Fluoxetine in Pulmonary Arterial Hypertension (PAH) Trial

Sponsor
University of Texas Southwestern Medical Center (Other)
Overall Status
Completed
CT.gov ID
NCT03638908
Collaborator
(none)
8
1
1
61
0.1

Study Details

Study Description

Brief Summary

This protocol describes an open-label phase 2 clinical trial of fluoxetine in PAH looking at change in pulmonary vascular resistance (PVR) as the primary endpoint.

In this open-label clinical trial, 18 patients with pulmonary arterial hypertension will be given fluoxetine for 24 weeks. A Right Heart Catheterization will be performed at baseline and 24 weeks. Change in PVR will be the primary endpoint; other hemodynamic endpoints, quality of life, QIDS-SR depression scale, functional class and six-minute walk distance will also be evaluated.

Primary Hypothesis: Fluoxetine treatment for 24 weeks will lead to significantly lower pulmonary vascular resistance in 18 patients with PAH in patients treated in an open-label clinical trial.

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
8 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 2, Open-label, Clinical Trial of Fluoxetine, a Selective Serotonin Reuptake Inhibitor, in the Treatment of Pulmonary Arterial Hypertension
Study Start Date :
Nov 1, 2013
Actual Primary Completion Date :
May 1, 2017
Actual Study Completion Date :
Dec 1, 2018

Arms and Interventions

Arm Intervention/Treatment
Other: Fluoxetine

Dosing will be Week 1-4: 20 mg daily Week 5-8: 40 mg daily Week 9-12: 60 mg daily Week 13-24: 80 mg daily

Drug: Fluoxetine

Outcome Measures

Primary Outcome Measures

  1. Pulmonary Vascular Resistance (PVR) [Baseline and Week 24]

    Change in PVR between baseline and follow-up will be utilized. PVR is calculated as [(Pulmonary Artery mean - wedge) / Fick Cardiac Output]. Fick CO will be used in computing PVR over thermodilution because Fick appears to have greater precision (but not accuracy). The calculation of PVR above is measured in woods unit. Change is derived by getting the difference between baseline and week 24 PVR (Week 24 minus Baseline). mean is then computed by getting the average of the change

Secondary Outcome Measures

  1. 5-HIAA (HYDROXYINDOLE ACETIC ACID) Level [Baseline and Week 24]

    Urine for spot urine 5-HIAA will be collected at baseline and Week 24. Subjects will be on diet restriction 72 hours prior to urine collection. Sample will be the first morning urine on the visit day. Sample will be brought to site and then sent to affiliate outside laboratory for processing. 5HIAA results are expressed as a ratio to creatinine excretion in the unit "mg/g creatinine" Change 5-HIAA is derived by getting the difference between baseline and week 24 5HIAA results (Week 24 minus Baseline). mean is then computed by getting the average of the change

Other Outcome Measures

  1. Markers of Platelets and Endothelial Activation in PAH. [Baseline and Week 24]

    About 20ml blood will be obtained for plasma and serum at Baseline and Week 24. This will be placed in a red-top tube (serum, at least 1 ml) and blue-top tube. For the plasma tests, a plasma volume of 750 microL is required. Samples will be sent together, as a batch of 50 is required, on dry ice via overnight courier. Plasma will be obtained by drawing blood into a blue-top citrated tube, inverting the tube 6 times, and then centrifuging at 2000g for 10 minutes. The platelet poor plasma will be drawn off, and then re-centrifuged for 10 minutes before freezing.

  2. Exercise Capacity [baseline and 24]

    Exercise capacity will be measure using the 6-minute walk test. Data collected at baseline and 24 were analyzed. The test will follow the ATS guidelines for 6MWT at all time.

  3. Functional Class [baseline and 24]

    Functional class will be measured using the WHO functional class assessment. This is graded from WHO FC I to FC IV. Assessment will be completed by an investigator on the study at every visit.

  4. Quick Inventory of Depressive Symptomatology [baseline and Week 24.]

    Patient reported outcome will be assessed using the Quick Inventory of Depressive Symptomatology (16-Item) (Self-Report) (QIDS-SR16) completed at baseline, week 12 and Week 24; baseline and week 24 reported. Each question is scored from minimum of 0 to a maximum of 3; total score ranges from 0 to 42. With zero being better outcome and 42 being severe outcome

  5. Patient Global Impression of Severity - Symptoms (PGIS) [baseline]

    PGIS questionnaire will be administered for global assessment of severity. This questionnaire is categorical and measures outcome from "none" being best outcome to "severe" being the worst outcome

  6. Clinician Global Impression of Severity - Symptoms (CGIS) [Week 12 and Week 24.]

    Global assessment of severity will be determined using Clinician global impression of severity - symptoms (CGIS). This questionnaire is categorical and measures outcome from "none" being best outcome to "severe" being the worst outcome

  7. Short Form 36 [baseline, Week 12 and Week 24.]

    Patient reported outcome will also be assessed using SF-36 completed at baseline, Week 12 and Week 24. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. The eight sections are: vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health

  8. Clinician Global Impression of Change (CGI-change) [Weeks 12 and 24]

    CGI-change questionnaire will be completed for global assessment of severity. This questionnaire is categorical and measures outcome from "very much better" being best outcome to "very much worse" being the worst outcome

Eligibility Criteria

Criteria

Ages Eligible for Study:
16 Years to 80 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
Yes
Inclusion Criteria:
  1. WHO Group I PAH subtypes of idiopathic PAH and PAH associated with drugs / toxins, connective tissue disease, repaired congenital heart disease and unrepaired atrial septal defect

  2. Age 16-80

  3. WHO Functional Class II or III

  4. Right Heart Catheterization within 3 weeks of study entry with mPAP ≥ 25 mmHg, wedge ≤ 15 mmHg, and PVR ≥ 3 Wood units.

  5. Contraception use, (-) urine pregnancy test, not breast feeding (women of childbearing potential)

  6. One or more approved PAH therapies for ≥ 3 months, no change in dose for 1 month (endothelin-1 antagonist, phosphodiesterase-5 inhibitor, prostacyclin / prostacyclin analog). Novel approved therapies in one of the three existing classes will also be acceptable as background therapy if they become available during the course of the study; other medication classes are excluded

Exclusion Criteria:
  1. WHO Functional Class IV or listed for lung transplant

  2. Moderate or greater obstructive lung disease: FEV1/FVC <70% and FEV1 <60%

  3. Moderate or greater restrictive lung disease: TLC or FVC <60% (if 50-60%: OK if TLC or FVC ≥50% + PFT stable x1 year + CT with no more than mild lung disease)

  4. Other cause for pulmonary hypertension: all other WHO group I diseases (including but not limited to liver disease, HIV), and WHO Groups II-V (i.e. left heart disease, lung disease, chronic PE and miscellaneous causes)24.

  5. High probability VQ or positive CTA

  6. Left ventricular ejection fraction <40%

  7. Depression

  8. Severe liver, renal or other medical or physical disease preventing completion of the study procedures

  9. Use of antidepressants within 3 months

Contacts and Locations

Locations

Site City State Country Postal Code
1 UT Southwestern Medical Center Dallas Texas United States 75390

Sponsors and Collaborators

  • University of Texas Southwestern Medical Center

Investigators

  • Principal Investigator: Kelly Chin, MD, UT Southwestern Medical Center

Study Documents (Full-Text)

More Information

Publications

None provided.
Responsible Party:
University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier:
NCT03638908
Other Study ID Numbers:
  • NIKK23
  • STU 082013-045
First Posted:
Aug 20, 2018
Last Update Posted:
Jun 26, 2020
Last Verified:
Jun 1, 2020

Study Results

Participant Flow

Recruitment Details Subjects were recruited solely from the clinic from November 2013 to November 2016
Pre-assignment Detail This was an open label study and all subjects were assigned to receive Fluoxetine.
Arm/Group Title Fluoxetine
Arm/Group Description Dosing will be Week 1-4: 20 mg daily Week 5-8: 40 mg daily Week 9-12: 60 mg daily Week 13-24: 80 mg daily Fluoxetine
Period Title: Overall Study
STARTED 8
COMPLETED 7
NOT COMPLETED 1

Baseline Characteristics

Arm/Group Title Fluoxetine
Arm/Group Description Dosing will be Week 1-4: 20 mg daily Week 5-8: 40 mg daily Week 9-12: 60 mg daily Week 13-24: 80 mg daily Fluoxetine
Overall Participants 8
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
44.5
(10.7)
Sex: Female, Male (Count of Participants)
Female
8
100%
Male
0
0%
Race/Ethnicity, Customized (Count of Participants)
White non-hispanic
5
62.5%
Hispanic
3
37.5%
African American
0
0%
Region of Enrollment (Count of Participants)
United States
8
100%

Outcome Measures

1. Primary Outcome
Title Pulmonary Vascular Resistance (PVR)
Description Change in PVR between baseline and follow-up will be utilized. PVR is calculated as [(Pulmonary Artery mean - wedge) / Fick Cardiac Output]. Fick CO will be used in computing PVR over thermodilution because Fick appears to have greater precision (but not accuracy). The calculation of PVR above is measured in woods unit. Change is derived by getting the difference between baseline and week 24 PVR (Week 24 minus Baseline). mean is then computed by getting the average of the change
Time Frame Baseline and Week 24

Outcome Measure Data

Analysis Population Description
6 out of the 8 subjects enrolled had complete- baseline and week 24- data for analysis
Arm/Group Title Fluoxetine
Arm/Group Description Dosing will be Week 1-4: 20 mg daily Week 5-8: 40 mg daily Week 9-12: 60 mg daily Week 13-24: 80 mg daily
Measure Participants 6
Mean (Standard Deviation) [woods unit]
6.7
(2.7)
2. Secondary Outcome
Title 5-HIAA (HYDROXYINDOLE ACETIC ACID) Level
Description Urine for spot urine 5-HIAA will be collected at baseline and Week 24. Subjects will be on diet restriction 72 hours prior to urine collection. Sample will be the first morning urine on the visit day. Sample will be brought to site and then sent to affiliate outside laboratory for processing. 5HIAA results are expressed as a ratio to creatinine excretion in the unit "mg/g creatinine" Change 5-HIAA is derived by getting the difference between baseline and week 24 5HIAA results (Week 24 minus Baseline). mean is then computed by getting the average of the change
Time Frame Baseline and Week 24

Outcome Measure Data

Analysis Population Description
unable to adequately analyze outcome as there were several missing data- values provided below are not meaningful.
Arm/Group Title Fluoxetine
Arm/Group Description Dosing will be Week 1-4: 20 mg daily Week 5-8: 40 mg daily Week 9-12: 60 mg daily Week 13-24: 80 mg daily
Measure Participants 5
Mean (Standard Deviation) [mg/g CRT]
0.375
(0.182)
3. Other Pre-specified Outcome
Title Markers of Platelets and Endothelial Activation in PAH.
Description About 20ml blood will be obtained for plasma and serum at Baseline and Week 24. This will be placed in a red-top tube (serum, at least 1 ml) and blue-top tube. For the plasma tests, a plasma volume of 750 microL is required. Samples will be sent together, as a batch of 50 is required, on dry ice via overnight courier. Plasma will be obtained by drawing blood into a blue-top citrated tube, inverting the tube 6 times, and then centrifuging at 2000g for 10 minutes. The platelet poor plasma will be drawn off, and then re-centrifuged for 10 minutes before freezing.
Time Frame Baseline and Week 24

Outcome Measure Data

Analysis Population Description
unable to analyze outcome as this sub-study was dependent on obtaining additional funding- samples were collected but not processed to provide result
Arm/Group Title Fluoxetine- Baseline
Arm/Group Description Dosing will be Week 1-4: 20 mg daily Week 5-8: 40 mg daily Week 9-12: 60 mg daily Week 13-24: 80 mg daily
Measure Participants 0
4. Other Pre-specified Outcome
Title Exercise Capacity
Description Exercise capacity will be measure using the 6-minute walk test. Data collected at baseline and 24 were analyzed. The test will follow the ATS guidelines for 6MWT at all time.
Time Frame baseline and 24

Outcome Measure Data

Analysis Population Description
6 out of total enrolled had complete data for analysis
Arm/Group Title Fluoxetine- Baseline Fluoxetine- Week 24
Arm/Group Description subject data at baseline subject data at week 24
Measure Participants 6 6
Mean (Standard Deviation) [meters]
380
(80.7)
393
(78.6)
5. Other Pre-specified Outcome
Title Functional Class
Description Functional class will be measured using the WHO functional class assessment. This is graded from WHO FC I to FC IV. Assessment will be completed by an investigator on the study at every visit.
Time Frame baseline and 24

Outcome Measure Data

Analysis Population Description
analysis was not done as study primary endpoint was not met- since primary endpoint was not met, no further analyses were completed
Arm/Group Title Fluoxetine
Arm/Group Description Dosing will be Week 1-4: 20 mg daily Week 5-8: 40 mg daily Week 9-12: 60 mg daily Week 13-24: 80 mg daily Fluoxetine
Measure Participants 0
6. Other Pre-specified Outcome
Title Quick Inventory of Depressive Symptomatology
Description Patient reported outcome will be assessed using the Quick Inventory of Depressive Symptomatology (16-Item) (Self-Report) (QIDS-SR16) completed at baseline, week 12 and Week 24; baseline and week 24 reported. Each question is scored from minimum of 0 to a maximum of 3; total score ranges from 0 to 42. With zero being better outcome and 42 being severe outcome
Time Frame baseline and Week 24.

Outcome Measure Data

Analysis Population Description
7 subjects of the total enrolled were included in the descriptive analysis. 1 subject did not complete the study
Arm/Group Title Fluoxetine- Baseline Fluoxetine- Week 24
Arm/Group Description subject data at baseline subject data at week 24
Measure Participants 7 7
Mean (Standard Deviation) [score on a scale]
4.7
(2.3)
4.3
(3.3)
7. Other Pre-specified Outcome
Title Patient Global Impression of Severity - Symptoms (PGIS)
Description PGIS questionnaire will be administered for global assessment of severity. This questionnaire is categorical and measures outcome from "none" being best outcome to "severe" being the worst outcome
Time Frame baseline

Outcome Measure Data

Analysis Population Description
analysis was not done as study primary endpoint was not met- since primary endpoint was not met, no further analyses were completed
Arm/Group Title Fluoxetine
Arm/Group Description Dosing will be Week 1-4: 20 mg daily Week 5-8: 40 mg daily Week 9-12: 60 mg daily Week 13-24: 80 mg daily Fluoxetine
Measure Participants 0
8. Other Pre-specified Outcome
Title Clinician Global Impression of Severity - Symptoms (CGIS)
Description Global assessment of severity will be determined using Clinician global impression of severity - symptoms (CGIS). This questionnaire is categorical and measures outcome from "none" being best outcome to "severe" being the worst outcome
Time Frame Week 12 and Week 24.

Outcome Measure Data

Analysis Population Description
analysis was not done as study primary endpoint was not met- since primary endpoint was not met, no further analyses were completed
Arm/Group Title Fluoxetine
Arm/Group Description Dosing will be Week 1-4: 20 mg daily Week 5-8: 40 mg daily Week 9-12: 60 mg daily Week 13-24: 80 mg daily Fluoxetine
Measure Participants 0
9. Other Pre-specified Outcome
Title Short Form 36
Description Patient reported outcome will also be assessed using SF-36 completed at baseline, Week 12 and Week 24. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. The eight sections are: vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health
Time Frame baseline, Week 12 and Week 24.

Outcome Measure Data

Analysis Population Description
analysis was not done as study primary endpoint was not met- since primary endpoint was not met, no further analyses were completed
Arm/Group Title Fluoxetine
Arm/Group Description Dosing will be Week 1-4: 20 mg daily Week 5-8: 40 mg daily Week 9-12: 60 mg daily Week 13-24: 80 mg daily Fluoxetine
Measure Participants 0
10. Other Pre-specified Outcome
Title Clinician Global Impression of Change (CGI-change)
Description CGI-change questionnaire will be completed for global assessment of severity. This questionnaire is categorical and measures outcome from "very much better" being best outcome to "very much worse" being the worst outcome
Time Frame Weeks 12 and 24

Outcome Measure Data

Analysis Population Description
analysis was not done as study primary endpoint was not met- since primary endpoint was not met, no further analyses were completed
Arm/Group Title Fluoxetine
Arm/Group Description Dosing will be Week 1-4: 20 mg daily Week 5-8: 40 mg daily Week 9-12: 60 mg daily Week 13-24: 80 mg daily Fluoxetine
Measure Participants 0

Adverse Events

Time Frame 7 months
Adverse Event Reporting Description
Arm/Group Title Fluoxetine
Arm/Group Description Dosing will be Week 1-4: 20 mg daily Week 5-8: 40 mg daily Week 9-12: 60 mg daily Week 13-24: 80 mg daily Fluoxetine
All Cause Mortality
Fluoxetine
Affected / at Risk (%) # Events
Total 0/8 (0%)
Serious Adverse Events
Fluoxetine
Affected / at Risk (%) # Events
Total 0/8 (0%)
Other (Not Including Serious) Adverse Events
Fluoxetine
Affected / at Risk (%) # Events
Total 8/8 (100%)
Cardiac disorders
increased palpitations 2/8 (25%)
Gastrointestinal disorders
diarrhea 3/8 (37.5%)
General disorders
headaches 4/8 (50%)
excessive yawning 2/8 (25%)
fatigue 2/8 (25%)
dizziness 2/8 (25%)
Psychiatric disorders
anxiety 2/8 (25%)
Respiratory, thoracic and mediastinal disorders
acute bronchitis 2/8 (25%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title Kelly Chin, MD
Organization UTSouthwestern medical center
Phone 2146456493
Email kelly.chin@utsouthwestern.edu
Responsible Party:
University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier:
NCT03638908
Other Study ID Numbers:
  • NIKK23
  • STU 082013-045
First Posted:
Aug 20, 2018
Last Update Posted:
Jun 26, 2020
Last Verified:
Jun 1, 2020