Erythrocytes-Mediated Delivery Of Dexamethasone 21-Phosphate In Steroid-Dependent Ulcerative Colitis
- Registration Number
- NCT01171807
- Lead Sponsor
- Casa Sollievo della Sofferenza IRCCS
- Brief Summary
The purpose of this study is to investigate the efficacy and safety of erythrocyte-mediated delivery of dexamethasone in steroid-dependent ulcerative colitis patients
- Detailed Description
Medical treatment of patients with ulcerative colitis (UC) presents a constant challenge. Corticosteroids are effective in the majority of patients, but benefits are offset by adverse events. For steroid-dependent patients therapeutic choices are limited to azathioprine/6-mercaptopurine, methotrexate and infliximab; however, 25% of more patients do not respond, become intolerant, or have contraindications (e.g. history of neoplasia) to these drugs.
A novel method of corticosteroids delivery by loading dexamethasone 21-phosphate into red blood cells has been validated. Owing to their long life span in the circulation and the capability of their cellular membrane to be opened and resealed in appropriate conditions, erythrocytes are excellent drug carriers. An ideal drug to be encapsulated into erythrocytes is Dex 21-P, a biologically inactive compound which undergoes dephosphorylation by intra-erythrocyte enzymes releasing the active metabolite, dexamethasone, by simple passive diffusion through cell membranes. In a previous pilot study in a cohort of steroid-dependent patients with inactive inflammatory bowel disease, Dexamethasone 21-phosphate loaded into autologous erythrocytes allowed to complete withdrawal of systemic steroids, and the overall cumulative exposure to corticosteroids from Dex 21-P-encapsulated erythrocytes (about 5-10 mg per month) was far less than conventional corticosteroids, and this translated into a lower rate of steroid-related events.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 40
- adult patients
- steroid-dependent ulcerative colitis
- clinical remission or mild clinical activity
- uncontrolled diabetes
- severe comorbidities (renal failure, heart failure, cirrhosis, neoplasia)
- previous exposure to biologic therapy
- pregnancy of breast feeding
- alcohol or drug abuse
- mental illness
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Dex 21-P Dex 21-P In this arm a dose of 20 ml of Dex 2-P solution was administered every 15 or 30 days for a total of 3 or 6 treatment procedures, respectively. Specifically, steroid-dependant IBD patients had to undergo a total of 6 procedures at one month interval, while active mesalazine refractory UC patients had to undergo a total of 3 procedures at 15 days interval. Every procedure implies the collection and re-infusion of autologous erythrocytes previously loaded with Dex 21-P. Placebo Placebo In this arm placebo solution was administered every 15 or 30 days for a total of 3 or 6 treatment procedures, respectively. Specifically, steroid-dependant IBD patients had to undergo a total of 6 procedures at one month interval, while active mesalazine refractory UC patients had to undergo a total of 3 procedures at 15 days interval. Every procedure implies the collection and re-infusion of autologous erythrocytes previously NOT loaded with Dex21-P.
- Primary Outcome Measures
Name Time Method The Proportion of Patients Responders to Dex 21-P vs Placebo 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) 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.
- Secondary Outcome Measures
Name Time Method Count of Partecipants, Suffering From Mesalazine Refractory UC, With Modification in Endoscopic Result (Baron Score) From baseline to End of treatment = 28 weeks ± 5 days (in mesalazine refractory UC patients) 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)Number of Patients Experiencing at Least One TEAE (Not Steroid-related) 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) 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.
Number of Patients Experiencing at Least One TEAE (Steroid-related) 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) 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.
Change From Baseline in Endogenous Cortisole Blood Level After Receiving the Study Treatment 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) 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.Change From Baseline in Inflammatory Indexes After Receiving the Study Treatment: Erythrocyte Sedimentation Rate (ESR) 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) 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.Change From Baseline in Inflammatory Indexes After Receiving the Study Treatment: C-reactive Protein (CRP) 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) 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.
Trial Locations
- Locations (1)
Casa Sollievo della Sofferenza Hospital
🇮🇹San Giovanni Rotondo, Italy