XTMAB-16 for Pulmonary sarcoidosis

Inclusion criteria

• {"criterion_text":"- Participant between 18 to 80 years (inclusive) of age.\n- In the opinion of the Investigator, the participant is capable of understanding and complying with protocol requirements.\n- Weighs between 45 kg and 160 kg (99 to 353 lbs) at Screening.\n- 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).\n- Modified Medical Research Conference (mMRC) Dyspnea Scale of ≥ l.\n- 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.\n- 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.\n- 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.\n- Polymerase chain reaction (PCR) test or rapid antigen test negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at Screening.\n- Able to provide written informed consent."}

Exclusion criteria

• {"criterion_text":"- 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\n- Clinically significant hepatic or renal disease, including uncontrolled diabetes at the discretion of the investigator.\n- Any severe prior reaction to any type of biologics or human blood product such as albumin, IgG, etc.\n- PART A ONLY: Any prior TNFα inhibitor therapy.\n- Concurrent emphysema.\n- Known hypercalcemia due to non-sarcoidosis conditions such as untreated hyperparathyroidism, at the discretion of the investigator\n- 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.\n- 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.\n- Known uncontrolled hypertension. Note: Uncontrolled hypertension is noted as blood pressure ≥ 160/100 mmHg despite antihypertensive therapy within 3 months of randomization.\n- 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.\n- In the opinion of the investigator, inability to tolerate corticosteroid taper.\n- 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.\n- Concurrent systemic steroid use for non-sarcoidosis conditions.\n- Concurrent known auto-immune disease requiring treatment.\n- 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.\n- Clinically significant extra-pulmonary sarcoidosis requiring systemic therapy as determined by the investigator\n- Any condition that required hospitalization within the 3 months prior to Day 1 or is likely to require so during the study.\n- 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.\n- PART B ONLY: Any therapy with an anti-TNF α monoclonal antibody (e.g., infliximab, adalimumab, golimumab and their biosimilars) within 6 months.\n- Baseline percent predicted forced vital capacity (FVC) of <50%.\n- Prior treatment with rituximab or repository corticotropin injection within the previous 12 months.\n- Clinically significant Central Nervous System (CNS) sarcoidosis requiring therapy, except history of isolated seventh cranial nerve palsy or evidence of demyelinating neurologic disease.\n- Known hypersensitivity to any component of the formulation of XTMAB-16.\n- Advanced congestive heart failure (New York Heart Association [NYHA] 3 or 4).\n- 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).\n- Pregnant or breastfeeding women or women who are planning to become pregnant during the study.\n- PART A ONLY: Participants > 65 years of age.\n- 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.\n- Evidence of active or latent TB by interferon-gamma release assay (IGRA) or invasive fungal infections at Screening.\n- 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.\n- 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.\n- 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.\n- 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."}

Primary endpoints

• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Safety: rate of AEs/SAEs/DLTs/AESIs monitored throughout study. PK: Ctrough, Cmax, Caverage and AUC measured from plasma concentration-time profiles."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"PD markers measured at scheduled time points (Baseline, End of Infusion, Weeks 2,4,8,12); ADA presence/persistence assessed at planned visits; observed steroid dose reductions recorded."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Pulmonary endpoints: mean percent change in FVC% from Baseline to Week 12. QoL instruments: KSQ (Lung and General modules), LCQ, STQ assessed at scheduled visits."}
• {"endpoint_text":"- Part A •Observed DLT, rate of AESI throughout the study duration between dose levels and frequencies","definition_or_measurement_approach":"DLTs and AESI rates compared across dose levels/frequencies; events captured during on-study period per protocol definitions."}
• {"endpoint_text":"- Part B Efficacy Endpoints Proportion of participants who achieve the targeted tapered dose of corticosteroid (prednisone 5 mg/day or equivalent) by Week 12","definition_or_measurement_approach":"Proportion achieving prednisone 5 mg/day (or equivalent) by Week 12, assessed per steroid taper schedule."}

Secondary endpoints

• {"endpoint_text":"- 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","definition_or_measurement_approach":"Proportions measured at Week 12 per steroid dose records."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"PK parameters (clearance, volume, t1/2, AUEC0-t, Emax, tEmax) derived from concentration-time data; dose proportionality and accumulation ratio assessed across cohorts."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Absolute and percent change in listed biomarkers at specified timepoints compared to Baseline."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"ADA testing at Baseline, Weeks 4, 8, 12 with categorisation of transient vs persistent positivity."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Neutralising antibody (nAb) testing at scheduled visits; percentages reported by cohort and timepoint."}
• {"endpoint_text":"- Part B Safety Endpoints Rate of Adverse Events (AEs), including Serious Adverse Events (SAEs) throughout the study duration","definition_or_measurement_approach":"AE/SAE rates captured for Part B across study duration per safety reporting procedures."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Proportions measured at Weeks 12 and 24 from steroid dose records."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"PK parameters including AUC, Cmax, Ctrough, Caverage measured after first dose and at steady state."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Absolute and percent changes in listed biomarkers from Baseline to Weeks 12 and 24 measured per assay schedule."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"ADA testing from Baseline to Week 24 with transient/persistent status reporting."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"nAb testing from Baseline to Week 24; reporting by cohort and follow-up status."}

Methods

• Italy: K1_IT_Recruitment Procedure; K2_IT_Recruitment Material_Patient Letter_Italian (patient letter); K2_IT_Recruitment Material_Facebook Ad_Italian (Facebook ad); K2_IT_Recruitment Material_Advocacy Outreach Text_Italian (advocacy outreach text); K2_IT_Recruitment Material_Print Ad_Italian (print ad). Target audience: patients with pulmonary sarcoidosis (Italy).
• Denmark: K1_DK_Recruitment Procedure; K2_DK_Recruitment Material_Patient Letter_Danish (patient letter); K2_DK_Recruitment Material_Facebook Ad_Danish (Facebook ad); K2_DK_Recruitment Material_Advocacy Outreach Text_Danish (advocacy outreach text); K2_DK_Recruitment Material_Print Ad_Danish (print ad). Target audience: patients with pulmonary sarcoidosis (Denmark).

Czechia

Earliest CTIS Part Ii Submission Date

13-08-2024

Latest Decision Or Authorization Date

11-09-2024

Processing Time Days

29

Number Of Sites

1

Number Of Participants

2

Spain

Earliest CTIS Part Ii Submission Date

06-08-2024

Latest Decision Or Authorization Date

10-09-2024

Processing Time Days

35

Number Of Sites

3

Number Of Participants

4

Poland

Earliest CTIS Part Ii Submission Date

09-08-2024

Latest Decision Or Authorization Date

16-09-2024

Processing Time Days

38

Number Of Sites

2

Number Of Participants

3

Italy

Earliest CTIS Part Ii Submission Date

16-07-2024

Latest Decision Or Authorization Date

11-09-2024

Processing Time Days

57

Number Of Sites

4

Number Of Participants

5

Denmark

Earliest CTIS Part Ii Submission Date

05-06-2024

Latest Decision Or Authorization Date

10-09-2024

Processing Time Days

97

Number Of Sites

5

Number Of Participants

10

Primary sponsor

Full Name

Xentria Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Icon Clinical Research Limited

Responsibilities

Multiple sponsor duties listed including codes 1,12,13,15 (Imaging),2,3,4,5,6 (study-related operational responsibilities as listed)

Name

Primevigilance Limited

Responsibilities

Pharmacovigilance/safety duties (sponsorDuties code 8)

Name

Frontage Laboratories Inc.

Responsibilities

Sample analyses and storage (sponsorDuties code 15) and analytical responsibilities (code 4)

Third parties

• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"sponsorDuties codes: 1,12,13,15 (Imaging),2,3,4,5,6 (as listed)","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Primevigilance Limited","duties_or_roles":"sponsorDuties code: 8","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Frontage Laboratories Inc.","duties_or_roles":"sponsorDuties codes: 15 (Sample analyses and storage), 4","organisation_type":"Pharmaceutical company"}
• {"country":"Greece","full_name":"Pharmaceutical Research Associates Greece A.E","duties_or_roles":"sponsorDuties codes: 12, 15 (Study start up)","organisation_type":"Industry"}
• {"country":"United States","full_name":"Mms Holdings Inc.","duties_or_roles":"sponsorDuties code: 10","organisation_type":"Pharmaceutical company"}