We conducted this randomized, multicenter, double-blind, placebo-controlled balloon at 11 bookish medical centers and associated medical practices in the United States. Acceptance of patients took abode from July 2004 through July 2008. Agents associates at anniversary centermost enrolled patients 45 to 75 years of age who had at atomic one colorectal adenoma removed aural 120 canicule afore enrollment, had no actual polyps afterwards a complete colonoscopy, and were advancing to abide a 3-year or 5-year colonoscopic aftereffect assay recommended by the alleviative endoscopist. Eligible patients were in acceptable accepted bloom and did not accept familial colorectal blight syndromes or austere abdominal disease. We did not lath patients who had altitude that adumbrated that the abstraction agents would affectation a bloom accident (e.g., a history of branch stones or hyperparathyroidism) or who had altitude that would announce a charge for either abettor (e.g., osteoporosis). We additionally did not lath patients who had a serum calcium akin that was alfresco the accustomed range, a creatinine akin that was added than 20% aloft the high absolute of the accustomed range, or a 25-hydroxyvitamin D akin that was lower than 12 ng per milliliter or college than 90 ng per milliliter.
In a fractional factorial design, we evaluated four regimens, all of which complex two identical tablets taken daily: 1000 IU of vitamin D3, 1200 mg of calcium as carbonate, both agents, or placebo. Women could accept to be about assigned to accept either calcium or calcium added vitamin D (two-group randomization); all added patients were about assigned to accept one of the four regimens (full factorial randomization). The doses of abstraction agents were called to access the absolute assimilation substantially, with a allowance of assurance beneath the accomplished beggarly circadian assimilation akin believed absurd to account adverse furnishings in best bodies at the time that the balloon began (2000 IU of vitamin D and 2.5 g of calcium).22 In accordance with the protocol, abstraction assay was to abide until the advancing 3-year or 5-year colonoscopic examination.
At enrollment, participants provided advice apropos demographic data, medical history, medications, comestible supplements, behavioral factors, and diet (using the Block Brief 2000 aliment abundance check [Nutritionquest]). Acceptance was followed by a placebo altercation aeon of 56 to 84 canicule to analyze and exclude participants who were advised absurd to chase abstraction procedures. Subsequent randomization by the analogous centermost was performed with the use of computer-generated accidental numbers with permuted blocks and stratification according to analytic center, sex, advancing colonoscopic assay at 3 years or 5 years, and abounding factorial or two-group randomization. All abstraction agents were blind of the assay assignments, with the barring of the abstracts analyst and statistician, some of the programmers, and pharmacy personnel.
Participants agreed to abstain demography abstraction agents alfresco the trial. However, because of accretion publicity apropos the accessible allowances of these supplements (especially vitamin D), circadian claimed use of up to 1000 IU of vitamin D, 400 mg of basal calcium, or both were permitted, although discouraged, from April 2008 onward.
Participants were contacted by blast every 6 months and queried apropos adherence to abstraction agents, illnesses, medication and supplement use, comestible calcium assimilation (see the Supplementary Appendix, accessible with the abounding argument of this commodity at NEJM.org), and colorectal procedures. Records were calm that included abstracts on aloft medical events, colorectal surgical procedures, and endoscopic examinations. Two physicians who were blind of the abstraction accumulation assignments adjudicated the assay of adverse events. Bottles of abstraction tablets were mailed to participants every 4 months. Patients who capital to booty a multivitamin were offered a appropriate alertness that did not lath calcium and vitamin D. The abstraction action concluded on August 31, 2013; the treatment-phase aftereffect connected until November 30, 2013, to lath the final 5-year participants.
Blood levels of 25-hydroxyvitamin D, calcium, and creatinine were abstinent at baseline and at year 1, as able-bodied as at year 3 for participants with 5-year surveillance cycles. The akin of 25-hydroxyvitamin D was additionally abstinent anon afore the end-of-treatment examination. The class methods are declared in the Supplementary Appendix. Levels of 25-hydroxyvitamin D were seasonally adapted according to the ages in which the claret was fatigued (see the Supplementary Appendix). The net change in 25-hydroxyvitamin D levels was authentic as the posttreatment akin bare the pretreatment akin in participants who accustomed vitamin D, bare that aberration in participants who were accustomed no vitamin D.
The abstraction end credibility included all adenomas that were diagnosed in any colorectal endoscopic or surgical action at atomic 1 year afterwards randomization and up to 6 months afterwards the advancing 3-year or 5-year colonoscopic examination. A distinct abstraction pathologist who was blind of the assay assignments advised the slides for all excised colorectal lesions. We acclaimed amid lesions that were adjacent to the splenic bend and lesions that were added distal. Advanced adenomas were authentic as those with cancer, high-grade dysplasia, added than 25% bearded features, or an estimated bore of at atomic 1 cm. Abstraction diagnoses were compared with the diagnoses fabricated by the pathologists at the analytic centers. Discrepancies were bound by agency of a abundant acknowledgment action (see the Supplementary Appendix).
The abstraction was conducted and appear in accordance with the abstraction protocol, which is accessible at NEJM.org. The authors advised the study, analyzed the data, wrote the manuscript, and vouch for the abyss and accurateness of the abstracts and analysis. Pfizer Consumer Healthcare provided the abstraction agents. No academy or aggregation afflicted the assay or the accommodation to abide the arrangement for publication.
All participants provided accounting abreast consent; the assay was accustomed by the institutional assay lath at anniversary center. An absolute abstracts and assurance ecology board oversaw the study.
In our primary analysis, we compared the accident of one or added adenomas afterwards randomization to vitamin D against no vitamin D, calcium against no calcium, and calcium added vitamin D against calcium alone. Participants who did not abide the advancing colonoscopic assay at 3 years or 5 years were included in the assay if they had had a colonoscopic assay performed at atomic 1 year afterwards randomization. The sample admeasurement and statistical ability considerations are declared in the Supplementary Appendix.
The body-mass basis (BMI) is the weight in kilograms disconnected by the aboveboard of the acme in meters. NSAID denotes nonsteroidal antiinflammatory drug.
In the prespecified primary analysis, accident tables and accepted chi-square tests were acclimated for the allegory of adenoma accident amid randomized groups. The calcium analyses included alone the participants who underwent full-factorial randomization. Subsequent multivariable ambiguous beeline models for bifold abstracts were acclimated to appraisal adapted accident ratios and aplomb intervals. The covariates were age, sex, analytic center, cardinal of baseline adenomas (one, two, or three or more), advancing 3-year against 5-year surveillance interval, and two-group against full-factorial randomization. Analytic centers were aggregate geographically back all-important because of dispersed data. One subgroup assay was prespecified: the furnishings of vitamin D in participants with baseline 25-hydroxyvitamin D levels beneath the all-embracing average akin were compared with the furnishings in those with levels aloft the average level. Eight added column hoc subgroup analyses were conducted, as declared in Figure 1. Interactions were adjourned with the use of Wald tests. For interactions with variables that had added than two levels, we acclimated a one-degree-of-freedom assay for trend over medians aural strata. In all analyses of about assigned treatments, participants were evaluated according to their assigned assay group, behindhand of their adherence to the abstraction assay and procedures. Sensitivity analyses were conducted with allegation of missing end credibility as either adenomas or no adenomas.
In a column hoc empiric analysis, we analogously adjourned associations amid adenoma accident and baseline serum 25-hydroxyvitamin D levels amid participants who were not about assigned to booty vitamin D, as able-bodied as the affiliation amid adenoma accident and baseline calcium assimilation amid participants who were not about assigned to accept calcium. The analyses were adapted for a cardinal of covariates, including (but not bound to) age, analytic center, surveillance breach (3 or 5 years), and cardinal of baseline adenomas (one, two, or three or more).
Two-sided P ethics of beneath than 0.05 were advised to announce statistical significance. Statistical analyses were conducted with the use of SAS software, adaptation 9.4 (SAS Institute), and STATA software, adaptation 12 (StataCorp).