To assess the efficacy, safety, and pharmacokinetics of oral lubiprostone 12 or 24 mcg capsules dosed twice daily (BID) (based on subject body weight at baseline) as compared to matching placebo BID, when administered orally for 12 weeks in…
ID
Source
Brief title
Condition
- Gastrointestinal motility and defaecation conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Overall change from baseline in spontaneous bowel movement (SBM) frequency
across the 12-week treatment period
Secondary outcome
Primary efficacy endpoint:
* Overall change from baseline in SBM frequency across the 12-week treatment
period
Secondary endpoints:
EFFICACY
* Overall change from baseline in BM and SBM frequency at each treatment week
and each treatment month
* Time to first SBM following the first study medication administration
* Percentage of subjects with an SBM within 4, 8, 12, 24 and 48 hours of first
study medication administration
* Overall, weekly, and monthly assessments of the average degree of and changes
from baseline in:
o Straining associated with SBMs
o Stool consistency of SBMs
o Abdominal pain
o Constipation severity
o Treatment effectiveness
* Overall health-related quality of life (PedsQL*)
* Overall SBM responder rate
* Change from baseline in incontinence episodes frequency overall, during each
treatment week, and during each treatment month (analysis performed for subset
of subjects presenting with incontinence at baseline)
* Change from baseline in the production of large diameter stool (a stool that
clogs the toilet) frequency overall, during each treatment week, and during
each treatment month
* Frequency of faecal impaction overall, during each treatment week, and during
each treatment month
* Proportion of BMs and SBMs in toilet overall, during each treatment week, and
during each treatment month
* Frequency of retentive posturing or excessive volitional stool retention
overall, during each treatment week, and during each treatment month
SAFETY
* Incidence of adverse events grouped by MedDRA System Organ Class
* Changes in clinical laboratory parameters (haematology, serum chemistry,
urinalysis)
* Changes in vital sign measurements, including height and weight
o Height will be measured using a wall-mounted stadiometer for the evaluation
of height velocity
* Changes from baseline in physical examination
* Percent changes from baseline in bone mineral density (BMD) and bone mineral
content (BMC for DXA Subgroup (Subjects 6 to 9 and 14 to 17 years of age)
* Changes from baseline in BMD Z-scores and in height-adjusted Z-scores, as
assessed by DXA for DXA Subgroup (Subjects 6 to 9 and 14 to 17 years of age)
* Changes from baseline in height- and weight-adjusted Z-scores for DXA
Subgroup (Subjects 6 to 9 and 14 to 17 years of age)
* Incidence of clinical fractures
A Data Safety Monitoring Board (DSMB) will monitor safety data on a regular
basis throughout the study. Specific details, including frequency stoppage
criteria, are provided in the DSMB Charter.
PHARMACOKINETICS
Plasma samples will be collected for population pharmacokinetic (PK) modeling
as follows:
* Visit 2 (First Dose): Pre-dose and 1 sample between 30 and 90 minutes after
dose administration (2 samples total);
* Visit 5 (Day 29): 1 sample at any time during the visit; and
* Visit 7 (End of treatment): Pre-dose and 1 sample between 30 and 90 minutes
after dose administration (2 samples total)
A population pharmacokinetic analysis will be performed using the
concentration-time data from the sparse PK samples in this study. The analysis
may include data from other studies with lubiprostone in adults, paediatric
patients, or healthy volunteers. A separate analysis plan for the population
pharmacokinetic analysis will be prepared prior to database lock.
Background summary
Study of the new IMP lubiprostone in the paediatric population suffering on
functional constipation. This study is one of the studies proposed in the PIP.
The study will be conducted in 9 EU member states, USA and Canada.
Study objective
To assess the efficacy, safety, and pharmacokinetics of oral lubiprostone 12 or
24 mcg capsules dosed twice daily (BID) (based on subject body weight at
baseline) as compared to matching placebo BID, when administered orally for 12
weeks in paediatric subjects with functional constipation.
Study design
Multicentre, randomised, parallel, placebo-controlled, double-blinded over 12
weeks.
Intervention
Treatment with either 12 or 24 mcg lubiprostone or matching placebo twice daily
over 12 weeks
Study burden and risks
RISKS:
no favorable clinical effects, occurence of adverse events (most likely nausea)
BURDEN:
donation of blood samples for PK analysis and serum biochemistry, undergoing
physical examinations, undergoing DXA scans
BENEFITS:
Relief from signs and symptoms of functional constipation (increase of SBMs,
decrease of bloating and straining, improvement of stool consistency, increase
of quality of life)
Baarerstrasse 22
Zug 6300
CH
Baarerstrasse 22
Zug 6300
CH
Listed location countries
Age
Inclusion criteria
Written informed consent obtained from subject or parent/legal guardian (and assent from subject where applicable).
2. Subject is at least 6 years of age but less than 18 years of age at the time of randomisation.
3. Subject is capable of and willing to swallow capsules.
4. Subject fulfills the modified Rome III Diagnostic Criteria for Childhood Functional Constipation (Child/Adolescent; Section H3a) as follows:
Must include two or more of the following in a child with a developmental age of at least 4 years*: with insufficient criteria for diagnosis of irritable bowel syndrome (IBS)*:
* Two or fewer defecations in the toilet per week
* At least one episode of faecal incontinence per week
* History of retentive posturing or excessive volitional stool retention
* History of painful or hard bowel movements
* Presence of a large faecal mass in the rectum
* History of large diameter stools which may obstruct the toilet
* Criteria fulfilled at least once per week for at least 2 months prior to diagnosis.
5. If subject is taking a concomitant medication (prescribed or over-the-counter) that affects gastrointestinal motility, he/she must discontinue use at the time of the Screening Visit (Visit 1); these medications include:
a. Cholinesterase inhibitors; anti-spasmodic, anti-diarrheal, anti-constipation, or prokinetic agents; laxative agents (e.g., PEG 3350), including homeopathic remedies;
b. Tricyclic antidepressants; and/or c. Any medication, at the discretion of the Investigator, known to cause constipation or constipation-related symptoms.
Any medication, at the discretion of the Investigator, known to relieve or cause constipation or constipation-related symptoms, and which the Investigator, based on the medical history of the subject, suspects to be a contributing factor to the patient*s chronic constipation, or may otherwise confound the evaluation of treatment response.
Exceptions: Treatment with anticholinergic agents, SSRIs, SNRIs, or MAO inhibitors is allowed if a stable dose has been used for at least 30 days prior to the Screening Visit and not likely to change during the study.
6. Subject (and, if necessary, parent/legal guardian) must be willing and able to use or administer recommended (rectal and/or oral) rescue medications if needed.
7. If subject is taking a fibre supplement (e.g., Metamucil®, PerDiem®, Fybogel), usage must have been at a stable dose and schedule for at least 30 days prior to the Screening Visit (Visit 1) and not likely to change during the study.
8. Subject and his/her parent/legal guardian must be willing and able to fill out his/her own diary.
9. Subject daily diary is at least 70% compliant for evening/end-of-day assessments during the Screening period.
10. Subject daily diary indicates an average of less than 3 spontaneous bowel movements (SBMs) per week during the Screening period.
11. Subject has at least one of the following for at least 25% of SBMs during each week of the screening period (as reported in the daily diary):
* Modified Bristol Stool Scale Type 1 or 2; and/or
* Some to extreme straining associated with SBMs.
Note: For subjects with no reported SBMs during the Screening Period, it is not necessary to meet criteria for bowel movement characteristics, e.g., hard or very hard stools.;All study subjects who are 6-9 or 14-17 years old and meet the additional DXA evaluation sub-study entry criteria
Inclusion Criteria*:
1. Subject is 6 to 9 years or 14 to 17 years of age at time of informed consent.
2. Subject has a bone mineral density (BMD) Z-score (normalized for age and gender) greater than -2.0, as assessed by DXA at Screening.
Exclusion criteria
1. Subject*s constipation is known to be attributed to any of the following:
a. Physical/Mental/Cognitive * any condition, other than functional constipation, that in the Investigator*s opinion would interfere with meaningful study participation or evaluation.
b. Anatomic * associated with a mechanical bowel obstruction (tumour, hernia, obstructive polyps, etc.), or pseudo-obstruction.
c. Neurological * associated with spinal cord disorder, congenital disorder, or Guillain-Barre syndrome.
d. Endocrine/Metabolic * associated with hypothyroidism, diabetes, hypercalcaemia, or hypokalaemia.
e. Inflammatory bowel disease (e.g., Crohn*s disease, ulcerative colitis, celiac disease).
f. Medication * associated with the use of medication known to cause constipation.
2. Subject is a candidate for, or undergone abdominal surgery including bowel resection, colectomy, gastric bypass surgery (exceptions: appendectomy, cholecystectomy, benign polypectomy and inguinal hernia).
3. Subject has any gastrointestinal (GI) condition, other than constipation, affecting GI motility or defecation.
4. Subject has Hirschsprung*s disease.
5. Subject reports episodes of faecal incontinence that are not associated with retention of stool (e.g., non-retentive faecal incontinence as defined by the Rome III Diagnostic Criteria).
6. Subject has current evidence of untreated faecal impaction at the time of screening.
7. Subject has experienced an unexplained significant weight loss.
8. Subject has a medical/surgical condition that might interfere with the absorption, distribution, metabolism, or excretion of the study medication.
9. Subject has an uncontrolled cardiovascular, liver or lung disease, neurologic or psychiatric disorder, or other systemic disease, which the Investigator feels is clinically significant and would limit the subject*s ability to participate in the trial.
10. Subject is currently using an indwelling peritoneal catheter.
11. Subject has impaired renal function identified at the Screening Visit (i.e., serum creatinine concentration > 1.5 times the median of normal range).
12. Subject has abnormal laboratory test (haematology, urinalysis, or blood chemistry), which in the Investigator*s opinion is clinically significant, unexplained, and would limit the subject*s ability to participate in the trial.
13. Subject has current evidence of, or has been treated for, cancer within the past 5 years.
14. Subject (female of childbearing potential) has a positive pregnancy test, refuses/unwilling to undergo pregnancy testing, and/or does not agree to use protocol-specified contraceptive for the duration of the study.
15. Subject or parent/legal guardian demonstrates a potential for non-compliance with study protocol (i.e., dosing schedule, visit schedule, diary completion, or study procedures).
16. Subject has received an investigational medication within 30 days prior to the Screening Visit (Visit 1), or plans to participate in another clinical trial during the study period.
17. Subject has received AMITIZA, lubiprostone, SPI-0211, or RU-0211 at any time prior to participation in this study.;Exclusion Criteria*:
1. Subject has serum 25(OH) vitamin D level <20 ng/mL at Screening.
2. Subject has a history of bone disorders (e.g., rickets, osteogenesis imperfecta, rheumatoid arthritis, severe scoliosis), back surgery/injuries, endocrine disorders, anorexia nervosa, and/or use of anticonvulsants, bisphosphonates, or Depo-Provera.
3. Subject has a history of chronic use of inhaled/oral corticosteroids within 6 months prior to the Screening Visit (Visit 1), or plans to initiate use of inhaled/oral corticosteroids at any point during the study.
* These criteria will be used to determine subjects who qualify for the DXA evaluation subgroup, and not for overall study eligibility.
A subject*s participation in the DXA evaluation sub-study will be re-assessed for the following criteria post randomization once the results from the central DXA reading are obtained and results from the central lab are received:
* Inclusion Criterion #2: Subject has a bone mineral density (BMD) Z-score (normalized for age and gender) greater than -2.0, as assessed by DXA.
* Exclusion Criterion #1: Subject has serum 25(OH) vitamin D level <20 ng/mL
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
EudraCT | EUCTR2013-003468-30-NL |
CCMO | NL46082.018.14 |