Erythrocytes-Mediated Delivery Of Dexamethasone 21-Phosphate In Steroid-Dependent Ulcerative Colitis (Crocodex)

Dexamethasone Intra-Erythrocyte Therapy in Patients With Chron's Disease or Ulcerative Colitis

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.

Study Overview

• Status: Completed
• Conditions: Ulcerative Colitis
• Intervention / Treatment: Drug: Dex 21-P; Drug: Placebo

Detailed Description

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
• Enrollment (Actual): 33
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • San Giovanni Rotondo, Italy, 71013
    • Casa Sollievo della Sofferenza Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. More than 18 years of age

2. Patients suffering from one of the following chronic inflammatory intestinal disease:

   • Steroid-dependent Chron's Disease or Ulcerative Colitis following ECCO definition or mild-moderate active UC ( Powell Tuck between 3 and 14- an index of 14 was allowed; endoscopic Baron score >1) refractory to mesalazine.
3. Disease extension over the rectum (at least 15 cm) in patients suffering from Ulcerative Colitis
4. Patients willing and be able to give written informed consent.

Exclusion Criteria:

1. Intestinal sub occlusion or a suspected abdomen abscess or a severe degree of the disease (CDAI > 450) in patient suffering from Chron's Disease
2. Patient affected by a severe Ulcerative Colitis (more than 6 evacuations of liquid, mucous-blooding stools combined at least one systemic sign as body temperature > 37.8 °C, heart rate < 90 bpm, ESR > 30 mm/h or haemoglobin < 10.5 g/dL)

3. Severe concurrent disease(s) as:

   • Medullar deficit: white blood cells < 3000/mm3; platelets < 75000/mm3; haemoglobin < 10 g/dL;
   • Hepatic diseases presenting total bilirubin ≥ 3 mg/dL; AST (GOT) ≥ 5 UNL; alkaline phosphatase ≥ 5 UNL:
   • Renal failure with serum creatinine ≥ 3 mg/dL;
   • Heart failure
   • Respiratory failure
   • Disabling neurological diseases
   • Neoplasia
   • Patient deemed candidate to surgery due to Chron's Disease or Ulcerative Colitis
   • Chronic alcohol or drug abuse
   • Patient for whom the use of steroids is contraindicated (e.g. systemic infections)
4. Treatment with Infliximab in the previous 4 months
5. Pregnant woman or female for whom the possibility of a pregnancy during the study could not be excluded.
6. Non-collaborating patient or subject unable to regularly undergo the scheduled study procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Dex 21-P; 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.; Other Names: Dexamethasone 21-phosphate
Placebo Comparator: 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.	Drug: Placebo; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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); = abnormal mucosa but non-haemorrhagic appearances between scores 0 and 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)	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.	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.	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)

Collaborators and Investigators

• Sponsor: Quince Therapeutics S.p.A.
• Collaborators: Casa Sollievo della Sofferenza IRCCS
• Investigators: Principal Investigator: Angelo Andriulli, MD, Casa Sollievo della Sofferenza Hospital

Publications and helpful links

General Publications

• Bossa F, Annese V, Valvano MR, Latiano A, Martino G, Rossi L, Magnani M, Palmieri O, Serafini S, Damonte G, De Santo E, Andriulli A. Erythrocytes-mediated delivery of dexamethasone 21-phosphate in steroid-dependent ulcerative colitis: a randomized, double-blind Sham-controlled study. Inflamm Bowel Dis. 2013 Aug;19(9):1872-9. doi: 10.1097/MIB.0b013e3182874065.

Study record dates

Study Major Dates

• Study Start (Actual): July 22, 2003
• Primary Completion (Actual): May 15, 2007
• Study Completion (Actual): May 15, 2007

Study Registration Dates

• First Submitted: July 28, 2010
• First Submitted That Met QC Criteria: July 28, 2010
• First Posted (Estimated): July 29, 2010

Study Record Updates

• Last Update Posted (Actual): September 24, 2024
• Last Update Submitted That Met QC Criteria: September 17, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Ulcerative colitis; Erythrocytes; Steroid-dependency; Steroid adverse events
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone; Dexamethasone 21-phosphate
• Other Study ID Numbers: Crocodex; 2018-004763-31 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No