This study will evaluate the efficacy, safety, and tolerability of sildenafil or placebo added to pirfenidone treatment (study treatments) in patients with advanced idiopathic pulmonary fibrosis (IPF) and intermediate or high probability of Group 3…
ID
Source
Brief title
Condition
- Pleural disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy objective for this study is to evaluate the efficacy of
adding sildenafil compared with placebo to pirfenidone treatment in patients
with advanced IPF and intermediate or high probability of Group 3 PH. The
primary efficacy endpoint will be evaluated based on a comparison of the
proportion of patients showing disease progression over 52 weeks of treatment
period, as evidenced by reaching the following combined endpoint:
* Relevant decline in 6-minute walk distance (6MWD) of at least 15% from
baseline (as defined below*), respiratory-related non-elective hospitalization,
or all-cause mortality
* Relevant decline in 6MWD from baseline is defined as:
* Any decline >25% from baseline or
* A decline between 15-25% from baseline, if accompanied by at least one of the
following:
o worsening of oxyhemoglobin (SpO2) desaturation during the 6-minute walk test
(6MWT) compared to baseline
o worsening of the maximum Borg scale during the 6MWT compared to baseline
o Increased O2 requirements during the 6MWT compared to baseline
Secondary outcome
Secondary Efficacy Objectives (Full details are given in Protocol Section 6.4.2)
The secondary efficacy objective for this study is to evaluate the efficacy of
adding sildenafil compared with placebo to pirfenidone treatment on the basis
of the following endpoints:
* Progression-free survival (PFS), defined as the time to decline in 6MWD of
>=15% compared with baseline as defined above, respiratory-related non-elective
hospitalization, or death from any cause
* Proportion of patients with decline in 6MWD of >=15% from baseline as defined
above
* Time to respiratory-related non-elective hospitalization
* Time to death from any cause
* Lung transplantation
* Time to all-cause non-elective hospitalization
* Time to respiratory-related death
* Change from baseline in transthoracic echocardiography (ECHO) parameters
* Change from baseline in pulmonary function tests (PFTs)
* Change from baseline in oxyhemoglobin saturation (SpO2) at rest and during
the 6-minute walk test (6MWT)
* World Health Organization (WHO) Functional Class
* Dyspnea (assessed by the University of California San Diego Shortness of
Breath Questionnaire - UCSD SOBQ)
* Health-related quality of life (HRQoL) (assessed by the Saint George*s
Respiratory Questionnaire [SGRQ])
* N-terminal pro-brain natriuretic peptide (NT-proBNP) level
Background summary
The diagnosis of IPF carries a bleak prognosis, with progressive disability due
to respiratory insufficiency (Hallstrand et al. 2005). Pulmonary hypertension
is a major contributor to morbidity and mortality in patients with advanced IPF
with an adverse impact on survival (Nadrous et al. 2005, Lettieri et al.
2006.). This study is designed to assess the treatment of patients with
advanced IPF who have evidence suggesting PH, that is most likely caused by IPF.
While drugs used to treat PH have either not been effective for treatment of
IPF (bosentan, ambrisentan, macicentan) or are unlikely to be able to address
the parenchymal changes in the fibrotic process, anti-fibrotic drugs are
unlikely to have any notable effect on the perfusion aspects of interstitial
lung diseases (ILDs). Therefore, combination treatment appears as a promising
approach to the major clinical problem of combined IPF and PH (Wuyts et al.
2014).
In this study, pirfenidone (Esbriet®) administration will be combined with
sildenafil. As sildenafil induces vasodilatation preferentially in
well-ventilated lung areas, such vasodilatation could improve
ventilation-perfusion matching and thus gas exchange in patients with IPF
(Ghofrani et al. 2002). The combination of pirfenidone and sildenafil
represents a promising approach to treat patients with advanced IPF and
secondary PH.
Study objective
This study will evaluate the efficacy, safety, and tolerability of sildenafil
or placebo added to pirfenidone treatment (study treatments) in patients with
advanced idiopathic pulmonary fibrosis (IPF) and intermediate or high
probability of Group 3 pulmonary hypertension (PH) who are on a stable dose of
pirfenidone with demonstrated tolerability.
Study design
This is a Phase IIb, randomized, placebo-controlled, multicenter, international
study of the efficacy, safety, and tolerability of combination treatment with
sildenafil and pirfenidone in patients with advanced IPF and intermediate or
high probability of Group 3 PH who are on pirfenidone in a dose range of 1602
to 2403 mg/day with demonstrated tolerability. For the purposes of this study,
patients have to present with:
* advanced IPF as defined by a measurable pulmonary diffusing capacity (carbon
monoxide diffusing capacity [DLCO]) <=40% of predicted value at Screening;
AND
* intermediate and high probability of Group 3 PH as defined by
o mean pulmonary artery pressure (mPAP) >=20 mmHg together with pulmonary artery
wedge pressure (PAWP) <=15 mmHg on a previous right heart catheterization (RHC)
of acceptable quality
OR
o in the absence of a previous RHC, patients with ECHO showing intermediate or
high probability of Group 3 PH, as defined by the 2015 European Society of
Cardiology/European Respiratory Society (ESC/ERS) (Peak tricuspid regurgitation
velocity [TRV] >= 2.9 m/s), will be considered eligible for the study, assuming
that they meet all other eligibility criteria [Galie et al. 2015]
Intervention
The test products for this study are pirfenidone and sildenafil.
Pirfenidone (5-methyl-1-phenyl-2-1(H)-pyridone) will be administered orally
three times per day (TID) with meals, in a range of 1602 to 2403 mg/day. Each
pirfenidone capsule contains 267 mg of pirfenidone. Pirfenidone (Esbriet®) will
be supplied by the Sponsor as white, hard gelatin capsules printed with *267
mg* in brown ink.
Sildenafil 20 mg will be administered orally TID, about 4 to 6 h apart.
Sildenafil will be supplied by the Sponsor as white, round, biconvex
film-coated, tablets. Sildenafil tablets will by encapsulated by a compounding
pharmacy to be identical in appearance and size to matching placebo.
Comparator
Placebo will be administered orally TID, about 4 to 6 h apart. Placebo will be
supplied by the Sponsor as a capsule with the same appearance and size as the
encapsulated sildenafil.
Study burden and risks
Adverse events known to be associated with pirfenidone
Very common (definition: affects more than 10 in every 100 patients)
• anorexia (weight loss)
• headache
• dizziness
• dyspepsia (upset stomach)
• nausea
• diarrhea
• photosensitivity (sunburn)
• rash
• tiredness
Common (definition: affects 1 to 10 patients in 100)
• weight loss
•decreased appetite
• dysgeusia (taste disturbance)
• hot flushes
• Abdominal distention (bloating)
• abdominal discomfort (dyspepsia)
• abdominal pain
• insomnia (difficulty sleeping)
• somnolence (sleepiness)
• constipation (constipation)
• gastroesophageal reflux disease
• vomiting
• concentration increased ALT (liver enzymes)
• increased levels of AST (liver enzymes)
• increased levels of GGT (liver enzymes)
• pruritus (itching)
• arthralgia (joint pain)
• asthenia (weakness)
Uncommon (definition: affects less than 1 in 100 patients)
• angioedema (swelling of the throat or mouth)
Rare but serious (definition: affects less than 1 in 1000 patients)
• agranulocytosis (low white blood cell counts)
• increased total bilirubin concentration in serum (blood) in combination with
an elevated concentration of ALT and AST (liver enzymes)
For more risks and side effects, see the informed consent form
Beneluxlaan 2a Beneluxlaan 2a
Woerden 3440 GR
NL
Beneluxlaan 2a Beneluxlaan 2a
Woerden 3440 GR
NL
Listed location countries
Age
Inclusion criteria
- Age 40-80 years (inclusive) at Screening
- Diagnosis of IPF for at least 3 months prior to screening
- Confirmation of IPF diagnosis by the Investigator, in accordance with the 2011 international consensus guidelines, at Screening
- Advanced IPF as defined by a measurable carbon monoxide diffusing capacity/pulmonary diffusing capacity [DLCO] < 40% of predicted value at Screening and intermediate or high probability of Grade 3 PH (as defined in the protocol)
- Prior to the start of Screening, receiving pirfenidone for at least 12 weeks, and on a dose in the range of 1602 to 2403 mg/day for at least 4 weeks prior to the first Screening Visit.
- WHO Functional Class II or III at Screening
- 6MWD of 100 to 450 meters at Screening
- For women of childbearing potential: agreement to remain abstinent or use a non-hormonal contraceptive method with a failure rate <1% per year during the treatment period and for at least 58 days after the last dose of study treatment
- For men who are not surgically sterile: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm for at least 118 days after the last dose of study treatment
Exclusion criteria
- History of any of the following types of PH: Group 1 pulmonary arterial hypertension (PAH); Group 2 (left-heart disease); Group 3 (due to conditions other than interstitial lung disease; Group 4 (chronic thromboembolic pulmonary hypertension); Group 5 (other disorders);- History of clinically significant cardiac disease in the opinion of the Investigator;- History of coexistent and clinically significant (in the opinion of the Investigator) COPD, bronchiectasis, asthma, inadequately treated sleep-disordered breathing, or any clinically significant pulmonary diseases or disorders other than IPF or PH secondary to IPF;- Hypotension, autonomic dysfunction, or conditions in which vasodilation may cause an unsafe drop in blood pressure (BP);- History of use of drugs and toxins known to cause PAH
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 | EUCTR2015-005131-40-NL |
| CCMO | NL59044.056.16 |