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Docosahexaenoic Acid (DHA) for Women With Breast Cancer in the Neoadjuvant Setting (DHA-WIN)

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ClinicalTrials.gov Identifier: NCT03831178
Recruitment Status : Recruiting
First Posted : February 5, 2019
Last Update Posted : October 2, 2019
Sponsor:
Collaborators:
Canadian Institutes of Health Research (CIHR)
University of Alberta
Information provided by (Responsible Party):
AHS Cancer Control Alberta

Tracking Information
First Submitted Date  ICMJE January 14, 2019
First Posted Date  ICMJE February 5, 2019
Last Update Posted Date October 2, 2019
Actual Study Start Date  ICMJE August 28, 2019
Estimated Primary Completion Date March 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 4, 2019)
Percent change in Ki67 index from baseline to surgical excision. [ Time Frame: Pre-intervention (on the baseline biopsy) and post- intervention (at the time of surgical excision). ]
Ki67 will be measured by image analysis at baseline biopsy and at experimental end (surgical excision).
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03831178 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 4, 2019)
  • Percent of DHA in plasma phospholipids between DHA and placebo arms. [ Time Frame: At day 0 and day 20 of cycles 1 to 6 of chemotherapy (each cycle is 20 days). ]
    Changes in level of DHA incorporation in plasma phospholipids will be assessed to identify the range of DHA incorporation in this patient population. Fatty acid composition of plasma phospholipids will be measured after lipid extraction, phospholipid separation on thin layer chromatography followed by methylation and separation identification by gas-liquid chromatography.
  • Change in immune function (e.g. ability to produce IL-2 after stimulation) following DHA supplementation in combination with chemotherapy. [ Time Frame: Baseline (within 21 days before cycle 1 of chemotherapy) and at the end of chemotherapy cycle 3 (each cyle is 20 days) ]
    Systemic immune function will be assessed on stored plasma by U-PLEX Biomarker Group 1 electrochemiluminescent multiplex assays (MesoScale Discovery).
  • Age of participants and other factors affecting DHA incorporation [ Time Frame: Once participants undergo their breast surgery (within 3-6 weeks after the last chemotherapy cycle, each cycle is 20 days). ]
    If incorporation of DHA in plasma phospholipids is variable within the DHA treatment arm, possible factors that may influence incorporation (e.g. age of participants) will be explored between high and low incorporators.
  • Percent change on markers of apoptosis (e.g. caspase-3) following DHA or placebo supplementation. [ Time Frame: Once participants undergo their breast surgery (within 3-6 weeks after the last chemotherapy cycle, each cycle is 20 days). ]
    Breast tissue from participants receiving DHA or placebo will be assessed for markers of apoptosis (e.g. caspase-3) by immunohistochemistry and calculated by image analysis.
  • Pathological complete response rate [ Time Frame: Once participants undergo their breast surgery (within 3-6 weeks after the last chemotherapy cycle, each cycle is 20 days). ]
    Pathological complete response in resected breast tissue and all sampled axillary nodes will be assessed as absence of invasive cancer on haematoxylin and eosin evaluation as per standard of care.
  • Comparison of rate of chemotherapy associated grade 3 and 4 toxicities between treatment arms. [ Time Frame: At day 20 of chemotherapy cycles 1 to 6 (each cycle is 20 days). ]
    Rate of chemotherapy associated grade 3 and 4 toxicities, and chemotherapy- associated hospitalizations will be compared between DHA and placebo arms.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 4, 2019)
  • Percent of DHA in plasma phospholipids between DHA and placebo arms. [ Time Frame: At day 0 and day 20 of cycles 1 to 6 of chemotherapy (each cycle is 20 days). ]
    Changes in level of DHA incorporation in plasma phospholipids will be assessed to identify the range of DHA incorporation in this patient population. Fatty acid composition of plasma phospholipids will be measured after lipid extraction, phospholipid separation on thin layer chromatography followed by methylation and separation identification by gas-liquid chromatography.
  • Systemic immune function [ Time Frame: Baseline (within 21 days before cycle 1 of chemotherapy) and at the end of chemotherapy cycle 3 (each cyle is 20 days) ]
    Systemic immune function will be assessed on stored plasma by measuring plasma chemokines, cytokines and inflammatory markers by U-PLEX Biomarker Group 1 electrochemiluminescent multiplex assays (MesoScale Discovery) in peripheral blood samples at the end of each chemotherapy cycle
  • Age of participants and other factors affecting DHA incorporation [ Time Frame: Once participants undergo their breast surgery (within 3-6 weeks after the last chemotherapy cycle, each cycle is 20 days). ]
    If incorporation of DHA in plasma phospholipids is variable within the DHA treatment arm, possible factors that may influence incorporation (e.g. age of participants) will be explored between high and low incorporators.
  • Percent change on markers of apoptosis (e.g. caspase-3) following DHA or placebo supplementation. [ Time Frame: Once participants undergo their breast surgery (within 3-6 weeks after the last chemotherapy cycle, each cycle is 20 days). ]
    Breast tissue from participants receiving DHA or placebo will be assessed for markers of apoptosis (e.g. caspase-3) by immunohistochemistry and calculated by image analysis.
  • Pathological complete response rate [ Time Frame: Once participants undergo their breast surgery (within 3-6 weeks after the last chemotherapy cycle, each cycle is 20 days). ]
    Pathological complete response in resected breast tissue and all sampled axillary nodes will be assessed as absence of invasive cancer on haematoxylin and eosin evaluation as per standard of care.
  • Comparison of rate of chemotherapy associated grade 3 and 4 toxicities between treatment arms. [ Time Frame: At day 20 of chemotherapy cycles 1 to 6 (each cycle is 20 days). ]
    Rate of chemotherapy associated grade 3 and 4 toxicities, and chemotherapy- associated hospitalizations will be compared between DHA and placebo arms.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Docosahexaenoic Acid (DHA) for Women With Breast Cancer in the Neoadjuvant Setting
Official Title  ICMJE Docosahexaenoic Acid (DHA) for Women With Breast Cancer in the Neoadjuvant Setting
Brief Summary

Docosahexaenoic acid (DHA) is an omega-3 long chain polyunsaturated fatty acid (n-3 LCPUFA). N-3 LCPUFA are essential fatty acids in the diet. The majority of n-3 LCPUFA in the diet is alpha-linolenic acid (ALA). While DHA can be synthesized from ALA and other n-3 LCPUFA in the body, endogenous synthesis is low. Consequently, the only way to significantly increase levels of DHA in tissues is by directly consuming this fatty acid. Common sources of DHA are fatty fish, fish oil and omega-3 supplements and fortified foods.

DHA is readily incorporated into membrane phospholipids and induces changes in the properties of the cell membrane including altered fluidity; permeability and membrane transport as well as activity of membrane bound receptors and enzymes.

It is well established that changes in membrane DHA has multiple effects in the body, including modulation of neurological, immune, and cardiovascular functions. In breast cancer, DHA increases sensitivity of breast cancer cells to different chemotherapeutic agents, and in animal models of breast cancer, dietary DHA decreases tumour growth. The investigator's preclinical studies demonstrate that DHA increases efficacy of both doxorubicin and docetaxel, two agents commonly used in the adjuvant setting for breast cancer treatment. Furthermore, DHA mitigates chemotherapy induced weight loss in mice, and reduces paclitaxel toxicities in breast cancer patients, strongly indicating that DHA protects against toxicity in normal tissues. Directly relevant to this study, increased DHA in breast adipose tissue correlates with improved response to chemotherapy, and increased dietary intake of n-3 LCPUFA, including DHA, results in increased DHA incorporation in breast adipose tissue. Lastly, in advanced metastatic breast cancer, DHA supplementation correlated with improved outcomes in a subset of patients. Consequently, the Investigators hypothesize that the therapeutic index (efficacy: toxicity ratio) will be improved with the addition of DHA. In this clinical trial, the Investigators will explore the benefit of DHA supplementation in combination with neoadjuvant chemotherapy in patients with early breast cancer.

RESEARCH QUESTION & OBJECTIVES: The Investigators propose to evaluate incorporation of DHA in women with breast cancer in treatment naïve patients in combination with chemotherapy, and assess potential benefit of DHA supplementation in breast cancer patients, using change in Ki67 labeling index (marker of proliferation) as a marker of efficacy. This study will further investigate the relationship between DHA in plasma phospholipids (as a potential biomarker of tumour incorporation) and effect on systemic immune function.

METHODS: Patients directed to receive chemotherapy will receive capsules, each containing a minimum of 400 mg of DHA in the form of DHA enriched triglyceride oil or placebo (corn/soy oil blend) to be taken orally (11 capsules/day, throughout day as preferred by participant) for a total of 5 g DHA or placebo, for 12-18 weeks (84-126 days) beginning at the start of the first cycle of chemotherapy, and continued throughout 4-6 cycles of chemotherapy (3 weeks/ cycle). DHA will be discontinued 21 days after the last administration of cytotoxic chemotherapy. Tumour biopsies at baseline and post surgical removal will be assessed for Ki67 status as well as for markers of apoptosis and stem cell presence (by immunohistochemistry). Blood samples taken at baseline prior to each round of chemotherapy will be assessed for immune markers and plasma phospholipid content.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • Dietary Supplement: Docosahexaenoic acid (DHA)
    Participants will take 11 capsules of DHA oil for 12-18 weeks (84-126 days), beginning on day 1 of initial cycle of chemotherapy, and continuing for 4-6 cycles of chemotherapy prior to definitive breast surgery. Study will end when subject undergoes breast surgery.
  • Drug: Placebo oral capsule
    Participants will take 11 capsules of placebo (corn/soy oil blend) for 12-18 weeks (84-126 days), beginning on day 1 of initial cycle of chemotherapy, and continuing for 4-6 cycles of chemotherapy prior to definitive breast surgery. Study will end when subject undergoes breast surgery.
Study Arms  ICMJE
  • Experimental: DHA
    Participants will take 11 capsules per day containing DHA-enriched triglyceride oil (1 g capsules containing at least 400 mg DHA) for a total of 5 g DHA/day divided into three times daily with meals or as tolerated.
    Intervention: Dietary Supplement: Docosahexaenoic acid (DHA)
  • Placebo Comparator: Placebo
    Participants will take 11 capsules per day containing corn/soy oil blend capsules divided into three times daily with meals or as tolerated.
    Intervention: Drug: Placebo oral capsule
Publications * Newell M, Mackey JR, Bigras G, Alvarez-Camacho M, Goruk S, Ghosh S, Schmidt A, Miede D, Chisotti A, Postovit L, Baker K, Mazurak V, Courneya K, Berendt R, Dong WF, Wood G, Basi SK, Joy AA, King K, Meza-Junco J, Zhu X, Field C. Comparing docosahexaenoic acid (DHA) concomitant with neoadjuvant chemotherapy versus neoadjuvant chemotherapy alone in the treatment of breast cancer (DHA WIN): protocol of a double-blind, phase II, randomised controlled trial. BMJ Open. 2019 Sep 17;9(9):e030502. doi: 10.1136/bmjopen-2019-030502.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 4, 2019)
52
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2021
Estimated Primary Completion Date March 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Women with invasive (clinical stage I, II and III) breast cancer, for whom neoadjuvant systemic therapy with chemotherapy is recommended prior to surgery.
  2. ECOG Performance status of 0 or 1.
  3. Hematology and Biochemistry assessments (CBC and differential, PTT, PT/INR, AST, Alk Phos, Bilirubin, and Creatinine) within normal range unless determined not clinically significant by the qualified investigator.
  4. Ability to take oral medications.
  5. Adequate tissue specimen for diagnosis, biomarkers, and endpoint Ki67 assays.

Exclusion Criteria:

  1. Patients undergoing surgery prior to chemotherapy.
  2. Current or previous (within 2 months) daily use (>1 day/week) use of omega-3, fish oil, or other supplements or functional foods containing docosahexaenoic acid (at daily doses > 200 mg).
  3. Known allergy to soy or corn.
  4. Continued intake of supplements containing Vitamin C, Vitamin E or β-carotene exceeding the DRI, or other anti-oxidant supplements.
  5. Symptomatic but untreated cholelithiasis.
  6. History of deep venous thrombosis, active thrombophlebitis, pulmonary embolism, stroke, acute myocardial infarction, congestive cardiac failure, untreated hypertension, known inherited hypercoagulable disorder.
  7. Diagnosis of any other malignancy within the previous year except for adequately treated basal cell or squamous cell skin cancer.
  8. Medically documented history of a psychiatric disorder that would preclude consent
  9. Partial or complete loss of vision or diplopia, from ophthalmic vascular disease.
  10. Hypersensitivity to DHA or to any ingredient in the formulation or component of the container.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Gender Based Eligibility: Yes
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Deborah Miede, RN 780-432-8644 Deborah.Miede@albertahealthservices.ca
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03831178
Other Study ID Numbers  ICMJE IIT-0005
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: The Cross Cancer Institute and the University of Alberta encourages and supports the responsible and ethical sharing of data from clinical trials. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Time Frame: Documents will be published within 6 months after starting the trial.
Responsible Party AHS Cancer Control Alberta
Study Sponsor  ICMJE AHS Cancer Control Alberta
Collaborators  ICMJE
  • Canadian Institutes of Health Research (CIHR)
  • University of Alberta
Investigators  ICMJE
Principal Investigator: John Mackey, MD Cross Cancer Institute
PRS Account AHS Cancer Control Alberta
Verification Date September 2019

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