| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10014778 |
| E.1.2 | Term | Endometriosis |
|
| 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 evaluate the efficacy of 150 mg and 250 mg once-daily doses of NBI-
56418 in the treatment of pelvic pain due to endometriosis. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety of 150 mg and 250 mg once-daily doses of
NBI-56418.
• To evaluate the effect of 6 months of NBI-56418 treatment on bone
mineral density (BMD).
• To describe the temporal characteristics of NBI-56418 and
leuprorelin in terms of safety and efficacy outcome measures. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| A sub-study to evaluate RNA and protein expression will also be conducted. Sub-study participation will be optional. For subjects who agree to participate, blood samples will be obtained at the beginning of Week 1 and at the end of Weeks 12 and 24. The procedure for the RNA and protein expression sub-study is contained within protocol NBI-56418-0703. |
|
| E.3 | Principal inclusion criteria |
To participate in this study, subjects must:
• Be female, aged 18 to 45 years, inclusive.
• Have a total Composite Pelvic Signs and Symptoms Score (CPSSS)
of ≥6 at screening.
• Have a score of at least 2 for the dysmenorrhea CPSSS component and at least 1
for the nonmenstrual pelvic pain CPSSS component at baseline (Day 1, Week 1).
• Be at 2 to 5 days (inclusive) after the onset of menses prior to randomization
• Have had a diagnosis of endometriosis made following laparoscopic visualization of
the disease within 5 years of the start of screening with recurrent or persistent
symptoms.
• Have documented negative mammogram results within 12 months of screening if
over the age of 40 years.
• Have a history of regular spontaneous menstrual cycles. Assessment of cycle
duration should be based on observations in the absence of drugs or conditions that
are known to affect the cycle (e.g., oral contraceptives, leuprorelin, pregnancy)
• Have a spontaneous menstrual cycle of 28 days (±5 days) prior to randomization.
• Have a Body Mass Index (BMI) of 18 to 32 kg/m2, inclusive.
• Agree to use two forms of nonhormonal contraception (e.g. condom and spermicide)
during the study (from the signing of the consent until the final study visit [end of
Week 30 or early termination]).
• Have a negative urine pregnancy test at screening and prior to dosing (at baseline)
at the beginning of Week 1.
• Have a minimum of 7 days of e-Diary data entries prior to randomization.
• Be willing to comply with all study procedures and restrictions.
• Be able to read and understand the Patient Information Sheet (PIS), and sign the
consent before entering into the study. |
|
| E.4 | Principal exclusion criteria |
Subjects will be excluded from the study if they:
• Were administered a GnRH agonist, GnRH antagonist, danazol, or have received
any of these agents within 6 months of the start of screening.
• Were administered subcutaneous medroxyprogesterone acetate (DMPA-SC) or i.m.
medroxyprogesterone acetate (DMPA-IM), or have received either of these agents
within 3 months of the start of screening.
• Have been nonresponsive to GnRH agonist or antagonist therapy for the
management of endometriosis.
• Are currently using hormonal contraception (for endometriosis or contraception) or
other forms of hormonal therapy for endometriosis or have received such therapy
within 1 month of the start of screening.
• Have had diagnostic laparoscopy or surgical intervention for endometriosis within
1 month of the start of screening.
• Have had a hysterectomy or oopherectomy.
• Have had prior treatment with NBI-56418.
• Have uterine fibroids ≥3 cm in diameter as determined by transvaginal ultrasound at
screening.
• Have any of the following abnormal cervical smear results at screening (based on
the 2001 Bethesda System [Solomon et al., 2002]):
- Atypical squamous cells of undetermined significance (ASC-US) present,
and human papilloma virus (HPV) reflex testing is positive for high risk
types or the testing outcome is unknown
- High-grade squamous intraepithelial lesion (HSIL) present
- Adenocarcinoma in situ (AIS) / malignant cells present
• Have BMD with either lumbar spine or femur T-scores below -1.5 at screening as
determined by the central DXA facility or have a history of pathologic or compression
fractures.
• Have been pregnant within 6 months of the start of screening.
• Are currently breastfeeding.
• Are using systemic steroids on a chronic or regular basis within 3 months of the start
of screening.
• Have a chronic, unstable endocrine abnormality causing dysregulation of the
hypothalamic-pituitary-gonadal axis that leads to ovarian dysfunction.
• Have an unstable medical condition or chronic disease (including history of
neurological [including cognitive], psychological, hepatic, renal, cardiovascular, GI,
or pulmonary disease), irritable bowel syndrome, interstitial cystitis, or malignancy
that could confound interpretation of the study outcomes.
• Have chronic pelvic pain that is not caused by endometriosis (e.g., uterine fibroids).
• Have a history of poor compliance in clinical research studies.
• Have a medically significant illness in the 30 days before the beginning of Week 1.
• Have a clinically significant abnormality based on assessments at screening or the
beginning of Week 1.
• Are using any investigational drug within 2 months of the start of screening.
• Have a positive human immunodeficiency virus antibody (HIV-Ab), hepatitis B
surface antigen (HBsAg), or hepatitis C virus antibody (HCV-Ab) assay at screening
or have a history of a positive result.
• Have an allergy, hypersensitivity, or intolerance to a GnRH agonist or antagonist. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety endpoints will include the following:
• Adverse events
• Clinical laboratory data (clinical chemistry, hematology, and urinalysis)
• Posttreatment menses and ovulation
• Hot flashes
• Serum N-telopeptide
• BMD (spine and femur)
• Vaginal bleeding
• Vital signs
• 12-lead ECGs
• Concomitant medications
• Physical examinations
Efficacy: Statistical comparisons between each NBI-56418 dose level (150 mg and 250 mg) and placebo, between each NBI-56418 dose level and leuprorelin, and between leuprorelin and placebo, will be performed for the numerical rating scale (NRS) change from baseline (CFB) mean values at Weeks 4, 8, and 12 using an analysis of covariance (ANCOVA) model. A preliminary efficacy analysis will be conducted after all subjects have completed Week 12 of the study, but prior to full study completion (and therefore prior to full database lock). The purpose of this early analysis is to explore and understand the efficacy of the two NBI-56418 dose levels, and to fully characterize the study efficacy endpoints (analysis variables), for purposes of planning future efficacy studies in the
NBI-56418 development program in conjunction with an end-of-Phase II meeting with the US Food and Drug Administration (FDA). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 12 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 12 |
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