Mucositis can be a serious complication of hematopoietic SCT (HSCT). A previous phase II trial in 32 children undergoing HSCT reported a beneficial effect of the homeopathic remedy Traumeel S. The Children's Oncology Group sought to replicate the results in a multi-institutional trial. The study was an international multi-center, double-blind, randomized trial comparing Traumeel with placebo in patients aged 3–25 years undergoing myeloablative HSCT. Traumeel/placebo was started on Day −1 as a five-time daily mouth rinse. Efficacy of the treatment was assessed using the modified Walsh scale for mucositis, scored daily from Day −1 to 20 days after HCST. The main outcome was the sum of Walsh scale scores (area-under-the-curve (AUC)) over this period. Other outcomes included narcotic use, days of total parenteral feeding, days of nasogastric feeding and adverse events. In 181 evaluable patients, there was no statistical difference in mucositis (AUC) in the Traumeel group (76.7) compared with placebo (67.3) (P=0.13). There was a trend towards less narcotic usage in the Traumeel patients. No statistically beneficial effect from Traumeel was demonstrated for mucositis. We could not confirm that Traumeel is an effective treatment for mucositis in children undergoing HSCT.
Oral mucositis is a common and debilitating complication of chemotherapy, occurring in 52–80% of children treated with chemotherapy and 95% of patients undergoing SCT.1, 2, 3, 4 Mucositis evolves through a complex series of events involving the epithelium, extracellular matrix, connective tissue and a submucosal cellular infiltrate.1, 5, 6, 7 It is associated with pain and trouble swallowing, which can lead to dehydration and malnutrition. Narcotic analgesics and parenteral nutrition are frequent necessary supportive care measures. Systemic infection, extended hospital stay, decreased quality of life and increased risk of mortality are associated with severe mucositis.1, 2, 8, 9, 10 No available treatment has proven to reliably ameliorate mucositis.11 Thus, there is a need for alternative therapeutic approaches.
Up to one-half of the adult population in developed countries use some form of complementary and alternative medicine (CAM).12, 13, 14, 15This increasing trend is also apparent among cancer patients, ranging from 40–91%,16, 17, 18, 19 and from 31–91%20, 21, 22, 23, 24, 25 in pediatric cancer patients. In the latter, CAM is usually used as a supportive therapy.26 The few studies of pediatric hematopoietic SCT (HSCT) patients and CAM therapies published have been primarily examining mind/body or health promotion techniques27, 28, 29 rather than ingestible or parenteral agents.
Homeopathy is a popular system of CAM, founded by the German physician Samuel Hahneman in the early 1800s. It is based on treating disease using minute doses of a drug (called a ‘remedy’) that produces symptoms in healthy persons similar to those of the disease.30 ‘Classical’ homeopathy employs highly diluted individualized remedies, whereas ‘complex’ homeopathy uses combinations of dilute agents for specific clinical conditions. Traumeel is a complex homeopathic remedy sold over-the-counter for over 50 years primarily as an anti-inflammatory medication. It is traditionally used to treat a variety of conditions related to trauma and inflammation. It contains 14 medicinal plants and minerals in very low concentrations (Table 1).
In 2001, Oberbaum et al.31 published the results of a small, randomized, double-blind pilot study using Traumeel to treat mucositis in 32 children undergoing HSCT, showing Traumeel to be substantially superior to placebo in preventing or ameliorating mucositis. This was one of the first reported randomized controlled trials of a CAM intervention in children with cancer.
In 2005, the Committee of the American Institute of Medicine on the use of CAM recommended that the same principles and standards of evidence of treatment effectiveness apply to all treatments, whether currently labeled as conventional medicine or CAM.32 Following this recommendation, the CAM subcommittee of the Children's Oncology Group (COG) sought to replicate the Oberbaum study in a larger, multi-center, double-blind, randomized controlled trial. We report here on that trial.
Materials and methods
Eligible patients were 3–25 years old, undergoing myeloablative HSCT, allogeneic or autologous, for malignant and nonmalignant conditions. Patients entered the trial between April 2004 and December 2006 at 1 out of 28 COG member institutions and at 2 Israeli institutions. Each institution obtained institutional review board approval. Patients receiving a non-myeloablative HSCT, those taking glutamine or vancomycin oral paste, and any individuals allergic or sensitive to Echinacea (a component of Traumeel) were excluded. All the patients or their guardians gave signed informed consent. In all, 195 patients were enrolled.
Traumeel S and a placebo identical in appearance and taste were provided free of charge by Heel (Baden-Baden, Germany) in sterile 2.2 mL glass ampoules. Traumeel S is manufactured in accordance with the European Union Guidelines on good manufacturing practice for medicinal products. It was prepared by serial dilution and agitation in saline according to the German Homeopathic Pharmacopoeia. Normal saline was used as placebo.
The study was an international multi-center, double-blind, placebo-controlled randomized trial conducted under the auspices of COG. Patients were assigned by block randomization to receive Traumeel or placebo in a 1:1 ratio, stratified by TBI (yes/no), allogeneic vs autologous transplant and COG vs Israeli institution.
Patients were registered in the COG Cancer Registry and identified throughout the study by the COG patient-identification number. Patients were enrolled in the study once all eligibility requirements had been met and not later than 4 days before transplant. The study medications were prepared by Heel and were identified by serial number only. The code was kept by the company and the COG statistician only and was not broken until completion of the trial. Patient assignment was communicated to McKesson Bioservices Corporation (Rockville, MD, USA) who dispensed the study drug or placebo in blinded fashion. Treatment began on the day before transplant, so that in all the cases, treatment began before the first symptoms of regimen-induced mucositis appeared. Treatment ended when patients met the completion criteria (see below) and not later than the twentieth day after transplant.
A pharmacist drew the contents of the blinded ampoules into an oral syringe. Patients were instructed to rinse the mouth vigorously with the study medication, retain it for thirty seconds and then swallow. This was repeated five times daily. Patients were instructed not to eat or drink for 30 min after each dose. Patients were permitted any type of analgesic for pain control. Narcotics could be taken orally, i.v. or by patch. The type and amount of narcotics were subsequently normalized to morphine equivalents according to a conversion table.33
Efficacy of the treatment was assessed using the three-grade modified Walsh scale for mucositis34 recorded daily from the day before transplant to the twentieth day thereafter. The simpler five-grade World Health Organization oral-toxicity scale35 was also recorded over the same period. Additionally recorded were: amount of narcotic equivalents used per day, number of days of total parenteral nutrition, number of days of nasogastric feeding, occurrences of adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events v. 3.0 (CTCAE),36 mortality up to 30 days after termination of protocol therapy, veno-occlusive disease of the liver, acute GVHD and invasive infection within 100 days post transplant.
Study therapy was terminated when: (i) a Walsh score of 1 was recorded for two consecutive days following an episode of mucositis or (ii) a Walsh score of 1 from the day before transplant until the twelfth day after transplant or (iii) 20 days post transplant (22 days of drug) was reached with no occurrence of criteria (i) and (ii). Patients were removed from study therapy if the patient, parent or guardian refused further therapy, or if the physician determined that it was in the patient's interest to discontinue.
The primary outcome for this trial was area-under-the-curve (AUC) of the Walsh score from the day before transplant to 20 days post transplant. For patients with complete follow-up data, this outcome was simply the sum of the total scores over the 22 days. The mean AUCs in the Traumeel and placebo groups were compared, and the probability of a patient on Traumeel having a lower AUC than a patient on placebo was estimated. Differences between the groups were tested using the Mann–Whitney test.37
The target sample size of 180 was based on a power of 90% to detect an effect significant at the 5% level, assuming a 0.65 probability that a Traumeel patient had a lower AUC than a placebo patient, and a 14% loss to follow-up.
Missing follow-up data were imputed by linear interpolation when 3 consecutive days or less were missing. Other missing scores were imputed randomly 10 times from scores of similar patients with complete data, and the method of multiple imputation38 was applied to the 10 full data sets so created.
The treatment groups were compared for balance on potential prognostic factors. Where substantial imbalance was seen, the comparison between the treatment groups was adjusted for the imbalance using a stratified Mann–Whitney test.
Maximum treatment duration was 22 days. For any day of treatment, a patient was defined as compliant if he/she took three or more of the five doses of study drug and noncompliant otherwise. A ‘noncompliant center’ was defined as one in which more than half of their patients were noncompliant on 70% of the treatment days. A secondary analysis compared AUCs in the Traumeel and placebo groups excluding the ‘noncompliant centers’. Another analysis was conducted according to individual patient compliance. Patients were classified as compliant on 100%, 65–99%, 30–65% or <30% of treatment days. The AUCs for Traumeel and placebo were then compared within each of these subgroups and also as a combined group excluding the fourth (least compliant) subgroup.
The Traumeel and placebo groups were also compared with respect to the World Health Organization score for oral mucositis, using the same approach as for the Walsh score, the amount of narcotics used and days of total parenteral nutrition, using Mann–Whitney tests, the proportions of patients requiring nasogastric feeding, of patients with serious adverse events (including veno-occlusive disease and GVHD), and of deaths up to 31 days after termination of protocol therapy, using the Chi-squared test.
Study monitoring was performed after 40, 80 and 120 evaluable patients were entered. Group differences in AUCs for the Walsh score were tested at two-sided significance levels 0.003, 0.004 and 0.0049, respectively. No significant differences were found on monitoring. The final analysis critical significance level was 0.047 to yield an overall 5% level. All the other outcomes were tested at the 5% level. Statistical analysis was conducted by COG statisticians (TZ and ZC).
A total of 195 patients entered the trial, of whom 190 met study eligibility. A flow diagram is presented in Figure 1. Five patients were ineligible to participate, one allocated to Traumeel and four allocated to placebo. Treatment groups were well balanced on all baseline variables except gender (Table 2).
The protocol required recording of the Walsh score on each of the 22 study days. Full data were obtained on 106 (56%) of the eligible patients. A further 35 (18%) had 4 missing scores, 24 (13%) between 5 and 10 missing scores and 25 (13%) had more than 11 scores missing, including 9 patients with no follow-up data. Among patients with full data, AUCs ranged from 0 to 238.5. The mean Walsh AUCs were similar in the two groups: 71.7 (s.e.=7.2) in the Traumeel group (56 patients) and 69.8 (s.e.=8.2) in the placebo group (50 patients). After imputation of missing values for the 181 patients with follow-up data, the mean AUCs were 76.7 (s.e.=5.5) for Traumeel and 67.3 (s.e.=6.3) for placebo, with an estimated probability of 0.43 (95% confidence interval: 0.34, 0.52) that a Traumeel patient would have a lower AUC than a placebo patient (z=−1.56, P=0.13) (Table 3).
Each patient was classified as being compliant with study medication on 100%, 65–99%, 30–65% or <30% of treatment days. There was no clear evidence of a beneficial effect of Traumeel in any category of compliance (Table 3). Stratification by gender strengthened the evidence against Traumeel having a beneficial effect (z=−2.23, P=0.026).
In all, 4 out of the 28 participating centers had >50% of their patients compliant on <than 30% of days. Excluding these four centers from the analysis, the estimated probability that a Traumeel patient would have a lower AUC than a placebo patient was 0.48 (z=−0.34, P=0.73).
The analysis of World Health Organization oral mucositis score was based on 171 patients (91 Traumeel and 80 placebo) with at least some follow-up data. After performing multiple imputation for missing values, the mean AUC scores were 21.6 (s.e.=2.07) for the placebo group and 24.4 (s.e.=1.80) for the Traumeel group, with an estimated probability of 0.45 that a Traumeel patient would have a lower AUC than a placebo patient (z=−1.18, P=0.24).
The average total doses (in equivalent mg/kg) of morphine were 17.7 (s.e.=3.1) for Traumeel and 28.5 (s.e.=10.9) for placebo (P=0.2). Although not statistically significant, there is clearly a trend towards less narcotic usage in the Traumeel-treated group. The average number of days of total parenteral nutrition were 15.3 (s.e.=0.56) for Traumeel and 15.2 (s.e.=0.65) for placebo (P=0.9). The number of patients with nasogastric feeding was 11 in the Traumeel group and 9 in the placebo group (P=0.75).
The mortality proportion to 31 days after termination of protocol therapy was 17% (17/98) for Traumeel vs 14% (13/92) for placebo (P=0.54). The proportion of patients with veno-occlusive disease of the liver was 6% (5/86) for Traumeel vs 5% (4/76) for placebo (P=0.88). The proportion with GVHD was 21% (18/86) for Traumeel vs 18% (14/76) for placebo (P=0.69). Finally, there was no statistically significant difference in the numbers of adverse events between the groups (Table 4).
Our multicenter trial did not confirm the results of the previous small single-center trial, which reported a beneficial effect of Traumeel on chemotherapy-induced mucositis compared with placebo. We did not observe any statistically significant advantage of the Traumeel group over the placebo group in mucositis scores, narcotic use, days of total parenteral nutrition or days of nasogastric feeding feeding. However, there was a trend towards less narcotic usage in the Traumeel-treated group of patients.
We cannot fully explain the negative results obtained in the current study compared with the study of Oberbaum et al.31 One possible difference in practice was that in the pilot study, a standardized oral care protocol was used (twice daily mouth washes with chloroheximide, oral amphoterin B and gentle tooth brushing), whereas in the current study, each center used its own oral care protocol. However, such a standard oral care protocol is quite thorough, as well as similar, and we would not expect this difference to influence the outcome of the trial. A second difference relates to administration of the study drug. Oral administration of Traumeel is not simple. The medicine is supplied in glass ampoules. Some skill is required to extract the full amount of liquid and deliver it entirely to the patient's mouth. Patients must also be encouraged to retain the liquid in their mouths for at least 30 s. In Oberbaum's trial, a single trained study nurse administered the study drug to all patients. In the current study, each center employed separate staff. As mentioned elsewhere, more than half of the centers entered five or fewer patients, limiting the experience that staff members could gain in this rather complex process. One further potential difference in practice should also be noted. The standard practice in most, but not all, North American hospitals is to use a 5-μm filtered straw needle to draw liquid medication from glass ampoules to reduce the number of glass particle contaminants. This was not the practice in the Israeli hospitals at the time of the pilot and is a potential confounding factor. We were initially concerned that the filtering process might change the bioactivity of the Traumeel formulation. In one of our labs, the filtered Traumeel was studied (JAI) and found to have higher silica content than unfiltered drug. The higher silica content, interestingly, was found to positively correlate with increased enzyme activity (39), in which case we might expect to have found the Traumeel group to show less mucositis, which was not the case.
During the study, we encountered a lack of compliance, both in patients taking the study drug or placebo and in obtaining the necessary daily mucositis scoring. Patients were required to take the drug five times daily, to swish for 30 s and swallow, and neither eat nor drink for the following 30 min. Administering five daily oral doses in the pediatric transplant setting was itself difficult. Patients with mucositis often have thickened oral secretions that are expectorated frequently; swallowing these secretions with the medication was difficult. In addition, the 30-min fasting after each dose proved especially challenging, causing a high rate of drug refusal. Pediatric SCT patients frequently feel too nauseated or uncomfortable to take an oral substance, but patients nevertheless found it difficult to be denied food and drink for 2.5 h/day. Refusal was similar in both treatment groups, suggesting that Traumeel per se was not the cause of the noncompliance.
Compliance problems may have been related to recruitment of small numbers of patients at some centers. In all, 16 out of the 28 institutions entered five or fewer patients. Perhaps researchers/health care providers at these centers were less experienced or successful in encouraging patients to persevere with the study protocol and perform the study-required oral evaluations. There was variation between institutions in who was completing the daily forms, ranging from the bedside nurses, research nurses, transplant coordinators or other health care providers. Those institutions that assigned one nurse to evaluation and reporting were generally the most successful. Weekend observations, in particular, were often missing. Future mucositis trials should encourage centers to assign a small number of trained observers to assess the patient's oral cavity. This will increase reliability and accuracy. In addition, contingencies need to be made for weekend evaluations.
It should be noted that this international and multicenter trial accrued patients over a short period of time, suggesting that parents or caretakers are interested in CAM and are willing for their children to participate in a CAM study that may improve treatment of a significant complication such as mucositis.
In view of the considerable level of missing data, we used the method of multiple imputation in our analysis, different from the usual ‘last observation carried forward’ approach.40 The latter method has been shown to introduce bias into the comparison and is no longer recommended.41 Multiple imputation both avoids bias in the treatment comparison and adjusts the confidence limits for the extra uncertainty due to the missing data. It should be noted that using this method, the 95% confidence limits for the Traumeel–placebo difference were still narrow enough to exclude a clinically useful benefit of Traumeel.
The result of this trial reinforces for CAM research, a common observation in conventional medicine, namely the importance of confirming observations in the multicenter randomized setting. We were not able to reproduce the earlier positive result, and Traumeel cannot be recommended for mucositis prevention.
Despite the results of this study, Traumeel may yet prove to be an interesting therapeutic agent for other conditions. Research has found anti-inflammatory biological activity, both in cell culture42 and in animal models,43 and we believe that further research on Traumeel may be warranted for other conditions in which an inflammatory process is involved. In addition, the high degree of acceptance of trialing a biological yet complementary agent by both the pediatric HSCT medical community and the patients/families is testimony to the recognition of the need to study those therapies that show promise in reducing the pain and suffering of transplant, whether ‘conventional’ or ‘complementary.’ Currently, the COG cancer control and HSCT disciplines are collaborating on several supportive care protocols. The transplant community is actively engaged in studying ways to reduce transplant morbidity and mortality. As we develop new trials, however, we must carefully consider how patient and caregiver compliance will affect the outcome of the intervention.
This research is supported by the CCOP Grant U10 CA95861, Chair's Grant U10 CA98543 and the Statistics and Data Center Grant U10 CA98413 of the Children's Oncology Group from the National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. The authors would also like to thank the CRA's and nurses of the participating COG institutions; they are the backbone of clinical research.
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