Doubly blind: a systematic review of gender in randomised controlled trials

Figures & data

Fig. 1 Flow diagram of study search, randomisation, and selection.

Table 1 Summary of reviewed RCTS

Author, Funding (public, industry, both), (reference number)	Aim/Question	Outcome	Population characteristics number, sex, race/ethnicity, age, measure of SES	Additional notes on method
Aberele (industry) (20)	Comparison of low dose CT and x-ray screening for detection and survival of lung cancer	Earlier detection with CT but also more false positives Decrease in the number of advanced-stage cancers detected	N>53,000 Women=39% Documented race, marital status, education, BMI, workplace risk	Compared participants to overall population to show external validity
Anderson (public) (21)	Comparison of Dalteparin versus ASA for extended DVT prophylaxis after hip arthroplasty	ASA was equally beneficial and much less costly	N=785 Women=43% Documented BMI, smoking	Reported as non-inferior
Boyd (primarily industry) (22)	Comparison of two drug regimens for HIV after failure of first-line treatment	Found no benefit to new treatment	N= 558 Women=47% Age >16 Documented ethnicity, sexual orientation	Reported as non-inferior
Burmester (industry) (23)	Comparison of methotrexate+or – tofacitinib for second-line treatment of RA	Combination treatment was effective	N=399 Women=84% Documented race	Phase 3 drug trial
Byrd (industry) (24)	Comparison of two doses of a drug to treat CLL	Outcome described drug as effective but without a control group	N=85 Women=24%	Protocol changed during study Preponderance of men 34% attrition from study – unclear if they dropped out or were removed or whether they were included in analyses Endpoints unclear
Chakravarthy (public) (25)	A comparison of two drugs to treat macular degeneration	Outcomes were similar for each group but one drug was less costly	N=628 Women=60% Age >50 Documented quality of life, depression	Unclear why study included depression as an independent variable
Cooper (public/ industry) (26)	Comparison of medication alone or with stenting for renal artery stenosis and hypertension or chronic renal disease	No difference in outcomes	N=931 Women=50% Age 18+ Documented race, BMI, smoking	Pre-specified secondary analyses of interactions with sex, race, and medical variables
Cotton (public/industry provided drugs) (27)	Comparison of early versus deferred anti-retrovirals for infants with HIV	Early treatment improved long-term outcomes	N=377 Sex not specified Age >12 weeks	Could have compared boys and girls to assess differences in immune response
Dennis (public/industry) (28)	Does intermittent pressure reduce DVT risk days to weeks post-stroke better than no treatment?	Absolute risk reduction 3.6% with more skin problems in treatment group	N=2,876 Women ~50% Documented ‘overweight’ and ‘lives alone’	Not blinded
Devanand (public) (29)	Does stopping risperidone precipitate psychosis among Alzheimer's patients?	Increased psychosis when drug stopped	N=110 Women=60% Age 50–90 Documented race, place of residence
Doody (industry) (30)	Comparison of drug versus no treatment for Alzheimer's disease	Treatment group had worse outcomes and more side effects	N=1,537 Women=54% Age <55	Phase 3 drug trial Many (~1/3) subjects removed from study despite meeting inclusion criteria
Dooley (industry) (31)	Comparison of mycophenolate versus azathioprine for lupus-induced renal failure	Mycophenolate significantly better for all outcomes	N=227 Women=86% Age 12–75 Documented weight, urban/rural residence	Phase 3 drug trial 45% withdrawal secondary to side effects (sex undisclosed)
Douillard (industry) (32)	Comparison of new and conventional treatments for colorectal cancer based on genetic markers	Outcomes were associated with presence of gene mutations	N=620 Women=30% Age 18+ Documented race, ethnicity
Elkenboom (industry) (33)	Comparison of dabigatran and warfarin in patients with mechanical heart valves	Excess thrombolysis and bleeding in dabigatran group such that study was terminated	N=252 Women=35% Age 18–75	Reported a harmful outcome from the study drug and terminated the study early
Estruch (primarily public) (34)	Can a Mediterranean diet prevent cardiovascular disease among those at high risk?	Diet was effective	N=7,447 Women=57% Age 55–80 (men) and 60–80 (women) Documented BMI, race, smoking	Despite randomisation there were baseline differences in groups
Fayad (industry) (35)	Comparison of dalcetrapib versus placebo on atherosclerosis	No significant benefit	N=130 Women=18% Age 18–75 Documented race (white=93%)	Preponderance of men suggesting inclusion bias
Fleshner (industry) (36)	Comparison of dutasteride versus placebo in low-risk prostate cancer	unclear	N=289 Single sex condition Age 48–81 Documented race, BMI, anxiety regarding cancer	Complex statistical analyses to look for some benefit for the test medication
Forster (public) (37)	Comparison of structured education program to none for informal caregivers of stroke patients	No differences in patient outcomes	N=928 patients Women=44% N=928 caregivers Women=68% Documented race, education, employment	Comments in paper re excess of women as caregivers
Gebre (public) (38)	Comparison of twice- or once-yearly treatment for trachoma	No significant difference in outcome	N=33,190 Women=48% Age >9 Documented distance to hospital	Documented that only predictor of greater infection was greater proportion of girls/women in cluster but did not discuss potential issue of gender equality
Griffin (public/industry) (39)	Comparison of the impact of less or more intensive treatment of diabetics on CVD after 5 years	No significant difference in outcome	N=3,057 Women=0% Age 40–69 Documented race (white=96%), unemployment	No explanation for how recruitment of diabetics via GP practices yielded no women Authors call theirs a representative, population-based sample No mention of lack of women in discussing external validity
Hoffman (public) (40)	Does emergency room use of coronary CT angiography decrease time in hospital for chest pain?	Time in hospital decreased but later testing and radiation increased	N=1,000 Women=47% Age 40–74 Documented race, BMI
Horton (industry) (41)	Cross-over study of thalidomide for cough in severe idiopathic pulmonary fibrosis	Treatment improved cough and respiratory quality of life	N=23 Women=22% Age >50 Documented race
Kang (public) (42)	Comparison of early surgery versus standard treatment for infective endocarditis	Intervention decreased embolic events and death	N=76 Women=33% Age 18–80
Karim (public) (43)	Comparison of timing of antiretroviral and TB treatments to prevent AIDS progression	No significant differences arising from timing	N=429 Women=51% Age >16 Documented education, autonomy	Noted some sex-specific side effects, e.g. cervical dysplasia, menorrhagia
Katz (public) (44)	A comparison of partial meniscectomy versus physiotherapy for symptomatic meniscal tears	No real difference in outcome by intention to treat but 30% of physio group underwent surgery	N=330 Women=57% Age >44 Documented race, BMI, mood	Not blinded 83% of those assessed were not included, reasons not clear
Kolle (public/industry) (45)	Comparison of expanded adipose tissue derived stem cells and ordinary fat grafts	Better graft survival with stem cells at 121 days	N=10 Women=90% Age 18–45
Lebwohl (industry) (46)	Comparison of a new gel (Ingenol mebutate) with other treatments of actinic keratosis	New treatment was no better than existing ones	N=1,005 Women=25% Age >18 Documented race (white=100%)	Could have commented that actinic keratosis more common and reported elsewhere to be more treatable in men
Lewycka (public and NGOs) (47)	Does peer health education of mothers improve breastfeeding rates and lower mortality in rural Malawi?	Unclear – overall – no significant impact	Cluster randomisation: 48 clusters, 26,262 births (?) Age of women: 10–49 Recorded tribe, education, occupation, religion, marital status, SES, parity	Designed as a single sex study but men included in groups 20% lost to f/u Selected data used to find some benefit to intervention
Liem (public) (48)	Can pessary insertion at 16–20 weeks’ gestation decrease preterm birth in multiple pregnancy	Pessary did not decrease risks and did increase vaginal discharge	N=813 Single sex condition Documented race, BMI, education	Not blinded
Lo-Coco (primarily public, drugs donated by industry) (49)	Comparison of two drug regimens to treat promyelocytic leukaemia	New drug treatment was no better than old treatment	N=156 Women=51%	Reported as non-inferior
Mallick (public/industry) (50)	Comparison of low- and high-dose radioiodine for treating thyroid cancer	No difference in effect and lower dose had fewer side effects	N=438 Women=74% Age 16–80
Marchioli (industry) (51)	Comparison of phlebotomy, hydroxurea or both for treatment of lower or higher hematocrits in polycythemia	Those with lower hematocrit had significantly better outcomes, i.e. fewer deaths from cardiovascular or thrombotic events	N=365 Women=38%	No comment on whether smaller hematocrit elevations have greater impact on health of women
Mateos (industry) (52)	Comparison of drug to no drug for smouldering multiple myeloma	Drug more effective than no treatment	N=119 (10% withdrawn from study by researchers) Women=55%	Phase 3 drug trial Only 42% completed study
Milstone (public/ industry) (53)	A comparison of chlorhexidine and regular baths to decrease bacteraemia in critically ill children	No statistically significant difference found	N=4,947 sex not specified age <2 months Documented race	Not blinded 371 in treatment group excluded for lack of consent versus none excluded in control group Enrolment biases identified
Montalescot (industry) (54)	Does prasugrel prior to rather than at the time of angioplasty post-non-STEMI decrease mortality?	Outcome: no benefit of pre-treatment and greater harm from life-threatening bleeding	N=4,033 Women=28% Documented race: (Caucasian=97%), BMI, health behaviours	Phase 3 drug trial Supplemental data says women more likely than men to bleed (p=0.09) – not reported in paper, itself No explanation for low enrolment of women
Motzer (industry) (55)	A comparison of two chemotherapies for metastatic renal cancer	Trial drug was no better than control	N=1,110 Women=27% Geographic and ethnic subgroups used for analyses	Trial drug reported as ‘non-inferior’ No documented exclusion criteria yet 300 excluded Protocol changed mid-study Often reported numbers without statistical significance
Nguyen-Khac (public) (56)	Comparison of Prednisolone with and without N-acetylcysteine for severe alcoholic hepatitis	No benefit to 2 drug regime	N=174 Women=40% Age >18	Not blinded
O'Dell (public) (57)	A cross-over comparison of 2 second-line treatments for RA	New treatment was no better than old	N=353 Women=46% Age >17 Documented race, BMI, smoking	Study treatment reported as non-inferior Although women responded better to new treatment than expected and similar to men's response, didn't comment on this
Parker (industry) (58)	Assessed efficacy and safety in treating metastatic prostate cancer with radiation vs. placebo	Life expectancy with radiation versus placebo: 14.9 versus 11.3 months.	N=921, single sex condition Documented race, Many medical exclusions	-reported relative risk reduction (30%) rather than absolute
Pickard (public) (59)	Comparison of antimicrobial and regular urethral catheters for short-term use	No significant difference in infection rate	N=6,394 Women=62% Age >15	Not blinded No consideration of whether anatomical differences might lead to differences in infection risk for men and women that could have been seen by disaggregating data
Pirmohamed (public) (60)	Comparison of genotype guided and standard dosing of warfarin for atrial fibrillation or DVT	Genotype-guided dosing reduced number of days with high INR and time to steady state dosage	N=455 Women=39% Documented race, BMI, smoking	Treating physician could exclude subjects for undefined reasons
Roberts (industry) (61)	Does point of care genetic testing identify those for whom clopidogrel presents a high risk?	Effective identification of carriers of gene	N=187 Women=22% Documented race, weight, smoking
Roe (industry) (62)	Comparison of prasugrel versus clopidogrel for acute coronary syndromes without re-vascularisation	No significant differences found	N=9,326 Women=39% Documented race, weight, smoking	Large enrolment would have allowed for assessing sex differences in side effects like bleeding, but not done
Shaukat (public) (63)	Comparison of long-term outcomes among those undergoing faecal occult blood screening for colon cancer	After 30 years those screened had significantly lower mortality from colon cancer but not lower overall mortality	N=46,551 Women=52% Age 50–80	Assessed sex-specific relative risks of dying from colon cancer
Sihvonen (public) (64)	Comparison of partial meniscectomy and sham operation for degenerative meniscal tear with no osteoarthritis.	No differences in outcomes found	N=146 Women=39% Age 35–65 Documented BMI
Silbergleit (public) (65)	Comparison of IM midazolam versus IV lorazepam after 5 minutes of seizures	Midazolam of significant benefit	N=893 Women=43% Documented race (African Am.=51%)	Phase 3 drug trial
Soofi (NGO/industry) (66)	Can 1 year of zinc+or – micronutrients improve growth and limit infection and diarrhoea in infants	Supplementing with zinc decreased Fe deficiency anaemia but increased side effects	N=2,746 Sex unspecified Documented water source, sewage system, household income	Could have considered whether giving supplements might change food offered to infants and particularly to girls
Thiele (public/industry) (67)	Comparison of intra-coronary versus IV abciximab post-STEMI	Of multiple endpoints only heart failure might be improved with intra-coronary treatment	N=2,065 Women=25% Age <75 Documented race (all ‘white’)	Not blinded Although women had significantly better outcomes than men this was attributed to chance Enrolment bias noted
Tylleskar (public) (68)	Does peer counselling mothers of infants decrease diarrheal disease by increasing breast feeding in Africa?	No significant decrease in diarrhoea despite increase in breast feeding	N=2,579 Sex-specific study Documented education, marital status, SES, electricity in home, water source, toilet, parity, previous child death, antenatal care, place of birth, BMI	Data on main outcome downplayed and instead authors conclude breast feeding must be beneficial and might shorten course of diarrhoea despite no evidence for this
Von Hoff (industry) (69)	Comparison of new and standard drug combinations for treating pancreatic cancer	New combination prolonged survival by about 2 months	N=861 Women=42% Age 18+ Documented race and region	Phase 3 drug trial
Wang 98b (public) (70)	Comparison of ASA+or – clopidogrel for stroke prevention after TIA	Additional drug decreased stroke without increasing haemorrhage	N=5,170 Women=34% Age 40+ years BMI, smoking	Interactions assessed in subgroups and documented
Walmsley (industry) (71)	Comparison of new and older combinations of treatments for HIV	New combination reported as more efficient and safer	N=833 Women=16% Age >18 Documented race	Preponderance of men was commented on by authors as arising from exclusion of pregnant or potentially pregnant women
White (public/industry) (72)	Comparison of alogliptin versus placebo in diabetics hospitalised for unstable angina or MI	Drug was found to be no better than placebo	N=5,830 Women=32% Documented race, BMI, smoking, region	Reported outcome as non-inferior Stratified results by region Reported sex stratification in appendix
Wiviott (industry) (73)	Comparison of prasugrel and clopidogrel post-non-STEMI and without re-vascularisation	Unclear – reported that test drug was beneficial	N=7,243 Women=36% Age <75	Phase 3 drug trial No explanation for disproportion of men Women were less likely to be investigated with angiography
Young (public) (74)	Can social media networks increase HIV testing among African American and Latino men who have sex with men?	Intervention increased HIV testing	N122 Single sex study Age 18+ Documented race, education, birthplace, income social connectedness, urban/rural, sex behaviours
Zeuzem (industry) (75)	Comparison of faldaprevir plus deleobuvir at different doses, with or without ribaviron to induce a sustained virologic response in chronic Hep C	Including Ribavirin improved outcome	N=362 Women=48% Documented age, race, BMI	Phase 2 drug study Not blinded Initial trial halted by FDA Changed protocol during study and redefined endpoint
Zhu (public/industry) (76)	Comparison of vaccine versus placebo to prevent enterovirus infection	The vaccine was effective and produced no more side effects than placebo	N=10,245 Girls=44% Age 6–34 months Documented BMI	Phase 3 trial

Table 2 Inclusion/exclusion of individual characteristics in reviewed RCTS (N=57)

	Age	Sex/gender	BMI	Health behaviours	Race, ethnicity	SES, education	Other individual characteristics
In demographics	23, 26, 27, 29, 33, 37, 40, 41, 42, 45, 46, 50, 51, 59, 60–64, 69, 71, 72, 74	20–26, 28, 29–31, 33–35, 36 (sex-specific condition), 37–46, 48, 49–52, 54–57, 58 (sex-specific disease), 59–65, 67, 68 (sex specific), 69–76	20, 21, 26, 28 (overweight noted), 31 (weight), 34, 36, 40, 44, 48, 54,57, 61 (weight), 62 (weight), 64, 68, 70, 72, 73, 75, 76	21 (smoker), 26 (smoker), 34 (smoker), 47, 54, 57 (smoker) 60 (smoker), 61 (smoker), 62 (smoker), 70, 72 (smoker), 74	20, 22, 23, 29, 31, 34,35 (93% white), 36, 37, 39 (96% white), 40, 41, 44, 46 (all white), 47, 48, 53, 54, 57, 58, 60–62, 65, 67 (all white), 69, 71, 72, 74, 75	20, 37, 39, 43, 47, 48, 66, 68, 74	22 (sexual orientation), 25 (quality of life, depression), 28 (lives alone), 29 (residence), 31 (location), 36 (anxiety re cancer), 37 (employment), 38 (location), 43 (Karnofsky score), 44 (mental health), 47 (social connectedness, marital status), 55 (site), 68 (marital status, community traits), 69 (region), 72 (world region), 74 (birthplace, social connectedness, urban/rural)
Among explicit exclusion criteria	20, 22, 23, 25, 27 (infant study), 28, 29, 31,33–36, 38–47, 49, 50, 52, 53, 56, 57, 63, 64, 66, 70, 73, 76	26 (pregnancy), 32 (pregnant), 36 (sex-specific condition), 39 (no women although not an explicit exclusion), 41 (pregnancy potential), 45 (pregnant), 47 (failed to exclude men), 48 (sex-specific condition), 51 (pregnancy or no contraception), 57 (women without contraception), 60 (pregnancy), 61 (pregnancy), 65 (pregnancy), 67 (pregnancy), 68 (breastfeeding study), 70 (pregnancy), 71 (if no proof not pregnant), 72 (planning pregnancy), 74 (women)	34 (>40), 40, 45	20 (non-smokers), 34 (substance abuse), 45 (smoker), 51, 57 (substance abuse), 72 (drugs, alcohol abuse)		34 (literacy), 65 (prisoners)	21 (distance to study centre), 30 (none stated but >1/3 withdrawn by industry researchers during trial without explanation), 31 (no exclusions but more than ½ withdrew due to side effects), 32 (no contraception for either men or women), 34 (possible difficulty following a diet), 44 (English illiteracy), 47 (sterilisation), 52 (none named but >10% of treatment group withdrawn by researchers without explanation), 53 (5–10% withdrawn overall but all from treatment group for lack of consent), 55 (none named but 300 excluded), 65 (weight of children, also more than 2/3 excluded for unnamed reasons), 60 (treating MD determined eligibility),
							67 (medical conditions), 72 (investigators’ opinion re debility), 75 (1/4 of those screened excluded, without explanation)

Table 3 Addressing sex/gender in reviewed RCTS (N=57)

	Yes (reference number)	No (reference number)
Sex-specific condition^a	36, 47,48, 58,68 74 (although HIV not sex-specific target population was gay men)	20–35, 37–46, 49–57, 59–67, 69–3, 75,76
Information on sex/gender of participants documented	20–26, 28–30, 33–35, 37–46, 49–52, 54–57, 59–65, 67, 69–73, 75, 76	27, 31 (proportions of overall cohort reported but not of those who completed trial), 32 (incomplete numbers and only in appendix), 53 (children), 66 (children)
Women and men in non-sex-specific studies (n=51)
Overall	20–35, 36–38, 40–46, 49–57, 59–67, 69–73, 75, 76	39
Proportions of men and women stated	20–6, 28–30, 32 (info in appendix only), 33–35, 37–46, 49–52, 54–57, 59–65, 67, 69–73, 75, 76	27, 31 (noted proportions of whole group but not of group that was analysed and completed study), 53, 66
Disproportion of men to women,  i.e.>or=60:40	20, 24, 32, 33, 35, 39, 41, 42, 46, 51, 54–56, 60–62, 64, 67, 70–73	22, 23, 25, 26, 28–30, 34, 37, 38, 40, 43–45, 49, 50, 52, 57, 59, 63, 65, 68, 69, 75, 76
Disproportion of women to men,  i.e.>or=60:40	23, 37 (assuming caregivers were primary participants, rather than patients), 45, 50, 59	20–22, 24–26, 28–30, 32–35, 38–44, 46, 49, 51, 52, 54–57, 60–65, 67, 69–73, 75, 76
Proportion of men to women approximately  equal, i.e. each at least 40% of sample	21, 22, 25, 26, 28–30, 34, 38, 40, 43, 44, 49, 52, 57, 63, 65, 69, 75, 76	20, 23, 24, 32, 33, 35, 37, 39, 41, 42, 45, 46, 50, 51, 54–56, 59–62, 64, 67, 70–73
Sex/gender included in analysis and/or discussion (n=57)^b
Overall	20, 26, 34, 38, 62, 63, 69–72, 75	21–25, 27–33, 35–37, 39–61, 64–68, 73, 74, 76
Via data disaggregation (separate analyses for  women and men)	20, 34, 63, 67 (mentioned subgroup analyses), 69–71, 72 (compared hazard ratios in appendix)	21–33, 35–62, 64–66, 73,–76
As an independent variable	26, 38 (proportion of girls in each cluster) 62 (in appendix), 69, 71, 75	20–25, 27–37, 39–61, 63–68, 70, 72–74, 76
Via interaction with other variables	26, 63, 70	20–25, 27–33, 34 (could have examined gender via known interaction of sex*BMI), 35–62, 64–69, 71–76
Sex/gender included in interpretation/ discussion	20, 48 (commented re benefit of a low cost intervention), 51, 54 (comment in supplement that women had more adverse outcomes), 57 (one statement), 60 (disproportion of men mentioned), 63, 67 (dismissed significant gender differences as likely due to chance), 71 (disproportion of men mentioned, as was same outcomes both sexes)	21–25, 26 (despite excellent methodology), 27–46, 47 (confusing analysis but didn't appear to discuss social traits), 49, 50, 52, 53, 55, 56, 58, 59, 61, 62, 64, 65, 66 (no consideration of whether girl children might be systemically disadvantaged, i.e. whether giving supplements might precipitate parental redirecting of food to other children), 68 (one statement that SES was not a confounder), 69, 70, 72–76

^aConditions affecting either men or women but not both.

^bIncludes studies of sex-specific conditions.

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