NCT02338999

Role of PPAR-y Agonists in Immunomodulation and Vascular Prevention in SLE (PPAR-SLE)

Completed Phase 1, PHASE2 Results posted Last updated 14 September 2021

What this trial tests

Phase 1, PHASE2 trial testing PET/CT in Systemic Lupus Erythematosus in 88 participants. Completed in 14 July 2020.

Timeline

18 June 2015

Primary endpoint
14 July 2020

14 July 2020

Quick facts

Lead sponsor	National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Phase	Phase 1, PHASE2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	crossover
Masking	double
Primary purpose	prevention
Enrollment	88
Start date	18 June 2015
Primary completion	14 July 2020
Estimated completion	14 July 2020
Sites	1 location across United States

Drugs / interventions tested

• PET/CT
• Pioglitazone (pioglitazone) — full drug profile →
• Placebo

Conditions studied

• Systemic Lupus Erythematosus — all drugs for Systemic Lupus Erythematosus →

Sponsor

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Who can join

Adults 18 to 99, any sex, with Systemic Lupus Erythematosus. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change in Vascular Function and Cardiometabolic Risk as Measured by Left CAVI at Month 3 Primary · 3 months after start of first intervention (Baseline to 3 months)

Change in vascular function using non-invasive vascular tests, measuring vascular compliance - Cardio ankle vascular index (CAVI). CAVI is an index reflecting the stiffness of the artery from the heart to ankles; it increases with atherosclerosis progression. CAVI was measured using VaSera-1500A (Fukuda Denshi Co. Redmond, WA)

Group	Value	95% CI
Pioglitazone, Then Placebo	-0.32	± 0.96
Placebo, Then Pioglitazone	0.09	± 0.68

Change in Vascular Function and Cardiometabolic Risk as Measured by Left CAVI at Month 8 Primary · 3 months after start of second intervention (5 months to 8 months)

Change in vascular function using non-invasive vascular tests, measuring vascular compliance - Cardio ankle vascular index (CAVI). CAVI is an index reflecting the stiffness of the artery from the heart to ankles; it increases with atherosclerosis progression. CAVI was measured using VaSera-1500A (Fukuda Denshi Co. Redmond, WA)

Group	Value	95% CI
Pioglitazone, Then Placebo	-0.29	± 0.55
Placebo, Then Pioglitazone	-0.07	± 0.63

Change in Vascular Function and Cardiometabolic Risk as Measured by Right CAVI at Month 3 Primary · 3 months after start of first intervention (Baseline to 3 months)

Change in vascular function using non-invasive vascular tests, measuring vascular compliance - Cardio ankle vascular index (CAVI). CAVI is an index reflecting the stiffness of the artery from the heart to ankles; it increases with atherosclerosis progression. CAVI was measured using VaSera-1500A (Fukuda Denshi Co. Redmond, WA)

Group	Value	95% CI
Pioglitazone, Then Placebo	-0.42	± 0.88
Placebo, Then Pioglitazone	0.12	± 0.65

Change in Vascular Function and Cardiometabolic Risk as Measured by Right CAVI at Month 8 Primary · 3 months after start of second intervention (5 months to 8 months)

Change in vascular function using non-invasive vascular tests, measuring vascular compliance - Cardio ankle vascular index (CAVI). CAVI is an index reflecting the stiffness of the artery from the heart to ankles; it increases with atherosclerosis progression. CAVI was measured using VaSera-1500A (Fukuda Denshi Co. Redmond, WA)

Group	Value	95% CI
Pioglitazone, Then Placebo	-0.26	± 0.61
Placebo, Then Pioglitazone	-0.08	± 0.71

Change in Vascular Function and Cardiometabolic Risk as Measured by PWV at Month 3 Primary · 3 months after start of first intervention (Baseline to 3 months)

Change in vascular function using non-invasive vascular tests, measuring vascular compliance -Pulse, wave, velocity (PWV). The central aortic pressure PWV was determined by using the pressure tonometer and an EKG signal was used simultaneously to visualize ventricular-vascular interactions. It increases with atherosclerosis progression. Central aortic BP and stiffness were quantified using SphygmoCor CP system (AtCor Medical Pty Ltd.; New South Wales, Australia).

Group	Value	95% CI
Pioglitazone, Then Placebo	-0.31	± 2.06
Placebo, Then Pioglitazone	0.03	± 2.03

Change in Vascular Function and Cardiometabolic Risk as Measured by PWV at Month 8 Primary · 3 months after start of second intervention (5 months to 8 months)

Change in vascular function using non-invasive vascular tests, measuring vascular compliance -Pulse, wave, velocity (PWV). The central aortic pressure PWV was determined by using the pressure tonometer and an EKG signal was used simultaneously to visualize ventricular-vascular interactions. It increases with atherosclerosis progression. Central aortic BP and stiffness were quantified using SphygmoCor CP system (AtCor Medical Pty Ltd.; New South Wales, Australia).

Group	Value	95% CI
Pioglitazone, Then Placebo	-0.31	± 1.86
Placebo, Then Pioglitazone	-0.25	± 0.94

Change in Vascular Function and Cardiometabolic Risk as Measured by RHI at Month 3 Primary · 3 months after start of first intervention (Baseline to 3 months)

Change in vascular function using non-invasive vascular tests, measuring vascular compliance -Reactive hyperemia index (RHI). RHI is a measure of endothelial dysfunction using noninvasive peripheral arterial tonometry (PAT). It is a ratio of the post-to-pre occlusion PAT amplitude of the tested arm, divided by the post-to-pre occlusion ratio of the control arm. RHI less than 1.67 is considered sign of endothelial dysfunction and RHI equal to or greater than 1.67 is considered normal function. The possible range of scores is 1 to 3. Increasing score indicates the improvement of coronary endoth

Group	Value	95% CI
Pioglitazone, Then Placebo	0.07	± 0.35
Placebo, Then Pioglitazone	0.02	± 0.48

Change in Vascular Function and Cardiometabolic Risk as Measured by RHI at Month 8 Primary · 3 months after start of second intervention (5 months to 8 months)

Change in vascular function using non-invasive vascular tests, measuring vascular compliance -Reactive hyperemia index (RHI). RHI is a measure of endothelial dysfunction using noninvasive peripheral arterial tonometry (PAT). It is a ratio of the post-to-pre occlusion PAT amplitude of the tested arm, divided by the post-to-pre occlusion ratio of the control arm. RHI less than 1.67 is considered sign of endothelial dysfunction and RHI equal to or greater than 1.67 is considered normal function. The possible range of scores is 1 to 3. Increasing score indicates the improvement of coronary endoth

Group	Value	95% CI
Pioglitazone, Then Placebo	-0.05	± 0.35
Placebo, Then Pioglitazone	0.02	± 0.36

Effect of Pioglitazone on Vascular Inflammation and Cardiometabolic Risk as Measured by TBR Value at Month 3 Primary · 3 months after start of first intervention (Baseline to 3 months)

Change in vascular inflammation using non-invasive vascular test, measuring changes in target to blood pool ratio (TBR) value by positron emission tomography (PET) computerized tomography (CT). The higher the value, the higher the degree of vascular inflammation.

Group	Value	95% CI
Pioglitazone, Then Placebo	0.0337	± 0.1991
Placebo, Then Pioglitazone	0.0351	± 0.2954

Adverse events — posted to ClinicalTrials.gov

Time frame: 8 months. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Pioglitazone

Serious: 1/77 (1%)

Deaths: 0/77

Placebo

Serious: 5/77 (6%)

Deaths: 0/77

Serious adverse events (5 terms)

Reaction	System	Pioglitazone	Placebo
Enterocolitis infectious	Infections and infestations	—	—
Thyroid mass	Endocrine disorders	—	—
Sepsis	Infections and infestations	—	—
Limb mass	Musculoskeletal and connective tissue disorders	—	—
Peripheral ischaemia	Vascular disorders	—	—

Other adverse events (103 terms — click to expand)

Reaction	System	Pioglitazone	Placebo
Upper respiratory tract infection	Infections and infestations	—	—
Urinary tract infection	Infections and infestations	—	—
White blood cell count decreased	Investigations	—	—
Dizziness	Nervous system disorders	—	—
Headache	Nervous system disorders	—	—
Fatigue	General disorders	—	—
Alanine aminotransferase increased	Investigations	—	—
Nausea	Gastrointestinal disorders	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Abdominal distension	Gastrointestinal disorders	—	—
Viral upper respiratory tract infection	Infections and infestations	—	—
Aspartate aminotransferase increased	Investigations	—	—
Cardiac murmur	Investigations	—	—
Weight increased	Investigations	—	—
Somnolence	Nervous system disorders	—	—
Dysuria	Renal and urinary disorders	—	—
Dyspepsia	Gastrointestinal disorders	—	—
Gastritis	Gastrointestinal disorders	—	—
Gastrooesophageal reflux disease	Gastrointestinal disorders	—	—
Non-cardiac chest pain	General disorders	—	—
Gastritis viral	Infections and infestations	—	—
Platelet count decreased	Investigations	—	—
Paraesthesia	Nervous system disorders	—	—
Micturition disorder	Renal and urinary disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Laryngeal inflammation	Respiratory, thoracic and mediastinal disorders	—	—
Rhinitis allergic	Respiratory, thoracic and mediastinal disorders	—	—
Wheezing	Respiratory, thoracic and mediastinal disorders	—	—
Leukopenia	Blood and lymphatic system disorders	—	—
Lymphadenopathy	Blood and lymphatic system disorders	—	—
Osler's nodes	Cardiac disorders	—	—
Tachycardia	Cardiac disorders	—	—
Dry eye	Eye disorders	—	—
Episcleritis	Eye disorders	—	—
Lacrimation increased	Eye disorders	—	—
Vision blurred	Eye disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Constipation	Gastrointestinal disorders	—	—

Most-reported serious reactions: Enterocolitis infectious, Thyroid mass, Sepsis, Limb mass, Peripheral ischaemia.

Data from ClinicalTrials.gov NCT02338999 adverse events section.

Sponsor's own description

Background:

\- Lupus causes a person s immune system to attack the body. It can cause blood vessel problems, heart attack, or stroke. Researchers want to see if the drug pioglitazone may help.

Objectives:

\- To see how well pioglitazone improves blood vessel function and decreases blood vessel inflammation. To study its effect on lupus symptoms.

Eligibility:

\- Adults at least 18 years old with lupus.

Design:

* Participants will be screened with medical history, heart test, and blood and urine tests. They may have a bone density test.
* Visit 1:
* Participants will have:
* Physical exam and blood drawn.
* Peripheral Arterial Tonometry (Endopat). A cup will be placed on the finger and a pressure cuff on the arm.
* Cardio-ankle vascular index (CAVI) and/or Sphygmocor. Electrodes will be placed on both wrists, a microphone on the chest, and a blood pressure cuff on each arm and leg. Another test will involve placing a small device on a fingertip.
* 18-Fluorodeoxyglucose (FDG) positron emission tomography/computerized tomography (PET/CT) (some participants). A radioactive sugar will be injected into a small plastic tube in an arm vein. Participants will lie on a bed that moves in and out of a scanner that takes pictures.
* Participants will get a 3-month-supply of the study drug or placebo. After 1 week, their dose may increase.
* After those 3 months, they will not take either drug for 8 weeks. Then they will switch and take the other drug for 3 months.
* Participants will have 6 more visits over 8 months after Visit 1. Tests from Visit 1 may be repeated. They may have a urine test.

Publications & conference data

5 peer-reviewed publications reference this trial (live from Europe PMC):

1. Drugging the efferocytosis process: concepts and opportunities.
   Mehrotra P, Ravichandran KS. · · 2022 · cited 319× · PMID 35650427 · DOI 10.1038/s41573-022-00470-y
2. Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence.
   Cheng HS, Tan WR, Low ZS, Marvalim C, et al · · 2019 · cited 196× · PMID 31614690 · DOI 10.3390/ijms20205055
3. Current Paradigms of Tolerogenic Dendritic Cells and Clinical Implications for Systemic Lupus Erythematosus.
   Ritprajak P, Kaewraemruaen C, Hirankarn N. · · 2019 · cited 32× · PMID 31640263 · DOI 10.3390/cells8101291
4. Nuclear receptors, the aryl hydrocarbon receptor, and macrophage function.
   Lamorte S, Shinde R, McGaha TL. · · 2021 · cited 29× · PMID 33451803 · DOI 10.1016/j.mam.2021.100942
5. Peroxisome proliferator activated receptor-γ agonist pioglitazone improves vascular and metabolic dysfunction in systemic lupus erythematosus.
   Hasni S, Temesgen-Oyelakin Y, Davis M, Chu J, et al · · 2022 · cited 20× · PMID 35914929 · DOI 10.1136/ard-2022-222658