| 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 |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10011402 |
| E.1.2 | Term | Crohn's disease (colon) |
| E.1.2 | System Organ Class | 100000004856 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10011403 |
| E.1.2 | Term | Crohn's disease aggravated |
| E.1.2 | System Organ Class | 100000004856 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10058815 |
| E.1.2 | Term | Crohn's disease acute episode |
| E.1.2 | System Organ Class | 100000004856 |
|
| 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 |
| The primary objective is to evaluate the efficacy of PRV-6527 for 12 weeks in the treatment of moderately to severely active CD, as measured by the Crohn’s Disease Activity Index (CDAI). |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to evaluate the effect of PRV-6527 for 12 weeks on:
Clinical
• Colonic and ileal mucosa, based upon the Simple Endoscopic Score for CD (SES-CD)
• Clinical symptoms, based upon the frequency of diarrheal stools and abdominal pain
• Clinical symptoms, based upon the PRO-2 portion of CDAI
Safety
• Safety and tolerability of PRV-6527 in subjects with active CD
Pharmacokinetics (PK)
• Trough plasma concentrations of PRV-6527 and its active metabolites, M2 and M7 and their sum, in subjects with active CD
Pharmacodynamics (PD)
• PD effects measured by fecal calprotectin (FC) and ultrasensitive C-reactive protein (CRP) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Each subject must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. All subjects must be capable of signing their own ICF and complete the eDiary.
2. Subject must be a man or woman between 18 years and 75 (inclusive) years of age.
3. Has moderate to severe CD with a CDAI score between 220 and 450 (inclusive) and a histologic diagnosis of CD for at least 3 months before screening. The histological diagnosis should be confirmed locally from the screening colonoscopy if not previously documented at the site.
4. Has screening laboratory test results within the following parameters:
a. Hemoglobin ≥8 g/dL
b. WBC ≥2000 cells/μL
c. Neutrophils ≥1500 cells/μL
d. Creatinine ≤1.7 mg/dL
e. Serum AST or ALT ≤2 x upper limit of normal (ULN)
f. Total bilirubin ≤2 x ULN
g. CPK ≤3 x ULN
h. LDH ≤3 x ULN
5.SES-CD score ≥6 or ≥4 for ileal-only disease
6. Subject may be either biologic naïve or biologic experienced. Subjects who have had prior experience with anti-TNF, anti-integrin, or anti-MAdCAM-1 treatment would be eligible if they were primary nonresponders, secondary nonresponders, intolerant or allergic to anti-TNF agents (e.g. infliximab), or stopped such treatment for other reasons Subjects who have had prior experience with anti-IL-12/23 (e.g. ustekinumab)or anti-IL-23 agents would be eligible if they were responders, secondary nonresponders, or stopped the treatment due to intolerance or reasons unrelated to efficacy. Primary nonresponders to anti-IL-12/23 or anti-23 are excluded (see exclusion #6).
7. Female subjects must meet the following inclusion criteria:
a. Women not of childbearing potential:
Postmenopausal is defined as being >45 years of age with amenorrhea for at least 18 months) or >45 years of age with amenorrhea for at least 12 months and a confirmatory serum follicle stimulating hormone (FSH) level >40 IU/L with luteinizing hormone (LH) level >40 IU/L in woman not receiving hormone replacement therapy; permanently sterilized (eg, hysterectomy, bilateral salpingectomy, bilateral oophorectomy); or otherwise be incapable of pregnancy. Note: tubal ligation is not considered permanent sterilization.
b. Women of childbearing potential:
1) Must have a negative serum β-human chorionic gonadotropin (β-hCG) at screening and a negative urine pregnancy test at Week 0 prior to dosing
2) Must practice a highly effective method of birth control ( <1% failure rate) consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies such as established use (>3 months) of oral, injected or implanted highly effective hormonal methods of contraception; placement of an intrauterine device or intrauterine system; male partner sterilization (the vasectomized partner should be the sole partner for that subject); true abstinence (when this is in line with the preferred and usual lifestyle of the subject).
3).Must agree to use highly effective methods of birth control throughout the study for 3 months after receiving the last dose of study drug (placebo or PRV-6527).
4) Must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 3 months after receiving the last dose of study drug.
8. Male subjects must meet the following criterion: A man who is sexually active with a woman of childbearing potential and has not had a vasectomy or otherwise surgically sterile must agree to highly effective birth control for their female partner as outlined above and must use condoms with spermicide during sexual intercourse, and this must continue for 3 months after receiving the last dose of study drug. All men must also not donate sperm during the study and for 3 months after receiving the last dose of study drug.
9. Subject must be able to read, understand and complete study questionnaires.
10. Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol. |
|
| E.4 | Principal exclusion criteria |
1.Ileostomy, colostomy, or short gut syndrome or is anticipated to require surgery in the next 6 months, or has tight stricture that prevents the passage of any colonoscope.
2.Untreated active external or perianal fistula or abscess.
3.Other gastrointestinal inflammatory diseases.
4.Any malignancy or lymphoproliferative disorder other than nonmelanoma cutaneous malignancies or cervical carcinoma
5.Colon cancer or severe dysplasia. Subjects with CD for ≥8 years involving the colon are not excluded if they had a colonoscopy to assess for the presence of dysplasia w/in 1 year before baseline or if they had a colonoscopy at the scr. (Any polyps revealed during the scr. endoscopy should be appr evaluated and removed. Larger polyps >1 cm should be
fully resected and histologically evaluated)
6.Is a primary nonresponder to anti-IL-12/23 or anti-IL-23 biologic tx
7.Prev treatment w/natalizumab
8.Treatment w/tofacitinib, cyclosporine, or other immunosuppressives incl biologics w/in 5 half-lives before randomization. A serum concentration level below the limit of quantitation is acceptable
9.Has been on a variety of doses of thiopurines or MTX w/in 8 wks of scr
10.Treatment w/unstable doses of mesalamine (5-ASA) or chronic antibiotics within 30 days before scr
11.Treatment w/oral prednisone or prednisolone >20 mg or budesonide >6 mg per day, or other corticosteroids of equivalent doses, w/in 2 wks of scr. Doses of steroids must remain stable from at least 2wks prior to
scr to wk12. Tx w/rectal steroids or systemic corticosteroids (IV os IM) is prohibited throughout the study except for the tx of AE
12.Treatment w/proton pump inhibitors (PPIs) or cimetidine within 7 days before baseline. Subjs may take non-cimetidine H2 receptor agonists incl. high doses for RGRD. Antacids may be used except w/in 2 hrs of dosing
13.Subj is receiving and/or is anticipated to require strong inhibitors or inducers of CYP3A4, CYP2C8, and CYP2C19 isoenzymes
14. Subj is receiving and/or is anticipated to require substrates of pglycoprotein during the study
15.Ongoing, chronic or recurrent infectious disease, including but not limited to endemic fungal infections, chronic renal infection, chronic chest infection, recurrent urinary tract infection, or a history of serious infection
16.Acute infection or infected skin wounds or ulcers, w/the exception of nonserious infections in the opinion of the PI
17.Non-TB mycobacterial infection or serious opportunistic infection
18.Female subj is pregnant, lactating, planning to become pregnant, or sexually active of childbearing potential and refuses to use highly effective birth control. Male subj is planning on fathering a child during and w/in 3 mos after study tx
19.Has received an investigational drug or used an invasive investigational medical device within 12 wks before the planned 1st administration of IP
20.Has antibody to p24 antigen for HIV 1 or 2 confirmed by Western blot, hepatitis C virus at scr, [anti-HCV+ w/HCV RNA+]; hepatitis B Virus (HBV) [HBsAg+ or Total anti-HBc+ w/HBV DNA+]
21.Has a stool culture or microscopic exam pos for enteric pathogens, ova, and parasites. Positive Clostridium difficile toxin OR Glutamate dehydrogenase (C DIFF QUIK CHEK) w/confirmatory positive PCR at scr
22.Subj meets any of the following TB scr criteria:
a.History of untreated latent or untreated active TB prior to scr.
b.Signs or symptoms suggestive of active TB upon medical history and/or physical examination.
c.Has had recent close contact w/ person w/active TB and has not been evaluated by a specialist in TB.
d.Has a positive QuantiFERON®-TB Gold Plus test result during scr. Subjs who have a newly identified positive QuantiFERON®-TB Gold Plus test result but have been ruled out for active TB and have completed appropriate tx for latent TB may be enrolled
e.Chest radiograph (posterior-anterior and lateral views), taken within 3 mos before baseline and read by a qualified radiologist, w/evidence of current active TB or old inactive TB that has not been fully treated
23.Severe, progressive, or uncontrolled renal, hepatic impairment including Hy's Law (ALT and/or AST ≥3 x ULN AND total bilirubin ≥2 x ULN) and primary sclerosing cholangitis, hematological, endocrine, pulmonary, cardiac, neurologic, cerebral, or psychiatric disease, or signs and symptoms thereof
24.Has a transplanted organ; a corneal transplant >12 weeks before screening is allowed
25.Is unable or unwilling to undergo multiple venipunctures because of poor tolerability or lack of easy access to veins
26.Participation in any other study using an investigational agent/procedure
27.Has any condition for which, in the opinion of the Investigator, participation wouldn't be in the best interest of the subj
28.Employees of the PI or site, w/direct involvement in the proposed study
29 Substance abuse or refusal to refrain from the use of marijuana and illicit drugs. Occasional alcohol use is permitted |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Clinical
• Change from baseline to Week 12 in SES-CD score
• Change from baseline to Week 12 in abdominal pain based on a Numerical Rating Scale (NRS) (0-10 scale)
• Change from baseline to Week 12 in the number of daily loose or watery stools (type 6 or 7 stools) per week, as defined by the Bristol Stool Form Scale (BSFS)
• Change from baseline to Week 12 in PRO-2 score
Safety
• Treatment Emergent Adverse Events (TEAEs), adverse events (AEs) leading to withdrawal and Serious Adverse Events (SAEs)
• Clinically significant changes in vital signs, electrocardiogram (ECG), and laboratory tests
PK
• Cmin of PRV-6527 and its active metabolites, M2 and M7 and their sum PD
• Change from baseline to Week 12 in ultrasensitive CRP
• Change from baseline to Week 12 in FC |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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 | 2 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Germany |
| Hungary |
| Poland |
| Russian Federation |
| Spain |
| Ukraine |
|
| 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
|
| A subject will be considered to have completed the study if he or she has completed assessments at Week 16. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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