in Inflammatory Biomarkers Levels (SFTPD) in Plasma Samples as Assessed by ELISA [From baseline up to 6 months]

    The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years to 79 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed bronchial dysplasia in ≥ 1 site AND meets one of the following criteria:

• Current or former smoker with ≥ a 30 pack-year smoking history and no history of lung cancer

• Stage 0 or I non-small cell lung cancer (NSCLC) curatively treated by surgery (local ablation or resection), adjuvant chemotherapy, or radiotherapy with a ≥ 30 pack-year smoking history

• At least 6 months since prior surgery, adjuvant chemotherapy, or radiotherapy

• No current evidence of lung cancer by CT scan

• No non-calcified lung nodules ≥ 10 mm diameter on spiral CT scan unless cancer is ruled out by PET/CT scan or by biopsy

• ECOG performance status 0-1

• Hemoglobin normal

• Leukocyte count ≥ 3,000/mm³

• Absolute neutrophil count ≥ 1,500/mm³

• Platelet count ≥ 100,000/mm³

• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

• Alkaline phosphatase ≤ 1.5 times ULN

• ALT and AST ≤ 1.5 times ULN

• BUN ≤ 1.5 times ULN

• Chloride ≤ 1.5 times ULN

• Total CO_2 ≤ 1.5 times ULN

• Sodium ≤ 1.5 times ULN

• Calcium ≤ 1.5 times ULN

• Potassium ≤ 1.5 times ULN

• Phosphorus ≤ 1.5 times ULN

• Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 30mL/min

• Fasting blood glucose normal

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No cancer within the past 3 years except stage 0 or I NSCLC, nonmelanomatous skin cancer, localized prostate cancer, carcinoma in situ of the cervix, or superficial bladder cancer that was treated > 6 months ago

• No concurrent uncontrolled illness including, but not limited to, any of the following:

• Ongoing or active infection

• Symptomatic congestive heart failure

• Unstable angina pectoris

• Cardiac arrhythmia

• Severe chronic obstructive pulmonary disease requiring supplemental oxygen

• Uncontrolled hypertension

• Psychiatric illness or social situation that would limit compliance with study requirements

• No schizophrenia or bipolar disorder

• No diabetes

• No requirement for supplemental oxygen (continuous or intermittent)

• SaO_2 ≥ 90% on room air

• No history of allergic reactions attributed to inositol

• No history of allergies to any ingredient in the study agent or placebo

• No other concurrent investigational agents

• At least 7 days since prior anticoagulant use (e.g., coumadin or heparin)

• More than 6 months since prior participation in another chemoprevention clinical trial

• No prior pneumonectomy

• No prior solid organ transplantation

• No concurrent lithium, carbamazepine, or valproate

• No concurrent use of other natural health products containing inositol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Arizona	Scottsdale	Arizona	United States	85259
2	Mayo Clinic	Rochester	Minnesota	United States	55905
3	Albuquerque Veterans Administration Medical Center	Albuquerque	New Mexico	United States	87108-5128
4	BCCA-Vancouver Cancer Centre	Vancouver	British Columbia	Canada	V5Z 4E6

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Paul Limburg, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00783705
• Other Study ID Numbers: NCI-2009-00839; NCI-2009-00839; CDR0000617846; MAY06-8-01; MAY06-8-01; P30CA015083
• First Posted: Nov 2, 2008
• Last Update Posted: Dec 5, 2017
• Last Verified: Oct 1, 2017

• Additional relevant MeSH terms: Lung Neoplasms; Inositol

Study Results

Participant Flow

Recruitment Details	448 subjects were pre-registered through 3 Cancer Prevention Network (CPN) member organizations from 2008 to 2013.
Pre-assignment Detail	363 subjects were excluded from pre-assignment: 342 ineligible via bronchoscopy, 3 participant decision, 13 lab values out of range, 1 screening time line issue and 4 suspicious of cancer.

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Period Title: Overall Study
STARTED	44	41
COMPLETED	38	36
NOT COMPLETED	6	5

Baseline Characteristics

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)	Total
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Total of all reporting groups
Overall Participants	44	41	85
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	58.5	58.0	58.0
Sex: Female, Male (Count of Participants)
Female	10 22.7%	13 31.7%	23 27.1%
Male	34 77.3%	28 68.3%	62 72.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 4.5%	3 7.3%	5 5.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	42 95.5%	38 92.7%	80 94.1%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	8 18.2%	8 19.5%	16 18.8%
Canada	36 81.8%	33 80.5%	69 81.2%
Body Mass Index, kg/m^2 (kg/m^2) [Median (Full Range) ]
Median (Full Range) [kg/m^2]	27.2	26.0	26.5
Smoking Status (participants) [Number]
Current	27 61.4%	26 63.4%	53 62.4%
Former	17 38.6%	15 36.6%	32 37.6%
Prior NSAID (nonsteroidal anti-inflammatory drugs) Use (participants) [Number]
No	28 63.6%	29 70.7%	57 67.1%
Yes	16 36.4%	12 29.3%	28 32.9%
Alcohol Intake (participants) [Number]
1 or fewer drinks per day	27 61.4%	11 26.8%	38 44.7%
2-3 drinks per day	7 15.9%	13 31.7%	20 23.5%
4 or more drinks per day	1 2.3%	4 9.8%	5 5.9%
None	9 20.5%	13 31.7%	22 25.9%
Dysplastic Lesions Identified (participants) [Number]
1 Dysplastic lesion	22 50%	19 46.3%	41 48.2%
>1 Dysplastic lesions	22 50%	22 53.7%	44 51.8%
Mucosal Biopsies Obtained (biopsies) [Median (Full Range) ]
Median (Full Range) [biopsies]	6.0	7.0	7.0
Most Advanced Histology (participants) [Number]
Mild dysplasia	15 34.1%	13 31.7%	28 32.9%
Moderate dysplasia	28 63.6%	22 53.7%	50 58.8%
Severe dysplasia	1 2.3%	6 14.6%	7 8.2%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Response Determined by Change in the Histologic Grade of Bronchial Dysplasia as Measured by Mucosal Biopsy Samples on Participant-specific Analysis.
Description	The definitions of responses are: Complete response: regression of all dysplastic lesion (DL) found at baseline to lesions that were no worse than hyperplasia and no new DL that were mild dysplasia or worse; Partial response: regression of some but not all of the DL with no new lesions that are mild dysplasia or worse; Progressive disease: progression of one or more sites by two or more grades or new DL that were mild dysplasia or worse; Stable disease: no complete response, partial response or progression.
Time Frame	From baseline up to 6 months

Outcome Measure Data

Analysis Population Description

The analysis population included the participants who received study intervention and completed both the pre- and post-intervention bronchoscopy.

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Measure Participants	38	36
Complete response	26.3 59.8%	13.9 33.9%
Partial response	10.5 23.9%	16.7 40.7%
Stable disease	15.8 35.9%	36.1 88%
Progressive disease	47.4 107.7%	33.3 81.2%

2. Primary Outcome

Title	Percentage of Participants With Response Determined by Change in the Histologic Grade of Bronchial Dysplasia as Measured by Mucosal Biopsy Samples on Lesion-specific Analysis.
Description	The definitions of responses are: Complete response: the regression of a dysplastic lesion (DL) of any grade to one classified as being hyperplastic/normal; Progressive disease: appearance of lesions that were classified as mild dysplasia or worse; Stable disease: lesions that are not classified as complete response or progressive disease
Time Frame	From baseline up to 6 months

Outcome Measure Data

Analysis Population Description

The analysis population included the participants who received study intervention and completed both the pre- and post-intervention bronchoscopy.

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Measure Participants	38	36
Complete response	10.2 23.2%	7.4 18%
Stable disease	15.9 36.1%	22.6 55.1%
Progressive disease	12.5 28.4%	10.3 25.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Myo-inositol), Arm B (Placebo)
	Comments	Generalized estimating equation model on lesions (progressive disease vs. complete response/stable disease) was used to account for intra-patient correlation in the lesion-specific analysis.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.39
	Comments
	Method	Generalized estimating equation model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; 0.7 to 3.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percent Change in the Number of Bronchial Dysplastic Lesions Before and After Treatment
Description	The change in the number of bronchial dysplastic lesions is defined as disappearance or appearance of lesions.
Time Frame	From baseline up to 6 months

Outcome Measure Data

Analysis Population Description

The analysis population included the participants who received study intervention and completed both the pre- and post-intervention bronchoscopy with lesions biopsied.

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Measure Participants	38	36
Mean (Standard Deviation) [percentage change in number of lesions]	-53.5 (116.1)	-50.0 (115.8)

4. Secondary Outcome

Title	Mean Percent Change in Ki-67 Expression Level in the Bronchial Biopsies With Dysplasia
Time Frame	From baseline up to 6 months

Outcome Measure Data

Analysis Population Description

The analysis population included the participants who received study intervention and completed both the pre- and post-intervention bronchoscopy with lesions biopsied.

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Measure Participants	33	32
Mean (Standard Deviation) [percentage of Ki67 expression level]	-22.8 (105.3)	-6.2 (98.7)

5. Secondary Outcome

Title	Change in Gene Expression Profiles of RNA in Bronchial Brush Cell Samples as Assessed by Microarray
Time Frame	From baseline up to 6 months

Outcome Measure Data

Analysis Population Description

Data were not collected due to a study team decision not to analyze this endpoint.

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Measure Participants	0	0

6. Secondary Outcome

Title	Change in Inflammatory Biomarkers Levels (CC-16) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA)
Description	The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).
Time Frame	From baseline up to 6 months

Outcome Measure Data

Analysis Population Description

The analysis population included the participants who received study intervention and completed both the pre- and post-intervention bronchoscopy with bronchoalveolar lavage samples available

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Measure Participants	38	36
Median (Inter-Quartile Range) [ng/mL]	-66.96	-54.32

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Myo-inositol), Arm B (Placebo)
	Comments	Comparison of the median difference in biomarker CC-16 level between arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.10
	Comments
	Method	Wilcoxon Rank-Sum
	Comments

7. Secondary Outcome

Title	Change in Inflammatory Biomarkers Levels (IL-6) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA)
Description	The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).
Time Frame	From baseline up to 6 months

Outcome Measure Data

Analysis Population Description

The analysis population included the participants who received study intervention and completed both the pre- and post-intervention bronchoscopy with bronchoalveolar lavage samples available

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Measure Participants	38	36
Median (Inter-Quartile Range) [pg/mL]	-0.68	-0.27

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Myo-inositol), Arm B (Placebo)
	Comments	Comparison of the median difference in biomarker IL-6 level between arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Wilcoxon Rank-Sum
	Comments

8. Secondary Outcome

Title	Change in Inflammatory Biomarkers Levels (CCL-2) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA)
Description	The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).
Time Frame	From baseline up to 6 months

Outcome Measure Data

Analysis Population Description

The analysis population included the participants who received study intervention and completed both the pre- and post-intervention bronchoscopy with bronchoalveolar lavage samples available

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Measure Participants	38	36
Median (Inter-Quartile Range) [pg/mL]	-9.25	9.41

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Myo-inositol), Arm B (Placebo)
	Comments	Comparison of the median difference in biomarker CCL-2 level between arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.58
	Comments
	Method	Wilcoxon Rank-Sum
	Comments

9. Secondary Outcome

Title	Change in Inflammatory Biomarkers Levels (MPO) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA)
Description	The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).
Time Frame	From baseline up to 6 months

Outcome Measure Data

Analysis Population Description

The analysis population included the participants who received study intervention and completed both the pre- and post-intervention bronchoscopy with bronchoalveolar lavage samples available

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Measure Participants	38	36
Median (Inter-Quartile Range) [ng/mL]	-3.46	-1.15

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Myo-inositol), Arm B (Placebo)
	Comments	Comparison of the median difference in biomarker MPO level between arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments
	Method	Wilcoxon Rank-Sum
	Comments

10. Secondary Outcome

Title	Change in Inflammatory Biomarkers Levels (CC18) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA)
Description	The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).
Time Frame	From baseline up to 6 months

Outcome Measure Data

Analysis Population Description

The analysis population included the participants who received study intervention and completed both the pre- and post-intervention bronchoscopy with bronchoalveolar lavage samples available

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Measure Participants	38	36
Median (Inter-Quartile Range) [ng/mL]	-121.47	10.70

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Myo-inositol), Arm B (Placebo)
	Comments	Comparison of the median difference in biomarker CC18 level between arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.63
	Comments
	Method	Wilcoxon Rank-Sum
	Comments

11. Secondary Outcome

Title	Change in Inflammatory Biomarkers Levels (SFTPD) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA)
Description	The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).
Time Frame	From baseline up to 6 months

Outcome Measure Data

Analysis Population Description

The analysis population included the participants who received study intervention and completed both the pre- and post-intervention bronchoscopy with bronchoalveolar lavage samples available

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Measure Participants	38	36
Median (Inter-Quartile Range) [ng/mL]	-12.39	7.21

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Myo-inositol), Arm B (Placebo)
	Comments	Comparison of the median difference in biomarker SFTPD level between arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.22
	Comments
	Method	Wilcoxon Rank-Sum
	Comments

12. Secondary Outcome

Title	Change in Inflammatory Biomarkers Levels (Total Glutathione) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA)
Description	The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).
Time Frame	From baseline up to 6 months

Outcome Measure Data

Analysis Population Description

The analysis population included the participants who received study intervention and completed both the pre- and post-intervention bronchoscopy with bronchoalveolar lavage samples available

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Measure Participants	38	36
Median (Inter-Quartile Range) [umol/L]	-0.25	-0.56

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Myo-inositol), Arm B (Placebo)
	Comments	Comparison of the median difference in biomarker Total Glutathione level between arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments
	Method	Wilcoxon Rank-Sum
	Comments

13. Secondary Outcome

Title	Change in Inflammatory Biomarkers Levels (CC-16) in Plasma Samples as Assessed by ELISA
Description	The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).
Time Frame	From baseline up to 6 months

Outcome Measure Data

Analysis Population Description

The analysis population included the participants who received study intervention and completed both the pre- and post-intervention bronchoscopy with plasma samples available

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Measure Participants	38	36
Median (Inter-Quartile Range) [ng/mL]	-0.08	-0.58

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Myo-inositol), Arm B (Placebo)
	Comments	Comparison of the median difference in biomarker CC-16 level between arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.35
	Comments
	Method	Wilcoxon Rank-Sum
	Comments

14. Secondary Outcome

Title	Change in Inflammatory Biomarkers Levels (CRP) in Plasma Samples as Assessed by ELISA
Description	The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).
Time Frame	From baseline up to 6 months

Outcome Measure Data

Analysis Population Description

The analysis population included the participants who received study intervention and completed both the pre- and post-intervention bronchoscopy with plasma samples available

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Measure Participants	38	36
Median (Inter-Quartile Range) [ng/mL]	161.18	-74.11

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Myo-inositol), Arm B (Placebo)
	Comments	Comparison of the median difference in biomarker CRP level between arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.80
	Comments
	Method	Wilcoxon Rank-Sum
	Comments

15. Secondary Outcome

Title	Change in Inflammatory Biomarkers Levels (IL-6) in Plasma Samples as Assessed by ELISA
Description	The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).
Time Frame	From baseline up to 6 months

Outcome Measure Data

Analysis Population Description

The analysis population included the participants who received study intervention and completed both the pre- and post-intervention bronchoscopy with plasma samples available

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Measure Participants	38	36
Median (Inter-Quartile Range) [pg/mL]	0.06	0.01

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Myo-inositol), Arm B (Placebo)
	Comments	Comparison of the median difference in biomarker IL-6 level between arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.22
	Comments
	Method	Wilcoxon Rank-Sum
	Comments

16. Secondary Outcome

Title	Change in Inflammatory Biomarkers Levels (CCL-2) in Plasma Samples as Assessed by ELISA
Description	The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).
Time Frame	From baseline up to 6 months

Outcome Measure Data

Analysis Population Description

The analysis population included the participants who received study intervention and completed both the pre- and post-intervention bronchoscopy with plasma samples available

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Measure Participants	38	36
Median (Inter-Quartile Range) [pg/mL]	2.19	9.08

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Myo-inositol), Arm B (Placebo)
	Comments	Comparison of the median difference in biomarker CCL-2 level between arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.74
	Comments
	Method	Wilcoxon Rank-Sum
	Comments

17. Secondary Outcome

Title	Change in Inflammatory Biomarkers Levels (MPO) in Plasma Samples as Assessed by ELISA
Description	The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).
Time Frame	From baseline up to 6 months

Outcome Measure Data

Analysis Population Description

The analysis population included the participants who received study intervention and completed both the pre- and post-intervention bronchoscopy with plasma samples available

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Measure Participants	38	36
Median (Inter-Quartile Range) [ng/mL]	0.20	0.09

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Myo-inositol), Arm B (Placebo)
	Comments	Comparison of the median difference in biomarker MPO level between arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.55
	Comments
	Method	Wilcoxon Rank-Sum
	Comments

18. Secondary Outcome

Title	Change in Inflammatory Biomarkers Levels (Nitrotyrosine) in Plasma Samples as Assessed by ELISA
Description	The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).
Time Frame	From baseline up to 6 months

Outcome Measure Data

Analysis Population Description

The analysis population included the participants who received study intervention and completed both the pre- and post-intervention bronchoscopy with plasma samples available

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Measure Participants	38	36
Median (Inter-Quartile Range) [mmol/L]	0.77	0.88

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Myo-inositol), Arm B (Placebo)
	Comments	Comparison of the median difference in biomarker Nitrotyrosine level between arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.91
	Comments
	Method	Wilcoxon Rank-Sum
	Comments

19. Secondary Outcome

Title	Change in Inflammatory Biomarkers Levels (CC18) in Plasma Samples as Assessed by ELISA
Description	The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).
Time Frame	From baseline up to 6 months

Outcome Measure Data

Analysis Population Description

The analysis population included the participants who received study intervention and completed both the pre- and post-intervention bronchoscopy with plasma samples available

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Measure Participants	38	36
Median (Inter-Quartile Range) [ng/mL]	1.50	-0.16

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Myo-inositol), Arm B (Placebo)
	Comments	Comparison of the median difference in biomarker CC18 level between arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments
	Method	Wilcoxon Rank-Sum
	Comments

20. Secondary Outcome

Title	Change in Inflammatory Biomarkers Levels (SFTPD) in Plasma Samples as Assessed by ELISA
Description	The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems).
Time Frame	From baseline up to 6 months

Outcome Measure Data

Analysis Population Description

The analysis population included the participants who received study intervention and completed both the pre- and post-intervention bronchoscopy with plasma samples available

Arm/Group Title	Arm A (Myo-inositol)	Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.	Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
Measure Participants	38	36
Median (Inter-Quartile Range) [ng/mL]	-0.28	-0.22

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Myo-inositol), Arm B (Placebo)
	Comments	Comparison of the median difference in biomarker SFTPD level between arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.52
	Comments
	Method	Wilcoxon Rank-Sum
	Comments

Adverse Events

Adverse Event Reporting Description	Adverse events reported on all participants. The adverse events: cardiac disorders, blood disorders, gastrointestinal disorder and etc. which are simply repeating their organ system names were referred to other, specify category of the adverse events.
Arm/Group Title	Arm A (Myo-inositol)		Arm B (Placebo)
Arm/Group Description	Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.		Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
All Cause Mortality
	Arm A (Myo-inositol)		Arm B (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm A (Myo-inositol)		Arm B (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/44 (2.3%)		0/41 (0%)
Cardiac disorders
Cardiac disorder	1/44 (2.3%)	1	0/41 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm A (Myo-inositol)		Arm B (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	36/44 (81.8%)		32/41 (78%)
Blood and lymphatic system disorders
Blood disorder	1/44 (2.3%)	1	0/41 (0%)	0
Cardiac disorders
Palpitations	0/44 (0%)	0	1/41 (2.4%)	1
Sinus tachycardia	0/44 (0%)	0	1/41 (2.4%)	1
Ear and labyrinth disorders
Middle ear inflammation	1/44 (2.3%)	1	0/41 (0%)	0
Tinnitus	0/44 (0%)	0	2/41 (4.9%)	3
Endocrine disorders
Hypothyroidism	0/44 (0%)	0	2/41 (4.9%)	2
Eye disorders
Cataract	1/44 (2.3%)	2	0/41 (0%)	0
Vitreous hemorrhage	0/44 (0%)	0	1/41 (2.4%)	1
Gastrointestinal disorders
Abdominal distension	3/44 (6.8%)	5	0/41 (0%)	0
Abdominal pain	3/44 (6.8%)	5	2/41 (4.9%)	2
Constipation	1/44 (2.3%)	1	0/41 (0%)	0
Diarrhea	18/44 (40.9%)	26	9/41 (22%)	14
Dyspepsia	1/44 (2.3%)	1	0/41 (0%)	0
Dysphagia	0/44 (0%)	0	1/41 (2.4%)	1
Flatulence	13/44 (29.5%)	16	3/41 (7.3%)	5
Gastrointestinal disorder	4/44 (9.1%)	5	2/41 (4.9%)	2
Nausea	7/44 (15.9%)	7	3/41 (7.3%)	3
Stomach pain	0/44 (0%)	0	2/41 (4.9%)	2
Tooth disorder	1/44 (2.3%)	1	0/41 (0%)	0
Vomiting	4/44 (9.1%)	6	2/41 (4.9%)	2
General disorders
Chest pain	5/44 (11.4%)	5	0/41 (0%)	0
Chills	5/44 (11.4%)	5	2/41 (4.9%)	2
Fatigue	6/44 (13.6%)	6	7/41 (17.1%)	10
Fever	4/44 (9.1%)	4	7/41 (17.1%)	8
General symptom	0/44 (0%)	0	1/41 (2.4%)	1
Injection site reaction	1/44 (2.3%)	1	0/41 (0%)	0
Localized edema	1/44 (2.3%)	1	0/41 (0%)	0
Pain	3/44 (6.8%)	3	2/41 (4.9%)	2
Hepatobiliary disorders
Hepatobiliary disease	1/44 (2.3%)	1	0/41 (0%)	0
Infections and infestations
Bladder infection	1/44 (2.3%)	1	0/41 (0%)	0
Bronchitis	0/44 (0%)	0	2/41 (4.9%)	2
Peripheral nerve infection	0/44 (0%)	0	1/41 (2.4%)	2
Pneumonia	0/44 (0%)	0	1/41 (2.4%)	1
Sinusitis	0/44 (0%)	0	1/41 (2.4%)	1
Skin infection	0/44 (0%)	0	1/41 (2.4%)	1
Soft tissue infection	0/44 (0%)	0	1/41 (2.4%)	1
Upper respiratory infection	0/44 (0%)	0	1/41 (2.4%)	1
Injury, poisoning and procedural complications
Bruising	2/44 (4.5%)	2	0/41 (0%)	0
Fracture	1/44 (2.3%)	1	0/41 (0%)	0
Investigations
Laboratory test abnormal	2/44 (4.5%)	2	0/41 (0%)	0
Platelet count decreased	2/44 (4.5%)	2	0/41 (0%)	0
Weight gain	2/44 (4.5%)	2	0/41 (0%)	0
Weight loss	0/44 (0%)	0	1/41 (2.4%)	1
Metabolism and nutrition disorders
Anorexia	1/44 (2.3%)	1	0/41 (0%)	0
Blood glucose increased	1/44 (2.3%)	1	1/41 (2.4%)	1
Blood uric acid increased	1/44 (2.3%)	1	0/41 (0%)	0
Serum sodium decreased	1/44 (2.3%)	1	0/41 (0%)	0
Musculoskeletal and connective tissue disorders
Arthritis	0/44 (0%)	0	1/41 (2.4%)	1
Back pain	1/44 (2.3%)	1	1/41 (2.4%)	1
Bone pain	1/44 (2.3%)	1	0/41 (0%)	0
Joint disorder	1/44 (2.3%)	2	0/41 (0%)	0
Joint effusion	1/44 (2.3%)	1	0/41 (0%)	0
Joint pain	2/44 (4.5%)	7	4/41 (9.8%)	5
Joint range of motion decreased cervical spine	1/44 (2.3%)	1	1/41 (2.4%)	1
Muscle weakness upper limb	1/44 (2.3%)	1	0/41 (0%)	0
Musculoskeletal disorder	1/44 (2.3%)	1	0/41 (0%)	0
Neck pain	1/44 (2.3%)	1	1/41 (2.4%)	1
Pain in extremity	2/44 (4.5%)	5	2/41 (4.9%)	3
Nervous system disorders
Dizziness	4/44 (9.1%)	4	2/41 (4.9%)	2
Headache	1/44 (2.3%)	1	6/41 (14.6%)	6
Memory impairment	0/44 (0%)	0	1/41 (2.4%)	1
Peripheral sensory neuropathy	1/44 (2.3%)	1	1/41 (2.4%)	1
Syncope	0/44 (0%)	0	1/41 (2.4%)	1
Psychiatric disorders
Agitation	1/44 (2.3%)	1	0/41 (0%)	0
Depression	1/44 (2.3%)	1	2/41 (4.9%)	3
Insomnia	2/44 (4.5%)	2	2/41 (4.9%)	2
Renal and urinary disorders
Hemoglobin urine positive	0/44 (0%)	0	1/41 (2.4%)	1
Urinary frequency	2/44 (4.5%)	2	1/41 (2.4%)	1
Urogenital disorder	1/44 (2.3%)	1	0/41 (0%)	0
Reproductive system and breast disorders
Penile pain	1/44 (2.3%)	1	0/41 (0%)	0
Prostatic pain	1/44 (2.3%)	1	0/41 (0%)	0
Reproductive tract disorder	1/44 (2.3%)	1	1/41 (2.4%)	1
Testicular pain	1/44 (2.3%)	1	0/41 (0%)	0
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	5/44 (11.4%)	6	3/41 (7.3%)	3
Bronchial obstruction	0/44 (0%)	0	1/41 (2.4%)	1
Bronchopulmonary hemorrhage	1/44 (2.3%)	1	0/41 (0%)	0
Bronchospasm	2/44 (4.5%)	2	2/41 (4.9%)	3
Cough	13/44 (29.5%)	17	13/41 (31.7%)	16
Dyspnea	3/44 (6.8%)	4	2/41 (4.9%)	2
Laryngeal edema	0/44 (0%)	0	1/41 (2.4%)	1
Nasal congestion	2/44 (4.5%)	2	5/41 (12.2%)	8
Pharyngolaryngeal pain	7/44 (15.9%)	7	7/41 (17.1%)	8
Respiratory disorder	2/44 (4.5%)	2	6/41 (14.6%)	9
Voice alteration	1/44 (2.3%)	1	2/41 (4.9%)	2
Skin and subcutaneous tissue disorders
Dry skin	0/44 (0%)	0	1/41 (2.4%)	1
Pruritus	1/44 (2.3%)	1	3/41 (7.3%)	3
Rash desquamating	1/44 (2.3%)	1	3/41 (7.3%)	3
Skin disorder	0/44 (0%)	0	1/41 (2.4%)	1
Skin ulceration	0/44 (0%)	0	1/41 (2.4%)	1
Sweating	2/44 (4.5%)	3	2/41 (4.9%)	2
Vascular disorders
Hematoma	1/44 (2.3%)	1	0/41 (0%)	0
Hemorrhage	0/44 (0%)	0	1/41 (2.4%)	1
Hot flashes	1/44 (2.3%)	1	1/41 (2.4%)	1
Hypertension	1/44 (2.3%)	1	1/41 (2.4%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.