The following datasets contain the data available for EPPT UAZ2017-09-02. The description and documentation for each file is listed below. SAS7bdat and CSV versions of the actual data will be available to CDAS projects approved to use this study's data.

Analysis Datasets

Raw Datasets

These 20 datasets contain the raw form data received, excluding PII.

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Trial Summary

This open-label, randomized, cross-over study, evaluates whether two different doses of Avmacol® (4 tablets per day for 10-14 days; 8 tablets per day for 10-14 days) increase the detoxification of tobacco carcinogens in otherwise healthy, current heavy smokers.

Randomized trial with two arms:

• ARM I: High-Low arm (8 tablets of Avmacol® per day for 2 weeks followed by 4 tablets of Avmacol® per day for 2 weeks).
• ARM II: Low-High arm (4 tablets of Avmacol® per day for 2 weeks followed by 8 tablets of Avmacol® per day for 2 weeks).

Target Randomizable Enrollment: 60

Statistical Analysis:

For changes in the urinary excretion of SFN as well as the mercapturic acids of tobacco carcinogens, concentrations were normalized to creatinine then log-transformed due to high right skew. The changes following low- and higher-dose BSSE were determined independently. The ratio of the geometric means between post and pre concentrations and the associated 95% CI were derived from log-normal regression. Spearman correlation coefficient was calculated to evaluate the correlation between effective SFN dose, as measured by urinary SFN metabolites, and carcinogen detoxification. Changes in buccal expression of gene transcripts associated with effective SFN dose were computed using the Pearson correlation between log2(fold change in expression) and log2(fold change in creatinine-normalized SFN metabolite concentration) for each participant. Functional enrichment was evaluated by using ClusterProfiler to perform overrepresentation analysis on the top thirty genes most positively or negatively correlated with effective SFN dose. The background universe was set to only the 770 genes probed in the customized NanoString panel. Linear mixed effects models were fit to determine whether there was a dose-response relationship between effective SFN dose, carcinogen detoxification, and the change in NRF2 target gene transcripts. To explore whether the GSTM1 and GSTT1 genotypes were associated with detoxification, two-sided, two-sample t tests were performed. Bonferroni correction was used to correct for multiple comparisons. McNemar's test was performed to compare the frequency of each specific AE between low and higher-dose treatment. The SAS 9.4 software package was used for all statistical analyses.

Enrollment Statistics

Actual Registration: 54

• 49 people randomized (49 of 54 registered)
• 24 in Arm I: High-Low (24 of 49 randomized)
• 23 participants completed study
• 1 participant did not complete study due to adverse event
• 25 in Arm II: Low-High (25 of 49 randomized)
• 25 participants completed study
• 5 people not randomized (5 of 54 registered)
• 4 were not eligible
• 1 due to non-compliance

Statistical Analysis and Total Study Population Demographics:

• Age, years: Median (range)
  • 57 (37, 73)
• Sex: N (%)
  • Male: 23 (47)
  • Female: 26 (53)
• Race: N (%)
  • Black or African American: 1 (2)
  • White: 44 (90)
  • More than one: 3 (6)
  • Unknown or not reported: 1 (2)
• Ethnicity: N (%)
  • Hispanic or Latino: 4 (8)
  • Not Hispanic or Latino: 44 (90)
  • Unknown or not reported: 1 (2)
• Karnofsky performance status: N (%)
  • 90%: 6 (12)
  • 100%: 43 (88)
• Tobacco use: Median (range)
  • Pack-years: 36 (24, 60)
  • Cigarettes per day: 20 (10, 30)
• GST genotype: N (%)
  • GSTM1 null: 23 (47)

Final Analysis Population: 49

Eligibility Criteria

Inclusion Criteria

• Male or female current tobacco smokers with ≥ 20 pack years of self-reported smoking exposure and a current average use of ≥ 10 cigarettes/day.
• Age ≥18 years.
• Karnofsky performance scale ≥ 70% (see Appendix A).
• Participants must have normal organ and marrow function as defined below:
  • Leukocytes ≥3,000/microliter
  • Absolute neutrophil count ≥1,500/microliter
  • Platelets ≥100,000/microliter
  • Total bilirubin ≤ 2 x institutional upper limit of normal (ULN)
  • AST (SGOT)/ALT (SGPT) ≤ 1.5 x ULN
  • Creatinine ≤ ULN
• Fertile subjects must use adequate contraception (abstinence, barrier methods, or birth control pills) prior to study entry and for the duration of study participation. The effects of Avmacol® on the developing human fetus are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

• History of invasive cancer within the past 2 years, with the exception of excised and cured non-melanoma skin cancer or carcinoma in situ of the cervix.
• Chronic, current or recent (within the past 2 weeks) use of systemic steroid doses equivalent to prednisone > 5 mg daily for continued use > 14 days. Use of inhaled steroids, nasal sprays, and topical creams for small body areas is allowed.
• Participants may not be receiving any other investigational agents.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to Avmacol®.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant or lactating women.

The Schema is a timeline of the study. It indicates start/end points, visits expected, major testing to be done, and any other information that is crucial to understanding how the study was completed.

Results/Findings:

Low and higher-dose BSSE showed a mean bioavailability of 11% and 10%, respectively. Higher-dose BSSE significantly upregulated urinary excretion of the mercapturic acids of benzene (p = 0.04), acrolein (p < 0.01), and crotonaldehyde (p = 0.02), independent of GST genotype. Retention and compliance were high resulting in early study completion. In conclusion, BSSE significantly upregulated detoxification of the tobacco carcinogens benzene, acrolein, and crotonaldehyde in current tobacco smokers.