Grodstein 2007.
| Methods | Substudy of the Physicians’ Health Study II, a randomised, double‐blind, placebo‐controlled, 2 x 2 x 2 x 2 factorial trial testing ß‐carotene, vitamin E, ascorbic acid, and a multivitamin for their role in preventing chronic diseases including total and prostate cancer, cardiovascular disease, and age‐related eye disease among 14,641 male physicians aged 50 years or older The trial was done from 1997 to 1 June 2011. The cognitive function substudy began in 1998. Those eligible for the cognitive substudy were PHS II participants older than 65 years in November 1998. The Physicians’ Health Study II was a continuation of the Physicians’ Health Study, which began in 1982 and had randomised male participants to low‐dose aspirin and ß‐carotene. Participants included those continuing their original ß‐carotene assignment from the Physicians’ Health Study and newer recruits randomised from 1998 onwards. |
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| Participants |
Location: not reported Recruitment: The Physicians’ Health Study II. Quote: "In July 1997, invitations to enrol in PHS II were mailed to eligible participants from PHS I who had been part of an earlier trial of aspirin and ß‐carotene among 22071 physicians aged 40 to 84 years in 1982. Second, in July 1999, invitation letters were mailed to a new group of male physicians identified from a list provided by the American Medical Association." Quote: "PHS I participants who are willing and eligible for participation in PHS II will retain their randomized ß‐carotene assignment from PHS I and will be also randomized to vitamin E..." "new physician participants will be randomly assigned to the same interventions" Number randomised:
Participant (baseline) characteristics (at entry PHS III): All participants were men. Age, mean:
Inclusion criteria: not reported Exclusion criteria: history of cirrhosis or active liver disease, patients receiving anticoagulants, or reported a serious illness that may interfere with study participation Men were also required to forgo current use of multivitamins or individual supplements containing more than 100% of the recommended daily allowance of vitamin E, vitamin C, ß‐carotene, or vitamin A during PHS II follow‐up For those newly recruited: no history of cancer, active liver disease, current renal disease, peptic ulcer, or gout Quote: "Only physicians who comply with the pill‐taking regimen at least two‐thirds of the time and remain willing and eligible to participate will be subsequently randomized". |
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| Interventions |
Intervention:
NB: Grodstein 2007 reported on the ß‐carotene and Grodstein 2013 on multivitamin supplementation. Comparator group: placebo ß‐carotene. Exposure to study intervention: 2031 patients in ß‐carotene and 2021 placebo continued from the PHS study (started in 1982) in which they were receiving ß‐carotene versus placebo ß‐carotene. As most of the cognitive assessments were done in 2001, some of the patients continuing from PHS had been exposed to ß‐carotene (or placebo ß‐carotene) for about 19 years, whereas the "new recruiters" had been exposed from 1997 to 2001, thus for about 4 years. The mean time from randomisation to cognitive assessment was 18 years (range, 15‐20 years) in 4052 continuing participants from the PHS,and was 1 year in 2021 new recruits (range, 2 months–3 years). Quote: "PHS participants, who remained blinded to beta carotene assignment." Quote: "Treatment assignment to beta carotene or beta carotene placebo was retained from the PHS (although participants may have stopped taking beta carotene during the 18‐month interval between studies), and the men were newly randomized to receive vitamin E, ascorbic acid, multivitamin, or placebo." Use of additional interventions (common to both treatment arms): not reported |
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| Outcomes |
Primary Outcomes: A global composite score averaging 5 tests of global cognition, verbal memory, and category fluency. The cognitive battery included the Telephone Interview for Cognitive Status (TICS); immediate and delayed recall on the East Boston Memory Test (EBMT); delayed recall of a 10‐word list; and a category fluency task. The cognitive function substudy began in 1998. The beta carotene arm of the PHS II continued until May 2003, its planned stopping date, but most of the assessments were done in 2001. Quote: "Second cognitive assessments were begun in 2002. The beta carotene arm was terminated prior to completion of second assessments (second and third assessments were planned to allow further data collection in the continuing trial of other vitamins). Nonetheless, some data from the second interview were available (n = 4074, with 88.3% participation of those who were contacted before termination of the beta carotene study)." Eligible cognitive outcomes:
Function outcome extracted: none reported Quality of life outcome extracted: none reported Safety outcome extracted: none reported * outcome data used in statistical analyses |
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| Notes |
Funding source: “This study was supported by grants from the National Institutes of Health (CA34944, CA40360, CA97193, HL26490, HL34595, and AG15933), and from BASF Corporation (Florham Park, New Jersey), Wyeth (New Jersey), and DMS (New Jersey). Dr Grodstein was partially supported by a New Scholars in Aging award from the Ellison Medical Foundation. Role of the Sponsor: No supporting organization had any role in the study design; conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript." Declaration of interest: “None reported". Treatment adherence: ß‐carotene study: "Overall, 79.3% reported taking at least 2 of 3 of their study pills; this was similar in those assigned to active treatment (79.1%) or placebo (79.5%), and in the continuing participants from the PHS (79.2%) vs new recruits (79.4%)". |
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| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: “The PHS II is a randomized, double‐blind, placebo‐controlled, 2x2x2x2 factorial trial". "Randomization..using a computer‐generated list of random numbers". Comment: adequate method of random generation |
| Allocation concealment (selection bias) | Unclear risk | Quote: “The PHS II is a randomized, double‐blind, placebo‐controlled, 2x2x2x2 factorial trial". Comment: method of allocation concealment not reported |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote: “The PHS II is a randomized, double‐blind, placebo‐controlled, 2x2x2x2 factorial trial". Comment: method of blinding not reported |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Quote: “The PHS II is a randomized, double‐blind, placebo‐controlled, 2x2x2x2 factorial trial". "An Endpoint Committee of physicians blinded to the participants' treatment assignment, will review the medical records for final confirmation of a reported diagnosis". Comment: The method of blinding of outcome assessment for the cognitive substudy was not reported. The statement about the Endpoint Committee is contained in the design paper which, however, does not mention any cognitive outcome. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Quote: "of the 7045 age‐eligible patients, 271 were no longer active PHSII participants (3.8%) and 4 were deceased (0.06%). Of the remaining 6770, we were unable to reach 315 (4.7%). Of the 6455 participants contacted, 5956 (92.3%) completed a cognitive assessment: 4052 from the original PHS and 1904 new recruits.." "Participation (in the cognitive substudy) was virtually identical in those assigned to beta‐carotene (92.0%) vs placebo (92.6%) and in continuing participants (from the PHS) (92.1%) vs new recruits (to PHS II) (92.7%)." |
| Selective reporting (reporting bias) | Low risk | Comment: no differences found between the protocol (clinicaltrials.gov Identifier: NCT00270647) and article. In addition, all outcomes specified in the Methods were reported in the Results. |
| Other bias | Low risk | No other source of bias identified |