Phase 1b/2 Multiple Ascending Dose Study of Intravenous XTMAB-16 in Patients with Pulmonary Sarcoidosis (with or without Extrapulmonary Manifestations)
- Trial ID
- 2022-502877-41-00
- Protocol
- XTMAB-16-201
- Sponsor
- Xentria Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and **tolerability** of multiple ascending doses of XTMAB-16 in participants with pulmonary sarcoidosis, with or without extrapulmonary manifestations. This is crucial for determining the recommended Phase 2 dose level and frequency for XTMAB-16, which will inform the subsequent phase of the study. Additionally, the study aims to establish the **efficacy** of XTMAB-16 by assessing its ability to reduce background oral corticosteroid use in the same patient population. This is clinically relevant as it may offer a therapeutic alternative for managing pulmonary sarcoidosis, potentially reducing the reliance on corticosteroids and their associated side effects.
Secondary objectives include: - Evaluating the potential therapeutic effect of XTMAB-16 in reducing oral corticosteroid use and maintaining this reduction. - Assessing the **pharmacokinetic** (PK) profile and **pharmacodynamic** (PD) effects of XTMAB-16, including its impact on immunogenicity and biomarkers. - Continuing to evaluate the safety and tolerability of XTMAB-16. - Further assessing the PK and PD of XTMAB-16 in patients with sarcoidosis, with or without extrapulmonary manifestations.
Participants
The clinical trial involves a total of **47 participants** diagnosed with **pulmonary sarcoidosis** with or without extrapulmonary manifestations. The study population includes both male and female subjects, aged between 18 to 80 years. Participants were selected based on their ability to understand and comply with protocol requirements, and they must weigh between 45 kg and 160 kg. The trial includes individuals who have been diagnosed with pulmonary sarcoidosis for at least six months prior to screening, as per the 2020 American Thoracic Society Clinical Practice Guideline or equivalent criteria. Participants are required to have a Modified Medical Research Conference Dyspnea Scale of ≥ 1 and must be receiving treatment with oral prednisone or equivalent, as well as other specified medications, with stable dosing prior to screening. Lifestyle considerations include refraining from grapefruit consumption during Part A of the study. The trial population also includes vulnerable groups, and all participants must have tested negative for SARS-CoV-2 at screening and provided written informed consent.
Plans and Procedures
The clinical trial is designed to evaluate the **safety** and efficacy of XTMAB-16 in patients diagnosed with pulmonary sarcoidosis, with or without extrapulmonary manifestations. This is a phase 1b/2 study, structured as a randomized, double-blind, placebo-controlled trial. The trial is divided into two parts: Part A focuses on safety and dose determination, while Part B assesses efficacy. The trial is expected to last until July 2026, with recruitment starting in September 2023.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, weight, and a confirmed diagnosis of pulmonary sarcoidosis. The screening will also involve a negative test for SARS-CoV-2. Following successful screening, participants will be randomized to receive either XTMAB-16 or a placebo. The study includes multiple follow-up visits to monitor safety, pharmacokinetics, and pharmacodynamics, as well as to assess the reduction in corticosteroid use. The end-of-study visit will evaluate the overall outcomes and any long-term effects.
The expected duration of participant involvement is approximately 24 weeks, with conditions for early termination including the occurrence of serious adverse events or non-compliance with the study protocol. The primary endpoints include the rate of adverse events and the pharmacokinetic profile of XTMAB-16, while secondary endpoints focus on the reduction of corticosteroid dosage and changes in biomarkers. The trial aims to establish a recommended dose for phase 2 and to demonstrate the potential of XTMAB-16 in reducing corticosteroid dependency in the target patient population.
Treatment
The clinical trial involves the administration of **XTMAB-16**, a biologic agent formulated as a **solution for infusion**. The active substance, XTMAB-16, is a protein-based therapeutic developed by XENTRIA, INC. The solution is administered **intravenously** to participants. The dosing schedule involves multiple ascending doses to evaluate safety and determine the recommended phase 2 dose level and frequency for patients with pulmonary sarcoidosis, with or without extrapulmonary manifestations. Participant compliance is monitored through regular assessments and infusion records.
**Prednesol 5mg Tablets** are used as a standard-of-care therapy in this trial. The active ingredient is **prednisolone sodium phosphate**, a chemical entity provided by PHOENIX LABS. The tablets are administered **orally** at a dosage of 5 mg. The frequency of administration is determined based on the participant's condition and response to treatment. Compliance is monitored through pill counts and patient diaries.
**PREZOLON® 5 mg Tablets** are also included in the study as a comparator treatment. The active substance is **prednisolone**, a chemical entity manufactured by TAKEDA HELLAS S.A. These tablets are administered **orally** at a dosage of 5 mg. The administration schedule is similar to that of Prednesol, with compliance monitored through similar methods.
A **placebo** is utilized in the trial, formulated as a 100 mg solution in a 20 mL vial. The placebo is designed to match the formulation of the drug product, excluding the active substance XTMAB-16. The placebo is administered in a manner consistent with the active treatment to maintain blinding and ensure the integrity of the study results.
Efficacy
The efficacy of XTMAB-16 in the clinical trial for patients with pulmonary sarcoidosis will be assessed primarily by evaluating the ability to reduce background oral corticosteroid use. The primary efficacy endpoint for Part B of the study is the proportion of participants who achieve the targeted tapered dose of corticosteroid (prednisone 5 mg/day or equivalent) by Week 12. Secondary efficacy endpoints include the proportion of participants who achieve at least a 50% reduction in corticosteroid dose by Week 12 and the ability to maintain steroid reduction through Week 24.
Biomarker changes will also be assessed as part of the efficacy evaluation. These include absolute and percent changes in biomarkers such as **Interleukin-6 (IL-6)**, soluble tumor necrosis factor alpha (sTNFα), and C-reactive protein (CRP) from baseline to Week 12 and Week 24. The study will also monitor the presence of anti-drug antibodies (ADA) and neutralizing antibodies (nAb) to XTMAB-16 at various time points, including baseline, Week 4, Week 8, Week 12, and Week 24, to assess immunogenicity.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant between 18 to 80 years (inclusive) of age.
- Weighs between 45 kg and 160 kg (99 to 353 lbs) at Screening.
- Diagnosis of pulmonary sarcoidosis (at least 6 months before Screening) using the 2020 American Thoracic Society (ATS) Clinical Practice Guideline (Crouser et al, 2020), the European Respiratory Society (ERS) or the WASOG criteria including a compatible clinical and radiologic presentation with other causes of granulomatous disease ruled out(cutaneous and ocular involvement permitted).
- Modified Medical Research Conference (mMRC) Dyspnea Scale of ≥ l.
- Receiving treatment of 7.5 to 25 mg/day of oral prednisone (or equivalent), during the screening period and, at the determination of the investigator, is capable of undergoing the protocol specific corticosteroid taper regimen.
- Receiving treatment with methotrexate, azathioprine, mycophenolate, leflunomide, chloroquine or hydroxychloroquine for at least 3 months before Screening that has been at a stable dose for 4 weeks before Screening. All efforts should be made to maintain stable background therapy at the Screening dose through the intervention period at the Investigator s discretion.
- PART A only: Willing to refrain from consumption of grapefruit or grapefruit juice [pomelos, exotic citrus fruits or grapefruit hybrids] from screening visit until after the final dose.
- Polymerase chain reaction (PCR) test or rapid antigen test negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at Screening.
- Able to provide written informed consent.
- In the opinion of the Investigator, the participant is capable of understanding and complying with protocol requirements.
Exclusion Criteria
- PART A ONLY: Known potentially significant fibrotic disease and/or active inflammation contained solely in the hilar region as shown by high-resolution computed tomography (HRCT), confirmed by a central reader. Participants with current active inflammation in the hilar region with concurrent inflammation outside the hilar region may be included. For participants with disease onset of <2 years, a historical computed tomography (CT) within 6 months prior to screening confirmed by a central read is acceptable. For participants with disease onset of >2 years and without a CT within 6 months prior to screening, a CT will be performed at Screening. Note: For all participants, regardless of their time of disease onset, if a historical HRCT is to be submitted for diagnosis confirmation, that HRCT must have been performed within 6 months of screening. If their last HRCT was from > 6 months prior to screening, then they will need to have an HRCT performed during screening for diagnosis confirmation. Note: Significant fibrotic disease is defined as > 20% fibrosis on HRCT
- Clinically significant pulmonary hypertension requiring treatment. Note: Clinically significant pulmonary hypertension requiring treatment would be defined as treatment with, i.e., prostacyclins, phosphodiesterase 5 inhibitors, and endothelin receptor antagonists.
- Known hypersensitivity to any component of the formulation of XTMAB-16.
- Live or messenger ribonucleic acid (mRNA) vaccination within 2 weeks before Day 1 or inoculation with a live or mRNA vaccine is planned during study participation.
- Evidence of active or latent TB by interferon-gamma release assay (IGRA) or invasive fungal infections at Screening.
- Known positive history of malignancy other than non-melanomatous skin cancer in the last 2 years, including in-situ carcinoma of the uterine cervix completely cured by radical surgery.
- Positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, coronavirus disease(COVID 19), TB, or a known history of human immunodeficiency virus (HIV) infection at Screening.
- Women of childbearing potential who are sexually active with a non-sterilized male partner and are not willing to adhere to adequate birth control measures from the time of signing the informed consent, throughout the duration of the study, and for 90 days after 5 half-lives have elapsed since the last dose of study drug.
- Male participants who are non-sterilized and sexually active with a female partner of childbearing potential and are not willing to use adequate contraception from the time of signing the informed consent throughout the duration of the study, and for 90 days after 5 half-lives have elapsed since last dose of study drug.
- Clinically significant hepatic or renal disease, including uncontrolled diabetes at the discretion of the investigator.
- Any severe prior reaction to any type of biologics or human blood product such as albumin, IgG, etc.
- PART A ONLY: Any prior TNFα inhibitor therapy.
- Concurrent emphysema.
- Known hypercalcemia due to non-sarcoidosis conditions such as untreated hyperparathyroidism, at the discretion of the investigator
- Abnormal ECG: ventricular arrhythmias (non-sustained ventricular tachycardia (VT), multifocal or frequent premature ventricular contractions, bundle branch block, axis deviation, or abnormal Q waves). In the case of a QTcF (corrected QT interval by Fredericia) interval >450 ms (men) or >480 ms (women; participants with bundle branch block) or PR interval outside the range of 120 to 220 ms, the assessment may be repeated once for eligibility determination at Screening or Baseline.
- Donation or loss of 450 mL or more of his or her blood volume (including plasmapheresis) or transfusion of any blood product within 90 days prior to dosing.
- Known uncontrolled hypertension. Note: Uncontrolled hypertension is noted as blood pressure ≥ 160/100 mmHg despite antihypertensive therapy within 3 months of randomization.
- Clinical signs and symptoms consistent with COVID-19, e.g., fever, dry cough, dyspnea, sore throat, fatigue, new smell or taste disorder or confirmed infection by appropriate laboratory test within the last 4 weeks prior to Screening.
- In the opinion of the investigator, inability to tolerate corticosteroid taper.
- Concurrent systemic steroid use for non-sarcoidosis conditions.
- Concurrent known auto-immune disease requiring treatment.
- Participation in another clinical trial of an investigational agent within 3 months (small molecule) / 6 months (biologics) or 5 half-lives (if known) of the agent, whichever is longer.
- Clinically significant extra-pulmonary sarcoidosis requiring systemic therapy as determined by the investigator
- Any condition that required hospitalization within the 3 months prior to Day 1 or is likely to require so during the study.
- Clinically significant abnormalities in the Screening physical exam, medical history, vital signs, ECG, or clinical laboratory tests that are not known to be due to concurrent sarcoidosis, and in the opinion of the Investigator and Medical Monitor should preclude the participant participation in the clinical study.
- PART B ONLY: Any therapy with an anti-TNF α monoclonal antibody (e.g., infliximab, adalimumab, golimumab and their biosimilars) within 6 months.
- Baseline percent predicted forced vital capacity (FVC) of <50%.
- Prior treatment with rituximab or repository corticotropin injection within the previous 12 months.
- Clinically significant Central Nervous System (CNS) sarcoidosis requiring therapy, except history of isolated seventh cranial nerve palsy or evidence of demyelinating neurologic disease.
- Advanced congestive heart failure (New York Heart Association [NYHA] 3 or 4).
- Current disease presentation consistent with Lofgren's syndrome (i.e., presence of the triad of erythema nodosum, bilateral hilar lymphadenopathy on chest X-ray, and joint pain).
- Pregnant or breastfeeding women or women who are planning to become pregnant during the study.
- PART A ONLY: Participants > 65 years of age.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Yet Recruiting | 11 Sept 2023 | 5 |
 Denmark | Not Yet Recruiting | 11 Sept 2023 | 12 |
 Greece | Not Yet Recruiting | 11 Sept 2023 | 8 |
 Italy | Not Yet Recruiting | 11 Sept 2023 | 9 |
 Poland | Not Yet Recruiting | 11 Sept 2023 | 5 |
 Spain | Not Yet Recruiting | 11 Sept 2023 | 8 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Prednesol 5mg Tablets | Other | TABLETS | ORAL | — | — | PRD359923 |
Placebo is formulated as 100 mg placebo in a 20 mL vial. The matching placebo has the same formulation as the drug product except it contains no XTMAB-16. | Placebo | N/A | — | — | — | N/A |
XTMAB-16 | Test | SOLUTION FOR INFUSION | INTRAVENOUS | — | — | PRD10268831 |
PREZOLON® 5 mg Δισκίο. | Other | ΔΙΣΚΊΟ | ORAL | — | — | PRD9263037 |