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NCT07254429·Phase 2·INTERVENTIONAL

COMPASS - COpenhagen MenoPAuSe Study

TriptorelinOtherRecruiting

Status

Recruiting

Phase

Phase 2

Enrollment

192

Locations

1

Results

Not posted

Publications

12

Study summary

What the protocol is testing.

During menopause, estrogen levels drop while the level of another hormone - LH (luteinizing hormone) substantially increases. This hormonal shift is linked to bone Loss and other complications. Estrogen therapy can help, but some women avoid it due to the increased risk of blood clots and cancer. This project will investigate whether blocking LH could offer a safe alternative to alleviate symptoms and complications of menopause since it is known from previous research that high LH levels contribute to both bone deterioration and metabolic issues. The goal is to explore new treatment options that can improve health and quality of life for women both during and after menopause. This randomized clinical trial is a single center, sponsor-investigator-initiated single-blinded 8 weeks clinical trial with four parallel groups comparing the effect of an gonadotropin releasing hormone(GnRH)-analog with placebo, and with two additional arms given estrogen or testosterone on change on bone health in postmenopausal women with moderate-to-severe symptoms.

Full detailed description

The hormonal changes occurring in perimenopause and menopause exert multiple effects on several organs and the accompanied symptoms can be very distressing and impair quality of life. Vasomotor symptoms (VMS) defined as hot flashes and sweating are the most frequent and bothersome symptoms of menopause and are experienced by up to 80% of women. Additionally, in the Western world, 66% of postmenopausal women are obese and 54% have osteoporosis. Along with obesity comes a wide variety of health issues such as type 2 diabetes, metabolic syndrome, and atherosclerosis, which can lead to cardiovascular disease. Osteoporosis is a huge economic cost for society, it impairs quality of life and vertebral and hip fractures are associated with increased mortality. Postmenopausal symptoms and complications take a large toll on both the physical and mental well-being of women and are a huge cost to society. Menopausal Hormonal Therapy (MHT) with estrogen and gestagen is used by many women as it alleviates symptoms and reduces the risk of osteoporosis and cardiovascular disease. However, due to the increased risk of breast cancer and venous thromboembolism, some women refuse MHT and there is an ongoing search for new treatments. The newly approved Veoza® (Fezolinetant) is also approved and on the marked, but only targets VMS and not menopausal complications, but can be a treatment option, if the woman can or will not have MHT. Menopause is characterized by low circulating estrogen, but also by very high levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and these hormonal changes are linked with increased bone resorption and weight gain. Despite the high LH in menopause, LH pulses occur simultaneously with hot flashes also in postmenopausal women, and LH may be involved in the events. In a clinical study 10 postmenopausal women with severe VMS were given a GnRH antagonist cetrorelix 250 μg two times a day in 6 weeks. They found a significant decrease in VMS symptoms. Postmenopausal women experience a decline in core temperature, which we suggest is due to LH actions on brown and white fat cells leading to less heat generation, beta-oxidation, and more storing of fat. Furthermore, LH appears to be a rapid and potent inducer of renal calcium excretion, which induces a secondary and persistent increase in parathyroid hormone (PTH) that mobilizes calcium from the skeleton. The LH-induced calcium excretion occurs several hours before the subsequent changes in sex steroids, particularly estrogen, which indicates a direct effect of LH that can lead to increased bone resorption and eventually osteoporosis. This may be of great importance during the perimenopause/early phase of menopause, where the decrease in bone mineral density and increase in visceral adiposity is high concurrent with serum LH increasing dramatically, while serum estrogen is still not greatly reduced. The investigators propose to investigate if lowering LH using a gonadotropin releasing hormone (GnRH) analog against placebo can improve bone markers and secondarily reduce the frequency and severity of VMS in postmenopausal women with a direct comparison to estrogen - the gold standard treatment of women in menopause, and testosterone in the same RCT. The main aim of the study is to show that by targeting LH the investigators can change bone markers and maybe even combat hot flashes and night sweats (VMS) in postmenopausal women. For important biological knowledge purpose, the investigators also investigate the 2 additional treatment arms with estradiol and testosterone to compare the effect against the current gold standard treatment option (estradiol) and to testosterone, which is a common supplement to postmenopausal women off-label. A study by Glaser et al. effectively documents that testosterone can improve most common post-menopausal symptoms. Sample size calculation and statistics Previous studies have shown that CTX in postmenopausal women is usually between 0.44 ng/mL with a standard diviation on SD 0.2. The sample size is calculated based on a direct comparison between GnRH analog (pamorelin) and placebo on the primary outcome 'change in bone markers' (delta CTX between pamorelin and placebo), using a power of 80% and alpha of 0.05 leads to 44 participants in each group, and the investigators would be able to detect a change in CTX on 30 %. The calculations is based on only two arms, however for comparison reasons the investigators will include two extra arms with estradiol/testosterone and patients will be allocated 1:1:1:1 leading to a total sample size of 176 participants. Our design and analysis principles rely on the intent-to-treat (ITT) approach; the investigators strive to evaluate and include all randomized participants in the primary analysis, regardless of adherence to treatment assignment or protocol requirements. The investigators estimate to screen 250 to include 192 to be randomized and 176 to complete the study leaving 16 patients for dropout (9%). The design enables us to investigate multiple secondary outcomes where the primary comparison will be between GnRH analog treatment and placebo. The study is not powered to show significant differences between placebo and GnRH treatment for most secondary endpoints and should be considered as a pilot placebo-controlled intervention study for these outcomes. T-tests will be used for the primary endpoint, while Nonresponder imputation will be used for missing response data. Change in mean frequency and severity of VMS per 24 hours will be analyzed for each week using a mixed effect model for repeated measures, with change from baseline as the dependent variable and treatment group, visit, and smoking status as factors and baseline measurement as a covariate, as well as interaction of treatment by week and an interaction of baseline measurement by week. Predefined subgroups: Efficacy in patients with detectable versus undetectable serum hCG, high versus low LH at baseline, low versus high BMI, low versus high BMD, low versus high fat %. Ethics and side effects All patients will be informed of potential adverse effects, and that they can leave the trial at any point without any consequences. GnRH-analogs have been proven safe in numerous randomized clinical trials (RCT) and have for many years been involved in the treatment of several groups including children with precocious puberty, transgender hormone treatment, and as part of in vitro fertilization. MHT have been tested in previously large RCT, where an increased risk of breast cancer and thromboembolic events have been detected. It is estimated that the risk of breast cancer increases with 0.5 % after 5 years of hormonal treatment. It is therefore regarded safe for participant in this trial to be treated with estrogen in 8 weeks however women with increased risk of cancer or thromboembolic events will be excluded. All side effects will be closely monitored and reported. The study will be approved by the regional ethical committee, conducted in compliance with The Declaration of Helsinki, registered on clinicaltrial.gov, and monitored by the GCP unit of Copenhagen University Hospitals in compliance with International Conference on Harmonisation.

Interventions

Treatment arms and agents.

DRUG

Triptorelin 11.25 mg

Pamorelin 11.25 mg intramuscular injection once

DRUG

Sodium Chloride 0.9%

Saline intramuscular injection once

DRUG

Estradiol (E2)

Estreva gel 1.5 mg daily

DRUG

Testosterone

Tostran gel 10 mg every other day

DRUG

Placebo gel

Placebo gel every day or every other day

Timeline

From registration to results.

  1. First posted

    Nov 28, 2025

  2. Study start

    Oct 2, 2025

  3. Primary completion

    Dec 2027

  4. Study completion

    May 2028

  5. Results posted

    Not reported

  6. Registry updated

    Mar 2, 2026

Outcomes

What the study measures.

Primary outcomes

Change in bone remodeling from baseline to week 8.

Time frame · From baseline to week 8

Change in bone remodeling defined by change in bone marker (ΔCTX) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1. GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2. Combined analysis of all 4 arms of the RCT 3. GnRH analog and estradiol 4. GnRH analog and testosterone 5. Estradiol and placebo 6. Testosterone and placebo 7. Estradiol and testosterone

Change in bone remodeling from baseline to week 8.

Time frame · From baseline to week 8

Change in bone remodeling defined by change in bone marker (ΔP1NP) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone

Change in bone remodeling from baseline to week 8

Time frame · From baseline to week 8

Change in bone remodeling defined by change in bone marker-ratios (ΔCTX/ΔP1NP, and ΔBBI) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone

Secondary outcomes

Change in serum levels of Hypothalamic-Pituitary-Adrenal (HPA) axis from baseline to week 8

Time frame · Baseline to week 8

Change in serum levels of Hypothalamic-Pituitary-Adrenal (HPA) axis from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone

Change in serum levels of Hypothalamic-Pituitary-Gonadal (HPG) axis from baseline to week 8

Time frame · Baseline to week 8

Change in serum levels of Hypothalamic-Pituitary-Gonadal (HPG) axis from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone

Change in serum levels of Hypothalamic-Pituitary-Thyroid (HPT) axis from baseline to week 8

Time frame · Baseline to week 8

Change in serum levels of Hypothalamic-Pituitary-Thyroid (HPT) axis from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone

Change in quality of life evaluated with MENQOL-1 from baseline to week 8

Time frame · Baseline to week 8

Change in quality of life evaluated with The Menopause-specific Quality of Life (MENQOL) Questionnaire from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. MENQOL is ranging from 0 (asymptomatic woman) to 232 (extremely bothered).

Change in sexual function evaluated with female sexual function index from baseline to week 8

Time frame · Baseline to week 8

Change in sexual function evaluated with female sexual function index (FSFI) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. The FSFI use a 5-point Likert scale with higher scores indicating greater levels of sexual functioning on the respective item. The possible range is 2-36.

Change in sexual function evaluated with female sexual distress scale-revised from baseline to week 8

Time frame · Baseline to week 8

Change in sexual function evaluated with female sexual distress scale-revised (FSDS-R) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. FSDS-R has a total score ranging from 0 to 52, with higher scores indicating more sexually related distress.

Change in depressive symptoms evaluated by MDI from baseline to week 8

Time frame · Baseline to week 8

Change in depressive symptoms evaluated by Major Depression Inventory (MDI) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. Total score between 0 (no depression) to 50 (maximum depressed).

Change in depressive symptoms evaluated by CES-D from baseline to week 8

Time frame · Baseline to week 8

Description: Change in depressive symptoms evaluated by Center for Epidemiologic Studies Depression Scale (CES-D) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. Possible range of scores is zero to 60, with the higher scores indicating the presence of more symptomatology.

Change in anxiety symptoms evaluated by GAD-7 from baseline to week 8

Time frame · Baseline to week 8

Change in anxiety symptoms evaluated by General Anxiety Disorder-7 (GAD-7) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. Scores ranges from 0 (No anxiety) to 21 (severe anxiety).

Change in The Mean Patient-reported Outcomes Measurement Information System Sleep Disturbance - Short Form 8b (PROMIS SD SF 8b) from baseline to week 8

Time frame · Baseline to week 8

Change in The Mean Patient-reported Outcomes Measurement Information System Sleep Disturbance - Short Form 8b (PROMIS SD SF 8b) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. Scores ranges from 8-40. Higher scores indicate more severe sleep disturbance.

Eligibility

Who can take part.

Minimum age
40 Years
Maximum age
65 Years
Sex
FEMALE
Healthy volunteers
No

Inclusion Criteria: * Women \>40 years and ≤65 at screening visit * A body mass index between 18-35 * Confirmed menopause * Method 1 * Spontaneous amenorrhea for ≥12 consecutive months * Negative urine hCG test * Method 2 * Spontaneous amenorrhea for ≥6 months * FSH \>30 mIU/L * Negative urine hCG test * Moderate to severe vasomotor symptoms (VMS) * Within the 7 days prior to randomization, participants must report ≥ 14 moderate to severe VMS per week Exclusion Criteria: * Current or previous hormone replacement therapy (HRT) * Vaginal estradiol/vaginal inserts (e.g. Vagifem®) can be used, but will have to be pause 2 weeks prior to randomization and throughout the study period * Menopausal Hormone Therapy (MHT) can be used by participants, but must be paused 6 weeks prior to inclusion. * Current or previous cancer diagnosis * Except for basal cell carcinoma * Known BRCA gene mutation * Current hyperthyroid disease * Osteoporosis * Major psychiatric diagnosis including ongoing medication e.g. selective serotonin re-uptake inhibitors (SSRIs) * Known prolonged QT or other known clinically significant abnormal ECG, including taking medication that can prolong QT interval (e.g. sotalol, dronedarone, amiodarone, methadone, and several antipsychotic drugs) * Previous myocardial infarction or heart failure * Previous thromboembolic event * The use of opioids, anticoagulating treatment or unwilling to pause fish oil/Omega-3 supplements 3 days prior visit 1 and 3 * Current alcohol or drug abuse * Hypertension treated with more than two drugs * Severe history of allergy, hypersensitivity, or intolerance to drugs * Moderate to severe liver and kidney disease (eGFR \<60 mL/min) * Diagnosed with type 1 or 2 diabetes * Chronic diseases requiring immunomodulatory treatments such as rheumatoid arthritis, inflammatory bowel disease, and vasculitis etc. * Known uterine fibroids, Endometriosis, Systemic lupus erythematosus (SLE), otosclerosis, severe migraine or sleep apnea * Known Epilepsy or previous seizures or convulsive disorder

Study locations

1 registered sites.

Denmark. Showing up to 24 locations stored in the fast local snapshot.

Division of Translational Endocrinology, Department of Endocrinology and Internal Medicine, Copenhagen University Hospital Herlev.

Herlev, Denmark

Publications

Results and literature.

PMID 10652955 ↗Rosen HN, Moses AC, Garber J, Iloputaife ID, Ross DS, Lee SL, Greenspan SL. Serum CTX: a new marker of bone resorption that shows treatment effect more often than other markers because of low coefficient of variability and large changes with bisphosphonate therapy. Calcif Tissue Int. 2000 Feb;66(2):100-3. doi: 10.1007/pl00005830.PMID 39243386 ↗Langdahl B, Chung YS, Plebanski R, Czerwinski E, Dokoupilova E, Supronik J, Rosa J, Mydlak A, Rowinska-Osuch A, Baek KH, Urboniene A, Mordaka R, Ahn S, Rho YH, Ban J, Eastell R. Proposed Denosumab Biosimilar SB16 vs Reference Denosumab in Postmenopausal Osteoporosis: Phase 3 Results Up to Month 12. J Clin Endocrinol Metab. 2025 May 19;110(6):e1951-e1958. doi: 10.1210/clinem/dgae611.PMID 37084998 ↗Kline GA, Holmes DT. Bone turnover markers for assessment of anti-resorptive effect in clinical practice: A good idea meets the problem of measurement uncertainty. Clin Biochem. 2023 Jun;116:100-104. doi: 10.1016/j.clinbiochem.2023.04.007. Epub 2023 Apr 19.PMID 36096182 ↗Brown JP, Don-Wauchope A, Douville P, Albert C, Vasikaran SD. Current use of bone turnover markers in the management of osteoporosis. Clin Biochem. 2022 Nov-Dec;109-110:1-10. doi: 10.1016/j.clinbiochem.2022.09.002. Epub 2022 Sep 9.PMID 34059108 ↗Migliorini F, Maffulli N, Spiezia F, Peretti GM, Tingart M, Giorgino R. Potential of biomarkers during pharmacological therapy setting for postmenopausal osteoporosis: a systematic review. J Orthop Surg Res. 2021 May 31;16(1):351. doi: 10.1186/s13018-021-02497-0.PMID 31991007 ↗Everts-Graber J, Reichenbach S, Ziswiler HR, Studer U, Lehmann T. A Single Infusion of Zoledronate in Postmenopausal Women Following Denosumab Discontinuation Results in Partial Conservation of Bone Mass Gains. J Bone Miner Res. 2020 Jul;35(7):1207-1215. doi: 10.1002/jbmr.3962. Epub 2020 Feb 11.PMID 28789921 ↗Tsourdi E, Langdahl B, Cohen-Solal M, Aubry-Rozier B, Eriksen EF, Guanabens N, Obermayer-Pietsch B, Ralston SH, Eastell R, Zillikens MC. Discontinuation of Denosumab therapy for osteoporosis: A systematic review and position statement by ECTS. Bone. 2017 Dec;105:11-17. doi: 10.1016/j.bone.2017.08.003. Epub 2017 Aug 5.PMID 19671655 ↗Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009 Aug 20;361(8):756-65. doi: 10.1056/NEJMoa0809493. Epub 2009 Aug 11.PMID 22250775 ↗Yu L, Buysse DJ, Germain A, Moul DE, Stover A, Dodds NE, Johnston KL, Pilkonis PA. Development of short forms from the PROMIS sleep disturbance and Sleep-Related Impairment item banks. Behav Sleep Med. 2011 Dec 28;10(1):6-24. doi: 10.1080/15402002.2012.636266.PMID 16717171 ↗Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006 May 22;166(10):1092-7. doi: 10.1001/archinte.166.10.1092.PMID 1003364 ↗Greene JG. A factor analytic study of climacteric symptoms. J Psychosom Res. 1976;20(5):425-30. doi: 10.1016/0022-3999(76)90005-2. No abstract available.PMID 12082670 ↗Derogatis LR, Rosen R, Leiblum S, Burnett A, Heiman J. The Female Sexual Distress Scale (FSDS): initial validation of a standardized scale for assessment of sexually related personal distress in women. J Sex Marital Ther. 2002 Jul-Sep;28(4):317-30. doi: 10.1080/00926230290001448.

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