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A randomized, placebo-controlled, double-blind clinical trial of curcuminoids in oral lichen planus.

Abstract

We studied the efficacy of curcuminoids in the treatment of oral lichen planus (OLP), a chronic, mucocutaneous, immunological disease. Curcuminoids are components of turmeric (Curcuma longa) that have anti-inflammatory activity. Turmeric has been used in Ayurveda (Indian traditional medicine) for centuries. A randomized, double-blind, placebo-controlled trial was conducted. In all, 100 consecutive, eligible patients with OLP presenting to the oral medicine clinic at the University of California, San Francisco, were to be selected. Two interim analyses were to be conducted during the trial. The trial was conducted between February 2003 and September 2004. The first interim analysis was conducted in October 2004 using data from the first 33 subjects. Study subjects were randomized to receive either placebo or curcuminoids at 2000 mg/day for 7 weeks. In addition, all subjects received prednisone at 60 mg/day for the first 1 week. The primary outcome was a change in symptoms from baseline. Secondary outcomes were changes in clinical signs and occurrence of side effects.

The first interim analysis did not show a significant difference between the placebo and curcuminoids groups. Conditional power calculations suggested a less than 2% chance that the curcuminoids group would have a significantly better outcome as compared with the placebo group if the trial were continued to completion. Therefore, the study was ended early for futility. Reaching a conclusion regarding the efficacy of curcuminoids based on the results of this study is not possible as it was ended early for futility. Curcuminoids at this dose were well tolerated and the results suggest that for future studies a larger sample size, a higher dose and/or longer duration of curcuminoids administration should be considered; however, for the next step, an RCT of a shorter duration, using a higher dose of curcuminoids, and without an initial course of prednisone, should be considered.

[c] 2007 Elsevier GmbH. All rights reserved.

Keywords: Oral lichen planus; Curcuminoids; Turmeric; Clinical trial

Introduction

Lichen planus is a chronic immunological (Porter et al., 1997; Sugerman et al., 1993), mucocutaneous (Eisen, 1999) disease. When the oral mucosa is involved, white lace-like patterns, red atrophic changes, and ulcerations can occur (Lozada-Nur and Miranda, 1997). Symptoms can range from no soreness to severe soreness that greatly interferes with eating. Lichen planus is considered to be an autoimmune disease, and the most common current treatment for oral lichen planus (OLP) is systemic and/or topical corticosteroids (Lozada-Nur et al., 1994; Lozada and Silverman, 1980; Silverman et al., 1985). Short courses of high-dose systemic corticosteroids are followed by maintenance therapy with topical corticosteroids. These medications, although effective, have side effects that limit their effectiveness (Chainani-Wu et al., 2001). Turmeric, which comes from the plant Curcuma longa (Pierce, 1999), has been used for centuries in Ayurveda (Indian traditional medicine) for its anti-inflammatory properties (Eigner and Scholz, 1999; Majeed et al., 1996). In western scientific studies, including in vitro, animal, and human studies, components of turmeric called curcuminoids (including curcumin (diferuloyl methane), demethoxycurcumin, and bisdemethoxycurcumin) have been reported to have anti-inflammatory properties and to be very safe, with few side effects even at high doses (Chainani-Wu, 2003).

Methods

Protocol

This phase-2 randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of curcuminoids as an adjunct to short-course corticosteroids for the treatment of patients with OLP. Patients meeting the eligibility criteria below and at the baseline evaluation visit were randomized to one of two groups. The first group received 60 mg of prednisone per day for 7 days and 2000 mg of curcuminoids per day (in two divided doses) for 7 weeks. The second group received 60 mg of prednisone per day for 7 days and placebo for 7 weeks. The prednisone and the study medication were begun concurrently.

Eligible patients were those over age 21 years, with a current presentation of atrophic or erosive OLP, and a symptom score for OLP between 3 and 8 at enrollment. The range of scale, using the numerical rating scale, was from 0 (no oral discomfort) to 10 (worst imaginable oral discomfort). All patients had been diagnosed by clinical as well as histopathological examination of oral lesions. Exclusion criteria included pregnancy, lactation, a medical contraindication to prednisone or fluconazole, patients on long-term corticosteroid therapy, current use of anticoagulants or antiplatelet agents [curcumin has an inhibitory effect on platelet aggregation (Shah et al., 1999)], current orthodontic treatment, and history of gastric ulcers, duodenal ulcers, gallstones [prednisone and curcumin may cause gastric irritation and curcumin can stimulate gall bladder contractions (Rasyid and Lelo, 1999)] or liver disease [curcumin can cause hepatotoxicity in some species, including mice and rats (Chainani-Wu, 2003)].

The primary outcome of the study was a change in symptom scores from the baseline to the last follow-up visit at week 7. Secondary endpoints included changes in symptom scores from baseline at weeks 1 and 4, and changes in clinical signs from baseline at weeks 1, 4, and 7, as well as occurrence of adverse effects.

This study was approved by the Institutional Review Boards at the University of California, San Francisco (UCSF) and the University of California, Berkeley. An investigational New Drug Approval number was obtained from the Food and Drug Administration before the study was started.

Subjects were recruited from the oral medicine clinic at UCSF. Patients were screened by review of medical history, medications used, current symptom score (for OLP), and an oral examination. At this time potential subjects were identified, written informed consent was obtained, and consenting patients were scheduled for a baseline evaluation visit. They were instructed to discontinue all medications for OLP for a period of at least 2 weeks before the baseline evaluation and a course of antifungal therapy (fluconazole 50mg/day for 7 days), to be taken the week before the reevaluation visit, was dispensed to ensure that any subclinical oral candidiasis was treated and the signs and symptoms measured at baseline were from the OLP alone. At the time the 20th subject was enrolled, the protocol was modified to include a swab for fungal culture at the screening visit, at the baseline visit, and at the last follow-up visit. This was intended to detect any differences in the degree of oral candida colonization at baseline and follow-up between the two groups. At the baseline visit, patients were reevaluated to confirm that they met the eligibility criteria for the study. A consecutive sample of eligible patients was enrolled into the study. Subject enrollment and follow-up are outlined in Fig. 1.

Intervention

The study medication was a standardized extract of turmeric, which contains at least 95% curcuminoids, called 'Curcumin C3 Complex'. The turmeric rhizomes used for the manufacture of 'Curcumin C3 complex' were cultivated in Salem district, Tamilnadu, India. The company Sabinsa Corporation (Piscataway, NJ) holds a patent (US Patent #5,861,415 dated January 19, 1999), on the "Bioprotectant composition, method of use and extraction process of curcuminoids" for 'Curcumin C3 Complex'. According to the information provided by Sabinsa, the purity of curcuminoids in 'Curcumin C3 Complex' is as follows: curcumin between 70% and 80%, demethoxycurcumin between 15% and 25%, and bisdemethoxycurcumin between 2.5% and 6.5%, depending upon the batch.

[FIGURE 1 OMITTED]

Study medication capsules with 95% curcuminoids as well as identical opaque, placebo (Sunset Yellow FCF food color, rice powder, magnesium stearate) capsules packaged in blister packs were provided by Sabinsa Corporation. A "certificate of analysis" was provided by Sabinsa for Batch No. C21623 (used in the study), which showed potency assayed by HPLC and contaminant levels (heavy metals, arsenic, and lead) to be in the acceptable range. This was confirmed by an independent laboratory analysis obtained from American Analytical Chemistry Laboratories, IL. This independent laboratory analysis also included testing for microbes (yeast and molds, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and a Salmonella screen), which were all negative.

Randomization and blinding

A stratified, blocked randomization (block size of six) was used. Stratification was based on symptom score at baseline, with two strata (symptom score ranging from 3 to 5 and from >5 to 8). The randomization sequence was generated by the UCSF pharmacy, using the random number generator in Microsoft Excel. Both patients and investigators were blind to the treatment assignment.

Measurement of response variables

(1) The visual analog scale (VAS) is represented by a horizontal line, with the left end marked as no symptoms and the right end marked as the worst imaginable symptoms. The length from the left end to the vertical mark made by the patient to indicate intensity of symptoms was measured in millimeters using a millimeter ruler. (2) The numerical rating scale (NRS) ranged from 0 to 10 (0 = no symptoms and 10 = worst imaginable symptoms). At the baseline visit symptom intensity over the previous week was recorded, and at follow-up visits symptom intensity over the time period since the previous measurement was recorded. On follow-up visits, the patient was shown the symptom scores from the previous visits, before marking the VAS and NRS. (3) The change in symptoms scale (CSS) is a scale measuring the change in symptoms, which we developed to measure changes in symptoms as compared with the previous visit. One of the following was to be selected: significant worsening, moderate worsening, slight worsening, no change, slight improvement, moderate improvement, significant improvement, or complete resolution of symptoms. (4) For the modified oral mucositis index (MOMI), clinical signs of OLP were measured using a semi-quantitative scale. We developed this scale by modifying the 'oral mucositis index', which has been validated for use in measuring oral mucositis among patients receiving cancer chemotherapy (Schubert et al., 1992). An oral examination was conducted, and the atrophic and erosive changes were quantified based on the severity of the change and the number of sites involved. An intensity score for erythema ranging from 0 to 3 was used (0 = normal, 1 = mild erythema, 2 = moderate erythema, and 3 = severe erythema). The score for ulcerations was based on area of ulceration (0 = no ulcerations, 1 = between 0 and 0.25 [cm.sup.2], 2 = between 0.25 and 1 [cm.sup.2], and 3 = 1 [cm.sup.2] or greater). Sixteen different oral sites were evaluated, including buccal mucosa (right and left), labial mucosa (upper and lower), lateral tongue (right and left), dorsum of tongue (right and left), ventral tongue and floor of mouth (right and left), maxillary gingiva (right and left), mandibular gingiva (right and left), soft palate, and hard palate. The scores for erythema and ulcerations were obtained by summing the respective scores for these 16 sites and the total score for clinical signs was obtained by summing the erythema and ulceration scores. (5) Side effects were recorded using a 10-item questionnaire.

Each of these five assessments (VAS, NRS, CSS, MOMI, and side effects) was conducted for each patient at four different time points: (i) at enrollment, i.e., baseline (day 0); (ii) at the first follow-up visit after 1 week (day 7); (iii) at the second follow-up visit after an additional 3 weeks (day 28); and (iv) at the third follow-up visit after an additional 3 weeks (day 49). The total duration from baseline to final follow-up visit was 7 weeks. The first follow-up visit was on day 7 (plus or minus 1 day), the second follow-up on day 28 (plus or minus 2 days), and the final follow-up on day 49 (plus or minus 2 days).

Sample size calculations and interim analysis plan

The response of OLP to curcuminoids has not been quantified previously in clinical studies. A proportion of 45% or more of patients showing improvement in the curcuminoids group by the last follow-up was estimated to be clinically significant, with an estimated improvement in the placebo group of 15%. For a two-tailed [alpha] of 0.05, [beta] = 0.2, and assuming 15% drop out, a sample size of 50 per group was calculated.

Interim analysis was to be conducted after the first 30 and then 60 patients had completed the study. Stopping criteria, if the two groups were different at interim analysis, were predetermined. The Pocock-type sequential statistical method was to be used for monitoring, using an overall [alpha] of 0.05. This requires the comparison to be statistically significant at 0.02079, 0.01464, and 0.01457, to stop after 30, 60, or 100 subjects, respectively.

Statistical analysis

Descriptive statistics were calculated for baseline variables; means and standard deviations were calculated for continuous variables, including age, duration of OLP, and duration of symptomatic OLP; proportions were calculated for gender, low vs. high severity of symptoms at baseline, presence of ulcerations at baseline, and use of medications for OLP in the past. Changes in symptom scores and clinical sign scores from baseline to the final follow-up visit were calculated and compared between the placebo and curcuminoid groups. Means of percentage changes from baseline in symptoms and signs at each follow-up visit were calculated and compared between the placebo and curcuminoids groups. NRS, VAS, erythema, ulceration, and total clinical signs outcomes were analyzed using mixed-effects regression models. These models had fixed effects for drug (placebo or curcuminoids), time (baseline, weeks 1, 4, and 7), drug by time interaction, and a random subject effect to account for clustering within subjects. Comparisons included specific estimates of differences in drug means at each time, differences of time means within each drug group, and comparison of the change from week 0 to week 1, week 0 to week 4, and week 0 to week 7 between the two drug conditions. No patterns of heterogeneity of variance were found in plots of residual versus predicted values. An intention-to-treat analysis was performed, including all 33 randomized subjects analyzed according to group assignment. Occurrence of side effects in the two groups was compared using the two-sided Fisher's exact test. SAS, SPlus, and Primer of Biostatistics statistical software were used.

Results

Recruitment of subjects

Enrollment into the study began in February 2003 and ended in August 2004, with the 7-week protocol for the last (33rd) subject completed by September 2004.

Early termination of study: The first planned interim analysis was conducted when 33 subjects had been enrolled. Initial analysis showed no significant difference in reduction of symptoms or signs between the placebo and curcuminoids groups. The changes in NRS values from baseline to 7 weeks in the placebo and curcuminoids groups were -1.996 and -1.666, respectively, difference = -0.33 (95% CI: -2.021, 1.360); changes in VAS values were -19.743 and -15.476, respectively, difference = -4.267 (95% CI: -24.484, 15.949); changes in MOMI values were -2.8 and -3.583, respectively, difference = 0.783 (95% CI: -3.380, 4.947). Because no significant differences were found between the curcuminoids and placebo groups, a futility analysis was conducted. The conditional power, i.e., the conditional probability of rejecting the null hypothesis at the end of the trial, given the current interim data, was calculated. For the pre-trial expected probability of improvement and given the interim findings, the conditional power of finding a statistically significant result (at p = 0.05, one-sided), after enrollment of the full sample size of 100, was only 0.014. Therefore, the decision to end the study early for futility was made and the trial was halted.

Post-hoc power calculations

At interim analysis, the proportion of patients showing improvement in symptoms by the last follow-up visit (day 49) was more than expected in both groups: 13/16 patients (81.25%) on placebo and 10/12 (83.33%) on curcuminoids showed improvement in NRS scores by the last follow-up visit. The power to detect this difference at [alpha] = 0.05 (two-sided) was 4.8% at interim analysis and 5% if the trial continued to completion. For detection of the observed differences at interim analysis in symptom improvement as measured by NRS mean of responses and standard deviations, at [alpha] = 0.05 (two-sided), this study had a power of 7% for the sample size at the interim analysis of 33 subjects (28 with full follow-up), and a power of 11% for the final sample size of 100 subjects (estimated 84 with full follow-up) if the study were continued.

Patient characteristics at enrollment

Clinical characteristics at the time of enrollment into the study were similar in the two groups (Table 1).

Outcomes

Means of percentage changes from baseline in signs and symptoms are presented in Table 2a. Mixed-effects models showed no significant difference in the change from baseline in VAS, NRS, erythema, ulceration, and total clinical scores of erythema plus ulceration between the placebo and curcuminoids groups at weeks 1, 4, and 7. Results were similar when the analysis was repeated but restricted to the 28 subjects who had completed the entire 7-week protocol, and restricted to the 28 patients who had not used any topical corticosteroids during the 7-week protocol. The results were also similar when mixed-effects models were run as percent change from baseline (Table 2b). Adding co-variables of age, gender, duration of OLP, and prior systemic steroid or azathioprine use did not change the results significantly, and individually did not reach statistical significance.

Adverse effects

Curcuminoids were well tolerated and the frequencies of most side effects were similar between the placebo and curcuminoids groups (Table 3). Some of the side effects reported in both groups at day 0 and day 7 are likely to be from fluconazole and prednisone, e.g., insomnia, mood changes, and bloating are known side effects of prednisone. "Other" side effects reported by study subjects included: headache (five on placebo, one on curcuminoids), rash (one on placebo, one on curcuminoids), flatulence (none on placebo, two on curcuminoids), pitted fingernails (none on placebo, one on curcuminoids), dry mouth (two on placebo, one on curcuminoids), and metallic taste (one on placebo, none on curcuminoids). There was no significant effect on vital signs at the different follow-up visits and between groups.

Assessment of blinding

At the final follow-up visit, the investigator (NCW) and all the 33 study participants indicated whether they believed participants had been assigned to the treatment group or the placebo group. A total of 57.6% of subjects correctly guessed their treatment assignment and the investigator correctly guessed the treatment assignment of 53.5% of the study subjects. The [kappa] score for agreement between subject guess and correct assignment beyond chance was 0.163 (-0.20, 0.53), and that for agreement between the investigator's guess and correct assignment beyond chance was 0.07 (-0.29, 0.43). [chi square] tests for proportion correct for subject guesses (p = 0.43) and investigator guesses (p = 0.70) as compared with the proportion 0.5 were not significant. These results suggest adequate blinding of the study medication.

Compliance

Compliance was measured by pill counts. Among patients who completed the study, all patients in the placebo group (n = 16) had >85% compliance, and 14 had >95% compliance (range 87.7-100%); in the curcuminoids group (n = 12), all but one had >95% compliance (range 64.2-100%). A total of five patients used topical corticosteroids during the study. Of these, two were in the placebo group and three were in the curcuminoids group (one of whom dropped out of the study after 4 weeks, at the second follow-up visit).

Candida cultures

These were performed on the last 14 subjects enrolled, at three different times: at screening, baseline visit, and last follow-up visit. At the screening visit, two patients had positive cultures with [greater than or equal to]100 colony forming units (cfu), one in the placebo group (100 cfu) and the other in the curcuminoids group (940cfu). At the baseline visit (after 1 week on fluconazole), all of these 14 subjects had negative cultures. By the last follow-up visit, only the patient in the curcuminoids group (with positive culture at the screening visit) had a positive culture (473 cfu). This was the only patient who had clinical signs of candidiasis, both at screening and at the last follow-up visit. At baseline visit, no patient had clinical signs of candidiasis.

Discussion

This was the first study of curcuminoids in the treatment of OLP. It was ended early at the first interim analysis for futility. This study did not find a significant effect of using curcuminoids as an adjunct to short-course systemic corticosteroids on the symptoms and signs of OLP as compared with placebo at the time of the first interim analysis, when data from one-third of the total sample size were available. The placebo group had a much more favorable response at 7-week follow-up than had been initially anticipated. Conditional power analysis showed that even if the study were completed with enrollment of the full sample size of 100, the likelihood of finding a statistically significant difference between the two groups was very small, and therefore the study was ended early.

At first and second follow-up, the differences in the mean of percentage changes in measures of symptoms and signs between the two groups were small and some measures showed greater improvement in the placebo group and others in the curcuminoids group (Tables 2a and b). However, by the third follow-up, the curcuminoids group showed greater mean percentage reduction in all of the measures of symptoms and signs, i.e. VAS scores, NRS scores, erythema scores, ulceration scores, and total of erythema and ulceration scores, although none reached statistical significance. A greater mean percentage reduction in ulceration score at the first follow-up visit was seen in the curcuminoids group as compared with the placebo group (difference = 31.5 (-0.4, 63.5), p = 0.053), but differences at the second and third follow-up were not statistically significant, and in the mixed-effects model this difference at the first follow-up was not statistically significant.

We had expected the effect of prednisone to be washed out in most patients by the time of the final follow-up visit, which was 6 weeks after the discontinuation of prednisone. That was the basis for the estimated proportion showing improvement in the placebo group of 15% in our pre-trial sample size calculations. The much higher proportion of 81.25% showing improvement in the placebo group at day 49 at the first interim analysis was unexpected and suggests an extended effect of the 1-week course of prednisone until day 49. This extended effect may have obscured the differences between the active and placebo groups up to that time point. The pattern of the differences in mean of percentage change between the placebo and curcuminoids groups in Tables 2a and b, described above, also suggests that a longer duration of follow-up may be required to evaluate differences in the two groups, when an initial course of prednisone is administered.

Lichen planus is an autoimmune disease that is known to worsen during periods of stress. Immunomodulatory responses to neural signals may play a significant role in affecting the natural history of this disease. This may be another reason why a pronounced placebo effect was observed in this study. It is possible that the study design, with close follow-up visits together with the initial decrease in symptoms from prednisone, may have resulted in patients in both groups reporting more improvement than we had initially anticipated, thus requiring a larger sample size to detect a difference than our pre-trial calculations had suggested.

It is also possible that there is a smaller but clinically important benefit of curcuminoids than the effect size we had estimated for the sample size calculations. These findings and the post-hoc power calculations suggest that a much larger and possibly a longer trial would be required to study this research question when an initial course of prednisone is administered. A multicenter trial may be needed to recruit the necessary sample size in a reasonable time frame.

Another possible explanation for the results is that the dose of curcuminoids used in this trial was insufficient and a larger dose may be required before an effect is seen. The dose of 2000 mg curcuminoids per day in two divided doses was well tolerated in this study. Other studies have also demonstrated the safety of curcumin, including a phase-1 trial in which doses of up to 8000 mg of curcumin per day were administered without toxicity (Chainani-Wu, 2003; Cheng et al., 2001). Use of a larger dose may allow designing a trial with a shorter follow-up period, thereby eliminating the need for an initial course of prednisone. The initial course of prednisone was used in this trial due to ethical concerns regarding a placebo-controlled trial extending for 7 weeks among patients with significant oral discomfort. Without the initial course of prednisone, a smaller sample size may be sufficient to detect a difference between the two groups. In addition, the shorter follow-up period this would allow may result in greater subject retention until the end of the trial.

These considerations point to a shorter trial using a higher dose of curcuminoids, without an initial course of prednisone, as the next step in studying the role of curcuminoids in OLP.

Reaching a conclusion regarding the efficacy of curcuminoids is not possible based on the results of this study, as it was ended early for futility. Curcuminoids at this dose were well tolerated and the results suggest that for future studies a larger sample size, possibly requiring a multi-center design, and a higher dose and/or longer duration of curcuminoids should be considered; however, for the next step, an RCT of a shorter duration, using a higher dose of curcuminoids without an initial course of prednisone, should be considered.

Acknowledgments

We would like to thank the late Priscilla Mayer for data entry and Candida cultures; Dr. Herve Sroussi, Dr. Sivapiri Velupillai, Dr. Deborah Greenspan, and Dr. Caroline Shiboski for referring patients to the study; Dr. Michael Kohn for creating the Microsoft Access database; Dr. Gertrude Buehring and Dr. Barbara Abrams for review of the manuscript; and the staff of the General Clinical Research Center at UCSF where study visits were conducted.

Funding/support: NIH/NIDCR T32 DE07204; Mount Zion Health Fund, through the Osher Center for integrative medicine, UCSF. These studies were carried out in part in the General Clinical Research Center, Moffitt Hospital, University of California, San Francisco, with funds provided by the National Center for Research Resources, 5 M01 RR-00079, US Public Health Service. Sabinsa Corporation (Dr. Vladimir Badmaev, Piscataway, NJ) donated the curcuminoids and placebo capsules.

ClinicalTrials.gov Identifier: NCT00226174.

References

Chainani-Wu, N., 2003. Safety and anti-inflammatory activity of curcumin: a component of turmeric (Curcuma longa). J. Altern. Complement. Med. 9, 161-168.

Chainani-Wu, N., Silverman Jr., S., Lozada-Nur, F., Mayer, P., et al., 2001. Oral lichen planus: patient profile, disease progression and treatment responses. J. Am. Dent. Assoc. 132, 901-909.

Cheng, A.L., Hsu, C.H., Lin, J.K., Hsu, M.M., et al., 2001. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 21, 2895-2900.

Eigner, D., Scholz, 1999. Ferula asafoetida and Curcuma longa in traditional medical treatment and diet in Nepal. J. Ethnopharmacol. 67, 1-6.

Eisen, D., 1999. The evaluation of cutaneous, genital, scalp, nail, esophageal, and ocular involvement in patients with oral lichen planus. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 88, 431-436.

Lozada, F., Silverman Jr., S., 1980. Topically applied fluocinonide in an adhesive base in the treatment of oral vesiculoerosive diseases. Arch. Dermatol. 116, 898-901.

Lozada-Nur, F., Miranda, C., 1997. Oral lichen planus: epidemiology, clinical characteristics, and associated diseases. Semin. Cutan. Med. Surg. 16, 273-277.

Lozada-Nur, F., Miranda, C., Maliksi, R., 1994. Double-blind clinical trial of 0.05% clobetasol propionate (corrected from proprionate) ointment in orabase and 0.05% fluocinonide ointment in orabase in the treatment of patients with oral vesiculoerosive diseases. Oral Surg. Oral Med. Oral Pathol. 77, 598-604.

Majeed, M., Badmaev, V., Frank, M., 1996. Turmeric and the Healing Curcuminoids. A Keats Good Health Guide. Keats Publishing, Inc, New Canaan, CT.

Pierce, A., 1999. The American Pharmaceutical Association Practical Guide to Natural Medicines. The Stonesong Press, Inc.

Porter, S.R., Kirby, A., Olsen, I., Barrett, W., 1997. Immunologic aspects of dermal and oral lichen planus. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 83, 358-366.

Rasyid, A., Lelo, A., 1999. The effect of curcumin and placebo on human gall-bladder function: an ultrasound study. Aliment. Pharmacol. Ther. 13, 245-249.

Schubert, M.M., Williams, B.E., Lloid, M.E., Donaldson, G., et al., 1992. Clinical assessment scale for the rating of oral mucosal changes associated with bone marrow transplantation. Development of an oral mucositis index. Cancer 69, 2469-2477.

Shah, B.H., Nawaz, Z., Pertani, S.A., Roomi, A., et al., 1999. Inhibitory effect of curcumin, a food spice from turmeric, on platelet-activating factor and arachidonic acid-mediated platelet aggregation through inhibition of thromboxane formation and Ca21 signaling. Biochem. Pharmacol. 58, 1167-1172.

Silverman Jr., S., Lozada-Nur, F., Migliorati, C., 1985. Clinical efficiency of prednisone in the treatment of patients with oral inflammatory ulcerative diseases: a study of fifty-five patients. Oral Surg. Oral Med. Oral Pathol. 59, 360-363.

Sugerman, P.B., Savage, N.W., Walsh, L.J., Seymour, G.J., 1993. Disease mechanisms in oral lichen planus. A possible role for autoimmunity. Australas. J. Dermatol. 34, 63-69.

N. Chainani-Wu (a,*), S. Silverman Jr. (a), A. Reingold (b), A. Bostrom (c), C. Mc Culloch (c), F. Lozada-Nur (a), J. Weintraub (d)

(a) Department of Orofacial Sciences, School of Dentistry, 521 Parnassus Avenue, C646, Box 0658, University of California, San Francisco, CA 94143-0658, USA

(b) Division of Epidemiology, School of Public Health, University of California, Berkeley, USA

(c) Department of Epidemiology and Biostatistics, University of California, San Francisco, USA

(d) Department of Preventive and Restorative Dental Sciences, School of Dentistry, University of California, San Francisco, USA

Received 28 November 2006; accepted 22 May 2007

*Corresponding author. Tel.: +1 415 577 5647; fax: + 1 408 830 9386.

E-mail address: nita.wu@ucsf.edu (N. Chainani-Wu).
Table 1. Baseline characteristics of the study participants

 Placebo, Curcuminoids,
 n = 17 n = 16

Age (mean, S.D.) 60.6, 9.8 60.6, 7.5
Male 6 (35.3%) 4 (25%)
Female 11 (64.7%) 12 (75%)
Duration of oral lichen 86.8, 131.4 64.4, 110.6
 planus in months
 (mean, S.D.)
Duration of symptomatic 83.0, 132.8 64.4, 110.6
 oral lichen planus in
 months (mean, S.D.)

Symptoms at baseline (numerical rating scale):
 (1) 3 n = 11 (64.7%) n = 11 (68.75%)
 (2) 5.5 n = 6 (35.3%) n = 5 (31.25%)

Ulcerations at baseline:
 (1) Yes 12 (70.6%) 11 (68.8%)
 (2) No 5 (29.4%) 5 (31.3%)

Number of subjects who used medications in the past for oral lichen
planus:
 (1) Topical steroids 11/17 (64.7%) 9/16 (56.3%)
 (2) Prednisone 10/17 (58.8%) 9/16 (56.3%)
 (3) Azathioprine 2/17 (11.8%) 1/16 (6.3%)

Table 2a. Mean of percentage changes in symptoms and signs at follow-up
visits

 Placebo Curcuminoids Difference (95% CI) p Value

Visual analog scale (mean of % change from baseline visit)
At 1st follow-up -47.8 -45.8 -1.9 (-28.8, 24.9) 0.88
At 2nd follow-up -35.5 -45.5 9.9 (-46.2, 66.2) 0.71
At 3rd follow-up 2.44 -38.6 41.1 (-74.1, 156.4) 0.42

Numerical rating scale (mean of % change from baseline visit)
At 1st follow-up -43.3 -41.7 -1.6(-22.0, 18.8) 0.87
At 2nd follow-up -43.0 -36.6 -6.4(-33.5, 20.7) 0.63
At 3rd follow-up -33.1 -36.7 3.55(-30.1, 37.2) 0.83

Modified oral mucositis index: clinical signs total score (mean of %
change from baseline visit)
At 1st follow-up -32.1 -38.1 5.9 (-9.2, 21.1) 0.43
At 2nd follow-up -25.6 -18.1 -7.5 (-33.0, 17.9) 0.54
At 3rd follow-up -9.03 -28.4 19.45 (-22.2, 61.1) 0.34

Modified oral mucositis index: erythema only (mean of % change from
baseline visit)
At 1st follow-up -32.5 -29.0 -3.4 (-21.6, 14.7) 0.70
At 2nd follow-up -23.5 -19.3 -4.1 (-28.0, 19.7) 0.72
At 3rd follow-up -9.9 -23.8 13.8 (-25.5, 53.2) 0.47

Modified oral mucositis index: ulceration only (mean of % change from
baseline visit)
At 1st follow-up -31.8 -63.4 31.5 (-0.4, 63.5) 0.05
At 2nd follow-up -42.8 -0.7 -42.0 (-109.9, 25.7) 0.26
At 3rd follow-up -38.3 -63.4 25.1 (-21.9, 72.2) 0.27

Table 2b. Difference of predicted percentage changes in symptoms and
signs between placebo and curcuminoids groups at follow-up visits from
the mixed-effects model

 Placebo Curcuminoids Difference (95% CI) p Value

Visual analog scale (mean of % change from baseline visit)
At 1st follow-up -1.9 (-67.9, 63.9) 0.95
At 2nd follow-up 10.3 (-58.8, 79.6) 0.76
At 3rd follow-up 40.6 (-31.4, 112.6) 0.26

Numerical rating scale (mean of % change from baseline visit)
At 1st follow-up -1.6 (-26.7, 23.4) 0.89
At 2nd follow-up -6.2 (-32.4, 20.0) 0.63
At 3rd follow-up 2.0 (-25.1, 29.2) 0.88

Modified oral mucositis index: clinical signs total score (mean of %
change from baseline visit)
At 1st follow-up 5.9 (-20.2, 32.2) 0.65
At 2nd follow-up -7.3 (-34.8, 20.2) 0.59
At 3rd follow-up 20.3 (-8.3, 49.0) 0.16

Modified oral mucositis index: erythema only (mean of % change from
baseline visit)
At 1st follow-up -3.4 (-29.0, 22.1) 0.78
At 2nd follow-up -4.0 (-30.9, 22.7) 0.76
At 3rd follow-up 14.6 (-13.3, 42.7) 0.29

Modified oral mucositis index: ulceration only (mean of % change from
baseline visit)
At 1st follow-up 31.5 (-13.9, 77.1) 0.16
At 2nd follow-up -42.0 (-90.4, 6.4) 0.08
At 3rd follow-up 19.9 (-31.4, 71.3) 0.43

Table 3. Adverse events

Adverse events Visit Placebo Curcuminoids p Value

Diarrhea Baseline (day 0) 3/17 3/16 1.0
 1st follow-up (day 7) 3/17 2/16 1.0
 2nd follow-up (day 28) 2/16 3/14 0.64
 3rd follow-up (day 49) 0/16 3/12 0.06
Constipation Baseline (day 0) 1/17 1/16 1.0
 1st follow-up (day 7) 2/17 4/16 0.39
 2nd follow-up (day 28) 1/16 2/14 0.58
 3rd follow-up (day 49) 4/16 2/12 0.67
Abdominal pain Baseline (day 0) 3/17 2/16 1.0
 1st follow-up (day 7) 4/17 3/16 1.0
 2nd follow-up (day 28) 3/16 1/14 0.60
 3rd follow-up (day 49) 1/16 2/12 0.56
Heartburn Baseline (day 0) 1/17 2/16 0.60
 1st follow-up (day 7) 1/17 1/16 1.0
 2nd follow-up (day 28) 2/16 0/14 0.48
 3rd follow-up (day 49) 2/16 2/12 1.0
Nausea Baseline (day 0) 1/17 1/16 1.0
 1st follow-up (day 7) 1/17 0/16 1.0
 2nd follow-up (day 28) 1/16 1/14 1.0
 3rd follow-up (day 49) 1/16 1/12 1.0
Fatigue Baseline (day 0) 6/17 2/16 0.22
 1st follow-up (day 7) 5/17 7/16 0.48
 2nd follow-up (day 28) 2/16 4/14 0.37
 3rd follow-up (day 49) 2/16 2/12 1.0
Insomnia Baseline (day 0) 1/17 2/16 0.60
 1st follow-up (day 7) 9/17 11/16 0.48
 2nd follow-up (day 28) 2/16 2/14 1.0
 3rd follow-up (day 49) 0/16 3/12 0.06
Mood changes Baseline (day 0) 1/17 1/16 1.0
 1st follow-up (day 7) 5/17 5/16 1.0
 2nd follow-up (day 28) 2/16 1/14 1.0
 3rd follow-up (day 49) 2/16 1/12 1.0
Bloating Baseline (day 0) 2/17 1/16 1.0
 1st follow-up (day 7) 4/17 6/16 0.46
 2nd follow-up (day 28) 5/16 2/14 0.39
 3rd follow-up (day 49) 3/16 1/12 0.61

p Values calculated using two-sided Fisher's exact test.
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Author:Chainani-Wu, N.; Silverman, S., Jr.; Reingold, A.; Bostrom, A.; Mc Culloch, C.; Lozada-Nur, F.; Wein
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Date:Aug 1, 2007
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