Pharmacokinetics and Pharmacodynamics of Rifaximin Novel Formulations in Patients With Sickle Cell Disease

Phase 2

Conditions: Sickle Cell Disease patients with history of VOCs
Anemia, Hemolytic, Congenital, Hematologic Diseases,

Registration Number: LBCTR2022095104

Lead Sponsor: Bausch Health LLC

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Complete

Sex: All

Target Recruitment: 9

Inclusion Criteria

A subject will be eligible for inclusion in this study if he/she meets all the following criteria:
1. Subject must have the ability and willingness to sign a written informed consent form.
2. Subject is between the ages of 18 to 70 years old (inclusive) at the time of consent.
3. Subject has SCD of any genotype (HbSS, HbSC, HbS ß-thalassemia). If the subject’s genotype has not been previously documented, genotyping will be performed during Screening using high-performance liquid chromatography (HPLC)/electrophoresis.
4. Subject must have experienced at least 2 VOCs within the 12 months prior to Screening. A VOC is defined as:
a. The occurrence of appropriate symptoms consistent with a painful crisis, acute chest syndrome (ACS), or priapism (Section 2.2.3) , and
b. Requires a visit to a medical facility and/or healthcare professional, and
c. Receipt of either a parenteral or oral opioid or NSAID analgesia.
5. If subject is receiving hydroxyurea (HU)/hydroxycarbamide (HC), subject must have been receiving the treatment for at least 6 months prior to Screening and must agree to maintain the same dose and schedule for the duration of the study.
6. Subjects must have laboratory values at Screening as follows:
a. Absolute Neutrophil Count (ANC) =1.0 x 109/L
b. Platelets = 75 x 109/L
c. Hemoglobin (Hgb) = 6.0 g/dL
d. Glomerular filtration rate (GFR) = 45 mL/min/1.73 m2 using the CKD-EPI formula
e. Total bilirubin = 15 mg/dL
f. Alanine transaminase (ALT) = 3.0 x ULN
g. International Normalized Ratio (INR) = 2.0
7. Eastern Cooperate Oncology Group (ECOG) performance status = 2
8. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must have a negative serum pregnancy Test at Screening and agree to use standard prevention methods for the duration of the study.

Exclusion Criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. Subject is receiving concomitant treatment with voxelotor, crizanlizumab, or L-glutamine.
2. Subject has any history of stem cell transplant, is planning to begin or has received in past 30 days.
3. Subject experiences an acute VOC, requiring a visit to a medical facility and/or healthcare professional, ending within 7 days prior to Day 1 dosing.
4. Subject has received any blood products within 30 days prior to Day 1 dosing.
5. Subject has uncontrolled liver disease or renal impairment, ulcerative colitis, Crohn’s disease, or other chronic GI disorder.
6. Subject has received active treatment in another investigational trial within 30 days or 5 half-lives of the last dose of the investigational agent, Whichever is greater, prior to Screening.
7. Subject has received penicillin prophylaxis or antibiotics for treatment of infection within 30 days or 5 half-lives of the treatment, whichever is greater, prior to Screening.
8. Subject has a significant medical condition that required hospitalization (other than for a VOC) within 2 months prior to Screening.
9. Subject is planning on undergoing an exchange transfusion during the duration of the study or has completed one within 4 weeks prior to Day 1 dosing.
10. Subject has a hypersensitivity to rifaximin, rifampin, rifamycin antimicrobial agents, or any components of rifaximin ER and DER.
11. Subject is pregnant or a nursing woman.
12. Subject has a history of illicit drug use or abuse, either documented or in the opinion of the Investigator.
13. Subject is using any medication that is known to inhibit or induce CYP3A4, P-gp and OATP1B1/B3 within 30 days or 5 half-lives, whichever is longer, prior to Day 1 dosing, or in the opinion of the Investigator, may affect the evaluation of the study product or place the subject at undue risk.
14. Subject has had any prior gastrointestinal surgery which has altered the anatomy of the esophagus, stomach, or small/large intestine (with the exception of appendectomy, cholecystectomy, and fundoplication).
15. Subject has had a colonoscopy or sigmoidoscopy within 30 days prior to Day 1 or plans to undergo such a procedure during the duration of the study.
16. Subject has used bowel prep, laxative, or enema within 30 days prior to Day 1.
17. Subject has a bleeding disorder including, but not limited to, acquired or congenital platelet function defects, disseminated intravascular coagulation (DIC), bleeding factor deficiencies, hemophilia, idiopathic thrombocytopenia purpura (ITP), or von Willebrand’s disease.
18. Subject is planning to undergo a major surgical procedure during the duration of the study.
19. Subject has a positive test for human immunodeficiency virus (HIV)1 or HIV2.
20. Subject has an active Hepatitis B infection (HBsAg positive). Prior infection that is not active (i.e., HBsAg negative, HBcAb positive, and HBsAb positive) is permitted.
21. Subject has a positive test for Hepatitis C (HCV RNA). Prior infection with spontaneous resolution or sustained resolution for = 24 weeks after cessation of antivirals is permitted.
22. Subject has an active COVID-19 infection or complication(s) related to COVID-19 infection that are unresolved or, in the opinion of the Investigator, may affect evaluation of the study drug or place the subject at undue risk.
23. Subjects has received a vaccine (including COVID-19 vaccine) within 2

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
ame: Plasma concentration of rifaximin and 25-desacetyl rifaximin for PK profiles;Timepoints: Day 1 and Day 29;Measure: Blood samples for PK analysis;Name: Cmax and Ctrough;Timepoints: Days 8, 15, and 29;Measure: Blood samples for PK analysis;Name: PD biomarkers ;Timepoints: Day 1, 8, 15, 29, 31, 43 and during medical facility visit for VOC, when possible;Measure: Collection of PD biomarkers (ANC, CANs, serum CD62L, hsCRP, the gut permeability biomarkers serum iFABP and LPS, and the gut bacteria biomarker urine 3-indoxyl sulfate)

Secondary Outcome Measures

Name	Time	Method
ame: Safety;Timepoints: throughout the duration of the study;Measure: Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs);Name: Safety;Timepoints: throughout the duration of the study;Measure: Clinically significant changes from Baseline in clinical laboratory results (chemistry, coagulation, hematology, urinalysis, and high sensitivity C-reactive protein (hsCRP), physical examinations, and electrocardiograms (ECGs));Name: Safety;Timepoints: throughout the duration of the study;Measure: Changes from Baseline in vital signs (systolic and diastolic blood pressure, heart rate, oral body temperature, and oxygen saturation);Name: Safety;Timepoints: throughout the duration of the study;Measure: Information on any potential VOCs occurence

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