Drug Combinations for Bacterial Pneumonia

(REITAB-2 Trial)

No longer recruiting at 38 trial locations

Overseen By Yuanyuan Pan

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Sinovent Pty Ltd.

Must not be taking: Valproic acid, Divalproex sodium

Disqualifiers: Immunodeficiency, Seizure disorder, Liver disease, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 14 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug combination for treating bacterial pneumonia acquired in hospitals or while on ventilators. Researchers aim to determine if the new combination (IMI-XNW4107) matches the effectiveness of the current standard treatment (IMI/REL, which includes Imipenem and Relebactam) in reducing deaths from these infections. Individuals who develop bacterial pneumonia after being hospitalized for over two days or after being on a ventilator for at least 48 hours may be suitable candidates for this trial. As a Phase 3 trial, this study serves as the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop all current medications. However, you cannot take Valproic acid, divalproex sodium, or certain antibacterial, antifungal, or antiviral therapies for the infection being studied. If you have a seizure disorder requiring treatment, you may not be eligible.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot take certain antibiotics, antifungal, or antiviral drugs for the infection being studied. You also cannot take Valproic acid or divalproex sodium.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that imipenem/cilastatin/relebactam (IMI/REL) is generally safe for people. In studies, about 26.7% of patients experienced serious side effects, similar to other treatments for bacterial infections. This indicates that the safety of IMI/REL is comparable to existing options.

For imipenem/cilastatin-XNW4107 (IMI-XNW4107), less safety information is available. However, its current stage in clinical trials suggests it has demonstrated a reasonable safety profile so far. This stage typically confirms that the treatment is safe and effective compared to current treatments. Some studies have indicated that XNW4107 was well-tolerated by patients with similar infections.

Both treatments are being tested to ensure safety and effectiveness for hospital-acquired and ventilator-associated bacterial pneumonia. Always consult a healthcare provider for personal medical advice before joining a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for bacterial pneumonia because they offer potential advancements over standard antibiotics like amoxicillin-clavulanate or azithromycin. The combination of Imipenem, Cilastatin, and Relebactam is unique as it includes Relebactam, a beta-lactamase inhibitor that enhances the effectiveness of Imipenem against resistant bacteria. Meanwhile, the experimental combination with XNW4107 aims to boost the antibiotic activity further. These treatments target resistant strains more effectively, potentially improving outcomes for patients who don't respond to existing medications.

What evidence suggests that this trial's treatments could be effective for bacterial pneumonia?

Research has shown that the combination of imipenem, cilastatin, and relebactam (IMI/REL), which participants in this trial may receive, effectively treats bacterial pneumonia acquired in hospitals or through ventilators (HABP/VABP). In studies, about 87.5% of patients responded positively to this treatment, highlighting its strong effectiveness.

Another treatment option in this trial is imipenem/cilastatin-XNW4107 (IMI-XNW4107), a newer treatment being tested for similar conditions. Although limited data exist on its effectiveness in people, imipenem/cilastatin alone has demonstrated a 70% success rate in treating severe infections like pneumonia. XNW4107 is expected to enhance these results, but further research is needed to confirm its benefits. ^{1 2 6 7 8}

Who Is on the Research Team?

Jason Le

Principal Investigator

Evopoint Biosciences USA, Inc.)

Are You a Good Fit for This Trial?

This trial is for adults with hospital-acquired or ventilator-associated bacterial pneumonia who need IV antibiotics. They must have symptoms like cough, fever, and changes on chest X-rays suggestive of pneumonia. Women of childbearing age and men with partners must agree to use birth control during the study.

Inclusion Criteria

I have a lung infection needing IV antibiotics, starting after hospital stay or ventilation.

I have symptoms like coughing, difficulty breathing, or fever.

You have high levels of white blood cells or immature neutrophils in your laboratory tests.

Exclusion Criteria

I have been treated with antibiotics for a lung infection for more than 24 hours in the last 3 days.

You are expected to live for less than 3 days.

You have abnormal test results in your blood samples taken before the study starts.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Imipenem/Cilastatin-XNW4107 or Imipenem/Cilastatin/Relebactam for the treatment of bacterial pneumonia

Up to 14 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments at test-of-cure and late follow-up

Up to 31 days

What Are the Treatments Tested in This Trial?

Interventions

• Cilastatin
• Imipenem
• Relebactam

Trial Overview The study compares two antibiotic treatments for bacterial pneumonia: Imipenem/Cilastatin combined with XNW4107 versus Imipenem/Cilastatin/Relebactam. The goal is to see if the first combination is just as effective in reducing death rates as the second.

How Is the Trial Designed?

Group I: Imipenem/Cilastatin/XNW4107 Experimental Treatment 1 Intervention

Imipenem/Cilastatin 500mg/500mg in combination with XNW4107 250mg, Q6h (0.5h Infusion)

Group II: Imipenem/Cilastatin/Relebactam Active Control 1 Intervention

Imipenem/Cilastatin/Relebactam 1.25g Q6h (0.5h Infusion)

Cilastatin is already approved in United States, China for the following indications:

Approved in United States as Cilastatin for:

• Bone and joint infections
• Endocarditis
• Gynecological infection
• Infectious Diseases
• Intraabdominal Infections
• Lower Respiratory Tract Infections
• Sepsis
• Skin and skin structure infections
• Urinary Tract Infections

Approved in China as Cilastatin for:

• Bacterial Infections

Who Is Running the Clinical Trial?

Sinovent Pty Ltd.

Lead Sponsor

Trials

8

Recruited

1,500+

Evopoint Biosciences Inc.

Lead Sponsor

Trials

15

Recruited

2,800+

Published Research Related to This Trial

In a multicenter trial involving 14 patients with aspiration pneumonia, imipenem/cilastatin sodium (IPM/CS) demonstrated a high efficacy rate of 78.6%, with excellent or good clinical effects in 11 out of 14 cases.

While IPM/CS was generally effective, treatment failures were associated with Pseudomonas aeruginosa, indicating that this specific organism may be resistant to the therapy and could require alternative treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical evaluation of therapy for aspiration pneumonia with imipenem/cilastatin sodium]. Kikuchi, N., Onozaki, I., Kohno, N., et al.[2018]

In a study of 52 patients with moderate to severe infections, imipenem/cilastatin sodium (IPM/CS) demonstrated an overall clinical efficacy of 86.4%, with particularly high efficacy (93.9%) in patients who had not been previously treated with other antibiotics.

The treatment was found to be safe, with only mild and transient adverse reactions reported in six patients, indicating that IPM/CS is a useful option for managing bacterial infections in internal medicine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical evaluation of imipenem/cilastatin sodium in the internal medicine]. Fukuhara, H., Kusano, N., Nakamura, H., et al.[2018]

In a study involving 20 adult patients with severe bacterial infections, imipenem/cilastatin sodium demonstrated a high efficacy, with 90% of patients showing satisfactory clinical responses and a 90% pathogen eradication rate.

Both imipenem/cilastatin and cefotaxime were found to be safe, with no major adverse effects reported in either treatment group, indicating that imipenem/cilastatin is a viable option for treating severe infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative clinical evaluation of imipenem/cilastatin vs. cefotaxime in treatment of severe bacterial infections. Stamboulian, D., Argüello, EA., Jasovich, A., et al.[2019]

Imipenem/cilastatin is a highly effective beta-lactam antibiotic with a broad antibacterial spectrum, effective against a wide range of gram-positive, gram-negative, and anaerobic organisms, making it suitable for various infections.

The combination of imipenem with cilastatin enhances its effectiveness by preventing its breakdown in the kidneys, and clinical trials have shown it to be as effective as combination therapies for treating serious infections like soft tissue infections and pneumonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imipenem/cilastatin: the first carbapenem antibiotic. Lyon, JA.[2013]

Imipenem-cilastatin is a highly effective broad-spectrum antibiotic that works against a wide range of bacteria, including both gram-positive and gram-negative organisms, making it a strong option for treating serious infections.

While imipenem-cilastatin is generally safe and effective, it should be used with caution in patients with serious pseudomonal infections, as resistance can develop quickly; combining it with an aminoglycoside is recommended to prevent this issue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imipenem-cilastatin sodium, a broad-spectrum carbapenem antibiotic combination. Pastel, DA.[2018]

In a study of 25 patients with severe hospital infections, imipenem/cilastatin alone had a 62% response rate, while the combination with amikacin increased the response rate to 80%, indicating that the combination may enhance treatment efficacy.

Imipenem/cilastatin was generally well tolerated, but treatment was interrupted in some cases due to resistance development or side effects, suggesting that combining it with amikacin could help prevent resistance and improve outcomes, especially in challenging infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imipenem/cilastatin in the treatment of severe hospital infections. Patoia, L., Menichetti, F., Bucaneve, G., et al.[2013]

In a phase 3 trial involving 537 patients with hospital-acquired or ventilator-associated bacterial pneumonia, imipenem/cilastatin/relebactam demonstrated noninferior efficacy compared to piperacillin/tazobactam, with a lower day 28 all-cause mortality rate of 15.9% versus 21.3%.

Imipenem/cilastatin/relebactam was found to be a safe treatment option, with serious adverse events occurring in 26.7% of patients, which is lower than the 32.0% seen in the piperacillin/tazobactam group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized, Double-blind, Multicenter Trial Comparing Efficacy and Safety of Imipenem/Cilastatin/Relebactam Versus Piperacillin/Tazobactam in Adults With Hospital-acquired or Ventilator-associated Bacterial Pneumonia (RESTORE-IMI 2 Study). Titov, I., Wunderink, RG., Roquilly, A., et al.[2022]

Imipenem/cilastatin/relebactam (Recarbrio™) is effective against hospital-acquired and ventilator-associated bacterial pneumonia, as well as complicated urinary tract and intra-abdominal infections, particularly in patients with limited treatment options.

In clinical trials, it was found to be noninferior to piperacillin/tazobactam and imipenem/cilastatin, and it has a safety profile similar to imipenem/cilastatin, making it a well-tolerated option for treating serious gram-negative infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imipenem/Cilastatin/Relebactam: A Review in Gram-Negative Bacterial Infections. Heo, YA.[2022]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S1341321X20303524

The safety and efficacy of relebactam/imipenem/cilastatin ... The proportion of cIAI and cUTI patients achieving favorable responses were 85.7% (n = 24/28) and 100.0% (n = 39/39), respectively. All patients with sepsis ( ...

2. tandfonline.com tandfonline.com/doi/full/10.2147/IDR.S224228

A Clinical Review and Critical Evaluation of Imipenem ... The primary efficacy endpoint of favorable overall response was 71.4% and 70% in the modified microbiologic intent-to-treat I-R and IMI+CST ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12465972/

Efficacy and safety of imipenem/cilastatin/relebactam (IMI/ ... A total of 1087 patients participated in the study for clinical response. The clinical response rate of the IMI/CS/REL group was 87.5% (477/545) ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8662781/

PMC - PubMed Central We evaluated efficacy and safety of imipenem/cilastatin/relebactam in treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP).

5. academic.oup.com academic.oup.com/cid/article/70/9/1799/5546004

RESTORE-IMI 1: A Multicenter, Randomized, Double-blind ... Favorable overall response was observed in 71% imipenem/relebactam and 70% colistin+imipenem patients (90% confidence interval [CI] for ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2019/212819Orig1s000MultidisciplineR.pdf

Multi-Discipline Review - accessdata.fda.gov Safety Database for Imipenem/Relebactam ... No other genetic toxicology studies for relebactam, imipenem, or cilastatin were submitted.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02493764

NCT02493764 | Imipenem/Relebactam/Cilastatin Versus ... This study aims to compare treatment with a fixed-dose combination (FDC) of imipenem/relebactam/cilastatin (IMI/REL) with a FDC of piperacillin/tazobactam ...

8. list.essentialmeds.org list.essentialmeds.org/recommendations/1425/print?format=pdf

Imipenem + cilastatin + relebactam The applicants presented the safety data for imipenem + cilastatin + relebactam for each interventional study in the previous section. In the RESTORE-IMI 1 ...