| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Idiopathic Pulmonary Fibrosis (IPF) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lung scarring of the unknown cause |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10021240 |
| E.1.2 | Term | Idiopathic pulmonary fibrosis |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| 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 |
| To obtain clinical data establishing the efficacy, tolerability, safety, and dosing regimen of LYT-100 in patients with IPF. |
|
| E.2.2 | Secondary objectives of the trial |
Part B Objectives:
• Assess the safety and tolerability of long-term treatment with LYT-100
in the IPF population
• Compare the rate of change in FVC through the end of Part B Period 1
to that observed during Part A, by Part A treatment group assignment
and by Part B LYT-100 target dose |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Intensive PK Sub-study:
Intensive PK samIntensive PK Sub-study:
An optional, intensive PK sub-study will be conducted at a subset of sites
in approximately 8 completed patients per treatment arm in which each
patient will provide up to 16 blood samples for PK over a 24-hour period
at Study Visits 3, 5 and 8.pling over a 24-hour time period at steady-state will be collected in a subset of 8 patients per treatment group (up to 32 patients total) in which each patient will provide up to 16 blood samples for PK over a 24-hour period at Study Visits 3, 5 and 8. |
|
| E.3 | Principal inclusion criteria |
1. Written or electronic informed consent from the participant prior to
any study procedures in a manner approved by an IRB, IEC, or HREC
2. Male or female, age of ≥40 years at the time of informed consent
3. Able to perform and willing to comply with all study procedures and
requirements
4. Treatment-naïve patients or those with <6 months of exposure to
nintedanib with physician-diagnosed IPF based on ATS/ ERS/JRS/ALAT
2018 guidelines
5. IPF on high-resolution computed tomography (HRCT), performed
within 12 months of Visit 1 as confirmed by central readers
6. The extent of fibrotic changes is greater than the extent of
emphysema on the most recent HRCT scan as determined by the investigator and the central reader
7. Diffusing capacity of the lungs for carbon monoxide (DLCO) corrected
for hemoglobin (Hb) [Visit 1] ≥30% and ≤90% of predicted normal
where available at the study site.
8. FVC ≥45% of predicted normal
9. Women of childbearing potential (WOCBP) must be non-pregnant and
non-lactating, and must be abstinent from heterosexual intercourse
throughout the study and for 30 days following last dose of study
medication or agree to use 1 of the acceptable, highly effective methods
of double contraception which is defined as male use of a condom AND 1
form of the following:
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)
10. Male participants must be surgically sterile (>30 days since
vasectomy with no viable sperm), abstinent, or, if engaged in
heterosexual relations, any female partner must be postmenopausal,
surgically sterile (eg, 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 for no less than 90 days after the last
dose of study medication along with the use of male condom
11. Males will not donate sperm for at least 90 days after the last dose of
study medication
12. Female partners of male participants and female participants will
report pregnancy occurring within 90 days from cessation of study
medication
Part B:
1. Signed informed consent for Part B prior to any study-mandated
procedures
2. Participant must have completed Part A of the study, through Day 183
of treatment
3. In the opinion of the investigator, the participant is a good candidate
for continued treatment |
|
| E.4 | Principal exclusion criteria |
1.Participants who, in the judgement of the investigator, are unlikely to
be able to fulfill study participation requirements
2.Significant clinical worsening (as per investigator's discretion) of IPF
between Screening and Baseline Visits
3.AST or ALT>1.5 × ULN at Visit 1
4.Total bilirubin>1.5 × ULN at Visit 1. Exceptions may be made on a
case-by-case basis for participants with Gilbert's syndrome in
consultation with the medical monitor
5.Creatinine clearance <30 mL/min calculated by Cockcroft–Gault
formula at Visit 1
6.Participants with underlying chronic liver disease (Child-Pugh B or C
hepatic impairment)
7.Current or prior treatment with pirfenidone
8.Other investigational therapy received within 1 month prior to
randomization visit (Visit 2)
9.Significant pulmonary hypertension (PH) defined by any of the
following:
a.Previous clinical or echocardiographic evidence of significant right
heart failure
b.History of right heart catheterization showing a cardiac index ≤2 L/min/m²
c.PH inhaled requiring subcutaneous or intravenous therapy with
epoprostenol/treprostinil
d.In the principal investigator's opinion, the study participant's
symptoms are more related to their PH than to their IPF
10.Primary obstructive airway physiology (pre-bronchodilator FEV1/FVC
<0.7 at Visit 1)
11.Known explanation for interstitial lung disease, including but not
limited to radiation, sarcoidosis, hypersensitivity pneumonitis,
bronchiolitis obliterans organizing pneumonia, HIV, viral hepatitis, and
cancer
12.Diagnosis of any connective tissue disease, including but not limited
to scleroderma/systemic sclerosis, Sjogren's disease, mixed connective
tissue diseases, polymyositis/dermatomyositis, systemic lupus
erythematosus, and rheumatoid arthritis
13.In the opinion of the investigator, other clinically significant
pulmonary abnormalities, including prior or current lung cancer (treated
within the past 5 years)
14.Major extrapulmonary physiological restriction (eg, chest wall abnormality, large pleural effusion)
15.Cardiovascular diseases, any of the following:
a.Uncontrolled hypertension, within 3 months of Visit 1
b.Myocardial infarction within 6 months of Visit 1
c.Unstable cardiac angina within 6 months of Visit 1
16.Prior hospitalization within 3 months prior to Visit 1 for
confirmed COVID-19, acute exacerbation of IPF, or any lower
respiratory tract infection
17.Known symptoms of dysphagia or known difficulty in swallowing
capsules or tablets and/or total gastrectomy
18.Use of any of the following drugs within 2 weeks prior to Visit 2/
baseline or planned during the duration of the study:
a.Strong and moderate CYP1A2 inhibitors (ie, ciprofloxacin, fluvoxamine,
enoxacin, methoxsalen, mexiletine, vemurafenib) and phenytoin,
rifampin, and teriflunomide (inducers of CYP1A2)
b.Medications associated with substantial risk for prolongation of the
QTc interval (including but not limited to moxifloxacin, quinidine,
procainamide, amiodarone, sotalol)
c.Immunosuppressant medications such as azathioprine,
cyclophosphamide, cyclosporin A, methotrexate, prednisone at a steady
dose >10mg/day or equivalent
d.Medications used to treat PH such as endothelin receptor antagonists
(eg, ambrisentan, bosentan, and macitentan), phosphodiesterase-5
inhibitors (sildenafil and tadalafil used to treat erectile dysfunction are
allowed), guanylate cyclase stimulators (eg, riociguat), prostacyclin
analogs (eg, epoprostenol, treprostnil, iloprost), or prostacyclin receptor
agonists (eg, selexipag)
e.Warfarin, as it may worsen IPF
f.Vaccination with a live vaccine is not permitted during the period from
4 weeks prior to Screening to 4 weeks after the last dose.
19.A current immunosuppressive condition (eg, HIV)
20.Major surgical procedures during Screening or study periods, with the
exception of pre-planned procedures that will not interfere with study
participation
21.Active alcohol or drug abuse
22.Use of smoked (burnt) tobacco products or vaping/e-cigarettes
23.Other disease (including malignancy) that may interfere with testing
procedures or in the judgement of the investigator may interfere with
study participation or may put the participant at risk when participating
in this study
24.Participants with a documented hypersensitivity to LYT-100
25.Participants with a documented lactose or galactose intolerance
.AST, ALT, or total bilirubin >3 Ч ULN
.Any known factor or disease that interferes with treatment
compliance, study conduct, or interpretation of the results, as judged by
the investigator
Part B:
1.Participants must not meet any exclusion criteria listed for Part A
2.Participants who discontinued study medication and started receiving
commercially available antifibrotic medication during Part A will not be
eligible for Part B
3.Participants whose treatment assignment is unblinded during Part A
will not be eligible for Part B |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Rate of decline in FVC (in mL) over Part A (26 weeks) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Change in FVC % predicted (FVCpp) from baseline to the end of Part A
(Week 26)
Secondary Efficacy Endpoints
• Time to IPF progression through 26 weeks (the end of Part A), as
defined by a decline from baseline in FVCpp of 5% or greater, or death
• Time to hospitalization due to respiratory cause (as determined by the
investigator) or all-cause mortality through 26 weeks
Secondary Tolerability Endpoints
• Incidence of dose modifications (dose reductions and interruptions)
• Time to first dose modification (reductions or interruption)
• Duration of dose modifications (reductions and interruptions)
• Number of days on full assigned dose
• Incidence and duration of AESIs
• Time to treatment discontinuation due to an AE
Exploratory Endpoints
• Time to hospitalization due to respiratory cause (as determined by the
investigator) through 26 weeks
• Time to all-cause mortality through 26 weeks
• Change from baseline to Week 26 in King's Brief Interstitial Lung
Disease Questionnaire (K-BILD) total score
• Change from baseline to Week 26 in St. George's Respiratory
Questionnaire – IPF Version (SGRQ-I)
• Change from baseline to Week 26 in EuroQol 5-Dimensional Quality of
Life Questionnaire (EQ-5D)
• Change in serum biomarkers from baseline through Week 26
• Number and duration of respiratory hospitalizations or pulmonary
exacerbations (as determined by the investigator) through 26 weeks
• Rate of hospitalization due to respiratory cause (as determined by the
investigator) through 26 weeks
Part B
Key Secondary Efficacy Endpoints
• Change in FVCpp from the end of Part A (Week 26) to the end of Part B
Period 1 (Week 52)
• Rate of decline in FVC (in mL) from the end of Part A (Week 26) to the
end of Part B Period 1 (Week 52) using the values obtained from
spirometry assessments
Secondary Efficacy Endpoints
• Time to IPF progression in Part B, as defined by a decline from the end
of Part A (Week 26) to the end of Part B Period 1 (Week 52) in FVCpp of
5% or greater, or death
Secondary Tolerability Endpoints
• Incidence of dose modifications (dose reductions and interruptions)
• Time to first dose modification (reduction or interruption)
• Duration of dose modifications (reductions and interruptions)
• Number of days on full assigned dose
• Incidence and duration of AESIs
• Time to treatment discontinuation due to an AE
Exploratory Endpoints
• Time to hospitalization due to respiratory cause (as determined by the
investigator) from the start of Part B (Week 26) through the end of Part
B Period 1 (Week 52)
• Time to all-cause mortality from the start of Part B (Week 26) through
the end of Part B Period 1 (Week 52)
• Time to hospitalization due to respiratory cause (as determined by the
investigator) or all-cause mortality from the start of Part B (Week 26)
through the end of Part B Period 1 (Week 52)
• Total duration on assigned dose from the start of Part B through the
end of Part B Period 1 (Week 52)
• Change in EQ-5D from the end of Part A (Week 26) through the end of
Part B Period 1 (Week 52)
• Change in serum and plasma biomarkers from the end of Part A (Week
26) through the end of Part B Period 1 (Week 52)
• Number and duration of respiratory hospitalizations or pulmonary
exacerbations (as determined by the investigator) from the start of Part
B (Week 26) through the end of Part B Period 1 (Week 52)
• Rate of hospitalization due to respiratory cause (as determined by the
investigator) from the start of Part B (Week 26) through the end of Part
B Period 1 (Week 52)
Pharmacokinetic Endpoints
A sparse PK sampling strategy will be employed in which all participants
will provide pre-dose blood samples for determination of plasma
concentrations of LYT-100/pirfenidone and its metabolite(s). In
addition, an optional, intensive PK substudy will be conducted at a
subset of sites in approximately 8 completed participants per treatment
arm in which each participant will provide up to 16 blood samples for PK
over a 24-hour period at Study Visits 3, 5 and 8. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
at week 26 (Part A)
at week 52 (Part B) |
|
| 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 | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 |
| Double-blind Part A is followed by Part B long-term open-label extension |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 4 |
| 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 |
| Argentina |
| Chile |
| Colombia |
| Malaysia |
| Georgia |
| India |
| Korea, Republic of |
| Mexico |
| South Africa |
| Thailand |
| United States |
| Greece |
| Poland |
| Romania |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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