Treprostinil for Pulmonary Arterial Hypertension

(ARTISAN Trial)

Recruiting at 30 trial locations

Overseen By Mary Lou Tomson

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: United Therapeutics

Must be taking: Endothelin antagonists, PDE-5 inhibitors

Must not be taking: Epoprostenol, Treprostinil

Disqualifiers: Amphetamine use, Hepatic impairment, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 36 months

52 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The primary objective of this study is to assess the effect of early and rapid treprostinil therapy for mean pulmonary artery pressure (mPAP) reduction to improve right ventricular (RV) function and reverse RV remodeling in participants with pulmonary arterial hypertension (PAH).

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications, but you must be on a stable dose of certain medications like endothelin receptor antagonists or phosphodiesterase type 5 inhibitors, or be willing to start them along with the study drug.

How is the drug Treprostinil unique for treating pulmonary arterial hypertension?

Treprostinil is unique because it is available in multiple forms, including oral, inhaled, and injectable, which offers flexibility in administration. The oral form, Orenitram, is particularly novel as it provides the convenience of oral dosing, potentially improving patient compliance compared to other prostacyclin analogues that require more complex administration. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Treprostinil for treating pulmonary arterial hypertension?

Treprostinil, available in oral, inhaled, and injectable forms, has shown improvements in exercise capacity and survival in patients with pulmonary arterial hypertension. The oral form, Orenitram, offers the convenience of oral dosing and has been approved by the FDA after demonstrating improved exercise capacity in clinical trials. ^{1 2 4 5 6}

Are You a Good Fit for This Trial?

This trial is for people with pulmonary arterial hypertension (PAH) who have a mean pulmonary artery pressure over 35 mmHg and are on stable PAH medication or willing to start it. They should be able to walk more than 165 meters, not have severe liver issues, and can't be using certain other medications or have conditions that affect heart imaging tests.

Inclusion Criteria

Before joining the study, your heart catheterization must meet certain measurements, and you must be on specific medications for your condition.

My PAH is related to genetics, drugs (not amphetamines), heart repair, connective tissue disease, or HIV.

Exclusion Criteria

Criterion Summary: You will be excluded from the study if you have used specific medications, have certain types of pulmonary hypertension, have used certain drugs within the past year, have certain medical conditions, have used other investigational treatments recently, or have certain cardiac conditions or implants that could interfere with the study.

I have not had a CardioMEMS sensor implanted and can take blood thinners for 30 days post-implant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive early and rapid treprostinil therapy to reduce mean pulmonary artery pressure and improve right ventricular function

36 months

Monthly visits for mPAP assessments and dose adjustments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Oral Treprostinil
• Parenteral Treprostinil

Trial Overview The study is testing the effectiveness of Treprostinil therapy administered early and rapidly in two forms—parenteral (injected) and oral—to lower high blood pressure in the lungs' arteries, improve heart function on the right side, and reverse changes due to PAH.

How Is the Trial Designed?

Group I: Treprostinil Experimental Treatment 2 Interventions

Participants will receive parenteral treprostinil at initial dose of 1.25 nanograms/kilogram/minute (at minimum) either intravenously or subcutaneously. Based on mPAP assessments and after a minimum dose of parenteral treprostinil is reached, at Investigator's (PI's) discretion, participants may transition to oral treprostinil and continue dose uptitration for further reduction of mPAP. Based on Month 12 mPAP assessment, participants may transition from parenteral to oral treprostinil at PI's discretion after completion of Month 12 assessment and continue uptitration for further reduction of mPAP. If minimum dose of parenteral treprostinil is not reached at Month 6/12 at PI's discretion, uptitration of parenteral treprostinil or oral treprostinil transition may occur to maintain normal mPAP. Treprostinil therapy (parenteral or oral) may continue as tolerated toward goal of further reduction of mPAP until Month 36.

Oral Treprostinil is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Remodulin for:

• Pulmonary arterial hypertension (PAH)
• Pulmonary hypertension associated with interstitial lung disease

Approved in Canada as Remodulin for:

• Long-term treatment of pulmonary arterial hypertension in NYHA Class III and IV patients who did not respond adequately to conventional therapy

Approved in European Union as Treprostinil for:

• Pulmonary arterial hypertension (PAH)

Who Is Running the Clinical Trial?

United Therapeutics

Lead Sponsor

Trials

112

Recruited

14,500+

Dr. Martine Rothblatt

United Therapeutics

Chief Executive Officer since 1996

PhD in Medical Ethics from the Royal London College of Medicine and Dentistry, JD and MBA from UCLA

Dr. Michael Benkowitz

United Therapeutics

Chief Medical Officer since 2023

MD from Harvard Medical School

Lung Biotechnology PBC

Industry Sponsor

Trials

14

Recruited

710+

Published Research Related to This Trial

Treprostinil is an effective treatment for pulmonary arterial hypertension (PAH) and is available in three formulations: intravenous/subcutaneous (Remodulin®), inhaled (Tyvaso®), and oral (Orenitram®).

Pharmacokinetic studies in both healthy volunteers and PAH patients provide important insights that can help clinicians make informed decisions about the most suitable route of administration for individual patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Comprehensive Review of Treprostinil Pharmacokinetics via Four Routes of Administration. Kumar, P., Thudium, E., Laliberte, K., et al.[2018]

Treprostinil diolamine (Orenitram™) is a new oral formulation for treating pulmonary arterial hypertension (PAH) that offers similar pharmacokinetic properties to existing parenteral and inhaled therapies, potentially improving patient compliance due to its convenient oral dosing.

The FDA approved treprostinil diolamine after it demonstrated improved exercise capacity in patients with de novo PAH, indicating its efficacy as a monotherapy in this serious condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral treprostinil for the treatment of pulmonary arterial hypertension. de Lartigue, J.[2017]

In a study involving 30 subjects, including those with varying degrees of hepatic impairment, the pharmacokinetics of oral treprostinil showed that its clearance decreased significantly with worsening liver function, leading to increased drug exposure levels.

The most common side effects, such as headache, diarrhea, and nausea, were consistent with those seen in other studies of treprostinil, and their incidence increased with the severity of hepatic impairment, indicating the need for dosage adjustments in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of the pharmacokinetics of treprostinil diolamine in subjects with hepatic impairment. Peterson, L., Marbury, T., Marier, J., et al.[2017]

In a 9-day study involving 19 healthy subjects, three times daily dosing of 0.5 mg oral treprostinil was found to be well tolerated, with no significant drug accumulation and sustained plasma exposure at steady state.

The pharmacokinetics of oral treprostinil followed linear kinetics, achieving steady state within 2 days, and common side effects included headache and diarrhea, indicating a manageable safety profile for further evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of 3 times a day dosing of oral treprostinil in healthy volunteers. Jones, A., Wang-Smith, L., Pham, T., et al.[2017]

LIQ861, a dry-powder formulation of treprostinil, shows comparable bioavailability to the nebulized Tyvaso® inhalation solution, with exposure parameters indicating similar effectiveness in delivering the medication to patients with pulmonary arterial hypertension (PAH).

Both LIQ861 and Tyvaso® were well tolerated by participants, suggesting that LIQ861 offers a safe and convenient alternative for PAH patients, allowing for effective treatment in just 1 to 2 breaths.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative bioavailability of inhaled treprostinil administered as LIQ861 and Tyvaso® in healthy subjects. Roscigno, RF., Vaughn, T., Parsley, E., et al.[2021]

In a study of 29 prostacyclin-naïve patients, rapid induction with parenteral treprostinil allowed 79% of participants to reach a daily oral treprostinil dose of 12 mg or more by Week 16, significantly higher than typical doses achieved in standard treatment.

Patients showed substantial clinical improvements, including better exercise capacity and reduced symptoms of pulmonary arterial hypertension, as evidenced by various health scores and measures, indicating that this rapid induction method may enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Parenteral treprostinil induction for rapid attainment of therapeutic doses of oral treprostinil. Miller, CE., Franco, V., Smith, JS., et al.[2023]

Citations

1. Switzerland pubmed.ncbi.nlm.nih.gov

A Comprehensive Review of Treprostinil Pharmacokinetics via Four Routes of Administration. [2018]

2. Spain pubmed.ncbi.nlm.nih.gov

Oral treprostinil for the treatment of pulmonary arterial hypertension. [2017]

3. England pubmed.ncbi.nlm.nih.gov

An evaluation of the pharmacokinetics of treprostinil diolamine in subjects with hepatic impairment. [2017]

4. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of 3 times a day dosing of oral treprostinil in healthy volunteers. [2017]

5. United States pubmed.ncbi.nlm.nih.gov

Comparative bioavailability of inhaled treprostinil administered as LIQ861 and Tyvaso® in healthy subjects. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Parenteral treprostinil induction for rapid attainment of therapeutic doses of oral treprostinil. [2023]