A multicentre, single arm trial on contraceptive efficacy, safety and tolerability of LVDS (Levonorgestrel Vaginal Delivery System) during 13 cycles.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Chemo Research S.L.

Participant type

Pediatric, Healthy volunteers

Age range

0-17 years, 18-64 years

Gender

Female

Therapeutic area

Phenomena and Processes [G] - Reproductive and Urinary Physiological Phenomena [G08]

Trial duration

12 Jul 2023 → 1 Aug 2025

Decision date (initial)

2023-07-12

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Chemo Research S.L.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Efficacy, Safety

To demonstrate the contraceptive efficacy of LVDS.

Secondary objectives 3

1. [Secondary efficacy:] To demonstrate the contraceptive efficacy of LVDS.
2. [Secondary safety and tolerability:] To demonstrate the safety and tolerability of LVDS.
3. [Exploratory (bone mineral density assessment): For adolescents (except for Czech Republic and Germany) (15-17 years old at the time of enrolment):] To assess the effect of LVDS on bone mineral density in adolescents

Conditions and MedDRA coding

Prevention of pregnancy

Study design 1 period

Regulatory references

Scientific advice from competent authorities

Medical Products Agency, Medicines Evaluation Board

EMA paediatric investigation plan (PIP)

EMEA-002474-PIP02-18

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. [Visit 1a:] Sexually active, postmenarcheal and premenopausal female subjects at risk of pregnancy including breastfeeding women.
2. [Visit 1a:] Only for female subjects between the ages of 15 and 17 (inclusive) provided that: a. Applicable national, state and local laws allow subjects in this age group to consent/assent to receive contraceptive services, b. All applicable laws and regulations regarding the informed consent/assent of the subjects to participate in clinical trials are observed. c. All special radiation protection approval requirements have been confirmed by corresponding official approvals and the sponsor has authorised the recruitment of underage participants in writing to the trial site. (Adolescents will not be included in Czech Republic and Germany)
3. [Visit 1a:] Women who either a. have never used hormonal contraceptives before consent/assent (naïve users), or b. have used hormonal contraceptives in the past, but have had a hormonal contraceptive-free period before consent/assent and a full menstrual cycle during the drug-free period (previous users) or c. directly switch from another hormonal contraceptive (switchers).
4. [Visit 1a:] Only for subjects who were not pregnant and did not use hormonal contraception during the last 6 months before consent/assent: Regular cycles (i.e. cycle length between 24 and 35 days) during the last 6 months.
5. [Visit 1a:] Only for women who were pregnant within the last 6 months before consent/assent: At least 3 complete menstrual cycles after pregnancy. Breastfeeding women can be included 4 weeks after delivery irrespective of menstrual cycles post-delivery.
6. [Visit 1a:] Systolic blood pressure ≤ 140 mm Hg and diastolic blood pressure ≤ 90 mm Hg, subjects with controlled hypertension are allowed.
7. [Visit 1a:] A written informed consent/assent is available, prior to undergoing any trial-related procedure.
8. [Visit 1a:] Willing to use trial contraception for thirteen 28-day cycles.
9. [Visit 1a:] Be willing to have intercourse in each cycle of the trial without the need to use back-up contraceptive (not applicable to adolescents).
10. [Visit 1a:] Be willing to state that, to her best knowledge, her male sexual partner/partners has/have not had a vasectomy or been previously diagnosed as infertile (not applicable to adolescents).
11. [Visit 1a:] Agree not to participate in any other clinical trials during the course of this trial (participation in a non-interventional study is allowed).

Exclusion criteria 25

1. [Visit 1a / Visit 1b:] Pregnancy or wish of pregnancy.
2. [Visit 1a:] Subject is known to or suspected of not being able to comply with the trial protocol, the use of the trial medication or the use of the trial diary.
3. [Visit 1a:] History of infertility.
4. [Visit 1a:] Known bleeding disorder or history of unexplained bleeding or bruising within the last 12 months prior to V1a.
5. [Visit 1a:] Unexplained amenorrhoea.
6. [Visit 1a:] Abnormal finding on pelvic, breast or ultrasound examination that in the investigator’s opinion contraindicates participation in the trial.
7. [Visit 1a:] Women with a Papanicolaou (Pap) smear reading low-grade squamous intraepithelial lesion (LGSIL) or higher at screening. Subjects with atypical squamous cells of undetermined significance (ASC-US) can be included if they are negative for high-risk human papilloma virus (HPV) strains.
8. [Visit 1a:] Known contraindication including: a. Active venous thromboembolic disorder and/or a VTE history including a known positive family history in a sibling or parent. b. Arterial and cardiovascular disease, past or present (e.g. myocardial infarction, cerebrovascular accident, ischemic heart disease). c. Major surgery with prolonged immobilisation. d. Diabetes mellitus with vascular involvement. e. Presence or history of severe hepatic disease as long as liver function values have not returned to normal. f. Presence or history of liver tumours (benign or malignant). g. Known severe renal insufficiency or acute renal failure. h. Known adrenal insufficiency. i. Known or suspected sex steroid sensitive malignancies, including breast cancer. j. Hypersensitivity to the active substance or to any of the excipients.
9. [Visit 1a:] Uncontrolled concomitant chronic diseases (i.e., not on a stable treatment dose for at least 2 months at the time of assent/consent).
10. [Visit 1a:] Severe COVID-19 disease or less than 3 months after hospitalization due to a COVID-19 disease.
11. [Visit 1a:] Known HIV infection.
12. [Visit 1a:] Known current or chronic hepatitis B or C.
13. [Visit 1a / Visit 1b:] Prohibited previous medication/therapy (as given in the protocol).
14. [Visit 1a / Visit 1b:] Dependence on prohibited co-medication/- therapy (as given in the protocol).
15. [Visit 1a / Visit 1b:] Progestin-releasing intra-uterine device (IUD) or contraceptive implant received or in place within the last 2 months.
16. [Visit 1a:] Planned regular concomitant use of barrier contraceptive methods, spermicides, IUDs or other contraceptive measures.
17. [Visit 1a:] Subject is a member of the investigator’s or sponsor’s staff or a relative or family member thereof.
18. [Visit 1a:] Is in custody or submitted to an institution by a court order.
19. [Visit 1a / Visit 1b:] Any condition or any disease that, in the opinion of the investigator, may jeopardize protocol compliance or the scientific integrity of the trial.
20. [Visit 1a: Additional exclusion criteria for the BMD subgroup (adolescents) (except for Czech Republic and Germany):] History of low trauma fracture(s) defined as a fracture that results from a fall from a standing height or less, excluding fingers, toes, face and skull.
21. [Visit 1a: Additional exclusion criteria for the BMD subgroup (adolescents) (except for Czech Republic and Germany):] Known medical conditions associated with low bone mass: a. Metabolic bone disease such as osteogenesis imperfecta, Paget’s disease of the bone, osteomalacia/rickets b. Rheumatoid arthritis c. Collagen vascular diseases such as Marfan’s syndrome and Erhlos-Danlos syndrome d. Chronic kidney disease e. Hyperparathyroidism and abnormal bone mineral metabolism (hypocalcemia/ hypercalcemia, hypophosphatemia/ hyperphosphatemia, hypomagnesemia).
22. [Visit 1a: Additional exclusion criteria for the BMD subgroup (adolescents) (except for Czech Republic and Germany):] Current or ever use of medications or supplements known to increase BMD including bisphosphonates, denosumab, teriparatide, abaloparatide, romosozumab, calcitonin, fluoride and strontium.
23. [Visit 1a: Additional exclusion criteria for the BMD subgroup (adolescents) (except for Czech Republic and Germany):] Treatment with medications that are known to decrease bone mass: a. Glucocorticoids (oral, intravenous, chronic inhaled, chronic extensive topical) within the previous 3 months. Oral/intravenous glucocorticoids (prednisone ≥ 2.5 mg daily for ≥ 3 months, or the equivalent) within the last 12 months. b. Depo-medroxyprogesterone acetate within the previous 24 months. Depo-medroxyprogesterone acetate for a duration of use greater than 2 years ever in life. c. Aromatase inhibitors and/or raloxifene within the previous 24 months. d. Heparin, warfarin, thiazolidinedione, SGLT-2 inhibitors, tricyclic antidepressants, chronic proton pump inhibitor (PPI) use, selective serotonin reuptake inhibitors (SSRIs) within the previous 3 months.
24. [Visit 1a: Additional exclusion criteria for the BMD subgroup (adolescents) (except for Czech Republic and Germany):] Conditions that preclude BMD measurement i.e. lumbar spine/bilateral hip surgery with hardware in place, abdominal clips, umbilical ring (not willing to remove) or weight that exceeds the DXA machine limitation.
25. [Visit 1b: Additional exclusion criterion for the BMD subgroup (adolescents) (except for Czech Republic and Germany):] BMD Z-score below -1.5.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall Pearl Index (PI) in non-breastfeeding women aged 18 to 35 years (at the time of trial enrolment).

Secondary endpoints 27

1. [Secondary efficacy:] Overall PI in women aged ≤ 35 years and in women > 35 years (at the time of trial enrolment).
2. [Secondary efficacy:] PI after correction for back-up contraception and sexual activity (evaluable cycles).
3. [Secondary efficacy:] PI after correction for back-up contraception and sexual activity (evaluable cycles) in women aged ≤ 35 years and in women > 35 years (at the time of trial enrolment).
4. [Secondary efficacy:] PI for method failure.
5. [Secondary efficacy:] PI for method failure in women aged ≤ 35 years and in women > 35 years (at the time of trial enrolment).
6. [Secondary efficacy:] Pregnancy ratio by life table analysis.
7. [Secondary efficacy:] Pregnancy ratio by life table analysis in women aged ≤ 35 years and in women > 35 years (at the time of trial enrolment).
8. [Secondary safety and tolerability:] Adverse events (AEs).
9. [Secondary safety and tolerability:] Vital Signs.
10. [Secondary safety and tolerability:] Physical examination.
11. [Secondary safety and tolerability:] Gynaecological examination, incl. transvaginal ultrasound examination and cervical cytology.
12. [Secondary safety and tolerability:] Mastodynia/mastalgia/dysmenorrhoea.
13. [Secondary safety and tolerability:] Proportion of subjects with bleeding / spotting in each cycle.
14. [Secondary safety and tolerability:] Proportion of subjects with absence of bleeding.
15. [Secondary safety and tolerability:] Proportion of subjects with prolonged bleeding.
16. [Secondary safety and tolerability:] Number of days per cycle and reference period with bleeding and with spotting.
17. [Secondary safety and tolerability:] Number of bleeding / spotting episodes per reference period.
18. [Secondary safety and tolerability:] Duration of bleeding / spotting episodes by cycle and reference period.
19. [Secondary safety and tolerability:] Clinical laboratory parameters (haematology, biochemistry including estradiol levels, TSH and urinalysis).
20. [Secondary safety and tolerability:] IP acceptability.
21. [Secondary safety and tolerability:] Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF).
22. [Exploratory (bone mineral density assessment): For adolescents (except for Czech Republic and Germany) (15-17 years old at the time of enrolment):] Mean absolute changes in lumbar spine (L1-L4) Z-score from baseline to V6/EDV (and VBS) as measured by DXA.
23. [Exploratory (bone mineral density assessment): For adolescents (except for Czech Republic and Germany) (15-17 years old at the time of enrolment):] Mean absolute changes in Z-scores (femoral neck, total hip and total body less head [TBLH]) from baseline to V6/EDV (and VBS).
24. [Exploratory (bone mineral density assessment): For adolescents (except for Czech Republic and Germany) (15-17 years old at the time of enrolment):] Mean absolute and percentage changes in lumbar spine, femoral neck, total hip and total body less head [TBLH] BMD from baseline to V6/EDV (and VBS) as measured by DXA.
25. [Exploratory (bone mineral density assessment): For adolescents (except for Czech Republic and Germany) (15-17 years old at the time of enrolment):] Mean absolute and percentage changes in TBLH bone mineral content (BMC) from baseline to V6/EDV (and VBS) as measured by DXA.
26. [Exploratory (bone mineral density assessment): For adolescents (except for Czech Republic and Germany) (15-17 years old at the time of enrolment):] Proportion of subjects with percentage changes in lumbar spine, femoral neck, total hip and TBLH BMD by categories (≥ 0%; < 0% to -1.5%, < -1.5% to -3%, < -3% to -5%, < -5% to -8% and < -8%) from baseline to V6/EDV (and VBS).
27. [Exploratory (bone mineral density assessment): For adolescents (except for Czech Republic and Germany) (15-17 years old at the time of enrolment):] Proportion of subjects with absolute changes in Z-scores (lumbar spine, femoral neck, total hip and TBLH) by categories (≥ 0.5, < 0.5 to 0.3, < 0.3 to 0, < 0 to 0.3, < -0.3 to -0.5 and < -0.5) from baseline to V6/EDV (and VBS).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Chemo Research S.L.

Sponsor organisation

Chemo Research S.L.

Address

3rd Floor, Calle De Manuel Pombo Angulo 28 Calle De Manuel Pombo Angulo 28

City

Madrid

Postcode

28050

Country

Spain

Scientific contact point

Organisation

Chemo Research S.L.

Contact name

Chief Scientific Officer

Public contact point

Organisation

Chemo Research S.L.

Contact name

Chief Scientific Officer

Third parties 13

Locations

8 EU/EEA countries · 54 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 261 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

12 submissions — initial application plus substantial / non-substantial modifications