Trial Outcomes & Findings for Bioequivalence Trial of Liquid Versus Freeze-Dried Pergoveris® in Pituitary Suppressed Healthy Premenopausal Female Subjects (NCT NCT02317809)

Last Updated: 2018-07-16

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

34 participants

Primary outcome timeframe

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

Results posted on

2018-07-16

Participant Flow

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.

Participant milestones

Participant milestones
Measure	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.	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.
First Intervention Period (8 Days) STARTED	17	17
First Intervention Period (8 Days) COMPLETED	14	17
First Intervention Period (8 Days) NOT COMPLETED	3	0
Second Intervention Period (8 Days) STARTED	14	17
Second Intervention Period (8 Days) COMPLETED	14	17
Second Intervention Period (8 Days) NOT COMPLETED	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
First Intervention Period (8 Days) Protocol Non-Compliance	2	0
First Intervention Period (8 Days) Withdrawn Due To Multiple Follicles	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Subjects n=34 Participants 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.
Age, Continuous	28.6 Years STANDARD_DEVIATION 5.88 • n=5 Participants
Sex: Female, Male Female	34 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants

PRIMARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=22 Participants 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.	Freeze-dried Pergoveris n=22 Participants 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.
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 unitshour/liter (IUh/L) Geometric Coefficient of Variation 24.3	2775.4 International unitshour/liter (IUh/L) Geometric Coefficient of Variation 22.0

PRIMARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=22 Participants 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.	Freeze-dried Pergoveris n=22 Participants 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.
Baseline Corrected Area Under the Concentration-Time Curve From Zero to Last Quantifiable Concentration (AUC0-t,Adj) for Luteinizing Hormone (LH)	210.4 International unitshour/liter (IUh/L) Geometric Coefficient of Variation 25.8	195.2 International unitshour/liter (IUh/L) Geometric Coefficient of Variation 22.5

PRIMARY outcome

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

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

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=22 Participants 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.	Freeze-dried Pergoveris n=22 Participants 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.
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	42.55 International units per liter (IU/L) Geometric Coefficient of Variation 29.0

PRIMARY outcome

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

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

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=22 Participants 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.	Freeze-dried Pergoveris n=22 Participants 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.
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	9.782 International units per liter (IU/L) Geometric Coefficient of Variation 24.1

SECONDARY outcome

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

Population: PK analysis set. Here "n" signifies those subjects who were evaluable for the specified hormone level in each arm, respectively.

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=22 Participants 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.	Freeze-dried Pergoveris n=22 Participants 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.
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 unitshour/liter (IUh/L) Geometric Coefficient of Variation 24.2	2912.1 International unitshour/liter (IUh/L) Geometric Coefficient of Variation 22.2
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 unitshour/liter (IUh/L) Geometric Coefficient of Variation 25.2	201.1 International unitshour/liter (IUh/L) Geometric Coefficient of Variation 21.2

SECONDARY outcome

Population: As per statistical analysis plan, data was not planned to be summarized because AUCextra,adj was below 20% for all the participants.

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%.

Outcome measures

Outcome data not reported

SECONDARY outcome

Population: PK analysis set. Here "n" signifies those subjects who were evaluable for the specified hormone level in each arm, respectively.

The elimination rate constant was obtained from linear regression of the terminal phase of the log transformed concentration-time data.

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=22 Participants 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.	Freeze-dried Pergoveris n=22 Participants 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.
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	0.01963 Per Hour (1/hour) Geometric Coefficient of Variation 10.0
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	0.05094 Per Hour (1/hour) Geometric Coefficient of Variation 25.5

SECONDARY outcome

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=22 Participants 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.	Freeze-dried Pergoveris n=22 Participants 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.
Time to Reach the Maximum Serum Concentration (Tmax) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) Follicle-stimulating Hormone	23.983 Hour (h) Interval 8.23 to 36.0	16.575 Hour (h) Interval 9.0 to 36.12
Time to Reach the Maximum Serum Concentration (Tmax) for Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) Luteinizing Hormone	8.000 Hour (h) Interval 6.03 to 12.0	7.725 Hour (h) Interval 3.98 to 10.03

SECONDARY outcome

Population: PK analysis set. Here "n" signifies those subjects who were evaluable for the specified hormone level in each arm, respectively.

Terminal half-life is the time measured for the concentration to decrease by one half.

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=22 Participants 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.	Freeze-dried Pergoveris n=22 Participants 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.
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	35.31 Hour (h) Geometric Coefficient of Variation 10.0
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	13.608 Hour (h) Geometric Coefficient of Variation 25.5

SECONDARY outcome

Population: PK analysis set. Here "n" signifies those subjects who were evaluable for the specified hormone level in each arm, respectively.

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).

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=22 Participants 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.	Freeze-dried Pergoveris n=22 Participants 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.
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	0.3091 Liter per hour (L/h) Geometric Coefficient of Variation 22.2
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	2.238 Liter per hour (L/h) Geometric Coefficient of Variation 21.2

SECONDARY outcome

Population: PK analysis set. Here "n" signifies those subjects who were evaluable for the specified hormone level in each arm, respectively.

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.

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=22 Participants 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.	Freeze-dried Pergoveris n=22 Participants 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.
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	15.742 Liter (L) Geometric Coefficient of Variation 21.4
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	43.93 Liter (L) Geometric Coefficient of Variation 32.3

SECONDARY outcome

Timeframe: 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).

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.

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=34 Participants 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.	Freeze-dried Pergoveris n=31 Participants 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.
Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) AEs	12 Subjects	14 Subjects
Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) SAEs	1 Subjects	0 Subjects

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=34 Participants 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.	Freeze-dried Pergoveris n=31 Participants 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.
Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Related to Laboratory Assessments, Vital Signs or Electrocardiogram Findings	0 Subjects	0 Subjects

SECONDARY outcome

Timeframe: 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).

Transvaginal ultrasound (TVUS) was performed to determine the follicle size and number.

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=34 Participants 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.	Freeze-dried Pergoveris n=31 Participants 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.
Number of Subjects With Follicle Size Greater Than (>)13 Millimeter	0 Subjects	0 Subjects

SECONDARY outcome

Timeframe: Screening (up to 28 days), Day 1 (pre-dose) and Day 8 in Period 1, Day 1 (pre-dose), Day 8 and follow-up (Day 18) in Period 2

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).

Data was planned to be presented as per the sequence of treatment received.

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=17 Participants 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.	Freeze-dried Pergoveris n=17 Participants 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.
Serum Estradiol Levels Screening (n= 17, 16)	14.906 nanogram per liter (ng/L) Standard Deviation 9.1722	15.561 nanogram per liter (ng/L) Standard Deviation 4.8726
Serum Estradiol Levels Period 1: Day 1 (pre-dose) (n= 16, 17)	11.388 nanogram per liter (ng/L) Standard Deviation 3.7346	11.369 nanogram per liter (ng/L) Standard Deviation 2.7208
Serum Estradiol Levels Period 1: Day 8 (n= 16, 17)	11.833 nanogram per liter (ng/L) Standard Deviation 4.2363	12.077 nanogram per liter (ng/L) Standard Deviation 3.6155
Serum Estradiol Levels Period 2: Day 1 (pre-dose) (n= 14, 16)	12.469 nanogram per liter (ng/L) Standard Deviation 2.8548	11.975 nanogram per liter (ng/L) Standard Deviation 2.6377
Serum Estradiol Levels Period 2: Day 8 (n= 13, 17)	15.454 nanogram per liter (ng/L) Standard Deviation 6.6420	47.958 nanogram per liter (ng/L) Standard Deviation 141.2149
Serum Estradiol Levels Follow-up (Day 18) (n= 16, 17)	15.714 nanogram per liter (ng/L) Standard Deviation 7.5121	15.997 nanogram per liter (ng/L) Standard Deviation 6.5632

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=34 Participants 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.	Freeze-dried Pergoveris n=31 Participants 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.
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Itching: Day 1, 4 hour (n= 34, 30)	34 Subjects	30 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Itching: Day 1, 6 hour (n= 33, 30)	32 Subjects	30 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Itching: Day 1, 12 hour (n= 32, 30)	32 Subjects	30 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) Mild Itching: Day 1, 6 hour (n= 33, 30)	1 Subjects	0 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Itching: Day 1, 24 hour (n= 34, 28)	34 Subjects	28 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Redness: Day 1, 5 min (n= 34, 31)	30 Subjects	26 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) Mild Redness: Day 1, 5 min (n= 34, 31)	4 Subjects	5 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Redness: Day 1, 1 hour (n= 32, 31)	30 Subjects	30 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) Mild Redness: Day 1, 1 hour (n= 32, 31)	2 Subjects	1 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Redness: Day 1, 2 hour (n= 34, 31)	34 Subjects	30 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) Mild Redness: Day 1, 2 hour (n= 34, 31)	0 Subjects	1 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Redness: Day 1, 4 hour (n= 34, 30)	34 Subjects	29 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) Mild Redness: Day 1, 4 hour (n= 34, 30)	0 Subjects	1 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Redness: Day 1, 6 hour (n= 33, 30)	33 Subjects	29 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) Mild Redness: Day 1, 6 hour (n= 33, 30)	0 Subjects	1 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Redness: Day 1, 12 hour (n= 32, 30)	32 Subjects	30 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Redness: Day 1, 24 hour (n= 34, 28)	34 Subjects	28 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Swelling: Day 1, 5 min (n= 34, 31)	34 Subjects	31 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Swelling: Day 1, 1 hour (n= 32, 31)	32 Subjects	31 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Swelling: Day 1, 2 hour (n= 34, 31)	34 Subjects	31 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Swelling: Day 1, 4 hour (n= 34, 30)	34 Subjects	30 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Swelling: Day 1, 6 hour (n= 33, 30)	33 Subjects	30 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Swelling: Day 1, 12 hour (n= 32, 30)	32 Subjects	30 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Swelling: Day 1, 24 hour (n= 34, 28)	34 Subjects	28 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Bruising: Day 1, 5 min (n= 34, 31)	34 Subjects	31 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Bruising: Day 1, 1 hour (n= 32, 31)	32 Subjects	31 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Bruising: Day 1, 2 hour (n= 34, 31)	34 Subjects	31 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Bruising: Day 1, 4 hour (n= 34, 30)	34 Subjects	30 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Bruising: Day 1, 6 hour (n= 33, 30)	33 Subjects	30 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Bruising: Day 1, 12 hour (n= 32, 30)	32 Subjects	30 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Bruising: Day 1, 24 hour (n= 34, 28)	34 Subjects	28 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Itching: Day 1, 5 min (n= 34, 31)	34 Subjects	31 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Itching: Day 1, 1 hour (n= 32, 31)	32 Subjects	31 Subjects
Number of Subjects With Local Tolerability/Injection Site Reactions (ISRs) No Itching: Day 1, 2 hour (n= 34, 31)	34 Subjects	31 Subjects

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=34 Participants 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.	Freeze-dried Pergoveris n=31 Participants 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.
Pain Visual Analogue Scale (VAS) Score Day 1, 5 min (n= 34, 31)	1.9 mm Standard Deviation 4.04	2.5 mm Standard Deviation 4.19
Pain Visual Analogue Scale (VAS) Score Day 1, 1 hour (n= 32, 31)	0.2 mm Standard Deviation 0.59	1.3 mm Standard Deviation 5.01
Pain Visual Analogue Scale (VAS) Score Day 1, 2 hour (n= 34, 31)	0.2 mm Standard Deviation 0.52	0.3 mm Standard Deviation 0.51
Pain Visual Analogue Scale (VAS) Score Day 1, 4 hour (n= 34, 30)	0.1 mm Standard Deviation 0.54	0.2 mm Standard Deviation 0.57
Pain Visual Analogue Scale (VAS) Score Day 1, 6 hour (n= 33, 30)	0.2 mm Standard Deviation 0.46	1.0 mm Standard Deviation 5.10
Pain Visual Analogue Scale (VAS) Score Day 1, 12 hour (n= 32, 30)	0.2 mm Standard Deviation 0.45	0.2 mm Standard Deviation 0.48
Pain Visual Analogue Scale (VAS) Score Day 1, 24 hour (n= 34, 29)	0.1 mm Standard Deviation 0.24	0.1 mm Standard Deviation 0.35

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=34 Participants 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.	Freeze-dried Pergoveris n=31 Participants 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.
Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Luteinizing Hormone (LH) Subjects with ADAs to LH	0 Subjects	0 Subjects
Number of Subjects With Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Luteinizing Hormone (LH) Subjects with Neutralizing antibodies to LH	NA Subjects Neutralizing antibodies were not measured as there were no subjects who reported ADAs	NA Subjects Neutralizing antibodies were not measured as there were no subjects who reported ADAs

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1 pre-dose and Day 8 post-dose for IMP intervention periods

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=34 Participants 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.	Freeze-dried Pergoveris n=31 Participants 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.
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	1 Subjects
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	1 Subjects
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 As per sponsor decision, it was decided not to evaluate the NAb due to low titers (noise) for the ADA.	NA Subjects As per sponsor decision, it was decided not to evaluate the NAb due to low titers (noise) for the ADA.
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 As per sponsor decision, it was decided not to evaluate the NAb due to low titers (noise) for the ADA.	NA Subjects As per sponsor decision, it was decided not to evaluate the NAb due to low titers (noise) for the ADA.

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=34 Participants 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.	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.
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	—
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 As per sponsor decision, it was decided not to evaluate the NAb due to low titers (noise) for the ADA.	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=2 Participants 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.	Freeze-dried Pergoveris n=1 Participants 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.
Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH) Day 1: Subject 2	1.7 Log Titers	NA Log Titers Only 1 subject had the positive ADAs value in Freeze-dried Pergoveris arm.
Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH) Day 8: Subject 2	1.7 Log Titers	NA Log Titers Only 1 subject had the positive ADAs value in Freeze-dried Pergoveris arm.
Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH) Day 1: Subject 1	1.0 Log Titers	1.7 Log Titers
Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH) Day 8: Subject 1	1.0 Log Titers	1.0 Log Titers

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Liquid Pergoveris n=1 Participants 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.	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.
Anti-Drug Antibodies (ADAs) Titers for Follicle-stimulating Hormone (FSH) at Follow-up Visit	1.0 Log Titers	—

SECONDARY outcome

Timeframe: 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 .

Outcome measures

Outcome data not reported

Adverse Events

Liquid Pergoveris

Serious events: 1 serious events

Other events: 12 other events

Deaths: 0 deaths

Freeze-dried Pergoveris

Serious events: 0 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Liquid Pergoveris n=34 participants at risk 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.	Freeze-dried Pergoveris n=31 participants at risk 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-Hodgkin's lymphoma	2.9% 1/34 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods	0.00% 0/31 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods

Other adverse events

Additional Information

Merck KGaA Communication Center

Merck Healthcare, a business of Merck KGaA, Darmstadt, Germany

Phone: +49-6151-72-5200

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Liquid Pergoveris n=34 participants at risk 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.	Freeze-dried Pergoveris n=31 participants at risk 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.
Blood and lymphatic system disorders Lymphadenopathy	2.9% 1/34 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods	0.00% 0/31 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
Gastrointestinal disorders Nausea	2.9% 1/34 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods	9.7% 3/31 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
Gastrointestinal disorders Diarrhoea	2.9% 1/34 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods	0.00% 0/31 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
Gastrointestinal disorders Constipation	0.00% 0/34 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods	3.2% 1/31 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
Gastrointestinal disorders Abdominal Discomfort	2.9% 1/34 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods	3.2% 1/31 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
General disorders Injection Site Discolouration	2.9% 1/34 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods	0.00% 0/31 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
General disorders Catheter Site Related Reaction	2.9% 1/34 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods	12.9% 4/31 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
General disorders Catheter Site Pain	0.00% 0/34 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods	3.2% 1/31 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
Infections and infestations Rhinitis	2.9% 1/34 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods	3.2% 1/31 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/34 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods	3.2% 1/31 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
Nervous system disorders Presyncope	2.9% 1/34 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods	0.00% 0/31 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
Nervous system disorders Paraesthesia	0.00% 0/34 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods	3.2% 1/31 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
Nervous system disorders Headache	17.6% 6/34 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods	12.9% 4/31 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
Nervous system disorders Dizziness	2.9% 1/34 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods	9.7% 3/31 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
Reproductive system and breast disorders Vaginal Haemorrhage	0.00% 0/34 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods	3.2% 1/31 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
Reproductive system and breast disorders Breast Tenderness	0.00% 0/34 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods	3.2% 1/31 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
Respiratory, thoracic and mediastinal disorders Dysphonia	0.00% 0/34 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods	3.2% 1/31 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods
Skin and subcutaneous tissue disorders Rash	2.9% 1/34 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods	0.00% 0/31 • Day 1 post-IMP administration up to follow-up visit (Day 18) for IMP intervention periods