Interim safety and immunogenicity of COVID-19 omicron BA.1 variant-containing vaccine in children in the USA: an open-label non-randomised phase 3 trial.

BACKGROUND: Variant-containing mRNA vaccines for COVID-19 to broaden protection against SARS-CoV-2 variants are recommended based on findings in adults. We report interim safety and immunogenicity of an omicron BA.1 variant-containing (mRNA-1273.214) primary vaccination series and booster dose in paediatric populations. METHODS: This open-label, two-part, non-randomised phase 3 trial enrolled participants aged 6 months to 5 years at 24 US study sites. Eligible participants were generally healthy or had stable chronic conditions, without known SARS-CoV-2 infection in the previous 90 days. Individuals who were acutely ill or febrile 1 day before or at the screening visit or those who previously received other COVID-19 vaccines (except mRNA-1273 for part 2) were excluded. In part 1, SARS-CoV-2-vaccine-naive participants received two-dose mRNA-1273.214 (25 µg; omicron BA.1 and ancestral Wuhan-Hu-1 mRNA) primary series. In part 2, participants who previously completed the two-dose mRNA-1273 (25 µg) primary series in KidCOVE (NCT04796896) received a mRNA-1273.214 (10 µg) booster dose. Primary study outcomes were safety and reactogenicity of the mRNA-1273.214 primary series (part 1) or booster dose (part 2) as well as the inferred effectiveness of mRNA-1273.214 based on immune responses against ancestral SARS-CoV-2 (D614G) and omicron BA.1 variant at 28 days post-primary series (part 1) or post-booster dose (part 2). The safety set included participants who received at least one dose of the study vaccine; the immunogenicity set included those who provided immunogenicity samples. Interim safety and immunogenicity are summarised in this analysis as of the data cutoff date (Dec 5, 2022). This trial is registered with ClinicalTrials.gov, NCT05436834. FINDINGS: Between June 21, 2022, and Dec 5, 2022, 179 participants received one or more doses of mRNA-1273.214 primary series (part 1) and 539 received a mRNA-1273.214 booster dose (part 2). The safety profile within 28 days after either dose of the mRNA-1273.214 primary series and the booster dose was consistent with that of the mRNA-1273 primary series in this age group, with no new safety concerns or vaccine-related serious adverse events observed. At 28 days after primary series dose 2 and the booster dose, both mRNA-1273.214 primary series (day 57, including all participants with or without evidence of prior SARS-CoV-2 infection at baseline) and booster (day 29, including participants without evidence of prior SARS-CoV-2 infection at baseline) elicited responses that were superior against omicron-BA.1 (geometric mean ratio part 1: 25·4 [95% CI 20·1-32·1] and part 2: 12·5 [11·0-14·3]) and non-inferior against D614G (part 1: 0·8 [0·7-1·0] and part 2: 3·1 [2·8-3·5]), compared with neutralising antibody responses induced by the mRNA-1273 primary series (in a historical comparator group). INTERPRETATION: mRNA-1273.214 was immunogenic against BA.1 and D614G in children aged 6 months to 5 years, with a comparable safety profile to mRNA-1273, when given as a two-dose primary series or a booster dose. These results are aligned with the US Centers for Disease Control and Prevention recommendations for the use of variant-containing vaccines for continued protection against the emerging variants of SARS-CoV-2. FUNDING: Moderna.

Evaluation of mRNA-1273 Vaccine in Children 6 Months to 5 Years of Age.

BACKGROUND: The safety, reactogenicity, immunogenicity, and efficacy of the mRNA-1273 coronavirus disease 2019 (Covid-19) vaccine in young children are unknown. METHODS: Part 1 of this ongoing phase 2-3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled evaluation of the selected dose. In part 2, we randomly assigned young children (6 months to 5 years of age) in a 3:1 ratio to receive two 25-µg injections of mRNA-1273 or placebo, administered 28 days apart. The primary objectives were to evaluate the safety and reactogenicity of the vaccine and to determine whether the immune response in these children was noninferior to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives were to determine the incidences of Covid-19 and severe acute respiratory syndrome coronavirus 2 infection after administration of mRNA-1273 or placebo. RESULTS: On the basis of safety and immunogenicity results in part 1 of the trial, the 25-µg dose was evaluated in part 2. In part 2, 3040 children 2 to 5 years of age and 1762 children 6 to 23 months of age were randomly assigned to receive two 25-µg injections of mRNA-1273; 1008 children 2 to 5 years of age and 593 children 6 to 23 months of age were randomly assigned to receive placebo. The median duration of follow-up after the second injection was 71 days in the 2-to-5-year-old cohort and 68 days in the 6-to-23-month-old cohort. Adverse events were mainly low-grade and transient, and no new safety concerns were identified. At day 57, neutralizing antibody geometric mean concentrations were 1410 (95% confidence interval [CI], 1272 to 1563) among 2-to-5-year-olds and 1781 (95% CI, 1616 to 1962) among 6-to-23-month-olds, as compared with 1391 (95% CI, 1263 to 1531) among young adults, who had received 100-µg injections of mRNA-1273, findings that met the noninferiority criteria for immune responses for both age cohorts. The estimated vaccine efficacy against Covid-19 was 36.8% (95% CI, 12.5 to 54.0) among 2-to-5-year-olds and 50.6% (95% CI, 21.4 to 68.6) among 6-to-23-month-olds, at a time when B.1.1.529 (omicron) was the predominant circulating variant. CONCLUSIONS: Two 25-µg doses of the mRNA-1273 vaccine were found to be safe in children 6 months to 5 years of age and elicited immune responses that were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896.).

Humoral Immunogenicity of the mRNA-1273 Vaccine in the Phase 3 Coronavirus Efficacy (COVE) Trial.

BACKGROUND: Messenger RNA (mRNA)-1273 vaccine demonstrated 93.2% efficacy against coronavirus disease 2019 (COVID-19) in the Coronavirus Efficacy (COVE) trial. The humoral immunogenicity results are now reported. METHODS: Participants received 2 mRNA-1273 (100 µg) or placebo injections, 28 days apart. Immune responses were evaluated in a prespecified, randomly selected per-protocol immunogenicity population (n = 272 placebo; n = 1185 mRNA-1273). Serum binding antibodies (bAbs) and neutralizing antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-spike protein were assessed at days 1, 29, and 57 by baseline SARS-CoV-2-negative (n = 1197) and SARS-CoV-2-positive (n = 260) status, age, and sex. RESULTS: SARS-CoV-2-negative vaccinees had bAb geometric mean AU/mL levels of 35 753 at day 29 that increased to 316 448 at day 57 and nAb inhibitory dilution 50% titers of 55 at day 29 that rose to 1081 at day 57. In SARS-CoV-2-positive vacinees, the first mRNA-1273 injection elicited bAb and nAb levels that were 11-fold (410 049) and 27-fold (1479) higher than in SARS-CoV-2-negative vaccinees, respectively, and were comparable to levels after 2 injections in uninfected participants. Findings were generally consistent by age and sex. CONCLUSIONS: mRNA-1273 elicited robust serologic immune responses across age, sex, and SARS-CoV-2 status, consistent with its high COVID-19 efficacy. Higher immune responses in those previously infected support a booster-type effect. Clinical Trials Registration. NCT04470427.

Safety, Tolerability, and Immunogenicity of a 20-Valent Pneumococcal Conjugate Vaccine (PCV20) in Adults 60 to 64 Years of Age.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) have significantly decreased pneumococcal disease worldwide; however, expanding serotype coverage may further reduce disease burden. A 20-valent PCV (PCV20) containing capsular polysaccharide conjugates of serotypes present in the 13-valent PCV (PCV13) and 7 new serotypes (8, 10A, 11A, 12F, 15B, 22F, and 33F) is currently in development. This phase 2 study evaluated safety, tolerability, and immunogenicity of PCV20 in adults without prior pneumococcal vaccination. METHODS: In this randomized, active-controlled, double-blinded trial, 444 adults 60 through 64 years of age were randomized to receive either a single dose of PCV20 followed 1 month later by saline placebo or a single dose of PCV13 followed 1 month later by 23-valent polysaccharide vaccine. Local injection site reactions, select systemic symptoms, and adverse events (AEs) were recorded. Immunogenicity was assessed by measuring serotype-specific opsonophagocytic activity (OPA) titers before and approximately 1 month after each vaccination. RESULTS: Local reaction and systemic event rates were similar after vaccination with PCV20 or PCV13; no serious vaccine-related AEs were reported. In the PCV20 group, functional immune responses as measured by OPA were robust for all 20 serotypes included in the vaccine, with geometric mean fold rises from baseline ranging from 6.0 to 113.4. CONCLUSIONS: PCV20 was well tolerated in adults 60 to 64 years of age, with a safety profile consistent with historical experience of PCVs in this age group. Substantial OPA responses were elicited against all serotypes. Results demonstrate the potential for PCV20 to expand pneumococcal disease protection. CLINICAL TRIALS REGISTRATION: NCT03313037.

Case finding for chronic obstructive pulmonary disease in primary care: a pilot randomised controlled trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. However, much of the disease burden remains undiagnosed. AIM: To compare the yield and cost effectiveness of two COPD case-finding approaches in primary care. DESIGN AND SETTING: Pilot randomised controlled trial in two general practices in the West Midlands, UK. METHOD: A total of 1634 ever-smokers aged 35-79 years with no history of COPD or asthma were randomised into either a 'targeted' or 'opportunistic' case-finding arm. Respiratory questionnaires were posted to patients in the 'targeted' arm and provided to patients in the 'opportunistic' arm at routine GP appointments. Those reporting at least one chronic respiratory symptom were invited for spirometry. COPD was defined as pre-bronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC)<0.7 and FEV1<80% of predicted. Primary outcomes were the difference in the proportion of patients diagnosed with COPD and the cost per case detected. RESULTS: Twenty-six per cent (212/815) in the 'targeted' and 13.6% (111/819) in the 'opportunistic' arm responded to the questionnaire and 78.3% (166/212) and 73.0% (81/111), respectively, reported symptoms; 1.2% (10/815) and 0.7% (6/819) of patients in the 'targeted' and 'opportunistic' arms were diagnosed with COPD (difference in proportions = 0.5% [95% confidence interval {CI} = -0.5% to 3.08%]). Over a 12-month period, the 'opportunistic' case-finding yield could be improved to 1.95% (95% CI = 1.0% to 2.9%). The cost-per case detected was £424.56 in the 'targeted' and £242.20 in the 'opportunistic' arm. CONCLUSION: Opportunistic case finding may be more effective and cost effective than targeting patients with a postal questionnaire alone. A larger randomised controlled trial with adequate sample size is required to test this.

A multi-component stair climbing promotional campaign targeting calorific expenditure for worksites; a quasi-experimental study testing effects on behaviour, attitude and intention.

BACKGROUND: Accumulation of lifestyle physical activity is a current aim of health promotion, with increased stair climbing one public health target. While the workplace provides an opportunity for regular stair climbing, evidence for effectiveness of point-of-choice interventions is equivocal. This paper reports a new approach to worksite interventions, aimed at changing attitudes and, hence, behaviour. METHODS: Pre-testing of calorific expenditure messages used structured interviews with members of the public (n = 300). Effects of multi-component campaigns on stair climbing were tested with quasi-experimental, interrupted time-series designs. In one worksite, a main campaign poster outlining the amount of calorific expenditure obtainable from stair climbing and a conventional point-of-choice prompt were used (Poster alone site). In a second worksite, additional messages in the stairwell about calorific expenditure reinforced the main campaign (Poster + Stairwell messages site). The outcome variables were automated observations of stair and lift ascent (28,854) and descent (29,352) at baseline and for three weeks after the intervention was installed. Post-intervention questionnaires for employees at the worksites assessed responses to the campaign (n = 253). Analyses employed Analysis of Variance with follow-up Bonferroni t-tests (message pre-testing), logistic regression of stair ascent and descent (campaign testing), and Bonferroni t-tests and multiple regression (follow-up questionnaire). RESULTS: Pre-testing of messages based on calorific expenditure suggested they could motivate stair climbing if believed. The new campaign increased stair climbing, with greater effects at the Poster + Stairwell messages site (OR = 1.52, 95% CI = 1.40-1.66) than Posters alone (OR = 1.24, 95% CI = 1.15-1.34). Follow-up revealed higher agreement with two statements about calorific outcomes of stair climbing in the site where they were installed in the stairwell, suggesting more positive attitudes resulted from the intervention. Future intentions for stair use were predicted by motivation by the campaign and beliefs that stair climbing would help weight control. CONCLUSIONS: Multi-component campaigns that target attitudes and intentions may substantially increase stair climbing at work.

Multicenter, double-blind, placebo-controlled crossover study to assess the acute prokinetic efficacy of nizatidine-controlled release (150 and 300 mg) in patients with gastroesophageal reflux disease.

INTRODUCTION: The aim of the study is to test whether nizatidine delivered via a unique bimodal pulsatile-controlled release system, nizatidine controlled release (CR), accelerates gastric emptying in patients with gastroesophageal reflux disease (GERD). METHODS: Combined data were analyzed on 39 patients with delayed gastric emptying (DGE) from 2 studies (n = 84) assessing the prokinetic effect of nizatidine CR. A single-blind placebo baseline was followed by double-blind nizatidine CR (150 and 300 mg) in randomized sequence, 2 to 5 days apart. Each dose was followed 1 hour later by an egg-beater meal, labeled with Tc99m. Gamma camera images were obtained at meal completion, 1-, 2-, 3- and 4-hour postmeal. All the 84 patients were classified at baseline with DGE (gastric retention >6.3% at 4 hours) or normal gastric emptying. RESULTS: In the 39 patients identified with DGE, change from placebo baseline (CFB) for percent gastric retention at 4-hour postmeal with nizatidine CR (150 and 300 mg) was each improved and statistically significant (P < 0.05). In a subgroup of diabetic patients with DGE (n = 10), the CFB with nizatidine CR (300 mg) was significant (P < 0.05) at 3- and 4-hour postmeal. CONCLUSIONS: Nizatidine CR (150 and 300 mg) significantly enhanced gastric emptying of a standard meal in patients with GERD with DGE.

Evaluation of two nitrous oxide scavenging systems using infrared thermography to visualize and control emissions.

BACKGROUND: The authors conducted a study to determine the effectiveness of two waste anesthetic gas-scavenging systems. They also evaluated one of the systems to determine the effect of work practices in controlling waste nitrous oxide (N2O). METHODS: The authors collected a minimum of 13 data sets in each phase of the study that included infrared thermography, digital videography and real-time air analysis for ambient concentrations of waste N2O. Surgeon 1, who had experience using both systems, used the Safe Sedate Dental Mask (Airgas, Radnor, Pa.) system (system I) in phase I and the Porter Nitrous Oxide Sedation System (Porter Instruments, Hatfield, Pa.) (system II) in phase II. Surgeon 2, who did not have experience using system I, used it in phase III. To evaluate each system's effectiveness, the authors collected N2O air concentration data from phases I and II and compared the data with the National Institute for Occupational Safety and Health Recommended Exposure Limit (NIOSH REL). They also compared phases I and III to determine the effect of work practices on the systems' effectiveness. RESULTS: Surgeon 1 controlled occupational exposure to N2O significantly better using system I than using system II. Mean N2O air concentration levels during phases I and II were 61.6 parts per million (ppm) and 225.6 ppm, respectively. Surgeon 2 did not achieve results comparable to those of surgeon 1 in phase I using system I. Infrared thermography and air concentration data suggested that key work practices and patient and surgical variables accounted for the different results obtained in phases I and III. CONCLUSIONS: Although neither system was able to control occupational exposure of N2O oxide below the NIOSH REL, system I met the American Conference of Governmental Industrial Hygienists threshold limit value of less than 50 ppm during an eight-hour day and performed significantly better than did system II. CLINICAL IMPLICATIONS: System I achieved maximal efficiency when combined with consistent best work practices.

The effect of Transtheoretical Model based interventions on smoking cessation.

The Transtheoretical Model (TTM) proposes that stage matching improves the effectiveness of behaviour change interventions, such as for smoking cessation. It also proposes that standard smoking cessation interventions are matched to the relatively few smokers in the preparation stage and will not assist the majority of smokers, who are in the precontemplation or contemplation stages. This study tested the hypothesis that stage-matched interventions increase movement through the stages relative to interventions not stage-matched. It also tested the hypothesis that the relative effectiveness of stage-matched interventions is greater for people in precontemplation or contemplation (stage-matched for TTM but not for control) than for people in preparation (where both intervention and control were stage-matched). A total of 2471 UK adult smokers were randomised to either control or TTM-based self-help intervention and followed up 12 months after beginning the programme. Content analysis of the intervention and control self-help interventions examined whether control interventions were action-oriented, meaning they emphasised the processes of change relevant for preparation and action. Participants in the TTM arm were slightly more likely to make a positive move in stage, but this was not significant. There was no evidence that the TTM-based intervention was more effective for participants in precontemplation or contemplation than for participants in preparation. There was no evidence that TTM-based interventions were effective in this trial. The control intervention advocated process use appropriate for all stages and was not action-orientated. Stage matching does not explain the modest effects of TTM-based interventions over control interventions observed in some trials. These effects may instead have occurred because TTM-based interventions were more intensive than control interventions.

Modelling effects of stair width on rates of stair climbing in a train station.

OBJECTIVES: Commuters leaving a station often choose the stair as a quicker exit than the escalator. This paper models the effects of speed leaving the station and stair width on choice of the stairs or escalator. METHODS: Aggregated data from previous studies (n=82,347) revealed a plateau at about 45% stair use as the number leaving each train rose. Subsequently, the time taken by passengers on the stairs and escalator was measured in a station in Birmingham, UK in 2007 (n=5848). The resulting transport rates (passengers s(-1)) for stairs and escalators at the average commuting traffic were used to estimate the effects of increases in stair width on choice of the stairs. RESULTS: Average transport rates were higher for the escalator (0.93+/-0.33 passengers s(-1)) than the stairs (0.58+/-0.24 passengers s(-1)). Modelling of the effects of transport rate with multiple regression suggested 40.1% of passengers would use the stairs, a figure close to the observed rate. Using similar calculations, a doubling of width of the stairs could result maximally in a 17.2% increase in stair use. CONCLUSIONS: Changes to the width of stairs could produce a permanent increase in lifestyle physical activity immune to the effects of time on healthy intentions.

Cluster randomised controlled trial of the effectiveness of primary care mental health workers.

BACKGROUND: Mental health issues are a core part of the work of primary care and are the second most common reason for consultations. There is some evidence that the quality of primary care mental health provision is variable. AIM: To evaluate the effectiveness of primary care mental health workers with regards to satisfaction with care, mental health symptoms, use of the voluntary sector, and cost effectiveness of care. DESIGN OF STUDY: Cluster randomised controlled trial. SETTING: Practices in the Heart of Birmingham Primary Care Trust, Birmingham, England. METHOD: Nineteen practices and 368 patients (18 to 65 years of age) with a diagnosis of a new or ongoing common mental health problem were recruited. Sixteen practices and 284 patients completed the trial. RESULTS: Patients in intervention practices had a higher mean level of general satisfaction than those in control practices (difference between group scores of 8.3, 95% confidence interval = 1.3 to 15.3, P = 0.023). The two groups did not differ in mental health symptom scores or use of the voluntary sector. CONCLUSION: For patients with common mental health problems, primary care mental health workers may be effective at increasing satisfaction with an episode of care.

A randomized controlled trial of smoking cessation for pregnant women to test the effect of a transtheoretical model-based intervention on movement in stage and interaction with baseline stage.

OBJECTIVES: To examine whether, as predicted by the transtheoretical model (TTM), stage-matched interventions will be more effective than stage-mismatched interventions. DESIGN: Randomized controlled trial of smoking cessation advice to pregnant smokers. METHODS: Pregnant women currently smoking at 12 weeks gestation were enrolled in a pragmatic three-arm trial of TTM-based interventions to help them stop smoking. One arm constituted standard midwifery advice and a self-help leaflet on stopping smoking, which is generally appropriate for women in preparation. Two arms were TTM-based. Differences in positive movement in stage towards quitting from enrolment to 30 weeks gestation and 10 days post-partum were calculated for each arm of the trial. We then examined whether, as predicted from the TTM, the relative benefit of the TTM-based intervention was greater for women in precontemplation and contemplation, for whom the control intervention was stage-mismatched, than for women in preparation, for whom the control intervention was stage-matched. RESULTS: Women in the TTM-based arms were statistically significantly more likely to move forward in stage than were women in the control arm. Contrary to the TTM-derived hypothesis, the greater relative benefit of the TTM-based intervention was seen for women in preparation stage at baseline, rather than women in precontemplation and contemplation. CONCLUSIONS: The TTM-based intervention was more effective in stage movement, but this could be due to its greater intensity. The failure to confirm that stage-matching was important casts doubt on the validity of the TTM in explaining smoking cessation behaviour in pregnancy.

Does stage-based smoking cessation advice in pregnancy result in long-term quitters? 18-month postpartum follow-up of a randomized controlled trial.

AIMS: To evaluate the effect on quitting smoking at 18 months postpartum of smoking cessation interventions based on the Transtheoretical Model (TTM) delivered in pregnancy compared to current standard care. It has been claimed that TTM-based interventions will continue to create quitters after the end of the intervention period. DESIGN: Cluster randomized trial. SETTING: Antenatal clinics in general practices in the West Midlands, UK. PARTICIPANTS: A total of 918 pregnant smokers originally enrolled in the trial, of which 393 women were followed-up at 18 months postpartum. INTERVENTIONS: One hundred general practices were randomized into the three trial arms. Midwives in these practices delivered three interventions: A (standard care), B (TTM-based self-help manuals) and C (TTM-based self-help manuals plus sessions with an interactive computer program giving individualized smoking cessation advice). MEASUREMENTS: Self-reported continuous and point prevalence abstinence since pregnancy. FINDINGS: When combined together, there was a slight and not significant benefit for both TTM arms compared to the control, with an odds ratio (OR) 95% confidence interval (CI) of 1.20 (0.29-4.88) for continuous abstinence. For point prevalence abstinence, the OR (95%CI) was 1.15 (0.66-2.03). Seven of the 54 (13%) women who had quit at the end of pregnancy were still quit 18 months later, and there was no evidence that the TTM-based interventions were superior in preventing relapse. CONCLUSIONS: The TTM-based interventions may have shown some evidence of a short-term benefit for quitting in pregnancy but no benefit relative to standard care when followed-up in the longer-term.

Composite outcomes in randomized trials: greater precision but with greater uncertainty?

Composite outcomes, in which multiple end points are combined, are frequently used as primary outcome measures in randomized trials and are often associated with increased statistical efficiency. However, such measures may prove challenging for the interpretation of results. In this article, we examine the use of composite outcomes in major clinical trials, assess the arguments for and against them, and provide guidance on their application and reporting. To assess incidence and quality of reporting, we systematically reviewed the use of composite end points in clinical trials in Annals of Internal Medicine, BMJ, Circulation, Clinical Infectious Diseases, Journal of the American College of Cardiology, JAMA, Lancet, New England Journal of Medicine, and Stroke from 1997 through 2001 using a sensitive search strategy. We selected for review 167 original reports of randomized trials (with a total of 300 276 patients) that included a composite primary outcome that incorporated all-cause mortality. Sixty-three trials (38%) were neutral both for the primary end point and the mortality component. Sixty trials (36%) reported significant results for the primary outcome measure but not for the mortality component. Only 6 trials (4%) were significant for the mortality component but not for the primary composite outcome, whereas 19 trials (11%) were significant for both. Twenty-two trials (13%) were inadequately reported. Our review suggests that reporting of composite outcomes is generally inadequate, implying that the results apply to the individual components of the composite outcome rather than only to the overall composite. Current guidelines for the undertaking and reporting of clinical trials could be revised to reflect the common use of composite outcomes in clinical trials.

A controlled trial of an expert system and self-help manual intervention based on the stages of change versus standard self-help materials in smoking cessation.

AIM: To examine the population impact and effectiveness of the Pro-Change smoking cessation course based on the Transtheoretical Model (TTM) compared to standard self-help smoking cessation literature. DESIGN: Randomized controlled trial. SETTING: Sixty-five West Midlands general practices. PARTICIPANTS: Randomly sampled patients recorded as smokers by their general practitioners received an invitation letter and 2471 current smokers agreed. INTERVENTIONS: Responders were randomized to one of four interventions. The control group received standard self-help literature. In the Manual intervention group, participants received the Pro-Change system, a self-help workbook and three questionnaires at 3-monthly intervals, which generated individually tailored feedback. In the Phone intervention group, participants received the Manual intervention plus three telephone calls. In the Nurse intervention group, participants received the Manual intervention plus three visits to the practice nurse. MEASUREMENTS: Biochemically confirmed point prevalence of being quit and 6-month sustained abstinence, 12 months after study commencement. FINDINGS: A total of 9.1% of registered current smokers participated, of whom 83.0% were not ready to quit. Less than half of participants returned questionnaires to generate second and third individualized feedback. Telephone calls reached 75% of those scheduled, but few participants visited the nurse. There were small differences between the three Pro-Change arms. The odds ratio (95% confidence intervals) for all Pro-Change arms combined versus the control arm were 1.50 (0.85-2.67) and 1.53 (0.76-3.10), for point prevalence and 6-month abstinence, respectively. This constitutes 2.1% of the TTM group versus 1.4% of the control group achieving confirmed 6-month sustained abstinence. CONCLUSIONS: There was no statistically significant benefit of the intervention apparent in this trial and the high relapse of quitters means that any population impact is small.