Comparison of the effects of an oral contraceptive with those of a combined therapy with insulin sensitizers and anti-androgens in young girls with ovarian androgen excess and without pregnancy risk, on markers of cardiometabolic health
| ISRCTN | ISRCTN11062950 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN11062950 |
| EudraCT/CTIS number | 2015-005092-24 |
| Secondary identifying numbers | PI15/01078 |
- Submission date
- 16/09/2015
- Registration date
- 21/09/2015
- Last edited
- 04/10/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Nutritional, Metabolic, Endocrine
Plain English summary of protocol
Background and study aims
Polycystic ovary syndrome (PCOS) is a medical condition that affects the function of a woman’s ovaries. Women with PCOS may have cysts in the ovaries, irregular ovulation and high levels of androgens (male hormones). Symptoms include irregular periods (or no periods at all), difficulties getting pregnant, excessive hair (hirsutism), commonly on the face, chest, back and buttocks, gaining weight, hair thinning and acne. It is also associated with an increased risk of type 2 diabetes and other health problems later in life, such as cardiovascular disease. There is no approved therapy. Prime recommendation is to give an oral contraceptive (OC) which treats the symptoms, but may decrease the sensitivity to insulin, worsen markers of cardiovascular health, and therefore affect the long-term health. Here, we compare the long-term effects of an OC with those of a low-dose combination of medications that improve insulin sensitivity and decrease the affects of androgen to investigate whether besides the clinical symptoms, this combination is capable of improving the risks for future complications for young women with PCOS.
Who can participate?
Girls under 16 diagnosed with PCOS with decreased sensitivity to insulin, excess androgen levels and with no/irregular periods.
What does the study involve?
Participants are randomly allocated to one of two groups. Those in group 1 are given Loette Diario (OC). Those in group 2 are given SPIOMET, that is, spironolactone, pioglitazone and metformin; this combination aims to improve insulin sensitivity and reduce the effects of androgen. All participants are tested for insulinema (insulin in the blood) and their levels of visceral (abdominal) and hepatic (liver) fat.
What are the possible benefits and risks of participating?
This study compares the standard treatment with an alternative, pathophysiology-based therapy (with a low-dose combination of insulin sensitizers and anti-androgens). A preliminary study has been performed using the combinations to be used here and the results show a divergence in the outcomes, with the combination having more benefits on risk markers. The medications are safe and there is no evidence of side effects.
Where is the study run from?
Hospital Sant Joan de Déu, University of Barcelona (Spain)
When is the study starting and how long is it expected to run for?
December 2015 to December 2018
Who is funding the study?
Ministry of Science and Innovation, Institute of Health Carlos III (Spain)
Who is the main contact?
Prof Lourdes Ibañez
libanez@hsjdbcn.org
Contact information
Scientific
Hospital Sant Joan de Déu
University of Barcelona
Esplugues
08950
Spain
 ORCID ID |
0000-0003-4595-7191 |
|---|
Study information
| Study design | Interventional single-centre randomized controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet |
| Scientific title | Ethinylestradiol-levonorgestrel versus spironolactone-pioglitazone-metformin (SPIOMET) for adolescent girls with hyperinsulinemic androgen excess: effects on hepatic and visceral fat and on insulin sensitivity |
| Study acronym | OC vs SPIOMET |
| Study objectives | Oral contraceptives (OC) and SPIOMET will improve the measures of androgen excess comparably. SPIOMET treatment will be followed by more favorable changes of the primary outcomes (visceral and hepatic fat and insulinemia), and of secondary outcomes (lipids, CRP, carotic intima-media thickness [cIMT], high-molecular-weight adiponectin, miRNAs, leukocyte telomere length, microbiome, gene expression in subcutaneous adipose tissue). |
| Ethics approval(s) | Agencia Española del Medicamento y Productos Sanitarios, 22/01/2016 |
| Health condition(s) or problem(s) studied | Hyperinsulinemic androgen excess in adolescent girls |
| Intervention | In this single-centre, open-labelled, controlled trial, the randomization (1:1) will be web-based (http://www.SealedEnvelope.com), using random permuted blocks, with strata for age (<16.0 or ≥16.0 years) and BMI (<24.0 or ≥24.0 Kg/m2). Girls will be randomly assigned to receive once daily, at dinner time, either Loette Diario (Pfizer, Madrid, Spain; 20 mcg ethinylestradiol plus 100 mg levonorgestrel for 21/28 days, and placebo for 7/28 days) or SPIOMET, a low-dose combination of separate generics: 50 mg spironolactone (one half of a 100 mg tablet of Aldactone from Pfizer, Madrid, Spain); 7.5 mg pioglitazone (one half of a 15 mg tablet of Actos from Takeda, Madrid, Spain); and 850 mg metformin (one full 850 mg tablet of Metformina from Sandoz, Barcelona, Spain). The randomization will be performed by an investigator who will not be based in the recruiting hospital and who will be blinded to the patients’ characteristics (except for age and BMI). |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | 1. Loette Diario (Pfizer, Madrid, Spain; 20 mcg ethinylestradiol plus 100 mg levonorgestrel) 2. Spironolactone ( 100 mg tablets of Aldactone, Pfizer, Madrid, Spain) 3. Pioglitazone (15 mg tablet of Actos, Takeda, Madrid, Spain) 4. Metformin (850 mg tablet of Metformina, Sandoz, Barcelona, Spain) |
| Primary outcome measure | Current primary outcome measures as of 14/09/2018: 1. Insulinemia assessed by immunochemiluminescence every 6 months while on treatment and 6 months after end of treatment 2. Visceral and hepatic fat assessed by MRI every 6 months while on treatment and 6 months after end of treatment Post-treatment endpoints: 3. Ovulation rates assessed by ELISA of weekly salivary progesterone during the second and fourth quarter of the follow-up year Previous primary outcome measures as of 07/03/2016: On-treatment endpoints: 1. Insulinemia: on treatment every 6 months; 6 months off treatment. Method: immunoquimioluminescence 2. Visceral & hepatic fat: MRI. on treatment every 6 months; 6 months off treatment Post-treatment endpoints: 3. Ovulation rates Previous primary outcome measures: 1. Insulinemia: on treatment every 6 months; 6 months off treatment. Method: immunoquimioluminescence 2. Visceral & hepatic fat: MRI. on treatment every 6 months; 6 months off treatment |
| Secondary outcome measures | Current secondary outcome measures as of 17/09/2018: On-treatment endpoints: 1. Measures of androgen excess: hirsutism (Ferriman & Gallwey score); acne (Leeds score); testosterone (immunochemiluminescence), and AMH (ELISA) at baseline and after 12 months on treatment. 2. Measurements of cardio-metabolic risk: C-reactive protein (Architect c8000; Abbott); HMW adiponectin (ELISA), carotid intima-media thickness (ultrasound); insulinemia (Immunochemiluminiscence); visceral and hepatic fat (MRI); HMW adiponectin (ELISA), S100A4 (ELISA), at baseline and after 12 months of treatment. Post-treatment endpoints: 3. Measures of androgen excess: hirsutism (Ferriman & Gallwey score); acne (Leeds score); testosterone (immunochemiluminescence) and AMH (ELISA) after 6 and 12 months off treatment. 4. Measurements of cardio-metabolic risk: C-reactive protein (Architect c8000; Abbott); HMW adiponectin (ELISA), carotid intima-media thickness (ultrasound); insulinemia (Immunochemiluminiscence); visceral and hepatic fat (MRI); HMW adiponectin (ELISA), S100A4 (ELISA), at 6 and 12 months off treatment. Previous secondary outcome measures as of 13/09/2018: On-treatment endpoints: 1. Measures of androgen excess: hirsutism (Ferriman & Gallwey score); acne (Leeds score); testosterone (immunochemiluminescence) 2. C-reactive protein (Architect c8000; Abbott); HMW adiponectin (ELISA), carotid intima-media thickness (ultrasound) Post-treatment endpoints: 3. Insulinemia 4. Visceral & hepatic fat 5. Measures of androgen excess 6. C-reactive protein, HMW adiponectin, carotid intima-media thickness 7. Serum S100A4 on treatment 8. Anti-Mullerian hormone (AMH) at baseline and after 12 months on treatment Previous secondary outcome measures as of 07/03/2016: On-treatment endpoints: 1. Measures of androgen excess: hirsutism (Ferriman & Gallwey score); acne (Leeds score); testosterone (immunochemiluminescence) 2. C-reactive protein (Architect c8000; Abbott); HMW adiponectin (ELISA), carotid intima-media thickness (ultrasound) Post-treatment endpoints: 3. Insulinemia 4. Visceral & hepatic fat 5. Measures of androgen excess 6. C-reactive protein, HMW adiponectin, carotid intima-media thickness Previous secondary outcome measures: 1. Measures of androgen excess: hirsutism (Ferriman & Gallwey score); acne (Leeds score); testosterone (immunochemiluminescence) 2. C-reactive protein (Architect c8000; Abbott); HMW adiponectin (ELISA), carotid intima-media thickness (ultrasound) |
| Overall study start date | 02/12/2015 |
| Completion date | 20/09/2019 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Child |
| Sex | Female |
| Target number of participants | 40 |
| Total final enrolment | 41 |
| Key inclusion criteria | 1. Hyperinsulinemia, defined as fasting insulinemia >15 IU/mL and/or a peak insulinemia >150 IU/mL and/or mean insulinemia >84 IU/mL on a 2-hour oral glucose tolerance test (oGTT) 2. Presence of both clinical and endocrine androgen excess, as defined by hirsutism score >8 (Ferriman-Gallwey scale), amenorrhea (no menses for more than 3 months) or oligomenorrhea (menstrual intervals >45 days), and high circulating concentrations of testosterone in the follicular phase (cycle day 3-7) or after 2 months of amenorrhea |
| Key exclusion criteria | 1. Pregnancy risk (throughout the study) 2. Anemia or bleeding disorder 3. Evidence of thyroid, liver or kidney dysfunction; abnormal electrolytes 4. Hyperprolactinemia 5. 21-hydroxylase deficiency (17-hydroxyprogesterone levels ≥ 200 ng/dL in the follicular phase or after two months of amenorrhea) 6. Glucose intolerance or diabetes mellitus 7. Use of medication affecting gonadal or adrenal function, or carbohydrate or lipid metabolism |
| Date of first enrolment | 10/12/2015 |
| Date of final enrolment | 10/12/2016 |
Locations
Countries of recruitment
- Spain
Study participating centre
Esplugues
08950
Spain
Sponsor information
University/education
Passeig de Sant Joan de Déu, 2
Esplugues
08950
Spain
| Phone | +34 93 2804000 |
|---|---|
| aode@fsjd.org | |
| Website | www.hsjdbcn.org |
"ROR" |
https://ror.org/001jx2139 |
Funders
Funder type
Not defined
No information available
Results and Publications
| Intention to publish date | 30/06/2020 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Our aim is to publish together the on-treatment and off-treatment results after completion of the protocol. Should any of the novel variables result in outstanding and/or unexpected results, we may chose to publish those results separately. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from the study contact Prof Lourdes Ibañez, libanez@hsjdbcn.org. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | results | 14/03/2020 | 07/10/2020 | Yes | No |
| Results article | 29/03/2021 | 31/03/2021 | Yes | No | |
| Results article | Primary results | 14/07/2017 | 12/08/2022 | Yes | No |
| Protocol file | version 2.0 | 31/08/2018 | 16/08/2022 | No | No |
| Results article | 16/05/2024 | 04/10/2024 | Yes | No |
Additional files
Editorial Notes
04/10/2024: Publication reference added.
16/08/2022: Uploaded protocol (not peer reviewed)
12/08/2022: The following changes have been made:
1. Publication reference added.
2. IPD sharing statement has been changed.
31/03/2021: Publication reference added.
12/10/2020: IPD sharing statement added.
07/10/2020: Publication reference added.
10/12/2019: The following changes have been made:
1. The total final enrolment number has been added.
2. The overall trial end date has been changed from 30/12/2018 to 20/09/2019.
3. The intention to publish date has been changed from 30/01/2017 to 30/06/2020.
17/09/2018: The secondary outcome measures have been changed.
14/09/2018: The primary outcome measures have been changed.
13/09/2018: The secondary outcome measures have been changed.
24/03/2016: Ethics approval information added.
18/03/2016: Internal review
07/03/2016: Updated primary and secondary outcome measures. Details of changes are in appropriate fields.
