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
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- Xentria Inc.
- 入组人数
- 24
- 试验地点
- 15
- 主要终点
- Part A Safety Endpoints Rate of Adverse Events (AEs), including Serious Adverse Events (SAEs), Dose Limiting Toxicities (DLTs), and Adverse Events of Special Interests (AESIs) throughout the study duration Endpoints •Pharmacokinetics (PK) profile including o Ctrough o Cmax o Caverage o Area Under the Curve (AUC)
研究概览
简要总结
Part A Safety To evaluate the safety and tolerability of multiple ascending doses of XTMAB-16 in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations Determine recommended phase 2 dose To determine the recommended Phase 2 dose level and frequency for XTMAB-16 in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations for Part B of the study
Part B Efficacy To establish efficacy of XTMAB-16 as measured by the ability to reduce background oral corticosteroid use in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
研究设计
- 分配方式
- Randomized
- 主要目的
- Double blind
- 盲法
- Double (Investigator, Subject)
入排标准
- 年龄范围
- 18 years 至 65+ years（18-64 Years, 65+ Years）
- 接受健康志愿者
- 是
入选标准
- •Participant between 18 to 80 years (inclusive) of age.
- •In the opinion of the Investigator, the participant is capable of understanding and complying with protocol requirements.
- •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.
排除标准
- •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 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.
- •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.
- •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.
- •Known hypersensitivity to any component of the formulation of XTMAB-
- •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.
- •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.
结局指标
主要结局
Part A Safety Endpoints Rate of Adverse Events (AEs), including Serious Adverse Events (SAEs), Dose Limiting Toxicities (DLTs), and Adverse Events of Special Interests (AESIs) throughout the study duration Endpoints •Pharmacokinetics (PK) profile including o Ctrough o Cmax o Caverage o Area Under the Curve (AUC)
Part A Safety Endpoints Rate of Adverse Events (AEs), including Serious Adverse Events (SAEs), Dose Limiting Toxicities (DLTs), and Adverse Events of Special Interests (AESIs) throughout the study duration Endpoints •Pharmacokinetics (PK) profile including o Ctrough o Cmax o Caverage o Area Under the Curve (AUC)
Part A •Pharmacodynamics (PD) markers, including: o Angiotensin converting enzyme (ACE) o Soluble IL-2 receptor (sIL 2R) o C-reactive protein (CRP) o Interleukin -1b (IL-1b) o Calcitriol (vitamin D 1, 25) •Occurrence and persistence of anti-drug antibodies (ADA) •Observed reduction in dose of corticosteroid
Part A •Pharmacodynamics (PD) markers, including: o Angiotensin converting enzyme (ACE) o Soluble IL-2 receptor (sIL 2R) o C-reactive protein (CRP) o Interleukin -1b (IL-1b) o Calcitriol (vitamin D 1, 25) •Occurrence and persistence of anti-drug antibodies (ADA) •Observed reduction in dose of corticosteroid
Part A •Observed change in quality of life (QoL) and Pulmonary endpoints o Mean percent change in forced vital capacity (FVC)% from Baseline to Week 12 o Change in King's Sarcoidosis Questionnaire (KSQ) - Lung Score o KSQ - General Health Status Module o Leicester Cough Questionnaire (LCQ) o Steroid Toxicity Questionnaire (STQ)
Part A •Observed change in quality of life (QoL) and Pulmonary endpoints o Mean percent change in forced vital capacity (FVC)% from Baseline to Week 12 o Change in King's Sarcoidosis Questionnaire (KSQ) - Lung Score o KSQ - General Health Status Module o Leicester Cough Questionnaire (LCQ) o Steroid Toxicity Questionnaire (STQ)
Part A •Observed DLT, rate of AESI throughout the study duration between dose levels and frequencies
Part A •Observed DLT, rate of AESI throughout the study duration between dose levels and frequencies
Part B Efficacy Endpoints Proportion of participants who achieve the targeted tapered dose of corticosteroid (prednisone 5 mg/day or equivalent) by Week 12
Part B Efficacy Endpoints Proportion of participants who achieve the targeted tapered dose of corticosteroid (prednisone 5 mg/day or equivalent) by Week 12
次要结局
- Part A Efficacy Endpoints •Proportion of participants who achieve the targeted tapered dose of corticosteroid (prednisone 5 mg/day or equivalent) by Week 12 •Proportion of participants who achieve at least 50% reduction in dose of corticosteroid by Week 12
- Part A Pharmacokinetic Endpoints •Clearance and volume parameters and half-life in the intended patient population •Dose proportionality •Accumulation ratio repeat dosing •Area under the effect-time curve from time 0 (predose) to the last quantifiable effect-concentration time point, t (AUEC 0-t) •Maximum observed effect (Emax, obs) •Time to reach Emax, obs (tEmax, obs)
- Part A Change in Biomarker Endpoints •Absolute and percent change in biomarkers from Baseline to End of Infusion (EOI), Week 2, 4, 8, and 12 o Interleukin-6 (IL-6) o Soluble Tumor Necrosis Factor a (sTNFa)
- Part A Immunogenicity Number and percentage of participants by cohort who test positive for XTMAB-16 ADA at Baseline, Week 4, Week 8, and Week 12 and transient & persistent positive status at follow up assessments
- Part A Number and percentage of participants by cohort who test positive for XTMAB-16 nAb at Baseline, Week 4, Week 8, and Week 12 and transient & persistent positive status at follow up assessments
- Part B Safety Endpoints Rate of Adverse Events (AEs), including Serious Adverse Events (SAEs) throughout the study duration
- Part B Efficacy Endpoints •Proportion of participants who achieve at least 50% reduction in dose of corticosteroid by Week 12 •Proportion of patients able to maintain steroid reduction through Week 24
- Part B Pharmacokinetic Endpoints • Clearance and volume parameters and half-life in the intended patient population. • First dose and steady-state AUC, Cmax, Ctrough and Caverage.
- Part B Change in Biomarkers at Baseline to Week 12 and 24 • Absolute and percent change in biomarkers •ACE •Interleukin-6 (IL-6) •Soluble Interleukin-2 Receptor (sIL 2R) •Soluble tumor necrosis factor α(sTNF α) •CRP •Calcitriol (Vitamin D 1, 25) • Interleukin-1b (IL-1b)
- Part B Immunogenicity • Number and percentage of participants by cohort who test positive for XTMAB-16 ADA at Baseline to Week 24 and transient & persistent positive status at follow up assessments.
- Part B • Number and percentage of participants by cohort who test positive for XTMAB-16 nAb at Baseline to Week 24 and transient & persistent positive status at follow up assessments
研究者
Tom Matthews
Scientific
Xentria Inc.