Hadjieva, T., Cavallin-Stahl, E., Linden, M., & Tiberg, F. (2014). Treatment of oral mucositis pain following radiation therapy for head-and-neck cancer using a bioadhesive barrier-forming lipid solution. Supportive Care in Cancer, 22, 1557–1562. 

To test the analgesic effect of CAM2028 with benzydamine compared with CAM2028 without benzydamine (the FDA-approved prescription formula of episil) over an eight-hour period. During treatment with CAM2028, phospholipid and triglceride lipid components self-assemble with a volume of water (saliva) to form a bioadhesive and protective liquid crystalline lining of the oral mucosa. Additional objective of the study was to assess the safety and tolerability of a single-dose of the combined formulation.

1. All patients were receiving radical or postoperative radiotherapy to a significant part of clinically visible oral and/or pharyngeal mucosa at two or more anatomic sites.
2. Trial began during weeks 3 to 4 of radiotherapy and took place over a maximum duration of 12 days.
3. Treatment randomly was assigned after a radiotherapy treatment period of seven days.
4. Patients must have received at least one third of the planned total dosage of radiation.
5. At screening, participants were required to exhibit symptomatic oral mucositis (WHO grade 2 or above). 
6. Likert score of at least 6 was required at screening and before each treatment.
7. Patients were treated with randomized study medication on treatment days 1 and 3 and returned for a final follow-up evaluation on day 5.
8. At the first treatment visit, each patient was randomly allocated to one of two sequences: CAM2028-benzydamine on day 1 followed by CAM20208-control on day 3 or CAM2028-control followed by CAM2028-benzydamine.
9. Patients were assigned a random number and received trial medication sent from the study coordinating center with the corresponding number.
10. List of random numbers was generated at the coordinating center using the permuted bloc method.
11. Treatment allocation was concealed from the investigators, staff at the trial sites, trial monitors, data analysts, managers, and the patients.
12. Patients were given the trial medication after undergoing radiotherapy.
13. One milliliter of the medication was applied to the oral mucosa using a syringe, and patients were instructed to swirl the medication around in the mouth for approximately 15 seconds and then spit. Procedure was repeated after five minutes.
14. On each treatment day, oromucosal pain was assessed by the patient using the Likert scale, done before dosing and at 5 and 30 minutes, and one, two, three, six, and eight hours post dose.

• N = 38 participated (All completed the trial, and no patients discontinued.)
• MEDIAN AGE = 52 years (range = 2–72 years)
• MALES: 84.2%, FEMALES: 15.8%
• KEY DISEASE CHARACTERISTICS: Newly diagnosed head and neck cancer

• SITE: Five oncology centers
• LOCATION: Bulgaria

• PHASE OF CARE: Treatment
• APPLICATIONS: Mucositis

Crossover, double-blind, placebo-controlled, single-dose, randomized, proof of concept trial

• World Health Organization (WHO) 5 grade toxicity scale for oral mucositis
• Likert scale of 0 to 10 for pain

All patients completed the trial. With both treatments, patients experienced a mean 40% decrease in pain intensity at six hours. Both treatments resulted in significant pain relief within five minutes of application that was evident during the entire eight-hour assessment period. At no time did mean pain ratings or pain intensity difference differ statistically between the two treatments. The mean AUC of pain intensity over time did not differ between the two treatments. All of the analyses of pain intensity outcomes showed a statistically significant clinical center effect, with one center reporting larger pain intensity difference values than others. No reason was offered for this difference.

The similar treatment effects of CAM2028 with or without benzydamine suggest that benzydamine did not contribute additionally to the reduction of oral mucositis pain compared with the unmedicated CAM2028 control. CAM2028 resulted in immediate and significant pain relief with a duration that was maintained for up to eight hours.

• Small sample (< 100), split between five centers, and no mention of how many at each center
• No mention of how the outcome assessor was trained to do the assessments of the mucositis, or who did the assessment
• Women were over-represented in the group receiving placebo first.
• One center reported larger pain intensity difference than the others. No reason was offered for this difference.

• Results differences between centers needed further evaluation.
• No patients received chemotherapy in this study, so only applicable to radiotherapy treatment.
• No mention of whether radiation techniques were different between the centers.
• Study does not tell us who monitored the application of the medications.
• CAM2028 may not be a suitable vehicle with which to combine benzydamine.
• Other formulations for extended delivery of benzydamine need to be investigated and studied.