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)

NCT ID: NCT04026113

Last Updated: 2024-11-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 438 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-10-01
• Study Completion Date: 2024-05-29

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.

Conditions

Functional Constipation; Irritable Bowel Syndrome With Constipation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

FC Participants: Placebo

Placebo single dose, once daily at approximately the same time each day, 30 minutes before any meal.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

Matching placebo

FC Participants: Linaclotide 72 μg

Linaclotide 72 μg single dose, once daily at approximately the same time each day, 30 minutes before any meal.

Group Type: EXPERIMENTAL

Linaclotide

Intervention Type: DRUG

Oral capsule (For participants who do not wish to take the dose as a capsule, a sprinkled dose may be prepared)

IBS-C Participants: Linaclotide 145 μg

Linaclotide 145 μg single dose, once daily at approximately the same time each day, 30 minutes before any meal.

Group Type: EXPERIMENTAL

Linaclotide

Intervention Type: DRUG

Oral capsule (For participants who do not wish to take the dose as a capsule, a sprinkled dose may be prepared)

IBS-C Participants: Linaclotide 290 μg

Linaclotide 290 μg single dose, once daily at approximately the same time each day, 30 minutes before any meal

Group Type: EXPERIMENTAL

Linaclotide

Intervention Type: DRUG

Oral capsule (For participants who do not wish to take the dose as a capsule, a sprinkled dose may be prepared)

Interventions

Linaclotide

Oral capsule (For participants who do not wish to take the dose as a capsule, a sprinkled dose may be prepared)

Intervention Type: DRUG

Placebo

Matching placebo

Intervention Type: DRUG

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.

• Minimum Eligible Age: 6 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ironwood Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: collaborator

AbbVie

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

ABBVIE INC.

Role: STUDY_DIRECTOR

AbbVie

Locations

Central Research Associates /ID# 233124

Birmingham, Alabama, United States

G & L Research, LLC /ID# 233139

Foley, Alabama, United States

The Center for Clinical Trials Inc. /ID# 232755

Saraland, Alabama, United States

HealthStar Research of Hot Springs PLLC /ID# 232757

Hot Springs, Arkansas, United States

Preferred Research Partners /ID# 233023

Little Rock, Arkansas, United States

Applied Research Center of Arkansas /ID# 233135

Little Rock, Arkansas, United States

Advanced Research Center /ID# 233121

Anaheim, California, United States

Alliance Research Institute /ID# 232754

Bell Gardens, California, United States

Alliance Research Institute Llc /Id# 232637

Canoga Park, California, United States

Kindred Medical Institute, LLC /ID# 233042

Corona, California, United States

Center for Clinical Trials LLC /ID# 232781

Paramount, California, United States

Medical Ctr for Clin Research /ID# 233004

San Diego, California, United States

Paragon Rx Clinical Inc /ID# 232752

Santa Ana, California, United States

Lynn Institute of Denver /ID# 233137

Aurora, Colorado, United States

Children's National Medical Center /ID# 232655

Washington D.C., District of Columbia, United States

Prohealth Research Center /ID# 232805

Doral, Florida, United States

Dolphin Medical Research /ID# 232815

Doral, Florida, United States

Amedica Research Institute Inc /ID# 232809

Hialeah, Florida, United States

Nemours Children's Health System /ID# 233127

Jacksonville, Florida, United States

Elite Clinical Research /ID# 232801

Miami, Florida, United States

My Preferred Research LLC /ID# 233119

Miami, Florida, United States

South Miami Medical & Research Group Inc. /ID# 232803

Miami, Florida, United States

Valencia Medical & Research Center /ID# 232813

Miami, Florida, United States

Advanced Research for Health Improvement /ID# 233161

Naples, Florida, United States

Pediatric & Adult Research Center /ID# 232819

Orlando, Florida, United States

Nemours Children's Hospital /ID# 232919

Orlando, Florida, United States

Oviedo Medical Research /ID# 232830

Oviedo, Florida, United States

Treken Primary Care /ID# 232796

Atlanta, Georgia, United States

Children's Healthcare of Atlanta - Ferry Rd /ID# 233015

Atlanta, Georgia, United States

Children's Ctr Digestive, US /ID# 233070

Atlanta, Georgia, United States

River Birch Research Alliance /ID# 233122

Blue Ridge, Georgia, United States

Clinical Research Institute /ID# 232833

Stockbridge, Georgia, United States

Sleep Care Research Institute d/b/a Clinical Research Institute /ID# 232940

Stockbridge, Georgia, United States

Clinical Trials Specialist Inc /ID# 232802

Stone Mountain, Georgia, United States

Rophe Adult and Pediatric Medicine/SKYCRNG /ID# 232800

Union City, Georgia, United States

Univ Kansas Med Ctr /ID# 232645

Kansas City, Kansas, United States

Alliance for Multispecialty Research LLC /ID# 232681

Newton, Kansas, United States

Michael W. Simon, MD, PSC /ID# 232966

Lexington, Kentucky, United States

Meridian Research - Baton Rouge /ID# 232954

Baton Rouge, Louisiana, United States

Virgo Carter Pediatrics /ID# 232693

Silver Spring, Maryland, United States

MNGI Digestive Health, P. A. /ID# 232920

Minneapolis, Minnesota, United States

GI associates and Endoscopy Ce /ID# 233123

Flowood, Mississippi, United States

David M. Headley, MD, P.A. /ID# 233153

Port Gibson, Mississippi, United States

Private Practice - Dr. Craig Spiegel /ID# 232707

Bridgeton, Missouri, United States

Medclinical Research Partners LLC/ Foundation Pediatrics /ID# 232783

East Orange, New Jersey, United States

University of New Mexico /ID# 233011

Albuquerque, New Mexico, United States

Columbia Univ Medical Center /ID# 233094

New York, New York, United States

The Children's Hospital at Montefiore /ID# 232638

The Bronx, New York, United States

Advantage Clinical Trials /ID# 233117

The Bronx, New York, United States

East Carolina University - Brody School of Medicine /ID# 233062

Greenville, North Carolina, United States

PMG Research of Piedmont Healthcare-Statesville /ID# 233162

Statesville, North Carolina, United States

Univ Oklahoma HSC /ID# 233067

Oklahoma City, Oklahoma, United States

IPS Research Company /ID# 233081

Oklahoma City, Oklahoma, United States

Frontier Clinical Research, LLC - Scottdale /ID# 233129

Scottdale, Pennsylvania, United States

Frontier Clinical Research /ID# 233116

Smithfield, Pennsylvania, United States

Rhode Island Hospital /ID# 233112

Providence, Rhode Island, United States

Coastal Pediatric Research - West Ashley B /ID# 232816

Charleston, South Carolina, United States

Coastal Pediatric Research - Summerville /ID# 232814

Summerville, South Carolina, United States

The Jackson Clinic, PA /ID# 232998

Jackson, Tennessee, United States

Accellacare of Knoxville /ID# 232663

Jefferson City, Tennessee, United States

Monroe-Carell Jr. Children's Hospital at Vanderbilt /ID# 232659

Nashville, Tennessee, United States

Oak Cliff Research Company LLC /ID# 232729

Dallas, Texas, United States

Cook Children's Med. Center /ID# 233066

Fort Worth, Texas, United States

Valley Institute of Research /ID# 232674

Harlingen, Texas, United States

Vilo Research Group Inc /ID# 233155

Houston, Texas, United States

Cullen Research /ID# 232726

Houston, Texas, United States

Synergy Group US LLC /ID# 232669

Houston, Texas, United States

Pioneer Research Solutions - Houston /ID# 233006

Houston, Texas, United States

Synergy Group US LLC /ID# 232670

Missouri City, Texas, United States

AIM Trials /ID# 232934

Plano, Texas, United States

Sun Research Institute /ID# 233005

San Antonio, Texas, United States

ClinPoint Trials /ID# 232978

Waxahachie, Texas, United States

Chrysalis Clinical Research /ID# 232690

St. George, Utah, United States

Office of Maria Ona /ID# 232700

Franklin, Virginia, United States

Health Research of Hampton Roads, Inc. (HRHR) /ID# 233056

Newport News, Virginia, United States

Clinical Research Partners, LLC /ID# 233026

Richmond, Virginia, United States

Carilion Medical Center /ID# 232999

Roanoke, Virginia, United States

Duplicate_Multicare Institute for Research and Innovation /ID# 233010

Tacoma, Washington, United States

Marshall University Medical Center /ID# 232952

Huntington, West Virginia, United States

Duplicate_UZ Brussel /ID# 232875

Brussels, , Belgium

University Hospital Plovdiv /ID# 232775

Tsentar, Plovdiv, Bulgaria

UMHAT Kanev /ID# 233102

Ruse, Smolyan, Bulgaria

Medical center 1 Sevlievo /ID# 232915

Sevlievo, Smolyan, Bulgaria

MHATSv.Ivan Rilski /ID# 232831

Kozloduy, , Bulgaria

University of Alberta Hospital /ID# 233147

Edmonton, Alberta, Canada

London Health Sciences Center- University Hospital /ID# 233068

London, Ontario, Canada

Duplicate_SKDS Research Inc. /ID# 233000

Newmarket, Ontario, Canada

Bluewater Clinical Research Group Inc /ID# 232772

Sarnia, Ontario, Canada

Stouffville Medical Centre /ID# 232774

Stouffville, Ontario, Canada

Merelahe Family Doctors Centre /ID# 232881

Tallinn, Raplamaa, Estonia

Kliiniliste Uuringute Keskus /ID# 232883

Tartu, Raplamaa, Estonia

Al Mare Perearstikeskus /ID# 232879

Harjumaa, , Estonia

Duplicate_Klinikum Kassel /ID# 233029

Kassel, Hesse, Germany

Schneider Children's Medical Center /ID# 233064

Petah Tikva, Central District, Israel

Duplicate_Rambam Health Care Campus Ruth Rappaport Children's Hospital /ID# 232892

Haifa, H_efa, Israel

Shaare Zedek Medical Center /ID# 233092

Jerusalem, Jerusalem, Israel

Hadassah Hebrew University Hospital - Ein Kerem /ID# 232865

Jerusalem, Jerusalem, Israel

The Baruch Padeh Medical Center Poriya /ID# 232889

Tiberias, Northern District, Israel

The Edith Wolfson Medical Center /ID# 233134

Ashkelon, Southern District, Israel

The Chaim Sheba Medical Center /ID# 232986

Ramat Gan, Tel Aviv, Israel

Sant?Andrea University Hospital /ID# 232825

Rome, , Italy

Duplicate_Academisch Medisch Centrum /ID# 232895

Amsterdam, North Holland, Netherlands

Maasstad Ziekenhuis /ID# 233003

Rotterdam, South Holland, Netherlands

Isala /ID# 233031

Zwolle, South Holland, Netherlands

Szpital Uniwersytecki Nr 1 im. dr Antoniego Jurasza /ID# 232898

Bydgoszcz, Kuyavian-Pomeranian Voivodeship, Poland

Klinika Pediatrii Gastroenterologii Alergologii i Zywienia Dzieci GUM /ID# 232900

Gdansk, Kuyavian-Pomeranian Voivodeship, Poland

Poradnia Gastroenterologiczna /ID# 232899

Olsztyn, Kuyavian-Pomeranian Voivodeship, Poland

Korczowski Bartosz Gabinet Lekarski /ID# 232821

Rzeszow, Kuyavian-Pomeranian Voivodeship, Poland

San Juan Bautista School of Medicine /ID# 232913

Caguas, , Puerto Rico

Instituto Hispalense Pediatria /ID# 232793

Seville, , Spain

Kharkiv Regional Childrens Clinical Hospital Gastroent. Centre Kharkiv Natl. Me /ID# 232867

Kharkiv, Cherkasy Oblast, Ukraine

Municipal Nonprofit Enterprise Lviv City Children's Clinical Hospital /ID# 232851

Lviv, Cherkasy Oblast, Ukraine

Vinnytsya National Medical University Departement of Pediatrics No.1 /ID# 232890

Vinnytsia, Cherkasy Oblast, Ukraine

Communal Nonprofit Enterprise City Childrens Clinical Hospital 6 of Dnipro C /ID# 232863

Dnipro, , Ukraine

William Harvey Hospital /ID# 232806

Ashford, Kent, United Kingdom

Countries

United States; Belgium; Bulgaria; Canada; Estonia; Germany; Israel; Italy; Netherlands; Poland; Puerto Rico; Spain; Ukraine; United Kingdom

References

Di Lorenzo C, Khlevner J, Rodriguez-Araujo G, Xie W, Huh SY, Ando M, Hyams JS, Nurko S, Benninga MA, Simon M, Hewson ME, Saps M. Efficacy and safety of linaclotide in treating functional constipation in paediatric patients: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Gastroenterol Hepatol. 2024 Mar;9(3):238-250. doi: 10.1016/S2468-1253(23)00398-9. Epub 2024 Jan 8.

Reference Type: DERIVED

PMID: 38211604 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2019-001500-38

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

LIN-MD-64

Identifier Type: -

Identifier Source: org_study_id