Dataset Information

Efficacy and Safety of Topical Timolol for the Treatment of Infantile Hemangioma in the Early Proliferative Stage: A Randomized Clinical Trial.

ABSTRACT:

Importance

Treatment of infantile hemangioma (IH) with topical timolol in the first 2 months of life (early proliferative phase) may prevent further growth and the need for treatment with oral propranolol. To our knowledge, no studies have determined whether beginning early treatment with timolol for IH is better than in other proliferative stages.

Objective

To evaluate the efficacy and safety of timolol maleate solution, 0.5%, for the early treatment of IH in infants younger than 60 days.

Design, setting, and participants

This multicenter, randomized, double-blind, placebo-controlled, phase 2a pilot clinical trial included patients aged 10 to 60 days with focal or segmental hemangiomas (superficial, deep, mixed, or minimal/arrested growth). Patients were randomly assigned to treatment with topical timolol maleate solution, 0.5%, or placebo twice daily for 24 weeks. Changes in lesion size (volume, thickness) and color were evaluated from photographs taken at 2, 4, 8, 12, 24, and 36 weeks. Vital signs and adverse effects were recorded at each visit. The study was carried out from November 2015 to January 2017, and data analyses were completed in September 2019.

Main outcomes and measures

The primary outcome of complete or nearly complete IH resolution and the secondary outcomes of changes in lesion thickness, volume, and color were evaluated by a blinded investigator.

Results

Of the 69 patients recruited, the mean (SD) age was 48.4 (10.6) days; 55 (80%) were female; and 51 (74%), 11 (16%), 6 (9%), and 1 (1%) had superficial, mixed, abortive, or deep IHs, respectively. The IHs were localized, segmental, or indeterminate in 60 (87%), 7 (10%), and 2 (3%) patients, respectively. The IHs were located on the head and/or neck (n = 23 [33%]) or other body sites (n = 46 [67%]). The study was completed by 26 of 33 (79%) patients receiving timolol and 31 of 36 (86%) receiving placebo. There were no significant differences between timolol and placebo for complete or nearly complete IH resolution at 24 weeks (n = 11 [42%] vs n = 11 [36%]; P = .37). The odds ratio of complete or almost complete response vs no response at week 24 was 1.33 (95% CI, 0.45-3.89). There were no between-group differences in IH size (volume, thickness). An improvement in color was observed at week 4 in the timolol group, and timolol was well tolerated with no systemic adverse effects.

Conclusions and relevance

In this randomized clinical trial, results demonstrated that topical timolol is well tolerated for the treatment of early proliferative IH but provides limited benefit in lesion resolution when given during the early proliferative stage.

Trial registration

EudraCT Identifier: 2013-005199-17.

SUBMITTER: Munoz-Garza FZ

PROVIDER: S-EPMC8027942 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Efficacy and Safety of Topical Timolol for the Treatment of Infantile Hemangioma in the Early Proliferative Stage: A Randomized Clinical Trial.

Muñoz-Garza Fania Z FZ Ríos Mónica M Roé-Crespo Esther E Bernabeu-Wittel José J Montserrat-García María Teresa MT Puig Luís L Gich Ignasi I Baselga Eulalia E

JAMA dermatology 20210501 5

<h4>Importance</h4>Treatment of infantile hemangioma (IH) with topical timolol in the first 2 months of life (early proliferative phase) may prevent further growth and the need for treatment with oral propranolol. To our knowledge, no studies have determined whether beginning early treatment with timolol for IH is better than in other proliferative stages.<h4>Objective</h4>To evaluate the efficacy and safety of timolol maleate solution, 0.5%, for the early treatment of IH in infants younger than ...[more]

PMID: 33825828

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Project description:ImportanceThere are limited data from randomized clinical trials comparing propranolol and steroid medication for treatment of infantile hemangioma (IH).ObjectiveTo determine the efficacy and safety of propranolol compared with steroid as a first-line treatment for IH.Design, setting, and participantsThis randomized clinical noninferiority trial tested the efficacy and safety of propranolol vs steroid treatment for IH at a single academic hospital. All participants were diagnosed with IH between June 2013 and October 2014, had normal heart function, and had not been previously treated for IH.InterventionsThe participants were randomly assigned to either the propranolol group or the steroid group. In the propranolol group, the patients were admitted, observed for adverse effects for 3 days after treatment initiation, and then released and treated as outpatients for 16 weeks (2 mg/kg/d). In the steroid group, the patients were seen as outpatients from the beginning and were also treated for 16 weeks (2 mg/kg/d).Main outcomes and measuresThe primary efficacy variable was the response to treatment at 16 weeks, which was evaluated by the hemangioma volume using magnetic resonance imaging before and at 16 weeks after treatment initiation. While comparing the effect of medication between the groups, we monitored the adverse effects of both drugs.ResultsA total of 34 patients (15 boys, 19 girls; mean age, 3.3 months; range, 0.3-8.2 months) were randomized to receive either propranolol or steroid treatment (17 in each treatment group). Guardians for 2 patients in the steroid group withdrew their consent, and 1 patient in the propranolol group did not complete the efficacy test. The intention-to-treat analysis, applying multiple imputations, found the treatment response rate in the propranolol group to be 95.65%, and that of the steroid group was 91.94%. Because the difference in response rate between the groups was 3.71%, propranolol was considered noninferior. We found that there was no difference between the groups in safety outcomes.Conclusions and relevanceOur trial demonstrated that propranolol was not inferior to steroid with respect to therapeutic effects in IH.Trial registrationclinicaltrials.gov Identifier: NCT01908972.

Project description:ImportanceOral β-blockers used for the prevention of migraine headache are not effective for the treatment of acute pain. Small case series have suggested that topically applied β-blockers may be useful in the management of acute migraine pain, warranting evaluation with randomized clinical trials.ObjectiveTo evaluate the short-term efficacy and safety of topically applied timolol maleate ophthalmic solution, 0.5%, compared with topically applied placebo eyedrops in the treatment of acute migraine attacks.Design, setting, and participantsIn this randomized, masked placebo-controlled crossover trial conducted from May 27, 2015, to August 28, 2017, 50 patients with migraine were randomized to receive either timolol eyedrops, 0.5%, or a placebo eyedrop (carboxymethyl cellulose, 0.5%). After a 3-month treatment period, patients completed a 1-month washout period and were crossed over to receive the opposite treatment for a final 3 months. Analysis was performed on a modified intent-to-treat basis.InterventionAfter random assignment, patients were instructed to use 1 drop of the assigned medication in each eye at the earliest onset of migraine.Main outcomes and measuresThe main outcome measure was reduction in pain score with treatment. The primary end point was reduction of pain score by 4 points, or to zero, 20 minutes after instillation of the eyedrop.ResultsOf the 50 patients, 42 (84%) were females and the mean (SD) age was 27.3 (11.3) years. Of a total of 619 migraine attacks, 284 (46%) were treated with timolol, 271 (44%) were treated with the placebo, and 64 (10%) occurred during the washout period when no study medications were used. Seven patients (14%) withdrew after randomization. A total of 233 of the timolol-treated migraine attacks (82%) were associated with a reduction in pain score by 4 points, or to zero, at 20 minutes compared with 38 of the placebo-treated attacks (14%), with a difference of 68 percentage points (95% CI, 62-74 percentage points). A generalized estimating equation analysis revealed that pain score reduction at 20 minutes was greater in the timolol group compared with the placebo group by a mean (SE) of 4.63 points (0.34) (P < .001).Conclusions and relevanceThis randomized crossover trial supports consideration of timolol eyedrops in the acute treatment of migraine. Further research is warranted to determine if the improvements observed are sustained for a longer follow-up and with larger groups.Trial registrationCTRI/2015/05/005829, UTN: U1111-1167-6439.

Project description:ImportancePropranolol for infantile hemangiomas (IH) has been shown to be effective and relatively safe. However, other less lipophilic β-blockers, such as nadolol, may be preferable in individuals who experience propranolol unresponsiveness or adverse events.ObjectiveTo document the noninferiority and safety of oral nadolol compared with oral propranolol in infants with IH.Design, setting, and participantsThis double-blind noninferiority prospective study with a noninferiority margin of 10% compared propranolol with nadolol in infants aged 1 to 6 months with problematic IH. The study was conducted in 2 academic pediatric dermatology centers in Canada between 2016 and 2020. Infants aged 1 to 6 months with a hemangioma greater than 1.5 cm on the face or 3 cm or greater on another body part causing or with potential to cause functional impairment or cosmetic disfigurement.InterventionsOral propranolol and nadolol in escalating doses up to 2 mg/kg/d.Main outcomes and measureBetween-group differences comparing changes in the bulk (size and extent) and color of the IH at week 24 with baseline using a 100-mm visual analog scale.ResultsThe study included 71 patients. Of these, 36 were treated with propranolol. The mean (SD) age in this group was 3.1 (1.4) months, and 31 individuals (86%) were female. Thirty-five infants were treated with nadolol. The mean (SD) age in this group was 3.2 (1.6) months, and 26 individuals (74%) were female. The difference in IH between groups by t test was 8.8 (95% CI, 2.7-14.9) for size and 17.1 (95% CI, 7.2-30.0) for color in favor of the nadolol group, demonstrating that nadolol was noninferior to propranolol. Similar differences were noted at 52 weeks: 6.0 (95% CI, 1.9-10.1) and 10.1 (95% CI, 2.9-17.4) for size and color improvement, respectively. For each doubling of time unit (week), the coefficient of involution was 2.4 (95% CI, 0.5-4.4) higher with nadolol compared with propranolol. Safety data were similar between the 2 interventions.Conclusions and relevanceOral nadolol was noninferior to oral propranolol, indicating it may be an efficacious and safe alternative in cases of propranolol unresponsiveness or adverse events, or when faster involution is required.Trial registrationClinicalTrials.gov Identifier: NCT02505971.

Project description:BackgroundTo evaluate the efficacy and safety of topical β-blockers in the treatment of superficial infantile hemangiomas (SIH) and mixed infantile hemangiomas (MIH), respectively, and compare the efficacy and safety of topical β-blockers with other interventions.MethodsThe PRISMA guidelines were adhered to. We searched for randomized controlled trials in databases from 2010 to 2018 comparing topical β-blockers with other interventions for infantile hemangiomas. The outcomes evaluated were efficacy and adverse effects. Data analyses were performed using RevMan 5.3. Publication bias was assessed to account for bias in patient selection.ResultsEleven studies, involving 1,235 patients, were subjected to this meta-analysis. Six studies compared topical β-blockers with other interventions (propranolol, placebo, corticosteroids or pulsed dye laser) in treating SIH, and 5 studies evaluated the efficacy and safety of a topical β-blocker when it was combined with another intervention in treating MIH. A topical β-blocker was discovered to be as effective as oral propranolol in treating SIH (risk ratio, RR, 0.96, 95% confidence interval, CI, 0.91-1.02, p = 0.20, I2 = 0%), and topical β-blockers were more beneficial than placebo, corticosteroids or pulsed dye laser in treating SIH (RR 2.25, 95% CI 1.66-3.05, p < 0.00001, I2 = 0%). Topical β-blockers combined with another intervention gave rise to a better clinical response in the treatment of MIH than intervention alone (RR 1.99, 95% CI 1.10-3.60, p = 0.02, I2 = 55%) (standard mean difference 0.80, 95% CI 0.28-1.31, p = 0.002, I2 = 0%). Compared with oral propranolol, topical β-blockers were associated with fewer incidences of adverse effects (RR 0.05, 95% CI 0.01-0.39, p = 0.004, I2 = 0%). No significant difference in adverse effects was found when a topical β-blocker was combined with another intervention in treating MIH (RR 1.01, 95% CI 0.58-1.74, p = 0.98, I2 = 0%).ConclusionsThis meta-analysis provided evidence that topical β-blockers may replace oral propranolol as first-line therapy for SIH and that they are of additive value in treating MIH.

Project description:ImportanceGiven that mycosis fungoides-cutaneous T-cell lymphoma (MF/CTCL) is chronic, there is a need for additional therapies with minimal short- and long-term adverse effects. Topical synthetic hypericin ointment, 0.25%, activated with visible light is a novel, nonmutagenic photodynamic therapy (PDT).ObjectivesTo determine the efficacy and safety of topical synthetic hypericin ointment, 0.25%, activated with visible light as a nonmutagenic PDT in early-stage MF/CTCL.Design, settings, and participantsThis was a multicenter, placebo-controlled, double-blinded, phase 3 randomized clinical trial (FLASH study) conducted from December 2015 to November 2020 at 39 academic and community-based US medical centers. Participants were adults (≥18 years) with early-stage (IA-IIA) MF/CTCL.InterventionsIn cycle 1, patients were randomized 2:1 to receive hypericin or placebo to 3 index lesions twice weekly for 6 weeks. In cycle 2, all patients received the active drug for 6 weeks to index lesions. In cycle 3 (optional), both index and additional lesions received active drug for 6 weeks.Main outcomes and measuresThe primary end point was index lesion response rate (ILRR), defined as 50% or greater improvement in modified Composite Assessment of Index Lesion Severity (mCAILS) score from baseline after 6 weeks of therapy for cycle 1. For cycles 2 and 3, open label response rates were secondary end points. Adverse events (AEs) were assessed at each treatment visit, after each cycle, and then monthly for 6 months. Data analyses were performed on December 21, 2020.ResultsThe study population comprised 169 patients (mean [SD] age, 58.4 [16.0] years; 96 [57.8%] men; 120 [72.3%] White individuals) with early-stage MF/CTCL. After 6 weeks of treatment, hypericin PDT was more effective than placebo (cycle 1 ILRR, 16% vs 4%; P = .04). The ILRR increased to 40% in patients who received 2 cycles of hypericin PDT (P < .001 vs cycle 1 hypericin) and to 49% after 3 cycles (P < .001 vs cycle 1 hypericin). Significant clinical responses were observed in both patch and plaque type lesions and were similar regardless of age, sex, race, stage IA vs IB, time since diagnosis, and number of prior therapies. The most common treatment-related AEs were mild local skin (13.5%-17.3% across cycles 1-3 vs 10.5% for placebo in cycle 1) and application-site reactions (3.2%-6.9% across cycles 1-3 vs 4% for placebo in cycle 1). No drug-related serious AEs occurred.Conclusion and relevanceThe findings of this randomized clinical trial indicate that synthetic hypericin PDT is effective in early-stage patch and plaque MF/CTCL and has a favorable safety profile.Trial registrationClinicalTrials.gov Identifier: NCT02448381.

Dataset Information

Efficacy and Safety of Topical Timolol for the Treatment of Infantile Hemangioma in the Early Proliferative Stage: A Randomized Clinical Trial.

Importance

Objective

Design, setting, and participants

Main outcomes and measures

Results

Conclusions and relevance

Trial registration

Publications

Efficacy and Safety of Topical Timolol for the Treatment of Infantile Hemangioma in the Early Proliferative Stage: A Randomized Clinical Trial.

Similar Datasets

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