What side effects are associated with this type of intervention?

Common treatments for Pulmonary Arterial Hypertension (PAH) include Endothelin Receptor Antagonists (ERAs) like macitentan, phosphodiesterase-5 inhibitors (PDE5Is) such as sildenafil and tadalafil, and prostacyclin analogues like epoprostenol and treprostinil. ERAs, including macitentan, can cause side effects such as hepatotoxicity and peripheral edema. PDE5Is may lead to headaches, flushing, dyspepsia, and visual disturbances. Prostacyclin analogues often result in side effects like jaw pain, nausea, diarrhea, and flushing. These treatments aim to improve hemodynamic parameters, exercise capacity, and quality of life in PAH patients.

What prior FDA approvals exist?

The FDA has approved several Endothelin Receptor Antagonists (ERAs) for the treatment of Pulmonary Arterial Hypertension (PAH). These include bosentan, ambrisentan, and macitentan. Bosentan was one of the first ERAs approved and has been shown to delay clinical worsening and improve exercise capacity. Ambrisentan has also demonstrated efficacy in improving exercise tolerance and delaying disease progression. Macitentan, studied in the SERAPHIN trial, has been shown to slow disease progression and improve exercise capacity in patients with PAH. These drugs work by blocking the effects of endothelin-1, a potent vasoconstrictor, thereby reducing pulmonary vascular resistance and alleviating symptoms of PAH.

What other types of research exist?

Promising novel alternatives to Macitentan for PAH patients include: <ol> <li>Selexipag: An oral prostacyclin receptor agonist that targets the prostacyclin pathway, shown to improve exercise capacity and delay disease progression.</li> <li>Riociguat: A soluble guanylate cyclase stimulator that enhances the nitric oxide pathway, improving exercise capacity and functional class.</li> <li>Oral Treprostinil: A prostacyclin analog that has shown benefits in combination with other PAH therapies, improving exercise capacity and symptoms.</li> <li>Sotatercept: An investigational therapy targeting the transforming growth factor-beta (TGF-β) pathway, showing promise in early clinical trials for improving hemodynamics and exercise capacity.</li> </ol>

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Endothelin Receptor Antagonist

Macitentan for Pulmonary Hypertension (TOMORROW Trial)

Phase 3

Waitlist Available

Research Sponsored by Actelion

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Males or females between greater than or equal to (>=) 1 month and less than (<) 18 years of age

Males or females between 1 month and less than 18 years of age

Must not have

Participants receiving a combination of > 2 PAH-specific treatments at randomization

Participants with PAH associated with Eisenmenger syndrome, or with moderate to large left-to-right shunts

Timeline

Screening 3 weeks

Treatment Varies

Follow Up between randomization/visit 2 and eocp; up to 7 years

Awards & highlights

No Placebo-Only Group

Pivotal Trial

Summary

This trial is testing macitentan, a drug that helps lower lung blood pressure, in children with pulmonary arterial hypertension. Macitentan has shown significant effectiveness in improving the condition of patients with pulmonary arterial hypertension.

Who is the study for?

This trial is for children under 18 with pulmonary arterial hypertension (PAH), including those with Down Syndrome. They must have a confirmed PAH diagnosis and be in WHO Functional class I to III. Females of childbearing potential need negative pregnancy tests and must use contraception. Participants can't join if they have certain conditions like severe renal insufficiency, are on multiple PAH treatments, or have severe liver impairment.

What is being tested?

The study is testing the effects of Macitentan compared to standard care in children with PAH. It's an open-label Phase 3 trial where participants are randomly assigned to either receive Macitentan or continue with their usual treatment while researchers track how well the drug works and its safety.

What are the potential side effects?

While not specified here, common side effects of Macitentan may include symptoms like headache, cold-like symptoms (nasopharyngitis), anemia, bronchitis, urinary tract infections, and inflammation of the airways (bronchitis).

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am under 18 years old.

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I am under 18 years old.

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I have been diagnosed with PAH confirmed by a heart catheter test.

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My PAH is classified under Group 1 and may be related to a specific cause like heart disease or HIV.

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My body weight is at least 3.5 kg.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I am currently on more than two treatments for pulmonary arterial hypertension.

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I have PAH linked to Eisenmenger syndrome or significant heart defects.

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My liver is not working well (severe issues).

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My kidneys are not working well (severe renal insufficiency).

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I have been diagnosed with bronchopulmonary dysplasia.

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My PAH is caused by portal hypertension, schistosomiasis, or specific lung diseases.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ between randomization/visit 2 and eocp; up to 7 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~between randomization/visit 2 and eocp; up to 7 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and between randomization/visit 2 and eocp; up to 7 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Plasma Exchange

Participants Less than (<) 2 Years: Observed Steady-state Trough Plasma Concentration of Macitentan and its Active Metabolite ACT-132577 at Week 4

Secondary study objectives

Change from Baseline to Week 24 in Left Ventricular Eccentricity Index (LVEI) Measured by Echocardiography

Change from Baseline to Week 24 in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)

Change from Baseline to Week 24 in Pediatric Quality of Life Inventory version 4.0 (PedsQL 4.0) Generic Core Scales Short Form (SF-15)

+7 more

Side effects data

From 2019 Phase 4 trial • 89 Patients • NCT02310672

22%

Oedema Peripheral

21%

Headache

14%

Dizziness

11%

Haemoglobin Decreased

11%

Upper Respiratory Tract Infection

11%

Cough

10%

Myalgia

Diarrhoea

Nasal Congestion

Pyrexia

Back Pain

Pain in Extremity

Nausea

Nasopharyngitis

Flushing

Pneumonia

Pulmonary Arterial Hypertension

Pulmonary Embolism

Sepsis

Acute Myocardial Infarction

Cholangitis Infective

Epistaxis

Therapeutic Response Decreased

Escherichia Bacteraemia

Herpes Zoster

Cytomegalovirus Infection

Hypersensitivity

Urinary Tract Infection

Hypoglycaemia

Rheumatoid Arthritis

Pancreatic Carcinoma

Systemic Lupus Erythematosus

Syncope

Acute Kidney Injury

Dysfunctional Uterine Bleeding

Anaemia

Haemolytic Anaemia

Iron Deficiency Anaemia

Angina Pectoris

Atrial Fibrillation

Cardiac Arrest

Coronary Artery Disease

Right Ventricular Failure

Ventricular Hypokinesia

Rectal Haemorrhage

Dysmenorrhoea

Menorrhagia

Pelvic Haemorrhage

Dyspnoea

100%

80%

60%

40%

20%

Study treatment Arm

Macitentan 10 mg

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

2Treatment groups

Experimental Treatment

Group I: Standard-of-careExperimental Treatment1 Intervention

Standard-of-care as per site's clinical practice which may comprise treatment with pulmonary arterial hypertension (PAH) non-specific treatment and/or up to two PAH-specific medications excluding macitentan and intravenous/subcutaneous (IV/SC) prostanoids.

Group II: MacitentanExperimental Treatment1 Intervention

Macitentan is administered once daily via oral route. Children less than (\<) 2 years old (y.o.) will be assigned as a cohort to the macitentan group without randomization. The dose will be adjusted to the participant's age (for those \< 2 y.o.) or to the participant's body weight (for those greater than or equal to (\>=) 2 y.o.). single-arm extension period (SAEP) will start at end of core period (EOCP) visit and ends at end of study (EOS) visit.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Macitentan

2020

Completed Phase 4

~1920

0 / 11Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Pulmonary Arterial Hypertension (PAH) treatments often target the pathways that contribute to the disease's progression. Endothelin Receptor Antagonists (ERAs) like Macitentan work by blocking endothelin-1, a potent vasoconstrictor, thereby reducing blood vessel constriction and proliferation in the lungs. This helps lower pulmonary blood pressure and improve heart function. Other common treatments include Phosphodiesterase-5 Inhibitors (PDE5Is) such as sildenafil, which enhance nitric oxide signaling to promote vasodilation and improve blood flow. Prostacyclin analogs increase levels of prostacyclin, a vasodilator and inhibitor of platelet aggregation. These mechanisms are crucial for PAH patients as they help manage symptoms, improve exercise capacity, and slow disease progression, ultimately enhancing quality of life and survival.