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THE SUBJECTIVE AND ELECTROPHYSIOLOGICAL EFFECTS OF SMOKING CIGARETTES WITH CONSTANT TAR BUT VARYING NICOTINE LEVELS (PT)

-PROTOCOL P 0500/3203 930827 ,~c. "4.C'a PAGE 1 A clinical test is planned to investigate the subjective effects of smoking cigarettes with constant tar but varying nicotine levels. Electrophysiological responses will also be measured using the pattern reversal-evoked potential (PREP). The subjective responses to the cigarettes will be measured by means of a descriptive ballot. Using the ballot, the subjects will evaluate such factors as flavor, satisfaction, acceptability, and concentration. post-smoking EEG responses to a reversing (i.e., shifting) check- erboard pattern. Previous work (Gullotta and Shultz, 1982; Gullotta and Hayes, 1984) has indicated that a component of the PREP, the P1, is sensitive to nicotine as delivered in cigarette The PREP is used as a noninvasive technique involving the attach- ment of electrodes to the scalp and the recording of pre- and

PROTOCOL P 0500/3203 930827 PAGE 2 2 INTRODUCTION The sponsor of this study is attempting to optimize the ratio be- tween positive factors (e.g., taste quality, consumer satisfaction) and possible negative factors (e.g., toxicity). Considerable progress has been made in reducing the value of the denominator of this ratio. For example, the introduction of cigarette filters has substantially lessened the quantity of com- pounds with possible biological activity. Unfortunately, reducing the yalue of the denominator often has the negative effect of con- comitantly reducing taste quality and consumer acceptability. To improve overall quality, then, it would be necessary to find ~ methods to breakthis loop. Progress in this area has been dif- r---_ __.-`.--~-- - ficult for two reasons. First, until recently (Grubbs et al., 1991), it has not been possible to systematically and selectively modify tobacco constituents - a necessary prerequisite for con- ducting valid studies. Second, our ability to measure the results of this modifications has not progressed beyond the use of rela- tively primitive and notoriously unreliable descriptive ballots. n Recent advances in both tobacco technology and subjective measure- ment techniques now make it possible to conduct studies on cigarette taste and consumer acceptability in„a-scientifically sound manner. With respect to advances ~n tobacco technology, it has been demonstrated that tobacco qonjitituents can be selectively removed by using supercritical extraction methods. The subjective attributes of these constituents can then be systematically evailuated by comparing cigarettes made with extracted tobacco to cigarettes made from extracted tobacco blended in various propor- tions with normal tobacco. With respect to advances in subjective measurement techniques, studies conducted in our laboratory over the last several years have shown that the pattern-reversal evoked potential (PREP) can

•PROTOCOL P 0500/3203``930827 PAGE 3 ~. be used to obtain information about;cigarette taste and accept- waveformand that these changes correlate with subjective assess- ,t`~q.i".` ;. . :._ . , .. . :. produces p'redictable and'highly reproducible changes in the PREP abilityi'Specifically, we have demonstrated that cigarette smoking Cigarettes prepared from tobaccothat has been supercritically ex- ~tracted~.of~'.alkaloids indicate that.these compounds are significant contributors.to taste and satisfaction: The major tobacco alkaloid tributorthe subjective characteristic of cigarettes. Yet, is,'of oourse, nicotine, and it'is believed to be a prime con- surprisingly little is known aboutthe sensory characteristics of -. _: .. . ,........r nicotine.'.That is, few reports (Gullotta, unpublished report) ex- _.~? ;ist:where nicotine, and only nicotine,.has. been varied and its sensory:characteristics' evaluated. A scientifically sound inves.-_,} productawithout significant loss of acceptibility. amount.ofthis pharmacologically active substance in a consumer characteristic of cigarettes will allow the minimization of the ~. . ','i "y - . .. ,. . . . . . . . igation.,of the contribution of .nicotine on the subjective Thepurpose of the planned.investigation is to systematically in- have -beenprepared fromtobacco,,that-has been supercritically ex-. ': ' 'fi ` . . .. . . . . , . , - acceptability. The study will be conducted using cigarettes that -vestigate''-`the contribution of.nicotine to cigarette flavor and tracted`of;nicotine,blended in various proportions with normal. 'tobacco. Flavor and acceptability will be measured using the PREP, togetherwith traditional descriptive ballots. l1l,k'f A.p~OC, G..tZ SC. 04 M- YY ht g'Zb cY. ~ dca.0. Y ~ eC kt~fiC a.ti he risx associatea with tne participation in tni.s stuay is negii- , ;gible. The.outcome of this study will be of scientific merit in the"field of understanding the contribution of nicotine to cigarette taste,,flavor, acceptability, consumer satisfaction and • ability ..to, concentrate. The aquired knowledge will offer health benefits by facilitating the optimization' of the ratio between positive and possible negative factors of cigarettes. Therefore, N.

PROTOCOL P 0500/3203 930827 PAGE 4 we considered the performance of this study as very well jus- tified.

PROTOCOL P 0500/3203 930827 PAGE 5 3 DESIGN AND PROCEDURES --------------------- --------------------- 3.1 Research 3.1.1 Inclusion and exclusion criteria For the study, 30 healthy male volunteers with normal or corrected to normal vision will serve as subjects. All subjects will be recruited locally and will be paid for their participation. For inclusion in the study, the subjects must fulfill the following criteria: I (1) between 20 and`40 years of age (2) smoke at least 10 nonmenthol cigarettes per day for at least 2 years (3) be in good general health as determined by prior physical ex- amination including blood chemistry (4) agree to sign informed consent form __.(5)-'agree to sign a non-disclosure form (6) can be reached by telephone Participation in the study will not be permitted if the subjects meet any of the following exclusion criteria: (1) vision that is not normal or not corrected to normal (2) inability to completely understand informed consent (3) long-term medication (4) history of respiratory illness (5) history of neurological disorders (6) history of drug or alcohol abuse (7) concurrent participation in other clinical studies (8) staff of the institute and their relatives

PROTOCOL P 0500/3203 930827 PAGE 6 On testing days, subjects will be required to report to the in- stitute 2 hours prior to the beginning of the test. They will be required to abstain from smoking or ingesting any form of nicotine for 2 hours prior to testing. They will be required to abstain from ingesting caffeine in any form for 2 hours before the tests. Additionally, the subjects will be required to abstain from using alcohol, illegal drugs, drugs requiring a doctor's prescription or other medications that might produce drowsiness, excitation, or affect mental alertness for at least 8 hours prior to testing. Medications that might otherwise affect vision at times of testing are also prohibited. Subjects will be discontinued and replaced if they ask to withdraw from the study, meet any of the exclusion criteria, or have ad- verse reactions during the test session. Subjects will also be discontinued if they, on more than two occasions, fail to comply with any aspect of the experimental requirements. All records identifying subjects by name, will be locked in a secure location and will only be made available to the clinical study director, the attending physician and the experimenters. _.._ ._.._..~........_..._...._.,,.....~,._..._....,,....... s-v~ri3-l-be'~sYOpe~''Ty"disposed` of when no longer need'ed: All o~ records, such as data stored in computer data bases and hard copies will be coded. 3.1.2 Informed Consent (see Appendix 1) Subjects will read a detailed explanation of all the pertinent facts of the experiment. This will include:

PROTOCOL P 0500/3203 930827 PAGE 7 (1) data confidentiality, (2) what tobaccos are in the cigarettes, (3) what, if anything, has been added to the tobacco, (4) how nicotine was removed from the tobacco, (5) nicotine and tar deliveries, (6) what the PREP is and how it is recorded, (7) cleanliness and sterilization procedures. After the subjects have read the material, the attending physician will go over the important facts verbally to ascertain whether the subjects fully understood the information. Subjects will then be asked to sign an informed consent form agreeing to participate in the study. 3.1.3 Nondi$closure agreement ~ (see Appendix 2) 3.2 Ethical Principles The studies will adhere to the ethical guidelines for non- therapeutic biomedical research involving human subjects as set forth in the World Medical Association Declaration of Helsinki/Tokyo/Venice/Hongkong (1964, 1975, 1983, 1989) and those set forth by the council for International Organization of Medical Sciences (CIOMS) in the International Ethical Guidelines for Biomedical Research Involving Human Subjects (First Draft, January 1992).

•PROTOCOL P 0500/3203 930827 PAGE 8 3.3 Subiect Remuneration Subjects will be paid 50,-DM for the first test session. This amount will be increased by 10,-DM for each of the following ses- sions (max. 10). The subjects will be payed irrespective of whether the tests were successfully completed or not. The only ex- ceptions would be that subjects would not be paid for a test session if they failed to comply with the conditions specified in 3.1.1. 3.4 Subiect Insurance All subjects will be insured according to the legal requirements for the conducting of clinical studies (S40 AMG). 3.5 Cigarette Specifications (see also APPENDIX 3) -1 11 The cigarettes have been prepared using a American tobacco blend. A single lot of tobacco was divided into portions, one portion of which was extracted of nicotine using CO2 supercritical fluid ex- traction procedures (Grubbs et al., 1991). The extracteo, tobacco ~ was combined in varying proportions with unextracted tobcco. This resulted in cigarettes with constant tar (approx. 17 mg) but vary- ing levels of nicotine (0.12 to 1.56 mg/cig.). These tar and nicotine levels are well within the range of those found in cigarettes commercially available in Germany (see appendix 4). Nine cigarette types were produced with the following tar and nicotine levels:

PROTOCOL P 0500/3203 270893 PAGE 9 CIGARETTE CODE TAR NICOTINE (mg/cig.) (mg/cig.) AGH 17.0 0.12 AGI 16.8 0.19 AGJ 16.8 0.41 AGK 17.2 0.66 AGL 16.5 0.83 AGM 16.6 0.98 AGN 16.9 1.21 AGO 17.0 1.40 AGP 16.9 1.56 TABLE 1 TAR AND NICOTINE DELIVERIES OF TEST CIGARETTES Remarks: data provided by the client