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Oral evening primrose oil and borage oil for eczema

  1. Joel TM Bamford1,*,
  2. Sujoy Ray2,
  3. Alfred Musekiwa3,
  4. Christel van Gool4,
  5. Rosemary Humphreys5,
  6. Edzard Ernst6

Editorial Group: Cochrane Skin Group

Published Online: 30 APR 2013

Assessed as up-to-date: 29 AUG 2012

DOI: 10.1002/14651858.CD004416.pub2


How to Cite

Bamford JTM, Ray S, Musekiwa A, van Gool C, Humphreys R, Ernst E. Oral evening primrose oil and borage oil for eczema. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD004416. DOI: 10.1002/14651858.CD004416.pub2.

Author Information

  1. 1

    University of Minnesota Medical School, Department of Family Medicine and Community Health, Duluth, Minnesota, USA

  2. 2

    St. John's Medical College and Hospital, Department of Psychiatry, Bangalore, Karnataka, India

  3. 3

    University of the Witwatersrand, Wits Reproductive Health and HIV Institute (WRHI), Faculty of Health Sciences, Johannesburg, South Africa

  4. 4

    Maastricht University, Department of Epidemiology, CAPHRI, Maastricht, Netherlands

  5. 5

    The University of Nottingham, c/o Cochrane Skin Group, Nottingham, UK

  6. 6

    Peninsula Medical School, University of Exeter, Complementary Medicine Department, Exeter, UK

*Joel TM Bamford, PO 3247, Duluth, Minnesota, 55803-3247, USA. JoelTMBamford@icloud.com.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 30 APR 2013

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Characteristics of included studies [ordered by study ID]
Bahmer 1992

MethodsDesign: randomised, placebo-controlled, parallel

Duration: 3 months

Interval of assessment: baseline, 6 weeks, 3 months

This was a randomised controlled trial


ParticipantsNumber randomised: 12 (7 in the active group and 5 in the placebo group)

Sex (M/F): 6/6 total (3/4 in the active group and 3/2 in the placebo group)

Age of participants: active group = 31 (mean), placebo group = 27 (mean)

Unit of allocation: whole person

Country and setting: Saarlandes, Germany; single university dermatology clinic

Inclusion criteria of the study (specified)

  • Participants having atopic dermatitis
  • Having used topical steroids
  • Diagnostic criteria: not reported
  • Severity of condition: "mild to moderate", glandol group ADASI score = 1.63, control group ADASI score = 1.89


Exclusion criteria of the study

  • Participants using systemic steroids or antimetabolites


Interventions
  • Treatment group: glandol (BO), 3 capsules twice daily, each capsule 500 mg
  • Placebo group: palm kernel oil, 3 capsules twice daily, each capsule 500 mg


Outcomes
  1. ADASI score by clinician (method of scoring by mapping)
  2. Skin condition by participant (method of assessment subjective: participant diary)
  3. Serum lipids (lab)


NotesPrevious treatment was not stopped ("no limitations regarding other treatment were required")

Assessment of compliance was not undertaken


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskThe trial mentioned randomisation, but did not give a specific method

Allocation concealment (selection bias)Unclear riskThe trial did not give a method for allocation concealment

Incomplete outcome data (attrition bias)
All outcomes
Low riskThere were no dropouts or losses to follow up (7/7 glandol and 5/5 placebo completed)

Selective reporting (reporting bias)Low riskThe trial reported all outcomes

Other biasLow riskAll randomised participants were included in the analysis in the groups to which they were randomised. We contacted the author

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThis was adequate as both the participant and assessor were blinded

Bamford 1985

MethodsDesign: randomised, double-blind, placebo-controlled, cross-over

Duration: 6 months (3 months then 3 months reversed)

Interval of assessment: 3 months


ParticipantsNumber randomised: 154

Sex (M/F): not stated

Age of participants: completers were 49 children aged 2 to 16 years (mean age = 9.1) and 74 adults aged 16 to 66 years (mean age = 37.7)

Unit of allocation: single participant

Country and setting: USA, single dermatology outpatient department

Inclusion criteria of the study

  • Participants having atopic dermatitis
  • Having used topical steroids
  • Diagnostic criteria: clinical
  • Severity of condition: mild to moderate


Exclusion criteria of the study

  • Participants using systemic steroids or antimetabolites


Interventions
  • Treatment group divided as follows:


    • children < 15 years of age, who received 2 or 4 capsules twice daily each with 500 mg of EPO for 3 months, then crossed over;
    • children > 15 years of age, who received 6 or 8 capsules twice daily each with 500 mg of EPO


  • Placebo group divide in the same way as above and same dosage schedule with each capsule having 500 mg of paraffin oil


Outcomes
  1. Symptoms and signs of eczema (erythema, scaling, excoriation, weeping, etc) by physician (method = 0 to 10 scale, where 0 is none and 10 is most severe)
  2. Symptoms and signs of eczema (erythema, scaling, excoriation, weeping, etc) and effect on daily living (level of discomfort, inability to sleep, etc) by participant (method = 0 to 10 scale, where 0 is none and 10 is most severe)


Interval of assessment: unclear


NotesConcomittent treatment: permitted emollients, topical steroids, and antihistaminics

Compliance to treatment: undertaken

Previous treatment: continued

The trial report did not state the numbers randomised to each group (further information obtained from trial investigator)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe trial used block randomisation

Allocation concealment (selection bias)Low riskSpecific study numbers were used on labels, which did not contain medication/placebo name. (The trial investigator provided this further information)

Incomplete outcome data (attrition bias)
All outcomes
Low risk14/77 participants in the EPO group dropped out; 17/77 participants in the placebo group dropped out. They gave reasons

Selective reporting (reporting bias)Low riskThe trial reported all prespecified outcomes

Other biasUnclear riskWe were unsure whether all participants were included in the analysis in the groups to which they were randomised. We contacted the biostatistician author. A non-profit foundation funded the trial

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThis was adequate as both the participant and assessor were blinded. The placebo capsules were identical

Berth-Jones 1993

MethodsDesign: double-blind, randomised, parallel with 3 treatment arms

Duration: 24 weeks

Interval of assessment: Assessment was done at 4, 8, and 16 weeks, and then 8 weeks after wash-out


ParticipantsNumber randomised: 123 (41 in the active EPO group, 41 in the active EPO and Marine group, and 41 in the placebo group)

Sex (M/F): 25/16 in the active group, 22/19 in the active EPO and Marine group, and 22/19 in the placebo group

Age of participants: well-matched for age above and over 12 years

Unit of allocation: whole person

Country and setting: UK, single centre

Inclusion criteria of the study

  • Outpatients attending the dermatology department for treatment of AD, of either sex and all ages
  • Diagnostic criteria: Hanifin and Rajka


Exclusion criteria of the study

  • Not specified


Interventions
  • 2 treatment groups:
    • first treatment group: 6 capsules twice daily, each capsule contained 500 mg of evening primrose oil, largely made up of the n6 series EFAs linoleic (321 mg) and gamma-linolenic acid (40 mg)
    • second treatment group: 6 capsules twice daily, each contained 430 mg of evening primrose oil and 107 mg of marine fish oil. This fish oil included the n3 series EFAs eicosapentaenoic acid (17 mg) and docosahexaenoic acid (11 mg)
  • Placebo group: 6 capsules: Each capsule contained liquid paraffin for adults and olive oil for children


Outcomes
  1. Disease activity monitored by clinical severity scores (2 types of scoring systems were used) as recorded by the investigator (methods for scoring: Leicester Score, the body was divided into 10 zones: face, neck, abdomen, back, elbows, antecubital fossae, dorsa of hands, palms and wrists, popliteal fossae, and feet. Each zone was scored on a scale: 0 (absent) to 3 (severe) for erythema, excoriation, dryness, cracking, and lichenification. A second, simpler scoring system for clinical severity, as described by Costa 1989, was also used. In this system, only the most severely affected site was assessed. Erythema, oedema, vesiculation, crusting, excoriation scaling, lichenification, pigmentation, pruritus, and sleep disturbance were each graded on a 7-point scale. This score was only briefly reported)
  2. Topical steroid requirement (usage was assessed by weighing returned tubes of medication)
  3. Symptom scores recorded by participants. Every participant was given a diary containing a page of 10 cm visual analogue scales for baseline and each of the next 24 weeks. Scales were provided for itch, dryness, scaling, redness, and overall impression. All scales were labelled "none" at the left-hand end and "worst ever" at the right. Scores were added to give a maximum of 50 cm


Interval of assessment: 4, 8, and 16 weeks on treatment, and again after an 8-week wash-out


NotesConcomittent treatment: allowed continued emollients and low-dose steroids

Compliance to treatment: unsure


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Randomization in blocks of three..."

Comment: The trial used block randomisation

Allocation concealment (selection bias)Unclear riskThe trial did not state the method by which it concealed allocation

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe trial reported all outcomes

Selective reporting (reporting bias)Low riskThere was no selective reporting

Other biasUnclear riskWe were unsure whether all participants were included in the analysis in the groups to which they were randomised

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "The study had a double-blind design"

Comment: The trial stated blinding, but did not specify the method

Biagi 1994

MethodsDesign: double-blind, placebo-controlled using 2 different dosages

Duration: 8 weeks

Interval of assessment: start and end of study


ParticipantsNumber randomised: 48 (16 in each group)

Sex (M/F): 24/27 total (this applied to the whole group; there was no separation for the active and placebo groups)

Age of participants: children average 4.2 years (2.2 to 8.5 years)

Unit of allocation: whole person

Country and setting: Italy, single referral outpatient department

Inclusion criteria of the study

  • Diagnostic criteria: Hanifin and Rajka


Exclusion criteria of the study

  • Not specified


Interventions
  • 2 treatment groups:
    • first treatment group: high-dose group, EPO capsules (dose = 0.5 mg/kg body weight)
    • second treatment group: low-dose group, 50% EPO capsule and 50% placebo capsule (dose = 0.5 mg/kg body weight)
  • Placebo group: capsules of olive oil and vitamin E (0.5 mg/kg body weight)


Outcomes
  1. Severity of symptoms (method: clinical assessment by scoring 10 symptoms. Scoring from 0 to 3, 0 = absent, 1 = mild, 2 = moderate, 3 = severe)
  2. Red cell membrane fatty acid concentration
  3. Red cell membrane viscosity


NotesConcomittent treatment: allowed continued emollients and topical steroids

Compliance to treatment: unsure


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Children were randomised to receive either..."

Comment: The trial gave no method of generation

Allocation concealment (selection bias)High riskThe trial gave no details

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk3/48 participants did not attend for follow up. The dropouts or losses to follow up by assignment group were unclear, as were the reasons

Selective reporting (reporting bias)Low riskThe trial reported all prespecified outcomes

Other biasLow riskWe contacted the author; there was no other bias

Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: "...all assessments were made double blind"

Comment: This was adequate, but details were not given of who was blinded and how. This was probably done

Borrek 1997

MethodsDesign: randomised by draw, double-blind, placebo-controlled, cross-over

Duration: 20 to 24 weeks

Interval of assessment: 4 to 3 weeks


ParticipantsNumber randomised: 24 children and teenagers from 3 to 17 years of age

Sex (M/F): 14/10 total

Age of participants: 3 to 17 years (mean age = 10 years)

Unit of allocation: single person

Country and setting: Germany, 1 university pediatric clinic

Inclusion criteria of the study

  • Chronic recurrent atopic dermatitis at the time of enrolment in the study
  • Was clinically symptomatic within the last 6 months
  • Diagnostic criteria: Hanifin Rajka's criteria
  • Severity of condition: mild to moderate


Exclusion criteria of the study

  • Epilepsy
  • Fat storage disease
  • Participating in another study


Interventions
  • Treatment group: 3 capsules daily, each with 60 mg borage seed oil and 5 mg vitamin E
  • Placebo group: 3 capsules daily, each with 60 mg corn oil and 5 mg vitamin E


Outcomes
  1. Costa (Costa 1989) score by clinician (method: this simple scoring system (SSS) scores 10 severity criteria (0 to 7) and 10 topographic sites (0 to 3) giving a maximum score of 100)
  2. Acute, chronic, and subjective symptoms by participants (method: diaries)
  3. Use of steroidal creme and antihistamines (method: questionnaires)


NotesConcommitant treatment: permitted

Assessment of compliance: unsure


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation was by draw (entrance to study)

Allocation concealment (selection bias)Unclear riskThe trial did not specify this

Incomplete outcome data (attrition bias)
All outcomes
Low risk2 participants from each group withdrew due to non-compliance

Selective reporting (reporting bias)Low riskThe trial reported all prespecified outcomes

Other biasLow riskQuote (page 101): "No difference between the two groups in the most important variables"

Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote (page 101): "Patient and examiner were blinded with respect to after completion of the capsule contents"

Comment: This was adequate (both blinded)

Buslau 1996

MethodsDesign: randomised, double-blind, placebo-controlled, parallel

Duration: 12 weeks

Interval of assessment: daily by participant


ParticipantsNumber randomised: 50 (25 each in the active and placebo groups)

Sex (M/F): 18/32 total (8/17 in the active group and 10/15 in the placebo group)

Age of participants: not mentioned

Unit of allocation: whole person

Country and setting: Germany, not noted

Inclusion criteria of the study

  • Severity of condition: mild to moderate
  • Diagnostic criteria: Hanifin Rajka's criteria


Exclusion criteria of the study

  • Not specified


Interventions
  • Treatment group: 2 capsules daily each with 500 mg of BO
  • Placebo group: 2 capsules daily each with 500 mg of palm kernel oil


Outcomes
  1. ADASI score (method of assessment: mapping with the help of coloured markers)


NotesConcomitant treatment: not permitted

Compliance to treatment: not undertaken

Previous treatment: unsure


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskThe trial did not specify the method of sequence generation

Allocation concealment (selection bias)High riskThe trial did not specify the method of allocation concealment

Incomplete outcome data (attrition bias)
All outcomes
High risk7/25 participants in the active group withdrew, and 11/25 in the placebo group withdrew. The trial undertook ITT analysis, but dropouts were not balanced between the groups

Selective reporting (reporting bias)Low riskThe trial reported all prespecified outcomes

Other biasUnclear riskNo detail of funding or support was listed

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskThis was adequate for participants, but it was unclear if they blinded the clinician outcome assessor

Don 2003

MethodsDesign: double-blind, randomised, placebo-controlled, parallel

Duration: 12 weeks

Interval of evaluation: 4 weeks and 12 weeks


ParticipantsNumber randomised: 20 (10 each in the active and placebo groups)

Sex (M/F): 8/1 in the active group and 5/4 in the placebo group

Age of participants: 20 children aged 7 to 48 months (mean age = 22.9)

Unit of allocation: whole person

Country and setting: Italy, 1 centre

Duration of eczema: placebo = 9.44 years, borage = 9.66 years (averages)

Inclusion criteria of the study

  • Severity of condition: SCORAD figures at start = 39.44 for borage group, 44.93 for placebo group
  • Diagnostic criteria: Hanifin Rajka's criteria


Exclusion criteria of the study

  • Not specified


Number: 20


Interventions
  • Treatment group: 60 drops daily of BO
  • Control group: 60 drops daily of olive oil


Outcomes
  1. SCORAD (method of assessment: standard method)
  2. Quality of life (parents' evaluation) (method of assessment: scores of calm = 4, slightly distressed = 3, moderately distressed = 2, very distressed = 1)


NotesConcomittent treatment: allowed continued emollients and low-dose steroids

Compliance to treatment: undertaken by parental information and serum level changes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote (page 428): "Patients were assigned to two groups on the basis of a randomised list created by suitable statistical software"

Allocation concealment (selection bias)Low riskThe BO group was identified by letter A; the olive oil (placebo) group, by letter B. Investigators were unaware of this classification before and during the study. Comment: It is unclear if allocation was adequately concealed

Incomplete outcome data (attrition bias)
All outcomes
Low risk9/10 participants in the borage oil group completed the study, and 9/10 in the olive oil group completed the study

Selective reporting (reporting bias)Low riskThe trial reported all prespecified outcomes

Other biasLow riskWe contacted the author; there was no other bias

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskOils were dispensed in dark unlabelled bottles. Interventions had a different taste, smell, and colour

Quote: "None of the investigators was aware of (...the A vs B...) classification before or during the study." (Methods section)

Comment: Attempts were made to blind both participants and personnel, but it was unclear if this was adequate

Finlay 2001

MethodsDesign: double-blind, placebo-controlled, randomised

Duraton: 3 months

Interval of assessment: 3 weeks


ParticipantsNumber randomised: 60 (30 each in the active and placebo groups)

Sex (M/F): not stated

Age of participants: 5 to 12 years for both groups

Unit of allocation: whole person

Country and setting: UK, 12 sites

Duration of condition: problems for over a year, some intermittent

Inclusion criteria of the study

  • Children under 10 years of age from 12 sites in UK (1 to 17 cases per site) with AD
  • Diagnostic criteria: UK working party criteria and requiring treatment (though ˜24% used none during the 30 days prior to joining)
  • Severity of condition: not specified but stated equal in both groups


Exclusion criteria of the study

  • Any other itch condition
  • Active infection
  • Use of phenothiazines
  • Severe illness
  • Seizures
  • Use of anything stronger than 1% hydrocortisone


Interventions
  • Treatment group: 8 capsules daily each with 40 mg EPO and vitamin E
  • Placebo group: 8 capsules daily each with 40 mg coconut oil and vitamin E


Outcomes
  1. Pruritis by physician (method: VAS 0 to 100, where 0 = none and 100 = severe)
  2. Itch, erythema, edema, dryness, infection, scale, overall by physician (method: VAS 0 to 100, where 0 = none and 100 = severe)
  3. Overall by medical doctor (method: 1, 2, 3 = mild, moderate, severe)
  4. Quality of life (method: DLQI)
  5. Hydrocortisone use (method: weight of tubes)
  6. Area (method: rule of 9)


NotesPretreatment: stated needed treatment, but 25% not doing any treatment

Compliance: stated and undertaken

The results were evaluated - by other individuals - 6 years after the study completed


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe trial used block randomisation (blocks of 4). Searle held the randomisation code, which was not identified to the investigators unless in an emergency

Allocation concealment (selection bias)Low riskThe trial used sealed envelopes

Incomplete outcome data (attrition bias)
All outcomes
Low risk2/30 participants in the EPO group withdrew due to adverse events, as did 2/30 in the placebo group

Selective reporting (reporting bias)Low riskThe trial reported all prespecified outcomes

Other biasLow riskThere was no other bias

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThere was adequate blinding of both investigators and participants

France 1988

MethodsDesign: double-blind, placebo-controlled, randomised, parallel

Duraton: 16 weeks

Interval of assessment: 4 weeks


ParticipantsNumber randomised: 45 (25 in the active group and 20 in the placebo group)

Sex (M/F): numbers for sites were not recorded

Age of participants: not recorded (page 24)

Unit of allocation: whole person

Country and setting: UK in 10 centres

Inclusion criteria of the study

  • Either sex
  • Age 5 to 75 years
  • Written informed consent
  • Diagnosed with severe atopic eczema, as defined by extensive body involvement with a regular need for Betnovate or equivalent steroid, frequent need for more potent steroid or for systemic steroids, or both; cytotoxic therapy; combined with other measures (page 13)
  • Must begin out of hospital, continue into hospital. May start immediately after discharge from a hospital
  • Diagnostic criteria: not specified


Exclusion criteria of the study

  • Other itch cause, inflammatory, malignant, severe (liver/renal)
  • Pregnant/lactating
  • Needing cytotoxic currently


Interventions
  • Treatment group: EPO, 12 capsules daily, each capsule 500 mg
  • Placebo group: paraffin oil, 12 daily, each capsule 500 mg


Outcomes
  1. Participant perception of itch (method: VAS, from none to worst ever)
  2. Other Skin condition, such as itch, dryness, etc, by participant (method of assessment: VAS)


NotesPrevious treatment not stopped

Concomittant treatment permitted

Assessment of compliance undertaken but incomplete

The results were evaluated - by other individuals - 6 years after the study completed


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe trial used computer-generated block randomisation

Allocation concealment (selection bias)Low riskA Securitainer® was used for each participant and at each visit

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskOf 25 participants in the active group, 4 withdrew and 3 were lost to follow up. Of 20 participants in the placebo group, 2 withdrew and 2 were lost to follow up

Selective reporting (reporting bias)Unclear riskQuote: "Primary and secondary efficacy variables not stated in the study..."

Other biasHigh riskCase report forms (CRFs) varied at different sites. Ages were not recorded (page 24)

The results were evaluated 6 years after study completion and evaluated by other individuals

Quote (page 4): "Efficacy variables were not stated in the protocol...for the purpose of this report the patient assessment of itching was the primary efficacy variable"

3 participants were included in analyses that were not accounted for in the randomisation schedule (page 14)

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThis was adequate

Fraser 2001

MethodsDesign: randomised, double-blind, parallel, placebo-controlled

Duration: 3 months

Interval of assessment: 3 weeks

Unit of randomisation: whole person
Unit of analysis: whole person

Duration of trial: 12 weeks

Interval of assessment: 4 weeks


ParticipantsNumber randomised: 90 (43 in the active group and 47 in the placebo group)

Sex (M/F): 17/28 in the active group and 23/24 in the placebo group

Age of participants: 10 to 29 years old in the majority; both groups had 4 participants under 10 years old

Country and setting; UK, 4 sites

Duration of condition: average duration = 20.8 years for Efamol® and 16.7 years for placebo

Inclusion criteria of the study

  • Patients over the age of 3, attending dermatology clinic with a "history of signs and symptoms suggestive of a diagnosis of atopic eczema"
  • Diagnostic criteria: not stated
  • Severity of condition: moderate: 44.4% Efamol®, 57.9 % placebo group, rest not stated


Exclusion criteria of the study

  • Taking systemic steroids, NSAIDS, beta blockers, or phenothiazine
  • Having Epilepsy


Interventions
  • Treatment group: 8 capsules daily, each with 500 mg EPO
  • Placebo group: 8 capsules daily, each with 500 mg Olive oil


Outcomes
  1. Participant assessment of itch (method: VAS 1 to 100, where 0 = none and 100 = worst ever)
  2. All other measures by doctor and participant: redness, scale, dryness, and overall improvement (method: VAS, as above)


NotesPretreatment in both groups: 4 weeks' placebo

The results were evaluated - by other individuals - 6 years after the study completed


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskThe trial was randomised, but did not mention a method of generation

Allocation concealment (selection bias)Unclear riskThere was no statement about allocation concealment

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo participants dropped out in the EPO group. 4 participants dropped out in the placebo group

Selective reporting (reporting bias)Low riskThere was no selective reporting

Other biasLow riskThere was no other bias

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskThis was stated, but details were not specified

Harper 1990

MethodsDesign: randomised, double-blind, placebo-controlled, parallel

Duration of trial: 16 weeks

Interval of assessment: first weekly, then 4 weeks


ParticipantsNumber randomised: 20 (9 in the active group and 11 in the placebo group)

Sex (M/F): 1/8 in the active group and 4/7 in the placebo group

Age of participants: active group = 7.0, placebo group = 4.3

Unit of analysis: whole person

Country and setting: patients from single centre dermatology in UK, no other specifications

Inclusion criteria of the study

  • "Moderate to severe atopic eczema requiring constant treatment with mild to moderate potent steroids, emollients or antihistamines"
  • Aged 6 months to 12 years
  • No trial treatment to be started in hospital setting, none to be discontinued, if hospitalised. May enter study immediately after leaving hospital
  • Diagnostic criteria: clinical


Exclusion criteria of the study

  • Other cause of itch
  • Any other inflammatory disorder
  • Any severe intercurrent illness, including renal liver failure or cancer
  • Epilepsy
  • Phenothiazines


Interventions
  • Treatment (active) group:
    • 8 capsules daily, each with 500 mg EPO, for children between 6 months to 2 years;
    • 12 capsules daily, each with 500 mg EPO, for children between 2 years to 12 years
  • Placebo group: capsules each with 500 mg olive oil, divided into 2 groups as above


Duration: 16 weeks' treatment and 8 weeks' off therapy


Outcomes
  1. Parent evaluation of itch (method: VAS, from none to worst ever)
  2. Parental assessments of the participant's skin dryness, scaling, redness, and overall impression (method of assessment: VAS)
  3. Dermatologist assessments of the patient's skin dryness, scaling, redness, and overall impression (method of assessment: VAS)
  4. Adverse events


NotesPrevious treatment not stopped ("no limitations regarding other treatment were required")

Asessment of compliance: "Insufficient data were available to evaluate compliance"

Compliance treatment of the children's eczema was permitted to continue as usual

The results were evaluated - by other individuals - 6 years after the study completed


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe trial used computer-generated randomisation

Allocation concealment (selection bias)Low riskQuote (page 15): "A listing of the randomization schedule and code is not available. Appendix 4 contains a listing of children with their randomised assigned treatment"

Comment: This was adequate

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe trial undertook ITT analysis

Selective reporting (reporting bias)Low riskThere was no selective reporting

Other biasHigh riskPharmacia sponsored the trial

Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote (page 15): "Securicontainer #1 was given out by physician or pharmacist to the first patient entered in the trial"

Comment: This was adequate

Heddle 1990

MethodsDesign: randomised, double-blind, placebo-controlled, single-centre, cross-over

Unit of randomisation: whole person
Unit of analysis: whole person

Duration: There was a 4-week run-in period during which all participants received olive oil. Participants then received treatment with either EPO or safflower oil (SAFF) for 8 weeks (period 1)

Following a wash-out period of 4 weeks, during which participants again received olive oil, participants received the opposite treatment to that which they had received in period 1 for 8 weeks (period) (page 4)

"Number of patients (planned and analysed): Planned: not known. Enrolled and analysed: 25 patients." (page 3)

Use of concomitant treatment: not specified/mentioned

Previous treatment stopped/continued: not specified


ParticipantsNumber randomised: 25 (12 received EPO first and 13 received SAFF first)

Sex (M/F): not specified

Age of participants: 8 years (mean)

Unit of allocation/randomisation/analysis: whole person

Country/setting: participants from single centre in UK, no other specifications

Inclusion criteria of the study

  • Although no inclusion criteria are listed in the final report, we choose to believe that a physician made the diagnosis of eczema clinically and that was used as an inclusion criteria
  • Diagnosis: "dermatologist's assessment"
  • Severity of condition: not specified


Exclusion criteria of the study

  • Not specified


Interventions
  • Treatment group: 500 mg EPO in each capsule, total dose 1000 mg/kg body weight/per day
  • Placebo group: 500 mg olive in each capsule, total dose 1000 mg/kg body weight/per day


"Each capsule had 20 mg/gm vitamin E as an antioxidant"

Follow-up: treatment schedule = 8 weeks' treatment, 4 weeks' wash-out, then 2 groups switched over for the last 8 weeks


OutcomesTiming of outcome assessment: baseline and 8 weeks for each period of treatment (periods 1 and 2)

Primary outcomes

  1. Participant perception of itch (method: VAS, from none to worst ever)
  2. Participant/parent assessments of sleep loss due to itch and changes in general health and eczema (method of assessment: VAS)
  3. Dermatologist assessments of the participant's skin dryness, scaling, redness, and overall impression of all symptoms and signs of AD (method of assessment: VAS)


Secondary outcomes

  1. "EFA levels and cellular determinations were considered secondary efficacy endpoints"
  2. Asessment of compliance undertaken: "At each clinic visit patients returned all unused capsules. The returned capsules were used to assess treatment compliance"


Adverse events: none listed


NotesPrevious treatment stopped/continued: not specified

Asessment of compliance undertaken: "At each clinic visit patients returned all unused capsules. The returned capsules were used to assess treatment compliance"

Concommitant treatment permitted/not permitted: not specified

The sponsor was contacted and had no further information about the investigator or study

The results were evaluated - by other individuals - 6 years after the study completed


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskA randomisation table was given, but the method of sequence generation was not stated

Quote: "This was a single center, double-blind, randomised, placebo-controlled, crossover study of EPO versus safflower oil (SAFF, Placebo)"

Allocation concealment (selection bias)Unclear riskThe trial did not mention a method of concealment

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll (25/25) participants completed, and an ITT model was used

Selective reporting (reporting bias)Low riskThe trial reported all prespecified outcomes

Other biasHigh riskThe final write-up and statistical evaluation was done at least 6 years after the last participant was in the study

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskThe study did not state the method, but it was performed under double-blind conditions

Hederos 1996

MethodsDesign: randomised, double-blind, parallel

Duration: 16-week

Interval of assessment: 4-week


ParticipantsNumber randomised: 60 Active (30 each in the active and placebo groups)

Sex (M/F): 13/17 in the active group and 13/17 in the placebo group

Age of participants: active group = 7.5, placebo group = 8.6

Unit of allocation: whole person

Country and setting: Karlstad, Sweden, paediatric department of central hospital - 2 clinics

Inclusion criteria of the study

  • Outpatients
  • Either sex
  • 1 to 16 years of age
  • Diagnosis: Hanifin and Rajka


Exclusion criteria of the study

  • Not specified


Interventions
  • Treatment group:
    • < 12 years, = 8 Epogam® capsules daily (each containing 500 mg evening primrose oil providing 40 mg GLA with 10 mg vitamin E)
    • > 12 years = 12 Epogam® capsules daily (same composition)
  • Placebo group: same number of identical gelatin capsules as for the treatment group according to age (containing 500 mg of sunflower oil with 10 mg vitamin E)


Outcomes
  1. Clinician rating of redness, dryness, crusts, excoriation, itch, scaling, lichenification, fidget, overall impression of condition, area of involvement (method of assessment: VAS, scale = 0 to 10)
  2. Global assessment by parents (method: diary booklet)
  3. Total IgE and essential fatty acids (laboratory)
  4. Skin prick test with allergens (laboratory)
  5. DGLA levels (laboratory)


NotesN/A


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote (page 484): "A randomisation list was provided that allocated patients in blocks of two"

Allocation concealment (selection bias)Unclear riskNo details of concealment given

Incomplete outcome data (attrition bias)
All outcomes
Low risk2/30 participants in the EPO group withdrew before the end of therapy, as did 0/30 in the placebo group

Selective reporting (reporting bias)Low riskThe trial reported all prespecified outcomes

Other biasLow riskThere was no other bias

Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote (page 494): "The study was a double blind, randomised, placebo controlled trial"

Comment: Participants were blinded as "identical" capsules were given

Henz 1999

MethodsDesign: randomised, parallel, double-blind, placebo-controlled

Duration: -

Interval of assessment: -

Unit of randomisation: whole person
Unit of analysis: whole person

Duration of trial: 24 weeks

Interval of assessment: at 1, 2, 6, 12, 18, and 24 weeks


ParticipantsNumber randomised: 160 (80 each in the active and placebo groups)

Sex (M/F): 66% women in the borage oil group and 54% women in the miglyol group

Age of participants: 14 to 65 years

Unit of allocation: whole person

Country and setting: Switzerland, multicentre

Duration of condition: average duration = 22 years for BO and 20 years for miglyol

Inclusion criteria of the study

  • Severity of condition: moderate
  • Diagnostic criteria: Hanifin Rajka's criteria


Exclusion criteria of the study

  • Not specified


Interventions
  • Treatment group: BO, 6 capsules per day, each capsule 500 mg
  • Placebo group: miglyol, 6 capsules per day, each capsule 500 mg


Outcomes
  1. Improvement of individual eczema symptoms
  2. Method of assessment by 50% reduction in Costa score


NotesPrevious treatment: stopped at the beginning of study

Concommitant treatment: allowed and assessed

Asessment of compliance undertaken by measuring blood levels of drug and use of corticosteroids

"The primary efficacy of the treatment was assessed by counting the number of patients achieving a 50% reduction in Costa score (as defined as clinical response) as a function of corticosteroid use"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskThis was provided from external sources, which were not specified

Allocation concealment (selection bias)Unclear riskThis was unclear

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThis was unclear

Selective reporting (reporting bias)Unclear riskThis was unclear

Other biasUnclear riskThis was unclear

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskThis was unclear

Kenicer 2001

MethodsDesign: randomised, double-blind, placebo-controlled

Duration: 16 weeks

Interval of assessment: start, 4 weeks


ParticipantsNumber randomised: 66 (32 in the active group and 34 in the placebo group)

Sex (M/F): both

Age of participants: between 10 and 70 years of age

Unit of allocation: whole body

Country and setting: UK at Ninewells Hospital, Dundee or Hull Royal Infirmary

Inclusion criteria of the study

  • Diagnosis: satisfying previously defined and published criteria for atopic eczema (Hanifin 1980)
  • Informed consent
  • Active disease
  • No severe intercurrent disease


Exclusion criteria of the study

  • Not pregnant, lactating
  • Child-bearing age and not on contraception
  • Non-compliant
  • Epileptic
  • Taking phenothiazines or immunosuppressive drugs
  • Receiving UV treatments


Interventions
  • Treatment group: 8 capsules daily, with 400 mg GLA and 11 mg vitamin A in each capsule
  • Placebo group: 8 capsules daily, with 500 mg olive oil in each capsule


Outcomes
  1. Participant assessment of itch
  2. Participant assessment of dermatology (global score)
  3. Physician assessment of dermatology (global score)
  4. Physician assessment of redness (method of assessment: all participant and dermatological assessment were done on a VAS and scoring system used as 0 = no lesion to 100 = worse lesion)


NotesConcomittent treatment: previous treatment with moderate to potent topical steroids, emollients continued for first 8 weeks of study, or both Next 8 weeks' steroids discontinued

Compliance to treatment: Although the protocol called for pill counting and cream weighing to determine use of treatments, the final report did not include any evaluation of these measures

Quote (page 29): "34% of Active and 32% of placebo participants did not satisfy the inclusion criterion"

The results were evaluated - by other individuals - 6 years after the study completed

There were a large number of dropouts


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation was by computer-generated sequence in blocks of 4, which was adequate

Allocation concealment (selection bias)Low riskThis was adequate

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe trial undertook ITT analysis

Selective reporting (reporting bias)Low riskThere was no selective reporting

Other biasHigh riskQuote (page 29): "34% of Active and 32% of placebo participants did not satisfy the inclusion criterion"

Quote (page 3): "For the purpose of this report the primary and secondary objectives have been re-defined"

The results were evaluated 6 years after the completion of the study; other individuals evaluated the results

Blinding of participants and personnel (performance bias)
All outcomes
High riskQuote (page 19): "There was no evidence in the protocol that the study was performed under blind conditions"

Kiehl 1994

MethodsDesign: double-blind, placebo-controlled

Duration of trial: 3 months

Interval of assessment: at baseline, after 4 weeks, and at end of study (12 weeks)


ParticipantsNumber randomised: not reported

Sex (M/F): not reported

Age of participants: not reported

Unit of allocation: whole person

Country and setting: single centre in Germany

Duration of disease: not reported

Inclusion criteria of the study

  • Mild to moderate eczema
  • Diagnostic criteria: clinical
  • Severity of disease: not reported


Exclusion criteria of the study

  • If participants were not corticoid-free 1 month before start of the trial, they were excluded
  • Participants using corticosteroids during trial


Interventions
  • Treatment: 6 capsules twice daily for 4 weeks, each with 40 mg of glandol, followed by 3 capsules twice daily for 10 days
  • Placebo group: 4 capsules daily, each with 480 mg GLA for 4 weeks, followed by 2 capsules daily for children 1 to 3 years of age, and 3 capsules daily for children 4 to 12 years of age


Outcomes
  1. Immune profile (method of assessment: blood)
  2. ADASI score (method: not reported)
  3. Plasma concentrations of linolenic acid (method of assessment: blood)
  4. Plasma gamma-linolenic acid concentration (method of assessment: blood)


NotesPrevious treatment stopped for 4 weeks

Concomittent treatment: antihistaminics permitted

Compliance to treatment: unstated


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskThe trial did not state the method of sequence generation

Allocation concealment (selection bias)Unclear riskThe paper stated "double-blind", but did not specify the method

Incomplete outcome data (attrition bias)
All outcomes
Low riskThere were no dropouts (39/39 in the glandol group; 23/23 in the EPO group)

Selective reporting (reporting bias)Unclear riskThe trial reported all prespecified outcomes

Other biasLow riskThere was no other bias

Blinding of participants and personnel (performance bias)
All outcomes
Low riskBoth participants and personnel were blinded; it is unclear if the outcome assessors were blinded

Comment: This was probably done

Kovar 1992

MethodsDesign: 2 separate phases: first phase was double-blind and placebo-controlled with a trial duration of 8 weeks; the second phase was single-blind - with no placebo control - with a trial duration of 8 weeks

Duration: 8 weeks each phase

Interval of assessment: 4 weeks by physician and weekly by parent


ParticipantsNumber randomised: 48 (24 each in the active and placebo groups)

Sex (M/F): 16/8 in the active group and 12/12 in the placebo group

Age of participants: active group = 1.9 years, placebo group = 1.7 years

Duration of eczema before trial: 1.3 years for both groups

Unit of allocation: whole person

Country and setting: single centre in Germany

Inclusion criteria of the study

  • Children of either sex
  • Children up to 5 years of age
  • Children with moderate to severe atopic eczema requiring constant treatment with mild to moderately potent topical steroids, emollients, antihistamines, or a combination of the aforementioned
  • Diagnostic criteria: clinical, Hanifin


Exclusion criteria of the study

  • Children with pruritus from any other cause
  • Children with an inflammatory skin disorder other than atopic eczema
  • Children with systemic inflammatory disorders.
  • Children with severe intercurrent illnesses, including liver failure, renal failure, or malignancy
  • Children with epilepsy or on phenothiazines


Interventions
  • Treatment group: 8 capsules per day, each containing 500 mg of EPO (total dose of 4000 mg per day)
  • Control group: 8 capsules per day, each containing 500 mg of paraffin oil (total dose of 4000 mg per day)


Outcomes
  1. Parent assessment of itching (for assessment, the status of itch was recorded by placing a vertical mark in the diary card on a 100 mm VAS), ranging from none/no symptoms to worst ever for itch and from worst ever to best ever for overall impression
  2. Parent assessment of overall symptoms and clinical picture
  3. Physician assessment of itch, redness, and overall symptoms (method used again was VAS - 2 types: 1 as by parent, other as mild, moderate, or severe)
  4. Laboratory assessments of IgE, RAST (radioallergosorbent test) essential fatty acid (EFAs) in plasma phospholipids and in red blood cells
  5. Profilometric (surface roughness or texture) measurements of silicon casts were performed


NotesThe results were evaluated - by other individuals - 6 years after the study completed


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Computerized, block method for the 8 week double blind, parallel, placebo controlled study"

Allocation concealment (selection bias)Low riskCodes were kept in sealed envelopes, which were only to be opened if needed

Incomplete outcome data (attrition bias)
All outcomes
Low riskThere were no withdrawals. 3/24 participants in the active group were lost to follow up, as were 2/24 in the placebo group

Selective reporting (reporting bias)Unclear riskThis was unclear

Other biasHigh riskQuote (page 22): "No statistical methodology was planned in the protocol..."

Comment: A statistical analysis plan was developed in June 2001 (some years after the study was completed)

Quote (page 23): "A primary objective for this study was not stated within the protocol"

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThis was adequate: Pill appearance was the same, and the medication was dispensed in a blind fashion

Lovell 1981

MethodsDesign: randomised, double-blind, placebo-controlled, cross-over

Duration: 6 weeks (2 periods of 3 weeks each)

Interval of assessment: 4 weeks


ParticipantsNumber randomised: 64 (32 each in the active and placebo groups)

Sex (M/F): not listed

Age of participants: 17 children = 3 months to 13 years, 15 adults = 24 to 32 years

Unit of allocation: whole person

Country and setting: Bistol, United Kingdom; single centre

Duration of eczema: 6 months and more

Inclusion criteria of the study

  • Diagnosis: "had atopic dermatis"
  • Severity of condition: not stated


Exclusion criteria of the study

  • Not specified


Interventions
  • Treatment group: 8 capsules daily for adult and 4 capsules daily for child, each with 500 mg EPO
  • Placebo group: 8 capsules daily for adult and 4 capsules daily for child, each with 500 mg paraffin oil


Outcomes
  1. Severity of eczema rated by physician (method of assessment: severity as measured on a continuous 10 cm linear scale ranging from no eczema (zero) to most severe (10 cm))
  2. Severity of eczema rated by participant (method of assessment: severity as measured on a continuous 10 cm linear scale ranging from no eczema (zero) to most severe (10 cm))


NotesPrevious treatment: unsure

Concommitant treatment: mild topical steroids and emollient allowed

Asessment of compliance: not undertaken

No power calculation


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote (page 278): "...received on a randomised, double-blind crossover basis..."

Allocation concealment (selection bias)Unclear riskThe paper did not state this (a short 5-paragraph report)

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll randomised participants were included in the results

Selective reporting (reporting bias)Unclear riskThis was unclear

Other biasHigh risk1 author (DFH) worked full time for the company. We contacted the author

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe first phase was double-blind

The second phase was only participant-blinded

MacKie Adult 1990

MethodsDesign: randomised, double-blind, placebo-controlled

Duration: 24 weeks (16 weeks' therapy and 8 weeks off therapy)

Interval of assessment: 4 weeks


ParticipantsNumber randomised: 20 (10 each in the active and placebo groups)

Sex (M/F): 11/9 total (5/5 in the active group and 6/4 in the placebo group)

Age of participants: active group = 26.8, placebo group = 25.0 (means)

Unit of allocation: whole body

Country and setting: Glasgow, UK; single dermatology centre

Inclusion criteria of the study

  • Diagnosis: patients with "moderate to severe atopic eczema, as defined by extensive body involvement with a regular need for moderately potent or potent steroids (MIMS (Monthly Index of Medical Specialties) classification) or frequent need for very potent steroid or for systemic steroids, cytotoxic therapy, combined with other measures, particularly antipruritic agents and antibiotics as require" (page 15)
  • Participants of either sex
  • Participants between the ages of 12 and 75 years
  • Outpatients. No one could start in the hospital; no treatment was to be stopped if going into hospital. On hospital discharge they could immediately enter the study


Exclusion criteria of the study

  • Pruritis of any other cause
  • Any other inflammatory skin disorder or any systemic disorder
  • Any severe intercurrent illness, including liver failure, renal failure, malignancy
  • Participants pregnant or trying to conceive
  • Participants with epilepsy
  • Participants on phenothiazines


Interventions
  1. Treatment group: 8 capsules daily, each with 40 mg GLA and 11 mg vitamin E
  2. Placebo group: 8 capsules daily, each with 500 mg olive oil


Outcomes
  1. Participant assessment of itching (method of assessment: VAS 0 to 100; none to worst ever)
  2. Participant assessment of all other signs and symptoms of eczema except itch (method of assessment: VAS)
  3. Skin assessments by the dermatologist (method of assessment: Glasgow method and skin profilimetry)
  4. EFA levels
  5. Adverse events


NotesAsessment of compliance: "There were no details relating to any assessments of compliance in the protocol. All unused capsules were returned to Scotia Pharmaceuticals at the end of the study"

Continued or new concomitant treatment of eczema was permitted

The results were evaluated - by other individuals - 6 years after the study completed


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation was computer-generated

Allocation concealment (selection bias)Low riskAllocation concealment was done through sealed coded envelopes

Incomplete outcome data (attrition bias)
All outcomes
Low riskThis was low risk

Selective reporting (reporting bias)Low riskThis was low risk

Other biasHigh riskThe results were evaluated 6 years after the completion of the study; other individuals evaluated the results

Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding was adequate

MacKie Child 1990

MethodsDesign: double-blind, randomised, placebo-controlled

Duration: 24 weeks (16 weeks' intervention, 8 weeks off treatment)

Interval of assessment: 4 weeks


ParticipantsNumber randomised: 19 (10 in the active group and 9 in the placebo group)

Sex (M/F): 10/10 total (3/7 in the active group and 7/3 in the placebo group)

Age of participants: active group = 6.2, placebo group = 5.8 (means)

Unit of allocation: whole person

Country and setting: Glasgow, UK; single dermatology centre

Inclusion criteria of the study

  • Participants of either sex
  • Participants < 12 years
  • Participants with moderate to severe atopic eczema, as defined by extensive body involvement
  • Diagnosis: severity of condition: moderate to severe eczema defined as extensive body involvement with regular need for moderately potent or potent steroid or frequent need for systemic steroids, cytotoxic therapy, combined with other measures, particularly antipruritic agents or antibiotics as required


Exclusion criteria of the study

  • Pruritis of any other cause
  • Any other inflammatory skin disorder or any systemic disorder
  • Any severe intercurrent illness, including liver failure, renal failure, malignancy
  • Participants pregnant or trying to conceive
  • Participants with epilepsy
  • Participants on phenothiazines


Interventions
  1. Treatment group: 8 capsules daily, each with 40 mg GLA and 11 mg vitamin E
  2. Placebo group: 8 capsules daily, each with 500 mg olive oil


Outcomes
  1. Participant assessment of itching (method of assessment: VAS 0 to 100; none to worst ever)
  2. Participant assessment of all other signs and symptoms of eczema except itch (method of assessment: VAS)
  3. Skin assessments by the dermatologist (method of assessment: Glasgow method and skin profilimetry)
  4. EFA levels
  5. Adverse events (mild, moderate, severe)


NotesPrevious treatment not stopped

Assessment of compliance: "There were no details relating to any assessments of compliance in the protocol. All unused capsules were returned to Scotia Pharmaceuticals at the end of the study"

Concommitant treatment of the children's eczema was permitted to continue as usual

The results were evaluated - by other individuals - 6 years after the study completed


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation was computer-generated

Allocation concealment (selection bias)Low riskThe trial used sealed envelopes

Incomplete outcome data (attrition bias)
All outcomes
Low riskThere were no withdrawals, but defaults: 4/10 in the active group and 2/9 in the placebo group

Selective reporting (reporting bias)Low riskThis was low risk

Other biasHigh riskThe results were evaluated 6 years after the completion of the study; other individuals evaluated the results. 1 child was included against protocol (age 12)

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThis was adequately blinded

MacLeod 2001

MethodsDesign: randomised, double-blind, placebo-controlled

Duration: 16 weeks

Interval of assessment: 4 weeks


ParticipantsNumber randomised: 19 (10 in the active group and 9 in the placebo group)

Sex (M/F): 4/4 in the active group, 3/5 in the EPO/Marine group, and 6/2 in the placebo group

Age of participants: EPO group = 29.1, EPO/Marine group = 25.3, placebo group = 26.4 years

Unit of allocation: whole person

Country and setting: Glasgow, UK; single dermatology centre

Inclusion criteria of the study

  • Participants of either sex
  • Participants 16 to 30; and, yet, the range of participants' ages was from 17 to 35
  • Participants with moderate to severe atopic eczema, as defined by extensive body involvement
  • Diagnosis: severity of the condition: moderate to severe atopic eczema, as defined by extensive body involvement with a regular need for moderately potent or potent steroid or frequent need for systemic steroids; cytotoxic therapy, combined with other measures, particularly antipruritic agents and antibiotics as required


Exclusion criteria of the study

  • Pruritis of any other cause
  • Any other inflammatory skin disorder or any systemic disorder
  • Any severe intercurrent illness, including liver failure, renal failure, malignancy
  • Participants pregnant or trying to conceive
  • Participants with epilepsy
  • Participants on phenothiazines


Interventions
  • Treatment group - 2 groups:


    • Efamol® - 12 capsules daily, each with 40 mg GLA and 11 mg vitamin E
    • Efamol® - marine, 12 capsules, each 500 mg, with 80% Efamol® and 20% fish oil


  • Placebo: 12 capsules daily each with 500 mg paraffin oil


Outcomes
  1. Participant assessment of itching (method of assessment: VAS 0 to 100; none to worst ever)
  2. Participant assessment of all other signs and symptoms of eczema except itch (method of assessment: VAS and diary)
  3. Dermatologist assessment of all other signs and symptoms of eczema (method of assessment: VAS)


NotesPrior and concomitant treatment: allowed

Compliance assessment: undertaken by counting the returned capsules

The results were evaluated - by other individuals - 6 years after the study completed


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskA computer-generated sequence was used

Allocation concealment (selection bias)Low riskThe trial used sealed opaque envelopes

Incomplete outcome data (attrition bias)
All outcomes
High riskThere were 3/8 withdrawals in the active group, and there were 4/8 withdrawals in the placebo group

Selective reporting (reporting bias)Unclear riskThis was unclear

Other biasHigh riskThe results were evaluated 6 years after completion of the study; other individuals evaluated the results

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThis was adequate

Schalin-Karrila 1987

MethodsDesign: double-blind, placebo-controlled, parallel

Duration: 12 weeks

Interval of assessment: 3 weeks


ParticipantsNumber randomised: 25 (14 in the active group and 11 in the placebo group)

Sex (M/F): 9/16

Age of participants: 19 to 31 years

Unit of allocation: whole person

Country and setting: Finland, Turku Pediatrics single centre

Inclusion criteria of the study

  • Maintain normal diet
  • No other specifications
  • Diagnosis: clinical appearance. Many also had personal history of respiratory atopy with family history of atopy
  • Severity of condition: moderate to severe


Exclusion criteria of the study

  • Not specified


Interventions
  • Treatment group: 8 capsules daily, each with 500 mg of EPO
  • Placebo group: 8 capsules daily, each with 500 mg paraffin oil


Outcomes
  1. Consumption of emollient cream and topical steroids
  2. Overall severity and grade of inflammation
  3. Response to treatment (method of assessment of above 3 by discussion between doctor and participant)
  4. Fatty acid composition of plasma phospholipids (method of assessment was by laboratory testing)
  5. Blood levels of prostaglandins and thromboxane (method of assessment was by laboratory testing)


NotesPrior treatment: 2 weeks off topical steroids and systemic medications

Concomitant treatment: permitted

Compliance undertaken by recording of mild topical cortisone, antihistamines, emollient, and blood assays


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskThe trial was described as 'randomly divided', but the method was not stated

Allocation concealment (selection bias)High riskThe method was not stated

Incomplete outcome data (attrition bias)
All outcomes
Low risk1 participant out of 14 in the EPO group dropped out due to allergy to concomitant medication (unrelated to EPO); there were no dropouts (out of 11 participants) in the placebo group

Selective reporting (reporting bias)Low riskThe trial reported all prespecified outcomes

Other biasLow riskThere was no other bias. A non-profit foundation provided funding

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote (page 12): "...14 patients receiving evening primrose oil (EPO) and 11 patients receiving placebo, in a double-blind trial. EPO was provided in capsules containing 360 mg linoleic acid, 50 mg oleic acid and 45 mg GLA (Efamol®). The placebo capsules contained 500 mg of liquid paraffin"

Comment: This was probably identical and adequate, but it was unclear if assessors were blinded (described as 'double blind')

Senapati 2008

MethodsDesign: randomised, double-blind, parallel

Duration: 5 months

Interval of assessment: 4 weeks


ParticipantsNumber randomised: 50 (25 each in the active and placebo groups)

Sex (M/F): 11/14 in the active group and 7/18 in the placebo group

Age of participants: detailed to decade, similar in the active and placebo groups

Unit of allocation: whole person

Country and setting: Kolkata, India; single centre, referral hospital's outpatient department

Inclusion criteria of the study

  • Diagnostic criteria: Hanifin and Rajka
  • Severiity: "all degrees from mild to severe using 'Intensity Item Score Aggregate (IISA)"


Exclusion criteria of the study

  • Pregnant and lactating women
  • Epilepsy patients
  • Those with history of peptic ulceration, intake of phenothiazines
  • Patients who received UVB phototherapy or photochemotherapy in the last month
  • Patients who received systemic steroid or other immunosuppressive drugs in the last 3 months


Interventions
  • Treatment (active) group:
    • 1 to 4 capsules/day for participants up to 1 year of age;
    • 5 to 6 capsules/day for those aged 2 to 5 years;
    • 7 to 8 capsules/day for those aged 6 to 10 years;
    • 9 to 10 capsules/day for those 11 to 16 years;
    • 12 capsules/day for participants above 16 years of age (each capsule had 500 mg of EPO and vitamin E 10IU)
  • Placebo: dose the same way according to age groups as the treatment arm (each capsule had 300 mg of sunflower oil and vitamin E 10IU)


Outcomes
  1. Extent (method: extent of the disease: if only 1 area of predilection or less than 20% of body surface area (BSA) was involved, score was as follows: 1. If 2 to 3 areas or < 40% of BSA was involved, the participant scored 2. For any involvement more than the aforementioned, the score was 3)
  2. Intensity (method: individual scores from 6 separate clinical items - erythema, edema/papulation, vesiculation/oozing/crusting, excoriation, scaling, and lichenification (each graded as 0, 1, 2, and 3 for absence, mild, moderate, and severe degrees) - were summated to develop 'Intensity Item Score Aggregate (IISA)', which reflects the actual intensity of the disease. From this IISA, 'intensity score' was derived. For IISA 0, intensity score was 0. For IISA 1 to 6, score was 1. For IISA 7 to 12, score was 2)
  3. Itching (method: Itching was also graded as 0, 1, 2, and 3 for absence, mild, moderate, and severe degrees, respectively)
  4. Dryness (method: Dryness was evaluated only on uninvolved areas as follows: absence = score 0; mild = score 1; moderate = score 2; and, severe = score 3)
  5. Total score (method: adding all 4 major parameter scores. The case was labelled as mild, moderate, or severe when the total score ranged from 1 to 4, 5 to 8, and 9 to 12, respectively)


NotesConcomittent treatment: allowed continued emollients

Compliance to treatment: unsure


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "...using a random number table"

Comment: This trial did not specify the method of sequence generation

Allocation concealment (selection bias)High riskThe paper did not specify this

Incomplete outcome data (attrition bias)
All outcomes
Low riskThis was low risk

Selective reporting (reporting bias)Low riskThis was low risk

Other biasLow riskThis was low risk

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskThe study title did not state this: "Evening primrose oil is effective in atopic dermatitis: A randomised placebo-controlled trial". The study did not mention blinding

Takwale 2003

MethodsDesign: double-blind, placebo-controlled, parallel

Participants stratified into 2 groups of equal size: those aged up to 12 and those aged over 12

Duration: 12-week

Interval of assessment: 2, 4, 8, and 12 weeks


ParticipantsNumber randomised: 140

Sex (M/F): not mentioned other than (page 1) "...evaluable population 140 (including 69 children)"

Age of participants: not listed

Unit of allocation: whole person

Country and setting: UK, acute district general hospital in Nuneaton, England; single centre

Inclusion criteria of the study

  • Participants of either sex aged over 2 years attending the hospital for treatment of atopic dermatitis
  • Diagnosis: Hanifin and Rajka criteria
  • Severity of condition: not specified


Exclusion criteria of the study

  • Pregant, lactating, and fertile women not using effective contraception


Interventions
  • Treatment groups:
    • 4 capsules of 500 mg of BO each for adults
    • 2 capsules of 500 mg of BO each for adults
  • Placebo group: same dosage as above with liquid paraffin oil for adults and olive oil for children


Outcomes
  1. Mean change in SASSAD score by physicians (method: SASSAD 6 signs (erythema, exudation, excoriation, dryness, cracking, and lichenification) at 6 sites (hands, feet, arms, legs, head and neck, and trunk). Each sign is graded at each site on a 4-point scale (0 to 3, representing grades of none, mild, moderate, and severe)
  2. Overall assessment of treatment response by participant with 5-point visual analogue scale: worse, same, improved, much improved, or cleared
  3. Assessment of tolerability by participant (4-point scale: very good, good, fair, or poor)


NotesConcomitant treatment: allowed participants to use conventional treatment for atopic eczema throughout the study

Prior treatment: previous treatment continued, except for "potent" topical steroids, which were prohibited for children. Systemic antihistamines were allowed, but no other systemic treatment or ultraviolet light treatment was permitted

A minimum 4-week wash-out period was needed for participants who had received systemic steroids, psoralen plus ultraviolet A (PUVA), or other oral immunosuppressive treatment

Assessment of compliance: not specified


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "...using computer generated random numbers"

Allocation concealment (selection bias)Low riskThe study used sealed containers

Incomplete outcome data (attrition bias)
All outcomes
Low risk1 participant withdrew, out of 14, in the active group due to severe allergic reaction; there were 0 dropouts in the placebo group

Selective reporting (reporting bias)Unclear risk-

Other biasUnclear risk-

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskThe study stated "blinded", with no details

Valsecchi 2006

MethodsDesign: randomised, placebo-controlled, parallel

Duration: 16-week

Interval of assessment: 4 weeks


ParticipantsNumber randomised: 31 (15 in the active group and 16 in the placebo group)

Sex (M/F): not mentioned

Age of participants: 18 children = 2 to 14 years, 13 adults = 15 to 38

Unit of allocation: whole person

Country and setting: Bergamo, Italy; single clinic

Inclusion criteria of the study

  • "Having active lesions" (page 77)
  • Diagnosis: Hanifin and Rajka
  • Severity of condition: mild to severe


Exclusion criteria of the study

  • Not taken systemic corticosteroids for the past 3 weeks


Interventions
  • Treatment group: 5 capsules daily, each with 500 mg EPO for adults, and 3 capsules daily each with 500 mg of borage for children
  • Placebo group: 5 capsules, each with 500 mg paraffin oil, number of capsules daily for adult and child same as treatment group


Outcomes
  1. Quantitative measurement, which included both area involved and severity of signs and symptoms of eczema


The Atherton area and severity scoring system was used to measure eczema symptoms and signs. Laboratory investigations were performed


NotesPrevious treatment: if using systemic steroids, stopped at 3 weeks prior to inclusion in study. If using topical steroid, stopped at start Emollients continued

Compliance assessment: not specified

Concomitant treatment: only emollient


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskThe paper stated 'randomly divided', but no details were given

Allocation concealment (selection bias)Unclear riskThe paper did not state the method of allocation concealment

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk2/15 participants in the GLA group dropped out, and 1 participant, out of 16, dropped out in the placebo group; the reasons were unclear

Selective reporting (reporting bias)Low riskThe trial reported all prespecified outcomes

Other biasUnclear riskThere was no other bias

Blinding of participants and personnel (performance bias)
All outcomes
High riskThe trial report did not mention blinding

Wishart 1992

MethodsDesign: randomised, double-blind, placebo-controlled

Duration: 16 weeks

Interval of assessment: 4 weeks


ParticipantsNumber randomised: 75 (38 in the active group and 37 in the placebo group)

Sex (M/F): 43/32 total (22/16 in the active group and 21/16 in the placebo group)

Age of participants: active group = 25.5 years, placebo group = 22.0 years

Unit of allocation: whole person

Country and setting: New Zealand, multicentre

Inclusion criteria of the study

  • Participants of either sex
  • Participants between the ages of 16 and 75 years
  • Treatment was only to be commenced on outpatients. Participants who needed hospitalisations for treatment of eczema were not permitted to enter the study during their stay in the hospital. They were permitted to be entered into the study immediately upon discharge from hospital. If they were in the study, they were to continue the study regimen in hospital
  • Diagnosis: severity of the condition 'moderate to severe atopic eczema, as defined by extensive body involvement with a regular need for high potency or equivalent steroid, frequent need for more potent steroid (Dermovate or equivalent) or for systemic steroids, or both; cytotoxic therapy, combined with other measures, particularly antipruritic agents and antibiotics as required


Exclusion criteria of the study

  • Participants with pruritus from any other cause other than atopic eczema
  • Participants with an inflammatory skin disorder, other than atopic eczema, or other systemic inflammatory disorders
  • Participants with severe intercurrent illnesses, including liver failure, renal failure, malignancy
  • Participants who were pregnant or actively trying to conceive
  • Participants with epilepsy
  • Participants on phenothiazines


Interventions
  • Treatment group: 12 capsules of Efamol® daily, each with 40 mg GLA and 11 mg vitamin E
  • Placebo group: 12 capsules daily, each with 500 mg sunflower oil


Outcomes
  1. Dermatologist assessment of excoriation/itch (VAS)
  2. Dermatologist assessment of other parameters of eczema except itch, individually and overall impression (VAS)


NotesPrevious treatment not stopped

Concommitant treatment of eczema was permitted to continue as usual

The results were evaluated - by other individuals - 6 years after the study completed


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation was computer-generated

Allocation concealment (selection bias)Low riskThe trial used sealed opaque envelopes

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThis was unclear

Selective reporting (reporting bias)Unclear riskThis was unclear

Other biasHigh riskThe results were evaluated 6 years after the completion of the study; other individuals evaluated the results

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe trial used Securitainers® for medication handling

Wright 1982

MethodsDesign: randomised, double-blind, placebo-controlled, cross-over

Duration: 24 weeks (12 and 12)

Interval of assessment: 3 weeks


ParticipantsNumber randomised: 99 (60 in the active group and 39 in the placebo group)

Sex (M/F): not mentioned

Age of participants: 60 adults = 15 to 58 years, 39 children = 4 months to 14 years

Unit of allocation: whole person

Country and setting: UK, Bristol; single dermatology department

Inclusion criteria of the study

  • Diagnosis: clinical "atopic eczema" with personal or family history of atopic conditions and using mild topical steroid, emollients, and oral antihistamine
  • Severity: moderate or severe (no criteria)


"None was receiving potent topical steroids or systemic steroids" (page 1121)


Interventions
  • Adults = 3 groups:
    • 4 Efamol® capsules
    • 8 Efamol® capsules daily
    • 12 Efamol® capsules daily
  • Children = 2 groups:
    • 2 Efamol® capsules daily
    • 4 Efamol® capsules daily


Each Efamol® capsule had 500 mg of Efamol® (LA and GLA)

Each group had a corresponding placebo control taking the same number of capsules daily with 500 mg of liquid paraffin


Outcomes
  1. Doctor's assessment of degree of scaling, redness, and overall severity (method: 10 cm linear scale)
  2. Participant's assessment of same as above, plus severity of itch (method: 10 cm linear scale)


NotesPrevious treatment not stopped

Asessment of compliance: unsure

Concommitant treatment of eczema was permitted to continue as usual

Author S Wright did not respond to email. Dr Burton said he had did not have the records and was retired


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe trial used block randomisation

Allocation concealment (selection bias)Unclear riskThe paper did not describe allocation concealment

Incomplete outcome data (attrition bias)
All outcomes
Low risk8/60 participants in the active group dropped out, as did 8/39 in the placebo group

Selective reporting (reporting bias)Unclear riskThis was unclear there was no ITT statement

Other biasUnclear riskThis was unclear. We contacted the second author, who replied: "...retired, I do not know how to contact first author or [know the] whereabouts of records"

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThis was adequate

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Biagi 1988This was an open study

Bordoni 1988The paper did not give mean data, and the lead author did not reply to inquiry

Coskery 1988This was an abstract only (no detailed data). The corresponding author had no details about the clinical course. It was a double-blind, placebo-controlled study (EPO/placebo), but not randomised. It measured the texture of skin

Courage 1991This was not randomised

Guenther 1987The results of the study were shredded (author, 2011). 17 children in a double-blind cross-over study of the sign of figiting in people with atopic dermatitis. There was no significant difference in atopic dermatitis between placebo and EPO using this measure

Melnick 1995This had no placebo; both had the same amount of GLA/weight

NCT00878670This was initially found as an RCT on www.clinicaltrials.gov. After contacting the author, we checked the web site again and learned that it was not an RCT but an open study. The study has now closed

Swapan 2008Even though randomisation was stated, consecutive participant selection was carried out

 
Comparison 1. EPO versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Participant-reported global improvement in symptoms (0 to 100 VAS reduction)7176Mean Difference (IV, Random, 95% CI)-2.22 [-10.48, 6.04]

    1.1 Children only
230Mean Difference (IV, Random, 95% CI)-11.92 [-39.34, 15.49]

    1.2 Other (adults only or adults and children)
5146Mean Difference (IV, Random, 95% CI)0.98 [-5.47, 7.42]

 2 Parent assessment at end of treatment (VAS)1Mean Difference (Random, 95% CI)Totals not selected

 3 Parents global improvent in eczema symptoms at 8 weeks1Mean Difference (IV, Random, 95% CI)Totals not selected

 4 Physician-reported global improvement in symptoms (0 to 100 VAS reduction)8289Mean Difference (IV, Random, 95% CI)-3.26 [-6.96, 0.45]

    4.1 Children only
3101Mean Difference (IV, Random, 95% CI)-2.94 [-9.18, 3.30]

    4.2 Other (adults only or adults and children)
5188Mean Difference (IV, Random, 95% CI)-3.39 [-8.12, 1.33]

 5 Physician assessment at the end of treatment (VAS - MD)1Mean Difference (Random, 95% CI)Subtotals only

 6 Physician-reported improvement in symptoms (VAS 0 to 50)1Mean Difference (IV, Random, 95% CI)Totals not selected

 7 Physician-reported assessment at end of treatment (0 to 3 scale): high-dose1Mean Difference (IV, Random, 95% CI)Totals not selected

 8 Physician-reported assessment at end of treatment (0 to 3 scale): low-dose1Mean Difference (IV, Random, 95% CI)Totals not selected

 9 Physician-reported assessment at end of treatment (total disease scores)1Mean Difference (IV, Random, 95% CI)Totals not selected

 10 Physician-reported improvement in Leicester scores1Mean Difference (IV, Random, 95% CI)Totals not selected

 11 Physician-reported assessment at end of treatment (VAS 0 to 100)1Mean Difference (IV, Random, 95% CI)Totals not selected

 12 Dermatology Life Quality Index (DLQI) at the end of treatment1Mean Difference (IV, Random, 95% CI)Totals not selected

 13 Adverse events4264Risk Ratio (M-H, Random, 95% CI)0.97 [0.71, 1.33]

 14 Adverse event (minor signs or symptoms)3172Risk Ratio (M-H, Random, 95% CI)1.00 [0.64, 1.57]

 15 Concurrent treatment (emollient cream) (kg)1Mean Difference (IV, Random, 95% CI)Totals not selected

 16 Concurrent treatment (topical steroid) (kg)1Mean Difference (IV, Random, 95% CI)Totals not selected

 
Comparison 2. Borage oil versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Participant-reported improvement in symptoms1Risk Ratio (M-H, Random, 95% CI)Totals not selected

 2 Participant-reported complaints at end of treatment1Mean Difference (IV, Random, 95% CI)Totals not selected

 3 Physician-reported Costa scores at end of treatment1Mean Difference (IV, Random, 95% CI)Totals not selected

 4 Physician-reported number showing improvement (ADASI score)1Risk Ratio (M-H, Random, 95% CI)Totals not selected

 5 Physician-reported severity of eczema at end of treatment (SCORAD Index)1Mean Difference (IV, Random, 95% CI)Totals not selected

 6 Physician-reported SASSAD score at end of treatment1Mean Difference (IV, Random, 95% CI)Totals not selected

 7 Physician-reported clinical score improvement from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected

 8 Adverse events1Risk Ratio (M-H, Random, 95% CI)Totals not selected

 9 Adverse event (flu-like symptoms)1Risk Ratio (M-H, Random, 95% CI)Totals not selected

 10 Adverse event (upper respiratory tract infection)1Risk Ratio (M-H, Random, 95% CI)Totals not selected