Clinical trial NCT02317809: Bioequivalence Trial of Liquid Versus Freeze-Dried Pergoveris® in Pituitary Suppressed Healthy Premenopausal Female Subjects
Official title: An Open-label, Randomized, Two-period, Two-sequence Crossover Trial to Assess the Bioequivalence of the Liquid Formulation Versus the Freeze-dried Formulation of 900 IU r-hFSH and 450 IU r-hLH in Pergoveris®, Administered Subcutaneously in Pituitary Suppressed Healthy Premenopausal Female Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Healthy
Pergoveris
Bioequivalence
Infertility
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2014-12-16
Enrollment: 34
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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)
* History or presence of drug or alcohol abuse
* Positive test for drugs of abuse (including alcohol)
* Loss or donation of more than 500 mL of blood within 90 days prior to the first IMP administration
* Administration of any IMP or use of any investigational device within 60 days prior to the first IMP administration
* Use of drugs that may reduce the effectiveness of COCP from the start of the Marvelon cycle until last pharmacokinetic sample. For example, phenytoin, barbiturates, primidone, carbamazapine, oxcarbazepine, topiramate, felbamate, rifampicin, nelfinavir, ritonavir, griseofulvin, oral ketoconazole, and herbal remedies containing Hypericum perforatum (St John's Wort)
* Unlikely to comply with the protocol requirements, instructions, and trial-related restrictions for example, uncooperative attitude, inability to return for follow-up, and improbability of completing the trial
* Is (or is a relative of) the Principal Investigator or any Sub-investigator, Research Assistant, Pharmacist, Trial Coordinator, or other staff directly involved in the conduct of the trial
* Vulnerable subjects (for example, persons kept in detention)

Primary outcomes:
measure: Baseline Corrected Area Under the Concentration-Time Curve From Zero to Last Quantifiable Concentration (AUC 0-t,Adj) for Follicle-Stimulating Hormone (FSH)
timeFrame: 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
measure: Baseline Corrected Area Under the Concentration-Time Curve From Zero to Last Quantifiable Concentration (AUC0-t,Adj) for Luteinizing Hormone (LH)
timeFrame: 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
measure: Baseline Corrected Maximum Serum Concentration (Cmax,Adj) for Follicle-Stimulating Hormone (FSH)
timeFrame: 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
measure: Baseline Corrected Maximum Serum Concentration (Cmax,Adj) for Luteinizing Hormone (LH)
timeFrame: 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:
measure: 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)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: Apparent Terminal Elimination Rate Constant (Lambda[z]) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH)
timeFrame: 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
measure: Time to Reach the Maximum Serum Concentration (Tmax) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH)
timeFrame: 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
measure: Apparent Terminal Half-life (t1/2) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH)
timeFrame: 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
measure: Apparent Serum Clearance (CL/F) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH)
timeFrame: 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
measure: Apparent Volume of Distribution During Terminal Phase (Vz/F) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH)
timeFrame: 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
measure: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
measure: Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Related to Laboratory Assessments, Vital Signs or Electrocardiogram Findings
timeFrame: Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
measure: Number of Subjects With Follicle Size Greater Than (>)13 Millimeter
timeFrame: Day 1 (pre-dose) up to follow-up visit (Day 18) for IMP intervention periods
measure: Serum Estradiol Levels
timeFrame: Screening (up to 28 days), Day 1 (pre-dose) and Day 8 in Period 1, Day 1 (pre-dose), Day 8 and follow-up (Day 18) in Period 2
measure: Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs)
timeFrame: 5 minutes, 1, 2, 4, 6, 12, and 24 hours post-dose in each period
measure: Pain Visual Analogue Scale (VAS) Score
timeFrame: 5 minutes, 1, 2, 4, 6, 12, and 24 hours post-dose in each period
measure: Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Luteinizing Hormone (LH)
timeFrame: Day 1 pre-dose up to follow-up visit (Day 18) for IMP intervention periods
measure: Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) Titers for Luteinizing Hormone (LH)
timeFrame: Day 1 pre-dose up to follow-up visit (Day 18) for IMP intervention periods
measure: Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Follicle-stimulating Hormone (FSH)
timeFrame: Day 1 pre-dose and Day 8 post-dose for IMP intervention periods
measure: Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Follicle-stimulating Hormone (FSH) at Follow-up Visit
timeFrame: At follow-up visit (Day 49)
measure: Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH)
timeFrame: Day 1 pre-dose and Day 8 post-dose for IMP intervention periods.
measure: Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH) at Follow-up Visit
timeFrame: At follow-up visit (Day 49)
measure: Neutralizing Antibodies (NAbs) Titers for Follicle-stimulating Hormone (FSH)
timeFrame: Day 1 pre-dose, Day 8 post-dose, follow-up visit (Day 49)
Other outcomes:
Locations:
city: Darmstadt
country: Germany
facility: Please contact the Merck KGaA Communication Center
Study officials:
affiliation: Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: 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.