The Effect of Additive On-Demand Sildenafil vs. Dextrose Candy on Maximum Exercise Capacity in Pulmonary Arterial Hypertension (Pocket-PH)

The Effect of Additive On-Demand Sildenafil vs. Dextrose Candy on Maximum Exercise Capacity in Pulmonary Arterial Hypertension: A Randomized, Cross-Over Trial.

The goal of this clinical study is to investigate whether the additional intake of sildenafil 20mg on top of standard medical treatment results in a benefit on maximum exercise workload (Wmax) in patients with pulmonary arterial hypertension (PAH).

Study Overview

• Status: Recruiting
• Conditions: Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH)
• Intervention / Treatment: Drug: Dextrose; Drug: Sildenafil 20mg

Detailed Description

This study is a prospective, randomized, cross-over trial evaluating the effects of additive 20 mg sildenafil versus placebo/sham dextrose candy on exercise capacity in patients with previously diagnosed pulmonary arterial hypertension (PAH).

PAH is a progressive and debilitating disease characterized by increased mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR), leading to right ventricular overload, and ultimately right heart failure. Despite advancements in pharmacological therapy, treatment options remain limited and optimizing individualized approaches to improve exercise capacity and manage symptom burden remains a challenge.

Phosphodiesterase type 5 inhibitors, such as sildenafil, are cornerstones of PAH treatment, enhancing pulmonary vasodilation and improving haemodynamics. While three times daily dosing is standard with three time 20-80mg daily. On-demand additive sildenafil use before exercise has not been studied, but as recent trials have shown that dosing up to three times 80mg is as safe as 20mg, there is a potential that additive therapy may be beneficial. Given sildenafil's rapid onset of action with peak effects after 30-120 minutes, it may offer acute functional benefits regarding maximum workload (Wmax) when administered shortly beforehand, in the terms of a "pill-in-the pocket" intake.

After providing informed consent, eligible participants (aged 18 - 80 years, with PAH diagnosed according to the ESC/ERS 2022/2019 guidelines) will be randomly assigned to receive either 20 mg sildenafil or dextrose candy (Dextro Energy). 45 minutes post-intake, they will undergo incremental spiroergometry (10-20 W increases) and right heart focused stress-echocardiography on a cycle ergometer until exhaustion. After a rest phase of 30 minutes, patients will perform CWRET at 75% of achieved Wmax until exhaustion. Then, after a washout period of minimum 24 hours up to 12 weeks, participants will cross over to the opposite treatment, repeating the same protocol.

In case of a beneficial result, our study could support the use of an additive pill-in-the-pocket therapy strategy which may allow treatment to be tailored to the individual activity demands of patients.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Arcangelo F Carta, MD; Phone Number: +41 44 255 22 20; Email: arcangelo.carta@usz.ch
• Study Contact Backup: Name: Silvia Ulrich, Prof. MD; Phone Number: +41 44 255 22 21; Email: silvia.ulrich@usz.ch

Study Locations

• Switzerland
  • Canton of Zurich
    • Zurich, Canton of Zurich, Switzerland, 8091
      • Recruiting
      • University Hospital of Zurich, Department of Pulmonology
      • Contact: Arcangelo F Carta, Dr. med.; Phone Number: +41 44 255 22 20; Email: arcangelo.carta@usz.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signed Informed consent
• Age 18 - 80 years (both sexes)
• Pulmonary hypertension (PH) class I (PAH) previously diagnosed according to ESC/ERS 2022/2019 guidelines (mPAP ≥ 20 mmHg, PVR ≥ 2 WU, PAWP ≤ 15 mmHg) during diagnostic right-heart catheterization.
• Stable condition, on the same PH-medication for >4 weeks

Exclusion Criteria:

• Severe resting hypoxia (PaO2 <7.3 kPa)
• Moderate-to-severe chronic obstructive or restrictive pulmonary disease (FEV1 ≤ 60% predicted, FVC ≤ 60% predicted)
• Women with known pregnancy or breast feeding
• Other clinically significant concomitant disease states (e.g., severe renal or hepatic disease, unstable cardiovascular disease, etc.)

• Concurrent medication with:

  • Nitric oxide donors (molsidomine, nicrorandil, etc.)
  • Soluble guanylate cyclase stimulators (riociguat)
  • Potent CYP3A4 inhibitors (azoles, clarithromycin, protease inhibitors)
• History of anterior ischemic optic neuropathy or hereditary retinal disease
• Participation in another study with investigational drug with potential influence the study data within the 30 days preceding and during the present study.
• Known allergies or hypersensitivity to sildenafil 20mg (Revatio 20mg) or dextrose candy (Dextroenergy) including any of its components

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Intervention Order A; Group A will receive the active comparator first (Sildenafil 20mg) in accordance with the Cross-Over trial design.	Drug: Dextrose; Administration of Dextrose Candy by mouth as a tablet.; Other Names: Dextro Energy; Dextrose Candy; Drug: Sildenafil 20mg; Administration of Sildenafil 20mg by mouth as a tablet.; Other Names: Revatio 20mg
Other: Intervention Order B; Group B will receive the placebo comparator first (Dextrose Candy) in accordance with the Cross-Over trial design.	Drug: Dextrose; Administration of Dextrose Candy by mouth as a tablet.; Other Names: Dextro Energy; Dextrose Candy; Drug: Sildenafil 20mg; Administration of Sildenafil 20mg by mouth as a tablet.; Other Names: Revatio 20mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum workload (Wmax)	The difference in maximum workload (Wmax) attained during maximum spiroergometry 45 minutes after treatment with Sildenafil 20mg (Revatio 20mg) versus dextrose candy (Dextro Energy).	Within 1 - 90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Exhaustion (Tmax)	Difference in Time to Exhaustion (Tmax)attained during CWRET after treatment with Sildenafil 20mg (Revatio 20mg) versus dextrose candy (Dextro Energy)	Within 1 - 90 days
Cardiometabolic parameters (CPET, CWRET): Oxygen Saturation (SpO2)	Change in Oxygen Saturation (SpO2) during CPET / CWRET	Within 1 - 90 days
Focused Stress-Echocardiography (Right Heart): Stroke Volume (SV)	Change in Stroke Volume (SV) during CPET	Within 1 - 90 days
Arterial blood gases: Arterial Partial Pressure of Oxygen (PaO2)	Change in Arterial Partial Pressure of Oxygen (PaO2) during CPET.	Within 1 - 90 days
Borg CR10 (Borg Category-Ratio 10 Scale)	Changes in Borg CR10 questionnaire (Borg Category-Ratio 10 Scale) after CPET / CWRET (0-10, higher values indicate more severe symptoms)	Within 1 - 90 days
Focused Stress-Echocardiography (Right Heart): Tricuspid Regurgitation Pressure Gradient (TRPG)	Change in Tricuspid Regurgitation Pressure Gradient (TRPG) during CPET	Within 1 - 90 days
Cardiometabolic parameters (CPET / CWRET): Blood Pressure (BP)	Change in Blood Pressure (BP) during CPET / CWRET	Within 1 - 90 days
Cardiometabolic parameters (CPET / CWRET): Heart Rate (HR)	Change in Heart Rate (HR) during CPET / CWRET	Within 1 - 90 days
Cardiometabolic parameters (CPET / CWRET): Rate Pressure Product (RPP)	Change in Rate Pressure Product (RPP) during CPET / CWRET	Within 1 - 90 days
Cardiometabolic parameters (CPET / CWRET): Maximum Uptake of Oxygen (V'O2max)	Change Maximum Uptake of Oxygen (V'O2max) during CPET / CWRET	Within 1 - 90 days
Cardiometabolic parameters (CPET / CWRET): Maximum Carbon Dioxide Production (V'CO2max)	Change in Maximum Carbon Dioxide Production (V'CO2max) during CPET / CWRET	Within 1 - 90 days
Cardiometabolic parameters (CPET / CWRET): Maximum Minute Ventilation (V'Emax)	Change in Maximum Minute Ventilation (V'Emax) during CPET / CWRET	Within 1 - 90 days
Cardiometabolic parameters (CPET / CWRET): Maximum Ventilatory Equivalent for Oxygen (V'E/VO2)	Change in Maximum Ventilatory Equivalent for Oxygen (V'E/VO2) during CPET / CWRET	Within 1 - 90 days
Cardiometabolic parameters (CPET / CWRET): Maximum Ventilatory Equivalent for Carbon Dioxide (V'E/VCO2)	Change in Maximum Ventilatory Equivalent for Carbon Dioxide (V'E/VCO2) during CPET / CWRET	Within 1 - 90 days
Cardiometabolic parameters (CPET / CWRET): Breathing Frequency (BF)	Change in Breathing Frequency (BF) during CPET / CWRET	Within 1 - 90 days
Cardiometabolic parameters (CPET / CWRET): Breathing Reserve (BR)	Change in Breathing Reserve (BR) during CPET / CWRET	Within 1 - 90 days
Arterial blood gases: Arterial Partial Pressure of Carbon Dioxide (PaCO2)	Change in Arterial Partial Pressure of Carbon Dioxide (PaCO2) during CPET.	Within 1 - 90 days
Arterial blood gases: Bicarbonate (HCO3-)	Change in Bicarbonate HCO3- before and after CPET.	Within 1 - 90 days
Arterial blood gases: Arterial Oxygen Saturation (SaO2)	Change in Arterial Oxygen Saturation (SaO2) before and after CPET.	Within 1 - 90 days
Arterial blood gases: Base Excess (BE)	Change in Base Excess (BE) before and after CPET.	Within 1 - 90 days
Arterial blood gases: Lactate (lac)	Change in Lactate (lac) concentration before and after CPET.	Within 1 - 90 days
Arterial blood gases: Hemoglobin (Hb)	Change in Hemoglobin (Hb) before and after CPET.	Within 1 - 90 days
Arterial blood gases: Hematocrit (Hct)	Change in Hematocrit (Hct) before and after CPET.	Within 1 - 90 days
Focused Stress-Echocardiography (Right Heart): Tricuspid Regurgitation Velocity (TRV)	Change in Tricuspid Regurgitation Velocity (TRV) during CPET	Within 1 - 90 days
Focused Stress-Echocardiography (Right Heart): Right Atrial Pressure (RAP)	Change in Right Atrial Pressure (RAP) during CPET	Within 1 - 90 days
Focused Stress-Echocardiography (Right Heart): Systolic Pulmonary Arterial Pressure (sPAP)	Change in Systolic Pulmonary Arterial Pressure (sPAP) during CPET	Within 1 - 90 days
Focused Stress-Echocardiography (Right Heart): Fractional Area Change (FAC)	Change in Fractional Area Change (FAC) during CPET	Within 1 - 90 days
Focused Stress-Echocardiography (Right Heart): Tricuspid Annular Plane Systolic Excursion (TAPSE)	Change in Tricuspid Annular Plane Systolic Excursion (TAPSE) during CPET	Within 1 - 90 days
Focused Stress-Echocardiography (Right Heart): Ratio of Tricuspid Regurgitation Pressure Gradient to Cardiac Output (TRPG/CO)	Change in Ratio of Tricuspid Regurgitation Pressure Gradient to Cardiac Output (TRPG/CO) during CPET	Within 1 - 90 days
Focused Stress-Echocardiography (Right Heart): Cardiac Output (CO)	Change in Cardiac Output (CO) during CPET	Within 1 - 90 days
Focused Stress-Echocardiography (Right Heart): Pulmonary Vascular Resistance (PVR)	Change in Pulmonary Vascular Resistance (PVR) during CPET	Within 1 - 90 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Profile / (S)AEs	Safety and (S)AEs of each Intervention [sildenafil 20mg (Revatio 20mg) and dextrose candy (Dextro Energy)] will be assessed.	(S)AEs will be assessed immediately after each intervention (A or B) during the corresponding study visits (1 and 2).

Collaborators and Investigators

• Sponsor: Silvia Ulrich
• Investigators: Principal Investigator: Silvia Ulrich, Prof. Dr. med., University of Zurich; Principal Investigator: Arcangelo F Carta, Dr. med., University of Zurich

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: August 17, 2026
• First Submitted That Met QC Criteria: September 12, 2026
• First Posted (Actual): September 17, 2026

Study Record Updates

• Last Update Posted (Actual): September 17, 2026
• Last Update Submitted That Met QC Criteria: September 12, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: RCT; Pulmonary Arterial Hypertension; Sildenafil; CPET; Cardiopulmonary Testing; CWRET; Pill-In-The-Pocket
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Carbohydrates; Amides; Purines; Sugars; Sulfonamides; Sulfones; Piperazines; Hexoses; Monosaccharides; Sildenafil Citrate; Glucose
• Other Study ID Numbers: KEK-ZH-Nr. 2025-02557

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Access to anonymised IPD that underlie results in a publication will be considered individually upon reasonable request.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No