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| Name | Class |
|---|---|
| Massachusetts General Hospital | OTHER |
| Purdue University | OTHER |
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This study will determine whether the negative effects of combined oral contraceptive (COC) therapy on the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis and bone turnover are dependent on the route of administration such that an attenuation of these effects is observed when a comparable dose of non-oral transdermal contraceptive (TDC) and contraceptive vaginal ring therapy (CVR) are also tested.
This study is a preclinical, multi-site trial (Penn State University and Purdue University) that will determine whether the negative effects of combined oral contraceptive (COC) therapy on bone turnover are dependent on the route of administration such that an attenuation of these effects is observed when a comparable dose of non-oral transdermal contraceptive (TDC) therapy and contraceptive vaginal ring (CVR) therapy are also tested. Millions of women use COC therapy for birth control purposes or regulation of menstrual cycles. TDC and CVR therapies are relatively new FDA-approved contraceptive alternatives to COC. The purpose of the proposed project is to address the potential mechanism(s) by which oral ethinyl estradiol (EE) may negatively impair bone via "first pass" effects on the liver and compare these effects to transdermally-administered and vaginally-administered EE in young women. We will assess mechanistic effects by way of 2-day serial sampling and by an insulin-like growth factor (IGF-1) generation test. The IGF-1 generation test was developed over 20 years ago and is currently used to diagnose growth hormone (GH) insensitivity. IGF-1 generation tests may also be used to amplify effects not observable by the assessment of fasting or serial concentrations of systemic IGF-1(secreted by the liver) and its associated binding proteins. This study will be the first study to examine the physiological mechanisms whereby the route of estrogen administration affects the GH/IGF-1 axis and bone turnover in young women.
The overall purpose of this study is to explore differences in liver metabolism and bone turnover of oral versus transdermal and vaginal contraceptive therapy. In an effort to expose the route-dependent effects of oral versus transdermal and vaginal contraceptive therapy on liver and bone metabolism, we will examine the effects of ethinyl estradiol on serially-assessed fasting concentrations of the GH/IGF-1 axis and bone turnover and explore physiological mechanisms underlying hepatic responsiveness to oral versus transdermal and vaginal contraceptive therapy using an IGF-1 Generation Test as a probe.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Combined Oral Contraceptives (COC) | Experimental | Apri (or generic equivalent - Reclipsen) (30µg/d EE, 150 µg/d desogestrel) is a monophasic dosing regimen of 21 active and 7 placebo pills. On Day 1 of the Intervention, participants in the COC group will begin taking the COC pill. Each participant in this group will ingest active pills from the first pack each day for the first 21 days. Pills ingested on days 22 through 28 are placebo pills. A second pill pack will begin on day 29 and pills with active ingredients will be ingested from the second pack each day for days 29-49. On day 50, the participants will immediately begin a 3rd pill pack, if the post-study testing is still occurring, and will ingest a pill with active ingredients from the third pack for days 50-56 (or for as long as the post-study testing is occurring). |
|
| Transdermal Contraceptive (TDC) | Experimental | Participants in the TDC group will apply a 20 cm2 patch (Xulane: 20µg/d EE,150µg/d norelgestromin) to the abdomen, upper arm or buttock. The patch will be changed once weekly on the same day each week for weeks 1-3 (days 1-21, removed on day 22) and weeks 5-8 (days 29-56). Week 4 (days 22-28) will be a patch-free week. As soon as the post-study testing is complete, subjects will remove the patch. |
|
| Contraceptive Vaginal Ring (CVR) | Experimental | Participants in the CVR group (NuvaRing - 15µg/d EE/120µg/d etonogestrel) will insert a vaginal ring into the vagina on Day 1 of the intervention. The vaginal ring will be removed and discarded after 3 weeks of continuous use (days 1-21 of continuous use and removed on day 22). There will be one week (days 22-28) that will be ring-free. A new ring will be inserted for days 29-49. On day 50, the second ring will be removed, and a third ring will be immediately inserted into the vagina (if the post-study testing is still occurring). The third ring will remain in the vagina for the last week of the post-study period (days 50-56). As soon as the post-study testing is complete, subjects will remove the ring. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Combined Oral Contraceptive | Drug | The proposed study is a preclinical, multi-site trial comparing the short-term effects of oral and non-oral ethinyl estradiol on the GH/IGF-1 axis and bone metabolism. Using a prospective repeated measures design, we will test the effects of 2 cycles of combined oral contraceptive (Apri or Reclipsen) on the GH/IGF-1 axis. |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in Insulin-like Growth Factor-1 (IGF-1), IGF Binding Proteins (IGFBP-1, IGFBP-3), and Acid Labile Subunit (ALS) | Changes in serially-sampled fasting serum concentrations of insulin-like growth factor-1 (IGF-1) before and after 49 days of contraceptive therapy. Data were only collected for IGF-1 levels, no assays were performed for IGFBP-1, IGFBP-3, and acid labile subunit (ALS) and no raw data were collected due to insufficient funds. | Baseline and post-49 days of contraceptive therapy |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in Bone Turnover Markers | Changes in serially-sampled fasting serum concentrations of markers of bone formation (osteocalcin, P1NP) and bone resorption (NTx, and CTx) before and after contraceptive therapy. | Baseline and post-49 days of contraceptive therapy |
| Changes in GH-stimulated IGF-1 Secretion |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Mary Jane De Souza, PhD | The Pennsylvania State University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Women's Health and Exercise Laboratories, The Pennsylvania State University | University Park | Pennsylvania | 16802 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21343758 | Background | Grossman D, White K, Hopkins K, Amastae J, Shedlin M, Potter JE. Contraindications to combined oral contraceptives among over-the-counter compared with prescription users. Obstet Gynecol. 2011 Mar;117(3):558-565. doi: 10.1097/AOG.0b013e31820b0244. | |
| 32612574 | Derived | Allaway HCM, Misra M, Southmayd EA, Stone MS, Weaver CM, Petkus DL, De Souza MJ. Are the Effects of Oral and Vaginal Contraceptives on Bone Formation in Young Women Mediated via the Growth Hormone-IGF-I Axis? Front Endocrinol (Lausanne). 2020 Jun 16;11:334. doi: 10.3389/fendo.2020.00334. eCollection 2020. |
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A total of 60 participants enrolled in the study and 34 participants did not pass the screening phase.
Participants were recruited from the Penn State University and Purdue University campuses from January 2015 to June 2016.
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| ID | Title | Description |
|---|---|---|
| FG000 | Combined Oral Contraceptives (COC) | Apri (or generic equivalent - Reclipsen) (30µg/d EE, 150 µg/d desogestrel) is a monophasic dosing regimen of 21 active and 7 placebo pills. On Day 1 of the Intervention, participants in the COC group will begin taking the COC pill. Each participant in this group will ingest active pills from the first pack each day for the first 21 days. Pills ingested on days 22 through 28 are placebo pills. A second pill pack will begin on day 29 and pills with active ingredients will be ingested from the second pack each day for days 29-49. On day 50, the participants will immediately begin a 3rd pill pack, if the post-study testing is still occurring, and will ingest a pill with active ingredients from the third pack for days 50-56 (or for as long as the post-study testing is occurring). |
| FG001 | Contraceptive Vaginal Ring (CVR) | Participants in the CVR group (NuvaRing - 15µg/d EE/120µg/d etonogestrel) will insert a vaginal ring into the vagina on Day 1 of the intervention. The vaginal ring will be removed and discarded after 3 weeks of continuous use (days 1-21 of continuous use and removed on day 22). There will be one week (days 22-28) that will be ring-free. A new ring will be inserted for days 29-49. On day 50, the second ring will be removed, and a third ring will be immediately inserted into the vagina (if the post-study testing is still occurring). The third ring will remain in the vagina for the last week of the post-study period (days 50-56). As soon as the post-study testing is complete, subjects will remove the ring. |
| FG002 | Control Group | The Control group will complete all procedures with the exception of contraceptive therapy. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Control Group | The Control group will complete all procedures with the exception of contraceptive therapy. |
| BG001 | Combined Oral Contraceptives (COC) | Apri (or generic equivalent - Reclipsen) (30µg/d EE, 150 µg/d desogestrel) is a monophasic dosing regimen of 21 active and 7 placebo pills. On Day 1 of the Intervention, participants in the COC group will begin taking the COC pill. Each participant in this group will ingest active pills from the first pack each day for the first 21 days. Pills ingested on days 22 through 28 are placebo pills. A second pill pack will begin on day 29 and pills with active ingredients will be ingested from the second pack each day for days 29-49. On day 50, the participants will immediately begin a 3rd pill pack, if the post-study testing is still occurring, and will ingest a pill with active ingredients from the third pack for days 50-56 (or for as long as the post-study testing is occurring). |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Changes in Insulin-like Growth Factor-1 (IGF-1), IGF Binding Proteins (IGFBP-1, IGFBP-3), and Acid Labile Subunit (ALS) | Changes in serially-sampled fasting serum concentrations of insulin-like growth factor-1 (IGF-1) before and after 49 days of contraceptive therapy. Data were only collected for IGF-1 levels, no assays were performed for IGFBP-1, IGFBP-3, and acid labile subunit (ALS) and no raw data were collected due to insufficient funds. | Posted | Mean | Standard Error | ng/mL | Baseline and post-49 days of contraceptive therapy |
|
Adverse event data were collected during period of study enrollment through study completion, a period of approximately 4 months.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Control Group | The Control group will complete all procedures with the exception of contraceptive therapy. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Mary Jane De Souza | Penn State University | 8148630045 | mjd34@psu.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 15, 2016 | Dec 12, 2018 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D003277 | Contraceptives, Oral, Combined |
| D017135 | Desogestrel |
| C511292 | Ortho Evra |
| ID | Term |
|---|---|
| D004338 | Drug Combinations |
| D004364 | Pharmaceutical Preparations |
| D003276 | Contraceptives, Oral |
| D003271 | Contraceptive Agents, Female |
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|
| Control Group | No Intervention | The Control group will complete all procedures with the exception of contraceptive therapy. |
|
|
| Transdermal Contraceptive | Drug | The proposed study is a preclinical, multi-site trial comparing the short-term effects of oral and non-oral ethinyl estradiol on the GH/IGF-1 axis and bone metabolism. Using a prospective repeated measures design, we will test the effects of 2 cycles of a transdermal contraceptive (Xulane) on the GH/IGF-1 axis. |
|
|
| Contraceptive Vaginal Ring | Drug | The proposed study is a preclinical, multi-site trial comparing the short-term effects of oral and non-oral ethinyl estradiol on the GH/IGF-1 axis and bone metabolism. Using a prospective repeated measures design, we will test the effects of 2 cycles of vaginal ring contraceptive (Nuva Ring) on the GH/IGF-1 axis. |
|
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Changes in IGF-1, IGFBP-1, IGFBP-3,and ALS in response to exogenously administered GH before and after contraceptive therapy. |
| 49 days of contraceptive therapy |
| BG002 | Contraceptive Vaginal Ring (CVR) | Participants in the CVR group (NuvaRing - 15µg/d EE/120µg/d etonogestrel) will insert a vaginal ring into the vagina on Day 1 of the intervention. The vaginal ring will be removed and discarded after 3 weeks of continuous use (days 1-21 of continuous use and removed on day 22). There will be one week (days 22-28) that will be ring-free. A new ring will be inserted for days 29-49. On day 50, the second ring will be removed, and a third ring will be immediately inserted into the vagina (if the post-study testing is still occurring). The third ring will remain in the vagina for the last week of the post-study period (days 50-56). As soon as the post-study testing is complete, subjects will remove the ring. |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
Apri (or generic equivalent - Reclipsen) (30µg/d EE, 150 µg/d desogestrel) is a monophasic dosing regimen of 21 active and 7 placebo pills. On Day 1 of the Intervention, participants in the COC group will begin taking the COC pill. Each participant in this group will ingest active pills from the first pack each day for the first 21 days. Pills ingested on days 22 through 28 are placebo pills. A second pill pack will begin on day 29 and pills with active ingredients will be ingested from the second pack each day for days 29-49. On day 50, the participants will immediately begin a 3rd pill pack, if the post-study testing is still occurring, and will ingest a pill with active ingredients from the third pack for days 50-56 (or for as long as the post-study testing is occurring).
| OG002 | Contraceptive Vaginal Ring (CVR) | Participants in the CVR group (NuvaRing - 15µg/d EE/120µg/d etonogestrel) will insert a vaginal ring into the vagina on Day 1 of the intervention. The vaginal ring will be removed and discarded after 3 weeks of continuous use (days 1-21 of continuous use and removed on day 22). There will be one week (days 22-28) that will be ring-free. A new ring will be inserted for days 29-49. On day 50, the second ring will be removed, and a third ring will be immediately inserted into the vagina (if the post-study testing is still occurring). The third ring will remain in the vagina for the last week of the post-study period (days 50-56). As soon as the post-study testing is complete, subjects will remove the ring. |
|
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| Secondary | Changes in Bone Turnover Markers | Changes in serially-sampled fasting serum concentrations of markers of bone formation (osteocalcin, P1NP) and bone resorption (NTx, and CTx) before and after contraceptive therapy. | No data was collected due to insufficient funds. | Posted | Baseline and post-49 days of contraceptive therapy |
|
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| Secondary | Changes in GH-stimulated IGF-1 Secretion | Changes in IGF-1, IGFBP-1, IGFBP-3,and ALS in response to exogenously administered GH before and after contraceptive therapy. | No data was collected due to insufficient funds. | Posted | 49 days of contraceptive therapy |
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|
| 0 |
| 8 |
| 0 |
| 8 |
| 0 |
| 8 |
| EG001 | Combined Oral Contraceptives (COC) | Apri (or generic equivalent - Reclipsen) (30µg/d EE, 150 µg/d desogestrel) is a monophasic dosing regimen of 21 active and 7 placebo pills. On Day 1 of the Intervention, participants in the COC group will begin taking the COC pill. Each participant in this group will ingest active pills from the first pack each day for the first 21 days. Pills ingested on days 22 through 28 are placebo pills. A second pill pack will begin on day 29 and pills with active ingredients will be ingested from the second pack each day for days 29-49. On day 50, the participants will immediately begin a 3rd pill pack, if the post-study testing is still occurring, and will ingest a pill with active ingredients from the third pack for days 50-56 (or for as long as the post-study testing is occurring). | 0 | 9 | 0 | 9 | 0 | 9 |
| EG002 | Contraceptive Vaginal Ring (CVR) | Participants in the CVR group (NuvaRing - 15µg/d EE/120µg/d etonogestrel) will insert a vaginal ring into the vagina on Day 1 of the intervention. The vaginal ring will be removed and discarded after 3 weeks of continuous use (days 1-21 of continuous use and removed on day 22). There will be one week (days 22-28) that will be ring-free. A new ring will be inserted for days 29-49. On day 50, the second ring will be removed, and a third ring will be immediately inserted into the vagina (if the post-study testing is still occurring). The third ring will remain in the vagina for the last week of the post-study period (days 50-56). As soon as the post-study testing is complete, subjects will remove the ring. | 0 | 9 | 0 | 9 | 0 | 9 |
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| D003270 | Contraceptive Agents |
| D012102 | Reproductive Control Agents |
| D045505 | Physiological Effects of Drugs |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D045506 | Therapeutic Uses |
| D009652 | Norpregnenes |
| D009650 | Norpregnanes |
| D009654 | Norsteroids |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |