Study design

This is a multicenter, double-blind, randomized, placebo-controlled clinical trial, alternated according to a cross-over model, lasting eight months overall. Since the beginning of the trial, for a period of 3 months, all individuals enrolled in the study were treated with low dose cytokines or with placebo solution. After a wash-out period of 60 days, the administration of the experimental product was resumed for a further three-month period, thus implementing the cross-over experimental model. After signing an informed consent the patients were enrolled progressively in the different experimental sites and identified with their initials as well as through a serial number.

A randomization procedure performed using a tailored software has generated two equal parts, one containing cytokines and one containing placebo. These preparations were marked with a serial number and an identifying code of the three products. Each preparation was allocated to the related subject. The chief of the Guna Labs (GUNA Spa, Milan-Italy) was the only one aware of the product content. A yellow label identified the products prepared for the first period of treatment; a green label identified the products prepared for the second period of treatment. One group was treated with Guna-Interleukin 4, Guna-Interleukin 10, Guna-Interleukin 11 at the concentration of 10 fg/ml in a hydroalcoholic solution 30% for oral use (GUNA Spa, Milan, Italy) administered at a dose of 20 drops twice daily, taken on an empty stomach from 8.00 to 10.00 and from 19.00 to 21.00. The other group was treated with placebo (hydroalcoholic solution at 30% containing no active ingredients) with the same mode of administration. Neither the doctor nor the patient were aware of the nature of the preparation assigned. At the end of the first 3 months of treatment, patients underwent a new clinical control and after a washout period of 60 days, the 2 experimental groups were inverted (cross-over model). This in order to reduce the possible error factors in the evaluation, as well as to give the possibility to both groups to benefit from the therapy (Fig. 1).