A study to assess the efficacy and safety of OATD-01 for the treatment of active pulmonary sarcoidosis.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Molecure S.A.

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Decision date (initial)

2024-01-16

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To evaluate the response to a 12-week treatment with OATD-01 as a reduction of granulomatous inflammation in pulmonary
parenchyma evaluated by [18F]FDG PET/CT imaging in subjects with active pulmonary sarcoidosis

Secondary objectives 8

1. To quantify the change in granulomatous inflammation in pulmonary parenchyma, mediastinal/hilar nodes, and extrathoracic locations using [ 18F]FDG PET/CT imaging SUV in subjects with active pulmonary sarcoidosis
2. To evaluate the pulmonary function in subjects with active pulmonary sarcoidosis following treatment with OATD-01
3. To evaluate the quality of life of subjects with active pulmonary sarcoidosis following treatment with OATD-01
4. To assess the overall safety and tolerability of OATD-01 in subjects with active pulmonary sarcoidosis
5. To characterize cardiac safety of OATD-01 administered to subjects with active pulmonary sarcoidosis
6. To evaluate the risk for clinically relevant phospholipidosis in male subjects with active pulmonary sarcoidosis treated with OATD-01
7. To evaluate the thyroid and renal function in subjects with active pulmonary sarcoidosis
8. To characterize the PK exposure of OATD-01 administered to subjects with active pulmonary sarcoidosis as to assess the PK parameters and allow for an exploratory post-hoc PK/PD analysis

Conditions and MedDRA coding

Active Pulmonary Sarcoidosis

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Male or female subject aged ≥18 years at Screening
2. 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:
3. Parenchymal pulmonary involvement evidenced by [ 18F]FDG PET/CT imaging at Screening
4. Body Mass Index within the range of 18 - 46 kg/m2
5. 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: • Woman of nonchildbearing potential* • Woman 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: - combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation :  oral  intravaginal  transdermal - progestogen-only hormonal contraception associated with inhibition of ovulation:  oral  injectable  implantable - intrauterine device - intrauterine hormone-releasing system - bilateral tubal occlusion - vasectomised partner** - sexual abstinence*** • Man 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.
6. Capable of understanding and complying with protocol requirements
7. Written informed consent given by the subject before the initiation of any study procedures Note: A witnessed consent is not all

Exclusion criteria 34

1. 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
2. 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)
3. Creatinine clearance (CrCL) <60 mL/min (by CockcroftGault formula
4. Cardiac sarcoidosis (known or diagnosed at Screening using cardiac Magnetic Resonance Imaging [MRI])
5. Hypokalemia (<3.6 mmol/L, mmol/L) or hypocalcemia (<2.1 mmol/L) at Screening
6. 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
7. 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.
8. Known positivity for Human Immunodeficiency Virus (HIV 1/2 antibodies), hepatitis B virus (HBV), or hepatitis C virus (HCV), or detected at screening
9. Subjects with psychiatric disorder that could affect the conduct of the study and/or compliance with the study treatment
10. Alcohol consumption above 20 units/week for men and 10 units/week for women
11. Known allergy to excipients of the study drug
12. Any contraindication to cardiac MRI and PET CT procedure, including severe claustrophobia and known hypersensitivity to the contrast medium
13. 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
14. Current smoker of >5 cigarettes or e-cigarettes per day or user of nicotine releasing alternatives (patches, chewing gums etc.)
15. Unable to take oral medications
16. History of or active Löfgren’s syndrome
17. Participation in another clinical study within 1 month prior to enrolment
18. Subject deprived of liberty by a judicial or administrative decision, subject admitted to a social institution or who is under a measure of legal protection, subject hospitalized without consent or who is in an emergency situation
19. Established alternative diagnosis of a non-infectious or infectious systemic disease, or suspicion thereof, undermining the suspicion/diagnosis of sarcoidosis
20. 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)
21. 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
22. 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
23. Known repeated demonstration of QTcF interval prolongation (>450 ms in a male and QTc >470 ms in a female) at Screening
24. Current systemic pharmacological treatment for sarcoidosis or any inflammatory or immunological systemic disease, including any investigational drugs
25. Primary systemic treatment indication being an extrapulmonary location of sarcoidosis (e.g., neurological)
26. Subjects currently treated with P-glycoprotein and/or BCRP strong inhibitors
27. Subjects currently treated with drugs that are sensitive substrates of OCT1, MATE1, MATE2K, OAT3 with a narrow therapeutic index
28. Concomitant use or need for treatment with a drug known for QT prolongation effect or a thiazide diuretic
29. History or current diagnosis of cardiac arrhythmia (other than non-sustained supraventricular arrhythmia)
30. 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
31. Subjects currently treated with strong CYP3A4 inhibitors and/or inducers
32. 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.
33. Known neurosarcoidosis or small fiber neuropathy or medical conditions causing primary ataxia
34. Subjects currently treated with pirfenidone

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Response to treatment from baseline to End-of-Treatment (EOT) (i.e., complete or partial response) using the criteria determined for each subject

Secondary endpoints 15

1. 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
2. Absolute change in Forced Vital Capacity (FVC, % predicted) and Forced Expiratory Volume in the first second (FEV1)
3. Change in the quality of life measured by the Kings Sarcoidosis Questionnaire General and Lung (KSQ GENERAL and LUNG) scores
4. Occurrence of Treatment-emerging Adverse Events (TEAEs), SAEs, Adverse Events of Special Interest (AESIs), TEAEs leading to discontinuation and TEAEs leading to death
5. Occurrence of clinically significant laboratory (hematology and biochemistry) parameter abnormalities
6. Change in the Fatigue Assessment Scale total score
7. Mean change in vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate) from baseline to each post-baseline evaluation time point
8. Occurrence of any clinically significant abnormalities in 12- lead electrocardiography (ECG) or 24-h ECG
9. Change from baseline and in between visits in cardiac safety parameters evaluated by 12-lead ECG [Heart Rate (HR) , PR QTcF and QRS]
10. Heart rhythm abnormalities including supraventricular arrhythmias, ventricular arrhythmias, and non-sustained ventricular tachycardias
11. Occurrence of a clinically significant abnormality of sperm parameters
12. Occurrence of clinically significant abnormality of free testosterone concentration
13. Occurrence of TEAEs of sensation abnormalities or ataxia
14. 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)]
15. Mean plasma concentrations of OATD-01 measured at various timepoints post-baseline (sparse sampling)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Molecure S.A.

Sponsor organisation

Molecure S.A.

Address

Ul. Zwirki I Wigury 101

City

Warsaw

Postcode

02-089

Country

Poland

Scientific contact point

Organisation

Molecure S.A.

Contact name

Theodore Charitos

Public contact point

Organisation

Molecure S.A.

Contact name

Contact

Third parties 12

Locations

6 EU/EEA countries · 14 investigational sites

By country

Investigational sites

Application history

1 submissions — initial application plus substantial / non-substantial modifications