5-(4-((2S,5S)-5-(4-CHLOROBENZYL)-2-METHYLMORPHOLINO)PIPERIDIN-1-YL)-1H- 1,2,4-TRIAZOL-3-AMINE for Active pulmonary sarcoidosis

Inclusion criteria

• {"criterion_text":"- Male or female subject aged ≥18 years at Screening\n- Diagnosis of active and currently symptomatic pulmonary sarcoidosis, either treatment-naive or previously treated but currently untreated, with diagnostic criteria adapted from Official American Thoracic Society Clinical Practice Guideline 2020 and with limitations described in the exclusion criteria section:\n- Parenchymal pulmonary involvement evidenced by [ 18F]FDG PET/CT imaging at Screening\n- Body Mass Index within the range of 18 - 46 kg/m2\n- Subjects willing to avoid pregnancy or fathering a child and agree to use acceptable effective methods of birth control (per recommendations from Heads of Medicines Agencies - Clinical Trials Facilitation and Coordination Group) defined as those, alone or in combination, that result in a low failure rate for the entire duration of the study including: •\tWoman of nonchildbearing potential* •\tWoman of childbearing potential* who has a negative serum pregnancy test at Screening and at any timepoint before the first study drug dose on Day 1 and who agrees to take highly effective contraceptive measure to avoid pregnancy (with a failure rate of less than 1% per year when used consistently and correctly) from Screening until 7 months after EOT. As highly effective contraceptive measures are considered: -\tcombined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation : \toral \tintravaginal \ttransdermal -\tprogestogen-only hormonal contraception associated with inhibition of ovulation: \toral \tinjectable \timplantable -\tintrauterine device -\tintrauterine hormone-releasing system -\tbilateral tubal occlusion -\tvasectomised partner** -\tsexual abstinence*** •\tMan who agrees to use double barrier contraception (condoms - or diaphragm/ cervical cap used by their female partner- plus spermicidal agent: foam, gel, film etc.) to avoid fathering a child from Screening until 100 days after EOT, or is surgically sterilized. *A woman is considered of childbearing potential i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. **Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical success. ***Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.\n- Capable of understanding and complying with protocol requirements\n- Written informed consent given by the subject before the initiation of any study procedures Note: A witnessed consent is not all"}

Exclusion criteria

• {"criterion_text":"- Evidence of pulmonary sarcoidosis that requires immediate start of treatment (or start within the next 3 months) with corticosteroids, immunosuppressants, or anti-TNF agents (or other anti-inflammatory/anti-fibrotic treatment),according to the treating physician following the evaluation of risk for: future mortality from sarcoidosis, permanent disability from sarcoidosis, and deterioration of quality of life due to sarcoidosis\n- Total serum bilirubin >1.5 x upper limit of normal (ULN) or alanine aminotransferase (ALT) or asparagine aminotransferase (AST) > 2.5 x ULN, or alkaline phosphatase (ALP) >1.5 x ULN, or liver failure and/or cirrhosis or subjects with moderate to severe hepatic impairment (i.e., Child-Pugh score ≥7)\n- If performed pre-study, mediastinal and/or hilar lymph node biopsy result not consistent with sarcoidosis (as per Key Pathological Features of Sarcoidosis by the Official American Thoracic Society Clinical Practice Guideline, Crouser et al. 2020)\n- Clinically significant lung disease other than sarcoidosis (including but not limited to tuberculosis, asthma, Chronic Obstructive Pulmonary Disease, interstitial lung disease, lung cancer) or any current inflammatory or immunological systemic disease other than sarcoidosis\n- Previous potentially effective systemic or inhaled pharmacological (including investigational) therapy for sarcoidosis (whether pulmonary or other disease), with the exception of any of the following: a. corticosteroids received not later than 3 months prior to enrolment b. immunosuppressants or anti-TNF agents (or other anti-inflammatory/anti-fibrotic treatment) received not later than 4 months prior to enrolment\n- Known repeated demonstration of QTcF interval prolongation (>450 ms in a male and QTc >470 ms in a female) at Screening\n- Current systemic pharmacological treatment for sarcoidosis or any inflammatory or immunological systemic disease, including any investigational drugs\n- Primary systemic treatment indication being an extrapulmonary location of sarcoidosis (e.g., neurological)\n- Subjects currently treated with P-glycoprotein and/or BCRP strong inhibitors\n- Subjects currently treated with drugs that are sensitive substrates of OCT1, MATE1, MATE2K, OAT3 with a narrow therapeutic index\n- Concomitant use or need for treatment with a drug known for QT prolongation effect or a thiazide diuretic\n- History or current diagnosis of cardiac arrhythmia (other than non-sustained supraventricular arrhythmia)\n- Creatinine clearance (CrCL) <60 mL/min (by CockcroftGault formula\n- Heart failure (New York Heart Association class III or IV) and/or known myocardial hypertrophy or Left Ventricle Ejection Fraction <50% in the cardiac MRI\n- Subjects currently treated with strong CYP3A4 inhibitors and/or inducers\n- PET imaging, or other diagnostic or therapeutic procedure with administration of a radiopharmaceutical, performed within 6 weeks before Screening.*Additionally, with respect to Polish national regulations, subjects included in the study by Polish clinical sites must not have received a total effective dose of radiation of 10 mSv during the 10 years prior to study enrolment due to exposure from participating in biomedical research, clinical trials of medicinal products, clinical investigations of medical devices, clinical performance studies of in vitro diagnostic medical devices, or radiotherapy, if applicable.\n- Known neurosarcoidosis or small fiber neuropathy or medical conditions causing primary ataxia\n- Subjects currently treated with pirfenidone\n- Cardiac sarcoidosis (known or diagnosed at Screening using cardiac Magnetic Resonance Imaging [MRI])\n- Hypokalemia (<3.6 mmol/L, mmol/L) or hypocalcemia (<2.1 mmol/L) at Screening\n- Marked fasting hyperglycemia or uncontrolled diabetes at Screening with plasma glucose exceeding 8.3 mmol/L, or other contraindication to [18F]FDG administration and/or PET procedure (including body temperature >37°C and any metabolic disease affecting the energy metabolism of muscles) as described in the separately provided PET protocol\n- Pregnancy, breastfeeding, or planning to become pregnant or breastfeed, oocyte or sperm donation and cryopreservation during the study and 7 months after EOT. For the purposes of detecting pregnancy occurrence after EOT, the Sponsor will provide urine pregnancy test to subjects to perform at home at monthly intervals after the end of the study last follow-up visit for up until 7 months post last administration of the study drug. The subjects will be advised to report to the sponsor any pregnancies occurring in that time.\n- Known positivity for Human Immunodeficiency Virus (HIV 1/2 antibodies), hepatitis B virus (HBV), or hepatitis C virus (HCV), or detected at screening\n- Subjects with psychiatric disorder that could affect the conduct of the study and/or compliance with the study treatment\n- Alcohol consumption above 20 units/week for men and 10 units/week for women\n- Known allergy to excipients of the study drug\n- Any contraindication to cardiac MRI and PET CT procedure, including severe claustrophobia and known hypersensitivity to the contrast medium\n- Severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, thyroid, renal or metabolic disease) at Screening, or other condition, which in the opinion of the investigator, would compromise the safety of the subject or the subject’s ability to participate in the study\n- Current smoker of >5 cigarettes or e-cigarettes per day or user of nicotine releasing alternatives (patches, chewing gums etc.)\n- Unable to take oral medications"}

Primary endpoints

• {"endpoint_text":"- Response to treatment from baseline to End-of-Treatment (EOT) (i.e., complete or partial response) using the criteria determined for each subject","definition_or_measurement_approach":"Response defined as reduction of granulomatous inflammation in pulmonary parenchyma evaluated by [18F]FDG PET/CT imaging (as stated in the main objective). Assessed as complete or partial response using the criteria determined for each subject."}

Secondary endpoints

• {"endpoint_text":"- Granulomatous inflammation evaluated by [18F]FDG PET/CT imaging, quantified as the percent change of maximum, mean, peak SUV (SUVmax, SUVmean, SUVpeak), DocuSign Envelope ID: F57C5576-6512-4FF0-BFC4-DC20E82978C1 Study code OATD-01-C-03 Version 1.0, 21 June 2023 Confidential Clinical Study Protocol Page 9 of 75 and volume of the lesions in pulmonary parenchyma, mediastinal/hilar nodes, and extrathoracic locations\n- Absolute change in Forced Vital Capacity (FVC, % predicted) and Forced Expiratory Volume in the first second (FEV1)\n- Change in the quality of life measured by the Kings Sarcoidosis Questionnaire General and Lung (KSQ GENERAL and LUNG) scores\n- Occurrence of Treatment-emerging Adverse Events (TEAEs), SAEs, Adverse Events of Special Interest (AESIs), TEAEs leading to discontinuation and TEAEs leading to death\n- Occurrence of clinically significant laboratory (hematology and biochemistry) parameter abnormalities\n- Change in the Fatigue Assessment Scale total score\n- Mean change in vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate) from baseline to each post-baseline evaluation time point\n- Occurrence of any clinically significant abnormalities in 12- lead electrocardiography (ECG) or 24-h ECG\n- Change from baseline and in between visits in cardiac safety parameters evaluated by 12-lead ECG [Heart Rate (HR) , PR QTcF and QRS]\n- Heart rhythm abnormalities including supraventricular arrhythmias, ventricular arrhythmias, and non-sustained ventricular tachycardias\n- Occurrence of a clinically significant abnormality of sperm parameters\n- Occurrence of clinically significant abnormality of free testosterone concentration\n- Occurrence of TEAEs of sensation abnormalities or ataxia\n- Proportion of subjects with clinically significant thyroid parameters (Thyroid Stimulating Hormone [TSH], Free Triiodothyronine [FT3], and Free Thyroxine [FT4] and renal function parameters [blood urea nitrogen (BUN)/total urea, creatinine, creatinine clearance (CrCL)]\n- Mean plasma concentrations of OATD-01 measured at various timepoints post-baseline (sparse sampling)","definition_or_measurement_approach":"Secondary endpoints are assessed using imaging ([18F]FDG PET/CT) quantified by changes in SUV metrics and lesion volume for granulomatous inflammation; spirometry for FVC and FEV1; KSQ GENERAL and LUNG questionnaires for quality of life; standard safety monitoring for TEAEs/SAEs/AESIs/clinical labs/vital signs/ECG; sperm parameters and free testosterone measurements for reproductive safety; and sparse plasma sampling for PK (mean plasma concentrations at specified timepoints). Specific measurement details are provided in the endpoint descriptions (e.g., percent change of SUVmax/SUVmean/SUVpeak and lesion volume for PET/CT)."}

Methods

• Advertising — Absolutely Advertising Limited (United Kingdom) is listed with duty 'Advertising'

Denmark

Earliest CTIS Part Ii Submission Date

06-12-2023

Latest Decision Or Authorization Date

16-01-2024

Processing Time Days

41

Number Of Sites

1

Number Of Participants

4

France

Earliest CTIS Part Ii Submission Date

12-12-2023

Latest Decision Or Authorization Date

22-01-2024

Processing Time Days

41

Number Of Sites

2

Number Of Participants

10

Germany

Earliest CTIS Part Ii Submission Date

07-12-2023

Latest Decision Or Authorization Date

18-01-2024

Processing Time Days

42

Number Of Sites

1

Number Of Participants

7

Greece

Earliest CTIS Part Ii Submission Date

01-12-2023

Latest Decision Or Authorization Date

22-01-2024

Processing Time Days

52

Number Of Sites

3

Number Of Participants

9

Norway

Earliest CTIS Part Ii Submission Date

07-12-2023

Latest Decision Or Authorization Date

22-01-2024

Processing Time Days

46

Number Of Sites

2

Number Of Participants

17

Poland

Earliest CTIS Part Ii Submission Date

14-12-2023

Latest Decision Or Authorization Date

22-01-2024

Processing Time Days

39

Number Of Sites

5

Number Of Participants

25

Primary sponsor

Full Name

Molecure S.A.

Organisation Type

Pharmaceutical company

Country Of Registered Address

Poland

Contract research organisations

Name

Simbec Research Limited

Responsibilities

sponsorDuties: code 4

Name

Intertek Pharmaceutical Services Manchester

Responsibilities

sponsorDuties: code 4

Third parties

• {"country":"France","full_name":"Orion Sante","duties_or_roles":"sponsorDuties: code 1; code 15 (Onsite Monitoring in Greece - Registered CRA - Anatoli Amperiadou)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Unisphere Travel Ltd. Inc. (dba: Colpitts Clinical), a Direct Travel Company","duties_or_roles":"sponsorDuties: code 15 (Patient travel and expense management system)","organisation_type":"Industry"}
• {"country":"Poland","full_name":"Medicalgorithmics S.A.","duties_or_roles":"sponsorDuties: code 15 (Central Holter ECG)","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Oracle France","duties_or_roles":"sponsorDuties: code 3; code 7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Absolutely Advertising Limited","duties_or_roles":"sponsorDuties: code 15 (Advertising)","organisation_type":"Industry"}
• {"country":"United Kingdom","full_name":"Simbec Research Limited","duties_or_roles":"sponsorDuties: code 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Veeva Systems Inc.","duties_or_roles":"sponsorDuties: code 15 (eTMF, CTMS, QMS)","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Keosys","duties_or_roles":"sponsorDuties: code 15 (Central Imaging)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"France","full_name":"Orion Sante","duties_or_roles":"sponsorDuties: code 1; code 15 (Onsite Monitoring in Denmark and Norway - Annette Pommer)","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Creapharm Clinical Supplies","duties_or_roles":"sponsorDuties: code 14","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Intertek Pharmaceutical Services Manchester","duties_or_roles":"sponsorDuties: code 4","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Orion Sante","duties_or_roles":"sponsorDuties: codes 1,10,11,12,13,2,5,6,8,9 (multiple responsibilities as listed)","organisation_type":"Pharmaceutical company"}