Rifampin for Genetic Disorders Related to High Calcium Levels

(RICHH Trial)

Overseen By Vashisht Arshanapally

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's Hospital of Philadelphia

Must not be taking: CYP3A4 inhibitors

Disqualifiers: Pregnancy, Breastfeeding, Hepatic disease, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 12

Duration: 16 weeks

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test whether rifampin, a medication, can lower high calcium levels in individuals with a specific genetic mutation. The focus is on those with elevated calcium in their blood or urine due to a change in the CYP24A1 gene. Participants will take rifampin for 16 weeks to determine if it improves their condition. Ideal candidates have high calcium levels and this genetic change and are not currently on medications that interact with rifampin. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

You may need to stop taking your current medications if they interact with rifampin, specifically if they affect certain liver enzymes (CYP3A4 or CYP3A5). It's best to discuss your current medications with the study team to see if they are compatible with the trial.

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

Research has shown that rifampin is usually well-tolerated when used to lower high calcium levels in certain conditions. In past studies, patients taking rifampin generally did not experience many serious side effects. For instance, one study found that people treated with rifampin had stable reductions in calcium levels without major problems. Another study reported that even high doses of rifampin, used for other conditions, were as safe and tolerable as standard doses. This suggests that rifampin is likely safe for managing high calcium levels related to genetic disorders. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for high calcium levels?

Rifampin is unique because, unlike standard treatments for high calcium levels that generally focus on calcium reduction or hormone regulation, it acts on the underlying genetic disorders causing these imbalances. Researchers are excited about rifampin because it targets specific genetic pathways, potentially offering a more precise treatment with fewer side effects. This approach could provide a novel way to manage conditions associated with high calcium levels, which traditional therapies may not address directly.

What evidence suggests that rifampin might be an effective treatment for high calcium levels?

Research has shown that rifampin effectively lowers high calcium levels in patients with certain genetic disorders. Studies indicate that rifampin helps normalize blood calcium levels and improves kidney function in these individuals. For instance, one study found that after two months of treatment, patients had normal calcium levels and better kidney function. Additionally, rifampin has proven safe for long-term use, making it a promising treatment for high calcium levels caused by genetic mutations. Participants in this trial will receive escalating doses of rifampin to further evaluate its effectiveness and safety. ^{2 3 4 6 7}

Who Is on the Research Team?

Michael A Levine, MD

Principal Investigator

Children'sHospital of Philadelphia

Are You a Good Fit for This Trial?

This trial is for individuals aged 6 months to 65 years with genetic disorders causing high calcium in blood/urine due to CYP24A1 mutations. They must have normal or elevated vitamin D3 and low parathyroid hormone levels. Excluded are those allergic to rifampin, on conflicting meds, pregnant/breastfeeding, or with significant liver/kidney disease.

Inclusion Criteria

I am between 6 months and 65 years old.

My calcium levels are higher than normal.

My tests show a CYP24A1 mutation.

Exclusion Criteria

Pregnancy or breastfeeding

Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures

Your liver or kidney function tests show significant abnormalities, with levels more than twice the normal limit for certain substances in the blood.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Observation

Participants are observed for baseline measurements and initial assessment

8 weeks

Baseline and every 4 weeks

Treatment

Participants receive escalating doses of rifampin (5 and 10 mg/kg/day) to assess effect, safety, and tolerability

16 weeks

Baseline and every 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 weeks

Every 4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Rifampin

Trial Overview The study tests the effectiveness of rifampin in treating high calcium levels in blood and urine linked to specific genetic mutations. Participants will take rifampin for 16 weeks to see if it helps manage their condition.

How Is the Trial Designed?

Group I: All Subjects Experimental Treatment 1 Intervention

SingleArm: Escalating doses of rifampin (5 and 10 mg/kg/day) (SingleArm)

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

Approved in United States as Rifampin for:

• Tuberculosis
• Meningitis
• Osteomyelitis
• Brucellosis
• Legionnaires' disease

Approved in European Union as Rifampicin for:

• Tuberculosis
• Meningitis
• Osteomyelitis
• Brucellosis
• Legionnaires' disease

Approved in Canada as Rifampin for:

• Tuberculosis
• Meningitis
• Osteomyelitis
• Brucellosis
• Legionnaires' disease

Who Is Running the Clinical Trial?

Children's Hospital of Philadelphia

Lead Sponsor

Trials

749

Recruited

11,400,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Published Research Related to This Trial

Familial Mediterranean fever (FMF) is a genetic condition primarily affecting populations around the Mediterranean, characterized by recurrent inflammatory attacks, and can lead to severe complications like amyloidosis and renal failure.

Colchicine is the standard treatment for FMF, effectively controlling attacks and preventing amyloidosis in most patients; however, 5-10% of patients do not respond to this treatment, highlighting the need for new therapeutic options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Familial mediterranean fever - a review and update. Orbach, H., Ben-Chetrit, E.[2022]

Familial Mediterranean fever (FMF) is an under-diagnosed hereditary auto-inflammatory disorder primarily affecting populations around the Mediterranean, caused by mutations in the MEFV gene that regulates inflammation.

Colchicine remains the only effective treatment for preventing acute FMF episodes and the associated risk of amyloidosis, despite the emergence of alternative therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Familial Mediterranean fever: an ancient hereditary disease]. Nucera, G., La Regina, M., Diaco, M., et al.[2006]

Familial Mediterranean fever (FMF) is a hereditary inflammatory disease caused by mutations in the MEFV gene, leading to uncontrolled inflammation and potentially severe complications like amyloidosis and chronic renal failure.

Daily colchicine treatment is effective in managing FMF, providing complete remission or significant reduction in symptoms for most patients, and it also helps prevent the development of renal amyloidosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Familial Mediterranean fever. Onen, F.[2022]

In a study of 110 patients with familial Mediterranean fever (FMF), those who did not respond to colchicine treatment had significantly lower concentrations of colchicine in their mononuclear cells compared to responders, suggesting that treatment failure may be linked to inadequate drug levels in these cells.

Both responders and nonresponders primarily carried the M694V mutation in the MEFV gene, but nonresponders tended to come from lower socioeconomic backgrounds and had a more severe form of the disease, indicating that factors beyond genetics may influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Colchicine nonresponsiveness in familial Mediterranean fever: clinical, genetic, pharmacokinetic, and socioeconomic characterization. Lidar, M., Scherrmann, JM., Shinar, Y., et al.[2022]

A 9-year-old boy was diagnosed with both Familial Mediterranean Fever (FMF) and Gitelman syndrome, highlighting the importance of genetic testing for accurate diagnosis in patients with overlapping symptoms.

The patient was effectively managed with oral potassium and magnesium supplements alongside colchicine for FMF, demonstrating a successful treatment strategy for managing both conditions simultaneously.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concomitance of Familial Mediterranean Fever and Gitelman syndrome in an adolescent. Atmış, B., Kışla-Ekinci, RM., Melek, E., et al.[2020]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35569070/

Long-term Efficacy and Safety of Rifampin in the Treatment ... Rifampin could represent an effective choice to induce a stable reduction of calcium levels in patients with HCINF1, with a good safety profile.

2. research.chop.edu research.chop.edu/study-of-rifampin-as-a-treatment-for-elevated-calcium-levels-in-patients-with-genetic-vitamin-d

Study of Rifampin as a Treatment for Elevated Calcium ... This study will take approximately 36 weeks (up to 48 weeks) and include 6 research study visits to the Children's Hospital of Philadelphia and an additional 5 ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0960076023000560

Rifampin monotherapy for children with idiopathic infantile ... More recently rifampin was shown to be a safe and effective long-term treatment for HCINF1 that induced normalization of serum calcium and improved renal ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10974048/

Exploring Variability in Rifampicin Plasma Exposure and ... Genetic polymorphisms can exert a considerable impact on drug pharmacokinetics (PK) and the development of adverse drug reactions (ADR).

5. researchgate.net researchgate.net/publication/364161892_Long-term_Efficacy_and_Safety_of_Rifampin_in_the_Treatment_of_a_Patient_Carrying_a_CYP24A1_Loss-of-Function_Variant

Long-term Efficacy and Safety of Rifampin in the Treatment ... Results In 2 months, rifampin induced a normalization of serum calcium (9.6 mg/dL) associated with an improvement of kidney function (eGFR 92 mL/min/1.73 m2) ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10441173/

Rifampin monotherapy for children with idiopathic infantile ... More recently rifampin was shown to be a safe and effective long-term treatment for HCINF1 that induced normalization of serum calcium and improved renal ...

7. journals.asm.org journals.asm.org/doi/10.1128/aac.01054-17

Pharmacokinetics, Tolerability, and Bacteriological Response ... Doses of 900 and 1,200 mg of rifampin in combination with other first-line anti-TB drugs were safe and as well tolerated as the standard dose ...