| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderately to severely active Crohn's Disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Moderately to severely active Crohn's Disease |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10011401 |
| E.1.2 | Term | Crohn's disease |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Controlled versus placebo confirmation of the ability of a single intravenous (i.v.) injection of 1.10^6 cells dose of Ovasave (Ova-Treg cells) to induce a CDAI response (CDAI decrease ≥ 100 points) 6 weeks post administration compared to placebo. |
|
| E.2.2 | Secondary objectives of the trial |
- Safety assessment of a first and second i.v. injection of Ovasave (CATS29-DB) and of a 3rd and 4th i.v. injection of Ovasave (CATS29-OL).
- Assessment of different doses (placebo, 1.10^4, 1.10^6 and 1.10^7 cells) and comparison of the efficacy and the safety between doses.
- Assessment of the safety and efficacy (response and remission) of a second injection of 1.10^6 cells at Week 8.
- Reduction of steroids treatment of different doses (placebo, 1.10^4, 1.10^6 and 1.10^7 cells) at week 14.
- Assesment of safety during the 3-year long-term follow-up after first dose. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
At the screening visit (V1):
1) Willing and able to provide written informed consent (IC);
2) Male or Female aged between 18 and 70 (inclusive) years of age;
3) Crohn's Disease diagnosis defined as patients with medical history of signs, symptoms and biological evidence of active bowel inflammation: Documented endoscopic evidence of Crohn's diagnosis at least 1 year prior to V1 (an endoscopy will be perform if the one available has more than 1 year at V1);
4) Elevated High sensitive C-reactive protein (hs-CRP) > 10 mg/L at V1;
5) Calprotectin ≥ 250 μg/g;
6) Failure or intolerance to conventional treatments including corticosteroid, immunosuppressant and at least one biologic; and had not responded (primarily failure) or responded and then lost response completely (no response or need to increase the dose / secondary failure) or were intolerant to this therapy at a dose indicated for CD (Refer to Appendix 17.6 for the definition of refractoriness);
7) Documented CDAI (Crohn's Disease Activity Index) ≥ 250 at V1 or within the past 3 months prior to V1;
8) Total white cell count ≥ 4.0.10^9 / L;
9) Platelets between 150.10^9 and 600.10^9 / L (included);
10) Hemoglobin > 8.5 g/dL;
11) Full blood count (FBC) and biochemistry without any clinically significant abnormalities except if CD-related, at Investigator's discretion;
12) Normal, or no clinically significant abnormality in the electrocardiogram (ECG) at Investigator's discretion;
13) Patients willing and able to observe an intake of ovalbumin through the ingestion of a meringue daily after the first administration until the end of the Double-blind phase and during the OL-phase if the patient receives additional administration;
At the Visit 3 (week-4):
1) CDAI ≥ 250;
2) Evidence of inflammation by an elevated hs-CRP value (> 5 mg/L) OR endoscopic / MRI evidence of local intestinal inflammation, OR elevated calprotectin (≥ 250μg/g) to be confirmed before V4 (first administration);
Between visit 8 (week14) and visit 9 (week16):
1) Upon Investigator recommendation, patient qualification will be based on acceptable safety and tolerability profile of the IMP before continuing to receive intravenous administrations of Ovasave at a dose of 10^6 cells. |
|
| E.4 | Principal exclusion criteria |
1) Current or recent history (12 preceding months before V1) of major organ or system failure or condition, acute or chronic that in the opinion of the Investigator should preclude enrolment, except Crohn’s Disease;
2) Current or previous history of malignancy except a local basal cell carcinoma without metastases;
3) First degree family or personal history of clinically significant venous, arterial or pulmonary thromboembolism events;
4) History of thrombocytosis over 600.10^9 / L in the previous 12 months prior to V1;
5) History of major immune deficiency disorder, except Crohn’s Disease;
6) Concomitant clinically active infection at V1 or V2 or V3 or V4 or V7 or V9 CATS29-OL or V11 CATS29-OL;
7) History of intestinal resection or intra-abdominal surgery within 6 months prior to V1;
8) Have complication of Crohn’s Disease such as strictures, stenosis, short gut syndrome, or any other manifestation that might require surgery, could preclude the use of CDAI to assess response to therapy, or would possibly confound the evaluation of benefit from treatment with Ovasave;
9) Patients with intestinal functional fibrotic structuring responsible for the patient’s symptoms or previous major Gastro Intestinal (GI) resection;
10) Patients with short bowel syndrome or with less than 1.5 m of small bowel;
11) Presence of actively draining fistula at V3 or V4;
12) Concomitant abdominal or anal undrained abscess at V3 or V4;
13) History of documented hypersensitivity or intolerance to chicken eggs;
14) Parenteral nutrition if not compatible with the meringue intake;
15) History of known hypersensitivity or intolerance to any component of the IMP (Refer to Appendix 17.7 of the Protocol for the composition of the Drug Product);
16) Patients with ileostomia or colostomy;
17) History of tuberculosis (TB) except if documentation of adequate compliance to treatment is provided,
18) Gamma immunoglobulinaemia < 6 g/L at Screening visit (V1) or Pre-entry visit (V3) or any signs or history of major immune deficiency disorder;
19) Recent history of contamination by the Epstein-Barr virus (EBV), Cytomegalovirus (CMV) and/or toxoplasma within 6 months prior to V1;
20) History of human immunodeficiency virus (HIV);
21) Females of childbearing potential who are either pregnant, breast-feeding or without the use of birth control. Female patients of child-bearing potential must have a negative pregnancy test at screening and must agree to use an acceptable method of birth control with a low failure rate (i.e. less than 1% per year) in a consistent and correct manner for the whole duration of the study treatment period and during the 3 months following the end of the study treatment period (V13/week 32). Abstinence, oral birth control pills administered for at least 2 monthly cycles prior to study drug administration, a contraceptive vaginal ring (e.g. NuvaRing or equivalent) or a contraceptive transdermal patch (e.g. EVRA or equivalent) administered for at least 2 monthly cycles prior to study drug administration, an IUD, or medroxyprogesterone acetate administered intramuscularly or a subcutaneous implant of etonogestrel (Implanon or equivalent) for a minimum of one month prior to study drug administration are acceptable methods of birth control for inclusion into the study. Female subjects are considered of childbearing potential unless they are postmenopausal (absence of menstrual bleeding for 1 year - or 6 months if laboratory confirmation of hormonal status), or have had a hysterectomy, bilateral tubular ligation or bilateral ovariectomy.
22) A history of poor clinic attendance or, in the opinion of the Investigator, is considered unlikely to comply with the required visit schedule and other protocol requirements.
23) Use of any experimental medicinal product within the 3 months prior to Screening, or during the study, except Ovasave and any experimental medicinal product up to the end of the 3-year long-term safety followup. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary clinical efficacy endpoint is the percentage of patients with a CDAI response (CDAI decrease from baseline ≥ 100 points) in the active group of 10^6 Ova-Treg cells, 6 weeks after 1 Ovasave administration (Week 6= V6) compared to placebo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 6 Weeks after 1 Ovasave administration |
|
| E.5.2 | Secondary end point(s) |
- CDAI:
• Percentage of patients with a CDAI remission and response (CDAI decrease from baseline ≥ 100 points) 6 weeks after the second administration (week 14) for the 4 groups,
• Percentage of patients with a CDAI response at each other post-baseline visit for the 4 groups,
• Percentage of patients achieving a CDAI remission (CDAI < 150 points) at each post-baseline visit,
• Raw value in CDAI total score at each post-baseline visit for the 4 groups
• Raw value in each CDAI sub-score at each post-baseline visit for the 4 groups
• Change from baseline in CDAI total score at each post-baseline visit for the 4 groups
- Steroids sparing effect
• Steroid decrease from week 8 will be recorded at week 14 (including the daily dose taken at each week between visit 7 and visit 8)
• Percentage of patient by decrease steroids dose (decrease in total of 20, 15, 10, 5 or 0 mg/day) at week 14.
- Inflammatory markers:
• Raw value in hs-CRP at each post-baseline visit;
• Change from baseline in hs-CRP at each post-baseline visit;
• Raw value in Calprotectin at each post-baseline visit;
• Change from baseline in Calprotectin at each post-baseline visit
- Investigator’s opinion on the investigational product
• Qualify the investigational product
• Would you like to test the investigational product again? |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- CDAI:
• At week 14
• At each post-baseline visit
• At each post-baseline visit
• At each post-baseline visit
• At each post-baseline visit
• At each post-baseline visit
• Steroids sparing effect:
• At week 14
• At week 14
- Inflammatory markers:
• At each post-baseline visit
• At each post-baseline visit
• At each post-baseline visit
• At each post-baseline visit
- Investigator’s opinion on the investigational product:
• At weeks 16 and 32
• At weeks 16 and 32 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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