Bioequivalence Trial of Liquid Versus Freeze-Dried Pergoveris® in Pituitary Suppressed Healthy Premenopausal Female Subjects

NCT02317809 | Completed Phase 1 Results

• 2 other identifiers: 200061-0062014-003506-32
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief Summary

Some women cannot have children because they cannot produce enough follicle stimulating hormone (FSH) and luteinising hormone (LH). When this happens the ovaries fail to produce an egg during the menstrual cycle - a condition known as anovulation. Anovulation can be treated by giving replacement FSH and LH. Pergoveris is a medication that contains both FSH and LH. It is used for the treatment of anovulation in women who do not produce enough FSH and LH. A new, liquid formulation of Pergoveris is being tested in this study. It will be compared with the current freeze-dried marketed formulation to see if the new formulation gets into the blood stream as easily as the current formulation. This study will involve 38 healthy female subjects and 2 treatment periods and will last for approximately 77 days. Each subject will receive a single dose of the new liquid formulation and a single dose of the current marketed formulation separated by an interval of two weeks in a randomised (by chance) order. Blood samples will be taken at regular intervals over 2 weeks after each dose to measure levels of FSH and LH. To participate female subjects must have normal ovaries on internal ultrasound scan, a normal result from a cervical smear test, be taking the combined oral contraceptive (OC) pill. Eligible subjects will have their usual OC pill replaced with another called Marvelon throughout the study. After 14 days subjects will have their levels of FSH and LH checked and if sufficiently reduced will only then proceed to dosing. Subjects will then receive one of the formulations. An ultrasound scan of the ovaries will be performed 7 days later, and another one 7 days later just before the next dose. Subjects whose ovaries show signs of stimulation will not be given the second dose. The ultrasound scan will be repeated 7 days after the second dose.

Conditions

Healthy

Keywords

Healthy; Pergoveris; Bioequivalence; Infertility

Outcome Measures

Primary Outcomes (4)

• Baseline Corrected Area Under the Concentration-Time Curve From Zero to Last Quantifiable Concentration (AUC 0-t,Adj) for Follicle-Stimulating Hormone (FSH)

  The AUC (0-t) was defined as the area under the serum concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration. Baseline-corrected AUC0-t (AUC0-t,adj) = AUC0-t - (baseline concentration \* t).

  Pre-dose, 2, 4, 6, 7, 8, 9, 10, 12, 15, 18, 24, 36, 48, 60, 72, 96, 120 and 168 hours post-dose in each period

• Baseline Corrected Area Under the Concentration-Time Curve From Zero to Last Quantifiable Concentration (AUC0-t,Adj) for Luteinizing Hormone (LH)

  The AUC (0-t) was defined as the area under the serum concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration. Baseline-corrected AUC0-t (AUC0-t,adj) = AUC0-t - (baseline concentration \* t).

  Pre-dose, 2, 4, 6, 7, 8, 9, 10, 12, 15, 18, 24, 36, 48, 60, 72, 96 and 120 hours post-dose in each period

• Baseline Corrected Maximum Serum Concentration (Cmax,Adj) for Follicle-Stimulating Hormone (FSH)

  Baseline-corrected Cmax (Cmax,adj) = Cmax - baseline concentration

  Pre-dose, 2, 4, 6, 7, 8, 9, 10, 12, 15, 18, 24, 36, 48, 60, 72, 96, 120 and 168 hours post-dose in each period

• Baseline Corrected Maximum Serum Concentration (Cmax,Adj) for Luteinizing Hormone (LH)

  Baseline-corrected Cmax (Cmax,adj) = Cmax - baseline concentration.

  Pre-dose, 2, 4, 6, 7, 8, 9, 10, 12, 15, 18, 24, 36, 48, 60, 72, 96 and 120 hours post-dose in each period

Secondary Outcomes (20)

• Baseline Corrected Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUC0-inf, Adj) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH)

  Pre-dose, 2, 4, 6, 7, 8, 9, 10, 12, 15, 18, 24, 36, 48, 60, 72, 96, 120, 168 hours post-dose in each period for FSH; Pre-dose, 2, 4, 6, 7, 8, 9, 10, 12, 15, 18, 24, 36, 48, 60, 72, 96, 120 hours post-dose in each period for LH

• Baseline Corrected Area Under the Serum Concentration-time Curve From Time Tlast Extrapolated to Infinity (%AUCextra,Adj) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH)

  Pre-dose, 2, 4, 6, 7, 8, 9, 10, 12, 15, 18, 24, 36, 48, 60, 72, 96, 120, 168 hours post-dose in each period for FSH; Pre-dose, 2, 4, 6, 7, 8, 9, 10, 12, 15, 18, 24, 36, 48, 60, 72, 96, 120 hours post-dose in each period for LH

• Apparent Terminal Elimination Rate Constant (Lambda[z]) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH)

  Pre-dose, 2, 4, 6, 7, 8, 9, 10, 12, 15, 18, 24, 36, 48, 60, 72, 96, 120, 168 hours post-dose in each period for FSH; Pre-dose, 2, 4, 6, 7, 8, 9, 10, 12, 15, 18, 24, 36, 48, 60, 72, 96, 120 hours post-dose in each period for LH

• Time to Reach the Maximum Serum Concentration (Tmax) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH)

  Pre-dose, 2, 4, 6, 7, 8, 9, 10, 12, 15, 18, 24, 36, 48, 60, 72, 96, 120, 168 hours post-dose in each period for FSH; Pre-dose, 2, 4, 6, 7, 8, 9, 10, 12, 15, 18, 24, 36, 48, 60, 72, 96, 120 hours post-dose in each period for LH

• Apparent Terminal Half-life (t1/2) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH)

  Pre-dose, 2, 4, 6, 7, 8, 9, 10, 12, 15, 18, 24, 36, 48, 60, 72, 96, 120, 168 hours post-dose in each period for FSH; Pre-dose, 2, 4, 6, 7, 8, 9, 10, 12, 15, 18, 24, 36, 48, 60, 72, 96, 120 hours post-dose in each period for LH

Study Arms (2)

First Liquid Pergoveris, Then Freeze-dried Pergoveris

EXPERIMENTAL

Drug: Liquid pergoveris; Drug: Freeze-dried pergoveris

First Freeze-dried Pergoveris, Then Liquid Pergoveris

EXPERIMENTAL

Drug: Liquid pergoveris; Drug: Freeze-dried pergoveris

Interventions

Liquid pergoveris DRUG

All subjects will be administered with 900 IU of r-hFSH and 450 IU of r-hLH solution (Liquid Pergoveris) as subcutaneous injection using a disposable pen-injector on Day 1 in either first intervention period or second intervention period.

First Freeze-dried Pergoveris, Then Liquid Pergoveris; First Liquid Pergoveris, Then Freeze-dried Pergoveris

Freeze-dried pergoveris DRUG

All subjects will be administered with 900 IU of r-hFSH and 450 IU of r-hLH freeze-dried powder (Freeze-dried Pergoveris) as subcutaneous injection on Day 1 in either first intervention period or second intervention period.

First Freeze-dried Pergoveris, Then Liquid Pergoveris; First Liquid Pergoveris, Then Freeze-dried Pergoveris

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Premenopausal women aged 18 to 40 years (both inclusive) at Screening
• Taking a combined oral contraceptive (COCP) for at least 1 year prior to Screening and willing to recommence taking their own COCP from Day 43 of the Marvelon cycle until follow-up
• Normal follicle-stimulating hormone (FSH) (less than \[\<\] 12 international units per liter \[IU/L\]) and estradiol levels (\<100 picogram per milliliter \[pg/mL\])
• Gave written informed consent prior to any trial-related procedure
• Forearm veins suitable for cannulation or repeated venipuncture
• Body weight of greater than or equal to (\>=) 48 kilogram (kg) and a body mass index (BMI) between 18.5 and 29.9 kilogram per square meter (kg/m\^2) (both inclusive)
• Clinically acceptable values for vital signs (systolic blood pressure \[SBP\], diastolic blood pressure \[DBP\], pulse rate, and body temperature), as assessed by the Investigator
• Non-smoking or having refrained from smoking for at least 6 months prior to Screening and with a history of \<10 pack years \[number of pack years = (number of cigarettes per day/20)\*number of years smoked\]
• Able to communicate well with the Investigator, understanding the protocol requirements and restrictions, and willing to comply with the requirements of the entire trial
• Negative pregnancy test at Screening, before the start of the Marvelon cycle, and at admission (Day -1 Period 1 and Day -1 Period 2)
• Willing to use additional nonhormonal contraceptives (for example, condoms or occlusive cap \[diaphragm or cervical/vault cap\] with spermicide, nonhormonal intrauterine device, previous sterilization of the subject or her partner, being sexually inactive) from Day 1 of the Marvelon cycle up to follow-up
• Normal liquid-based cervical cytology assessment (Papanicolaou test score \<II) within the last 12 months before Screening. If not performed as part of routine clinical care, a cervical cytology assessment must be performed as part of the Screening assessments and the result must be normal

You may not qualify if:

• Any surgical or medical condition, including findings in the medical history or in the pre-trial assessments, that in the opinion of the Investigator, constitutes a risk or a contraindication for the participation of the subject in the trial or that could interfere with the trial objectives, conduct, or evaluation
• Any clinically relevant abnormality in the safety laboratory parameters, as judged by the Investigator
• Any clinically significant abnormality on the 12-lead resting electrocardiogram (ECG), as judged by the Investigator
• Positive results from the serology examination for hepatitis B surface antigen, hepatitis C virus, or the human immunodeficiency virus
• Contraindications to COCP use shown by a history of conditions specified in the protocol
• History of tumors of the pituitary gland or hypothalamus
• Clinically significant abnormalities of the genital organs as determined by gynecological examination and transvaginal ultrasound (TVUS) and based on the Investigator's judgment for example, ovarian tumors, nonfunctional ovarian cysts, endometrial hyperplasia)
• Not successfully down-regulated by showing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels above 1.0 IU/L and estradiol levels above 100 pg/mL before investigational medicinal product (IMP) administration or showing more than12 immature follicles per ovary. In that case there should be no signs of polycystic ovary syndrome (PCOS) morphology
• Polycystic ovarian syndrome as defined in the protocol
• Ovarian follicle-like structures larger than 13 millimeter (mm) during COCP use (at Screening)
• Contraindication to treatment with gonadotropins (ovarian enlargement or cyst not due to PCOS and of unknown origin, gynecological hemorrhages of unknown etiology, ovarian, uterine, or mammary carcinoma, tumors of the hypothalamus and pituitary gland, hypersensitivity to gonadotropins or to any of the excipients, extrauterine pregnancy in the previous 3 months, and medical history or risk factors for thromboembolic events)
• Pregnant or breastfeeding a child
• Prior treatment with FSH and or LH containing products
• Definite or suspected personal history or family history of an adverse drug reaction or hypersensitivity to drugs with a similar chemical structure to FSH or LH
• History or presence of asthma (with the exception of childhood asthma) or any serious allergy (requiring hospitalization or prolonged systemic treatment)

Sponsors & Collaborators

• Merck KGaA, Darmstadt, Germany: lead

Study Sites (1)

Please contact the Merck KGaA Communication Center

Darmstadt, Germany

Location

Related Publications (1)

• Bagchus W, Yalkinoglu O, Wolna P. Open-Label, Randomized, Two-Way, Crossover Study Assessing the Bioequivalence of the Liquid Formulation versus the Freeze-Dried Formulation of Recombinant Human FSH and Recombinant Human LH in a Fixed 2:1 Combination (Pergoveris(R)) in Pituitary-Suppressed Healthy Women. Front Endocrinol (Lausanne). 2018 Jan 11;8:371. doi: 10.3389/fendo.2017.00371. eCollection 2017.

  PMID: 29375477 DERIVED

MeSH Terms

Conditions

Infertility

Condition Hierarchy (Ancestors)

Genital Diseases; Urogenital Diseases

Results Point of Contact

• Title: Merck KGaA Communication Center
• Organization: Merck Healthcare, a business of Merck KGaA, Darmstadt, Germany

service@merckgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 11, 2014
• First Posted: December 16, 2014
• Study Start: January 31, 2015
• Primary Completion: October 31, 2015
• Study Completion: October 31, 2015
• Last Updated: July 16, 2018
• Results First Posted: December 13, 2016

Record last verified: 2017-10

Locations

DE (1)