Study to Evaluate the Safety and Tolerability of AC-1101 Topical Gel in Patients with Granuloma Annulare

Overseen By Nicole Olszewski, study coordinator

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: TWi Biotechnology, Inc.

Must not be taking: Biologics, Immunosuppressives

Disqualifiers: Active malignancy, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: 5

Duration: 4 weeks

13 Participants Needed

Trial Summary

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

The trial protocol does not specify if you must stop taking your current medications, but it mentions that prescription medications should not be used within 14 days before the first dose, except for ongoing treatments for existing conditions as judged by the Investigator.

What safety data exists for the treatment known as AC-1101?

The treatment AC-1101, also known as BIA 10-2474, was involved in a first-in-human clinical trial that resulted in serious adverse events, including one death. This highlights the potential risks associated with novel treatments in early-phase trials, emphasizing the importance of careful safety assessments and monitoring. ^{1 2 3 4 5}

What is the purpose of this trial?

This trial tests a special skin-applied gel called AC-1101 on patients with Granuloma Annulare, a specific skin condition. The gel likely works by reducing inflammation or changing the immune response in the skin.

Research Team

William Damsky, M.D., Ph.D.

Principal Investigator

Yale Department of Dermatology

Eligibility Criteria

Inclusion Criteria

Adequate organ function and marrow function meaured at screening (Visit 1) and enrollment (Visit 2) as defined below: Hemoglobin ≥ 12.0 g/dL for male and 10.5 g/dL for female; Absolute neutrophil count ≥ 1,300 /µL; Absolute lymphocytes: 1.0-4.0 x 109/L (1000-4000 cells/mm3) as the reference range; Platelets ≥ 75,000/µL; Total bilirubin ≤ 1.5 x upper normal limit; AST(SGOT)/ALT(SGPT) ≤ 2.5 x upper normal limit; eGFR ≥ 60mL/min/1.73m2

Patients with 1-20% BSA of active Granuloma Annulare lesions will be enrolled.

Other subtypes of GA, such as linear, perforating, and subcutaneous will be excluded from the study. If there is suspicion that GA is medication-induced, the patient will not be enrolled. GA in association with human immunodeficiency virus (HIV) or malignancy will be excluded.

Exclusion Criteria

History of allergic reactions to tofacitinib or other related drugs, or to any excipient in the formulation.

Women of childbearing potential who are unable or unwilling to use birth control (oral pills, rings or patches are not permitted) while taking the medication.

Pregnant or breast-feeding women.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

Treatment

Participants receive AC-1101 topical gel for 4 weeks to assess safety, tolerability, and efficacy

4 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

1 visit (in-person)

Treatment Details

Interventions

• AC-1101

Participant Groups

Group I: Patients with Granuloma Annulare Experimental Treatment 1 Intervention

4-week treatment and 2-week follow-up period (without treatment)

Who Is Running the Clinical Trial?

TWi Biotechnology, Inc.

Lead Sponsor

Trials

10

Recruited

690+

Findings from Research

The first-in-human clinical trial of BIA 10-2474 resulted in serious adverse events for 6 healthy volunteers, including 1 death, highlighting the heightened risks associated with novel investigational drugs transitioning from animal studies to human trials.

The symposium emphasized the need for careful planning and communication in clinical trials to minimize risks to participants, suggesting that a complex matrix of factors must be considered to ensure safety and integrity in first-in-human studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety in FIH Trials: A Summary of the Symposium "Fatal Drug Trial in Phase 1: Understanding Risk, Subject Safety, Timelines, and Cost". Greenberg, HE., van Iersel, MT., Westrick, ML., et al.[2020]

In a five-year analysis of 1,559 healthy volunteers across 142 phase I studies, the overall incidence of adverse events (AEs) was 8.8%, with most AEs being mild or moderate in severity, indicating that while AEs are common, they are generally not severe.

The incidence of AEs was significantly higher in multiple-dose studies compared to single-dose trials, highlighting the importance of study design in assessing the safety profile of active drugs, with a notable increase in AEs on the first day of drug administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events in volunteers participating in phase I clinical trials: a single-center five-year survey in 1,559 subjects. Lutfullin, A., Kuhlmann, J., Wensing, G.[2019]

In a meta-analysis of 11,028 healthy participants across 394 non-oncology phase I studies, 63.7% experienced adverse events, but 85% of these were classified as mild, indicating a relatively safe profile for the study drugs.

Only 0.31% of participants experienced serious adverse events, with no deaths or life-threatening incidents reported, suggesting that while adverse events are common, they are mostly not severe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantifying the risks of non-oncology phase I research in healthy volunteers: meta-analysis of phase I studies. Emanuel, EJ., Bedarida, G., Macci, K., et al.[2018]

The recent fatal adverse event in the BIA-102474-101 clinical trial highlights significant limitations in the current safety review process for first-into-human trials, despite previous trials with similar compounds being conducted without incident.

To improve safety in future trials, it is crucial to implement sequential dosing strategies, thorough reviews of preclinical toxicity studies, and systematic risk assessments, especially for novel compounds that may pose higher risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implications of the BIA-102474-101 study for review of first-into-human clinical trials. Eddleston, M., Cohen, AF., Webb, DJ.[2021]

In a review of 24 Phase I studies involving 430 healthy male volunteers over 5 years, the overall incidence of adverse events was 13.5%, with a higher rate for active drug treatments (15.3%) compared to placebo (7.4%).

Severe adverse events occurred in 20 cases (0.36%), but there were no deaths or life-threatening incidents, indicating that while adverse events are common, they are generally not severe in Phase I trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events in phase one studies: a study in 430 healthy volunteers. Sibille, M., Deigat, N., Olagnier, V., et al.[2019]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Safety in FIH Trials: A Summary of the Symposium "Fatal Drug Trial in Phase 1: Understanding Risk, Subject Safety, Timelines, and Cost". [2020]

2. Germany pubmed.ncbi.nlm.nih.gov

Adverse events in volunteers participating in phase I clinical trials: a single-center five-year survey in 1,559 subjects. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Quantifying the risks of non-oncology phase I research in healthy volunteers: meta-analysis of phase I studies. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Implications of the BIA-102474-101 study for review of first-into-human clinical trials. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

Adverse events in phase one studies: a study in 430 healthy volunteers. [2019]