Crohn's Disease
Conditions
Keywords
dexamethasone, ery-dex, Chron's disease, CD
Brief summary
Primary objective: Assessment of the efficacy of EryDex vs PLACEBO in maintaining patients with steroid-dependent Crohn's disease in clinical remission throughout 12 months without oral steroids. Secondary objectives: 1. safety of EryDex 2. emergence of new adverse effects from steroids or disappearance of those possibly pre-existing in the various subgroups of patients; 3. duration of the period of remission; 4. evaluation of the hypophysis-adrenal function; 5. study of plasma concentrations of dexamethasone; 6. effect of therapy on the metabolism of calcium and on indexes of inflammation; 7. assessing the quality of life; 8. rate of surgical resection 9. evaluation of the indirect costs of care.
Detailed description
This was a multicenter, randomized, double-blind, PLACEBO-controlled, parallel-group study comparing EryDex versus PLACEBO. Patients with steroid-dependent Crohn's disease were enrolled and randomized to undergo 12 infusions of intraerythrocyte dexamethasone (EryDex), or PLACEBO. A balanced (1:1) randomization between the two treatment groups (EryDex / PLACEBO) was employed. At the time of randomization, study patients were stratified at each study site according to their previous therapy with AZT/6MP/MTX (never treated with AZT/6MP/MTX or intolerant/resistant to the therapy with AZT/6MP/MTX). The treatment was planned to be performed with 12 monthly infusions of EryDex or PLACEBO. Patients were followed-up after completion of the treatment for 6 months in patients regularly completing the study and 3 months in patients discontinuing from the study prematurely. The evaluation of the primary and secondary objectives was to be done at the 12th month of study (one month after the last study drug infusion), or upon relapse.
Interventions
DRUGDexamethasone
500 mg/20 ml encapsulated in erythrocytes, every month for 12 months
Sponsors
Quince Therapeutics S.p.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Male and female subjects; 2. Age \> 18 years; 3. Patients with steroid-dependent Crohn's disease, documented in the medical history, having suffered from at least one episode of relapse (CDAI \> 150) in the last 12 months. Patients should have been in clinical remission (CDAI \< 150) for at least four weeks, on stable therapy with at least 10 mg of methylprednisolone (or equivalent), or been on steroidal tapering after a recent relapse. Patients with intolerance or resistance to AZT/6-MP/MTX were eligible; 4. Patients willing and able to give written informed consent.
Exclusion criteria
1. Patients with Crohn's disease with intestinal sub-occlusion, or suspect of abdominal abscess, or with active perianal disease, or with clinically active disease at randomization (CDAI ≥150); 2. Patients already on therapy with immunosuppressant agents (AZT, 6-MP, MTX) for less than 4 months; 3. Patients having received therapy with infliximab (or other anti-TNF) in the previous 3 months; 4. Investigational treatments in the previous 3 months prior to randomization; 5. Pregnant women, or women who were not using valid birth-control measures, except those in surgical menopause; breast feeding; 6. Non collaborating subjects or those unable to be compliant with the treatment and the study schedules; 7. Severe concomitant diseases such as : 1. patients with inadequate bone marrow reserve: WBC \< 3000 /mm3; PLTs \< 75000 /mm3; Hb \< 8 g/dl 2. liver disease with total bilirubin ≥ 3 times the upper limit of normal (ULN), AST (GOT) ≥ 3x ULN, alkaline phosphatase ≥ 3x ULN 3. renal disease with serum creatinine ≥ 3 mg/dl 4. serious cardiac, allergic, lung, neurological diseases, neoplastic or pre-neoplastic disease 5. diseases (other than Crohn's) requiring chronic steroid treatment; 8. Elective surgery already scheduled at the start of the study (NB: patients having undergone previous surgery for Crohn's disease could be enrolled, if the patient had fully recovered and had been in remission for at least 4 weeks); 9. Chronic use of alcohol; drug addiction; 10. Subjects with contra-indication to the use of steroids (i.e. systemic fungal infections); 11. Evidence of clostridium difficilis in the stools.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Maintaining Steroids-free Clinical Remission (CDAI<150) Without Surgery for 12 Months | after 12 months | Clinical remission was defined as a Crohn's Disease Activity Index (CDAI) \< 150. A therapy failure was considered to have occurred in patients with a CDAI score over 150 for \> 2 weeks and/or the need for systemic steroids (with / without surgery). Hence, the higher the index, the worse the outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | after 12 months | This evaluation of safety was made by the comparison of treatment emergent adverse events (TEAE). Treatment emergent adverse events (TEAE) are undesirable events not present prior to medical treatment, or an already present event that worsens either in intensity or frequency following the treatment. |
| Percentage of Patients Interrupting the Study Because of Adverse Events | after 12 months | An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. |
| Duration of the Period of Steroid-free Clinical Remission | From end of the steroid therapy to relapse, up to 545 days | The mean time between the end of the steroid therapy and a confirmed relapse of the disease. |
| Dosing of Serum Cortisol | At Baseline and at the end of the study (18 months) | Levels of serum cortisol were measured at baseline and following Adrenocorticotropic Hormone (ACTH) trigger. |
Countries
Italy, Romania, Spain
Participant flow
Recruitment details
There were 63 patients enrolled into the screening phase at 10 sites; of these, 51 patients (representing the Safety population) were randomized at 9 sites.
Participants by arm
| Arm | Count |
|---|---|
| Ery-dex Ery-dex (dexamethasone sodium phosphate)is administered as intra-erythrocyte drug at monthly interval
Dexamethasone: 500 mg/20 ml encapsulated in erythrocytes, every month for 12 months | 28 |
| Placebo placebo comparator (sodium chloride instead of dexamethasone sodium phosphate) is administered in infusion at monthly interval.
Dexamethasone: 500 mg/20 ml encapsulated in erythrocytes, every month for 12 months | 23 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | consent withdrawn | 1 | 1 |
| Overall Study | fragile vein | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | premature closure of the study | 4 | 2 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | therapy failure and/or Crohn's surgery | 13 | 16 |
Baseline characteristics
| Characteristic | Ery-dex | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 3 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants | 20 Participants | 44 Participants |
| Age, Continuous | 47.3 years STANDARD_DEVIATION 14.9 | 43.4 years STANDARD_DEVIATION 12.5 | 45.5 years STANDARD_DEVIATION 13.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 28 Participants | 23 Participants | 51 Participants |
| Region of Enrollment Italy | 27 participants | 22 participants | 49 participants |
| Region of Enrollment Romania | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Spain | 0 participants | 1 participants | 1 participants |
| Sex: Female, Male Female | 20 Participants | 7 Participants | 27 Participants |
| Sex: Female, Male Male | 8 Participants | 16 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 1 / 23 |
| other Total, other adverse events | 19 / 28 | 16 / 23 |
| serious Total, serious adverse events | 6 / 28 | 4 / 23 |
Outcome results
Primary
Percentage of Patients Maintaining Steroids-free Clinical Remission (CDAI<150) Without Surgery for 12 Months
Clinical remission was defined as a Crohn's Disease Activity Index (CDAI) \< 150. A therapy failure was considered to have occurred in patients with a CDAI score over 150 for \> 2 weeks and/or the need for systemic steroids (with / without surgery). Hence, the higher the index, the worse the outcome.
Time frame: after 12 months
Population: Safety population, defined as all randomized patients who took at least one dose of the study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ery-dex | Percentage of Patients Maintaining Steroids-free Clinical Remission (CDAI<150) Without Surgery for 12 Months | 5 Participants |
| Placebo | Percentage of Patients Maintaining Steroids-free Clinical Remission (CDAI<150) Without Surgery for 12 Months | 2 Participants |
Secondary
Dosing of Serum Cortisol
Levels of serum cortisol were measured at baseline and following Adrenocorticotropic Hormone (ACTH) trigger.
Time frame: At Baseline and at the end of the study (18 months)
Population: Safety Set defined as all randomized patients who took at least one dose of the study medication
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ery-dex | Dosing of Serum Cortisol | At Baseline - before ACTH | 6.8 μg/dl | Standard Deviation 4.6 |
| Ery-dex | Dosing of Serum Cortisol | At the end of the study - before ACTH | 11.3 μg/dl | Standard Deviation 8.6 |
| Ery-dex | Dosing of Serum Cortisol | At baseline - after ACTH | 10.3 μg/dl | Standard Deviation 7.6 |
| Ery-dex | Dosing of Serum Cortisol | At the end of the study - after ACTH | 18.4 μg/dl | Standard Deviation 4.7 |
| Placebo | Dosing of Serum Cortisol | At the end of the study - after ACTH | 12.7 μg/dl | Standard Deviation 7.6 |
| Placebo | Dosing of Serum Cortisol | At Baseline - before ACTH | 7.1 μg/dl | Standard Deviation 6.2 |
| Placebo | Dosing of Serum Cortisol | At baseline - after ACTH | 11.0 μg/dl | Standard Deviation 6.5 |
| Placebo | Dosing of Serum Cortisol | At the end of the study - before ACTH | 6.4 μg/dl | Standard Deviation 5.4 |
Secondary
Duration of the Period of Steroid-free Clinical Remission
The mean time between the end of the steroid therapy and a confirmed relapse of the disease.
Time frame: From end of the steroid therapy to relapse, up to 545 days
Population: Data reported only for 9 subjects for the EryDex group and for 13 subjects in the placebo group of the safety set. For the remaining subjects, data are not included because of no treatment with steroids, or no last date available on the use of steroids, or steroids still ongoing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ery-dex | Duration of the Period of Steroid-free Clinical Remission | 55.3 Days | Standard Deviation 73.2 |
| Placebo | Duration of the Period of Steroid-free Clinical Remission | 84.9 Days | Standard Deviation 72.9 |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
This evaluation of safety was made by the comparison of treatment emergent adverse events (TEAE). Treatment emergent adverse events (TEAE) are undesirable events not present prior to medical treatment, or an already present event that worsens either in intensity or frequency following the treatment.
Time frame: after 12 months
Population: Safety population, defined as all randomized patients who took at least one dose of the study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ery-dex | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 13 Participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 6 Participants |
Secondary
Percentage of Patients Interrupting the Study Because of Adverse Events
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Time frame: after 12 months
Population: Safety population, defined as all randomized patients who took at least one dose of the study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ery-dex | Percentage of Patients Interrupting the Study Because of Adverse Events | 2 Participants |
| Placebo | Percentage of Patients Interrupting the Study Because of Adverse Events | 1 Participants |