E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Thyroid autoimmunity and history of miscarriage or infertility. |
|
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To test the hypothesis that in women with normal thyroid function but with thyroid peroxidase antibodies (TPO), levothyroxine (50mcg, oral, once daily), started pre-conceptually and continued to the end of pregnancy, compared with placebo, increases the proportion of women who attain a live birth beyond 34 completed weeks of gestation by at least 10%. |
|
E.2.2 | Secondary objectives of the trial |
1. To test the hypothesis that levothyroxine improves secondary outcomes such as on-going pregnancy at 11-13 weeks, gestation at delivery and survival at 28 days of neonatal life. 2. To explore subgroup effects of levothyroxine in prognostic subgroups (maternal age, number of previous miscarriages, women undergoing infertility treatment and initial serum TSH concentration). 3. To test the hypothesis that levothyroxine, compared with placebo, does not incur substantial adverse effects to the mother or the neonate. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Women trying to conceive 2. History of one or more miscarriage(s)or primary/secondary infertility 3. Age 16 - 40 years at randomisation. 4. Biochemically euthyroid (Free T4 and TSH within specified reference ranges) 5. Thyroid Peroxidase Antibody (TPO) positive 6. Willing and able to give written informed consent |
|
E.4 | Principal exclusion criteria |
1. Current or past treatment for thyroid disease. 2. Contraindication to levothyroxine treatment. -Thyrotoxicosis. Hypersensitivity to any components tablets. 3. Women taking amiodarone or lithium therapy. 3. Participants in any other blinded, placebo controlled trials on Investigational Medicinal Products in pregnancy. 4. Participants with previous or current cardiac disease. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Live births beyond 34 completed weeks of gestation, as a proportion of all women randomised. This proportion will be calculated with the denominator of all women randomised, and the numerator of women who conceive within 1 year of randomisation and go on to give live birth beyond 34 weeks gestation. Women who fail to conceive within a year, or who become pregnant but either miscarry, give birth before 34 weeks or experience a still birth will thus be included in the denominator but not the numerator. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
When Pregnancy has ended for women who have concieved. For women who have not concieved, 12 months after randomisation. |
|
E.5.2 | Secondary end point(s) |
1. To test the hypothesis that levothyroxine improves secondary outcomes such as on-going pregnancy at 11-13 weeks, gestation at delivery and survival at 28 days of neonatal life. 2. To explore subgroup effects of levothyroxine in prognostic subgroups (maternal age, number of previous miscarriages, women undergoing infertility treatment and initial serum TSH concentration). 3. To test the hypothesis that levothyroxine, compared with placebo, does not incur substantial adverse effects to the mother or the neonate. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.11-13 week ultrasound scan, 28 days after birth 2.Thyroid function tests @ 3 and 6 months pre pregnancy, 6-8 wks, 16-18wks and 28 wks in pregnancy and when pregnancy has ended. 3. 28 days after birth |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 20 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of the interventional phase of the trial will be when the last participant has either ended their pregnancy (whether live birth or miscarriage) or has reached 12 months post-randomisation without getting pregnant. The end of observational phase will be when the last live birth has reached 28 days of age. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 29 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 29 |