Recruitment for an efficacy study in chemoprevention—The concerned smoker study

PREVENTIVE MEDICINE 18, 700-710 (1989)

Recruitment for an Efficacy Study in Chemoprevention-The Concerned Smoker Study’

ANDREW ARNOLD, M.B.Bs.,MRCP,FRCP,* BRENDAJOHNSTONE, R.N., BARBARA STOSKOPF, R.N., PETER~KINGLEY, M.D.,M.Sc.,FRCPC,

GEORGE BROWMAN,MARK LEVINE, M.D.,M.Sc.,FRCPC, AND WILLIAM HRYNIUK, M.D.,FRCPC

Ontario Cancer Treatment and Research Foundation, Hamilton Regional Cancer Centre, St. Joseph’s Hospital Clinic, 50 Charlton Avenue East, Hamilton L.%N 4A6,

and McMaster University, Hamilton, Ontario, Canada

Efficacy studies are important for the development of long-term cancer prevention strategies. Recruitment aims for a highly motivated group of participants. The Concerned Smoker Study is aimed at smokers with at least a 15 pack-year history and bronchial atypia on sputum sampling Recruitment has been primarily through use of the media. During the first year of randomization 905 potential participants expressed interest. Of these, 80 were eventually randomized. With over 60 participants having completed the study only one has defaulted and compliance with the study protocol has been high. Participants became aware of the study through the following sources: daily newspaper 36.6%, weekly newspaper 16.2%, television 14.9%, radio 13.8%, community television 1.3%, other sources 13.3%. Over 90% of potential participants who initially express interest in such a chemoprevention project may not ultimately be suitable. The population chosen for such studies may not be very representative of the more general population; however, a high degree of compliance can be obtained which will provide valuable information on treatment efficacy. a 1989

Academic Press. Inc.

INTRODUCTION

Bronchial atypia is a potentially premalignant lesion and its reversal can serve as an intermediate biological endpoint for trials testing the efficacy of chemopre- ventive agents. In smokers atypia increases with age and, by inference, duration of exposure to the carcinogen (l-3). While serial sputum sampling does not always show progression, and spontaneous regression is known to occur, there appears to be an average period of 4-5 years during which individuals exfoliate markedly atypical cells prior to developing invasive carcinoma.

The Concerned Smoker Study is a double-blind placebo controlled study carried out in a single center and recruiting from a total population base of approximately 500,000. The target population is heavy smokers, who are otherwise in good health and who have bronchial atypia on sputum sampling. The study ad- dresses the following questions:

a. Does administration of the synthetic retinoid etretinate, at an oral dose of 25

r Funded by a grant from the Ontario Ministry of Health. Additional support provided by Hoffmann- La Roche, Canada.

* To whom reprint requests should be addressed.

700

0091-7435/89 $3.00 Copyright 0 1989 by Academic Press, Inc. All rights of reproduction in any form reserved.

CONFERENCE: PREVENTION OF HUMAN CANCER 701

mg daily, to a group of smokers with atypia on sputum sampling, produce a clinically significant reduction in the level of atypia when compared with a placebo?

b. Are the side effects of etretinate, at an oral dose of 25 mg daily, acceptable to this group of participants?

The study is the first major chemoprevention trial to be carried out in Canada and has a planned duration of 4 years. Agrass and Bradford have acknowledged that the complexities and difficulties of the recruitment process of clinical trials have been underestimated (4). This is particularly relevant when trying to recruit healthy members of the public and screen them for a potentially premalignant disorder.

Much of the published literature concerning the recruitment process relates to large multicenter trials. Hunninghake et al. have made a strong plea for the increased reporting of recruitment results from all clinical trials to obtain solutions to many of the potential problems that can arise (5).

The Concerned Smoker Study was designed to test the efficacy of the pre- scribed intervention under optimal experimental conditions. This required the recruitment of a highly motivated, compliant group of participants. To aid subsequent recruitment efforts recruitment data were collected prospectively and reviewed monthly. The purpose of this article is to describe the recruitment strategy and enrollment experience during the first year and a half and to give some preliminary data on compliance.

METHODS

Pilot Study

From June to September 1986 a pilot study was carried out for the following purposes: (a) to provide preliminary recruitment experience; (b) to collect sputum samples for development of laboratory techniques; and (c) to provide an approx- imate estimate of the prevalence of bronchial atypia in the target population.

Heavy smokers were recruited mainly from staff working in local hospitals by posting notices on bulletin boards. Smokers were asked to return 3-day sputum samples to the laboratory. During this phase the only entry requirement was that subjects had a 15 or more pack-year smoking history; however, a number of participants later met the full entry requirements (see below) and were suitable for inclusion in the main study. On completion of the pilot study the experience gained was used to finalize details of the main study.

Main Study Details

The study schema is shown in Fig. 1. Contacts with at least a 15 pack-year smoking history, and judged potentially suitable after an initial phone call, were invited to attend a chemoprevention clinic run by the Hamilton Regional Cancer Centre. At the first protocol visit the study was explained in detail and possible side effects were discussed. Potential participants, not obviously excluded by the application of preliminary ineligibility criteria (Table I), were provided with spu-

702 ARNOLD ET AL.

ADVERTISE FOR VOLUNTEERS

APPLY ELIGIBILITY CRITERIA

PROGNOSTIC STRATIFICATION

Degree of Atypia Mild vs. Moderate or Severe Gender Female vs. Male

RANDOM ALLOCATION

I

&, &, FIG. 1. The concerned Smoker study: Schema.

turn jars and instructed on technique. They were asked to return to the clinic with three, 3-day early morning sputum samples collected at weekly intervals. The preparation of the slides and criteria used for sputum screening has been described in a separate publication (6).

If atypia, as specified in Table 2, was present and potential participants were not excluded on the basis of abnormal triglycerides, cholesterol, liver or renal function, or chest X-ray, they were eligible for study entry and asked to give informed consent. Entered participants were allocated to etretinate 25 mg po daily or an identical placebo for a 6-month period. Follow-up visits were scheduled at monthly intervals for return of subsequent sputum samples, to administer a toxicity questionnaire and for bloodwork. If necessary, dose reductions were made for toxicity. Both participants and study personnel were blind to the treatment allocation.

To encourage participation and compliance, the clinic was run to reflect the needs of well and predominantly employed pool population. Timing of visits was


TABLE 1 THECONCERNED SMOKERSTUDY:INELIGIBILITYCRITERIA

1. Subject is not able to produce an early morning sputum sample. 2. Pneumonia or acute bronchitis within the past 2 months. 3. Clinically significant ischemic heart disease or previous lung cancer. 4. A risk of pregnancy within the next 2 years, or presently pregnant. 5. A medical disorder likely to preclude safe drug administration. 6. Subject on large doses of vitamin A. 7. Unable to attend the clinic at specified intervals for 7 months. 8. Chest X-ray suspicious for carcinoma. 9. Cholesterol or triglycerides outside acceptable range for age and sex.

10. Unwilling to sign an informed consent.

flexible within the constraints of adhering to the overall protocol. Participants were reimbursed for out of pocket expenses such as travel and parking. Those fasting to provide triglyceride and cholesterol levels were offered breakfast vouchers following blood sampling.

Compliance was monitored, at each visit, by using an HPLC assay for serum etretinate level, by performing pill counts, and by monitoring the timely return of sputum samples.

Recruitment Strategy

The recruitment process is outlined in Fig. 2. The recruitment strategy aimed at steady accrual over a 2-year period. At the outset potential participants were to be sought from two main sources: (a) referral from other physicians, and (b) promotion through the media. Two other options, recruitment from occupational health units of large local employers and extension of the project to a second center, were held in reserve pending the recruitment experience of the first year.

The health profession. The health profession was approached immediately after the project received funding. The purpose of the study and entry criteria were presented at internal medicine and respirology rounds and discussions were held with heads of academic family practice units in Hamilton. Promotional material for physician’s oflices was prepared and sent, together with a cover letter from the investigators, to a list of over 100 local family physicians. Interviews with the investigators, outlining the study goals, were arranged in a number of medical newspapers distributed to all physicians.

The media. Initial media publicity was to be coordinated by the Public Relations Department at McMaster University. On completion of the pilot project a press

TABLE 2 THECONCERNEDSMOKERSTUDY:ELIGIBILITY CRITERIA

A 15 pack-year smoking history with one of the following: 1. At least two of three satisfactory sputum samples showing mild atypia or 2. At least one of three satisfactory sputum samples showing moderate or severe atypia.

704 ARNOLD ET AL.

ATTEND CLINIC

BRIEF HISTORY TO COVER SPECIFIC EXCLUSION CRITERIA

. CRITICAL INDICATION OF SUBJECT’S COMPLIANCE

1 FIG. 2. The concerned smoker study: Recruitment procedure.

release announcing the study was followed by a news conference which was covered by both local and national television and radio networks and the press. Once initial promotion of the study was complete, further publicity was coordinated by the investigators themselves. This comprised continued contact with local media for follow-up stories, local advertisements, and publicity material distributed in public places.

Management, Data Collection, and Coordination of Recruitment

At times of increased publicity, extra phone lines were installed and extra staff hired to facilitate the recruitment process. At the time of initial contact, prospec- tive information was sought from all potential participants concerning (a) the source from which they first learned of the study; (b) reasons for considering entry; and (c) demographic details. The recruitment process and accrual were monitored at monthly intervals and one member of the clinic staff was specifically assigned to review progress and to develop new sources of potential participants.

Recruitment Results

The recruitment experience leading to all randomizations during the first year of the project is presented in detail. Due to the lag-time between developing a source of recruitment and actual randomizations, from that source, the recruitment effort reported here extends over 1% years. It takes into account participants found eligible, during the period of the pilot study, and therefore describes the recruitment of all subjects randomized during 1987.


Planned orderly and steady recruitment of participants during the first year was interrupted by a premature press release from the Public Relations Department at McMaster University announcing the start of the study before the clinic was fully prepared. Within a few days of the press release pressure from the media forced the investigators to convene a news conference which received extensive broad- cast and press coverage. The reporting was generally both responsible and helpful in outlining the aims of the study and in listing entry criteria. The large public response nearly overwhelmed the clinic which received several hundred calls over a period of a few days. The investigators were required to seek additional funding for extra staff.

The predicted vs actual accrual during the first study year is shown in Table 3. The initial brisk response meant that, over the whole year, accrual was slightly ahead of that predicted though most participants were recruited within the first 4 months. As the year progressed, recruitment fell off and there was a considerable deterioration in the proportion of initial contacts eventually proceeding to entry. The ratio of screenees to actual randomizations during the first 4 months was approximately 3: 1. The final average for the whole year was 11: 1.

Subject flow through the various phases of recruitment is outlined in Fig. 3. From June 1986 to December 1987,905 potential participants (474 males and 431 females) contacted the clinic and 80 were eventually randomized. The mean time from initial contact to randomization was aproximately 3 months.

Of the 506 contacts invited to the clinic, 319 attended giving an overall efficiency of initial contact to first protocol visit of 319/905 (35%). Of the 319 making at least one protocol visit, 197 participants subsequently returned three satisfactory sputum samples while 122 did not complete the sputum screening process and were deemed noncompliant; 116 contacts successfully completing the screening process were ruled ineligible on the basis of having no significant atypia, abnormal blood tests, or abnormal chest X-ray. As an incidental finding, 2 participants had sputum positive for malignant cells and were referred for further investigation. Of those completing the sputum screening process, 81 were finally eligible for randomization but 1 refused consent.

Three hundred and ninety-nine contacts were not thought suitable for a protocol visit after an initial phone call (Table 4). Of these 110 (27.5%) were seeking a smoking cessation program and were referred to an appropriate source. A further 73 (18.3%) expressed interest but were unable to produce sputum. Fifty-six (14.0%) younger women were excluded as etretinate is contraindicated in those of child-bearing potential.

TABLE 3 THE CONCERNED SMOKER STUDY: PREDICTED VERSUS ACTUAL MEAN MONTHLY ACCRUAL

Estimated Actual

Number screened 21.0 19.3 Number with atypia 6.3 9.0 Number randomized 5.0 5.9

706 ARNOLD ET AL.

905 RESPOND TO ADVERTISING

I--

> 399 INELIGIBLE FOR INTERVIEW

506 ELIGIBLE FOR INTERVIEW

I-

> 187 DID NOT ATTEND INTERVIEW

319 ATTENDED THE INTERVIEW

I-

> 122 NON-COMPLIANT

47 COMPLETED RUN-IN PERIOD

I- > 116 INELIGIBLE by ENTRY CRITERIA

81 ELIGIBLE

t-

> 1 REFUSED TO CONSENT

ii0 RANDOMIZED

REQUIRED SAMPLE SIZE 128

FIG. 3. The Concerned Smoker Study: Flow through the steps in the recruitment pathway.

Sources of Contacts and Reasons for Interest in the Study

The sources that prompted initial contacts to call the clinic are indicated in Table 5. During the first year there were no direct referrals from physicians and a decision was made early on to rely upon media and community advertising as the main soruce of subsequent recruitment. Newspapers were the source of nearly 50% of initial contacts but accounted for 65% of all participants eventually randomized. Overall newspapers, television, and radio accounted for 93% of randomizations with a mean efficiency of approximately 10%. Other sources had a mean efficiency of about 3%.

Table 6 provides information on why smokers were initially interested in the study. One hundred forty-nine (16.5%) misunderstood the goals of the study and wished to stop smoking. It is of interest that 39 of these did not indicate such an interest until they had attended for the first protocol visit despite being told the


TABLE 4 THE CONCERNED SMOKER STUDY: REASONS INITIAL CONTACTS WERE UNSUITABLE FOR

FIRST INTERVIEW

Reason Number (%)

Seeking a smoking cessation program 110 Unable to produce sputum 13 Potential risk of pregnancy 56 Health problems 45 Insufficient pack-years 38 Time commitment too great 15 Not really interested 13 Geographically inaccessible 10 Sounded inappropriate 5 Other 17 Unknown 17

Total 399

(27.5) (18.3) (14.0) (11.3) (9.5) (3.8) (3.2) (2.5) (1.3) (4.3) (4.3)

purpose of the study at the time of the initial phone contact. For ethical reasons none of those seeking smoking cessation programs were considered for the study and they were referred elsewhere for smoking cessation counseling. Three hundred fifty-four (39.1%) expressed a definite concern about the risk of cancer and wished to be considered for participation in a study that might reduce such a risk; 64 (7.1%) were curious to know whether their smoking had led to damage. One hundred forty-three (15.8%) contacted the clinic for essentially altruistic reasons and wished to participate in a clinical research project.

Compliance Preliminary information concerning compliance is available on the first 75 par-

ticipants completing the 6-month treatment period and is described in detail in a separate publication (7). The expected to actual pill count ratio was in excess of 85%, while return of follow-up sputum samples was in excess of 95%. Serum sampling for etretinate levels showed that 91% subjects, on active treatment, had detectable levels. During the first year only 1 subject dropped out and refused follow-up.

TABLE 5 THE CONCERNED SMOKER STUDY: SOURCE LEADING TO INITIAL CLINIC CONTACT AND

EVENTUAL RANDOMIZATIONS

Source

Daily newspaper Weekly newspaper Television news Radio Community television Other Unknown

Initial contact

331 (36.6%) 137 (15.1%) 128 (14.1%) 115 (12.7%) 30 (3.3%)

120 (13.3%) 44 (4.8%)

Randomizations

39 (48.8%) 13 (16.2%) 12 (14.9%) 11 (13.8%) 1 (1.3%) 3 (3.7%) 1 (1.3%)

Totals 339 80

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TABLE 6 THECONCERNED SMOKERSTUDY:REASONSFORPOTENTIALPARTICIPANTSINITIATINGCONTACT

WITH THE CLINIC

Reason Number m

Concerned about cancer Wants to stop smoking Wishes to participate in a research project Curious about extent of lung damage Family pressure Other Unknown

Totals

354 (39.1%) 149 (16.5%) 143 (15.8%) 64 (7.1%) 14 (1.5%) 8 (0.9%)

173 (19.1%)

905

DISCUSSION

Several ongoing trials in the United States and Europe are testing the effective- ness of cancer chemoprevention in general or targeted populations (8,9). In most of these studies, the endpoints sought are reductions in cancer incidence or mor- tality rates. Before committing resources to such long-term studies, some indication of treatment efftcacy is desirable when potential interventions are delivered under optimal experimental conditions. The use of an intermediate biological endpoint such as reversal of a premalignant lesion can lead to a more efficient trial design as all entrants have the disorder in question (10). This reduces the sample size requirement and, for the entrant, the knowledge that a potentially premalignant lesion is present may increase motivation and increase the subsequent like- lihood of compliance with the experimental protocol.

The Concerned Smoker Study presented some unique problems for the investigators: (a) none had had previous experience undertaking such a project; (b) the response to the project by the health profession, media, and public was uncertain; and (c) there was no reliable information on the frequency or severity of atypia to be expected in the target population pool. Despite the specific nature of its ob- jectives the recruitment experience presented here is relevant to other projects that require healthy volunteers.

Hunninghake et al. (5) have recently presented a comprehensive literature review on the recruitment experience of clinical trials. Only 1 of 85 annotations concerned the recruitment of subjects for cancer prevention projects. Mettlin er al. (11) carried out an extensive survey to determine willingness of those free of cancer to participate in prevention studies. There have been no reports of the practical experiences of those attempting to recruit for chemoprevention projects.

During the first year overall recruitment was ahead of schedule which is unusual (12). As a result it is unlikely that there will be a need to relax the entry criteria or extend the projected trial period. Nevertheless the need for alternative strategies has been assessed by charting the monthly accrual rates, estimating the ratio of potential participants to actual randomizations, and taking into account the lag-time before new recruitment sources yield potential participants.

After the first few months, there has been an anticipated fall-off in recruitment.


The overall recruitment efficiency, during the first year, defined as the number of contacts required to obtain one entrant, was 11:l which is considerably better than most other reports (5). The phenomenon of local pool exhaustion and the fall-off in the proportion of initial contacts proceeding to randomization have been noted, in previous studies, and should be planned for in any similar investigation (13). In anticipation of the potential for continued decline in recruitment during subsequent years new sources of subjects for the Concerned Smokers Study are being developed. Approaches have been made to a large local steel company to start screening in the workplace and moves are underway for limited extension to another nearby urban center.

From the outset, information was obtained on recruitment source and this information has been reviewed monthly for subsequent strategies. Such close monitoring of sources is essential for effective planning (14,15). It has allowed the investigators to concentrate on sources producing the highest yield. Poor recruitment from the local medical community has been noted in other studies (16). At the time the study was initiated there were a number of other projects aimed at smokers in the Hamilton Region. This may have influenced physicians’ referral patterns. In addition, despite public enthusiasm, many physicians had concerns about a study that was not designed to help participants stop smoking.

The Concerned Smoker Study has relied extensively upon the mass media for recruitment. The media has been responsive and responsible in promoting the aims of the study. However, media sources were unpredictable (17). A premature press release nearly overwhelmed the clinic staff, within the first few months, and required the investigators to apply for more funding for extra staff. After an initial flurry of activity, media interest in a new project can quickly fall off, requiring continued search for new sources.

Of the media sources, used in the Concerned Smoker Study, daily newspapers have been most effective. The efficiency of 11.7% for daily newspapers was similar to the 14.5% reported for the coronary primary prevention trial (18). While the reason for this is unclear it may be that newspapers are able to give more information than shorter television or radio items. Furthermore, newspapers stay in circulation longer, potential contacts clip articles for further reference or to pass on to others, and they are more likely to remember contact phone numbers.

While much of the publicity for the study has outlined its goals and given information on general entry criteria, many of the smaller sources gave only limited information. It is clear that such limited information can be misinterpreted, as indicated by the large number of subjects seeking a smoking cessation program. As in previous studies a significant number of subjects were interested in participating in a prevention-related research program for apparently altruistic reasons (19).

Compliance in this study has been very high as measured by pill counts return of samples and drug level monitoring. This may reflect the fact that those who do not believe in the benefits of the study are unlikely to reach randomization. Similar attitudes have been responsible for high compliance in other studies (20). The initial phone contact with the study nurse provides the opportunity to assess a potential participant’s suitability to attend for more extensive screening. Clearly

710 ARNOLD ET AL.

unsuitable contacts, or those seeking a smoking cessation program, can be excluded from further consideration. As a result the study nurses can concentrate more time on potentially suitable candidates.

Close attention to detail and a considerable effort to accommodate to the vary- ing schedules of participants may have contributed to achieving a low drop-out rate and a high degree of participant compliance. While this population probably differs significantly from the general population of heavy smokers (21), a positive result would provide the justification for proceeding to larger studies in a more generalized population.

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chogenic carcinoma. Cancer 1956; 9:76. 2. Saccomanno G, Archer VE, Auerbach 0, Saunders RP, Brennan LM. Development of carcinoma

of the lung as reflected in exfoliated cells. Cancer 1974; 33:256. 3. Auerbach 0, Gere B, Forman JB, et al. Changes in the bronchial epithelium in relation to smoking

and cancer of the lung. N Engl J Med 1957; 256:97. 4. Agras WS, Bradford RH. Recruitment: An introduction. Circulation 1982; 66:(Suppl. IV), 2-4. 5. Hunninghake, DB, Darby CA, Probstfield JL. Recruitment experience in clinical trials: Literature

summary and annotated bibliography. Controlled Clin Trials (Suppl.) 1987; 86-30. 6. Browman GP, Arnold A, D’Souza T, Turner-Smith L, Cayco R, Johnstone B. Use of screening

phase data from a chemoprevention trial to evaluate observer variation of sputum cytodiagnosis as an outcome measure. Cancer Res. In press.

7. Browman GP, Arnold A, Booker L, Johnstone B, Skingley P, Levine MN. Etretinate blood levels to monitor compliance and contamination in a chemoprevention trial. JNCI 1989; 81:795-798.

8. Goodman GE, Omenn GS, Feigl P, et al. Chemoprevention of lung cancer with retinoids/ beta-carotene. Second International Conference on the Modulation and Mediation of Cancer by Vitamins and Micronutrients, Tucson, Arizona, 1985. (Abstract)

9. Proceedings of the IV World Conference on Lung Cancer, Toronto, Canada, 1985. 10. Zelen M. Are primary cancer prevention trials feasible? JNCI 1988; 80:1442-1444. 11. Mettlin C, Cummings KM, Walsh D. Risk factor and behavioral correlates of willingness to

participate in cancer prevention trials. Nutr Cancer 1985; 7:189-198. 12. Collins JF, Williiord WO, Weiss DG, Bingham SF, Klett CJ. Planning patient recruitment: Fan-

tasy and reality. Stat Med 1984; 3:435-443. 13. Schoenberger JA. Recruitment experience in the aspirin myocardial infarction study. Controlled

Clin Trials (Suppl.) 1987; 8:74-78. 14. Dunbar J, McKeown M. Organization and management of recruitment. Circularion 1982;

66:(Suppl. IV),49-53. 15. Lee JY. Interim recruitment goals in clinical trials. J Chron Dis 1983; 36379-389. 16. Marshall GD. Overview of recruitment to the coronary primary prevention trial. Circulation 1982;

ti(Supp1. IV),5-9. 17. Levenkron JC, Farquhar JW. Recruitment using mass media strategies. Circularion 1982;

ti(Supp1. IV),32-36. 18. Agras WS, Marshall GD, Kraemer HC. Planning recruitment. Circulation 1982; ti(Supp1. IV),54-

58. 19. Mattson ME, Curb JD, Mcardle R. Participation in a clinical trial; the patient’s point of view.

Controlled Clin Trials 1985; 6156-167. 20. Reiser J, Warner JO. The value of participating in an asthma trial. Lancer 1985; 1:206-207. 21. Wilhelmsen L, Ljungberg S, Wedel H, Werko L. Comparison between participants and non-

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Recruitment for an efficacy study in chemoprevention—The concerned smoker study

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