Methods

This study was a single-center, prospective, randomized, double-masked clinical trial. Ethics committee approval (institutional review board) was obtained, and all participants gave informed consent (National Bioethics Commission of Brazil Identifier No.: 0613.0.146.000-10). The trial was registered in October 2011 and began in November 2011 (Influence of Trimethoprim-Sulfamethoxazole on the Recurrence of Ocular Toxoplasmosis. Clinicaltrials.gov Identifier No.: NCT01449877 ; http://clinicaltrials.gov/show/NCT01449877 ).

The original manuscript (first report) included the first 100 subjects who completed the 1-year follow-up. This cohort included all 151 subjects recruited from a uveitis clinic at a public hospital in Campinas, Brazil. The only incentive provided was free medication. The subjects were followed up for at least 36 months. The inclusion criterion was unilateral active recurrent toxoplasmic retinochoroiditis (defined as a new focal area of necrotizing retinochoroiditis with active inflammation either adjacent to or remote from preexisting retinochoroidal scars, with IgG that was positive for toxoplasmosis). There were no IgM+ cases. Subjects who were under 18 years of age, were immunocompromised (eg, AIDS patients), were undergoing immunosuppressive treatments, or had concomitant retinochoroiditis from other causes (eg, tuberculosis) were excluded.

All subjects were treated for active toxoplasmic retinochoroiditis with 1 tablet of TMP-SMZ (160 mg/800 mg) twice daily for 45 days, and all lesions healed after this treatment (there were no subjects with unhealed lesions). Subsequently, 10 subjects dropped out of the study ( Figure 1 ). The remaining subjects were randomly assigned to Group 1 (1 TMP-SMZ tablet every 2 days for 311 days) or to Group 2 (1 identical placebo tablet containing starch with no active ingredients every 2 days for 311 days). The regimen was chosen empirically based on a mix of 3 factors: the local experts’ experience, patient compliance, and a previous report by Silveira and associates regarding toxoplasmic retinochoroiditis prophylaxis. It was not based on pharmacokinetic data.

Trimethoprim-sulfamethoxazole (TMP-SMZ) vs placebo in reducing the risk of toxoplasmic retinochoroiditis recurrences: CONSORT flow diagram. After the initial treatment, the subjects were randomly assigned to Group 1 (1 TMP-SMZ tablet every 2 days for 311 days) or Group 2 (1 identical placebo tablet containing starch with no active ingredients every 2 days for 311 days). At the second- and third-year follow-up appointments, none of the subjects received treatment unless a new recurrence episode had occurred.

Randomization was 1:1. It was stratified by sex, and block sizes of 4 were used. One nurse generated the random allocation sequence, and another nurse enrolled and assigned the participants to the interventions in a masked fashion. Compliance with the drug regimen was evaluated by a count of the number of remaining tablets.

At the second-year and third-year follow-up appointments, the subjects did not receive treatment unless a new recurrence episode had occurred. Recurrences were treated with 1 tablet of TMP-SMZ (160 mg/800 mg) twice daily for 45 days. Patients were instructed to attend follow-up consultations every 3 months or when they experienced symptoms consistent with recurrent disease, such as redness, decreased vision, eye pain, and photophobia. Five patients in Group 1 and 10 patients in Group 2 missed their follow-up visits because they moved to other cities. Six patients in Group 1 and 4 patients in Group 2 discontinued interventions.

The trial was sponsored by the São Paulo State Research Foundation (FAPESP), Protocol No. 2010/15980-2. Trimethoprim/sulfamethoxazole tablets cost US $0.31 each and placebo tablets cost US $0.15 each.

Data were collected using a medical history form completed by the physician during the first medical examination. Best-corrected visual acuity (BCVA) based on ETDRS charts, as well as biomicroscopy, tonometry, indirect ophthalmoscopy with location of scars, recurrence of toxoplasmic retinochoroiditis, and medical events, were all recorded on a standardized form by a member of the medical staff in a masked fashion. Side effects were defined as any symptoms, signs, or biochemical abnormalities possibly related to treatment.

The primary outcomes were recurrent toxoplasmic retinochoroiditis within the first year of follow-up and recurrent toxoplasmic retinochoroiditis within the third year of follow-up.

Sample size calculations based on presumed recurrence rates of 0% in the treatment group and 15% in the placebo group indicated that a sample size of 35 in each group would be significant for detecting a difference of this magnitude with a power of 80% and type 1 error probability of 5%. However, to account for losses in follow-ups and based on feedback obtained after the study was begun, 151 subjects were enrolled.

Descriptive statistics were calculated. Continuous data were expressed as the mean, median, and standard deviation (SD). Between-group differences of continuous variables were compared using the Mann-Whitney U test, and categorical variables were compared using χ ² test or Fisher exact test when appropriate. The probabilities of recurrence and of missing follow-up visits were assessed using the Kaplan-Meier survival analysis (log-rank test). Intention-to-treat analyses were conducted using SPSS, version 21 (IBM Corporation, Armonk, New York, USA). P values were 2-tailed. Statistical significance was set at .05.

Results

Between August 24, 2011 and February 1, 2013, 141 subjects were enrolled at a public hospital in Campinas, São Paulo State, Brazil and were randomized either to therapy using trimethoprim/sulfamethoxazole (72 subjects) or to placebo (69 subjects) ( Figure 1 ). The mean age was 33 (SD 13) years, and 75 subjects (53.2%) were female. Age, sex distributions, lesion location, and the frequency of contralateral lesions were similar between the 2 groups ( Table 1 ). The mean interval between the pre-enrollment recurrence episode and the recurrence observed during study follow-up was 263 (SD 219) days (median: 144 days).

The Kaplan-Meier survival analysis was used to compare missed follow-up visits between the 2 groups. No significant difference was found. The cumulative probability of missing follow-ups at 3 years was 14.5% (10/69) in the placebo group (mean follow-up of 984 days) and 6.9% (5/72) in the TMP-SMZ group (mean follow-up of 1046 days; P = .139, log-rank test).

Kaplan-Meier survival analysis was used to compare recurrence between the 2 groups ( Figure 2 ). A significantly higher probability of recurrence was observed in the placebo group relative to the TMP-SMZ group. The cumulative probability of recurrence at 1, 2, and 3 years of follow-up was, respectively, 13.0% (9/69), 17.4% (12/69), and 20.3% (14/69) in the placebo group and 0% (0/72) in the TMP-SMZ group ( P < .001, log-rank test). There were no cases of multiple recurrences in the same individual.

Kaplan-Meier plots of the probability of recurrence of toxoplasmic retinochoroiditis: graph of time to recurrence by treatment. TMP-SMZ = after prophylaxis with trimethoprim-sulfamethoxazole. All subjects were treated with 1 tablet of TMP-SMZ (160 mg/800 mg) twice daily for 45 days, and all lesions healed after this treatment. After this initial treatment, the subjects were randomly assigned to Group 1 (1 TMP-SMZ tablet every 2 days for 311 days) or Group 2 (1 identical placebo tablet containing starch with no active ingredients every 2 days for 311 days). At the second- and third-year follow-up appointments, none of the subjects received treatment unless a new recurrence episode had occurred.

The mean changes in BCVA within 36 months were 22 (SD 20) letters (range −4 to 54) in the TMP-SMZ group and 22 (SD 18) letters (range −19 to 54) in the placebo group ( P = .768, Table 2 and Figure 3 ).

Stay updated, free articles. Join our Telegram channel

Join