This study has been transitioned to CTIS with ID 2023-509784-24-00 check the CTIS register for the current data. Core phase: The overall objective of the core phase is to investigate the efficacy, safety and tolerability of 2 dose regimens of HZN-…
ID
Source
Brief title
Condition
- Respiratory disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Core phase:
Change in FVC % predicted from Baseline to Week 52.
Extension phase:
The primary endpoint is the change from both Baselines in FVC % predicted at
Week 104.
Secondary outcome
Core phase:
Key secondary efficacy endpoint:
Proportion of subjects with decline in FVC % predicted >=10% from Baseline at
Week 52.
Other secondary efficacy endpoints:
1. Change from Baseline in the 6MWT results to Week 52.
2. Change from Baseline in K-BILD scores to Week 52.
3. Change from Baseline in L-IPF scores to Week 52.
4. Change from Baseline in LCQ scores to Week 52.
5. Time to first hospitalization due to respiratory distress from Baseline up
to Week 52.
6. Time to first onset of the composite endpoint of PFS from Baseline up to
Week 52, where progression includes decline in FVC % predicted >=10% or death.
For exploratory and safety endpoints please refer to the study protocol
Extension phase:
Safety and tolerability endpoints:
• Incidence of TEAEs and the AESI (orthostatic hypotension) in the Extension
Phase
• Concomitant medication use in the Extension Phase
• Change from Trial Baseline in vital signs in the Extension Phase
• Change from Trial Baseline in 12-lead ECG measurements in the Extension Phase
• Change from Trial Baseline in clinical safety laboratory test results in the
Extension Phase
For exploratory please refer to the study protocol
Background summary
IPF is an advancing and fatal lung disease with significant morbidity and
reported increasing incidence and prevalence. Pirfenidone and nintedanib were
approved by the FDA in 2014 for the treatment of IPF based on positive results
in Phase 3 trials, and both of these antifibrotic drugs are conditionally
recommended in the 2015 ATS/ERS/JRS/ALAT Clinical Practice Guideline [Raghu et
al., 2015]. Although an improvement over previously suggested therapies, their
capacity to reduce but not completely arrest progression of lung fibrosis or
improve lung function over time presents an opportunity for novel or add-on
pharmacologic agents.
Pirfenidone should be taken 3 times daily with food at a target dose that is
generally achieved
over 14 days [Lancaster et al., 2017]. Nintedanib recommended dosage includes
BID dosing with food. In randomized, double-blind, placebo controlled trials,
gastrointestinal adverse reactions occurring in >=10% of treated subjects that
may require temporary dosage reductions or discontinuations for pirfenidone and
nintedanib included diarrhea, nausea, abdominal pain and vomiting [ESBRIET Full
Prescribing Information; OFEV Full Prescribing Information]. While significant
advances have been made in the past decade using pharmacological therapy, there
remains a substantial unmet clinical need for treatment regimens with improved
efficacy, tolerability and dosing convenience for patients with IPF.
HZN-825 is under investigation as a novel therapy for IPF because it
selectively antagonizes LPAR1, which has been shown to be associated with skin,
pulmonary, cardiac, peritoneal and tubulointerstitial fibrosis and has
potential as a new therapeutic for treating fibrotic diseases, including IPF.
This trial is designed to evaluate the efficacy and safety of HZN-825 in
subjects with IPF. The trial will be conducted in 2 parts, Part 1 (Core Phase)
and Part 2 (Extension Phase). In the Core Phase of the trial, subjects will
receive HZN-825 300 mg QD, HZN-825 300 mg BID or placebo during the 52-week
Double-blind Treatment Period. Subjects who complete the Double-blind
Treatment Period (Week 52) in the Core Phase may be eligible for the Extension
Phase and will receive open-label HZN-825 300 mg BID for 52 weeks (up to Week
104). This Extension Phase will allow subjects to have up to 24 months of
treatment with HZN-825, as well as limit the duration subjects are exposed to
placebo. The trial is designed with the Extension Phase to allow examination
of long-term safety and tolerability of HZN-825, assessment of the durability
of response and/or improved response in subjects who received HZN-825 in the
Core Phase and evaluation of efficacy in subjects who received placebo in the
Core Phase.
Study objective
This study has been transitioned to CTIS with ID 2023-509784-24-00 check the CTIS register for the current data.
Core phase:
The overall objective of the core phase is to investigate the efficacy, safety
and tolerability of 2 dose regimens of HZN-825, a selective antagonist of
lysophosphatidic acid receptor-1 (LPAR1), administered once daily (QD) or twice
daily (BID) for 52 weeks in the treatment of subjects with idiopathic pulmonary
fibrosis (IPF).
Primary Objective:
The primary objective is to demonstrate the efficacy of 2 dose regimens of
HZN-825 versus placebo in subjects with IPF, as determined by a comparison of
change in forced vital capacity (FVC) % predicted after 52 weeks of treatment.
Secondary Objectives:
1. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on the
proportion of subjects with decline in FVC % predicted >=10% from Baseline after
52 weeks of treatment.
2. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on the
changes from Baseline in the 6 Minute Walk Test (6MWT) after 52 weeks of
treatment.
3. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on the
King's Brief Interstitial Lung Disease Questionnaire (K-BILD) after 52 weeks of
treatment.
4. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on the
Living with IPF (L-IPF) after 52 weeks of treatment.
5. Evaluate the effect of 2 dose regimens HZN-825 versus placebo on the
Leicester Cough Questionnaire (LCQ) after 52 weeks of treatment.
6. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on the rate
of hospitalization due to respiratory distress up to 52 weeks of treatment.
7. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on the
composite endpoint of progression-free survival (PFS), where progression
includes decline in FVC % predicted >=10% from Baseline or death over 52 weeks
of treatment.
8. Assess safety and tolerability of HZN-825, inclusive of, but not limited
to, adverse events (AEs), SAEs and AESI.
9. Evaluate the PK of HZN-825.
For exploratory objectives please refer to the study protocol.
Extension phase:
The overall objective of the Extension Phase is to investigate the long-term
efficacy, safety and tolerability of HZN-825, a selective antagonist of LPAR1,
administered at a dose of 300 mg BID to subjects with IPF in a 52-week OLE
following completion of the Core Phase of the trial. The dose for the
Extension Phase may be modified based on the results of the Core Phase.
Two types of Baseline are defined for the Extension Phase:
• OLE Baseline, defined as the latest measurement prior to the first dose of
HZN-825 in Extension Phase
• HZN-825 Baseline, defined as the latest measurement prior to the first dose
of HZN-825 in either the Core Phase or the Extension Phase. For subjects who
received placebo in the Core Phase, OLE Baseline will be the same as HZN-825
Baseline.
Primary objective:
The primary efficacy objective is to assess the efficacy of HZN 825 in subjects
with IPF after 52 weeks of open-label treatment.
Safety objective:
The safety objective is to examine the safety and tolerability of 52 weeks of
open-label treatment with HZN 825 based on:
• TEAE assessment
• Concomitant medication use
• Vital signs
• 12-lead electrocardiogram (ECG)
• Clinical safety laboratory results
For exploratory objectives please refer to the study protocol.
Study design
HZNP-HZN-825-303 (HARBOR) will be conducted at approximately 85 trial sites in
North America, Europe, South America, Africa, Asia (including Japan) and
Australia. The trial comprises 2 parts. Part 1 (Core Phase) is a randomized,
double-blind, placebo-controlled, repeat-dose, multicenter trial to evaluate
the efficacy, safety and tolerability of HZN-825 in subjects with IPF. Part 2
(Extension Phase) is an optional, open-label, repeat-dose, multicenter
extension of the Core Phase.
Design of the Core Phase of the Trial
This is a randomized, double-blind, placebo-controlled, repeat-dose,
multicenter trial to evaluate the efficacy, safety and tolerability of HZN-825
in subjects with IPF. Subjects will be screened within 8 weeks prior to the
Baseline (Day 1) Visit. Approximately 135 subjects who meet the trial
eligibility criteria will be randomly assigned in a 1:1:1 ratio on Day 1 to
receive HZN-825 300 mg QD, HZN-825 300 mg BID or placebo for 52 weeks using the
following 2 stratification factors:
1. Concomitant use of approved IPF therapy (i.e., nintedanib or pirfenidone):
yes or no
2. FVC % predicted at Baseline: >=70% or <70%
The Core Phase will include up to an 8-week Screening Period and a 52-week
Double-blind Treatment Period. Subjects will take their first dose of trial
drug at the clinic on Day 1 (Week 0) and will participate in trial visits at
Week 4 and every 6 weeks thereafter until Week 52. Subjects who complete the
52-week Double blind Treatment Period may be eligible to enroll into the
Extension Phase of the trial. If the subject does not enroll into the
Extension Phase, a Safety Follow-up Visit will occur 4 weeks after the last
dose of trial drug.
If a subject prematurely discontinues trial drug, he/she will be asked to
remain in the trial, participating in the scheduled trial visits through Week
52. If a subject prematurely discontinues trial drug and does not wish to
continue in the trial, he/she will be asked to return for a clinic visit and
undergo the Week 52 assessments.
Design of the Extension Phase of the Trial
The Extension Phase of the trial is an optional, open-label, repeat-dose,
multicenter extension of the Core Phase. Subjects who complete the
Double-blind Treatment Period (Week 52) in the Core Phase of the trial may be
eligible to enter this 52 week Extension Phase. Subjects entering the
Extension Phase will complete the Week 52 Visit, which will be considered Day 1
of the Extension Phase, and will receive their first dose of open-label HZN-825
in the Extension Phase at the clinic and return to the clinic for trial visits
at Weeks 56, 62 and 68, then every 12 weeks through Week 104. The Week 52
Visit activities will serve as Baseline for the Extension Phase. Subjects will
return to the clinic for a Safety Follow-up Visit 4 weeks after the last dose
of HZN 825.
If a subject prematurely discontinues HZN-825, he/she will be asked to remain
in the trial, participating in the scheduled trial visits through Week 104. If
a subject prematurely discontinues HZN-825 and does not wish to continue in the
trial, he/she will be asked to return for a clinic visit and undergo the Week
104 assessments.
Intervention
Core phase: Subjects will take 2 tablets of trial drug orally in the morning
and evening with a meal.
• HZN-825 300 mg QD regimen: 2 HZN-825 tablets in the morning and 2 placebo
tablets in the evening
• HZN-825 300 mg BID regimen: 2 HZN-825 tablets in the morning and 2 HZN-825
tablets in the evening
• Placebo regimen: 2 placebo tablets in the morning and 2 placebo tablets in
the evening
Extension Phase: The dose regimen for all subjects will be HZN-825 300 mg BID.
Subjects will take 2 HZN 825 150 mg tablets orally in the morning and evening
with a meal. The dose for the Extension Phase may be modified based on the
results of the Core Phase.
Study burden and risks
HZN-825 is a new therapeutic agent under development for treating fibrotic
diseases, including SSc. The anti-inflammatory and anti-fibrotic properties of
LPAR1 antagonism have been demonstrated in both animal models and in a Phase 2a
clinical trial. Positive changes in mRSS, HAQ-DI and LPAR1 pathway genes were
detected in the completed Phase 2a trial in diffuse cutaneous SSc. Results of
trials to date support the safety and potential efficacy of 300 mg BID for up
to 24 weeks of treatment. The exposure, PK and safety profiles of HZN-825 were
similar across the completed trials.
Based on the cumulative safety data available to date on HZN-825, orthostatic
hypotension, drug-drug interactions, embryo-fetal toxicity and liver toxicity
are considered as important potential risks. No severe AEs or SAEs were
reported in healthy subjects in Phase 1 trials. TEAEs of orthostatic
hypotension, postural dizziness, flatulence and abdominal pain were slightly
more frequent in HZN-825-treated than in placebo-treated subjects. Orthostatic
hypotension was mainly observed in healthy subjects and tended to be less
marked in subjects with diffuse cutaneous SSc treated with HZN-825. The
potential safety risk of HZN-825 due to drug-drug interactions is considered
low as medications that may have potential interactions with HZN-825 are
restricted in this protocol (Section 9.4.9).
Participants with IPF receiving HZN-825 may benefit from the LPAR1 antagonism
by slowing the decline of lung function due to progressive fibrotic disease.
Subjects in the trial will also benefit from receiving trial-related medical
examinations, imaging and laboratory tests at no cost.
AESIs are considered monitorable. Taking into account mitigation measures to
minimize risk to subjects in this trial, the potential risks identified in
association with HZN 825 treatment and the trial as a whole are justified by
the anticipated benefits that may be afforded to patients with IPF.
Additional information regarding the benefit and risks of HZN-825 are located
in the current Investigator*s Brochure Section 6.2 and Section 1.2.
St. Stephen's Green 70
Dublin 2 D02E2X4
IE
St. Stephen's Green 70
Dublin 2 D02E2X4
IE
Listed location countries
Age
Inclusion criteria
Core phase:
1. Written informed consent.
2. Male or female >=18 years of age at Screening.
3. Current diagnosis of IPF, as defined by American Thoracic Society
(ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society
(JRS)/Latin American Thoracic Society (ALAT) guidelines [Raghu et al., 2022]
and determined by central review; the date of initial diagnosis of IPF should
be <=7 years prior to Screening.
4. No recent changes or planned changes to the dose or regimen for IPF therapy,
defined as:
• Receiving a stable dose of IPF-approved therapy (i.e., nintedanib or
pirfenidone) for a minimum of 3 months prior to Day 1 with no plans to change
the background regimen during trial participation, or
• Not currently receiving background IPF-approved therapy at Screening (either
naïve to IPF-approved therapy or previously discontinued any IPF-approved
therapy at least 4 weeks prior to Day 1 or drug-specific, 5 half-lives
elimination period if longer than 4 weeks), and with no current plans to
restart treatment during trial participation
• Subjects receiving any additional agent for IPF therapy must be on a stable
regimen for at least 3 months prior to Day 1 with no current plans to change
the treatment regimen during trial participation. Any previously discontinued
therapy used to treat IPF must have been discontinued at least 4 weeks prior to
Day 1 or 5 half-lives for that specific therapy must have elapsed, whichever is
longer, with no plans to restart the therapy during trial participation.
5. Lung HRCT historically performed within 6 months prior to the Screening
Visit and according to the minimum requirements for IPF diagnosis by central
review based on subject's HRCT. If an evaluable HRCT is not available within 6
months prior to Screening, an HRCT will be performed at Screening to determine
eligibility, according to the same requirements as the historical HRCT. The
HRCT must demonstrate a usual interstitial pneumonia or probable usual
interstitial pneumonia pattern based on central review vendor interpretation.
Histopathology in combination with HRCT results supportive of an IPF or IPF
likely diagnosis according to Raghu et al., 2022 can be submitted to support
subject eligibility.
6. HRCT shows >=10% to <50% parenchymal fibrosis (reticulation) and the extent
of fibrotic changes is greater than the extent of emphysema on the most recent
HRCT scan (central reviewer determined).
7. Meets all of the following criteria during the Screening Period, as
determined by central review:
a. FVC >=45% predicted of normal
b. forced expiratory volume in 1 second (FEV1)/FVC >=0.7
c. DLCO corrected for hemoglobin is >=25% and <=90% predicted of normal
8. Estimated minimum life expectancy of >=30 months for non-IPF-related disease,
in the opinion of the Investigator.
9. Vaccinations are up to date, according to the Investigator*s discretion,
given age, comorbidities and local availability prior to trial drug dosing.
10. Willing and able to comply with the prescribed treatment protocol and
evaluations for the duration of the trial.
Extension phase:
1. Written informed consent.
2. Completed the Double-blind Treatment Period (Week 52) of the Core Phase of
the trial; subjects prematurely discontinued from trial drug in the Core Phase
of the trial for reasons other than safety or tolerability may be included at
the discretion of the Investigator after completing scheduled visits, including
Week 52 assessments.
3. Willing and able to comply with the prescribed treatment protocol and
evaluations for the duration of the Extension Phase of the trial.
Exclusion criteria
Core phase:
1. Any of the following cardiovascular diseases:
a. uncontrolled, severe hypertension (>=160/100 mmHg), within 6 months of
Screening
b. myocardial infarction within 6 months of Screening
c. unstable cardiac angina within 6 months of Screening
2. Interstitial lung disease (ILD) associated with known primary diseases
(e.g., sarcoidosis, amyloidosis and coronavirus disease 2019 [COVID-19]),
connective tissue disorders (e.g., rheumatoid arthritis, systemic lupus
erythematosus, Sjogren*s, dermatomyositis, scleroderma), exposures (e.g.,
radiation, silica, asbestos and coal dust) or drugs (e.g., amiodarone).
3. Known active bacterial, viral, fungal, mycobacterial or other infection,
including tuberculosis or atypical mycobacterial disease (fungal infections of
nail beds are allowed). The subject must be 3 months beyond any acute
infection with COVID-19 if there has been a prior infection.
4. Clinically significant pulmonary hypertension requiring chronic medical
therapy.
5. Use of any of the following therapies within 4 weeks prior to Screening,
during the Screening Period or planned during the trial: prednisone at steady
dose >10 mg/day or equivalent or cyclosporine. Prednisone <=10 mg/day (or
equivalent dosing of glucocorticoids) is allowed. Change in regimen or dosage
of any immunosuppressant during the Screening Period through the end of trial
participation will require consultation with and approval by the trial Medical
Monitor. See Section 9.4.9 for full details. Avoiding the use of listed
prohibited treatments must not be considered detrimental and must be indicated
by the treating physician. Subjects must not be withdrawn from any
standard-of-care treatment that is considered necessary for the clinical
management of the subject in order to fulfill the trial eligibility
requirements.
6. Use of rifampin within 2 weeks prior to Day 1 or planned during the trial.
7. Malignant condition in the past 5 years (except successfully treated
basal/squamous cell carcinoma of the skin or cervical cancer in situ).
8. Women of childbearing potential (WOCBP) or male subjects not agreeing to use
highly effective method(s) of birth control throughout the trial and for 4
weeks after last dose of trial drug. Females must refrain from egg/ova
donation for 4 weeks after the last dose of trial drug and males must refrain
from sperm donation for 3 months after the last dose of trial drug. Women are
considered of childbearing potential if they are not postmenopausal and not
surgically sterile (documented bilateral salpingectomy, bilateral oophorectomy
or hysterectomy). 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 postmenopausal
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. Fertile male subjects must use a condom
throughout the trial and for 4 weeks after the last dose of trial drug. A man
is considered fertile after puberty unless permanently sterile by bilateral
orchidectomy.
9. Pregnant or lactating women and women who plan to become pregnant or breast
feed during the trial and within 4 weeks after the last dose of trial drug.
10. Current drug or alcohol abuse or history of either within the previous 2
years, in the opinion of the Investigator or as reported by the subject.
11. Previous enrollment in this trial or participation in a prior HZN-825 or
SAR100842 clinical trial.
12. Known history of positive test for human immunodeficiency virus (HIV). HIV
testing is optional based on Investigator assessment, institutional practices
or local guidelines to rule out suspected HIV or potential for a positive HIV
result. Subject consent is required prior to HIV testing.
13. Active hepatitis (any of the following at Screening):
Hepatitis B:
• positive hepatitis B surface antigen
• positive for anti-hepatitis B core antibody (anti HBcAb) and a positive test
for hepatitis B surface antibody (HBsAb) and presence of hepatitis B virus DNA
• positive for HBcAb and a negative test for HBsAb and presence of hepatitis B
virus DNA
Hepatitis C:
• positive anti hepatitis C virus (anti HCV) and positive HCV RNA.
14. Current alcoholic liver disease, primary biliary cirrhosis or primary
sclerosing cholangitis.
15. Previous organ transplant (including allogeneic and autologous marrow
transplant).
16. International normalized ratio >2, prolonged prothrombin time >1.5 × the
upper limit of normal (ULN) or partial thromboplastin time >1.5 × ULN at
Screening.
17. Alanine aminotransferase or aspartate aminotransferase >2.0 × ULN.
18. Estimated glomerular filtration rate <30 mL/min/1.73 m2 at Screening.
19. Total bilirubin >1.5 × ULN. Subjects with documented diagnosis of
Gilbert*s syndrome may be enrolled if their total bilirubin is <=3.0 mg/dL.
20. Moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment
according to the Child-Pugh scoring system.
21. Any confirmed Grade 3 or higher laboratory abnormality.
22. Any laboratory abnormality at Screening that, in the opinion of the
Investigator, would preclude the subject*s participation in the trial.
23. Exposure to an experimental drug or experimental vaccine within either 30
days, 5 half-lives of the test agent, or twice the duration of the biological
effect of the test agent, whichever is the longest, prior to Day 1.
24. Any other condition that, in the opinion of the Investigator, would
preclude enrollment in the trial.
Extension phase:
1. Anticipated use of another investigational agent for any condition during
the course of the trial.
2. New diagnosis of malignant condition after enrolling in Trial
HZNP-HZN-825-303 (except successfully treated basal/squamous cell carcinoma of
the skin or cervical cancer in situ).
3. Estimated minimum life expectancy <=18 months, in the opinion of the
Investigator.
4. WOCBP or male subjects not agreeing to use highly effective method(s) of
birth control throughout the Extension Phase and for 4 weeks after last dose of
HZN-825. Females must refrain from egg/ova donation for 4 weeks after the last
dose of trial drug and males must refrain from sperm donation for 3 months
after the last dose of trial drug. Women are considered of childbearing
potential if they are not postmenopausal and not surgically sterile (documented
bilateral salpingectomy, bilateral oophorectomy, or hysterectomy). A
postmenopausal state is defined as no menses for 12 months without an
alternative medical cause. A high FSH level in the postmenopausal range may be
used to confirm a postmenopausal 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. A man is
considered fertile after puberty unless permanently sterile by bilateral
orchidectomy.
5. Pregnant or lactating women.
6. Any other new development of the disease/condition/significant laboratory
test abnormality during the course of the Core Phase of the trial, in the
opinion of the Investigator, that would potentially put the subject at
unacceptable risk.
7. In the opinion of the Investigator, unlikely to comply with the trial
protocol or has a concomitant disease or condition that could interfere with
the conduct of the trial.
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 |
|---|---|
| Other | NCT05032066 |
| EU-CTR | CTIS2023-509784-24-00 |
| EudraCT | EUCTR2021-001253-32-NL |
| CCMO | NL79812.028.22 |