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The goal of this pilot trial is to learn if a novel non-hormonal treatment, metformin hydrochloride, works to treat pelvic pain in young women with endometriosis. The main questions it aims to answer are:
Researchers will compare metformin to a placebo (a look-alike substance that contains no drug) to see if metformin works to treat pelvic pain.
Participants will:
Endometriosis is a chronic illness defined by the presence of endometrial glands and stroma outside the uterine lining. While prevalence estimates vary depending on the population studied, endometriosis is thought to affect approximately one in ten reproductive aged women, up to 50% of women with infertility, and up to 70% of adolescents with chronic pelvic pain. Over 10 million women in the United States have endometriosis and incur significantly higher direct and indirect healthcare costs than those without. Annual health care costs are estimated at $100 billion in the United States alone. While the majority of patients report the onset of endometriosis symptoms during adolescence, delays in diagnosis are common and range from 7 to 12 years. During these delays, women may suffer from debilitating symptoms interfering with school and social activities, and commonly experience reduced health-related quality of life and work productivity. When left untreated, endometriosis can progress significantly in over 50% of patients and result in a higher stage of disease. Therefore, timely intervention and maintenance of therapy is critical for preventing the progression of disease and patient burden.
Therapeutic options for endometriosis include surgical and medical management. Because surgery is not curative, long-term medical therapy is often advised to prevent recurrence of symptoms and retard the progression of disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for endometriosis-related pain but do not remove or decrease deposits of ectopic endometrium. Hormonal therapies are the mainstay of medical therapy as they can inhibit prostaglandin production that contributes to pain, and cause decidualization and atrophy of ectopic endometrial tissue. Unfortunately, hormonal treatments have varied degrees of success and no data support one treatment over another. Additionally, the treatment choice may be limited to medication side effects, availability, costs, and contraceptive needs. Hormonal treatments do not cure endometriosis; 11-19% of women may not experience any relief with medical therapy, and up to a third of women experience recurrence of pain symptoms after treatment cessation. Additionally, as endometriosis is predominantly a disease of young reproductive-aged women, patients may desire a treatment with a different mechanism of action that does not impact ovarian function and fertility. There remains an unmet clinical need among women with endometriosis for effective and well-tolerated medical therapies.
Metformin, an insulin-sensitizing oral biguanide, is approved for the treatment of type 2 diabetes. Several published studies using in vitro and animal models have implicated metformin with a regression of endometriotic implants and reduction of inflammatory activity. Yet, the mechanisms of action of metformin remain to be further elucidated. Only one prospective study to date has investigated the use of metformin in humans as monotherapy for endometriosis; this study had substantial limitations. Further investigation will be improved with participant and provider blinding, use of validated pain measures, and inclusion of a broader population of patients affected by endometriosis. A randomized clinical trial is necessary to investigate the mechanisms and efficacy of metformin as an anti-endometriotic drug.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | Placebo tablets orally daily for a total of 6 months of treatment. |
|
| Metformin | Experimental | metformin hydrochloride 500 mg capsules daily for a total of 6 months of treatment |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metformin Hydrochloride | Drug | Metformin dosage titrated from 500 mg/daily for 2 weeks, then 1000 mg/daily for 2 weeks, 1500 mg/daily for 2 weeks, and then achieving 2000 mg/daily for a duration of 6 months of treatment. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in pain assessed by the Brief Pain Inventory Interference Scale (BPI) over 6 months | The BPI Interference Scale is a 7-item composite pain measurement. This self-report measure assesses the extent to which pain interferes with various components of physical and emotional functioning and sleep. The items in this scale can be grouped into those that assess physical functioning (general activity; walking ability; normal work, including both work outside the home and housework), those that assess emotional functioning (mood; relations with people; enjoyment of life), and a single item that assess the extent to which pain interferes with sleep. The arithmetic mean of the seven interference items can be used as a measure of pain interference. The BPI is anchored between a scale of zero (no pain/interference) to ten (maximum pain/interference). The magnitude of treatment-associated change in BPI Interference Scale scores in open-label and randomized clinical trials ranges from 1 to 3 points, depending on the specific pain conditions and treatments studied. | once at each of the three visits (at baseline, 3 months, 6 months) |
| Change in pain severity measured by Visual Analog Scale (VAS) over 6 months | VAS: A measurement of pain intensity, assessed by a 0 to 10 numerical rating scale, to rate maximum and average pain intensity over the preceding 7 days. Higher scores indicate more severe pain intensity. | once at each of the three visits (at baseline, 3 months, 6 months) |
| Change in emotional functioning assessed by Beck Depression Inventory-II (BDI) over 6 months | The BDI is a 21-item self-report instrument that provides a rapid assessment of depressive symptoms. BDI has been used in many studies of chronic pain, including chronic pelvic pain and endometriosis. Total scores on the BDI range from 0 to 63. The BDI takes about 5-10 minutes to complete. Scores below 13 should be considered to reflect "minimal or no" depression, with score ranges of 14 to 19, 20 to 28, and 29 to 63 reflect "mild to moderate," "moderate to severe," and "severe" depression, respectively. | once at each of the three visits (at baseline, 3 months, 6 months) |
| Measure | Description | Time Frame |
|---|---|---|
| Change in quality of life, measured via Endometriosis Health Profile-30 (EHP-30) | The EHP-30 is a reliable instrument and recommended by the American Society for Reproductive Medicine and the European Society for Human Reproduction and Embryology. The questionnaire includes 30 questions in five subcategories, with each category addressing specific problem areas of pain, control and powerlessness, emotional wellbeing, social support, and self-image. |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in school and/or work attendance | School and/or work attendance will be assessed at each visit. | once at each of the three visits (at baseline, 3 months, 6 months) |
| Change in pregnancy status | Urine pregnancy test throughout the study as current pregnancy is an exclusion criteria |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Mari Garza, BA | Contact | 6173557648 | GYNResearch@childrens.harvard.edu | |
| Jessica Shim, MD | Contact | 6173557648 | GYNResearch@childrens.harvard.edu |
| Name | Affiliation | Role |
|---|---|---|
| Jessica Shim, MD | Boston Children's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Boston Children's Hospital | Recruiting | Boston | Massachusetts | 02115 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 9391902 | Background | Laufer MR, Goitein L, Bush M, Cramer DW, Emans SJ. Prevalence of endometriosis in adolescent girls with chronic pelvic pain not responding to conventional therapy. J Pediatr Adolesc Gynecol. 1997 Nov;10(4):199-202. doi: 10.1016/s1083-3188(97)70085-8. | |
| 21718982 | Background | Nnoaham KE, Hummelshoj L, Webster P, d'Hooghe T, de Cicco Nardone F, de Cicco Nardone C, Jenkinson C, Kennedy SH, Zondervan KT; World Endometriosis Research Foundation Global Study of Women's Health consortium. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril. 2011 Aug;96(2):366-373.e8. doi: 10.1016/j.fertnstert.2011.05.090. Epub 2011 Jun 30. |
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IPD will not be shared so that patient privacy and confidentiality is maintained during this study.
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| ID | Term |
|---|---|
| D017699 | Pelvic Pain |
| D004715 | Endometriosis |
| D010146 | Pain |
| D059350 | Chronic Pain |
| D052776 | Female Urogenital Diseases |
| D005831 | Genital Diseases, Female |
| ID | Term |
|---|---|
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
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| ID | Term |
|---|---|
| D008687 | Metformin |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
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| Placebo | Drug | 1 tablet orally with evening meal for 2 weeks, then 1 tablet twice daily for 2 weeks, then 3 tablets split twice daily for 2 weeks, then 4 tablets split twice daily, for a total of 6 months of treatment. |
|
|
| Change in ratings of overall improvement assessed by the Patient Global Impression of Change scale (PGIC) | The PGIC is a seven-point single-item scale with options ranging from 'very much worse' to 'very much improved'. There has been widespread use of the PGIC in recent endometriosis clinical trials, as it readily interprets a person's evaluation of the importance of their improvement or worsening. | once at each of the three visits (at baseline, 3 months, 6 months) |
| once at each of the three visits (at baseline, 3 months, 6 months) |
| Changes in sexual satisfaction for participants who are sexually active measured by the New Sexual Satisfaction Scale | The NSSS is a 20-item measure assessing sexual sensations, sexual presence/awareness, sexual exchange, emotional connection/closeness, and sexual activity. The full scale takes 5 minutes to complete. | once at each of the three visits (at baseline, 3 months, 6 months) |
| Complete health and medication history assessed by the World Endometriosis Research Foundation (WERF) questionnaire | Study participants will complete an expanded version of the WERF questionnaire for a complete health and medication history | once at each of the three visits (at baseline, 3 months, 6 months) |
| Changes in serum angiogenic/inflammatory markers | Serum samples will also be obtained for measures of inflammation, to test the hypothesis that endometriosis-relevant inflammatory markers will decrease over time in patients treated with metformin compared to those receiving placebo. These markers will include IL-6, IL-8, and VEGF based on the results of prior studies in which metformin appeared to reduce these levels in humans with endometriosis and from endometriotic implants in rats. C-reactive protein (CRP) will also be assessed; CRP has been shown to be upregulated, especially when examined with a high sensitivity assay making it possible to detect subclinical inflammation in women with endometriosis. | once at each of the three visits (at baseline, 3 months, 6 months) |
| once at each of the three visits (at baseline, 3 months, 6 months) |
| Changes in serum lactate levels | Serum lactate will be measured at baseline and then possibly at three and six months, if needed. | baseline, three and six months if needed |
| Changes in pain | Subjects will keep a daily symptom diary to track pain for 6 months. | daily for 6 months |
| Incidence of vaginal bleeding over six months | Measurement of the incidence of vaginal bleeding using a daily symptom diary to document the presence/absence of vaginal bleeding | daily for 6 months |
| Usage of any pain medications (both prescription and over the counter) | Usage of any pain medications (both prescription and over the counter) tracked in a daily symptom diary for 6 months | daily for 6 months |
| Changes in height | Height, in cm, will be obtained at each study visit (at baseline, 3 months, and 6 months). | once at each of the three visits (at baseline, 3 months, 6 months) |
| Changes in weight | Study subjects will have their weight obtained at each study visit given the potential impact on weight by metformin. | once at each of the three visits (at baseline, 3 months, 6 months) |
| Changes in serum insulin c-peptide level | Serum insulin c-peptide levels will be collected at baseline and again at 6-months given metformin impact on lowering c-peptide levels. | at baseline and 6 months |
| Changes in hemoglobin and mean corpuscular volume | A Complete Blood Count (CBC) will be collected at baseline and again at 6-months due to the potential adverse effect of megaloblastic anemia by metformin, which would be detected by the hemoglobin and mean corpuscular volume. | at baseline and 6 months |
| Changes in vitamin B12 levels | Serum vitamin B12 levels will be obtained at baseline and at 6 months due to the possible adverse effect of vitamin b12 deficiency by metformin | at baseline and 6 months |
| Changes in lipid levels | A lipid panel will be collected at baseline and again at 6-months due to the potential lipid-lowering activity of metformin. | at baseline and 6 months |
| Changes in hemoglobin A1c | At each study visit, (baseline, 3 months, and 6 months), HbA1c will be assessed serially given the glycemic impact and effect of reducing HbA1c by metformin. | once at each of the three visits (at baseline, 3 months, 6 months) |
| Changes in metabolic panel | At each study visit, (baseline, 3 months, and 6 months), a comprehensive metabolic panel will be assessed serially to monitor for any potential kidney impairment that might affect continuation of treatment or changes in electrolytes in the setting of gastrointestinal distress. | once at each of the three visits (at baseline, 3 months, 6 months) |
| Changes in temperature | A physical exam will be conducted at baseline, three months, and six months to obtain changes in temperature. | once at each of the three visits (at baseline, 3 months, 6 months) |
| Changes in heart rate | A physical exam will be conducted at baseline, three months, and six months to obtain changes in heart rate. | once at each of the three visits (at baseline, 3 months, 6 months) |
| Changes in blood pressure | A physical exam will be conducted at baseline, three months, and six months to obtain changes in blood pressure. | once at each of the three visits (at baseline, 3 months, 6 months) |
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| D000091642 | Urogenital Diseases |
| D000091662 | Genital Diseases |