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Curcumin/Turmeric as a Treatment for Patients With Subdural Hematomas Recurrence (CACTIS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03845322
Recruitment Status : Recruiting
First Posted : February 19, 2019
Last Update Posted : February 19, 2019
Information provided by (Responsible Party):
University of New Mexico

Tracking Information
First Submitted Date  ICMJE February 7, 2019
First Posted Date  ICMJE February 19, 2019
Last Update Posted Date February 19, 2019
Actual Study Start Date  ICMJE December 18, 2018
Estimated Primary Completion Date September 28, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 14, 2019)
Measurements by CT of subdural hematoma volume change [ Time Frame: 6 months ]
Change of the total hematoma cavity volume compared to post-subdural drain removal to volumes of less than 80 cc in post-surgical patients
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: February 14, 2019)
Recurrence rate of cSDH with and without CC treatment [ Time Frame: 6 months ]
Change re-accumulation rate of cSDH
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: February 14, 2019)
Patient's neurological status [ Time Frame: 6 months ]
Change rate of persistent or recurrent neurological symptoms
Original Other Pre-specified Outcome Measures Same as current
Descriptive Information
Brief Title  ICMJE Curcumin/Turmeric as a Treatment for Patients With Subdural Hematomas Recurrence
Official Title  ICMJE Clinical Action of Curcumin/Turmeric in Chronic Subdural Hematoma Recurrence
Brief Summary

Our long-term objective is to evaluate the efficacy of curcumin (CC) in preventing a recurrence of chronic subdural hematoma (cSDH) following surgical evacuation. Recurrence is defined as an increase in total hematoma volume on the operated side compared to a post-operative day one CT scan with persistent or recurrent neurological symptoms. The investigators propose this pilot study to assess feasibility and obtain preliminary benefit assessment of the proposed therapeutic approach.

Objective 1: To determine if the use of CC treatment reduces the total hematoma cavity volume over a 6-month interval, compared to a post-subdural drain removal CT scan. This evaluation is expected to offer sufficient evidence for a larger definitive trial.

Objective 2: Study the effect of CC on interleukin-8 (IL-8)-induced disruption of endothelial permeability in vitro using human vascular endothelial cells.

Central hypothesis: CC treatment prevents the re-accumulation of cSDH, which may occur by inhibition of IL-8 and allowing resolution of the total hematoma cavity volume over six months.

Detailed Description

Chronic subdural hematomas (cSDH) are extra-axial fluid collections in the cranium that can result in brain compression and neurological decline. cSDH commonly occurs after traumatic brain injury (TBI); though, many times there is no history of trauma. The incidence of cSDH is expected to significantly rise, due to an increasing elderly population worldwide.This is a common and challenging neurosurgical problem due to their ability to recur requiring repeated surgical reevacuation. Repeat surgery comes with additional morbidity as well as rising costs for both patients and hospitals. Operative decompression is the treatment of choice; however, an effective therapy preventing recurrence of cSDH after surgical intervention has not yet been found. Our long-term goal is to develop a therapeutic approach focused on the prevention of cSDH recurrence after initial surgical intervention.

The current literature and our own preliminary data have demonstrated that there is local elevation of pro-inflammatory chemokines and pro-angiogenic factors within the subdural hematoma cavity of chronic subdural hematomas that are not found systemically. Interleukin-8 (IL8 or chemokine (C-X-C motif) ligand 8, CXCL8) demonstrates both pro-inflammatory and pro-angiogenic properties. Curcumin has shown to directly inhibit the production and activity of CXCL-8 (IL-8) in vitro and in vivo, as well as down regulating the activity of VEGF (vascular endothelial growth factor) and bFGF (basic fibroblast growth factor). These combined effects make CC an important anti-inflammatory and antiangiogenic molecule that has the potential to reduce the recurrence rate of chronic subdural hematomas. The investigators expect that CC will prevent/reduce persistent hemorrhage within the subdural hematoma cavity, by blocking IL-8-induced disruption of the blood vessels. Specifically, CC is expected to preserve blood vessel leakage and accumulation of blood in SDH cavity, by blocking destructive effect of IL-8 on the vascular endothelial tight junctions.

CC has demonstrated promising results in multiple studies related to brain injury including intraparenchymal hemorrhage, acute stroke, subarachnoid hemorrhage, and general injury to the blood-brain-barrier. 6 hours following intracerebral hemorrhage in adult mice, curcumin was administered in clinically relevant doses of 75-300 mg/kg. After 72 hours, there was a reduction in hematoma size, decreased vasogenic edema secondary to a less damaged blood-brain-barrier, decreased inflammatory markers, and overall improved neurological outcome. After discussing the role of T-lymphocytes in contributing inflammation and worsening neuronal injury, mouse models were used to demonstrate a suppression of T-lymphocyte infiltration in the brain after administration of curcumin. There was also a reduction in cerebral edema and improvement of neurological scores. One study administered low dose (80mg/day) curcumin to healthy middle-aged adults (40-60 years of age), when compared to a placebo group. The CC group had lower levels of plasma triglyceride, salivary amylase levels, plasma beta amyloid protein concentrations (protein responsible for Alzheimer's disease and other forms of intracerebral hemorrhage), and other beneficial health effects.

It was recently detected that combining CC with piperine (black pepper extract, also known as peperine or BioPerine), a known inhibitor of hepatic and intestinal glucuronidation, enhances the serum concentration, extent of absorption and bioavailability of CC in both rats and humans. Therefore, CC supplement is now used in combination with the black pepper extract. The average amount of pepper consumed by a person during a day in the United States is 359 mg, which translates to 18-32 mg of piperine a day. Furthermore, rat trials show a daily intake of 5 to 20 times the average daily dose of humans produced no clinical symptoms. Studies on acute, subacute, and chronic piperine toxicity show no abnormalities or clinical symptomatology, or significant blood chemistry data in laboratory animals. Black pepper extract has a high degree of safety being used nutritionally. The amount of piperine that is formulated in the curcumin capsules is several thousand times less than the LD50 (lethal dose 50) established in mice and rats. Our capsule contains 270 mg of pure curcuminoids (curcumin) and 3mg of black pepper extract. The recommended serving size is 3 capsules a day. Therefore, the patients will receive 810mg of pure curcumin and 9mg of black pepper extract (peperine) per day, which is less than the average amount of pepper consumed by a person daily in the United States.

This is a double-blinded, randomized placebo-controlled pilot study. A total of 48 subjects will be recruited in this study. 24 patients will receive placebo pills, and 24 will receive Curcumin (CC) pills. Patients who have symptomatic unilateral chronic subdural hematomas, with no acute component and do not meet the exclusion criteria, will be evaluated. At the time of consent for evacuation of the subdural hematoma, patients will also be consented for this trial by the research team. Participants will be instructed that they will be randomized to either the placebo group or the curcumin group. Participants will take one capsule three times a day for a maximum of 60 days. Participants will undergo standard postoperative care in regard to imaging and clinical follow-up. Patients will begin taking placebo or CC within 24 hours post-operatively and able to take oral medication. It will then be continued three times a day (TID).

This is a single center study that will take place at the University of New Mexico Hospital (UNMH). New patients admitted directly to the UNM Neurosciences Intensive Care Unit (NSICU) as a transfer from an outside hospital as well as patients admitted directly through the UNM (University of New Mexico) Emergency Department (ED), with subdural hematomas will be identified and recruited as potential subjects. All surgical operations will take place in the main operating room (OR) at UNMH. The perioperative care of the enrolled patients, as well as the non-surgically managed patients will take place both in the NSICU as well as the Neurosurgical step-down unit. Once patients have been discharged from the hospital, all follow-up appointments will take place in the Clinical Neurosciences Center located adjacent to UNMH. Patients will follow-up in the subdural clinic, staffed by Dr. Howard Yonas, Principal Investigator.

Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
This is an experimental study, each consented subject will be instructed that he/she will be randomized to either the placebo group or the curcumin group.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
This is a double-blinded, randomized placebo-controlled pilot study. The patients, neurosurgeons, nurses and clinical coordinators will be blinded except for the research pharmacists who will keep a key linking a code # on a bottle handed to the clinical coordinator and the patient's medical record number (MRN #). The pill bottles handed to the clinical coordinator will be identical for placebo and CC.
Primary Purpose: Treatment
Condition  ICMJE Hematoma, Subdural, Chronic
Intervention  ICMJE
  • Drug: Curcumin Pill
    Curcumin (turmeric extract), over the counter supplement (1 capsule/three times a day). According to the Company, each capsule contains: 270 mg of pure curcuminoids (curcumin) and 3 mg of black pepper extract. Recommended serving size is 3 capsules per day in total, the patients will receive 810 mg of pure curcumin and 9 mg of black pepper extract (peperine/BioPerine) per day.
  • Drug: Placebo pills
    The placebo pill is a vegetarian cellulose capsule, with cellulose powder inside. The composition is cellulose and magnesium stearate.
Study Arms  ICMJE
  • Experimental: Curcumin pills group
    24 Patient will receive Curcumin (CC) pills, within 24 hours post-operatively (as long as they are able to take oral medication). It will then be continued TID
    Intervention: Drug: Curcumin Pill
  • Placebo Comparator: Placebo group
    24 Patient will receive Placebo pills, within 24 hours post-operatively (as long as they are able to take oral medication. It will then be continued TID.
    Intervention: Drug: Placebo pills
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 14, 2019)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 28, 2022
Estimated Primary Completion Date September 28, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Chronic subdural hematoma (cSDH)
  2. Age of 18 years old or older
  3. Unilateral cSDH with no other intracranial injuries

    o Membranes with minimal hemorrhage may be included but no clear acute component should be evident

  4. Subdural volume less than 115cc
  6. Patient or patient's power of attorney (POA) is available to sign consent
  7. Patient undergoes surgical evacuation of cSDH-

Exclusion Criteria:

  1. Age less than 18 years old
  2. Bilateral subdural hematomas
  3. Subdural volume less than 115cc
  4. Acute subdural hematoma
  5. Patient does not undergo surgical evacuation
  6. Other evidence of intracranial injury (i.e. epidural hematoma, intraparenchymal hemorrhage, skull fractures, subarachnoid hemorrhage, hydrocephalus)
  7. Patient's family not available for consent and requires emergent surgical evacuation
  8. Previous intracranial surgery
  9. Recent head trauma (less than1 week)
  10. Use of anti-coagulation (i.e. Coumadin, Heparin, Apixaban, and Rivaroxaban) or antiplatelets (Plavix) drugs, with the exception of Aspirin
  11. Known coagulopathy disorders
  12. Positive urine or serum pregnancy test in pre-menopausal female subjects, without a documented history of surgical sterilization; or currently breastfeeding (Since the nuclear group in an older population, the pregnancy test will be made in exceptional cases).
  13. Allergy to curcumin or turmeric.
  14. Allergy to black pepper
  15. Markwalder Grading Scale Score: 3-4
  16. Baseline dementia (for more than 6 months). Adult who cognitively impaired for more than 6 months will be excluded from the study, since this impairment might be due to other reasons than cSDH, such as dementia or cognitive impairment.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Devon A Lara, BS 505.925.4392
Contact: Laila M Mohammad, MD 505.272.6094
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03845322
Other Study ID Numbers  ICMJE 17-348
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of New Mexico
Study Sponsor  ICMJE University of New Mexico
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Howard Yonas, MD UNM
PRS Account University of New Mexico
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP