Randomized, double-blind trial of 220 mg zinc sulfate twice daily in the treatment of rosacea

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1 Clinical trial Randomized, double-blind trial of 220 mg zinc sulfate twice daily in the treatment of rosacea Joel T. M. Bamford 1, MD, Charles E. Gessert 2, MD, MPH, Irina V. Haller 2, PhD, MS, Kim Kruger 3, MD, and Brian P. Johnson 2, MPH 1 Essentia Health Duluth Clinic, 2 Essentia Institute of Rural Health, and 3 Duluth Family Medicine Residency Program, Duluth, MN, USA Correspondence Charles E. Gessert, MD, MPH Senior Research Scientist Essentia Institute of Rural Health 502 E 2nd Street Duluth MN USA cgessert@eirh.org Conflicts of interest: None. Abstract A 2006 article published in the International Journal of Dermatology reported that oral zinc sulfate 100 mg three times daily was associated with improvement in the severity of facial rosacea (Sharquie et al. 2006; 45: ). The current study was undertaken to further assess the role of zinc in the management of rosacea. This was a randomized, double-blind trial of 220 mg of zinc sulfate twice daily for 90 days in patients with moderately severe facial rosacea at baseline. Subjects were recruited in the Upper Midwest USA between August 2006 and April 2008, and followed until July Forty-four subjects completed the trial (22 in each arm). Rosacea improved in both groups. There were no differences in magnitude of improvement based on rosacea severity scores between subjects receiving zinc sulfate and subjects receiving placebo (P = 0.284). Serum zinc levels were higher in subjects receiving zinc (P < 0.001). Oral zinc sulfate was not associated with greater improvement in rosacea severity compared with placebo in this study. Additional studies are needed to determine what role oral zinc may have in the management of rosacea. Introduction Rosacea is a common chronic, relapsing condition characterized by recurrent or persistent erythema, telangiectasia, and papules/pustules. Despite strong interest in new treatment regimens, 1 3 the management of rosacea remains challenging. In 2006, Sharquie and colleagues reported efficacy of zinc in the treatment of rosacea in a small crossover trial of 100 mg oral zinc sulfate three times daily. 4 This report was of great interest, as the identification of a new, inexpensive, readily available, and safe therapy would be a welcome addition to current therapeutic options. Several limitations of this report are of note. Their study design did not include a washout period between the two treatment periods. Therefore, any effect of zinc on rosacea in the first treatment period may have been carried over to the second treatment period. In fact, the authors noted a potential utility of zinc in the prophylactic treatment of rosacea due to an apparent carry-over effect. Moreover, it is difficult to test a treatment effect in the presence of a carry-over effect. This may be why the authors did not present results of a direct comparison between the zinc and placebo groups. Their conclusions regarding zinc efficacy in the treatment of rosacea were based entirely upon changes observed during periods when subjects were on zinc. Zinc is an essential nutrient and has a wide range of physiological functions, including important roles in enzymatic reactions, wound healing, support of a healthy immune system, 5,6 and resistance to infection. 7 Zinc is present in many foods, multivitamins, and over-thecounter cold remedies (often about 15 mg of elemental zinc per dose). 8 It is also available as a dietary supplement (20 50 mg of elemental zinc per dose). The recommended daily allowance of zinc is 8 11 mg/d. 9 Larger daily doses of elemental zinc (50 mg or more) over extended periods of time can interfere with copper metabolism, 10,11 leading to impaired blood cell formation, 12 depression of the immune system, 13 and reduced levels of high-density lipoprotein cholesterol. 9 Acute zinc overdoses can cause irritation of the gastrointestinal tract, emesis, and, in severe cases, acute renal tubular necrosis and interstitial nephritis. 14 The goal of the current study was to determine whether a 90-day course of oral zinc sulfate would be associated with significant improvement in signs of facial rosacea. Materials and methods This study was approved by the Essentia Health Institutional Review Board. Adult subjects (18 and older) were recruited from outpatient family practice clinics and the dermatology 459 ª 2012 The International Society of Dermatology International Journal of Dermatology 2012, 51,

2 460 Clinical trial Zinc sulfate in the treatment of rosacea Bamford et al. department of a regional healthcare system in the upper Midwest. Recruitment occurred between August 2006 and April 2008, with follow-up continuing until July Subjects met inclusion criteria if they had a diagnosis of facial rosacea with severity greater than mild (scores 5 12 on the rosacea severity scale described below). Subjects were excluded if they had used zinc dietary supplements (>25 mg/d) or oral or topical treatment for rosacea during the three months before enrollment, had a diagnosis of rosacea fulminans, or were pregnant or breastfeeding. Subjects that were excluded because of rosacea treatment within three months prior to screening were allowed to be rescreened after three months off rosacea treatment. Planned enrollment was 80 subjects with an interim analysis scheduled after 40 subjects. The study was stopped after the interim analysis due to difficulty enrolling subjects and the finding of better rosacea outcomes in the placebo than the zinc group. It was decided that continuation of the trial could not be justified in terms of patient welfare. A total of 65 potential subjects were enrolled and evaluated for eligibility; 53 met inclusion criteria and were randomized at 1 : 1 ratio to receive capsules containing 220 mg of zinc sulfate (equivalent to 50.8 mg elemental zinc) or placebo twice daily for 90 days. Randomization was carried out following a sequence of random numbers using random block size created by a biostatistician and maintained at the research pharmacy of the healthcare organization. Treatment was masked from participants, investigators, and study staff. Subjects were required to refrain from using oral or topical treatments for rosacea while participating in the trial. Subjects were evaluated at baseline and three months. Baseline evaluation included demographic and clinical data, assessment of rosacea severity, laboratory data [hemoglobin (g/dl), zinc level (lg/ml), and ceruloplasmin (units/l)], and subject-reported rosacea-related quality of life (QoL). The threemonth evaluation included severity of rosacea assessment, laboratory, and subject-reported QoL. Digital photographs were taken of each subject at both time points. Rosacea severity was assessed using a scale based on four primary rosacea features adapted from the Standard Grading System for Rosacea : 15 transient erythema (flushing), nontransient erythema, papules, pustules, and telangiectasia. Each feature was measured on a four-point scale [absent (0) to severe (3)]. The total severity score (ranging from 0 to 12) was used as a primary outcome measure. Subjects quality of life (QoL) was evaluated using RosaQoL, a rosacea-specific QoL instrument. 16 The overall score and three subscale scores (symptoms, functioning, and emotion) were recorded. Efficacy analyses were completed on the subgroup of subjects who completed both baseline and three-month evaluations (n = 44). Adverse events were evaluated by telephone one and six weeks after enrollment and at the three-month visit. All subjects with at least one follow-up call were included in the analysis of adverse events (n = 53). All statistical analyses were conducted using SAS V9.2 (SAS, Inc. Cary, NC, USA) and performed with a two-sided significance level of Descriptive statistics of demographic and clinical variables at baseline for quantitative variables are given as means and 95% confidence intervals (CIs) and frequencies and percentages for categorical variables. Between-group comparisons for quantitative variables were done using t-test with Satterthwaite s approximation for the degrees of freedom. Comparisons for dichotomous variables were conducted using Fisher s exact test. Subjects assessment of improvement of rosacea was dichotomized (improved vs. no change or did not improve). The unconditional CI for the between-group difference in self-reported rates of improvement was determined according to the method of Santner and Snell 17 with the exact Pearson s chi-squared test P values reported. The treatment effect (zinc vs. placebo) on outcome measures (rosacea severity, laboratory values, and QoL) was evaluated using a general linear model with the baseline value as the covariate; the maximum likelihood estimates and 95% Wald CI were reported. Results Demographic characteristics, length of rosacea history, and baseline severity of rosacea did not differ significantly between the zinc and placebo groups among 53 randomized subjects (Table 1). Forty-four subjects (83%) completed the 90-day trial (22 subjects in each study arm). Among the nine subjects who did not complete the study, three zinc and four placebo group participants discontinued study medication and withdrew from the study due to adverse events; one subject from the zinc group did not attend the threemonth visit, and another withdrew before the end of the study without giving a reason. At baseline, subjects who Table 1 Demographics of randomized subjects by study group Placebo (n = 26) Zinc (n = 27) Age, mean (95% CI) (41.86, 52.68) (48.65, 56.98) Female gender, n (%) 19 (73.1) 20 (74.1) Caucasian, n (%) 24 (92.3) 26 (96.3) Married/living with 20 (76.9) 18 (66.7) partner, n (%) Length of rosacea, n (%) <1 year 1 (3.8) 2 (7.4) 1 2 years 0 3 (11.1) 2 5 years 12 (46.2) 4 (14.8) 5 10 years 4 (15.4) 10 (37.0) >10 years 9 (34.6) 8 (29.6) Baseline severity of rosacea, mean (95% CI) 6.77 (6.22, 7.32) 6.30 (5.83, 6.76) International Journal of Dermatology 2012, 51, ª 2012 The International Society of Dermatology

3 Bamford et al. Zinc sulfate in the treatment of rosacea Clinical trial 461 completed the study were similar in measured variables to those who were randomized. Among the 44 subjects who completed the trial, compliance was 94% (74 100%) in the zinc group and 92% (18 100%) in the placebo group, based upon returned pill count at the end of the study. Outcome measures On average, rosacea severity scores improved during the study period in both groups (Table 2). There were no differences in the magnitude of improvement between placebo and zinc groups (0.57-point difference in average rosacea severity scores, P = 0.284). As expected, serum zinc levels were significantly higher in the zinc group compared with controls (P < 0.001). There was no treatment effect on hemoglobin or ceruloplasmin. While average QoL scores (overall, symptoms, function, and emotion subscales) slightly decreased from baseline to follow-up in both groups, consistent with improvement in rosacea, there was no significant effect of treatment on subject-reported QoL (Table 2). At follow-up, six of 20 (30%) of zinc group and five of 18 (28%) of placebo group participants reported improvement of rosacea, suggesting no statistically significant difference in selfreported rates of rosacea improvement between the two groups [95% CI: ()33.6, 28.8); P = 1.00]. Adverse events The number of participants who reported adverse events during the study did not differ significantly by treatment: 17 of 27 (63%) in zinc group and 14 of 25 (56%) in placebo group (P = 0.778). A slightly higher proportion of zinc group subjects reported stomach upset, including nausea, discomfort, gas, diarrhea, constipation, and increased bowel movements [12 of 27 (44%) zinc vs. eight of 25 (32%) placebo, but the difference was not statistically significant (P = 0.404)]. Other reported events included headache, pneumonia, skin infection, and upper respiratory infection. Regardless of the group assignment, the majority of participants noticed adverse events within the first week of the study [20 of 31 (65%)]; 16 of 31 (52%) reported that the symptoms were resolved within 1 7 days. One zinc group subject had a severe allergic reaction. Three placebo group subjects reported outbreaks of rosacea, itching, or redness more frequently. Comment We found that the use of oral zinc sulfate was not associated with significant improvement in rosacea severity over a 90-day trial. The amount of zinc used in our study was sufficient to raise serum zinc levels but did not alter hemoglobin or ceruloplasmin levels. The rates of adverse events were similar in treatment and placebo groups. Our findings about the efficacy of zinc in rosacea treatment might be compared with those of Sharquie et al. 4 They reported that overall severity scores for rosacea improved when subjects were on zinc sulfate but not when they were on placebo in a double-blind, crossover study of 19 subjects. However, their study did not include a washout period before crossover nor a direct zinc-placebo group comparison. In addition, the report by Sharquie et al. 4 did not provide data on the validation of the rosacea severity scale that they used. However, the direct comparison between the two studies is confounded by the marked racial/ethnic, dietary, and socioeconomic differences between the two study populations. Rosacea is a chronic, recurrent condition. Subjects are usually enrolled in treatment trials when their condition Table 2 Outcome variables by study group and the treatment effect adjusted for baseline value Baseline a 3 months a Treatment effect b Placebo (n = 22) Zinc (n = 22) Placebo (n = 22) Zinc (n = 22) Estimate P value Rosacea severity 6.91 (6.31, 7.50) 6.32 (5.76, 6.87) 4.06 (4.07, 5.65) 5.09 (4.18, 6.00) 0.57 ()0.47, 1.62) Hemoglobin (13.72, 14.93) (13.56, 14.70) (13.48, 14.61) (13.40, 14.61) 0.12 ()0.31, 0.55) Serum zinc level 0.92 (0.84, 0.99) 0.91 (0.82, 0.99) 0.97 (0.89, 1.06) 1.30 (1.11, 1.50) 0.34 (0.16, 0.51) <0.001 Ceruloplasmin (121.32, ) (117.88, ) (116.70, ) (109.35, ) 1.93 ()10.60, 14.46) RosaQOL overall 3.29 (3.06, 3.53) 3.10 (2.88, 3.32) 2.99 (2.73, 3.26) 2.90 (2.67, 3.12) 0.07 ()0.14, 0.27) RosaQOL symptom 3.23 (2.90, 3.55) 3.16 (2.82, 3.50) 2.88 (2.57, 3.20) 2.96 (2.62, 3.29) 0.13 ()0.12, 0.38) RosaQOL function 2.65 (2.15, 3.15) 2.39 (1.99, 2.79) 2.39 (2.00, 2.79) 2.33 (1.97, 2.69) 0.12 ()0.13, 0.38) RosaQOL emotion 3.51 (3.30, 3.73) 3.25 (2.99, 3.50) 3.23 (2.94, 3.53) 3.00 (2.76, 3.25) )0.02 ()0.28, 0.25) a Unadjusted means and 95% confidence intervals. b Maximum likelihood estimates of treatment effect (zinc vs. placebo) adjusted for baseline values and 95% confidence intervals. ª 2012 The International Society of Dermatology International Journal of Dermatology 2012, 51,

4 462 Clinical trial Zinc sulfate in the treatment of rosacea Bamford et al. is in an active phase. After enrollment, subjects in both arms of a trial might be expected to improve as the active phase wanes. In the current study, the rosacea severity scores improved for subjects in both arms during the 90-day trial, but comparison of the two arms demonstrated that improvement in the placebo group was greater than in the treatment group. While the current study was inspired by the findings of Sharquie et al. 4 and was designed to provide a rigorous evaluation of the efficacy of oral zinc sulfate in rosacea management, it also has a number of limitations. Our study population was relatively small and predominantly Caucasian. Caution should be exercised in applying our findings to other populations, especially those that differ from our study population in regard to race/ethnicity, dietary, or socioeconomic characteristics. In addition, our study was stopped early resulting in a smaller trial, which subjects our findings to risk of larger errors and bias. At this time, neither the small study by Sharquie et al. 4 nor our current trial should be regarded as definitive evidence regarding the effect of zinc in the treatment of rosacea. Additional studies are needed to examine the role of zinc in rosacea and other dermatological conditions, and additional work is needed on the mechanism of action of zinc in inflammatory conditions. As our understanding of the role of inflammatory processes in rosacea improves, we should continue to look for potential roles for well-tolerated treatments such as zinc. Acknowledgments The authors are pleased to acknowledge Joseph Prohaska, PHD, of the University of Minnesota Duluth, and Pamela Larson, RN, of Essentia Health, for their contributions to this research, and thank the Duluth Clinic Foundation for grant support that made this study possible. References 1 Bikowski JB, Del Rosso JQ, Goldberg DJ, et al. Future trends in the treatment of rosacea. Cutis 2005; 75 (Suppl 3): Tuleya S. Research highlights: acne and rosacea treatments. Skin Aging 2003; 11: Thiboutot DM. Acne and rosacea. New and emerging therapies. Dermatol Clin 2000; 18: viii. 4 Sharquie KE, Najim RA, Al-Salman HN. Oral zinc sulfate in the treatment of rosacea: a double-blind, placebo-controlled study. Int J Dermatol 2006; 45: Fraker PJ, King LE. Reprogramming of the immune system during zinc deficiency. Annu Rev Nutr 2004; 24: Fraker PJ, King LE, Laakko T, Vollmer TL. The dynamic link between the integrity of the immune system and zinc status. J Nutr 2000; 5S (Suppl): 1399S 1406S. 7 Walker CF, Black RE. Zinc and the risk for infectious disease. Annu Rev Nutr 2004; 24: Mossad SB, Macknin ML, Medendorp SV, Mason P. Zinc gluconate lozenges for treating the comon cold. A randomized, double-blind, placebo controlled study. Ann Intern Med 1996; 125: What s New About Zinc. UC Berkeley Wellness Letter. 2004; 20: Hoffman HN, Phyliky RL, Fleming CR. Zinc-induced copper deficiency. Gastroenterology 1988; 94: Salzman MB, Smith EM, Koo C. Excessive oral zinc supplementation. J Pediatr Hematol/Oncol 2002; 24: Irving JA, Mattman A, Lockitch G, et al. Element of caution: a case of reversible cytopenias associated with excessive zinc supplementation. Can Med Assoc J 2003; 169: Chandra RK. Excessive intake of zinc impairs immune response. JAMA 1984; 252: Barceloux DG. Zinc. Clin Toxicol 1999; 37: Wilkin J, Dahl M, Detmar M, et al. Standard Grading System for Rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol 2004; 50: Nicholson K, Abramova L, Chren MM, et al. A pilot quality-of-life instrument for acne rosacea. J Am Acad Dermatol 2007; 57: Santner TJ, Snell MK. Small sample confidence limits for p1 p2 and p1.p2 in 2 2 contingency tables. J Am Stat Assoc 1980; 75: International Journal of Dermatology 2012, 51, ª 2012 The International Society of Dermatology

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