Objectives: The primary objective of this trial was to evaluate the patients response rate at the end of the study. Patients were considered responder if one of the following conditions occurs: * Disease remission (Powell Tuck ≤ 3 or CDAI \< 150) and withdrawal of oral steroids therapy from at least the second treatment procedure; * Disease marked improvement versus basal conditions (at least 5 point decrease in Powell Tuck index or 150 point decrease in CDAI score) and withdrawal of oral steroids therapy from at least the second treatment procedure. Secondary objectives: * to evaluate the endogenous cortisole production after receiving the study treatment * to evaluate the inflammatory indexes (ESR and CPR) after receiving the study treatment * to evaluate the endoscopic remission in patients suffering from mesalazine refractory Ulcerative Colitis * to evaluate the safety of dexamethasone intra-erythrocyte therapy with particular attention to steroid-related adverse events.
This was a single-center, placebo-controlled, randomised, phase II explorative study with the aim to investigate the ability of the new steroid delivery system to induce or maintain remission in steroid-dependent or mesalazine refractory patients suffering from Chron's disease (CD) or Ulcerative Colitis (UC) . Once the patient was deemed eligible for the study, the treatment plan was selected as follows In the Dexamethasone arm (DEX 21-P): * steroid-dependant patients: one treatment procedure every 30 days up to a total of 6 procedures * mesalazine refractory active UC patients: one treatment procedure every 15 days up to a total of 3 procedures. In the placebo arm: Patients assigned to placebo arm performed the same procedure as the patients assigned to the DEX 21-P group without loading in the Red Blood Cells the Dex 21-P. The planned duration of individual patient participation in the study was a maximum of 6 or 28 weeks, depending from the assigned treatment scheme.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
33
At each procedure 50 ml of patient whole blood was washed with saline solution and centrifugated. The isolated erythrocytes were suspended into 2 hypotonic solutions to make their membrane permeable and incubated with Dex 21-P sodium salt up to obtain a final concentration of 10 mM. The drug loaded erythrocytes were immediately re-infused by using a suitable filter.
Patients assigned to placebo arm performed the same procedure as the patients assigned to the DEX 21-P group without loading in the Red Blood Cells the Dex 21-P
Casa Sollievo della Sofferenza Hospital
San Giovanni Rotondo, Italy
The Proportion of Patients Responders to Dex 21-P vs Placebo
Patients were considered responder if, at the EoS, one of the following occurred: * Disease remission (Powell Tuck index ≤ 3 or CDAI \< 150) and withdrawal of oral steroids therapy from at least the second treatment procedure; * Disease marked improvement vs basal conditions (at least 5 point decrease in Powell Tuck or 150 point decrease in CDAI score) and withdrawal of oral steroids therapy from at least the second treatment procedure. The Powell-Tuck index was calculated by adding the subscores given by 7 items. A total score \< 10 indicated a mild activity of the UC, and a total score \>14 a severe one. The higher the score the worse the outcome. Crohn Disease Activity Index (CDAI) was a tool that combines subjective parameters, with objectives parameters. The score given to each parameter was inserted in an algorithm which provided the final Index value. A moderate CD showed a CDAI score between 220 and 450, while a CDAI \> 450 was an activity index indicating a severe disease.
Time frame: From baseline to End of treatment = 6 weeks ± 10 days (in chronic and steroid dependent IBD patients) or 28 weeks ± 5 days (in mesalazine refractory UC patients)
Change From Baseline in Endogenous Cortisole Blood Level After Receiving the Study Treatment
Blood levels of endogenous cortisol were determined before the first and 15 days/one month after the last intra-erythrocytes infusion, according to the assigned treatment scheme planned for each patient. As steroids suppress ACTH production resulting in lowering cortisol levels, the assessment of this parameter was intended to investigate the ability of the dexamethasone intra-erythrocytes administration in minimising this steroid adverse effect. In child, from 1 to 16 years, the total serum cortisol reference range is 5-23 mcg/dL at 8 am, and 3-13 mcg/dL at 4 pm.
Time frame: From baseline to End of treatment = 6 weeks ± 10 days (in chronic and steroid dependent IBD patients) or 28 weeks ± 5 days (in mesalazine refractory UC patients)
Change From Baseline in Inflammatory Indexes After Receiving the Study Treatment: Erythrocyte Sedimentation Rate (ESR)
The erythrocyte sedimentation rate (ESR) is the rate at which red blood cells in anticoagulated whole blood descend in a standardized tube over a period of one hour. It is a common hematology test, and is a non-specific measure of inflammation. To perform the test, anticoagulated blood is traditionally placed in an upright tube (Westergren tube) and the distance which the red blood cells fall is measured and reported in millimetres at the end of one hour. ESR was evaluated as supportive data for the assessment of the intestinal disease severity. It was determined before the first and 15 days/one month after the last intra-erythrocytes infusion, according to the assigned treatment scheme planned for each patient. ESR normal values in blood were from 0 to 20 mm/hour. Higher values are considered abnormal both in adults and in children. For ESR values \> 100 mm/hour, there is a high probability that an underlying cause would be found upon investigation.
Time frame: From baseline to End of treatment = 6 weeks ± 10 days (in chronic and steroid dependent IBD patients) or 28 weeks ± 5 days (in mesalazine refractory UC patients)
Change From Baseline in Inflammatory Indexes After Receiving the Study Treatment: C-reactive Protein (CRP)
CRP is a protein produced by the liver. A C-reactive protein test measures the level of C-reactive protein (CRP) in a blood sample. Normal levels of blood C-reactive protein are low (0.3 to 1.0 mg/L). In case of inflammation liver releases more CRP into your bloodstream: results equal to or greater than 8 mg/L or 10 mg/L are considered high. High levels of CRP may indicate a serious health condition that causes inflammation. C-reactive protein (CRP) was determined before the first and 15 days/one month after the last intra-erythrocytes infusion, according to the assigned treatment scheme planned for each patient. Inflammation parameters (CRP) were evaluated as supportive data for the assessment of the intestinal disease severity. C-reactive protein was measured in milligrams per liter (mg/L). Results equal to or greater than 8 mg/L or 10 mg/L were considered high.
Time frame: From baseline to End of treatment = 6 weeks ± 10 days (in chronic and steroid dependent IBD patients) or 28 weeks ± 5 days (in mesalazine refractory UC patients)
Count of Partecipants, Suffering From Mesalazine Refractory UC, With Modification in Endoscopic Result (Baron Score)
The Baron score was an endoscopic grading system for ulcerative colitis. Four grades are defined (0-3) by the Baron score according to the severity of macroscopic inflammation of the rectal mucosal appearances at rigid sigmoidoscopy: 0 = normal mucosa (ramifying vascular pattern clearly visible, no spontaneous bleeding, no bleeding to light touch); 1. = abnormal mucosa but non-haemorrhagic appearances between scores 0 and 2; 2. = moderately haemorrhagic (bleeding to light touch, but no spontaneous bleeding seen ahead of the instrument on initial inspection); 3= severely haemorrhagic (spontaneous bleeding seen ahead of instrument at initial inspection and bleeds to light touch). The higher the score the worst the outcome. Due to the nature of the score, its assessment was limited to patients suffering from UC, only. (CD or UC steroid-dependant patients were planned to receive the study treatment procedure every 30 days for a total of 6 administrations)
Time frame: From baseline to End of treatment = 28 weeks ± 5 days (in mesalazine refractory UC patients)
Number of Patients Experiencing at Least One TEAE (Not Steroid-related)
At each access to the clinic (except at the baseline visit one), patients were questioned and/or examined for evidence of adverse events. An adverse event was defined as any untoward medical occurrence or unfavourable and unintended sign in a subject administered a pharmaceutical product, biologic (at any dose), or medical device, whether or not considered related to the use of that product. This includes the onset of new illness and the exacerbation of pre-existing conditions.
Time frame: From baseline to End of treatment = 6 weeks ± 10 days (in chronic and steroid dependent IBD patients) or 28 weeks ± 5 days (in mesalazine refractory UC patients)
Number of Patients Experiencing at Least One TEAE (Steroid-related)
Steroid related adverse events were investigated to assess the ability of the therapeutic approach under study in reducing the occurrence or entity of steroid adverse effects.
Time frame: From baseline to End of treatment = 6 weeks ± 10 days (in chronic and steroid dependent IBD patients) or 28 weeks ± 5 days (in mesalazine refractory UC patients)
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