Rifaximin for Monoclonal Gammopathy

Overseen By Madhav Dhodapkar, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Emory University

Must not be taking: Antibiotics, Investigational agents

Disqualifiers: Clinical myeloma, Allergic to rifaximin, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 2 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of the antibiotic rifaximin for individuals with monoclonal gammopathy, a condition characterized by abnormal proteins or cells in the blood. Researchers aim to determine if rifaximin can reduce these proteins by targeting intestinal bacteria. The trial includes individuals diagnosed with specific types of monoclonal gammopathy, such as IgA, IgG, or IgM gammopathy, who have not taken antibiotics in the past three weeks. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this potentially groundbreaking therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have taken antibiotics in the last 3 weeks or be on other investigational agents for gammopathy.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that rifaximin is usually well-tolerated for various conditions. In studies involving individuals with irritable bowel syndrome with diarrhea (IBS-D), many participants tried rifaximin. Fewer than 10% experienced side effects such as nausea and headache. As an antibiotic, rifaximin primarily remains in the gut, limiting its spread through the body and reducing side effects.

Although specific information on using rifaximin for monoclonal gammopathy is lacking, its use in other conditions offers some insight into its safety. Prospective trial participants should consult a healthcare provider to understand the potential risks and benefits. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Rifaximin is unique because it offers a novel approach to treating monoclonal gammopathy by potentially modifying gut microbiota, which is a different strategy compared to standard treatments like chemotherapy or immunomodulatory drugs. This antibiotic is taken orally and works locally in the gut without significant systemic absorption, which could mean fewer systemic side effects. Researchers are excited about rifaximin because it targets the gut environment, offering a fresh angle that might improve patient outcomes with potentially lower toxicity.

What evidence suggests that rifaximin might be an effective treatment for monoclonal gammopathy?

Research suggests that rifaximin, an antibiotic, might help treat monoclonal gammopathy by eliminating certain gut bacteria. This could potentially lower levels of abnormal proteins or cells linked to the condition. Participants in this trial will receive rifaximin to explore its effects on monoclonal gammopathy. Although direct evidence on rifaximin's effectiveness for this condition is limited, its impact on gut bacteria is promising. In other contexts, rifaximin has changed the gut environment, which might help reduce harmful proteins. Early studies indicate a possible positive effect, but more research is needed to confirm its benefits specifically for monoclonal gammopathy. ^{5 6 7 8 9}

Who Is on the Research Team?

Ajay Nooka, MD

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

This trial is for individuals with monoclonal gammopathy, a condition where abnormal proteins are produced by the immune system. Participants must understand and sign consent, not have received antibiotics in the last 3 weeks or be on other investigational treatments for gammopathy. Women of childbearing potential and men must use contraception during and after the trial.

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent document

I have been diagnosed with a blood condition called MGUS.

Patients will be grouped based on the type of protein in their blood: IgA, IgG, or IgM.

Exclusion Criteria

Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of rifaximin administration

I have taken antibiotics in the last 3 weeks.

I am not on any experimental treatments for gammopathy and do not need therapy for clinical myeloma.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive rifaximin orally thrice daily for 2 weeks

2 weeks

Daily self-administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Rifaximin

Trial Overview The study is testing rifaximin, an antibiotic thought to reduce bacteria in the intestines that may be linked to monoclonal gammopathy. The goal is to see if it can decrease abnormal proteins or cells associated with this condition.

How Is the Trial Designed?

Group I: Treatment (rifaximin) Experimental Treatment 1 Intervention

Patients receive rifaximin PO TID on days 1-14 in the absence of disease progression or unacceptable toxicity.

Rifaximin is already approved in United States, Canada, European Union, India for the following indications:

Approved in United States as Xifaxan for:

• Traveler's diarrhea
• Irritable bowel syndrome with diarrhea
• Hepatic encephalopathy

Approved in Canada as Zaxine for:

• Traveler's diarrhea
• Irritable bowel syndrome with diarrhea
• Hepatic encephalopathy

Approved in European Union as Xifaxan for:

• Traveler's diarrhea
• Irritable bowel syndrome with diarrhea
• Hepatic encephalopathy

Approved in India as Ciboz and Xifapill for:

• Traveler's diarrhea
• Irritable bowel syndrome with diarrhea
• Hepatic encephalopathy

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

The Leukemia and Lymphoma Society

Collaborator

Trials

87

Recruited

26,200+

Published Research Related to This Trial

In a phase II study involving 37 patients with relapsed or refractory low-grade or follicular B-cell non-Hodgkin's lymphoma, Rituximab was found to be well tolerated, with most adverse events being mild and decreasing with subsequent infusions.

The treatment resulted in a 57% overall response rate, with 14% achieving a complete response and 43% a partial response, indicating significant clinical activity and suggesting that extended Rituximab treatment may be effective for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Piro, LD., White, CA., Grillo-López, AJ., et al.[2022]

In a phase II study involving newly diagnosed multiple myeloma patients, the addition of rituximab to melphalan and prednisone therapy did not improve response rates or event-free survival, indicating limited efficacy of this combination treatment.

Despite no complete remissions, 58% of patients achieved a partial response, and the treatment was generally well-tolerated, with manageable toxicity similar to standard MP chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of rituximab and oral melphalan and prednisone in newly diagnosed multiple myeloma. Baz, R., Fanning, S., Kunkel, L., et al.[2019]

Rituximab is a monoclonal antibody designed to target the CD20 antigen on B-lymphocytes, which is crucial for its role in treating lymphoproliferative disorders.

The review identifies four main mechanisms through which rituximab reduces B-lymphocyte populations, although the exact contributions of each mechanism to its overall clinical effectiveness are still not fully understood.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[THE MECHANISMS OF ACTION OF RITUXIMAB]. Gil'deeva, GN., Kudlai, DA., Luk'yanov, SV.[2016]

A retrospective review identified 19 patients with persistent hypogammaglobulinaemia after rituximab treatment, showing significantly low IgG levels and an inability to mount immune responses to vaccinations, indicating a potential long-term effect of the drug on immune function.

In an audit of 114 patients treated with rituximab, 23.7% exhibited hypogammaglobulinaemia, highlighting the need for clinicians to monitor for this condition and consider intravenous immunoglobulin (IVIG) therapy, even years after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypogammaglobulinaemia after rituximab treatment-incidence and outcomes. Makatsori, M., Kiani-Alikhan, S., Manson, AL., et al.[2015]

A patient developed drug-induced immune hemolytic anemia (DIIHA) after starting metaxalone, presenting with yellow skin and orange urine, highlighting that any medication can potentially cause this condition.

The patient's symptoms significantly improved after stopping metaxalone and starting treatment with glucocorticoids and rituximab, demonstrating effective management of DIIHA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metaxalone-induced Immune Hemolytic Anemia. Onyechi, A., Ohemeng-Dapaah, J., Patel, R., et al.[2023]

A patient with rifampicin-induced thrombocytopenia produced an antibody that specifically binds to the GPIb-IX complex, particularly the GPIX subunit, which was confirmed through various assays including flow cytometry and immunoprecipitation.

The study revealed that the binding site of the rifampicin-dependent antibody overlaps with that of quinine-dependent antibodies, suggesting a shared mechanism of drug-induced thrombocytopenia that could enhance our understanding of this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rifampicin-dependent antibodies bind a similar or identical epitope to glycoprotein IX-specific quinine-dependent antibodies. Burgess, JK., Lopez, JA., Gaudry, LE., et al.[2021]

Ciprofloxacin can cause serious side effects, including interstitial nephritis and autoimmune hemolytic anemia, with the combination of both being extremely rare.

In this case, the hemolytic anemia improved after discontinuing ciprofloxacin and starting steroid treatment, but the interstitial nephritis led to irreversible kidney damage and end-stage renal disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ciprofloxacin-induced acute interstitial nephritis and autoimmune hemolytic anemia. Lim, S., Alam, MG.[2019]

In a study of 177 patients with multisystem autoimmune disease treated with rituximab, 34% developed hypogammaglobulinaemia (low immunoglobulin levels) for at least three consecutive months, but severe infections were not directly linked to these low levels.

The incidence of hypogammaglobulinaemia was more closely associated with prior treatments like cyclophosphamide and glucocorticoids rather than the total dose of rituximab, suggesting that while rituximab is generally safe, careful monitoring is necessary, especially in patients with a history of these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of rituximab therapy on immunoglobulin levels in patients with multisystem autoimmune disease. Marco, H., Smith, RM., Jones, RB., et al.[2022]

Fluoroquinolone antibiotics generally have a favorable safety profile with mostly mild and reversible side effects, but postmarketing studies have revealed severe adverse events linked to some newer agents, leading to market withdrawals or restrictions due to serious risks like liver toxicity.

While older fluoroquinolones like ciprofloxacin and levofloxacin have not shown significant severe adverse events, caution is warranted with newer agents like moxifloxacin and gatifloxacin, as their long-term safety data is still limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety profile of the fluoroquinolones. Bertino, J., Fish, D.[2006]

Rifampin can cause serious side effects, including transient hemolytic anemia and acute renal failure, as demonstrated in a detailed case study.

The case revealed persistent anti-platelet antibodies even three weeks after stopping rifampin, suggesting that immune mechanisms may play a significant role in these adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse drug reaction to rifampin: a case with long lasting antiplatelet antibodies. Tricerri, A., Vangeli, M., Addario, C., et al.[2013]

Citations

1. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT07209371

Rifaximin Versus No Intervention for the Treatment of IgA ... Giving rifaximin may kill more precancerous cells in patients with IgA MGUS. OUTLINE: Patients are randomized to 1 of 2 arms.

2. georgiacancerinfo.org georgiacancerinfo.org/clinical-trials/detail/4629

Rifaximin in Treating Patients with Monoclonal Gammopathy Antibiotics, such as rifaximin, may help to kill bacteria in the intestines and reduce the abnormal protein or cells in patients with monoclonal gammopathy.

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2018-02106

Rifaximin in Treating Patients with Monoclonal Gammopathy Antibiotics, such as rifaximin, may help to kill bacteria in the intestines and reduce the abnormal protein or cells in patients with monoclonal gammopathy.

4. withpower.com withpower.com/trial/phase-1-monoclonal-gammopathy-of-undetermined-significance-4-2019-075a7

Rifaximin for Monoclonal Gammopathy · Info for Participants This trial studies how well rifaximin, an oral antibiotic, works in treating patients with monoclonal gammopathy. It aims to reduce abnormal blood proteins ...

5. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK362570/

DETAILED OUTCOME DATA - Rifaximin (Zaxine) Study 3001. RIFAXIMIN N = 140, PLACEB0 N = 159. Change in Conn Score. Increase, events at 6 months, 37, 77. Time to event, HR [95% CI], 0.463 [0.312, 0.685].

6. xifaxan.com xifaxan.com/hcp/ohe/safety-and-dosing/

Safety and Dosing for Overt HE | XIFAXAN® (rifaximin) Trial 1 safety data (occurring in ≥10% of patients)​​ Adverse reactions that occurred in ≥5% but <10% of patients receiving XIFAXAN and greater than in patients ...

7. go.drugbank.com go.drugbank.com/drugs/DB01220

Rifaximin: Uses, Interactions, Mechanism of Action Rifaximin is a rifamycin-based non-systemic antibiotic used for the treatment of gastrointestinal bacterial infections, such as traveler's diarrhea and ...

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2017/021361s023lbl.pdf

XIFAXAN® (rifaximin) tablets, for oral use - accessdata.fda.gov The safety of XIFAXAN for the treatment of IBS-D was evaluated in 3 placebo-controlled studies in which 952 patients were randomized to XIFAXAN 550 mg three ...

9. mayoclinic.org mayoclinic.org/drugs-supplements/rifaximin-oral-route/description/drg-20065817

Rifaximin (oral route) - Side effects & dosage Rifaximin is used to treat traveler's diarrhea that is caused by a bacteria called Escherichia coli. It is also used to prevent hepatic encephalopathy.