Efficacy of Pentoxifylline on Cerebrovascular Function in Patients With Cerebral Small Vessel Disease(PERFORM) (PERFORM)

Efficacy of Pentoxifylline on Cerebrovascular Function in Patients With Cerebral Small Vessel Disease(PERFORM)：A Randomized, Double-blinded, Placebo-controlled, Multi-center Trial

This is a randomized, double-blinded, placebo-controlled, multi-center trial. Cerebral small vessel disease (CSVD) patients will be diagnosed according to STRIVE standards and randomized into the Pentoxifylline sustained-release tablet group and placebo group. The purpose of this trial is to assess the efficacy of Pentoxifylline sustained- release tablets on CSVD.

Study Overview

• Status: Not yet recruiting
• Conditions: Cerebral Small Vessel Diseases
• Intervention / Treatment: Drug: Pentoxifylline sustained-release tablets placebo; Drug: Pentoxifylline sustained-release tablets

Detailed Description

Cerebral small vessel disease (CSVD) is a complex whole brain disease, which is a series of clinical, imaging, and pathological syndromes caused by various etiologies affecting small arteries, micro-arteries, capillaries, micro-venules, and small veins in the brain, and is a common clinical vascular disease of the brain, usually with insidious onset, slow progression, and some acute attacks.

The incidence of CSVD is positively correlated with age. Studies have shown that in people aged 60 to 70 years, 87% had subcortical white matter lesions and 68% had periventricular white matter changes, whereas, in people aged 80 to 90 years, 100% had subcortical white matter changes and 95% had periventricular changes. The incidence of cerebral microhemorrhage is approximately 6% in the 45-50 years old population and up to 36% in the 80-year-old population.

Pentoxifylline, a xanthine derivative, is mainly used for the improvement of cerebral circulation after ischemic cerebrovascular disease and for peripheral vascular disease, such as chronic occlusive vasculitis with intermittent claudication treatment. Pentoxifylline is a non-selective phosphodiesterase inhibitor that increases intracellular cyclic AMP (cAMP) and activates protein kinase A31, playing an anti-inflammatory, anti-oxidation, inhibition of platelet aggregation, and vasodilation. Pentoxifylline is a well-tolerated drug for improving peripheral blood flow disorders, primarily by increasing blood flow and increasing oxygenation of ischaemic tissues. In addition, it improves vasodilatation by increasing prostacyclin and has a specific effect on the immune response by inhibiting tumor necrosis factors.

Patients meeting the enrollment criteria will be randomly assigned to one of the two treatment groups with the use of a double-blind design (a dose of 1 tablet twice a day, from randomization to 6 months). Face-to-face interviews will be conducted at baseline, on day 30 after randomization, on day 90 after randomization, and on day 180 after randomization.

The primary endpoint was the change in cerebral blood flow (CBF) and pulsatility index of the middle cerebral artery (MCA) after 6 months of treatment based on transcranial doppler (TCD) assessment of enrolled patients. The secondary endpoints include changes in clinical symptoms, MRI imaging markers (white matter hyperintensity, lacunes, microbleeds, enlarged perivascular space), and cognitive function at 6 months. The safety endpoints include moderate or severe hemorrhage events, symptomatic and asymptomatic intracranial hemorrhage, overall mortality, and serious adverse events.

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Yilong Wang, PhD，MD; Phone Number: 0086-10-59975178; Email: yilong528@aliyun.com

Study Locations

• China
  • Beijing, China, 100050
    • Beijing Tiantan Hospital
    • Contact: Yilong Wang, M.D.; Email: yilong538@gmail.com
    • Sub-Investigator: yilong wang, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 41 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 45-75 years;

2. CSVD can be seen on MRI, which satisfies one of the following conditions:

   • Presence of white matter hyperintensities and Fazekas score ≥2;
   • Lacunar Infarction ≥1, with or without white matter hyperintensities;
3. is eligible for Transcranial Doppler (TCD) monitoring;

4. meeting the following clinical manifestations:

   • Patients with vascular cognitive impairment (abnormalities in memory and or other cognitive domains lasting at least 3 months) ;
   • MoCA ≤22 points; MoCA ≤21 points for primary education and below;
5. independent in daily life (modified mRS ≤2) ;
6. with signed informed consent.

Exclusion Criteria:

1. patients with acute cerebral infarction and acute cerebral hemorrhage;
2. patients with bleeding tendency: including platelet count < 100 × 10*9/L, active peptic ulcer, history of intracranial hemorrhage (such as epidural hematoma, subdural haematoma, subarachnoid hemorrhage, cerebral hemorrhage, etc.) , cerebral microbleedings (≥5 cerebral microbleedings) , brain tumor, cancer-related stroke, taking anticoagulant drugs, or using dual antiplatelet therapy;
3. patients who have a history of cognitive impairment caused by other causes, such as normal pressure hydrocephalus, Alzheimer's disease, Parkinson's disease, multiple sclerosis, encephalitis, etc.;
4. patients with acute coronary syndrome and severe coronary arteriosclerosis;
5. patients with severe hepatic insufficiency, renal insufficiency, or severe cardiac insufficiency before randomization (severe hepatic insufficiency refers to ALT ≥2.0 times the upper limit of normal or AST ≥2.0 times the upper limit of normal; severe renal insufficiency refers to CRE ≥1.5 times the upper limit of normal or EGFR < 40 ml/min/1.73 m2; severe cardiac insufficiency refers to NYHA grade of 3-4) ;
6. patients who are pregnant, lactating or likely to become pregnant and planning to become pregnant;
7. patients with refractory hypertension;
8. patients with known allergic history to pentoxifylline, methylxanthine (such as caffeine, aminophylline, dihydroxypropyltheophylline, etc.) ;
9. patients with use of other vasodilators or circulatory improvers within 1 week (e.g. Cilostazol, Vinpocetine, Dimitamol, Sildenafil, Butylphthalide, Betahistine, Uracillin, Alprostadil, etc.) May stop taking the drug for 1 week before enrolling if criteria are met;
10. Patients using other drugs that affect the safety or efficacy evaluation of the tiral drug and who do not agree to discontinue the drug, such as GLP-1 receptor agonists, Liraglutide, dulasapeptide, risperidone, and exenatide;
11. Patients with other life-threatening or serious diseases with an expected survival of < 36 months;
12. Patients with contraindications to MRI;
13. Patients who could not cooperate to complete the follow-up;
14. Patients who enrolled in other clinical trials within 30 days.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Pentoxifylline sustained- release tablets placebo group; This group will receive Pentoxifylline sustained-release tablets placebo, 1 tablet twice a day, from the day of randomization to 6 months.	Drug: Pentoxifylline sustained-release tablets placebo; Pentoxifylline sustained-release tablets placebo will be administrated at the same dosage and frequency as the experimental group
Experimental: Pentoxifylline sustained- release tablets group; This group will receive Pentoxifylline sustained-release tablets, 1 tablet twice a day, from the day of randomization to 6 months.	Drug: Pentoxifylline sustained-release tablets; a dose of 1 tablet twice a day of Pentoxifylline sustained-release tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change in cerebral blood flow at 6 months	TCD is used to evaluate the change in cerebral blood flow (cm/s) 6 months after treatment. Higher speed mean a worse outcome.	3 months and 6 months after randomization
The change of middle cerebral artery pulsatility index at 6 months	TCD is used to evaluate the change of middle cerebral artery pulsatility index at 6 months. Higher pulsatility index mean a worse outcome.	3 months and 6 months after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
cognitive function assessed by MoCA at 6 months	Cognition function assessed by Montreal Cognitive Assessment (MoCA) score. Score range 0-30. Higher scores mean a better outcome.	6 months after randomization
cognitive function assessed by Clinical Dementia Rating (CDR) at 6 months	Cognitive function assessed by Clinical Dementia Rating (CDR). Score range 0-3. Higher scores mean a worse outcome.	6 months after randomization
The change of White Matter hyperintense volume at 6 months	WMH volume is assessed on 3D fluid attenuated inversion recovery (FLAIR) sequence in mm3 or cm3. Larger volume indicates a worse outcome.	6 months after randomization
The change of White Matter hyperintensities Fazekas scores at 6 months	Fazekas score is used to describe the different types of hyperintense signal abnormalities surrounding the ventricles and in the deep white matter. Periventricular hyperintensity (PVH) is graded as 0 = absence, 1 = "caps" or pencil-thin lining, 2 = smooth "halo", 3 = irregular PVH extending into the deep white matter. Separate deep white matter hyperintensity (DWMH) is rated as 0 = absence, 1 = punctate foci, 2 = beginning confluence of foci, 3 = large confluent areas. Higher scores indicats a worse outcome.	6 months after randomization
The change of Cerebral blood flow values for MRI cerebral perfusion imaging at 6 months	MRI is used to evaluate the change of Cerebral blood flow values for MRI cerebral perfusion imaging at 6 months.	6 months after randomization
Digit span test	The Digit span test is used to assess cognitive function change for 6 months. The score ranges from 0 to 44. Higher scores mean a better outcome.	6 months after randomization
Stroop Color Word Test	The Stroop Color and Word Test is a neuropsychological test extensively used to assess the ability to inhibit cognitive interference that occurs when the processing of a specific stimulus feature impedes the simultaneous processing of a second stimulus attribute, well-known as the Stroop Effect. Shorter the test time, the better the outcome.	6 months after randomization
Hamilton Anxiety Scale(HAMA)	Mood function is assessed by Hamilton Anxiety Scale(HAMA). The Score ranges 0-56. Higher scores mean a worse outcome.	6 months after randomization
Hamilton Depression Scale(HAMD)	Mood function assessed by Hamilton Depression Scale(HAMD). The Score ranges 0-68. Higher scores mean a worse outcome.	6 months after randomization
The Short Physical Performance Battery(SPPB)	It is a composite measure assessing walking speed, standing balance, and sit-to-stand performance. It has primarily been used to assess elderly patients both in the hospital and community setting.	6 months after randomization
Urination and defecation	The score of the urination and defecation function scale changed at 6 months.	6 months after randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurovascular coupling index	Data are presented as peak population normalized mean changes from baseline, and median area under the curve (AUC).	3 months and 6 months after randomization
Electroencephalogram oscillations	The amplitude, frequency, phase, coherence will be measured.	3 months and 6 months after randomization
Blood-Brain Barrier (BBB) Permeability between groups.	BBB permeability is assessed by MRI and biomarker (including NSE, GFAP, S100β).	3 months and 6 months after randomization

Collaborators and Investigators

• Sponsor: Beijing Tiantan Hospital
• Collaborators: CSPC Ouyi Pharmaceutical Co., Ltd.
• Investigators: Principal Investigator: Yilong Wang, PhD，MD, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

Study record dates

Study Major Dates

• Study Start (Anticipated): November 1, 2022
• Primary Completion (Anticipated): March 3, 2023
• Study Completion (Anticipated): March 31, 2024

Study Registration Dates

• First Submitted: October 13, 2022
• First Submitted That Met QC Criteria: October 13, 2022
• First Posted (Actual): October 17, 2022

Study Record Updates

• Last Update Posted (Actual): October 17, 2022
• Last Update Submitted That Met QC Criteria: October 13, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: randomized controlled trial; placebo-controlled; Pentoxifylline; multicenter study; cerebral small vessel diseases; double blind study
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cerebral Small Vessel Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Antioxidants; Phosphodiesterase Inhibitors; Free Radical Scavengers; Radiation-Protective Agents; Pentoxifylline
• Other Study ID Numbers: KY2022-100-02

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No