Clinical trial NCT04026113: Linaclotide Safety and Efficacy in Pediatric Participants, 6 to 17 Years of Age, With Irritable Bowel Syndrome With Constipation (IBS-C) or Functional Constipation (FC)
Official title: A Phase 3, Multicenter, Randomized, Double-blind, Parallel-group, Safety and Efficacy Study of Linaclotide in Pediatric Participants, Ages 6 to 17 Years, With Irritable Bowel Syndrome With Constipation (IBS-C) and of Linaclotide Versus Placebo in Pediatric Participants With Functional Constipation (FC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Functional Constipation
Irritable Bowel Syndrome With Constipation
Keywords: Functional constipation in children
Irritable Bowel Syndrome with Constipation
LINZESS
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
Collaborators: name: Ironwood Pharmaceuticals, Inc.
First posted: 2019-07-19
Enrollment: 438
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objective of LIN-MD-64 is to evaluate the safety and efficacy of 12 weeks of linaclotide therapy (72 μg daily) in comparison with placebo in pediatric participants, 6 to 17 years of age, who fulfill modified Rome III Criteria for child/adolescent FC. The objective of LIN-MD-64 is to evaluate the safety and efficacy of 12 weeks of linaclotide therapy (145 μg or 290 μg daily) in pediatric participants 7 to 17 years of age, who fulfill the Rome III criteria for child/adolescent IBS and modified Rome III criteria for child/adolescent FC.


Eligibility criteria: Inclusion Criteria:

* Male and female participants must be ages 6 to 17 years (FC participants) or ages 7 to 17 years (IBS-C participants) (inclusive) at the time the participant provides assent for the study and parent/guardian/legally authorized representative (LAR) has provided signed consent;
* Participant weighs ≥18 kg at the time the participant provides assent and the parent/guardian/LAR has provided signed consent;
* Participants who meet the modified Rome III criteria for Child/Adolescent FC. For at least 2 months before the Screening Visit, the participant has had 2 or fewer defecations (with each defecation occurring in the absence of any laxative, suppository, or enema use during the preceding 24 hours) in the toilet per week.

In addition, participant meets one or more of the following criteria at least once per week for at least 2 months before the screening visit:

a. History of retentive posturing or excessive volitional stool retention; b. History of painful or hard BMs; c. History of large diameter stools that may obstruct the toilet; d. Presence of a large fecal mass in the rectum; e. At least 1 episode of fecal incontinence per week

* For IBS-C participants only: Participant meets Rome III criteria for child/adolescent IBS: At least once per week for at least 2 months before the Screening Visit, the participant experienced abdominal discomfort (an uncomfortable sensation not described as pain) or pain associated with 2 or more of the following at least 25% of the time:

  1. Improvement with defecation;
  2. Onset associated with a change in frequency of stool;
  3. Onset associated with a change in form (appearance) of stool;
* For IBS-C participants only: Participant has an average daytime abdominal pain score of ≥ 1 (at least "a tiny bit") during the 14 days before Visit 3;
* Participant is willing to discontinue any laxatives used before the Preintervention Visit in favor of the protocol- permitted rescue medicine;
* Participant has an average of fewer than 3 SBMs per week during the 14 days before the randomization day and up to the randomization (including the morning eDiary assessments reported before administration of first dose of double-blind study intervention on the randomization day). An SBM is defined as a BM that occurs in the absence of laxative, enema, or suppository use on the calendar day of the BM or the calendar day before the BM;
* Participant or parent/guardian/LAR or caregiver is compliant with eDiary requirements by completing both the morning and evening assessments for 10 out of the 14 days immediately preceding the Randomization Visit;
* Female participants of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Randomization Visit prior to dosing;
* Female participants who have had their first menstrual period and are sexually active must agree to use a reliable form of contraception;
* Participant must provide written or verbal informed assent and the parent/guardian/LAR and caregiver must provide written informed consent before the initiation of any study-specific procedures;
* Participant is able to read and/or understand the assessments in the eDiary device. If the participant is 6 to 11 years of age (FC participants) or 7 to 11 years of age (IBS-C participants) and does not meet this criterion, the interviewer-administered version of the eDiary must be used and the parent/guardian/LAR or caregiver who will be administering the interviewer-administered version of the eDiary must undergo training;
* Participant must have acquired toilet training skills.

Exclusion Criteria:

* For FC participants only: Participant meets Rome III criteria for Child/Adolescent IBS: At least once per week for at least 2 months before the Screening Visit, the participant has experienced abdominal discomfort (an uncomfortable sensation not described as pain) or pain associated with 2 or more of the following at least 25% of the time:

  1. Improvement with defecation
  2. Onset associated with a change in frequency of stool
  3. Onset associated with a change in form (appearance) of stool;
* Participant reports having more than 1 loose, mushy stool (eDiary-recorded stool consistency of 6 on the Pediatric Bristol Stool Form Scale \[p-BSFS\]) or any watery stool (eDiary-recorded stool consistency of 7 on the p-BSFS) with any SBM that occurred in the absence of laxative use on the calendar day of the BM or the calendar day before the BM during the 14 days before the randomization day and up to the randomization (including the morning eDiary assessments reported before administration of first dose of double-blind study intervention on the randomization day);
* Participant has a history of non-retentive fecal incontinence;
* Participant has (a) fecal impaction at Visit 2 after failing outpatient clean-out during the Screening Period or (b) fecal impaction at Visit 3;
* Participant has required manual disimpaction any time prior to randomization;
* Participant currently has both unexplained and clinically significant alarm symptoms (lower GI bleeding \[rectal bleeding or heme-positive stool\], iron-deficiency anemia, or any unexplained anemia, or weight loss) and systemic signs of infection or colitis, or any neoplastic process;
* Participant has clinically significant findings on a physical examination, vital sign assessment, electrocardiogram (ECG), or clinical laboratory test as determined by the investigator based on consideration of whether the finding could represent a safety concern or a condition that would be exclusionary, could prevent the participant from performing any protocol assessments, or could confound study assessments;
* Participant has a history of drug or alcohol abuse;
* Participant has any of the following conditions:

  1. Celiac disease, or positive serological test for celiac disease and the condition has not been ruled out by endoscopic biopsy;
  2. Cystic fibrosis;
  3. Hypothyroidism that is untreated or treated with thyroid hormone at a dose that has not been stable for at least 3 months prior to the Screening Visit;
  4. Down's syndrome or any other chromosomal disorder;
  5. Active anal fissure (Note: History of anal fissure is not an exclusion);
  6. Anatomic malformations (eg, imperforate anus, anal stenosis, anterior displaced anus);
  7. Intestinal nerve or muscle disorders (eg, Hirschprung disease, visceral myopathies, visceral neuropathies);
  8. Neuropathic conditions (eg, spinal cord abnormalities, neurofibromatosis, tethered cord, spinal cord trauma);
  9. Lead toxicity, hypercalcemia;
  10. Neurodevelopmental disabilities (early-onset, chronic disorders that share the essential feature of a predominant disturbance in the acquisition of cognitive, motor, language, or social skills, which has a significant and continuing impact on the developmental progress of an individual) producing a cognitive delay that precludes comprehension and completion of the daily eDiary (Electronic handheld device) or other study-related questionnaires (Note: Participants are excluded if the person who will be completing the daily eDiary or other study-related questionnaires meets this criterion);
  11. Inflammatory bowel disease;
  12. Childhood functional abdominal pain syndrome;
  13. Childhood functional abdominal pain;
  14. Poorly treated or poorly controlled psychiatric disorders that might influence his or her ability to participate in the study;
  15. Lactose intolerance that is associated with abdominal pain or discomfort and could confound the assessments in this study;
  16. History of cancer other than treated basal cell carcinoma of the skin; (Note: Participants with a history of cancer are allowed provided that the malignancy has been in a complete remission for at least 5 years before the Randomization Visit. A complete remission is defined as the disappearance of all signs of cancer in response to treatment);
  17. History of diabetic neuropathy.
* Participant has an acute or chronic condition that, in the investigator's opinion, would limit the participants' ability to complete or participate in this clinical study;
* Participant has a known or suspected mechanical bowel obstruction or pseudoobstruction;
* Participant has a known allergy or sensitivity to the study intervention or its components or other medications in the same drug class.
* Participant has had surgery that meets any of the following criteria:

  1. Bariatric surgery for treatment of obesity, or surgery to remove a segment of the GI tract at any time before the Screening Visit;
  2. Surgery of the abdomen, pelvis, or retroperitoneal structures during the 6 months before the Screening Visit;
  3. An appendectomy or cholecystectomy during the 60 days before the Screening Visit;
  4. Other major surgery during the 30 days before the Screening Visit;
* Participant used a protocol-specified prohibited medicine before the start of the Preintervention Period or failed to meet the stable-dose requirements of certain medications;
* Participant used rescue medication on the calendar day before the Randomization Visit and on the day of the Randomization Visit until randomized;
* Participant received a study intervention during the 30 days before the Screening Visit or is planning to receive a study intervention (other than that administered during this study);
* Participant has been randomized into any clinical study in which linaclotide was a study intervention.
* The participant has a condition or is in a situation; which, in the investigator's opinion, may put the participant at significant risk, may confound the study results ,or may interfere significantly with the participant's participation in the study;
* Participants who have positive urine drug screen results for cocaine, barbiturates, opiates, or cannabinoids will be excluded from study participation;
* Female participants who are currently pregnant or nursing, or plan to become pregnant or nurse during the clinical study;
* Participant's parent/guardian/LAR or caregiver has been directly or indirectly involved in the conduct and administration of this study as an investigator, study coordinator, or other study staff member. In addition, any participant, parent/guardian/LAR or caregiver who has a first-degree family member, significant other, or relative residing with him/her directly or indirectly who is involved in this study.

Primary outcomes:
measure: Functional Constipation (FC) Participants: Change From Baseline in 12-week SBM (Spontaneous Bowel Movement) Frequency Rate (SBMs/Week) During the Study Intervention Period
timeFrame: Baseline, up to 12 weeks
measure: Irritable Bowel Syndrome With Constipation (IBS-C) Participants: 6/12 Weeks APS (Abdominal Pain and SBM) + 2 Responder Rate
timeFrame: 12 Weeks
Secondary outcomes:
measure: Functional Constipation (FC) Participants: Change From Baseline in 12-week Stool Consistency During the Study Intervention Period
timeFrame: Baseline, up to 12 weeks
measure: Irritable Bowel Syndrome With Constipation (IBS-C) Participants: Change From Baseline in 12-week SBM Frequency Rate (SBMs/Week) During the Study Intervention Period
timeFrame: Baseline, up to 12 Weeks
measure: Irritable Bowel Syndrome With Constipation (IBS-C) Participants: Change From Baseline in 12-week Abdominal Pain During the Study Intervention Period
timeFrame: Baseline, up to 12 weeks
measure: Irritable Bowel Syndrome With Constipation (IBS-C) Participants: Change From Baseline in 12-week Stool Consistency During the Study Intervention Period
timeFrame: Baseline, up to 12 weeks
measure: Irritable Bowel Syndrome With Constipation (IBS-C) Participants: 6/12 Weeks SBM + 2 Responder Rate
timeFrame: 12 weeks
measure: Irritable Bowel Syndrome With Constipation (IBS-C) Participants: 6/12 Weeks Abdominal Pain Responder
timeFrame: 12 Weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Central Research Associates /ID# 233124
state: Alabama
city: Foley
country: United States
facility: G & L Research, LLC /ID# 233139
state: Alabama
city: Saraland
country: United States
facility: The Center for Clinical Trials Inc. /ID# 232755
state: Alabama
city: Hot Springs
country: United States
facility: HealthStar Research of Hot Springs PLLC /ID# 232757
state: Arkansas
city: Little Rock
country: United States
facility: Preferred Research Partners /ID# 233023
state: Arkansas
city: Little Rock
country: United States
facility: Applied Research Center of Arkansas /ID# 233135
state: Arkansas
city: Anaheim
country: United States
facility: Advanced Research Center /ID# 233121
state: California
city: Bell Gardens
country: United States
facility: Alliance Research Institute /ID# 232754
state: California
city: Canoga Park
country: United States
facility: Alliance Research Institute Llc /Id# 232637
state: California
city: Corona
country: United States
facility: Kindred Medical Institute, LLC /ID# 233042
state: California
city: Paramount
country: United States
facility: Center for Clinical Trials LLC /ID# 232781
state: California
city: San Diego
country: United States
facility: Medical Ctr for Clin Research /ID# 233004
state: California
city: Santa Ana
country: United States
facility: Paragon Rx Clinical Inc /ID# 232752
state: California
city: Aurora
country: United States
facility: Lynn Institute of Denver /ID# 233137
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center /ID# 232655
state: District of Columbia
city: Doral
country: United States
facility: Prohealth Research Center /ID# 232805
state: Florida
city: Doral
country: United States
facility: Dolphin Medical Research /ID# 232815
state: Florida
city: Hialeah
country: United States
facility: Amedica Research Institute Inc /ID# 232809
state: Florida
city: Jacksonville
country: United States
facility: Nemours Children's Health System /ID# 233127
state: Florida
city: Miami
country: United States
facility: Elite Clinical Research /ID# 232801
state: Florida
city: Miami
country: United States
facility: My Preferred Research LLC /ID# 233119
state: Florida
city: Miami
country: United States
facility: South Miami Medical & Research Group Inc. /ID# 232803
state: Florida
city: Miami
country: United States
facility: Valencia Medical & Research Center /ID# 232813
state: Florida
city: Naples
country: United States
facility: Advanced Research for Health Improvement /ID# 233161
state: Florida
city: Orlando
country: United States
facility: Pediatric & Adult Research Center /ID# 232819
state: Florida
city: Orlando
country: United States
facility: Nemours Children's Hospital /ID# 232919
state: Florida
city: Oviedo
country: United States
facility: Oviedo Medical Research /ID# 232830
state: Florida
city: Atlanta
country: United States
facility: Treken Primary Care /ID# 232796
state: Georgia
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Ferry Rd /ID# 233015
state: Georgia
city: Atlanta
country: United States
facility: Children's Ctr Digestive, US /ID# 233070
state: Georgia
city: Blue Ridge
country: United States
facility: River Birch Research Alliance /ID# 233122
state: Georgia
city: Stockbridge
country: United States
facility: Clinical Research Institute /ID# 232833
state: Georgia
city: Stockbridge
country: United States
facility: Sleep Care Research Institute d/b/a Clinical Research Institute /ID# 232940
state: Georgia
city: Stone Mountain
country: United States
facility: Clinical Trials Specialist Inc /ID# 232802
state: Georgia
city: Union City
country: United States
facility: Rophe Adult and Pediatric Medicine/SKYCRNG /ID# 232800
state: Georgia
city: Kansas City
country: United States
facility: Univ Kansas Med Ctr /ID# 232645
state: Kansas
city: Newton
country: United States
facility: Alliance for Multispecialty Research LLC /ID# 232681
state: Kansas
city: Lexington
country: United States
facility: Michael W. Simon, MD, PSC /ID# 232966
state: Kentucky
city: Baton Rouge
country: United States
facility: Meridian Research - Baton Rouge /ID# 232954
state: Louisiana
city: Silver Spring
country: United States
facility: Virgo Carter Pediatrics /ID# 232693
state: Maryland
city: Minneapolis
country: United States
facility: MNGI Digestive Health, P. A. /ID# 232920
state: Minnesota
city: Flowood
country: United States
facility: GI associates and Endoscopy Ce /ID# 233123
state: Mississippi
city: Port Gibson
country: United States
facility: David M. Headley, MD, P.A. /ID# 233153
state: Mississippi
city: Bridgeton
country: United States
facility: Private Practice - Dr. Craig Spiegel /ID# 232707
state: Missouri
city: East Orange
country: United States
facility: Medclinical Research Partners LLC/ Foundation Pediatrics /ID# 232783
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico /ID# 233011
state: New Mexico
city: Bronx
country: United States
facility: The Children's Hospital at Montefiore /ID# 232638
state: New York
city: Bronx
country: United States
facility: Advantage Clinical Trials /ID# 233117
state: New York
city: New York
country: United States
facility: Columbia Univ Medical Center /ID# 233094
state: New York
city: Greenville
country: United States
facility: East Carolina University - Brody School of Medicine /ID# 233062
state: North Carolina
city: Statesville
country: United States
facility: PMG Research of Piedmont Healthcare-Statesville /ID# 233162
state: North Carolina
city: Oklahoma City
country: United States
facility: Univ Oklahoma HSC /ID# 233067
state: Oklahoma
city: Oklahoma City
country: United States
facility: IPS Research Company /ID# 233081
state: Oklahoma
city: Scottdale
country: United States
facility: Frontier Clinical Research, LLC - Scottdale /ID# 233129
state: Pennsylvania
city: Smithfield
country: United States
facility: Frontier Clinical Research /ID# 233116
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital /ID# 233112
state: Rhode Island
city: Charleston
country: United States
facility: Coastal Pediatric Research - West Ashley B /ID# 232816
state: South Carolina
city: Summerville
country: United States
facility: Coastal Pediatric Research - Summerville /ID# 232814
state: South Carolina
city: Jackson
country: United States
facility: The Jackson Clinic, PA /ID# 232998
state: Tennessee
city: Jefferson City
country: United States
facility: Accellacare of Knoxville /ID# 232663
state: Tennessee
city: Nashville
country: United States
facility: Monroe-Carell Jr. Children's Hospital at Vanderbilt /ID# 232659
state: Tennessee
city: Dallas
country: United States
facility: Oak Cliff Research Company LLC /ID# 232729
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Med. Center /ID# 233066
state: Texas
city: Harlingen
country: United States
facility: Valley Institute of Research /ID# 232674
state: Texas
city: Houston
country: United States
facility: Vilo Research Group Inc /ID# 233155
state: Texas
city: Houston
country: United States
facility: Cullen Research /ID# 232726
state: Texas
city: Houston
country: United States
facility: Synergy Group US LLC /ID# 232669
state: Texas
city: Houston
country: United States
facility: Pioneer Research Solutions - Houston /ID# 233006
state: Texas
city: Missouri City
country: United States
facility: Synergy Group US LLC /ID# 232670
state: Texas
city: Plano
country: United States
facility: AIM Trials /ID# 232934
state: Texas
city: San Antonio
country: United States
facility: Sun Research Institute /ID# 233005
state: Texas
city: Waxahachie
country: United States
facility: ClinPoint Trials /ID# 232978
state: Texas
city: Saint George
country: United States
facility: Chrysalis Clinical Research /ID# 232690
state: Utah
city: Franklin
country: United States
facility: Office of Maria Ona /ID# 232700
state: Virginia
city: Newport News
country: United States
facility: Health Research of Hampton Roads, Inc. (HRHR) /ID# 233056
state: Virginia
city: Richmond
country: United States
facility: Clinical Research Partners, LLC /ID# 233026
state: Virginia
city: Roanoke
country: United States
facility: Carilion Medical Center /ID# 232999
state: Virginia
city: Tacoma
country: United States
facility: Duplicate_Multicare Institute for Research and Innovation /ID# 233010
state: Washington
city: Huntington
country: United States
facility: Marshall University Medical Center /ID# 232952
state: West Virginia
city: Brussels
country: Belgium
facility: Duplicate_UZ Brussel /ID# 232875
city: Tsentar
country: Bulgaria
facility: University Hospital Plovdiv /ID# 232775
state: Plovdiv
city: Ruse
country: Bulgaria
facility: UMHAT Kanev /ID# 233102
state: Smolyan
city: Sevlievo
country: Bulgaria
facility: Medical center 1 Sevlievo /ID# 232915
state: Smolyan
city: Kozloduy
country: Bulgaria
facility: MHATSv.Ivan Rilski /ID# 232831
city: Edmonton
country: Canada
facility: University of Alberta Hospital /ID# 233147
state: Alberta
city: London
country: Canada
facility: London Health Sciences Center- University Hospital /ID# 233068
state: Ontario
city: Newmarket
country: Canada
facility: Duplicate_SKDS Research Inc. /ID# 233000
state: Ontario
city: Sarnia
country: Canada
facility: Bluewater Clinical Research Group Inc /ID# 232772
state: Ontario
city: Stouffville
country: Canada
facility: Stouffville Medical Centre /ID# 232774
state: Ontario
city: Tallinn
country: Estonia
facility: Merelahe Family Doctors Centre /ID# 232881
state: Raplamaa
city: Tartu
country: Estonia
facility: Kliiniliste Uuringute Keskus /ID# 232883
state: Raplamaa
city: Harjumaa
country: Estonia
facility: Al Mare Perearstikeskus /ID# 232879
city: Kassel
country: Germany
facility: Duplicate_Klinikum Kassel /ID# 233029
state: Hessen
city: Haifa
country: Israel
facility: Duplicate_Rambam Health Care Campus Ruth Rappaport Children's Hospital /ID# 232892
state: H_efa
city: Ashkelon
country: Israel
facility: The Edith Wolfson Medical Center /ID# 233134
state: HaDarom
city: Petah Tikva
country: Israel
facility: Schneider Children's Medical Center /ID# 233064
state: HaMerkaz
city: Tiberias
country: Israel
facility: The Baruch Padeh Medical Center Poriya /ID# 232889
state: HaTsafon
city: Ramat Gan
country: Israel
facility: The Chaim Sheba Medical Center /ID# 232986
state: Tel-Aviv
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center /ID# 233092
state: Yerushalayim
city: Jerusalem
country: Israel
facility: Hadassah Hebrew University Hospital - Ein Kerem /ID# 232865
state: Yerushalayim
city: Rome
country: Italy
facility: Sant?Andrea University Hospital /ID# 232825
city: Amsterdam
country: Netherlands
facility: Duplicate_Academisch Medisch Centrum /ID# 232895
state: Noord-Holland
city: Rotterdam
country: Netherlands
facility: Maasstad Ziekenhuis /ID# 233003
state: Zuid-Holland
city: Zwolle
country: Netherlands
facility: Isala /ID# 233031
state: Zuid-Holland
city: Bydgoszcz
country: Poland
facility: Szpital Uniwersytecki Nr 1 im. dr Antoniego Jurasza /ID# 232898
state: Kujawsko-pomorskie
city: Gdansk
country: Poland
facility: Klinika Pediatrii Gastroenterologii Alergologii i Zywienia Dzieci GUM /ID# 232900
state: Kujawsko-pomorskie
city: Olsztyn
country: Poland
facility: Poradnia Gastroenterologiczna /ID# 232899
state: Kujawsko-pomorskie
city: Rzeszow
country: Poland
facility: Korczowski Bartosz Gabinet Lekarski /ID# 232821
state: Kujawsko-pomorskie
city: Caguas
country: Puerto Rico
facility: San Juan Bautista School of Medicine /ID# 232913
city: Sevilla
country: Spain
facility: Instituto Hispalense Pediatria /ID# 232793
city: Kharkiv
country: Ukraine
facility: Kharkiv Regional Childrens Clinical Hospital Gastroent. Centre Kharkiv Natl. Me /ID# 232867
state: Cherkaska Oblast
city: Lviv
country: Ukraine
facility: Municipal Nonprofit Enterprise Lviv City Children's Clinical Hospital /ID# 232851
state: Cherkaska Oblast
city: Vinnytsia
country: Ukraine
facility: Vinnytsya National Medical University Departement of Pediatrics No.1 /ID# 232890
state: Cherkaska Oblast
city: Dnipro
country: Ukraine
facility: Communal Nonprofit Enterprise City Childrens Clinical Hospital 6 of Dnipro C /ID# 232863
city: Ashford
country: United Kingdom
facility: William Harvey Hospital /ID# 232806
state: Kent
Study officials:
affiliation: AbbVie
name: ABBVIE INC.
role: STUDY_DIRECTOR
References: