Study reference

Study characteristics

Patient characteristics

Intervention (I)

Control (C)

Follow-up

Outcome measures and effect size

Comments

PYRIMETHAMINE VERSUS PLACEBO

Acers, 1964

Type of study:

RCT

Country:

USA

Competing interests:

Not reported, but drugs used in study were supplied by pharmaceutical companies

Inclusion criteria

Patients with toxoplasmic retinochoroiditis with following criteria: (1) an active retinitis, usually with overlying posterior vitreous opacities, (2) a positive intradermal toxoplasmin skin test, (3) a positive Sabin méthylène blue dye test, and (4) lack of significant clinical or laboratory evidence for any other etiology for the granulomatous focal type of retinochoroiditis.

Exclusion criteria

one-eyed persons with a lesion in the posterior segment which endangered the macular area. Also excluded were those patients who lived outside of the Baltimore area and could not be followed at regular intervals.

Intervention (N=10)

Pyrimethamine

Treatment regimen:

Pyrimethamine: 200 mg the first day, 100 mg the second day, 50 mg on days 3 through 15, and 25 mg from 16 through 56. Also trisulfapyrimidines (Neotrizine), 2 gm daily throughout the course, and prednisone (Deltasone), 40 mg daily for seven days and then 20 mg a day for the next seven weeks.

Control (N=10)

Lactose capsules and prednisolone

Treatment regimen:

Placebo lactose capsules and prednisone in the same dose as above regimen.

Length of follow-up

2 years

Lost to follow-up

Completeness of

follow up unclear.

Outcome measures

• Recurrence of lesions

Results

Recurrence of lesions:

In both groups 1 patient had recurrent lesions (RR=1.00; 95% CI 0.07-13.87).

Randomisation by using random list. Concealment of allocation unclear/not described.

Patients were blinded (identical capsules), blinding of outcome assessors not reported.

Completeness of follow-up unclear.

Small sample size (imprecision)

Co-medication (indirectness of effect).

GRADE: very low quality of evidence

Perkins, 1956

Type of study:

RCT

Country:

UK

Competing interests:

Not reported, but drugs used in study were supplied by pharmaceutical companies

Inclusion criteria

cases with positive toxoplasma antibody dye test and posterior uveitis (subgroup)

Exclusion criteria

Not reported

Intervention (N=17)

Pyrimethamine (Daraprim)

Treatment regimen:

1 tablet (25 mg) daily for 4 weeks

Control (N=12)

Placebo tablet

Treatment regimen:

1 tablet daily for 4 weeks

Length of follow-up

4 weeks

Lost to follow-up

unclear, some cases have had to be excluded because of difficulty in follow-up or interruption of treatment by intercurrent illness

Outcome measures

• Improvement in intraocular inflammation

Results

Improvement in intraocular inflammation

15/17 (88%) versus 6/12 (50%) had improvement (RR=1.76; 95% CI 0.98-3.19)

Randomisation by using random list. Concealment of allocation unclear/not described.

Patients and outcome assessors were blinded.

Completeness of follow-up unclear.

Small sample size (subgroup) (imprecision).

Only four weeks follow-up (indirectness).

GRADE: very low quality of evidence

PYRIMETHAMINE / AZITHROMYCIN VERSUS PYRIMETHAMINE / SULFADIAZINE

Bosch-Driessen, 2002

Type of study:

RCT

Country:

Netherlands

Competing interests:

Not stated

Inclusion criteria:

Active toxoplasmic retinochoroidal lesion located centrally within the major

temporal vascular arcades or a juxtapapillary lesion (within a distance of 1 disk diameter) in either eye. The inclusion criteria covered the ages between 16 and 80 years.

Exclusion criteria:

Patients on immunosuppressive medications, were known to have AIDS, were

known to have other ocular diseases, if they had used

antiparasitic drugs in a period 3 months prior to the study, or any combination of these factors.

Group 1 (N=24):

Pyrimethamine and azithromycin

Treatment regimen:

Pyrimethamine: 100 mg on

day 1, followed by 50 mg/day

Azithromycin: 250 mg/day,

N=7, or 500 mg every other day, n=17)

Group 2 (N=22):

Pyrimethamine and sulfadiazine

Treatment regimen:

Pyrimethamine: 100 mg on day 1, followed by 50 mg/day

Sulfadiazine: 4000 mg/day

Both groups received additional medication with folinic acid (15 mg/day) and prednisone (40 mg from day 3 to day 10, followed by a gradual tapering off).

Treatment was given for at least 4 weeks. Continuation of treatment was required in 10 patients who still had dense vitreous floaters, active retinal inflammation, or both despite the 4-week treatment.

Length of follow-up:

3 months after start treatment

Lost to follow-up:

3/22=14% from group 2 had to discontinue treatment because of side effects

Outcome measures:

• Visual acuity (improvement ≥ 0.5 logMAR units at 3 months
• Recurrences during first year after treatment of patients with ≥ 1 year follow-up
• Adverse effects

Results:

Visual acuity

Group 1: 5/24=21%

Group 2: 5/21=24%

P=0.81

Recurrences:

Group 1: 5/15=33%

Group 2: 7/12=58%

P=0.10

Adverse effects

Adverse effects were more frequent in the sulfadiazine group (8/24=33% in the azithromycin group, 14/22=64% in the sulfadiazine group P<0.04). Three patients of the sulfadiazine group had to discontinue treatment, one patient with known cardiovascular disease because of progressive complaints of stenocardia, one patient because of severe gastrointestinal and emotional distress, and another patient because of a skin rash due to allergy to sulfadiazine.

Randomisation method/concealment of allocation not described.

No blinding of patients. Only fundus photographs of the retinochoroidal lesions and the optic disk were evaluated by two independent ophthalmologists in a masked way.

For outcomes visual acuity and disappearance of inflammatory cells, data could not be determined for all patients.

Small sample size (imprecision)

Co-medication (indirectness of effect).

GRADE: low quality of evidence

TRIMETHOPRIM / SULFAMETHOXAZOLE VERSUS NO TREATMENT

Silveira,

2002

Type of study:

RCT

Country:

Brazil

Competing interests:

None declared

Inclusion criteria

Patients with history of ocular toxoplasmosis and with inactive retinochoroidal scars that were consistent with past episodes of ocular toxoplasmic retinochoroiditis and if they had a history of two or more recurrent episodes of active disease during the prior 5-year period.

Exclusion criteria

active intraocular inflammation, were pregnant, had HIV infection, were using

any systemic medications, had cataract or other media

opacity that prevented visualization of the fundus, had other diseases (such as syphilis and tuberculosis) that could result in retinal or choroidal inflammatory disease, or had known allergies to study medications.

Intervention (N=61)

Trimethoprim / sulfamethoxazole 800 mg, both orally every 3 days for 20 months

Treatment regimen:

Trimethoprim 160 mg and sulfamethoxazole 800 mg, both orally every 3 days for up to 20 months (the planned duration of the study)

Control (N=63)

No treatment

Length of follow-up

20 months

Lost to follow-up

Intervention:

6/61=9.8%

Four developed mild allergic reactions, 2 lost to follow-up

Control:

4/63=6.3%

Lost to follow-up

Outcome measures

• Recurrence of toxoplasmic retinochoroiditis, defined clinically as a new focus of retinal inflammation either adjacent to or remote from preexisting retinochoroidal scars.
• Adverse drug reaction

Results

Recurrence rate

Intervention: 4/61=6.6%

Control: 15/63=23.8%

P=0.01

Adverse drug reaction

Intervention: 4/61=6.6%

Randomisation by using computer-generated random list. Concealment of allocation unclear/not described.

Patients and outcome assessors not blinded.

Study from Southern Brazil where ocular toxoplasmosis is commonly seen and disease tends to be severe, with frequent recurrences (indirectness) (comparable to Dutch population?)

GRADE: low quality of evidence

TRIMETHOPRIM / SULFAMETHOXAZOLE VERSUS PYRIMETHAMINE / SULFADIAZINE

Soheilian, 2005

Type of study:

RCT

Country:

Iran

Competing interests:

None declared

Inclusion criteria:

Patients with ocular toxoplasmosis and:

1) Location of lesion within zone 1 of the retina (region

extending 3000 µm from the foveal center)7 or a

lesion > 2 disc diameters in size with 3 to 4+ vitreous

inflammation within zones 2 or 3. (Zone 2 is defined as the region extending anteriorly from the border of zone 1 to the equator, and zone 3 is defined as the region from the border of zone 2 to the ora serrata)

2) Presence of retinal lesion at least 500 µm outside the

center of the macula.

3) Lack of history of allergic reaction to the drugs used

in this study.

4) Lack of any other ocular disease.

Exclusion criteria:

1) Visual acuity (VA) of < 20/200 in the fellow eye, 2) location of the lesion within the center (500 µm) of the macula, 3) development of

allergic reaction to the medication, 4) leukopenia (white blood cell count < 5000) or platelet count < 120 000/ml, and 5) lesions

smaller than 2 disc diameters in zones 2 and 3.

Intervention (N=36):

Trimethoprim / sulfamethoxazole

Treatment regimen:

2 tablets of trimethoprim (80 mg)/ sulfamethoxazole (400 mg) every 12 hours for 6 weeks. Oral prednisolone was administered at 1 mg/kg daily starting from the third day of therapy, and the dose was tapered over 2 weeks.

Control (N=35):

Pyrimethamine / sulfadiazine

Treatment regimen:

initial dose of 100 mg of primethamine daily for 2 days, followed by a 25-mg dose daily, 2 g of sulfadiazine

daily for 2 days followed by 500-mg dosing every 6 hours, and 5 mg of folinic acid daily for 6 weeks. Oral prednisolone was administered at 1 mg/kg daily starting from the third day of therapy, and the dose was tapered over 2 weeks.

Length of follow-up:

At least 24 months after completion of treatment

Lost to follow-up:

Intervention: 6/36=17% (1 due to development of drug allergy and 5 due to incomplete follow-up)

Control:

5/35=14% (1 due to development of allergic reaction to sulfadiazine and 4

due to incomplete follow-up)

Outcome measures (secondary):

• Visual acuity: mean change in VA after 6 weeks treatment
• Recurrence rate: recurrence during 24 mos after treatment
• Adverse effects: adverse drug reaction

Results:

Visual acuity

Intervention: 0.56 logMAR (from 0.68 to 0.12)

Control: 0.52 logMAR (from 0.57 to 0.09)

P=0.75

Recurrence rate

Intervention: 3/29=10.3%

Control: 3/30=10%

P=0.64

Adverse drug reaction

Intervention: 1/29=2.9%

Control: 1/30=2.8%

P=0.98

Block randomisation using randomization tablets. Concealment of allocation unclear/not described.

Patients blinded, only fundus photographs evaluated

by 2 independent masked observers, other assessments unmasked.

No intention to treat analysis (loss to FU 17% and 14%).

Small sample size and study not powered for secondary outcomes (only for reduction in size of lesion) (imprecision)

Co-medication (prednisolone) (indirectness of effect).

Subjects received lower medication doses than are commonly used in clinical practice?

Study from Iran (comparable to Dutch situation/population?)

GRADE: low quality of evidence

TRIMETHOPRIM / SULFAMETHOXAZOLE VERSUS PLACEBO

Felix, 2014

Type of study:

RCT

Country:

Brazil

Competing interests:

None declared

Inclusion criteria:

Active recurrent Toxoplasma gondii retinochoroiditis (a new focus of necrotizing retinochoroiditis with active inflammation either adjacent to or remote from preexisting retinochoroidal

scars, with positive IgG for toxoplasmosis)

Exclusion criteria:

under 18 years of age, immunocompromised

(eg, acquired immunodeficiency syndrome), or undergoing immunosuppressive treatments, or who had concomitant retinochoroiditis from other causes (eg, tuberculosis).

Intervention (N=47):

Trimethoprim / sulfamethoxazole

Treatment regimen:

1 tablet of trimethoprim sulfamethoxazole (800 mg/160 mg) every 2 days.

Control (N=48):

Placebo tablet identical to intervention tablet

Treatment regimen:

1 identical placebo tablet containing starch without any active ingredients

every 2 days.

Before the randomisation, all patients were treated for active toxoplasmic retinochoroiditis with 1 tablet of trimethoprim sulfamethoxazole (800 mg/160 mg) 2 times daily for 45 days, and all lesions were healed after this treatment.

Length of follow-up:

12 months

Lost to follow-up:

Intervention:

1/47=2.1%

Control: 1/48=2.1%

Reasons not reported

Outcome measures:

• Recurrence rate: within 12 months (primary outcome measure)
• Visual acuity: mean change in letters

Results:

Visual acuity

Intervention: 21 letters (from 58 to 79 letters)

Control: 22 letters (from 52 to 74 letters)

P=0.90

Recurrence rate

Intervention: 0/46=0%

Control: 6/47=13%

P=0.03

Adverse effects

No treatment-limiting toxicity was observed.

Block randomisation was used. Concealment of allocation unclear/not described.

Patients and outcome assessors were blinded.

Study not powered for secondary outcomes (only for recurrence rate) (imprecision)

No intention to treat analysis.

All patients were treated with trimethoprim sulfamethoxazole before randomisation.

Duration of treatment (intervention and control) not reported.

Study from Brazil (comparable to Dutch spopulation?)

GRADE: moderate quality of evidence

INTRAVITREAL CLINDAMYCIN VERSUS PYRIMETHAMINE / SULFADIAZINE

Soheilian, 2011

Type of study:

RCT

Country:

Iran

Competing interests:

None declared

Inclusion criteria:

Diagnosis of ocular toxoplasmosis and at least 1 of following criteria: (1) optic nerve or macular involvement or threat thereof by

an adjacent lesion, (2) a lesion adjacent to large retinal vessels, and (3) severe vitreous inflammation (> 2+).

Exclusion criteria:

(1) visual acuity (VA) of worse than 20/200 in the fellow eye, (2) location of the lesion within the center

(500 µm) of the macula, (3) VA better than 20/30 in the involved eye, (4) peripheral lesions causing ≤ 2+ vitreous inflammation, and (5)

severe media opacity precluding clear photography

Intervention (N=40):

intravitreal clindamycin plus dexamethasone (IVCD)

Treatment regimen:

1-3 intravitreal injections of 1 mg clindamycin plus 400 µg dexamethasone

Control (N=41):

Classic therapy

Treatment regimen:

pyrimethamine 25 mg daily (initial dose of 75 mg daily for 2 days), sulfadiazine 500 mg every 6 hours (initial dose of 4 g daily for 2 days), and 5 mg folinic acid daily for 6 weeks, as well as oral prednisolone 1 mg/kg daily for 3 weeks starting from the third day of therapy

Length of follow-up:

2 years

Lost to follow-up:

Intervention:

6/40=15%

No specific reasons mentioned

Control:

7/41=17%

5 no specific reason, 2 due to severe skin rash, 1 due to thrombocytopenia

Outcome measures (secondary):

• Visual acuity: mean change in VA after 6 weeks treatment
• Recurrence rate: recurrence during 24 months after treatment
• Adverse effects: adverse drug reaction

Results:

Visual acuity

Intervention: 0.44 logMAR (from 0.59 to 0.17)

Control: 0.29 logMAR (from 0.50 to 0.21)

P=not reported

Recurrence rate

Intervention: 2/34=5.9%

Control: 2/34=5.9%

P=n.s.

Adverse drug reaction

Intervention: 2/36=5.6% (skin rash and thrombocytopenia)

Control: 4/34=11.8% (3 subconjunctival hemorrhage, 1 raised IOP)

Block randomisation using computer-generated randomized list. Concealment of allocation unclear.

Study investigators were blinded and assessment of VA and fundus photographs (patients and other outcome assessments were not blinded).

Small sample size and study not powered for secondary outcomes (only for reduction in size of lesion) (imprecision)

No intention to treat analysis (loss to FU 15% and 17% in groups).

Short follow-up for visual acuity and vitreous inflammation outcomes (6 weeks and 12 weeks after start).

Study from Iran (comparable to Dutch situation/population?)

GRADE: low quality of evidence

Baharivand, 2013

Type of study:

RCT

Country:

Iran

Competing interests:

None declared

Inclusion criteria:

Patients with active Toxoplasmic retinochoroiditis (TRC)

Exclusion criteria:

Patients with previous therapies for TRC, history of allergic reaction to the drugs used in this study, or presence of other ocular diseases

Intervention (N=32):

intravitreal clindamycin plus dexamethasone (IVCD)

Treatment regimen:

1-2 intravitreal injections of 1 mg clindamycin plus 400 µg dexamethasone

Control (N=34):

Classic therapy

Treatment regimen:

pyrimethamine 25 mg daily (initial dose of 75 mg daily for 2 days), sulfadiazine 1 g every 6 hours (initial dose of 2 g daily for 2 days), and 5 mg folinic acid daily for 6 weeks, as well as oral prednisolone 50 mg daily for 3 weeks starting from the third day of therapy.

Length of follow-up:

6 months after treatment

Lost to follow-up:

4 were lost to follow-up (not reported to which group they were allocated)

Outcome measures (secondary):

• Visual acuity: mean change in VA after 6 months
• Recurrence rate: recurrence during 24 months after treatment
• Adverse effects: adverse drug reaction

Results:

Visual acuity

Intervention: 0.38 logMAR (from 0.62 to 0.19)

Control: 0.35 logMAR (from 0.54 to 0.17)

P=0.31

Recurrence rate

Intervention: 4/32=12.5%

Control: 5/34=14.7%

P=0.54

Adverse drug reaction

Intervention: 0

Control: 1/34=2.9% (hepatotoxicity)

Randomisation by computer random number generation. Concealment of allocation unclear/not described

The outcome variables were evaluated by a masked skilled retina specialist at baseline and at follow-ups (patients not blinded).

Small sample size and study not powered for secondary outcomes (only for reduction in size of lesion) (imprecision)

No intention to treat analysis and groups and reasons for loss to FU not reported.

High dose of sulfadiazine used in this study compared to Soheilian 2011.

Study from Iran (comparable to Dutch situation/population?)

GRADE: low quality of evidence