Reduce Crohn's-Associated Diarrhea With Sodium Channel Therapy (REACT)

• ClinicalTrials.gov Identifier: NCT04456517
• Recruitment Status: Enrolling by invitation
• First Posted: July 2, 2020
• Last Update Posted: May 24, 2022
• Sponsor: Vanderbilt University Medical Center
• Information provided by (Responsible Party): Dawn Beaulieu, Vanderbilt University Medical Center

Study Description

Brief Summary:

Crohn's disease is an inflammatory disorder that can affect any part of the gastrointestinal (GI) tract. Some patients still experience persistent diarrhea or other symptoms such as abdominal pain even when their Crohn's disease is in remission. Diarrhea and/or abdominal pain that is not responsive to standard therapies can significantly affect a patient's quality of life and ability to work. The purpose of this study is to test the safety and effectiveness of the drug ranolazine in reducing Crohn's disease-associated diarrhea and other symptoms. Ranolazine is approved by the US Food & Drug Administration (FDA) for chronic angina (a heart condition). This study is investigating if ranolazine could be used in the setting of Crohn's disease.

Condition or disease	Intervention/treatment	Phase
Crohn's Disease; Inflammatory Bowel Disease	Drug: Ranolazine; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 16 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Participants receive one of two alternative interventions during the initial phase of the study and receive the other intervention during the second phase of the study
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: REACT Trial: A Randomized, Double Blind, Placebo-controlled, Crossover Study of Ranolazine for the Treatment of Crohn's Disease-associated Diarrhea
• Estimated Study Start Date: September 1, 2022
• Estimated Primary Completion Date: June 2025
• Estimated Study Completion Date: December 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ranolazine, Then Placebo; - Participants first receive a Ranolazine 500 mg tablet twice daily for 12 weeks, they then receive a Placebo tablet (matching Ranolazine 500 mg tablets) twice daily for 12 weeks. This treatment will be given to participants with either active CD or patients with CD that is in remission but who experience continued symptoms	Drug: Ranolazine; 500 mg tablet; Drug: Placebo; Ranolazine-matched placebo tablet
Experimental: Placebo, Then Ranolazine; - Participants first receive a Placebo tablet (matching Ranolazine 500 mg tablets) twice daily for 12 weeks, they then receive a Ranolazine 500mg tablet twice daily for 12 weeks. This treatment will be given to participants with either active CD or patients with CD that is in remission but who experience continued symptoms	Drug: Ranolazine; 500 mg tablet; Drug: Placebo; Ranolazine-matched placebo tablet

Outcome Measures

Primary Outcome Measures :

1. Mean change in daily number of loose stools from baseline [ Time Frame: Baseline to Week 36 ]
   Daily number of loose stools and antidiarrheal use will be collected directly from all subjects using MyCap or, if installation and use of an app is not possible, through email with a survey link. MyCap is a secure mobile application developed by the REDCap team at Vanderbilt and integrated into the REDCap database system.

Secondary Outcome Measures :

1. Mean change in Crohn's Disease Activity Index (CDAI) score [ Time Frame: Baseline to Week 36 ]
   The Crohn's Disease Activity Index (CDAI) combines weighted scores of clinical and laboratory variables to estimate disease severity. The CDAI consists of eight variables, two of which are subjective, related to the disease, each weighted according to its ability to be predictive of disease activity. The absolute score ranges from 0 to 600. CDAI scores of less than 150 indicate a clinical remission and scores over 450 indicate severely active disease. Since blood draws will not be performed as part of this study, the hematocrit component of the CDAI will not be assessed.
2. Mean change in Harvey Bradshaw Index (HBI) score [ Time Frame: Baseline to Week 36 ]
   The Harvey-Bradshaw index (Harvey-Bradshaw Index - HBI) assesses the degree of illness (activity) in patients with Crohn's disease. The HBI consists of 5 items with a minimum score of 0 and a maximum attainable score depending on the number of stools the patient identifies per day. HBI scores < 5 are defined as clinical remission, HBI between 5 and 7 as mild disease, HBI between 8 and 16 as moderate disease, and HBI > 16 as severe disease.
3. Short Inflammatory Bowel Disease Questionnaire (SIBDQ) score [ Time Frame: Baseline, Day 84, and Day 168 ]
   The SIBDQ is a 10-item questionnaire measuring quality of life in four domains: bowel symptoms, emotional health, systemic symptoms, and social function and is scored on a 7-point Likert scale from 1 (severe problem) to 7 (no problems at all). The absolute score ranges are from 10 (poor Health-related quality of life) to 70 (optimum Health-related quality of life).
4. Patient Health Questionnaire (PHQ-9) score [ Time Frame: Baseline, Day 84, Day 168 ]

   The PHQ-9 is a 9-item questionnaire that screens for the presence and severity of depression and can be used to make a depression diagnosis using DSM-IV criteria.

   The PHQ-9 is scored on a 3-point Likert scale from 0 (not at all) to 3 (nearly every day). The absolute score ranges are from 0 (none or minimal depression) to 27 (severe depression).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Meet diagnostic criteria for Crohn's Disease with active diarrhea Either with active disease or in remission (as defined by endoscopic or radiographic findings) but experiencing symptoms (e.g., diarrhea, abdominal pain)
• Have greater than three loose stools per day

Exclusion Criteria:

• Male and female subjects <18 years of age

• Significant change in medication including prednisone, antidepressant medications, or stimulants within the last 4 weeks

  a. Allowances include: Rectal hydrocortisone, rectal mesalamine, addition of prednisone (up to 20mg) for flares, etc.

• Regular (daily) use of opioids or other drugs of abuse including heavy alcohol or marijuana use
• Severe psychiatric disease including schizophrenia, psychosis, suicidal depression
• Previous use of ranolazine within 2 months prior to enrollment
• Prior use of ranolazine which was discontinued for safety or tolerability
• Metabolic derangement defined as liver function tests >3x upper limit of normal or severe renal disease defined as calculated creatinine clearance <30 mL/min
• Have liver cirrhosis

• Concurrent use of CYP3A inhibitors, inducers, or substrates

  a. These may include: ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir, diltiazem, verapamil, erythromycin, fluconazole, grapefruit juice or grapefruit-containing products, rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John's Wort.

• Concurrent use of statin medications, Digoxine, TCA antidepressants or anti-psychotics, or metformin
• Concurrent use of OCT2 substrates
• Concurrent use of drugs transported by P-gp or drugs metabolized by CYP2D6
• Concurrent use of drugs known to prolong the QT interval
• A family history of (or congenital) long QT syndrome or known acquired QT interval prolongation
• Inability or refusal to give informed consent for any reason including a diagnosis of dementia or cognitive impairment
• Patients who are pregnant or breastfeeding
• Patients who are enrolled in other investigational drug studies or who have taken investigational drugs within 30 days before enrollment
• Other factors which in the opinion of the investigator could potentially impact the study outcomes (e.g., underlying disease, medications, history) or prevent the participant from completing the protocol (poor compliance or unpredictable schedule)

Contacts and Locations

Locations

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37212

Sponsors and Collaborators

Vanderbilt University Medical Center

Investigators

• Principal Investigator: Dawn B. Beaulieu, MD; Vanderbilt University Medical Center

More Information

• Responsible Party: Dawn Beaulieu, Principle Investigator, Vanderbilt University Medical Center
• ClinicalTrials.gov Identifier: NCT04456517
• Other Study ID Numbers: 200640
• First Posted: July 2, 2020
• Last Update Posted: May 24, 2022
• Last Verified: May 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The investigators agree to the timely release and sharing of information to be no later than the acceptance for publication of the main findings from the final data set. Investigators are also committed to ensuring that all data are free of identifiers that would permit linkage to individual research participation as well as variables that could lead to deductive disclosure of individual subjects.

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

Keywords provided by Dawn Beaulieu, Vanderbilt University Medical Center:

Diarrhea

Additional relevant MeSH terms:

Crohn Disease; Inflammatory Bowel Diseases; Diarrhea; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases; Signs and Symptoms, Digestive; Ranolazine; Sodium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action