| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Long-term condition that results in inflammation of the gastrointestinal tract |
|
| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The coprimary objectives of the study are to evaluate the efficacy of SHP647 as maintenance
treatment in subjects with moderate to severe Crohn's Disease (CD) based on:
-Clinical remission based on 2-item patient-reported outcome (PRO) (abdominal pain
severity and very soft stool/liquid stool frequency)
-Enhanced endoscopic response based on centrally read colonoscopy. |
|
| E.2.2 | Secondary objectives of the trial |
The key secondary objectives of the study are:
To evaluate the efficacy of SHP647 as maintenance treatment:
-on clinical remission as measured by Crohn's Disease Activity Index (CDAI)
-on glucocorticoid-free clinical remission based on patient-reported clinical signs and symptoms (as measured by 2-item PRO)
-on clinical remission based on abdominal pain severity and very soft stool/liquid stool frequency (alternate thresholds)
-based on achieving clinical remission as well as achieving enhanced endoscopic response in the same subject
-on complete endoscopic healing.
To evaluate the efficacy of SHP647 on maintenance:
-of clinical remission among subjects in clinical remission at baseline of the SHP647-307 study based on patient-reported clinical signs and symptoms (as measured by 2-item PRO)
-of enhanced endoscopic response among subjects with enhanced endoscopic response at baseline of the SHP647-307 study based on centrally read colonoscopy
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects and/or their parent or legally authorized representative must have an understanding, ability, and willingness to fully comply with study procedures and restrictions.
2. Subjects must be able to voluntarily provide written, signed, and dated (personally or via a legally authorized representative) informed consent and/or assent, as applicable, to participate in the study.
3. Subjects must have completed the 16-week induction treatment period from study
SHP647-305 or SHP647-306 and met the following criteria at baseline in maintenance Study SHP647-307:
a) Meet endoscopic response criteria of a reduction in SES-CD from induction study
(SHP647-305 or SHP647-306) baseline by ≥25% at Week 16 of induction study (SHP647-305 or SHP647-306)
OR
b) Meet at least 1 of the following 4 criteria at baseline in maintenance study SHP647-307, in addition to no worsening of endoscopic score as measured by SES-CD relative to induction study (SHP647-305 or SHP647-306) baseline:
i. Achieving clinical remission as determined by meeting the criteria for clinical
remission using the 2-item PRO, ie, 2-item PRO subscores of average worst daily
abdominal pain ≤3 (based on 11-point numerical rating scale [NRS]) over the 7 most
recent days* and average daily stool type frequency ≤2 of type 6/7 (very soft
stools/liquid stools) as shown in the BSFS over the 7 most recent days*
ii. A decrease of at least 100 points in CDAI score (CDAI-100) from induction study
(SHP647-305 or SHP647-306) baseline.
iii. A decrease of ≥30% and at least 2 points from induction study (SHP647-305 or
SHP647-306) baseline in the average daily worst abdominal pain over the 7 most
recent days*, with the average daily stool frequency of type 6/7 (very soft
stools/liquid stools) either: (i) not worsening from induction study (SHP647-305 or
SHP647-306) baseline and/or (ii) meeting the criteria for clinical remission,
ie, 2-item PRO subscore of average daily stool frequency ≤2 of type 6/7 (very soft
stools/liquid stools) as shown in the BSFS over the 7 most recent days*
iv. A decrease of ≥30% from induction study (SHP647-305 or SHP647-306) baseline in
the average daily stool frequency of type 6/7 (very soft stools/liquid stools) as shown
in the BSFS over the 7 most recent days*, with the average daily worst abdominal
pain either: (i) not worsening from induction study (SHP647-305 or SHP647-306)
baseline and/or (ii) meeting the criteria for clinical remission, ie, 2-item PRO
subscore of average worst daily abdominal pain ≤3 (based on 11-point NRS) over the
7 most recent days*
*Note: The 7 days may or may not be contiguous during the 10 days of data
collection before colonoscopy preparation, depending on days to be excluded because
of missing data. If fewer than 7 days are available, the criterion will be calculated on
all available most recent 6 or 5 days. If fewer than 5 days are available, the criterion
will be treated as missing.
4. Subjects receiving any treatment(s) for CD are eligible provided they have been, and are anticipated to be, on a stable dose for the designated period of time. |
|
| E.4 | Principal exclusion criteria |
1. Subjects who had major protocol deviation(s) (as determined by the sponsor) in induction study SHP647-305 or SHP647-306.
2. Subjects who permanently discontinued investigational product because of an AE, regardless of relatedness to investigational product, in induction study SHP647-305 or SHP647-306.
3. Subjects who are likely to require surgery for CD during the study period, except minor interventions (eg, seton placement for anal fistulas).
4. Subjects are females who became pregnant during induction study SHP647-305 or SHP647-306, females who are planning to become pregnant during the study period, or males or females of childbearing potential not agreeing to continue using appropriate contraception methods through the conclusion of study participation.
5. Subjects who do not agree to postpone donation of any organ or
tissue, including male subjects who are planning to bank or donate sperm, or female subjects who are planning to harvest or donate eggs, for the duration of the study and through 16 weeks after last dose of investigational product.
6. Subjects who, in the opinion of the investigator or the sponsor, will be uncooperative or unable to comply with study procedures.
7. Subjects who have developed obstructive colonic stricture, or enterovesical or enterovaginal fistulae during the induction study (SHP647-305 or SHP647-306).
8. Subjects who have a newly diagnosed malignancy or recurrence of malignancy (other than resected cutaneous basal cell carcinoma, squamous cell carcinoma, or carcinoma in situ of the uterine cervix that has been treated with no evidence of recurrence).
9. Subjects who have developed any major illness/condition or evidence of an unstable clinical condition (eg, renal, hepatic, hematologic, gastrointestinal [except disease under study], endocrine, cardiovascular, pulmonary, immunologic [eg, Felty’s syndrome], or local active infection/infectious illness) that, in the investigator’s judgment, will substantially increase the risk to the subject if he or she participates in the study. 10. Subjects with any other severe acute or chronic medical or psychiatric condition or laboratory or electrocardiogram (ECG) abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
11. Subjects with known exposure to Mycobacterium tuberculosis since testing at screening in induction study SHP647-305 or SHP647-306 and who have been advised to require treatment for latent or active disease but who are without a generally accepted course of treatment.
12. Subjects with any of the following abnormalities in hematology and/or serum chemistry profiles during the evaluation of the last visit in the SHP647-305 or SHP647-306 studies. If the results are considered by the investigator to be transient and inconsistent with the subject’s clinical condition, may be repeated once prior to enrolment in Study SHP647-307.
-Alanine aminotransferase and aspartate aminotransferase levels ≥ 3 x the upper limit of normal (ULN)
-Total bilirubin level ≥1.5 times the ULN or >2 x ULN if the subject has a
known documented history of Gilbert's syndrome
-Hemoglobin level ≤80 g/L (8.0 g/dL)
- Platelet count ≤100 × 109/L (100,000 cells/mm3) or ≥1000 × 109/L (1,000,000 cells/mm3)*
- White blood cell count ≤3.5 × 109/L (3500 cells/mm3)
- Absolute neutrophil count<2 × 109/L (<2000 cells/mm3)
- Serum creatinine level >1.5 x ULN or estimated glomerular filtration rate <30 mL/min/1.73 m2 based on the abbreviated Modification of Diet in Renal Disease Study Equation.
*Note: If platelet count is <150,000 cells/mm3, a further evaluation
should be performed to rule out cirrhosis unless another etiology has
already been identified.
13. Subjects who are investigational site staff members or relatives of those site staff members or subjects who are sponsor employees directly involved in the conduct of the study.
14. Subjects who are participating in other investigational studies (other than induction study SHP647-305 or SHP647-306) or plan to participate in other investigational studies during Study SHP647-307
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Coprimary efficacy endpoints are:
-Clinical remission as defined by the following: 2- item PRO subscores of average worst daily abdominal pain ≤3 (based on 11-point NRS) over the 7 most recent days and average daily stool frequency ≤2 of type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most recent days. The 7 most recent days may or may not be contiguous during the 10 days of data collection before colonoscopy preparation, depending on days to be excluded because of missing data.
If fewer than 7 days are available, the endpoint will be calculated on all
available most recent 6 or 5 days. If fewer than 5 days are available, the endpoint will be treated as missing.
-Enhanced endoscopic response as measured by a decrease in SES-CD of at least 50% from induction study (SHP647-305 or SHP647-306) baseline.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The key secondary efficacy endpoints are as follows:
Clinical remission at the Week 52 visit as measured by CDAI <150
Glucocorticoid-free clinical remission at the Week 52 visit, among subjects using glucocorticoids at
induction study baseline. Glucocorticoid-free clinical remission is defined as clinical remission by
2-item PRO (as defined for the coprimary endpoint) in addition to not requiring any treatment with
glucocorticoids for at least 12 weeks prior to the Week 52 visit.
Clinical remission at the Week 52 visit as defined by the following: CD daily e-diary subscores of
average daily abdominal pain ≤1 (based on the 4-point scale) over the 7 most recent days and
average daily stool frequency ≤3 of type 6/7 (very soft stools/liquid stools) as shown in the BSFS over
the 7 most recent days. The 7 most recent days may or may not be contiguous during the 10 days of
data collection before colonoscopy preparation, depending on days to be excluded because of missing
data. If fewer than 7 days are available, the endpoint will be calculated on all available most recent 6 or
5 days. If fewer than 5 days are available, the endpoint will be treated as missing.
Sustained clinical remission, ie, in clinical remission at the SHP647-307 Week 52 visit, among subjects
who were in clinical remission by 2-item PRO (as defined for the coprimary endpoint) at the time of
baseline in Study SHP647-307
Sustained enhanced endoscopic response, ie, in enhanced endoscopic response at the SHP647-307
Week 52 visit, among subjects who showed enhanced endoscopic response (as defined for the
coprimary endpoint) at the time of baseline in Study SHP647-307
Both clinical remission by 2-item PRO and enhanced endoscopic response at Week 52 (composite
endpoint)
Complete endoscopic healing at Week 52 defined as SES-CD=0-2. |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 172 |
| 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 |
| Argentina |
| Australia |
| Austria |
| Belgium |
| Bosnia and Herzegovina |
| Brazil |
| Bulgaria |
| Canada |
| Colombia |
| Croatia |
| Czech Republic |
| Estonia |
| Germany |
| Greece |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Lithuania |
| Mexico |
| Netherlands |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Serbia |
| Slovakia |
| South Africa |
| Spain |
| Switzerland |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The Study Completion Date is defined as the date the final subject, across all sites, completes their final protocol-defined assessment.This includes the follow-up visit or contact, whichever is later. |
|
| 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 | 6 |
| 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 | 6 |
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