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| ID | Type | Description | Link |
|---|---|---|---|
| 2014-003506-32 | EudraCT Number |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| First Liquid Pergoveris, Then Freeze-dried Pergoveris | Experimental |
| |
| First Freeze-dried Pergoveris, Then Liquid Pergoveris | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | |
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Inclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Responsible | Merck KGaA, Darmstadt, Germany | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Please contact the Merck KGaA Communication Center | Darmstadt | Germany |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29375477 | Derived | 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. |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | First Liquid Pergoveris, Then Freeze-dried Pergoveris | Subjects were administered with 900 international units (IU) of recombinant human follicle-stimulating hormone (r-hFSH) and 450 IU of recombinant human luteinizing hormone (r-hLH) solution (Liquid Pergoveris) as subcutaneous injection using a disposable pen-injector on Day 1 in the first intervention period followed by 900 IU of r-hFSH and 450 IU of r-hLH freeze-dried powder (Freeze-dried Pergoveris) as subcutaneous injection on Day 1 in the second intervention period. Both the periods were separated by a washout period of 14 to 17 days. |
| FG001 | First Freeze-dried Pergoveris, Then Liquid Pergoveris | Subjects were 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 the first intervention period followed by 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 the second intervention period. Both the periods were separated by a washout period of 14 to 17 days. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention Period (8 Days) |
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| Second Intervention Period (8 Days) |
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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).
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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). | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | International units*hour/liter (IU*h/L) | 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 |
|
Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Liquid Pergoveris | 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 on Day 1 in either first intervention period or second intervention period. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Non-Hodgkin's lymphoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 17.1 | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Lymphadenopathy | Blood and lymphatic system disorders | MedDRA 17.1 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Merck KGaA Communication Center | Merck Healthcare, a business of Merck KGaA, Darmstadt, Germany | +49-6151-72-5200 | service@merckgroup.com |
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| ID | Term |
|---|---|
| D007246 | Infertility |
| ID | Term |
|---|---|
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
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| 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. |
|
| 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%. |
| 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) | The elimination rate constant was obtained from linear regression of the terminal phase of the log transformed concentration-time data. | 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) | Terminal half-life is the time measured for the concentration to decrease by one half. | 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 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). | 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 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. | 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 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. | Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods |
| 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 | Transvaginal ultrasound (TVUS) was performed to determine the follicle size and number. | Day 1 (pre-dose) up to follow-up visit (Day 18) for IMP intervention periods |
| Serum Estradiol Levels | Data was planned to be presented as per the sequence of treatment received. | 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 |
| 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. | 5 minutes, 1, 2, 4, 6, 12, and 24 hours post-dose in each period |
| 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. | 5 minutes, 1, 2, 4, 6, 12, and 24 hours post-dose in each period |
| 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) |
| NOT COMPLETED |
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| Years |
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| Sex: Female, Male | Count of Participants | Participants |
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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 on Day 1 in either first intervention period or second intervention period. |
| OG001 | Freeze-dried Pergoveris | All subjects who were 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. |
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| 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). | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | International units*hour/liter (IU*h/L) | 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 |
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| Primary | Baseline Corrected Maximum Serum Concentration (Cmax,Adj) for Follicle-Stimulating Hormone (FSH) | Baseline-corrected Cmax (Cmax,adj) = Cmax - baseline concentration | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | International units per liter (IU/L) | 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 |
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| Primary | Baseline Corrected Maximum Serum Concentration (Cmax,Adj) for Luteinizing Hormone (LH) | Baseline-corrected Cmax (Cmax,adj) = Cmax - baseline concentration. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | International units per liter (IU/L) | 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 |
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| 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) | PK analysis set. Here "n" signifies those subjects who were evaluable for the specified hormone level in each arm, respectively. | Posted | Geometric Mean | Geometric Coefficient of Variation | International units*hour/liter (IU*h/L) | 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 |
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| 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%. | As per statistical analysis plan, data was not planned to be summarized because AUCextra,adj was below 20% for all the participants. | Posted | 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 |
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| 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. | PK analysis set. Here "n" signifies those subjects who were evaluable for the specified hormone level in each arm, respectively. | Posted | Geometric Mean | Geometric Coefficient of Variation | Per Hour (1/hour) | 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 |
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| Secondary | Time to Reach the Maximum Serum Concentration (Tmax) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) | 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. | Posted | Median | Full Range | Hour (h) | 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 |
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| 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. | PK analysis set. Here "n" signifies those subjects who were evaluable for the specified hormone level in each arm, respectively. | Posted | Geometric Mean | Geometric Coefficient of Variation | Hour (h) | 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 |
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| 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). | PK analysis set. Here "n" signifies those subjects who were evaluable for the specified hormone level in each arm, respectively. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter per hour (L/h) | 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 |
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| 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. | PK analysis set. Here "n" signifies those subjects who were evaluable for the specified hormone level in each arm, respectively. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter (L) | 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 |
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| 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. | 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). | Posted | Number | Subjects | Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods |
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| Secondary | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Related to Laboratory Assessments, Vital Signs or Electrocardiogram Findings | 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). | Posted | Number | Subjects | Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods |
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| Secondary | Number of Subjects With Follicle Size Greater Than (>)13 Millimeter | Transvaginal ultrasound (TVUS) was performed to determine the follicle size and number. | 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). | Posted | Number | Subjects | Day 1 (pre-dose) up to follow-up visit (Day 18) for IMP intervention periods |
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| Secondary | Serum Estradiol Levels | Data was planned to be presented as per the sequence of treatment received. | 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). | Posted | Mean | Standard Deviation | nanogram per liter (ng/L) | 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 |
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| 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. | 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. | Posted | Number | Subjects | 5 minutes, 1, 2, 4, 6, 12, and 24 hours post-dose in each period |
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| 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. | 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. | Posted | Mean | Standard Deviation | mm | 5 minutes, 1, 2, 4, 6, 12, and 24 hours post-dose in each period |
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| Secondary | Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Luteinizing Hormone (LH) | 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). | Posted | Number | Subjects | Day 1 pre-dose up to follow-up visit (Day 18) for IMP intervention periods |
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| Secondary | Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) Titers for Luteinizing Hormone (LH) | Data could not be collected as there were no subjects with positive results for ADAs and NAbs. | Posted | Day 1 pre-dose up to follow-up visit (Day 18) for IMP intervention periods |
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| Secondary | Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Follicle-stimulating Hormone (FSH) | 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. | Posted | Number | Subjects | Day 1 pre-dose and Day 8 post-dose for IMP intervention periods |
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| Secondary | Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Follicle-stimulating Hormone (FSH) at Follow-up Visit | 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). | Posted | Number | Subjects | At follow-up visit (Day 49) |
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| Secondary | Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH) | 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. | Posted | Number | Log Titers | Day 1 pre-dose and Day 8 post-dose for IMP intervention periods. |
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| Secondary | Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH) at Follow-up Visit | 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. | Posted | Number | Log Titers | At follow-up visit (Day 49) |
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| Secondary | Neutralizing Antibodies (NAbs) Titers for Follicle-stimulating Hormone (FSH) | 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 . | Posted | Day 1 pre-dose, Day 8 post-dose, follow-up visit (Day 49) |
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| 1 |
| 34 |
| 12 |
| 34 |
| EG001 | Freeze-dried Pergoveris | All subjects who were 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. | 0 | 31 | 14 | 31 |
| Nausea | Gastrointestinal disorders | MedDRA 17.1 | Non-systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA 17.1 | Non-systematic Assessment |
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| Constipation | Gastrointestinal disorders | MedDRA 17.1 | Non-systematic Assessment |
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| Abdominal Discomfort | Gastrointestinal disorders | MedDRA 17.1 | Non-systematic Assessment |
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| Injection Site Discolouration | General disorders | MedDRA 17.1 | Non-systematic Assessment |
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| Catheter Site Related Reaction | General disorders | MedDRA 17.1 | Non-systematic Assessment |
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| Catheter Site Pain | General disorders | MedDRA 17.1 | Non-systematic Assessment |
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| Rhinitis | Infections and infestations | MedDRA 17.1 | Non-systematic Assessment |
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| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 17.1 | Non-systematic Assessment |
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| Presyncope | Nervous system disorders | MedDRA 17.1 | Non-systematic Assessment |
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| Paraesthesia | Nervous system disorders | MedDRA 17.1 | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 17.1 | Non-systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 17.1 | Non-systematic Assessment |
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| Vaginal Haemorrhage | Reproductive system and breast disorders | MedDRA 17.1 | Non-systematic Assessment |
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| Breast Tenderness | Reproductive system and breast disorders | MedDRA 17.1 | Non-systematic Assessment |
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| Dysphonia | Respiratory, thoracic and mediastinal disorders | MedDRA 17.1 | Non-systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | MedDRA 17.1 | Non-systematic Assessment |
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Not provided
Not provided
| Period 1: Day 8 (n= 16, 17) |
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| Period 2: Day 1 (pre-dose) (n= 14, 16) |
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| Period 2: Day 8 (n= 13, 17) |
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| Follow-up (Day 18) (n= 16, 17) |
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| No Bruising: Day 1, 2 hour (n= 34, 31) |
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| No Bruising: Day 1, 4 hour (n= 34, 30) |
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| No Bruising: Day 1, 6 hour (n= 33, 30) |
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| No Bruising: Day 1, 12 hour (n= 32, 30) |
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| No Bruising: Day 1, 24 hour (n= 34, 28) |
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| No Itching: Day 1, 5 min (n= 34, 31) |
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| No Itching: Day 1, 1 hour (n= 32, 31) |
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| No Itching: Day 1, 2 hour (n= 34, 31) |
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| No Itching: Day 1, 4 hour (n= 34, 30) |
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| No Itching: Day 1, 6 hour (n= 33, 30) |
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| Mild Itching: Day 1, 6 hour (n= 33, 30) |
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| No Itching: Day 1, 12 hour (n= 32, 30) |
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| No Itching: Day 1, 24 hour (n= 34, 28) |
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| No Redness: Day 1, 5 min (n= 34, 31) |
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| Mild Redness: Day 1, 5 min (n= 34, 31) |
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| No Redness: Day 1, 1 hour (n= 32, 31) |
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| Mild Redness: Day 1, 1 hour (n= 32, 31) |
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| No Redness: Day 1, 2 hour (n= 34, 31) |
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| Mild Redness: Day 1, 2 hour (n= 34, 31) |
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| No Redness: Day 1, 4 hour (n= 34, 30) |
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| Mild Redness: Day 1, 4 hour (n= 34, 30) |
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| No Redness: Day 1, 6 hour (n= 33, 30) |
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| Mild Redness: Day 1, 6 hour (n= 33, 30) |
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| No Redness: Day 1, 12 hour (n= 32, 30) |
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| No Redness: Day 1, 24 hour (n= 34, 28) |
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| No Swelling: Day 1, 5 min (n= 34, 31) |
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| No Swelling: Day 1, 1 hour (n= 32, 31) |
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| No Swelling: Day 1, 2 hour (n= 34, 31) |
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| No Swelling: Day 1, 4 hour (n= 34, 30) |
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| No Swelling: Day 1, 6 hour (n= 33, 30) |
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| No Swelling: Day 1, 12 hour (n= 32, 30) |
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| No Swelling: Day 1, 24 hour (n= 34, 28) |
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| Day 1, 2 hour (n= 34, 31) |
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| Day 1, 4 hour (n= 34, 30) |
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| Day 1, 6 hour (n= 33, 30) |
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| Day 1, 12 hour (n= 32, 30) |
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| Day 1, 24 hour (n= 34, 29) |
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| Day1: Subjects with NAbs to FSH (n= 34, 31) |
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| Day8: Subjects with NAbs to FSH (n= 34, 31) |
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| Day 1: Subject 2 |
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| Day 8: Subject 2 |
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