Healthy
Conditions
Keywords
Healthy, Pergoveris, Bioequivalence, Infertility
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.
Interventions
DRUGLiquid pergoveris
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.
DRUGFreeze-dried pergoveris
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.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
Yes
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline Corrected Area Under the Concentration-Time Curve From Zero to Last Quantifiable Concentration (AUC 0-t,Adj) for Follicle-Stimulating Hormone (FSH) | 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 | 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). |
| Baseline Corrected Area Under the Concentration-Time Curve From Zero to Last Quantifiable Concentration (AUC0-t,Adj) for Luteinizing Hormone (LH) | 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 | 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). |
| Baseline Corrected Maximum Serum Concentration (Cmax,Adj) for Follicle-Stimulating Hormone (FSH) | 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 Cmax (Cmax,adj) = Cmax - baseline concentration |
| Baseline Corrected Maximum Serum Concentration (Cmax,Adj) for Luteinizing Hormone (LH) | 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 Cmax (Cmax,adj) = Cmax - baseline concentration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Terminal half-life is the time measured for the concentration to decrease by one half. |
| Apparent Serum Clearance (CL/F) 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 | Clearance is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained is influenced by the fraction of the dose absorbed and was expressed as volume (Liter) per unit of time (hour). |
| Apparent Volume of Distribution During Terminal Phase (Vz/F) 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 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired concentration. Apparent volume of distribution (Vz/F) is influenced by the fraction absorbed. |
| Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods | An AE was any untoward medical occurrence in a subject, regardless of causal relationship with the treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs include both SAEs and non-serious AEs. |
| Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Related to Laboratory Assessments, Vital Signs or Electrocardiogram Findings | Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods | — |
| Number of Subjects With Follicle Size Greater Than (>)13 Millimeter | Day 1 (pre-dose) up to follow-up visit (Day 18) for IMP intervention periods | Transvaginal ultrasound (TVUS) was performed to determine the follicle size and number. |
| Serum Estradiol Levels | 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 | Data was planned to be presented as per the sequence of treatment received. |
| Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | 5 minutes, 1, 2, 4, 6, 12, and 24 hours post-dose in each period | Injection site was assessed by the study site staff for any local reaction (redness, swelling, bruising, and itching). Redness and bruising were scaled as None (no visible redness or bruising); Mild (less than or equal to \[\<=\] 2.0 centimeters \[cm\] redness or bruising); Moderate (greater than \[\>\] 2 to \<=5.0 cm redness or bruising); Severe (\>5.0 cm redness or bruising). Swelling was scaled as None (no swelling detected); Mild (palpable 'firmness' only); Moderate (\<= 4 cm swelling); Severe (\>4 cm swelling). Itching was scaled as None (no itching); Mild itching; Moderate itching and Severe itching. Only those scale categories which report at least 1 subject were presented. |
| 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 | — |
| Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Luteinizing Hormone (LH) | Day 1 pre-dose up to follow-up visit (Day 18) for IMP intervention periods | — |
| Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) Titers for Luteinizing Hormone (LH) | Day 1 pre-dose up to follow-up visit (Day 18) for IMP intervention periods | — |
| Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Follicle-stimulating Hormone (FSH) | Day 1 pre-dose and Day 8 post-dose for IMP intervention periods | — |
| Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Follicle-stimulating Hormone (FSH) at Follow-up Visit | At follow-up visit (Day 49) | — |
| Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH) | Day 1 pre-dose and Day 8 post-dose for IMP intervention periods. | — |
| Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH) at Follow-up Visit | At follow-up visit (Day 49) | — |
| Neutralizing Antibodies (NAbs) Titers for Follicle-stimulating Hormone (FSH) | Day 1 pre-dose, Day 8 post-dose, follow-up visit (Day 49) | — |
| Pain Visual Analogue Scale (VAS) Score | 5 minutes, 1, 2, 4, 6, 12, and 24 hours post-dose in each period | The severity of pain was evaluated by the subject and recorded using a 100 millimeter (mm) visual analogue scale (VAS) ranging from 0 to 100, where 0 mm = no pain and 100 mm = worst possible pain. |
| 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 | Area under the serum concentration-time curve from Tlast extrapolated to infinity given as a percentage of AUC0-inf. Data was not planned to be summarized if AUCextra,adj was less than 20%. |
| 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 | The elimination rate constant was obtained from linear regression of the terminal phase of the log transformed concentration-time data. |
| 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 | — |
Countries
Germany
Participant flow
Pre-assignment details
A total of 34 subjects were randomized and treated. Of these, 31 subjects completed the study. This was a crossover study with washout of 14 to 17 days between the two intervention periods.
Participants by arm
| Arm | Count |
|---|---|
| All Subjects All subjects who were administered with 900 IU of r-hFSH and 450 IU of r-hLH solution (Liquid Pergoveris) as subcutaneous injection using a disposable pen-injector or 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 or second intervention period. | 34 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention Period (8 Days) | Protocol Non-Compliance | 2 | 0 |
| First Intervention Period (8 Days) | Withdrawn Due To Multiple Follicles | 1 | 0 |
Baseline characteristics
| Characteristic | All Subjects |
|---|---|
| Age, Continuous | 28.6 Years STANDARD_DEVIATION 5.88 |
| Sex: Female, Male Female | 34 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 34 | 14 / 31 |
| serious Total, serious adverse events | 1 / 34 | 0 / 31 |
Outcome results
Primary
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).
Time frame: 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
Population: Pharmacokinetic (PK) analysis set: All randomized subjects who were treated with both liquid and freeze-dried formulations and had absence of relevant protocol violations, had availability of the primary target variables and successfully down regulated baseline levels of FSH and LH below 1.0 IU/L in both the screening and dedicated PK assays.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Liquid Pergoveris | Baseline Corrected Area Under the Concentration-Time Curve From Zero to Last Quantifiable Concentration (AUC 0-t,Adj) for Follicle-Stimulating Hormone (FSH) | 3187.4 International units*hour/liter (IU*h/L) | Geometric Coefficient of Variation 24.3 |
| Freeze-dried Pergoveris | Baseline Corrected Area Under the Concentration-Time Curve From Zero to Last Quantifiable Concentration (AUC 0-t,Adj) for Follicle-Stimulating Hormone (FSH) | 2775.4 International units*hour/liter (IU*h/L) | Geometric Coefficient of Variation 22 |
Comparison: Mixed model analysis was used.90% CI: [110.87, 118.15]
Primary
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).
Time frame: 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
Population: Pharmacokinetic (PK) analysis set: all randomized subjects who were treated with both liquid and freeze-dried formulations and had absence of relevant protocol violations, had availability of the primary target variables and successfully downregulated baseline levels of FSH and LH below 1.0 IU/L in both the screening and dedicated PK assays.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Liquid Pergoveris | Baseline Corrected Area Under the Concentration-Time Curve From Zero to Last Quantifiable Concentration (AUC0-t,Adj) for Luteinizing Hormone (LH) | 210.4 International units*hour/liter (IU*h/L) | Geometric Coefficient of Variation 25.8 |
| Freeze-dried Pergoveris | Baseline Corrected Area Under the Concentration-Time Curve From Zero to Last Quantifiable Concentration (AUC0-t,Adj) for Luteinizing Hormone (LH) | 195.2 International units*hour/liter (IU*h/L) | Geometric Coefficient of Variation 22.5 |
Comparison: Mixed model analysis was used.90% CI: [101.42, 112.86]
Primary
Baseline Corrected Maximum Serum Concentration (Cmax,Adj) for Follicle-Stimulating Hormone (FSH)
Baseline-corrected Cmax (Cmax,adj) = Cmax - baseline concentration
Time frame: 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
Population: Pharmacokinetic (PK) analysis set: all randomized subjects who were treated with both liquid and freeze-dried formulations and had absence of relevant protocol violations, had availability of the primary target variables and successfully downregulated baseline levels of FSH and LH below 1.0 IU/L in both the screening and dedicated PK assays.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Liquid Pergoveris | Baseline Corrected Maximum Serum Concentration (Cmax,Adj) for Follicle-Stimulating Hormone (FSH) | 47.92 International units per liter (IU/L) | Geometric Coefficient of Variation 27.3 |
| Freeze-dried Pergoveris | Baseline Corrected Maximum Serum Concentration (Cmax,Adj) for Follicle-Stimulating Hormone (FSH) | 42.55 International units per liter (IU/L) | Geometric Coefficient of Variation 29 |
Comparison: Mixed model analysis was used.90% CI: [106.44, 119.27]
Primary
Baseline Corrected Maximum Serum Concentration (Cmax,Adj) for Luteinizing Hormone (LH)
Baseline-corrected Cmax (Cmax,adj) = Cmax - baseline concentration.
Time frame: 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
Population: Pharmacokinetic (PK) analysis set: all randomized subjects who were treated with both liquid and freeze-dried formulations and had absence of relevant protocol violations, had availability of the primary target variables and successfully downregulated baseline levels of FSH and LH below 1.0 IU/L in both the screening and dedicated PK assays.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Liquid Pergoveris | Baseline Corrected Maximum Serum Concentration (Cmax,Adj) for Luteinizing Hormone (LH) | 10.126 International units per liter (IU/L) | Geometric Coefficient of Variation 31.1 |
| Freeze-dried Pergoveris | Baseline Corrected Maximum Serum Concentration (Cmax,Adj) for Luteinizing Hormone (LH) | 9.782 International units per liter (IU/L) | Geometric Coefficient of Variation 24.1 |
Comparison: Mixed model analysis was used.90% CI: [93.16, 114.47]
Secondary
Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) Titers for Luteinizing Hormone (LH)
Time frame: Day 1 pre-dose up to follow-up visit (Day 18) for IMP intervention periods
Population: Data could not be collected as there were no subjects with positive results for ADAs and NAbs.
Secondary
Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH)
Time frame: Day 1 pre-dose and Day 8 post-dose for IMP intervention periods.
Population: Safety analysis set included all subjects who received at least 1 dose of the investigational medicinal product (IMP) (that is, either liquid formulation or freeze-dried formulation). Here, Number of subjects analyzed included those who have positive ADAs values.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Liquid Pergoveris | Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH) | Day 1: Subject 1 | 1.0 Log Titers |
| Liquid Pergoveris | Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH) | Day 8: Subject 1 | 1.0 Log Titers |
| Liquid Pergoveris | Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH) | Day 1: Subject 2 | 1.7 Log Titers |
| Liquid Pergoveris | Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH) | Day 8: Subject 2 | 1.7 Log Titers |
| Freeze-dried Pergoveris | Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH) | Day 8: Subject 2 | NA Log Titers |
| Freeze-dried Pergoveris | Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH) | Day 1: Subject 1 | 1.7 Log Titers |
| Freeze-dried Pergoveris | Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH) | Day 1: Subject 2 | NA Log Titers |
| Freeze-dried Pergoveris | Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH) | Day 8: Subject 1 | 1.0 Log Titers |
Secondary
Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH) at Follow-up Visit
Time frame: At follow-up visit (Day 49)
Population: Safety analysis set included all subjects who received at least 1 dose of the investigational medicinal product (IMP) (that is, either liquid formulation or freeze-dried formulation). Here, Number of subjects analyzed included those who have positive ADAs values.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liquid Pergoveris | Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH) at Follow-up Visit | 1.0 Log Titers |
Secondary
Apparent Serum Clearance (CL/F) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH)
Clearance is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained is influenced by the fraction of the dose absorbed and was expressed as volume (Liter) per unit of time (hour).
Time frame: 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
Population: PK analysis set. Here n signifies those subjects who were evaluable for the specified hormone level in each arm, respectively.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Liquid Pergoveris | Apparent Serum Clearance (CL/F) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | Follicle-stimulating Hormone (n=22, 22) | 0.2673 Liter per hour (L/h) | Geometric Coefficient of Variation 24.2 |
| Liquid Pergoveris | Apparent Serum Clearance (CL/F) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | Luteinizing Hormone (n=21, 22) | 2.082 Liter per hour (L/h) | Geometric Coefficient of Variation 25.2 |
| Freeze-dried Pergoveris | Apparent Serum Clearance (CL/F) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | Follicle-stimulating Hormone (n=22, 22) | 0.3091 Liter per hour (L/h) | Geometric Coefficient of Variation 22.2 |
| Freeze-dried Pergoveris | Apparent Serum Clearance (CL/F) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | Luteinizing Hormone (n=21, 22) | 2.238 Liter per hour (L/h) | Geometric Coefficient of Variation 21.2 |
Secondary
Apparent Terminal Elimination Rate Constant (Lambda[z]) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH)
The elimination rate constant was obtained from linear regression of the terminal phase of the log transformed concentration-time data.
Time frame: 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
Population: PK analysis set. Here n signifies those subjects who were evaluable for the specified hormone level in each arm, respectively.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Liquid Pergoveris | Apparent Terminal Elimination Rate Constant (Lambda[z]) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | Luteinizing Hormone (n=21, 22) | 0.05542 Per Hour (1/hour) | Geometric Coefficient of Variation 17.1 |
| Liquid Pergoveris | Apparent Terminal Elimination Rate Constant (Lambda[z]) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | Follicle-stimulating Hormone (n=22, 22) | 0.01880 Per Hour (1/hour) | Geometric Coefficient of Variation 14.2 |
| Freeze-dried Pergoveris | Apparent Terminal Elimination Rate Constant (Lambda[z]) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | Follicle-stimulating Hormone (n=22, 22) | 0.01963 Per Hour (1/hour) | Geometric Coefficient of Variation 10 |
| Freeze-dried Pergoveris | Apparent Terminal Elimination Rate Constant (Lambda[z]) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | Luteinizing Hormone (n=21, 22) | 0.05094 Per Hour (1/hour) | Geometric Coefficient of Variation 25.5 |
Secondary
Apparent Terminal Half-life (t1/2) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH)
Terminal half-life is the time measured for the concentration to decrease by one half.
Time frame: 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
Population: PK analysis set. Here n signifies those subjects who were evaluable for the specified hormone level in each arm, respectively.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Liquid Pergoveris | Apparent Terminal Half-life (t1/2) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | Follicle-stimulating Hormone (n=22, 22) | 36.87 Hour (h) | Geometric Coefficient of Variation 14.2 |
| Liquid Pergoveris | Apparent Terminal Half-life (t1/2) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | Luteinizing Hormone (n=21, 22) | 12.507 Hour (h) | Geometric Coefficient of Variation 17.1 |
| Freeze-dried Pergoveris | Apparent Terminal Half-life (t1/2) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | Follicle-stimulating Hormone (n=22, 22) | 35.31 Hour (h) | Geometric Coefficient of Variation 10 |
| Freeze-dried Pergoveris | Apparent Terminal Half-life (t1/2) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | Luteinizing Hormone (n=21, 22) | 13.608 Hour (h) | Geometric Coefficient of Variation 25.5 |
Secondary
Apparent Volume of Distribution During Terminal Phase (Vz/F) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH)
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired concentration. Apparent volume of distribution (Vz/F) is influenced by the fraction absorbed.
Time frame: 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
Population: PK analysis set. Here n signifies those subjects who were evaluable for the specified hormone level in each arm, respectively.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Liquid Pergoveris | Apparent Volume of Distribution During Terminal Phase (Vz/F) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | Follicle-stimulating Hormone (n=22, 22) | 14.219 Liter (L) | Geometric Coefficient of Variation 27.1 |
| Liquid Pergoveris | Apparent Volume of Distribution During Terminal Phase (Vz/F) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | Luteinizing Hormone (n=21, 22) | 37.57 Liter (L) | Geometric Coefficient of Variation 28.8 |
| Freeze-dried Pergoveris | Apparent Volume of Distribution During Terminal Phase (Vz/F) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | Follicle-stimulating Hormone (n=22, 22) | 15.742 Liter (L) | Geometric Coefficient of Variation 21.4 |
| Freeze-dried Pergoveris | Apparent Volume of Distribution During Terminal Phase (Vz/F) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | Luteinizing Hormone (n=21, 22) | 43.93 Liter (L) | Geometric Coefficient of Variation 32.3 |
Secondary
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)
Time frame: 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
Population: PK analysis set. Here n signifies those subjects who were evaluable for the specified hormone level in each arm, respectively.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Liquid Pergoveris | 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) | Follicle-stimulating Hormone (n=22, 22) | 3366.6 International units*hour/liter (IU*h/L) | Geometric Coefficient of Variation 24.2 |
| Liquid Pergoveris | 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) | Luteinizing Hormone (n=21, 22) | 216.1 International units*hour/liter (IU*h/L) | Geometric Coefficient of Variation 25.2 |
| Freeze-dried Pergoveris | 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) | Follicle-stimulating Hormone (n=22, 22) | 2912.1 International units*hour/liter (IU*h/L) | Geometric Coefficient of Variation 22.2 |
| Freeze-dried Pergoveris | 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) | Luteinizing Hormone (n=21, 22) | 201.1 International units*hour/liter (IU*h/L) | Geometric Coefficient of Variation 21.2 |
Secondary
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)
Area under the serum concentration-time curve from Tlast extrapolated to infinity given as a percentage of AUC0-inf. Data was not planned to be summarized if AUCextra,adj was less than 20%.
Time frame: 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
Population: As per statistical analysis plan, data was not planned to be summarized because AUCextra,adj was below 20% for all the participants.
Secondary
Neutralizing Antibodies (NAbs) Titers for Follicle-stimulating Hormone (FSH)
Time frame: Day 1 pre-dose, Day 8 post-dose, follow-up visit (Day 49)
Population: Data could not be collected because as per spondor decision, there were no subjects evaluated for NAb due to low titers (noise) for the ADA .
Secondary
Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE was any untoward medical occurrence in a subject, regardless of causal relationship with the treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs include both SAEs and non-serious AEs.
Time frame: Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
Population: Safety analysis set included all subjects who received at least 1 dose of the investigational medicinal product (IMP) (that is, either liquid formulation or freeze-dried formulation).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Liquid Pergoveris | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 12 Subjects |
| Liquid Pergoveris | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 1 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 14 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Subjects |
Secondary
Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Follicle-stimulating Hormone (FSH)
Time frame: Day 1 pre-dose and Day 8 post-dose for IMP intervention periods
Population: Safety analysis set included all subjects who received at least 1 dose of the investigational medicinal product (IMP) (that is, either liquid formulation or freeze-dried formulation). Here n signifies those subjects who were evaluable for the specified hormone level in each arm, respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Liquid Pergoveris | Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Follicle-stimulating Hormone (FSH) | Day 1: Subjects with ADAs to FSH (n= 33, 31) | 2 Subjects |
| Liquid Pergoveris | Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Follicle-stimulating Hormone (FSH) | Day 8: Subjects with ADAs to FSH (n= 34, 31) | 2 Subjects |
| Liquid Pergoveris | Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Follicle-stimulating Hormone (FSH) | Day1: Subjects with NAbs to FSH (n= 34, 31) | NA Subjects |
| Liquid Pergoveris | Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Follicle-stimulating Hormone (FSH) | Day8: Subjects with NAbs to FSH (n= 34, 31) | NA Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Follicle-stimulating Hormone (FSH) | Day8: Subjects with NAbs to FSH (n= 34, 31) | NA Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Follicle-stimulating Hormone (FSH) | Day 1: Subjects with ADAs to FSH (n= 33, 31) | 1 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Follicle-stimulating Hormone (FSH) | Day1: Subjects with NAbs to FSH (n= 34, 31) | NA Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Follicle-stimulating Hormone (FSH) | Day 8: Subjects with ADAs to FSH (n= 34, 31) | 1 Subjects |
Secondary
Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Follicle-stimulating Hormone (FSH) at Follow-up Visit
Time frame: At follow-up visit (Day 49)
Population: Safety analysis set included all subjects who received at least 1 dose of the investigational medicinal product (IMP) (that is, either liquid formulation or freeze-dried formulation).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Liquid Pergoveris | Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Follicle-stimulating Hormone (FSH) at Follow-up Visit | Subjects with ADAs for FSH (n= 33) | 1 Subjects |
| Liquid Pergoveris | Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Follicle-stimulating Hormone (FSH) at Follow-up Visit | Subjects with NAbs for FSH (n= 34) | NA Subjects |
Secondary
Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Luteinizing Hormone (LH)
Time frame: Day 1 pre-dose up to follow-up visit (Day 18) for IMP intervention periods
Population: Safety analysis set included all subjects who received at least 1 dose of the investigational medicinal product (IMP) (that is, either liquid formulation or freeze-dried formulation).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Liquid Pergoveris | Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Luteinizing Hormone (LH) | Subjects with ADAs to LH | 0 Subjects |
| Liquid Pergoveris | Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Luteinizing Hormone (LH) | Subjects with Neutralizing antibodies to LH | NA Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Luteinizing Hormone (LH) | Subjects with ADAs to LH | 0 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Luteinizing Hormone (LH) | Subjects with Neutralizing antibodies to LH | NA Subjects |
Secondary
Number of Subjects With Follicle Size Greater Than (>)13 Millimeter
Transvaginal ultrasound (TVUS) was performed to determine the follicle size and number.
Time frame: Day 1 (pre-dose) up to follow-up visit (Day 18) for IMP intervention periods
Population: Safety analysis set included all subjects who received at least 1 dose of the investigational medicinal product (IMP) (that is, either liquid formulation or freeze-dried formulation).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liquid Pergoveris | Number of Subjects With Follicle Size Greater Than (>)13 Millimeter | 0 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Follicle Size Greater Than (>)13 Millimeter | 0 Subjects |
Secondary
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs)
Injection site was assessed by the study site staff for any local reaction (redness, swelling, bruising, and itching). Redness and bruising were scaled as None (no visible redness or bruising); Mild (less than or equal to \[\<=\] 2.0 centimeters \[cm\] redness or bruising); Moderate (greater than \[\>\] 2 to \<=5.0 cm redness or bruising); Severe (\>5.0 cm redness or bruising). Swelling was scaled as None (no swelling detected); Mild (palpable 'firmness' only); Moderate (\<= 4 cm swelling); Severe (\>4 cm swelling). Itching was scaled as None (no itching); Mild itching; Moderate itching and Severe itching. Only those scale categories which report at least 1 subject were presented.
Time frame: 5 minutes, 1, 2, 4, 6, 12, and 24 hours post-dose in each period
Population: Safety analysis set included all subjects who received at least 1 dose of the investigational medicinal product (IMP) (that is, either liquid formulation or freeze-dried formulation). Here n signifies those subjects who were evaluable for the specified injection site reaction at the specified time point for each arm, respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Redness: Day 1, 1 hour (n= 32, 31) | 30 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Bruising: Day 1, 6 hour (n= 33, 30) | 33 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | Mild Redness: Day 1, 1 hour (n= 32, 31) | 2 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Itching: Day 1, 2 hour (n= 34, 31) | 34 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Redness: Day 1, 2 hour (n= 34, 31) | 34 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Bruising: Day 1, 2 hour (n= 34, 31) | 34 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | Mild Redness: Day 1, 2 hour (n= 34, 31) | 0 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Itching: Day 1, 4 hour (n= 34, 30) | 34 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Redness: Day 1, 4 hour (n= 34, 30) | 34 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Bruising: Day 1, 12 hour (n= 32, 30) | 32 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | Mild Redness: Day 1, 4 hour (n= 34, 30) | 0 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Itching: Day 1, 6 hour (n= 33, 30) | 32 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Redness: Day 1, 6 hour (n= 33, 30) | 33 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Bruising: Day 1, 1 hour (n= 32, 31) | 32 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | Mild Redness: Day 1, 6 hour (n= 33, 30) | 0 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Bruising: Day 1, 24 hour (n= 34, 28) | 34 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Redness: Day 1, 12 hour (n= 32, 30) | 32 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Itching: Day 1, 12 hour (n= 32, 30) | 32 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Redness: Day 1, 24 hour (n= 34, 28) | 34 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Bruising: Day 1, 4 hour (n= 34, 30) | 34 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Swelling: Day 1, 5 min (n= 34, 31) | 34 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Itching: Day 1, 24 hour (n= 34, 28) | 34 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Swelling: Day 1, 1 hour (n= 32, 31) | 32 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Itching: Day 1, 5 min (n= 34, 31) | 34 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Swelling: Day 1, 2 hour (n= 34, 31) | 34 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Redness: Day 1, 5 min (n= 34, 31) | 30 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Swelling: Day 1, 4 hour (n= 34, 30) | 34 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Bruising: Day 1, 5 min (n= 34, 31) | 34 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Swelling: Day 1, 6 hour (n= 33, 30) | 33 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | Mild Redness: Day 1, 5 min (n= 34, 31) | 4 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Swelling: Day 1, 12 hour (n= 32, 30) | 32 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Itching: Day 1, 1 hour (n= 32, 31) | 32 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Swelling: Day 1, 24 hour (n= 34, 28) | 34 Subjects |
| Liquid Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | Mild Itching: Day 1, 6 hour (n= 33, 30) | 1 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Swelling: Day 1, 24 hour (n= 34, 28) | 28 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Bruising: Day 1, 5 min (n= 34, 31) | 31 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Bruising: Day 1, 1 hour (n= 32, 31) | 31 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Bruising: Day 1, 2 hour (n= 34, 31) | 31 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Bruising: Day 1, 4 hour (n= 34, 30) | 30 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Bruising: Day 1, 6 hour (n= 33, 30) | 30 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Bruising: Day 1, 12 hour (n= 32, 30) | 30 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Bruising: Day 1, 24 hour (n= 34, 28) | 28 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Itching: Day 1, 5 min (n= 34, 31) | 31 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Itching: Day 1, 1 hour (n= 32, 31) | 31 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Itching: Day 1, 2 hour (n= 34, 31) | 31 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Itching: Day 1, 4 hour (n= 34, 30) | 30 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Itching: Day 1, 6 hour (n= 33, 30) | 30 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | Mild Itching: Day 1, 6 hour (n= 33, 30) | 0 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Itching: Day 1, 12 hour (n= 32, 30) | 30 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Itching: Day 1, 24 hour (n= 34, 28) | 28 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Redness: Day 1, 5 min (n= 34, 31) | 26 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | Mild Redness: Day 1, 5 min (n= 34, 31) | 5 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Redness: Day 1, 1 hour (n= 32, 31) | 30 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | Mild Redness: Day 1, 1 hour (n= 32, 31) | 1 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Redness: Day 1, 2 hour (n= 34, 31) | 30 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | Mild Redness: Day 1, 2 hour (n= 34, 31) | 1 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Redness: Day 1, 4 hour (n= 34, 30) | 29 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | Mild Redness: Day 1, 4 hour (n= 34, 30) | 1 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Redness: Day 1, 6 hour (n= 33, 30) | 29 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | Mild Redness: Day 1, 6 hour (n= 33, 30) | 1 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Redness: Day 1, 12 hour (n= 32, 30) | 30 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Redness: Day 1, 24 hour (n= 34, 28) | 28 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Swelling: Day 1, 5 min (n= 34, 31) | 31 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Swelling: Day 1, 1 hour (n= 32, 31) | 31 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Swelling: Day 1, 2 hour (n= 34, 31) | 31 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Swelling: Day 1, 4 hour (n= 34, 30) | 30 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Swelling: Day 1, 6 hour (n= 33, 30) | 30 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) | No Swelling: Day 1, 12 hour (n= 32, 30) | 30 Subjects |
Secondary
Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Related to Laboratory Assessments, Vital Signs or Electrocardiogram Findings
Time frame: Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
Population: Safety analysis set included all subjects who received at least 1 dose of the investigational medicinal product (IMP) (that is, either liquid formulation or freeze-dried formulation).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liquid Pergoveris | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Related to Laboratory Assessments, Vital Signs or Electrocardiogram Findings | 0 Subjects |
| Freeze-dried Pergoveris | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Related to Laboratory Assessments, Vital Signs or Electrocardiogram Findings | 0 Subjects |
Secondary
Pain Visual Analogue Scale (VAS) Score
The severity of pain was evaluated by the subject and recorded using a 100 millimeter (mm) visual analogue scale (VAS) ranging from 0 to 100, where 0 mm = no pain and 100 mm = worst possible pain.
Time frame: 5 minutes, 1, 2, 4, 6, 12, and 24 hours post-dose in each period
Population: Safety analysis set included all subjects who received at least 1 dose of the investigational medicinal product (IMP) (that is, either liquid formulation or freeze-dried formulation). Here n signifies those subjects who were evaluable for the specified time point in each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liquid Pergoveris | Pain Visual Analogue Scale (VAS) Score | Day 1, 2 hour (n= 34, 31) | 0.2 mm | Standard Deviation 0.52 |
| Liquid Pergoveris | Pain Visual Analogue Scale (VAS) Score | Day 1, 6 hour (n= 33, 30) | 0.2 mm | Standard Deviation 0.46 |
| Liquid Pergoveris | Pain Visual Analogue Scale (VAS) Score | Day 1, 1 hour (n= 32, 31) | 0.2 mm | Standard Deviation 0.59 |
| Liquid Pergoveris | Pain Visual Analogue Scale (VAS) Score | Day 1, 12 hour (n= 32, 30) | 0.2 mm | Standard Deviation 0.45 |
| Liquid Pergoveris | Pain Visual Analogue Scale (VAS) Score | Day 1, 4 hour (n= 34, 30) | 0.1 mm | Standard Deviation 0.54 |
| Liquid Pergoveris | Pain Visual Analogue Scale (VAS) Score | Day 1, 24 hour (n= 34, 29) | 0.1 mm | Standard Deviation 0.24 |
| Liquid Pergoveris | Pain Visual Analogue Scale (VAS) Score | Day 1, 5 min (n= 34, 31) | 1.9 mm | Standard Deviation 4.04 |
| Freeze-dried Pergoveris | Pain Visual Analogue Scale (VAS) Score | Day 1, 24 hour (n= 34, 29) | 0.1 mm | Standard Deviation 0.35 |
| Freeze-dried Pergoveris | Pain Visual Analogue Scale (VAS) Score | Day 1, 5 min (n= 34, 31) | 2.5 mm | Standard Deviation 4.19 |
| Freeze-dried Pergoveris | Pain Visual Analogue Scale (VAS) Score | Day 1, 1 hour (n= 32, 31) | 1.3 mm | Standard Deviation 5.01 |
| Freeze-dried Pergoveris | Pain Visual Analogue Scale (VAS) Score | Day 1, 2 hour (n= 34, 31) | 0.3 mm | Standard Deviation 0.51 |
| Freeze-dried Pergoveris | Pain Visual Analogue Scale (VAS) Score | Day 1, 4 hour (n= 34, 30) | 0.2 mm | Standard Deviation 0.57 |
| Freeze-dried Pergoveris | Pain Visual Analogue Scale (VAS) Score | Day 1, 6 hour (n= 33, 30) | 1.0 mm | Standard Deviation 5.1 |
| Freeze-dried Pergoveris | Pain Visual Analogue Scale (VAS) Score | Day 1, 12 hour (n= 32, 30) | 0.2 mm | Standard Deviation 0.48 |
Secondary
Serum Estradiol Levels
Data was planned to be presented as per the sequence of treatment received.
Time frame: 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
Population: Safety analysis set included all subjects who received at least 1 dose of the investigational medicinal product (IMP) (that is, either liquid formulation or freeze-dried formulation).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liquid Pergoveris | Serum Estradiol Levels | Period 1: Day 1 (pre-dose) (n= 16, 17) | 11.388 nanogram per liter (ng/L) | Standard Deviation 3.7346 |
| Liquid Pergoveris | Serum Estradiol Levels | Period 2: Day 1 (pre-dose) (n= 14, 16) | 12.469 nanogram per liter (ng/L) | Standard Deviation 2.8548 |
| Liquid Pergoveris | Serum Estradiol Levels | Period 2: Day 8 (n= 13, 17) | 15.454 nanogram per liter (ng/L) | Standard Deviation 6.642 |
| Liquid Pergoveris | Serum Estradiol Levels | Screening (n= 17, 16) | 14.906 nanogram per liter (ng/L) | Standard Deviation 9.1722 |
| Liquid Pergoveris | Serum Estradiol Levels | Follow-up (Day 18) (n= 16, 17) | 15.714 nanogram per liter (ng/L) | Standard Deviation 7.5121 |
| Liquid Pergoveris | Serum Estradiol Levels | Period 1: Day 8 (n= 16, 17) | 11.833 nanogram per liter (ng/L) | Standard Deviation 4.2363 |
| Freeze-dried Pergoveris | Serum Estradiol Levels | Follow-up (Day 18) (n= 16, 17) | 15.997 nanogram per liter (ng/L) | Standard Deviation 6.5632 |
| Freeze-dried Pergoveris | Serum Estradiol Levels | Screening (n= 17, 16) | 15.561 nanogram per liter (ng/L) | Standard Deviation 4.8726 |
| Freeze-dried Pergoveris | Serum Estradiol Levels | Period 1: Day 1 (pre-dose) (n= 16, 17) | 11.369 nanogram per liter (ng/L) | Standard Deviation 2.7208 |
| Freeze-dried Pergoveris | Serum Estradiol Levels | Period 1: Day 8 (n= 16, 17) | 12.077 nanogram per liter (ng/L) | Standard Deviation 3.6155 |
| Freeze-dried Pergoveris | Serum Estradiol Levels | Period 2: Day 8 (n= 13, 17) | 47.958 nanogram per liter (ng/L) | Standard Deviation 141.2149 |
| Freeze-dried Pergoveris | Serum Estradiol Levels | Period 2: Day 1 (pre-dose) (n= 14, 16) | 11.975 nanogram per liter (ng/L) | Standard Deviation 2.6377 |
Secondary
Time to Reach the Maximum Serum Concentration (Tmax) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH)
Time frame: 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
Population: Pharmacokinetic (PK) analysis set: all randomized subjects who were treated with both liquid and freeze-dried formulations and had absence of relevant protocol violations, had availability of the primary target variables and successfully downregulated baseline levels of FSH and LH below 1.0 IU/L in both the screening and dedicated PK assays.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Liquid Pergoveris | Time to Reach the Maximum Serum Concentration (Tmax) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | Follicle-stimulating Hormone | 23.983 Hour (h) |
| Liquid Pergoveris | Time to Reach the Maximum Serum Concentration (Tmax) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | Luteinizing Hormone | 8.000 Hour (h) |
| Freeze-dried Pergoveris | Time to Reach the Maximum Serum Concentration (Tmax) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | Follicle-stimulating Hormone | 16.575 Hour (h) |
| Freeze-dried Pergoveris | Time to Reach the Maximum Serum Concentration (Tmax) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | Luteinizing Hormone | 7.725 Hour (h) |