Primary Objective:The primary objective is to demonstrate the efficacy of 1 or 2 dose regimens of HZN-825 versus placebo in subjects with diffuse cutaneous SSc, as determined by a comparison of change in forced vital capacity (FVC) % predicted after…
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Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change in FVC % predicted from Baseline to Week 52
Secondary outcome
1. Change from Baseline in HAQ-DI at Week 52.
2. Change from Baseline in MDGA at Week 52.
3. Change from Baseline in PTGA at Week 52.
4. Change from Baseline in the Physical Effects subscale of the SSPRO-18 at
Week 52.
5. Change from Baseline in the Physical Limitations subscale of the SSPRO-18 at
Week 52.
6. Proportion of subjects with an mRSS decrease of >=5 points and 25% from
Baseline at Week 52.
7. Responder rate (defined as ACR-CRISS [predicted probability] of at least
0.6) at Week 52.
8. Proportion of subjects with an improvement in >=3 of 5 core measures from
Baseline: >=20% in mRSS, >=20% in HAQ-DI, >=20% in PTGA, >=20% in MDGA and >=5% for
FVC % predicted at Week 52 (ACR-CRISS-20).
Background summary
Diffuse cutaneous SSc is a rare and devastating autoimmune disease
characterized by skin fibrosis, beginning on the fingers and face, that rapidly
becomes generalized with internal organ manifestations of fibrosis. The disease
carries a high morbidity and mortality rate; patients with
diffuse cutaneous SSc have a 10-year survival rate of 55%. Death is most often
caused by lung, heart and kidney involvement.
Currently, there is no effective treatment or cure for generalized SSc.
Treatment depends on the symptoms that are present and the organs that are
affected and may include medication and surgery. To date, all available
therapeutic options (e.g., corticosteroids, methotrexate, cyclophosphamide,
azathioprine and mycophenolate mofetil) have demonstrated only limited efficacy
and/or have safety issues that impact their use and are not indicated for use
in patients with SSc. One treatment, nintedanib, was approved, although it only
slows the decline of pulmonary function in adults with interstitial lung
disease (ILD) associated with SSc. Thus, there is a substantial unmet clinical
need for an effective and well-tolerated treatment for SSc.
HZN-825 is under investigation as a novel therapy for SSc because it
selectively antagonizes LPAR1, which has been shown to be associated with skin,
pulmonary, cardiac, peritoneal and tubulointerstitial fibrosis, and may be a
new therapeutic target for treating fibrotic diseases, including SSc.
Study objective
Primary Objective:
The primary objective is to demonstrate the efficacy of 1 or 2 dose regimens of
HZN-825 versus placebo in
subjects with diffuse cutaneous SSc, 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 Health
Assessment Questionnaire-Disability Index [HAQ-DI] after 52 weeks of treatment.
2. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on
Physician Global Assessment (MDGA) after 52 weeks of treatment.
3. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on Patient
Global Assessment (PTGA) after 52 weeks of treatment.
4. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on the
Physical Effects subscale of the scleroderma skin patient-reported outcome
(SSPRO-18) after 52 weeks of treatment.
5. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on the
Physical Limitations subscale of the SSPRO-18 after 52 weeks of treatment.
6. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on the
modified Rodnan skin score (mRSS), after 52 weeks of treatment.
7. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on American
College of Rheumatology-Composite Response Index in Systemic Sclerosis
(ACR-CRISS), defined as improvement from Baseline in mRSS, HAQ-DI, PTGA, MDGA
and FVC % predicted after 52 weeks of treatment.
8. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on
ACR-CRISS-20, defined as improvement in >=3 core set measures from Baseline of
>=20% in mRSS, >=20% in HAQ-DI, >=20% in PTGA,>=20% in MDGA and >=5% in FVC %
predicted after 52 weeks of treatment.
9. Assess safety and tolerability of HZN-825 based on adverse events (AEs), the
adverse event of special interest (AESI) (orthostatic hypotension), concomitant
medication use, vital signs, 12-lead electrocardiogram (ECG) and clinical
safety laboratory evaluations (hematology, chemistry, inflammatory parameters,
coagulation panel and urinalysis).
10. Evaluate the pharmacokinetics (PK) of HZN-825 and metabolite(s).
Exploratory Objectives:
1. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on the
SSPRO-18 after 52 weeks of treatment.
2. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on
University of California Los Angeles Scleroderma Clinical Trial Consortium
Gastrointestinal Tract (UCLA SCTC GIT 2.0) after 52 weeks of treatment.
3. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on
Raynaud*s phenomenon using the Raynaud*s Assessment.
4. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on
Scleroderma HAQ (SHAQ) at Week 52.
5. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on change
from Baseline in Systemic Sclerosis Quality of Life Questionnaire (SScQoL)
scores.
6. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on change
from Baseline in SF-12®Health Survey (SF-12) scores.
7. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on change
from Baseline in pain and pain component scale scores.
8. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on change
from Baseline in fatigue based on the Functional Assessment of Chronic Illness
Therapy - Fatigue Scale (FACIT-F) score.
9. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on change
from Baseline in protein expression of markers of inflammation and fibrosis in
skin biopsies.
10. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on change
from Baseline in transcriptomics associated with LPAR1 pathway, inflammation
and fibrosis in skin biopsies.
11. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on change
from Baseline in lung fibrosis after 52 weeks of treatment in subjects with
suitable Baseline high resolution computed tomography (HRCT).
12. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on change
from Baseline in diffusing capacity of the lungs for carbon monoxide (DLCO)
after 52 weeks of treatment.
13. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on change
from Baseline in serum and plasma biomarkers associated with LPAR1 pathway,
inflammation and/or fibrosis.
Study design
This is a randomized, double-blind, placebo-controlled, repeat-dose,
multicenter trial. Subjects will be screened within 4 weeks prior to the
Baseline (Day 1) Visit. Approximately 300 subjects who meet the trial
eligibility criteria will be randomized on Day 1 in a 1:1:1 ratio to receive
HZN-825 300 mg QD, HZN-825 300 mg BID or placebo for 52 weeks. Randomization
will be stratified according to Screening use of mycophenolate mofetil (yes/no)
and presence of interstitial lung disease (ILD) (yes/no) based on a Screening
HRCT scan.
The trial will include up to a 4-week Screening Period and a 52-week
Double-blind Treatment Period. Subjects will take their first dose of trial
drug at the clinic and will return to the clinic for trial visits at Week 4 and
every 6 weeks thereafter until Week 52. All subjects who complete the
Double-blind Treatment Period (Week 52) will be eligible to enter a 52-week
extension trial (HZNP-HZN-825-302). Subjects not entering the extension will
return to the clinic for a Safety Follow-up Visit 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.
Intervention
Subjects will take 2 tablets of trial drug orally in the morning and evening
with a meal.
Group A: HZN-825 300 mg QD regimen: 2 HZN-825 tablets in the morning and 2
placebo tablets in the evening
Group B: HZN-825 300 mg BID regimen: 2 HZN-825 tablets in the morning and 2
HZN-825 tablets in the evening
Group C: Placebo regimen: 2 placebo tablets in the morning and 2 placebo
tablets in the evening
Study burden and risks
The following side effects are common:
- Headache
- Orthostatic hypotension (blood pressure dropping when standing which can lead
to feeling of dizziness)
- Flatulence (gas)
- Abdominal pain
The following side effects noted in previous studies were rare and can be
serious:
- There was one serious side effect while taking HZN 825 of fainting in a
patient with a medical history of this in childhood.
- One participant on the HZN-825 300 mg twice a day dose experienced nausea and
abdominal pain that led to stopping the study.
There is always a chance that an unexpected or serious side effect of an
allergic reaction may happen. This can happen to people who take this or any
other drug. Some symptoms of allergic reactions are the following:
- Rash
- Wheezing and difficulty breathing
- Dizziness and fainting
- Swelling around the mouth, throat, or eyes
- A fast pulse
• Sweating
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Listed location countries
Age
Inclusion criteria
1. Written informed consent.
2. Male or female between the ages of 18 and 75 years, inclusive, at Screening.
3. Meets the 2013 American College of Rheumatology/European League Against
Rheumatism classification criteria for SSc with a total score of >=9 (Van den
Hoogen et al., 2013).
4. Classified as having skin involvement proximal to the elbow and/or knee
(diffuse cutaneous SSc subset by LeRoy and Medsger, 2001).
5. At the time of enrollment, less than 36 months since the onset of the first
SSc manifestation, other than Raynaud's phenomenon.
6. Skin thickening from SSc in the forearm suitable for repeat biopsy.
7. mRSS units >=15 at Screening.
8. FVC >=45% predicted at Screening, as determined by spirometry.
9. Willing and able to comply with the prescribed treatment protocol and
evaluations for the duration of the trial.
Exclusion criteria
1. Positive for anti-centromere antibodies.
2. Diagnosed with sine scleroderma or limited cutaneous SSc.
3. Diagnosed with other autoimmune connective tissue diseases, except for
fibromyalgia, scleroderma-associated myopathy and secondary Sjogren's syndrome.
4. Scleroderma renal crisis diagnosed within 6 months of the Screening Visit.
5. Any of the following cardiovascular diseases:
a. uncontrolled, severe hypertension (>=160/100 mmHg) or persistent low blood
pressure (systolic blood pressure <90 mmHg) within 6 months of Screening,
b. myocardial infarction within 6 months of Screening,
c. unstable cardiac angina within 6 months of Screening.
6. DLCO <40% predicted (corrected for hemoglobin). If severe acute respiratory
syndrome coronavirus2 (SARS-CoV-2) exposure is of clinical concern for any
subject, consider using a DLCO up to 6 months before the Screening Visit.
7. Pulmonary arterial hypertension (PAH) by right heart catheterization
requiring treatment with more than1 oral PAH-approved therapy or any parenteral
therapy. Treatment is allowed for erectile dysfunction and/or Raynaud's
phenomenon/digital ulcers.
8. Corticosteroid use for conditions other than SSc within 4 weeks prior to
Screening (topical steroids for dermatological conditions and
inhaled/intranasal/intra-articular steroids are allowed).
9.Use of any other non-steroid immunosuppressive agent, small biologic
molecule, cytotoxic or anti-fibrotic drug within 4 weeks of Screening,
including cyclophosphamide, azathioprine (Imuran®) or other immunosuppressive
or cytotoxic medication.
10. Known active bacterial, viral, fungal, mycobacterial or other infection,
including tuberculosis or atypical mycobacterial disease (fungal infections of
nail beds are allowed).
11. Use of a United States Food and Drug Administration-approved agent for SSc
or an investigational agent for any condition within 90 days or 5 half-lives,
whichever is longer, prior to Screening or anticipated use during the course of
the trial.
12. Malignant condition in the past 5 years (except successfully treated
basal/squamous cell carcinoma of the skin or cervical cancer in situ).
13. Women of childbearing potential or male subjects not agreeing to use highly
effective method(s) of birth control throughout the trial and for 1 month after
last dose of trial drug. Male subjects must refrain from sperm donation and
females from egg/ova donation for this same time period. 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. A man is
considered fertile after puberty unless permanently sterile by bilateral
orchidectomy.
14. Pregnant or lactating women.
15. 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.
16. Previous enrollment in this trial or participation in a prior HZN-825 or
SAR100842 clinical trial.
17. Known history of positive test for human immunodeficiency virus.
18. Active hepatitis (hepatitis B: positive hepatitis B surface antigen and
positive anti-hepatitis B core antibody [anti-HBcAb] and negative hepatitis B
surface antibody [HBsAb] or positive for HBcAb with a positive test for HBsAb
and with presence of hepatitis B virus DNA at Screening; hepatitis C: positive
anti-hepatitis C virus [anti-HCV] and positive RNA HCV).
19. Current alcoholic liver disease, primary biliary cirrhosis or primary
sclerosing cholangitis or moderate (Child-Pugh B) to severe (Child-Pugh C)
hepatic impairment by Child-Pugh scoring system.
20. Previous organ transplant (including allogeneic and autologous marrow
transplant).
21. International normalized ratio >2, prolonged prothrombin time >1.5 × the
upper limit of normal (ULN) or partial thromboplastin time >1.5 × ULN at
Screening.
22. Alanine aminotransferase or aspartate aminotransferase > × ULN.
23. Estimated glomerular filtration rate < 30 mL/min/1.73 m2 at Screening.
24. Total bilirubin >2 × ULN. Subjects with documented diagnosis of Gilbert's
syndrome may be enrolled if their total bilirubin is <=3.0 mg/dL.
25.Any other condition that, in the opinion of the Investigator, would preclude
enrollment in 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 |
|---|---|
| EudraCT | EUCTR2020-005764-62-NL |
| ClinicalTrials.gov | NCT04781543 |
| CCMO | NL78637.028.21 |