Condition category
Nutritional, Metabolic, Endocrine
Date applied
29/07/2012
Date assigned
08/08/2012
Last edited
21/07/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims:
Hyperandrogenism is a medical condition where the body produces too much of the male sex hormone androgen and insulin levels are elevated. Hyperandrogenism is one of the primary components symptoms of polycystic ovary syndrome (PCOS). It can cause a variety of symptoms, such as irregular or complete absence of periods, problems with getting pregnant, excessive hair growth (hirsutism), , thinning hair and acne. It may be also linked to other health conditions such as infertility, type 2 diabetes and high cholesterol. The aim of this study is to compare the effects of a low-dose combination of two insulin sensitizers (drugs developed to address insulin resistance) and an antiandrogen (a drug that blocks the function of androgen) with those of an oral contraceptive in girls with signs and symptoms of androgen excess or hyperandrogenism, such as hirsutism and menstrual disturbances. The researchers want to know which is the best treatment not only to ameliorate the clinical symptoms but also to reduce future risks for infertility, type 2 diabetes and cardiovascular disease, because these girls, as adults, may have more predisposition to suffer from these disorders.

Who can participate?
Adolescent girls with hyperandrogenism who are not at risk of pregnancy.

What does the study involve?
The girls are randomly allocated to one of two groups. Those in group 1 are given the insulin sensitizers plus antiandrogen treatment for 12 months. Those in group 2 are given an oral contraceptive for 12 months. At the start and at the end of the treatment , and then again 12 months after the treatment has been stopped, an oral glucose test is performed for all participants. Blood samples for androgens, lipids (fats) and insulin are also taken at the start of the treatment, 6 and 12 months into the treatment and then, finally, after 6 and 12 months after the treatment. All girls also have a DXA scan and a magnetic resonance of the abdomen to see whether there have been any changes in body composition, abdominal fat and lipids within the liver at the start of the study and then four further times, 6 months apart. An abdominal ultrasound and a carotid ultrasound are also performed. Between three months and six months after treatment, and then again between nine months and 12 months after treatment, ovulation is also tested, by measuring salivary progesterone every week for 12 consecutive weeks.

What are the possible benefits and risks of participating?
The researchers foresee no specific risks with any of the two treatments. This is an important study because it will clarify which is the best treatment option to give to adolescents with androgen excess, which is the most common endocrine disorder in adolescents and young women.

Where is the study run from?
University of Barcelona (Spain)

When is study starting and how long is it expected to run for?
October 2012 to April 2014

Who is funding the study?
National Health Service of Spain

Who is the main contact?
Professor Lourdes Ibáñez 

Trial website

Contact information

Type

Scientific

Primary contact

Prof Lourdes Ibañez

ORCID ID

Contact details

Hospital Sant Joan de Déu
University of Barcelona
Passeig de Sant Joan de Deu
2
Esplugues de Llobregat
08950
Spain

Additional identifiers

EudraCT number

2012-004100-35

ClinicalTrials.gov number

Protocol/serial number

ECO-120729

Study information

Scientific title

Ethinyloestradiol-Levonorgestrel versus Low-Dose Spironolactone-Pioglitazone-Metformin (SPIOMET) for Adolescent Girls with Polycystic Ovary Syndrome: On-Treatment and Post-Treatment Observations.

Acronym

Study hypothesis

As of 21/07/2016:
Treatment with low-dose spironolactone- + pioglitazone- + metformin will be accompanied by more reduction of central fat and hyperinsulinaemia, and will be followed by a higher ovulation rate than treatment with an oral oestro-progestagen contraceptive in adolescent girls with polycystic ovary syndrome.

Initial
Treatment with Spironolactone + Pioglitazone + Metformin will be more effective on ovulation rates, endocrine-metabolic parameters and body composition and in the normalization of cardiovascular risk markers than that with an oral contraceptive containing ethinylestradiol and levonorgestrel in girls with hyperinsulinemic androgen excess and without pregnancy risk.

Ethics approval

1. Ethical Committee of Clinical Research at Hospital Sant Joan de Déu, 16/10/2012, ref: AC-23-12
2. Spanish Agency for Medicines and Health Products (Agencia Española del Medicamento y Productos Sanitarios) (AEMPS), 17/12/2012, ref: EUDRACT: 2012-004100-35

Study design

As of 21/07/2016:
Randomized, open-label study with an on-treatment phase of 12 months followed by a post-treatment phase of 12 months.

Initial
Open prospective randomized study

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Polycystic ovary syndrome

Intervention

Two treatment subgroups:
Ethinylestradiol (20 ug) + levonorgestrel (100 mg), once daily at dinner time
Spironolactone (50 mg/d) + pioglitazone (7.5 mg/d) + metformin (850 mg/d), once daily, at dinner time.

Intervention type

Drug

Phase

Not Applicable

Drug names

1. Spironolactone
2. Pioglitazon
3. Metformin
4. Ethinylestradiol-levonorgestrel (added 18/03/2016)

Primary outcome measures

As of 21/07/2016:
1. Post-treatment ovulation rate: (judged by a combination of menstrual history and weekly salivary progesterone concentrations for 12 consecutive weeks, in the second and the fourth quarters of the first post-treatment year (months 15-18 and 21-24 of the study).

As of 15/03/2016:
1. Ovulation rate: (weekly salivary progesterone for 12 consecutive weeks, ELISA): post-treatment; second and fourth quarters of the post-treatment year (months 15-18 and 21-24)

Initial
1. Fasting insulin
2. Visceral fat
3. Hepatic fat
4. Carotid intima-media thickness

Secondary outcome measures

As of 15/03/2016:
1. Fasting insulinemia (immunochemiluminescence): at baseline, 6 months and 12 months on treatment and 6 and 12 months off treatment
2. Visceral fat (MRI): at baseline, 6 months and 12 months on treatment and 6 and 12 months off treatment
3. Hepatic fat (MRI): at baseline, 6 months and 12 months on treatment and 6 and 12 months off treatment
4. Carotid intima-media thickness (ultrasound): at baseline, 6 months and 12 months on treatment and 6 and 12 months off treatment
5. Hirsutism (Ferriman & Gallwey score): at baseline, 6 months and 12 months on treatment and 6 and 12 months off treatment
6. Testosterone and androstenedione (LC-MS/MS): at baseline, 6 months and 12 months on treatment and 6 and 12 months off treatment*
7. Lipids (absorption spectrometry): at baseline, 6 months and 12 months on treatment and 6 and 12 months off treatment
8. C-reactive protein (Architect c8000) : at baseline, 6 months and 12 months on treatment and 6 and 12 months off treatment
9. HMW adiponectin (ELISA): at baseline, 6 months and 12 months on treatment and 6 and 12 months off treatment

*changed from 6. Androgens (immunochemiluminescence): at baseline, 6 months and 12 months on treatment and 6 and 12 months off treatment on 21/07/2016)

Initial
1. Ferriman & Gallwey score
2. Androgens
3. Lipids
4. C-reactive protein
5. High molecular weight
6. Adiponectin
7. Insulin resistance index in adipocytes
8. Ovulation
9. Breast density (DXA)

Overall trial start date

05/12/2012

Overall trial end date

20/06/2016

Reason abandoned

Eligibility

Participant inclusion criteria

As of 21/07/2016:
1. Clinical androgen excess (hirsutism) and/or biochemical hyperandrogenismwith or without biochemical androgen excess
2. Chronological age between 14.0-17.9 years at study start
3. Gynecological age (= time post-menarche) >2.0 years at study start
4. Absence of sexual activity (intercourse)

Initial:
1.Clinical and biochemical hyperandrogenism
2. Hyperinsulinemia (fasting and/or after an oGTT)
3. Age >14 and >18 year
4. Menarche at least 2 years before
5. BMI <97th percentile and >10th percentile

Participant type

Patient

Age group

Child

Gender

Female

Target number of participants

n=40

Participant exclusion criteria

As of 21/07/2016:
1. Evidence for adrenal hyperplasia, Cushing syndrome, hypothyroidism
2. Evidence for lLiver or kidney dysfunction, diabetes, glucose intolerance
3. Treatment with oral contraceptives, antiandrogens, or insulin sensitizers in past 6 months

Initial:
1. Pregnancy or pregnancy risk
2. Late onset congenital adrenal hyperplasia, Cushing's syndrome, uncompensated hypothyroidism
3. Liver or renal dysfunction, diabetes, glucose intolerance
4. Treatment with oral contraceptives, antiandrogens, or insulin sensitizers over the previous 6 months
5. Severe bacterial infections

Recruitment start date

23/12/2012

Recruitment end date

01/07/2014

Locations

Countries of recruitment

Spain

Trial participating centre

Hospital Sant Joan de Déu
Esplugues de Llobregat
08950
Spain

Sponsor information

Organisation

Hospital Sant Joan de Deu

Sponsor details

University of Barcelona
Passeig de Sant Joan de Deu
2
Esplugues de Llobregat
Barcelona
08950
Spain

Sponsor type

Hospital/treatment centre

Website

http://www.hsjdbcn.org/

Funders

Funder type

Government

Funder name

National Health Service (Spain) ref: PFIS 0069

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Publication of on-treatment and post-treatment findings by mid-2017.

Intention to publish date

01/07/2017

Participant level data

To be made available at a later date

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

21/07/2016: Public title changed from "Efficacy of low-dose treatment with insulin sensitizers and antiandrogens versus that of an oral contraceptive on hirsutism, irregular menses, anovulation, body fat and markers of type 2 diabetes and cardiovascular risk in girls with androgen excess and elevated insulin levels (hyperinsulinemia) and without pregnancy risk.". Scientific title changed from "Ethnylestradiol-levonorgestrel versus low-dose Spironolactone+ +Pioglitazone+Metformin in adolescents with hyperinsulinemic androgen excess: Effects on ovulatory function, parameters of chronic inflammation, on cardiovascular risk factors and on risk factors for the development of type 2 diabetes ". Changes made study hypothesis, study design, interventions, outcome measures, eligibility criteria (all indicated in record) 18/03/2016: Ethics approval information was added to the record, an extra drug name was added to the drugs field and a EudraCT number was added. The recruitment start date was changed from 05/10/2012 to 23/12/2012. The recruitment end date was changed from 05/04/2014 to 01/07/2014. The overall trial start date was changed from 05/10/1212 to 05/12/2012. The overall trial end date was changed from 05/04/2014 to 20/06/2016 15/03/2016: The primary and secondary outcome measures were amended and plain English summary was added to the record