Primary: • Assessment of the safety and tolerability of PLN-74809 Secondary:• Assessment of pharmacokinetics (PK) of PLN-74809 Exploratory:• Assessment of change from baseline in forced vital capacity (FVC) • Assessment of change from baseline in…
ID
Source
Brief title
Condition
- Immune disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Nature and proportion of AEs between PLN-74809 and placebo groups (descriptive)
Safety data from all participants who received at least one dose of study drug
will be incorporated into the final safety analysis. Further details of the
safety analyses will be provided in the SAP. AEs will be collected from the
time the participant signs the ICF until the last study visit.
Treatment-emergent adverse events (TEAEs) are defined as AEs that emerged or
worsened in severity after the first administration of study drug.
AEs will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA®). All AEs will be graded for severity per the CTCAE grading scale and
listed by participant and summarized by last treatment taken at onset of AE.
All AEs will be listed by participant and
summarized by last treatment taken at onset of AE.
The incidence of AEs, the incidence of TEAEs, the incidence of
treatment-related AEs, and the severity of AEs will be summarized by system
organ class, preferred term, and maximum severity. In cases where a participant
reports multiple occurrences of the same event (preferred term), the greatest
severity will be included in the summary. The number and percentage of
participants with SAEs and treatment-related SAEs and participants who withdraw
prematurely due to an AE will be tabulated by study treatment and dose.
Clinical laboratory test parameters will be graded using the CTCAE grading
scale for individual participants and values outside the reference ranges will
be flagged. The incidence of treatment-emergent laboratory abnormalities will
be summarized by severity and treatment
group. For each parameter, summary statistics will be calculated for each
measure and summarized by treatment and dose.
Individual ECG results will be listed for each participant. Summaries of ECGs
by treatment and dose will include changes from baseline for each parameter.
Vital sign measurements other laboratory tests, concomitant medications,
medical history and changes in physical examinations at each time point will be
listed by participant. The number and percentage of participants with abnormal
ECGs will be summarized by treatment and
dose.
Concomitant medications will be coded using the most current World Health
Organization drug dictionary available.
Secondary outcome
Secondary Pharmacokinetic Endpoints
Plasma PLN-74809 concentrations (total and unbound concentrations) at each
sampling timepoint will be presented in listings and descriptive summary
statistics by dose and visit. The data will also be presented graphically.
Further details of the analyses will be provided in the SAP to be prepared and
agreed prior to final *database lock* at the end of the study. The PK analysis
plan and report may be prepared separately from the SAP as appropriate.
Secondary Pharmacodynamic Endpoints
Urine, plasma and serum samples will be analyzed for biomarkers (presence or
actual concentration). These samples will be used to determine the levels of
these markers in participants and the relationship between these markers.
Results will be presented by listings, descriptive summary statistics and in
graphical form by treatment and dose and expressed as the relative change (and
or absolute) for each participant. In addition, relationships between PK and PD
may be evaluated in an exploratory fashion and presented in graphical manner.
Background summary
Idiopathic Pulmonary Fibriosis (IPF) is the most common interstital lung
disease, a condition in which the tiny air sacs in the lungs become damaged.
This causes scarring and the build-up of scar tissue (called fibrosis). The
scar tissue causes the lungs to become stiffer, making breathing increasingly
difficult. The symptoms of IPF can include shortness of breath, persistent dry
cough, tiredness, weight loss, and rounded and enlarged fingertips.
Patients diagnosed with mild-to-moderate IPF and who do not present with other
major health conditions that could affect the study drug or co-found the study
outcomes will be recruited in the clinical study.
PLN-74809-000 is being developed for Idiopathic Pulmonary Fibriosis (IPF).
PLN-74809 is a small molecule and is expected to exert anti-fibrotic effects
through mechanisms that are different from those of current standards of care
for IPF. The proposed trial is a randomised, double-blind, dose-ranging,
placebo-controlled Phase 2a study evaluating he safety, tolerability and PK of
12 weeks treatment with PLN-74809 40mg or placebo.
Currently, treatment options for IPF are limited to 2 drugs approved for the
treatment of IPF (nintedanib [OFEV] or pirfenidone [Esbriet]), and supportive
treatments. In this study, PLN-74809 is being compared to a placebo (which
looks like the investigational medication, but it contains no active
ingredients) for the treatment of IPF. PLN-74809 has not been approved as a
treatment for any condition in any country.
This is a placebo controlled, double-blind, randomized research study, which
will be conducted in 3 parts (Parts A, B, C, and D). Part A has ended.
• Part B will evaluate the 40mg dose of PLN-74809.
• Part C will evaluate doses of 80mg and 160mg of PLN-74809
• Part D will evaluate 320 mg of PLN-74809
Study objective
Primary:
• Assessment of the safety and tolerability of PLN-74809
Secondary:
• Assessment of pharmacokinetics (PK) of PLN-74809
Exploratory:
• Assessment of change from baseline in forced vital capacity (FVC)
• Assessment of change from baseline in quantitative lung fibrosis (QLF) score
• Assessment of change from baseline in a visual analog scale (VAS) for cough
• Assessment of changes in selected biomarkers.
Study design
This is a Phase 2a, multicenter, 4-part, randomized, double-blind,
dose-ranging, placebo-controlled study to evaluate the safety, tolerability,
and PK of once-daily (QD) treatment with PLN-74809 in participants with
idiopathic pulmonary fibrosis (IPF).
Each study part consists of an up to 28-day screening period, a 4-week (Part
A), 12 week (Parts B and C), or at least 24-week (Part D) treatment period, and
a 2-week (±3 days) post treatment follow-up period. Part A enrollment has been
completed, so is not further described herein; no further participants will be
enrolled or treated in this part of the study. Part B enrollment has been
completed; no further participants will be enrolled or treated in this part of
the study. Part C enrollment was initiated following review by the Data Safety
Monitoring Board (DSMB) and Competent Authorities (if applicable) of the
clinical data supporting the evaluation of 40 mg dosing. The DSMB and Competent
Authorities (if applicable) recommended continuation of Study PLN 74809-IPF-202
to evaluate doses of 80 mg and 160 mg without modification. Part D enrollment
will initiate following review by the DSMB and Competent Authorities (if
applicable) of the 80 mg and 160 mg clinical data from Part C. The dose level
of Part D is supported by the clinical data from study PLN 74809-104 and the
duration is supported by the chronic toxicology data.
Potential participants who provide written informed consent will be screened
for study eligibility up to 28 days before administration of the first dose of
study drug.
In Parts B, C and D, eligible participants will be randomized on Day 1 (Visit
2). Randomization will be stratified by use of standard of care (SoC) IPF
therapy (pirfenidone or nintedanib) (SoC use; yes or no).
In Part B, 29 eligible participants were randomized in a 3:1 ratio
(active:placebo) and treated for 12 weeks.
In Part C, approximately 28 eligible participants per cohort (56 in total) will
be randomized in a 3:1 ratio (active:placebo) and treated for 12 weeks in
sequential treatment cohorts.
In Part D, an additional PLN-74809 dose of 320 mg is planned for evaluation
based on the following criteria:
• Part C has been completely enrolled (i.e., 56 participants have been
randomized
• Pending favorable review by the DSMB and Competent Authorities (if
applicable) of:
o All available safety and PK data from this study (Part C)
o Safety and PK data from study PLN-74809-104, an ongoing Phase 1 study
evaluating the safety, tolerability, and pharmacokinetics of PLN 74809 at
multiple doses ranging from 80 to 320 mg in healthy participants, as described
in the Investigator*s Brochure
In Part D, approximately 28 eligible participants will be randomized in a 3:1
ratio (320 mg PLN-74809:placebo) on Day 1 (Visit 2). Randomization will be
stratified by use of SoC IPF therapy (pirfenidone or nintedanib) (SoC use; yes
or no). Study treatment will be administered for at least 24 weeks. Treatment
will continue for all participants in Part D until the last participant
enrolled in Part D reaches Week 24. Participants who discontinue study drug for
safety reasons prior to completion of 12 weeks (Parts B and C) or at least 24
weeks (Part D) of treatment will be asked to remain in the study to complete
all remaining assessments; if this is not feasible, they will be asked to
return to the clinic for an Early Termination (ET) visit for follow-up
evaluations.
The DSMB and Competent Authorities (if applicable) will assess participant
safety at predetermined intervals during the study, including prior to
initiating Part D and following the enrollment of the last participant in Part
D. An adjudication committee will assess acute exacerbations,
respiratory-related hospitalizations, and/or respiratory-related deaths.
Intervention
Part B: 40 mg of PLN 74809 or matching placebo administered orally QD
Part C: 80 mg or 160 mg of PLN-74809 or matching placebo administered orally QD
Part D: 320 mg of PLN-74809 or matching placebo administered orally QD
PLN-74809 will be supplied by Pliant as a tablet for oral administration. Study
drug will be taken once daily at approximately 24-hour intervals. Participants
will take the study drug on an empty stomach (no food for 2 hours before or 2
hours after dosing) and will drink up to 240 mL (~1 cup of water) after
swallowing the study drug.
Study burden and risks
Side Effects of PLN-74809
The investigational study medication PLN-74809 is at a research stage, so it
may have adverse effects (side effects) that are not known at this time. As
with any new medication there is a risk that unexpected adverse effects may
occur. Almost all medications, both old and new, can cause severe reactions. In
a previous first-in human research study, healthy participants received
PLN-74809 at doses of up to 75 mg (as a single dose) and 40 mg (as multiple
doses). The investigational study medication was well tolerated and had an
acceptable safety.
To date, PLN-74809 has been given to 84 healthy participants in 2 completed
clinical studies, either as single doses (one time) between 15 and 75 mg, or
multiple doses (up to two weeks) between 10 and 40 mg.
One (1) serious adverse event (SAE) has been reported in an ongoing clinical
study. The SAE was a severe intravenous catheter site infection.
Placebo Risks
In the placebo group, there are no anticipated side effects* however,
participants may experience side effects related to the study procedures. In
addition, your symptoms of IPF may not improve or may even worsen.
Allergic Reactions
As with taking any medication, there is a risk of allergic reaction. Some
symptoms of allergic reactions are: shortness of breath, itchy rash (hives) or
swelling, flushing (feeling warm), low blood pressure, and slow heart rate.
Blood Sampling
The risks of taking blood include fainting and pain, bruising, swelling, or
rarely infection where the needle was inserted. These discomforts are brief and
transient. The total volume to be collected during your participation in this
research study will be about 110 mL (approximately half a cup).
Electrocardiogram
Skin irritation from the ECG electrode pads or pain when removing the pads are
possible side effects.
High-resolution Computerzied Tomography (CT) Scan
When a CT scan is performed, you will be exposed to radiation. The radiation
exposure during high resolution CT scan is 3-8 millisievert (mSv). This
radiation exposure is 6 to 16 times less than the annual radiation limit for
radiation workers.
Spirometry
Participants may experience lightheadedness, fainting, shortness of breath, or
chest tightness.
Spirometery (DLco)
Participants may experience lightheadedness, fainting, shortness of breath, or
chest tightness.
Fasting
Fasting could cause dizziness, headache, stomach discomfort, or fainting.
To ensure minimization of the above mentioned risks and discomforts during the
study, health-care professional will be available 24-hours for participants to
report any side-effects/adverse reactions and get immediate medical care.
Littlefield Avenue 260
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Age
Inclusion criteria
Inclusion Criteria:
1. Participants, aged 40 years or older
2. Diagnosis of IPF for up to 5 years prior to screening based on American
Thoracic Society (ATS)/ European Respiratory Society (ERS)/ Japanese
Respiratory Society (JRS)/ Latin American Respiratory Society (ALAT) 2018
guidelines (Raghu et al, 2018)
Note: If IPF diagnosis is within > 3 to <= 5 years at screening, the participant
must have evidence of progression within the last 24 months, as defined by
decline in FVC percent predicted based on a relative decline of >= 5%
3. FVC percent of predicted >= 45%; historical FVC for entry in the study is
permitted if within 1 month of screening
4. Diffusing capacity for carbon monoxide (DLco) (hemoglobin-adjusted) >= 30%;
historical DLco for entry in the study is permitted if within 1 month of
screening
5. Participants currently receiving treatment for IPF with nintedanib or
pirfenidone are allowed, provided these drugs have been given at a stable dose
for at least 3 months before the Screening visit and are expected to remain
unchanged during the study (stable dose is defined as the highest dose
tolerated by the participant during >= 3 months)
6. Estimated glomerular filtration rate >= 50 mL/min, according to the
Cockcroft-Gault equation
7. Female participants of non-childbearing potential must be surgically sterile
or postmenopausal
8. Female participants of childbearing potential must use a contraceptive
method with a failure rate of < 1% per year or remain abstinent (refrain from
heterosexual intercourse) during the treatment period and for 1 month after the
last dose of study treatment.
Male participants with female partners of childbearing potential must agree to
use contraceptive measures or remain abstinent (refrain from heterosexual
intercourse) during the treatment period and for at least 3 months after the
last dose of study treatment.
9. Participants must agree to abstain from sperm or egg donation for the
duration of the study, through to 3 months or 1 month, respectively, after
administration of the last dose of study drug.
10. Able to read and sign a written informed consent form (ICF)
Exclusion criteria
Exclusion Criteria:
1. Receiving any nonapproved agent intended for treatment of fibrosis in IPF
2. Forced expiratory volume during the first second (FEV1) over the FVC ratio
(FEV1/FVC ratio) < 0.7 at screening
3. Clinical evidence of active infection, including but not limited to
bronchitis, pneumonia, or sinusitis that can affect FVC measurement during
screening or at randomization
4. Any other condition that prevents the correct assessment of spirometry
performance (for example a broken rib or chest pain of other origin that
prevents adequate forced breathing)
5. Known acute IPF exacerbation or suspicion by the Investigator of such,
within 6 months of screening
6. The extent of emphysema is greater than the extent of fibrotic changes on
the most recent high-resolution computerized tomography (HRCT) scan (as
determined by central reader); a) HRCT scan performed within 2 years of the
screening date may be used
7. Severe pulmonary hypertension
8. Smoking of any kind (not limited to tobacco) within 3 months of screening or
unwilling to avoid smoking throughout the study
9. Lower respiratory tract infection requiring antibiotics within 4 weeks prior
to screening and/or during the screening period
10. History of malignancy within the past 5 years or ongoing malignancy other
than basal cell carcinoma, resected noninvasive cutaneous squamous cell
carcinoma, or treated cervical carcinoma in situ
11. End-stage liver disease
12. Renal impairment or end-stage kidney disease requiring dialysis
13. History of unstable or deteriorating cardiac or pulmonary disease (other
than IPF) within the 6 months prior to screening, including but not limited to
the following:
a. Unstable angina pectoris or myocardial infarction
b. Congestive heart failure requiring hospitalization during the 6 months prior
to screening
c. Uncontrolled clinically significant arrhythmias (e.g., potentially resulting
in health care utilization or hospitalization)
d. Any clinically relevant electrocardiogram (ECG) abnormalities, including but
not limited to, QT interval corrected for heart rate using Fridericia's formula
(QTcF) > 450 msec for males or > 460 msec for females at the Screening visit
(including Day -1) or prior to administration of the initial dose of study drug.
14. Any of the following liver function test criteria above specified limits:
total bilirubin > 1.5 × the upper limit of normal (ULN); aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) > 3 × ULN; alkaline
phosphatase > 2.5 × ULN.
Note: participants currently receiving nintedanib or pirfenidone as IPF SoC
treatment, who have previously presented any liver function test elevations
associated with nintedanib or pirfenidone treatment greater than that described
above or resulting in dose reduction, treatment interruption, or
discontinuation are not eligible.
15. Any of the following at screening: hemoglobin < 10.0 g/dL, or neutrophils <
1500 /mm3, or platelets < 100,000 /mL
16. Pregnant or lactating females
17. Daily use of phosphodiesterase-5 (PDE-5) inhibitor drugs (e.g., sildenafil,
tadalafil, other) (Note: Intermittent use for erectile dysfunction is allowed)
18. A medical or surgical condition known to affect drug absorption (e.g.,
major gastric surgery)
19. Surgical procedures planned to occur during the study period
20. Uncontrolled systemic arterial hypertension
21. Has participated in a clinical study with an investigational agent in the
30 days prior to screening or 5 half-lives of the investigational drug,
whichever is longer
22. Likely to have lung transplantation during the study (being on
transplantation list is acceptable)
23. Any medical condition that, in the opinion of the Investigator, may make
candidates not suitable for the study
24. Hypersensitivity to PLN-74809 or to any of the excipients, or placebo
25. Currently receiving and expected to remain on treatment during the study
with: potent (i.e., strong) inhibitors or inducers of cytochrome P450 (CYP) 3A4
and P glycoprotein (P-gp) (e.g., itraconazole), breast cancer resistance
protein (BCRP) or organic anion transporting polypeptide (OATP) 1B1/1B3
transporters
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-002709-23-NL |
| ClinicalTrials.gov | NCT04396756 |
| CCMO | NL74229.100.20 |