| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| COVID-19 respiratory disease |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10084270 |
| E.1.2 | Term | SARS-CoV-2 acute respiratory disease |
| E.1.2 | System Organ Class | 100000004862 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Study Objectives- Part A To evaluate the effect of LYT-100 on the change in distance walked on the six-minute walk test performed in line with the American Thoracic Society/European Respiratory Society Guidelines.
Study Objectives- Part B To assess the longer-term safety, tolerability, and efficacy of LYT-100 through up to 182 days of treatment. |
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| E.2.2 | Secondary objectives of the trial |
Key Second. Obj: To evaluate the effect of 91 days of treatment with LYT-100 compared to placebo on the Modified Borg Dyspnoea Scale (mBDS).
Other Second. Obj: To evaluate the effect in
Part A: of 91 days of treatment with LYT-100 compared to placebo
Part B: up to 182 days of treatment with LYT-100
1. SGR Questionnaire-I (SGRQ-I)
2. Dyspnoea-12
3. The WHO Ordinal Scale for Clinical Improvement
4. QoL assessment as collected using the SF-36 (v2)
5. Number of lung segments involved using CT Scan and QLF assessment
6. Inflammatory, fibrosis and other biomarkers
7. Pulmonary exacerbations, severe and non-severe
8. All-cause rehospitalizations
9. Severity of lung lobe(s) involvement, using CT Scan
10. Pulse oximetry
11. Chest X-ray
12. Length of hospital stay
13. All-cause mortality
14. Use of supplemental oxygen from Baseline to end of treatment
15. Change in distance walked on the six-minute walk test (only part B)
16. The mBDS Scale (only part B) |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be eligible for this study, participants have to meet all of the following inclusion criteria:
Inclusion Criteria - Part A:
1. Positive result of a molecular RT-qPCR diagnostic test or SARS-CoV-2 RNA result from a clinical specimen deemed clinically associated with the current episode of illness, warranting hospital admission as per investigator’s judgement, or previously hospitalized (central and/or local laboratory COVID-19 test results are accepted from any biological material source)
2. Hospitalization for COVID -19 respiratory disease and treated with supplemental oxygen (including MV, ECMO or any other means of oxygen administration) in hospital for at least 1 day
3. Written, electronic, or oral informed consent from the patient or Legally Authorized Representative prior to any study procedures in a manner approved by an IRB or Ethics Committee
4. Male or female, aged ≥18 to ≤80 years of age, inclusively at the time of informed consent
5. Able to perform and willing to comply with all study procedures and requirements
6. Able to bear weight and ambulate a minimum of 10 m distance (use of inhaled oxygen permitted)
7. Randomization day is dependent on type of qualifying respiratory support and date of initial confirmed COVID-19 diagnosis as described in Table 1.
8. COVID-19 pneumonia findings on imaging (chest X-ray or CT Scan) with a minimum of two lung lobes involvement
9. Shortness of breath ≥ grade 3 on mBDS dyspnea scale
10. Laboratory parameters (CBC, biochemistry) deemed by the investigator as acceptable and/or not clinically significant to enroll the patient
11. Women of childbearing potential (WOCBP) must be non-pregnant and non-lactating, and must be abstinent from heterosexual intercourse for 90 days following last dose of study medication or agree to use one of the acceptable, highly effective double contraception:
a. oral, intravaginal, or transdermal combined (estrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation
b. oral, injectable, or implantable progestogen-only hormonal contraception associated with inhibition of ovulation
c. intrauterine device (IUD)
12. Male patients must be surgically sterile (> 30 days since vasectomy with no viable sperm), abstinent, or if engaged in sexual relations with a WOCBP, the participant and his partner must be surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or using an acceptable, highly effective contraceptive method from screening until study completion, including the follow-up period and an additional 90 days after the last dose of study medication
13. Males will not donate sperm for at least 90 days after the last dose of study medication
14. Partners of male patients and female patients will report pregnancy occurring within 90 days from cessation of study medication
15. Patients can be on other medication (on and off label), apart from the ones specifically outlined in the Exclusion Criteria, to treat COVID-19 respiratory disease, that the investigator deems clinically relevant in combination with the study drug
16. Patients can concomitantly receive any standard of care as per investigators’ clinical decision; standard of care may encompass any approved medication, on or off label apart from the ones specifically outlined in the exclusion criteria. Concomitant medication may be other medication(s) apart from the ones specifically outlined in the Exclusion Criteria.
Inclusion Criteria-PART B:
1. Patient must have completed Part A of the study, through Day 91 of treatment.
2. In the opinion of the Investigator, the patient is a good candidate for continued treatment. |
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| E.4 | Principal exclusion criteria |
Exclusion Criteria - Part A:
1. Patients who cannot f-up with study participation requirements
2. Investigator considers patient is inappropriate to enroll in the trial
3. Pre-existing chronic respiratory condition(s), obstructive or restrictive, for which the patient is actively taking concomitant medication are excluded. Patients with history of Idiopathic Pulmonary Fibrosis (IPF), lung cancer, pulmonary arterial hypertension, other interstitial lung diseases, severe cardiac insufficiency (grade IV) are excluded irrespective of whether they are actively being medicated for those conditions or not
4. Pre-existing co-morbid conditions preventing outcome assessments, e.g. neurological, medical, orthopedic injury/disability, disease or condition that would prevent ability to transfer and walk for 6 min, prior to confirmed COVID-19 diagnosis
5. Co-morbid diagnosis of tuberculosis
6. Unstable angina or myocardial infarction in the last month prior to screening
7. Pre-existing co-morbidity associated with life expectancy less than 1 year
8. Present life expectancy less than 3 days and/or LDH >360
9. Body mass index ≥50 kg/m2
10. Resting heart rate of ≥ 120 bpm, systolic BP of >180 mm Hg and a diastolic BP of >100 mm Hg and/or or a fall in pulse oximetry oxygen saturation (SpO2) to <80% upon ambulation
11.Sepsis,septic/hypovolemic/cardiogenic/neurogenic shock
12. Patients on MV, ECMO, NIV, HFNO and/or other high flow oxygen FiO2 ≥35% and ≥8 lpm within the last 72 hrs prior to screening. Low flow supplemental oxygen is allowed
13. History of anaphylactic reaction (particularly reactions to general anesthetic agents); allergic reaction due to any drug which led to significant morbidity; prior allergic reaction to pirfenidone
14. Known symptoms of dysphagia or known difficulty in swallowing capsules and/or total gastrectomy
15. Patients undergoing dialysis or hemoperfusion, or with a history of, or anticipated to require dialysis or hemoperfusion within 72 hrs of screening or severe renal impairment (defined as creatinine clearance rate <30 mL/min) at the time of screening/ baseline
16. Use of any of the following drugs:
a. Fluvoxamine, enoxacin, ciprofloxacin
b. Treatment with steroids under institutional protocols and guidelines to manage
COVID-19 pneumonia/respiratory symptoms is allowed. Use of steroids off-label to treat non-COVID-19 related conditions is not allowed
c. Any Investigational Agents (i.e., non-approved or nonauthorized drugs), except those used for COVID-19 resp. diseases that the investigator deems clinically relevant in combination with the study drug, as described below:
i. Allowed agents
• Patients who had received prior investig. agents for COVID-19 but are no longer taking those drugs - allowed
• Inhaled corticosteroids - allowed
• Patients that received prior convalescent plasma - allowed; however concomitant convalescent plasma is excluded
ii. Excluded agents
Patients on concomitant experimental anti-viral, anti-fibrotic or anti-inflammatory therapies are excluded. Any investig. agent not explicitly on this list should be reviewed by the medical monitor prior to initiating therapy or enrolling participant
d. Other inhibitors of CYP1A2 (including but not limited to methoxsalen or mexiletine).
e. Inducers of CYP1A2 (phenytoin), CYP2C9 or 2C19 (including but not limited to carbamazepine or rifampin)
f. Drugs associated with substantial risk for prolongation of the QTc interval (including but not limited to moxifloxacin, quinidine, procainamide, amiodarone, sotalol). Note that QTc prolong. is not an all/nothing drug effect, and specifically the administration drugs such as hydroxychloroquine do not preclude participation in this trial but does mandate measurement of the QTc every 6 hrs until deemed necessary by investigator
g. Vaccination with a live vaccine is not permitted during the period from 4 weeks prior to screening to 4 weeks after the last dose
h. Tobacco and nicotine product and/or a positive cotinine test at screening
i. Pirfenidone or nintedanib
17. Any other reason that, in the opinion of the Investigator, might interfere with the evaluation required by the study18. For baseline AST ≥2.5xULN, AST ≥2.5xULN and/or total bilirubin >1.5xULN (in the absence of history of Gilbert syndrome and/or the absence of alkaline phosphatase ≥2xULN or clinical evidence of cholestasis), or severe hepatic impairment
18. For baseline AST ≥2.5xULN, ALT ≥2.5xULN and/or total bilirubin >1.5xULN (in the absence of history of Gilbert syndrome and/or the absence of alkaline phosphatase ≥2xULN or clinical evidence of cholestasis), or severe hepatic impairment
19. Patients requiring surgery due to an acute onset condition prior to randomization
20. Patients experiencing tachypnea. For the purposes of this study, tachypnea is defined as a resting respiratory rate ≥25 per minute
Exclusion Criteria- Part B
Patients must not meet any exclusion criteria listed for Part A. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoint - Part A:
6-minute walk test (6MWT) is the primary efficacy endpoint. All patients will complete a 6MWT test according to the Schedule of Assessments and aligned with the American Thoracic Society/European Respiratory Society Guidelines with COVID-19 modifications provided in the 6MWT study procedural manual. The 6MWT measures the distance a patient can quickly walk on a flat, hard surface in a period of 6 minutes. It evaluates the global and integrated response of all the systems involved during exercise. This is a self-paced test. Patients choose their own intensity of exercise and may stop and rest during the test. Changes from baseline in the 6MWT distance will be assessed using covariates in a mixed model. The mBDS and fatigue are also assessed a prior to the 6MWT and end of the test.
Endpoints- Part B
Safety Endpoints
Safety and tolerability endpoints include: Adverse events, concomitant medications, clinical laboratory findings (chemistry, hematology, coagulation, urinalysis), physical examinations, ECGs, and vital signs. These will be tabulated or summarized descriptively, where appropriate. Outcomes such as mortality and duration of hospital stay are considered efficacy outcomes in the context of the study objectives and disease being studied but will be included in the overall discussion of the safety and tolerability of LYT-100. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
All efficacy endpoints will be derived at each protocol-schedule time point for which they are collected, with analysis performed (e.g. change from baseline) for each time point.
The efficacy endpoints are consistent with the primary and secondary objectives of the study. Day 91 (the end of double-blind treatment) will be the primary timepoint from which efficacy conclusions will be drawn, with supportive outcomes at earlier time points assessed to better understand the time profile of any treatment effects. |
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| E.5.2 | Secondary end point(s) |
Key Secondary efficacy endpoints - PART A:
• Modified Borg Dyspnoea Scale (mBDS) is a measure of dyspnea. The mBDS is a self-administered unidimensional assessment tool that analyzes breathlessness under exertion. Changes over time will be derived.
Other Secondary and Exploratory Efficacy Endpoints:
• Saint George Respiratory Questionnaire-I (SGRQ-I) is an idiopathic pulmonary fibrosis disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in patients with interstitial lung disease. There are 34 self-completed items with 3 domain component scores (Symptoms, Activities, and Impacts), with higher scores indicating more limitations. Changes from baseline in the component scores of the SGRQ-I will be assessed.
• Dyspnoea-12 (D-12) is an instrument used to assess the effect of dyspnea in interstitial lung disease and COPD, and is used in reference to the patient’s breathlessness experience “these days”, i.e., current at baseline and at follow-up visits, and unlike other dyspnea tools, it has no reference to activity. The tool has 12 descriptor items ranging from none (0), mild (1), moderate (2) or severe (3). An overall score of breathlessness severity is provided that encompasses seven physical items and five affective items. Total scores range from 1 to 36 whereby severity correlates with greater severity.
• WHO Ordinal Scale for Clinical Improvement will be assessed for changes from baseline over time. The WHO ordinal scale has the following nine categories: (0) Uninfected (No clinical or virological evidence of infection); (1) Ambulatory (No limitation of activities); (3) Hospitalized Mild Disease (Hospitalized, no oxygen therapy); (4) Oxygen by mask or nasal prongs; (5) Hospitalized Severe Disease (Non-invasive ventilation or high-flow oxygen); (6) Intubation and mechanical ventilation; (7)Ventilation plus additional organ support (i.e. extracorporeal life support (ECLS), continuous renal replacement therapy (CRRT), vasopressors); (8) Dead (Death); (Table 8).
• The SF-36 (v2) is a self-administered questionnaire containing 36 items that measures functional status, well-being and overall evaluation of health in 8 domains. It requires approximately 5-10 minutes to complete and uses scaled, ordinal responses (e.g., All of the time, Most of the time, A good bit of the time, etc.) Changes in the standardized component scores and domain scores will be calculated (Table 16).
• The proportion of patients with “normal” CT scan images will be defined in a responder analysis. Patients with pre-existing chest pathology pre-COVID-19 should be considered “normal” for those pre-existing items/findings. Chest CT scans will be performed according to the CT Scan manual. Lung lobe involvement will be assessed for each of five lobes via central read with the terms defined by the Fleischner Society (Hansell et al 2018). CT scans may also be analyzed with semi-Quantitative Lung Fibrosis (QLF) and computer-Aided Diagnosis (CAD) QLF Scores (Kim et al, 2010). Table 9 shows how each lobe will be scored, the total score for each finding per lobe (range 0 to 5), each finding across the lung (range 0-25) and total score (range 0 to 100) will be derived accordingly. Changes from baseline in this total score will be assessed. A responder analyses will be performed, in which the proportion of patients showing ground glass opacities, fibrosis, consolidation, reticulation/bronchiectasis, and other radiographic abnormality improvement(s) by determining at least a 2-point score improvement for each abnormality across the five lobes (range 0-25), will be derived. For each of the five lobes, an assessment of lung lobe involvement using CT Scan will be assessed using the scale as shown in Table 10. Shifts in these characteristics over the course of treatment will be of interest.
• Biomarker changes in will be assessed, including C-reactive protein (CRP), lymphocyte count, d-dimer, cardiac troponin, ferritin, lactate dehydrogenase (LDH), IL-6, TGF-β1, TNF-α, IL-1β, PDGF- β, GCSF, and VEGF.
• The proportion of patients with ‘normal’ chest X-ray will be defined in a responder analysis. Patients with pre-existing chest pathology pre-COVID-19 should be considered 'normal' for those pre-existing items/findings.
• Pulse oximetry will be performed at rest and changes over time will be determined.
• Number of hospital stay days and time to all-cause mortality will be assessed.
• Percentage of patients who develop respiratory exacerbations, severe or non-severe
• All-cause rehospitalizations. Patients who are hospitalized at the time of randomization would
need to have been discharged and readmitted for inclusion in this assessment.
• Use of supplemental oxygen from Baseline to end of treatment
Exploratory Efficacy Endpoints-PART B:
The efficacy endpoints in Part B are considered exploratory, and all are as described for Part A (see above). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
All efficacy endpoints will be derived at each protocol-schedule time point for which they are collected, with analysis performed (e.g. change from baseline) for each time point.
The efficacy endpoints are consistent with the primary and secondary objectives of the study. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Study Part A - Double blind; Study Part B - Open Label |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Brazil |
| Moldova, Republic of |
| Philippines |
| Ukraine |
| United States |
| Romania |
| United Kingdom |
| Argentina |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last Visit Last Subject - LVLS. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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