Congenital Disorders, Microvillus Inclusion Disease, Rare Diseases
Conditions
Brief summary
A study that will evaluate the safety, tolerability and preliminary efficacy of multiple ascending doses of crofelemer, compared to placebo, using a randomized cross-over design within each dose level, when administered to participants with MVID receiving parenteral support (PS, defined as TPN with or without supplementary IV fluid requirements). Blinded study drug will be administered as a novel crofelemer formulation, Crofelemer Powder for Oral Solution, or a matching placebo powder formulation for oral solution. Assigned study drug will be reconstituted and administered orally (or enterally) three times daily (TID) as a concentrated liquid formulation in each of the three dose levels.
Detailed description
The study consists of an initial randomized double-blind placebo-controlled study, followed by an up to 48-week partially blinded extension phase. The double-blind study phase is a randomized, double-blind, placebo-controlled, dose-escalating study with a placebo crossover design within each dose level in this ultra-rare MVID participant population. For the primary objective, safety and tolerability, comparisons between the crofelemer and placebo, across treatment periods within each dose level and through the end of the double-blind treatment period will be descriptively summarized. For secondary objectives, changes from the Baseline Period will be assessed. After completion of the study and the No Treatment Period, if the Investigator and the DMC consider it appropriate for the participant's best interest based on safety and tolerability, the participant will be eligible to enter a Partially Blinded Extension Phase. Following approval by the DMC, the participant will enter the extension phase for up to 48 additional weeks of treatment with crofelemer at the dose selected by the DMC. The Investigator and the Sponsor will remain blinded to the selected dose.
Interventions
Crofelemer Powder for Oral Solution
Matching Placebo Powder for Oral Solution
Sponsors
Napo Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The double-blind phase is a randomized, double-blind, placebo-controlled, dose-escalating study with a placebo cross-over design within each participant at each dose level in this ultra-rare MVID participant population. During the partially blinded extension phase, participants will receive crofelemer at a dose selected by the DMC, with the Investigator and the Sponsor remaining blinded to the selected dose.
Intervention model description
Each dose level will include 2 4-week Treatment Periods for a total of 8 weeks. There will be 3 ascending dose levels for a total of 24 weeks of treatment with either crofelemer or placebo, with safety reviews between dose levels. Within the 24 weeks of treatment, each of crofelemer and placebo will have been administered at 3 ascending dose levels for 4 weeks each, totaling 12 weeks. After completion of the study and the No Treatment Period, eligible participants will be able to receive crofelemer at a blinded dose selected by the DMC for up to 48 additional weeks of treatment.
Eligibility
Sex/Gender
ALL
Age
No minimum to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Participants (assent for participants older than 7 years of age) and/or their legal parent/guardian sign an Informed Consent Form (ICF) indicating that they understand the purpose of the procedures required for the study and are willing to participate 2. When appropriate, pediatric participants, whose age, cognitive skills, reading abilities and maturity allow the understanding of the study protocol should provide written assent to participate. 3. Male or female participants from birth to \< 18 years at the time of signing the informed consent or providing assent 4. Have a confirmed diagnosis (genetic and/or histologic) of MVID 5. Are able to ingest reconstituted Crofelemer Powder for Oral Solution either orally (PO) or through a previously-placed G-tube or GJ-Tube (not via J-Tube) 6. Have, during the 8 weeks prior to baseline, an average weekly volume of PS that represents at least 50% (≥ 50%) of the participant's weekly hydration volume requirements 7. If female participants have reached menarche, the participant (and caregiver) agree that the participant will remain abstinent or use two accepted methods of birth control during the course of the treatment period and for an additional 30 days following the last dose of study drug. 8. Male participants (and caregiver) agree that the participant will remain abstinent or use contraception during the course of the treatment period and continue on for an additional 90 days following the last dose of study drug.
Exclusion criteria
1. Within the last 4 weeks before study initiation, participants have: 1. had significant changes to PS requirements (i.e., ± \> 20%) 2. had a new requirement for diuretics 3. had any infection requiring IV antibiotic administration 4. had a documented active gastrointestinal infection 5. initiated any new anti-diarrheal drug 6. had an increase in ALT, AST, or total bilirubin that is ≥2 times the participant's usual laboratory values 2. previously received an organ transplant 3. any currently-diagnosed malignancy 4. is pregnant or breastfeeding 5. any investigator determined criteria for inability to participate in this study 6. Known hypersensitivity to any of the components of study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability | 32 Weeks | Incidence of Adverse Events and Serious Adverse Events |
| Changes in Physical Examination | 32 Weeks | Changes from baseline in physical exam and signs of dehydration, such as decreased urine output, sunken eyes, lethargy and abnormal skin turgor. |
| Changes in Laboratory Values | 32 Weeks | Incidence in changes from baseline of individual lab values within a chemistry, hematology and metabolic panel analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average PS Volume Requirements Normalized to Body Weight | Average Weekly for 32 weeks | Record daily weekly TPN and IV fluid volume requirements in the Daily TPN and IV Fluid Diary, and divide the value per body weight for the corresponding study visit (mL/kg) |
| Average Loose/Watery Stool Volume | Average every 2 weeks for 32 weeks | Measure and record the volume of loose/watery stools using a toilet hat for stool collection during 24 hours before each study visit |
| Average TPN (including lipids) Volume Requirements | Average weekly for 32 weeks | Record daily weekly TPN volume requirements in the Daily TPN and IV Fluid Diary |
| Average Supplemental IV Fluids Volume Requirements | Average weekly for 32 weeks | Record daily weekly supplemental IV fluid volume requirements in the Daily TPN and IV Fluid Diary |
| Average Supplemental Electrolytes | Average weekly for 32 weeks | Record daily any supplements of Na+, K+, Cl- in PS and, separately in TPN and in IV fluids, in the Daily PS Diary |
| Average Acetate or Lactate Supplementation | Average weekly for 32 weeks | Record daily any supplements of acetate or lactate in PS and, separately in TPN and in IV fluids, in the Daily PS Diary |
| Stool Electrolytes | Measurement at baseline, week 20 and week 24 | Stool electrolytes (Na+, K+, Cl-) concentration measured in mEq/L |
Countries
Italy, United Arab Emirates, United States
Contacts
PRINCIPAL_INVESTIGATORLissette Jimenez, MD, MPH
Boston Children's Hospital
STUDY_CHAIRPravin Chaturvedi, PhD
Napo Pharmaceuticals, Inc.
Outcome results
None listed