Reduce Crohn's-Associated Diarrhea With Sodium Channel Therapy

• Ranolazine (Drug): 500 mg tablet
• Placebo (Drug): Ranolazine-matched placebo tablet

Primary outcomes

• Daily Number of Loose Stools [Baseline to 12 weeks]: Daily number of loose stools will be collected directly from all subjects using MyCap.

Secondary outcomes

• Crohn's Disease Activity Index (CDAI) Score [Baseline to 12 weeks]: 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.
• Harvey Bradshaw Index (HBI) Score [Baseline to Week 12]: 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.
• Short Inflammatory Bowel Disease Questionnaire (SIBDQ) Score [Baseline to 12 weeks]: 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).
• Patient Health Questionnaire (PHQ-9) Score [Baseline to week 12]: 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).

Sex: All, ages: 18 Years to any

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, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir, clarithromycin, or rifampin, rifapentine, phenobarbital, phenytoin, and St. John's Wort, digoxin.
* 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)

Participant flow

Outcome results

• Daily Number of Loose Stools (Primary), Mean, number of liquid stools: Ranolazine 3.6 +/- 2.5; Placebo 4.5 +/- 3.4
• Crohn's Disease Activity Index (CDAI) Score (Secondary), Mean, score on a scale: Ranolazine 169 +/- 90.5; Placebo 117 +/- 88.1
• Harvey Bradshaw Index (HBI) Score (Secondary), Mean, score on a scale: Ranolazine 6.7 +/- 1.5; Placebo 5 +/- 3.1
• Short Inflammatory Bowel Disease Questionnaire (SIBDQ) Score (Secondary), Mean, score on a scale: Ranolazine 52 +/- 10.5; Placebo 54 +/- 10.1
• Patient Health Questionnaire (PHQ-9) Score (Secondary), Mean, score on a scale: Ranolazine 8.3 +/- 5.5; Placebo 7 +/- 3.9

Adverse events

Time frame: Baseline to 24 weeks

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2022-09-01)
• Informed Consent Form (PDF, 2020-10-14)

• Dawn B. Beaulieu, MD, Principal investigator, Vanderbilt University Medical Center