A Safety Extension Study of SHP647 in Participants With Moderate to Severe Ulcerative Colitis or Crohn's Disease (AIDA)

• Sponsor: Shire
• Information provided by (Responsible Party): Shire

Study Description

Brief Summary:

The purpose of this study is to evaluate the safety and tolerability of long-term treatment with SHP647 in participants with moderate to severe Ulcerative Colitis (UC) or Crohn's disease (CD).

Condition or disease	Intervention/treatment	Phase
Crohn's Disease; Ulcerative Colitis	Drug: 25 mg SHP647; Drug: 75 mg SHP647	Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	2453 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Treatment
Official Title:	A Phase 3 Long-term Safety Extension Study of SHP647 in Subjects With Moderate to Severe Ulcerative Colitis or Crohn's Disease (AIDA)
Actual Study Start Date :	February 27, 2018
Estimated Primary Completion Date :	February 11, 2025
Estimated Study Completion Date :	June 3, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: 25 mg SHP647; Participants will be receiving 25 milligram (mg) of SHP647 subcutaneously every 4 weeks until the drug is commercially available, the participant withdraws from the study, or the investigator or sponsor decide to withdraw the participant, or the sponsor decides to close the study. Allocation will be decided based on how the participant entered into this study.	Drug: 25 mg SHP647; SHP647 sterile aqueous buffered solution will be administered in dose of 25 mg subcutaneously.
Experimental: 75 mg SHP647; Participants will be receiving 75 mg of SHP647 subcutaneously every 4 weeks until the drug is commercially available, the participant withdraws from the study, or the investigator or sponsor decide to withdraw the participant, or the sponsor decides to close the study. Allocation will be decided based on how the participant entered into this study.	Drug: 75 mg SHP647; SHP647 sterile aqueous buffered solution will be administered in dose of 75 mg subcutaneously.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Baseline up to 16 weeks post end of treatment (EOT) [up to 7 years] ]
   An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent AEs (TEAEs) are defined as AEs with start dates or worsening dates at the time of or following the first exposure to investigational product. The TEAEs will be further categorized based on severity as mild (may require only minimal treatment) to severe (may require intensive therapeutic intervention).
2. Number of Participants With Serious Infections [ Time Frame: Baseline up to 16 weeks post EOT (up to 7 years) ]
   Number of participants with serious infections will be assessed.
3. Number of Participants With Clinically Significant Change in Clinical Laboratory Tests Reported as an Adverse Event [ Time Frame: Baseline up to 16 weeks post EOT (up to 7 years) ]
   Clinical laboratory assessments include hematology, serum chemistry and urinalysis. Any clinically significant change in the clinical laboratory value from baseline will be recorded as an AE.
4. Number of Participants With Clinically Significant Change in Electrocardiogram (ECG) Reported as an Adverse Event [ Time Frame: Baseline up to EOT (up to 7 years) ]
   12-lead ECG will be recorded. Any clinically significant change in ECG will be recorded as an AE.
5. Number of Participants With Clinically Significant Change in Vital Signs Reported as an Adverse Event [ Time Frame: Baseline up to 16 weeks post EOT (up to 7 years) ]
   Vital sign assessments include blood pressure, pulse, respiratory rate and temperature. Any clinically significant change in vital signs from baseline will be recorded as an AE.
6. Number of Participants who Developed Antidrug Antibodies to SHP647 [ Time Frame: Baseline up to EOT (up to 7 years) ]
   Number of participants with presence of antidrug antibodies to SHP647 will be assessed.

Secondary Outcome Measures :

1. Number of Participants With Ulcerative Colitis With Remission Based on Composite Score [ Time Frame: Yearly once till EOT (up to 7 years) ]
   Remission is defined as a composite score of patient-reported symptoms using daily diary and locally read endoscopy as follows: stool frequency subscore of 0 or 1 with at least a 1-point change from induction study baseline and rectal bleeding subscore of 0 and locally-read endoscopic subscore of 0 or 1 (modified, excludes friability). The stool frequency subscore, rectal bleeding subscore and endoscopic subscore of mayo score ranges from 0 to 3 with higher scores indicating more severe disease. The Mayo score is a measure of UC disease activity. It ranges from 0 to 12 points and consists of 4 subscores, each graded from 0 to 3 with higher scores indicating more severe disease. The subscores are Stool frequency (0-3); Rectal bleeding (0-3); Findings of endoscopy (0-3); Physician global assessment (PGA, 0-3). The composite score is a recommended measure consisting of the Mayo score without the PGA subscore and ranges from 0 to 9 points.
2. Number of Participants With Ulcerative Colitis With Remission Based on Total Mayo Score [ Time Frame: Yearly once till EOT (up to 7 years) ]
   Remission is defined as a total mayo score less than or equal to (<=) 2 with no individual subscore (stool frequency, rectal bleeding, endoscopy [modified, excludes friability], and physician's global assessment) exceeding 1. The total mayo score ranges from 0 to 12 points and consists of the following 4 subscores, each graded from 0 to 3 with higher scores indicating more severe disease: bowel movement frequency (0-3); rectal bleeding (0-3); findings of flexible sigmoidoscopy or endoscopy (0-3); physician global assessment (PGA; 0-3).
3. Number of Participants With Ulcerative Colitis With Clinical Remission [ Time Frame: Yearly once till EOT (up to 7 years) ]
   Clinical remission as defined by stool frequency subscore of 0 or 1 with at least a 1-point change from induction study baseline in stool frequency subscore, and rectal bleeding subscore of 0. The stool frequency subscore and rectal bleeding subscore of mayo score ranges from 0 to 3 with higher scores indicating more severe disease. The Mayo score is a measure of UC disease activity. It ranges from 0 to 12 points and consists of 4 subscores, each graded from 0 to 3 with higher scores indicating more severe disease. The subscores are Stool frequency (0-3); Rectal bleeding (0-3); Findings of endoscopy (0-3); Physician global assessment (PGA, 0-3).
4. Number of Participants With Ulcerative Colitis With Partial Mayo Score Over Time [ Time Frame: Baseline up to EOT(up to 7 years) ]
   The partial mayo score ranges from 0 to 9 points and consists of the following 3 subscores, each graded from 0 to 3 with higher scores indicating more severe disease: bowel movement frequency (0-3); rectal bleeding (0-3); physician global assessment (PGA; 0-3). The Mayo score is a measure of UC disease activity. It ranges from 0 to 12 points and consists of 4 subscores, each graded from 0 to 3 with higher scores indicating more severe disease. The subscores are Stool frequency (0-3); Rectal bleeding (0-3); Findings of endoscopy (0-3); Physician global assessment (PGA, 0-3).
5. Number of Participants With Ulcerative Colitis With Endoscopic Remission [ Time Frame: Yearly once till EOT (up to 7 years) ]
   Endoscopic remission, as defined by locally read endoscopic subscore 0 or 1 (modified, excludes friability). The endoscopic subscore of mayo score ranges from 0 to 3 with higher scores indicating more severe disease. The Mayo score is a measure of UC disease activity. It ranges from 0 to 12 points and consists of 4 subscores, each graded from 0 to 3 with higher scores indicating more severe disease. The subscores are Stool frequency (0-3); Rectal bleeding (0-3); Findings of endoscopy (0-3); Physician global assessment (PGA, 0-3).
6. Number of Participants With Crohn's Disease With Clinical Remission Over Time as Measured by 2-Item Patient Reported Outcome [ Time Frame: Baseline up to EOT(up to 7 years) ]
   Clinical remission is defined by 2-item PRO CD daily e-diary subscore of average worst daily abdominal pain <=3 (based on 11-point numeric rating scale [0=no pain to 10= worst imaginable pain]) and average daily stool frequency of <=2 of type 6/7 (very soft stools/liquid stools) over the 7 most recent days. Stool consistency will be assessed by typical stool form based on Bristol Stool Form Scale: 1 - Separate hard lumps, hard to pass, 2 - Sausage-shaped, but lumpy, 3 - Like a sausage but with cracks on the surface, 4 - Like a sausage or snake, smooth and soft, 5 - Soft blobs with clear-cut edges, 6 - Fluffy pieces with ragged edges, a mushy stool, 7 - Watery, no solid pieces, entirely liquid.
7. Number of Participants With Crohn's Disease With Enhanced Endoscopic Response [ Time Frame: Yearly once till EOT (up to 7 years) ]
   Enhanced endoscopic response is measured as a decrease in simple endoscopic activity score for crohn's disease (SES-CD) of at least 50 percent (%) from induction study baseline. The SES-CD is a simple scoring system based on 4 endoscopic variables measured in the same 5 ileocolonic segments as the Crohn's disease index of severity. Overall, values on the SES-CD range from 0-56, with higher values indicating more severe disease. The 4 endoscopic variables are scored from 0-3 in each bowel segment (ileum, right/transverse/left colon, and rectum): Presence and size of ulcers (none = score 0; diameter 0.1-0.5 centimetre (cm) = score 1; 0.5-2 cm = score 2; diameter more than (>)2 cm = score 3); extent of ulcerated surface (none = 0; less than (<)10 % =1; 10%-30% = 2; >30% = 3); extent of affected surface (none = 0; <50% = 1; 50%-75% = 2; >75% = 3); Presence and type of narrowings (none = 0; single, can be passed = 1; multiple, can be passed = 2; cannot be passed = 3).
8. Number of Participants With Crohn's Disease With Clinical Remission Over Time as Measured by Crohn's Disease Activity Index (CDAI) Less Than (<)150 [ Time Frame: Baseline up to EOT (up to 7 years) ]
   The CDAI is a composite measure with 8 components; 3 components (abdominal pain severity, very soft stool/liquid stool frequency, and general wellbeing) will be self-reported by the participant and will be recorded as part of the daily e-diary and 5 components (weight, medical and physical examination, use of diarrhea treatment, and hematocrit value) will be collected at clinical visit. The CADI score scale ranges from 0 to > 451. 0-149 points: Asymptomatic remission; 150-220 points: Mild to moderate active Crohn's Disease (CD); 221-450 points: Moderate to severe active CD; >451 points: Severely active to fulminant disease.
9. Number of Participants With Crohn's Disease With Clinical Remission Over Time [ Time Frame: Baseline up to EOT(up to 7 years) ]
   Clinical remission over time is defined as CD daily e-diary subscores of average worst daily abdominal pain <=1 (based on the 4-point scale) and average daily stool frequency <=3 of type 6/7 (very soft stools/liquid stools) as per BSFS over the 7 most recent days.
10. Number of Participants With Crohn's Disease With Clinical Remission and Enhanced Endoscopic Response Over Time [ Time Frame: Baseline up to EOT (up to 7 years) ]
    Clinical remission over time is defined as CD daily e-diary subscores of average worst daily abdominal pain <=1 (based on the 4-point scale) and average daily stool frequency <=3 of type 6/7 (very soft stools/liquid stools) as per BSFS over the 7 most recent days. Enhanced endoscopic response is measured as a decrease in simple endoscopic activity score for crohn's disease (SES-CD- ranging from 0 to 56, with higher values indicating more severe disease) of at least 50% from induction study baseline.
11. Number of Participants With Crohn's Disease With Complete Endoscopic Healing [ Time Frame: EOT (Approximately 7 years) ]
    Complete endoscopic healing is defined as SES-CD = 0-2. The SES-CD is a simple scoring system based on 4 endoscopic variables measured in the same 5 ileocolonic segments as the Crohn's disease index of severity. Overall, values on the SES-CD range from 0-56, with higher values indicating more severe disease. The 4 endoscopic variables are scored from 0-3 in each bowel segment (ileum, right/transverse/left colon, and rectum): Presence and size of ulcers (none = score 0; diameter 0.1-0.5 centimetre (cm) = score 1; 0.5-2 cm = score 2; diameter more than (>)2 cm = score 3); extent of ulcerated surface (none = 0; less than (<)10 % =1; 10%-30% = 2; >30% = 3); extent of affected surface (none = 0; <50% = 1; 50%-75% = 2; >75% = 3); Presence and type of narrowings (none = 0; single, can be passed = 1; multiple, can be passed = 2; cannot be passed = 3).

Eligibility Criteria

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Ages Eligible for Study:	16 Years to 80 Years (Child, Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Participants and/or their parent or legally authorized representative must have an understanding, ability, and willingness to fully comply with study procedures and restrictions.
• Participants 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.

Participants with Ulcerative Colitis:

• Participants must have been previously enrolled in study SHP647-301 (NCT03259334), SHP647-302 (NCT03259308), or SHP647-303 (NCT03290781), and reached 1 of the following clinical trial milestones:

  1. Completed the Week 12 visit in induction study SHP647-301 (NCT03259334) or SHP647-302 (NCT03259308), and did not achieve a clinical response. Clinical response is defined as: 1. a decrease from baseline in the composite score of patient-reported symptoms using daily e-diary and centrally read endoscopy of at least 2 points and at least 30 percent (%), with an accompanying decrease in the subscore for rectal bleeding greater than or equal to (>=) 1 point or a subscore for rectal bleeding less than or equal to (<=) 1, or 2. a decrease from the induction study (SHP647-301 [NCT03259334] or SHP647-302 [NCT03259308]) baseline total Mayo score of at least 3 points and at least 30%, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1.
  2. Completed the Week 52 visit in maintenance study SHP647-303 (NCT03290781).
  3. Withdrew early from maintenance study SHP647-303 (NCT03290781) due to treatment failure, defined by an endoscopic subscore that has increased by at least 1 point over baseline in the maintenance study or a value >= 2 plus an increase in clinical subscore (stool frequency + rectal bleeding score) of at least 2 points. Centrally read endoscopic subscores will be used to determine treatment failure.
• Participants receiving any treatment(s) for UC are eligible provided they have been, and are anticipated to be, on a stable dose for the designated period of time.

Participants with Crohn's Disease:

• Participants must have been previously enrolled in study SHP647-305, SHP647-306, or SHP647-307, and reached 1 of the following clinical trial milestones:

  1. Completed the Week 16 visit in induction study SHP647-305 or SHP647-306, and did NOT meet the efficacy criteria (clinical and/or endoscopic response/remission as appropriate) for entry into maintenance study SHP647-307.
  2. Completed the Week 52 visit in maintenance study SHP647-307.
  3. Withdrew early from maintenance study SHP647-307 due to treatment failure (or were considered to have failed treatment, at the time of the last visit in study SHP647-307), as defined in the SHP647-307 protocol.
• Participants 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.

Exclusion Criteria:

Participants with Ulcerative Colitis:

• Participants who had major protocol deviation(s) (as determined by the sponsor) in study SHP647-301 (NCT03259334), SHP647-302 (NCT03259308), or SHP647-303 (NCT03290781).
• Participants who permanently discontinued investigational product because of an AE, regardless of relatedness to investigational product, in study SHP647-301 (NCT03259334), SHP647-302 (NCT03259308), or SHP647-303 (NCT03290781).
• Participants who are likely to require major surgery for UC.
• Participants are females who became pregnant during study SHP647-301 (NCT03259334), SHP647-302 (NCT03259308), or SHP647-303 (NCT03290781), 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.
• Participants who do not agree to postpone donation of any organ or tissue, including male participants who are planning to bank or donate sperm and female participants who are planning to harvest or donate eggs, for the duration of the study and through 16 weeks after last dose of investigational product.
• Participants who, in the opinion of the investigator or the sponsor, will be uncooperative or unable to comply with study procedures.
• Participants 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).
• Participants who have developed any major illness/condition or evidence of an unstable clinical condition (example [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 participant if he or she participates in the study.
• Participants 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 participant inappropriate for entry into this study.
• Participants with known exposure to Mycobacterium tuberculosis (TB) since testing at screening in study SHP647-301 (NCT03259334) or SHP647-302 (NCT03259308) and who have been advised to require treatment for latent or active disease, but who are without a generally accepted course of treatment.
• Participants who are investigational site staff members or relatives of those site staff members or participants who are sponsor employees directly involved in the conduct of the study.
• Participants who are participating in other investigational studies (other than SHP647-301 [NCT03259334], SHP647-302 (NCT03259308), or SHP647-303 [NCT03290781]) or plan to participate in other investigational studies during long-term extension study SHP647-304.

Participants with Crohn's Disease:

• Participants who had major protocol deviation(s) (as determined by the sponsor) in study SHP647-305, SHP647-306, or SHP647-307.
• Participants who permanently discontinued investigational product because of an adverse events (AE), regardless of relatedness to investigational product, in study SHP647-305, SHP647-306, or SHP647-307.
• Participants who are likely to require major surgery for CD or developed acute severe complications of CD (with or without fulfilling the treatment failure criteria in the maintenance study) that required immediate intervention (eg, need for immediate biologic treatment with proven effect) and/or Crohn's Disease Activity Index (CDAI) score more than (>) 450.
• Participants are females who became pregnant during study SHP647-305, SHP647-306, or SHP647-307, females who are planning to become pregnant during the study period, or males or females of childbearing potential not agreeing to continue appropriate contraception methods through the conclusion of study participation.
• Participants who do not agree to postpone donation of any organ or tissue, including male participants who are planning to bank or donate sperm and female participants who are planning to harvest or donate eggs, for the duration of the study and through 16 weeks after last dose of investigational product.
• Participants who, in the opinion of the investigator or the sponsor, will be uncooperative or unable to comply with study procedures.
• Participants 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).
• Participants 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 participant if he or she participates in the study.
• Participants 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 participant inappropriate for entry into this study.
• Participants with known exposure to Mycobacterium tuberculosis (TB) since testing at screening in 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.
• Participants who are investigational site staff members or relatives of those site staff members or participants who are sponsor employees directly involved in the conduct of the study.
• Participants who are participating in other investigational studies (other than SHP647-305, SHP647-306, or SHP647-307) or plan to participate in other investigational studies during long-term extension study SHP647-304.

Contacts and Locations

Contacts

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Contact: Shire Contact	+1 866 842 5335	ClinicalTransparency@shire.com

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Sponsors and Collaborators

Shire

Investigators

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Study Director:	Study Director	Shire

More Information

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Responsible Party:	Shire
ClinicalTrials.gov Identifier:	NCT03283085 History of Changes
Other Study ID Numbers:	SHP647-304; 2017-000574-11 ( EudraCT Number )
First Posted:	September 14, 2017
Last Update Posted:	March 5, 2019
Last Verified:	March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Shire:

Immunosuppressants; Mesalamine; Ulcerative Colitis; Crohn's disease; Gastroenteritis

Additional relevant MeSH terms:

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Crohn Disease; Colitis; Ulcer; Colitis, Ulcerative; Inflammatory Bowel Diseases; Gastroenteritis	Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases; Colonic Diseases; Pathologic Processes