Clinical trial NCT01178892: MsFLASH-02: Interventions for Relief of Menopausal Symptoms: A 3-by-2 Factorial Design Examining Yoga, Exercise, and Omega-3 Supplementation
Official title: MsFLASH-02: Interventions for Relief of Menopausal Symptoms: A 3-by-2 Factorial Design Examining Yoga, Exercise, and Omega-3 Supplementation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Hot Flashes
Menopause
Vasomotor Symptoms
Keywords: Hot Flashes
Menopause
Vasomotor symptoms
Yoga
Exercise
Omega-3
Fish oil
Lead sponsor: Fred Hutchinson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: National Center for Complementary and Integrative Health (NCCIH)
name: Office of Research on Women's Health (ORWH)
name: Nordic Naturals
First posted: 2010-08-10
Enrollment: 355
Sex: FEMALE
Minimum age (years): 40
Maximum age (years): 62
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: This study is the second clinical trial to be conducted by the Menopause Strategies - Finding Lasting Answers for Symptoms and Health (MsFLASH) research network, a group of investigators conducting clinical trials designed to find new ways to alleviate the most common, bothersome symptoms of the menopausal transition.

In this twelve-week clinical trial, 374 women aged 40-62 who are in the late menopausal transition or postmenopausal and experiencing bothersome hot flashes will be randomized to one of three behavioral intervention groups: yoga, exercise, or usual activity. All women will simultaneously be randomized to receive omega-3 supplementation or a matching placebo.

The primary aims of this trial are to compare the magnitude of changes in perceived, self-reported frequency and bother of vasomotor symptoms (VMS) before and after the intervention between yoga and the usual activity comparison group, between exercise and the usual activity comparison group, and between omega-3 fatty acid supplementation or placebo. The hypotheses to be tested are:

1. Women assigned to yoga will report lower frequency and less VMS bother than women assigned to the usual activity group at the end of a 12-week study period.
2. Women assigned to aerobic exercise at moderate-vigorous intensity will report lower frequency and less VMS bother than women assigned to the usual activity group at the end of a 12-week study period.
3. Women assigned to omega-3 fatty acid supplementation will report lower frequency and less VMS bother than women assigned to the placebo group at the end of a 12-week study period.

The omega-3 component of the study is double-blinded. For yoga, exercise, and usual activity, the outcomes assessors are blinded to the randomization assignments.

Detailed description: Over 33 million U.S. women will transition through menopause in the next decade. Among women with natural menopause, the transition typically lasts four years, with a mean age at menopause of 51 years. Menstrual irregularity (90%) and vasomotor symptoms (VMS) (80%) are the most common symptoms associated with the transition. Hormone therapy has been the gold standard for treating VMS symptoms against which other therapies are measured. However, resistance to hormone therapy use due to its risks and side effects continues to fuel the search for safer alternatives.

This research study will evaluate three low risk interventions (yoga, exercise, and omega-3 supplements) compared to either a usual activity group or a placebo pill. This factorial design is motivated by the desire to have all women receive some intervention. Neither comparisons between yoga and exercise nor tests of interaction between the behavioral interventions (yoga, exercise, usual activity) and omega-3 motivated this design. However, these aspects can be examined in secondary analyses in a more rigorous fashion through this design than would be permitted by separate trials.

Eligibility criteria: Inclusion Criteria:

* Females aged 40-62 years.
* Menopausal, including:

  * Women who have had a bi-lateral oophorectomy;
  * Women with a uterus who have skipped 2 or more menstrual cycles with an amenorrhea interval of 60 or more days in the past 12 months;
  * Women without a uterus and who still have one or both ovaries, with FSH level greater than 20 mIU/mL and estradiol less than or equal to 50 pg/mL;
  * Women who are using the Mirena IUD or who have had an endometrial ablation and who still have one or both ovaries, with FSH level greater than 20 mIU/mL and estradiol less than or equal to 50 pg/mL.
* Having bothersome hot flashes and/or night sweats.
* In general good health as determined by medical history, blood pressure, and heart rate:

  * Absence of uncontrolled hypertension greater than 160/100;
  * Resting heart rate less than 110 beats per minute;.
  * No history of myocardial infarction, angina, or cerebrovascular events;.
  * No history of liver, renal disease, or uncontrolled seizure disorder.
  * Absence of uncontrolled metabolic disease (such as diabetes) and absence of current infectious disease (such as acute symptoms of mononucleosis) that would put staff and other participants at risk.
* Signed informed consent.

Exclusion Criteria:

* Use of hormone therapy or hormonal contraceptives (with the exception of the Mirena IUD) during the 2 months before enrollment. Vaginal postmenopausal estrogens allowed, with the exception of vaginal creams used more than 3 times a week.
* Use of any other therapy that is taken specifically for hot flashes, including prescription, over-the-counter, or herbal therapies, in the past month.
* Any current severe or unstable medical illness.
* Body mass index (BMI) of 37 or higher, based on measured height and weight.
* Severe uncorrected hearing or vision problems.
* Current, regular use of anti-coagulants 3 or more times per week, e.g. Coumadin, Heparin, Clopidogrel, aspirin at full dose (due to possible omega-3 supplement interaction).
* Drug or alcohol abuse in the past 1 year.
* Major severe depressive episode in the past 3 months.
* Diagnosis of psychosis or psychotic disorder.
* Pregnancy, intending pregnancy, or breastfeeding.
* Current participation in another drug trial or intervention study.
* Inability or unwillingness to complete the study procedures or interventions.
* Physical limitations that limit the ability to participate in yoga or exercise, for example:

  * Limited mobility (paralyzed, cannot walk 2 blocks);
  * Back problems (severe spine abnormality, sciatica, prior back surgery, spine fracture in the past 3 months);
  * musculoskeletal problems that limit the ability to walk on a treadmill or ride a stationary bicycle;
* Presence of any absolute contraindications to exercise testing and training, as defined by the American College of Sports Medicine.
* Practiced or attended any of the following in the prior 3 months:

  * Yoga, tai chi, qi gong, or meditation more than one time per week on average;
  * Aerobic exercise (more than 30 minutes a day on at least 3 days a week);
  * Inability to achieve 85% of heart rate reserve (HRR; the difference between maximum heart rate and resting heart rate) on graded exercise treadmill test.
* Severe allergy to soy (defined as life-threatening reaction to soy that would require medical intervention).
* Allergy or sensitivity to fish.
* Currently eating 4 or more servings of fish per week.
* Currently taking an omega-3 fish oil supplement more than twice per week in the past 4 weeks and unwilling to stop for 12 weeks. Interest women can stop all omega-3 supplements and reevaluate eligibility 4 weeks after stopping the omega-3 supplements.

Primary outcomes:
measure: Frequency and bother of hot flashes measured by self-report diaries.
timeFrame: 12 weeks
Secondary outcomes:
measure: Frequency of hot flashes measured by objective biological marker.
timeFrame: 12 weeks
measure: Anxiety, health- and menopause-related quality of life, depressed mood, and sleep (subjective by diaries and objective by sleep watch worn on wrist).
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Oakland
country: United States
facility: Kaiser Division of Research
state: California
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Seattle
country: United States
facility: Group Health Research Institute
state: Washington
Study officials:
affiliation: Fred Hutchinson Cancer Center
name: Andrea Z. LaCroix, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Fred Hutchinson Cancer Center
name: Garnet Anderson, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Washington/Group Health Research Institute
name: Susan D Reed, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Group Health Research Institute
name: Katherine M Newton, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Kaiser Permanente
name: Bette Caan, DrPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Kaiser Permanente
name: Barbara Sternfeld, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Indiana University School of Medicine
name: Janet Carpenter, PhD, RN, FAAN
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusetts General Hospital
name: Hadine Joffee, MD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusetts General Hospital
name: Lee Cohen, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sternfeld B, LaCroix A, Caan BJ, Dunn AL, Newton KM, Reed SD, Guthrie KA, Booth-LaForce C, Sherman KJ, Cohen L, Freeman MP, Carpenter JS, Hunt JR, Roberts M, Ensrud KE. Design and methods of a multi-site, multi-behavioral treatment trial for menopausal symptoms: the MsFLASH experience. Contemp Clin Trials. 2013 May;35(1):25-34. doi: 10.1016/j.cct.2013.02.009. Epub 2013 Feb 24.
citation: Diem SJ, LaCroix AZ, Reed SD, Larson JC, Newton KM, Ensrud KE, Woods NF, Guthrie KA. Effects of pharmacologic and nonpharmacologic interventions on menopause-related quality of life: a pooled analysis of individual participant data from four MsFLASH trials. Menopause. 2020 Oct;27(10):1126-1136. doi: 10.1097/GME.0000000000001597.
citation: Guthrie KA, Larson JC, Ensrud KE, Anderson GL, Carpenter JS, Freeman EW, Joffe H, LaCroix AZ, Manson JE, Morin CM, Newton KM, Otte J, Reed SD, McCurry SM. Effects of Pharmacologic and Nonpharmacologic Interventions on Insomnia Symptoms and Self-reported Sleep Quality in Women With Hot Flashes: A Pooled Analysis of Individual Participant Data From Four MsFLASH Trials. Sleep. 2018 Jan 1;41(1):zsx190. doi: 10.1093/sleep/zsx190.
citation: Jones SM, Guthrie KA, LaCroix AZ, Sternfeld B, Landis CA, Reed SD, Dunn A, Caan B, Cohen LS, Hunt J, Newton KM. Is heart rate variability associated with frequency and intensity of vasomotor symptoms among healthy perimenopausal and postmenopausal women? Clin Auton Res. 2016 Feb;26(1):7-13. doi: 10.1007/s10286-015-0322-x. Epub 2015 Dec 21.
citation: Guthrie KA, LaCroix AZ, Ensrud KE, Joffe H, Newton KM, Reed SD, Caan B, Carpenter JS, Cohen LS, Freeman EW, Larson JC, Manson JE, Rexrode K, Skaar TC, Sternfeld B, Anderson GL. Pooled Analysis of Six Pharmacologic and Nonpharmacologic Interventions for Vasomotor Symptoms. Obstet Gynecol. 2015 Aug;126(2):413-422. doi: 10.1097/AOG.0000000000000927.
citation: Newton KM, Reed SD, Guthrie KA, Sherman KJ, Booth-LaForce C, Caan B, Sternfeld B, Carpenter JS, Learman LA, Freeman EW, Cohen LS, Joffe H, Anderson GL, Larson JC, Hunt JR, Ensrud KE, LaCroix AZ. Efficacy of yoga for vasomotor symptoms: a randomized controlled trial. Menopause. 2014 Apr;21(4):339-46. doi: 10.1097/GME.0b013e31829e4baa.
citation: Cohen LS, Joffe H, Guthrie KA, Ensrud KE, Freeman M, Carpenter JS, Learman LA, Newton KM, Reed SD, Manson JE, Sternfeld B, Caan B, Freeman EW, LaCroix AZ, Tinker LF, Booth-Laforce C, Larson JC, Anderson GL. Efficacy of omega-3 for vasomotor symptoms treatment: a randomized controlled trial. Menopause. 2014 Apr;21(4):347-54. doi: 10.1097/GME.0b013e31829e40b8.
citation: Sternfeld B, Guthrie KA, Ensrud KE, LaCroix AZ, Larson JC, Dunn AL, Anderson GL, Seguin RA, Carpenter JS, Newton KM, Reed SD, Freeman EW, Cohen LS, Joffe H, Roberts M, Caan BJ. Efficacy of exercise for menopausal symptoms: a randomized controlled trial. Menopause. 2014 Apr;21(4):330-8. doi: 10.1097/GME.0b013e31829e4089.
citation: Newton KM, Carpenter JS, Guthrie KA, Anderson GL, Caan B, Cohen LS, Ensrud KE, Freeman EW, Joffe H, Sternfeld B, Reed SD, Sherman S, Sammel MD, Kroenke K, Larson JC, Lacroix AZ. Methods for the design of vasomotor symptom trials: the menopausal strategies: finding lasting answers to symptoms and health network. Menopause. 2014 Jan;21(1):45-58. doi: 10.1097/GME.0b013e31829337a4.