A seamless, phase 1b/2 multiple ascending dose/proof of concept study of XTMAB-16 in patients with pulmonary sarcoidosis with or without extrapulmonary manifestations
- Trial ID
- 2022-502877-41-01
- 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. Additionally, the study aims to determine the recommended Phase 2 dose level and frequency for XTMAB-16. Establishing the safety profile and optimal dosing is crucial for ensuring patient safety and guiding future therapeutic use.
Secondary objectives include:
- Assessing the potential therapeutic effect of XTMAB-16 by its ability to reduce background oral corticosteroid use.
- Evaluating the pharmacokinetic (PK) profile and pharmacodynamic (PD) effects of XTMAB-16, including its impact on immunogenicity and biomarkers.
- Continuing to assess the safety and tolerability of XTMAB-16 in participants with pulmonary sarcoidosis, with or without extrapulmonary manifestations.
- Evaluating the efficacy of XTMAB-16 in maintaining reduced corticosteroid use.
Participants
The clinical trial involves a total of **70 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, at stable doses. Lifestyle considerations include refraining from grapefruit consumption during the trial. 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 seamless, phase 1b/2, multiple ascending dose/proof of concept study. The trial employs a randomized, double-blind, controlled design to ensure unbiased results. The estimated duration of the trial is from September 2024 to July 2026, with participant involvement expected to last up to 24 weeks, depending on the study part they are enrolled in.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, weight, and diagnosis. The screening visit will also include a **polymerase chain reaction (PCR)** test or rapid antigen test for SARS-CoV-2. Following successful screening, participants will be randomized to receive either XTMAB-16, a placebo, or Prednesol 5mg Tablets. The trial is divided into two parts: Part A focuses on safety and dose determination, while Part B assesses efficacy in reducing corticosteroid use.
Study visits will occur at regular intervals, including baseline, Week 4, Week 8, and Week 12, with additional follow-up assessments as needed. These visits will involve monitoring for adverse events, pharmacokinetic and pharmacodynamic assessments, and evaluation of biomarkers such as **angiotensin converting enzyme (ACE)** and **C-reactive protein (CRP)**. The end-of-study visit will occur at Week 24, where final assessments will be conducted to evaluate the long-term effects of the treatment.
Participants may be withdrawn from the study early if they experience severe adverse events, fail to comply with the protocol, or if the investigator deems it necessary for their safety. 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 use and changes in biomarkers. The trial aims to establish a recommended dose for phase 2 and demonstrate the potential of XTMAB-16 in managing pulmonary sarcoidosis.
Treatment
The clinical trial involves the administration of **XTMAB-16**, a biologic investigational drug, formulated as a **solution for infusion**. The active substance, XTMAB-16, is a protein of other origin, developed by XENTRIA, INC. The solution is administered **intravenously**. 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.
A **placebo** is utilized in the study, formulated as a 100 mg placebo in a 20 mL vial. The placebo matches the formulation of the drug product, excluding the active substance XTMAB-16. The placebo is administered in a manner consistent with the investigational drug to maintain blinding and ensure the integrity of the study results.
**Prednesol 5mg Tablets**, containing the active substance **prednisolone sodium phosphate**, are used as a standard-of-care therapy. These tablets are administered **orally**. Prednesol is a chemical entity provided by PHOENIX LABS, and it is used to manage background oral corticosteroid use in participants. The administration of Prednesol is adjusted based on the study's efficacy outcomes, specifically the ability of XTMAB-16 to reduce corticosteroid use. Compliance with Prednesol administration is monitored through patient diaries and pill counts.
Efficacy
The efficacy of XTMAB-16 in the clinical trial for patients with pulmonary sarcoidosis, with or without extrapulmonary manifestations, will be assessed primarily by evaluating the reduction in 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 evaluated as part of the efficacy assessment. These include absolute and percent changes in biomarkers such as **Interleukin-6 (IL-6)**, soluble tumor necrosis factor α (sTNFα), soluble interleukin-2 receptor (sIL-2R), C-reactive protein (CRP), calcitriol (Vitamin D 1, 25), and interleukin-1b (IL-1b) from Baseline to Week 12 and 24. The collection of these biomarkers will occur at specified timepoints, including Baseline, Week 4, Week 8, and Week 12, with follow-up assessments to determine transient and persistent positive status.
Patient-reported outcomes will be measured using validated tools such as the King's Sarcoidosis Questionnaire (KSQ) and the Leicester Cough Questionnaire (LCQ) to assess changes in quality of life and pulmonary endpoints. The efficacy assessments will be conducted in a structured manner, with data collection and analysis scheduled at predetermined intervals to ensure comprehensive evaluation of the treatment's impact on the disease.
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 | Recruiting | 11 Sept 2024 | 2 |
 Denmark | Recruiting | 11 Sept 2024 | 10 |
 Italy | Not Yet Recruiting | 11 Sept 2024 | 5 |
 Poland | Recruiting | 11 Sept 2024 | 3 |
 Spain | Recruiting | 11 Sept 2024 | 4 |
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 |
XTMAB-16 | Test | SOLUTION FOR INFUSION | INTRAVENOUS | — | — | PRD10268831 |
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 |