Phase 1 Study to Assess the Safety, Tolerability, and Pharmacokinetics of Recombinant Human C1 Esterase Inhibitor in Healthy Adult Subjects

A Randomized, Double-blind, Placebo-controlled, Ascending Dose, Phase 1 Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single Intravenous and Subcutaneous Doses of Recombinant Human C1 Esterase Inhibitor in Healthy Adult Subjects

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02663687

Enrollment

Registered

2016-01-26

Start date

2016-02-19

Completion date

2016-12-05

Last updated

2021-06-03

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hereditary Angioedema (HAE)

Brief summary

This trial is looking to gain information about the safety and tolerability of an investigational treatment (SHP623) in healthy adult volunteers. This study will also collect pharmacokinetic data (how the body absorbs and breaks down the study drug).

Interventions

DRUGRecombinant human C1 esterase inhibitor

Subjects will receive escalating doses I-IV as both IV and SC injections

DRUGPlacebo

Subjects will receive matching placebo

DRUGSHP623

SHP623

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 50 Years

Healthy volunteers

Yes

Inclusion criteria

1. Must be considered healthy. Healthy status is defined by absence of evidence of any active or chronic disease 2. Male, or non-pregnant, non-lactating female, who agrees to comply with any applicable contraceptive requirements of the protocol, or females of non-child-bearing potential. 3. Body mass index between 18.0 and 30.0 kg/m2 inclusive with a body weight \>50 kg (110 lbs.). This inclusion criterion will be assessed only at the first screening visit. 4. Hemoglobin ≥12.0g/ld.

Exclusion criteria

1. Have a history of allergic reaction to C1 INH products (e.g. C1 Inhibitor \[Human\], Berinert \[C1 Estrace Inhibitor (Human)\] and C1 estrace \[recombinant\] 2. Known history of alcohol or other substance abuse within the last year. 3. Donation of blood or blood products within 60 days prior to receiving investigational product. 4. Current use of any medication except hormonal replacement therapy, hormonal contraceptives and occasional use of any over-the-counter non-steroidal anti-inflammatory drug (NSAID) or acetaminophen. 5. Have a history of hypercoagulability or other predisposition to thrombotic events.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Treatment-emergent Adverse Events (TEAEs ) Including Serious Adverse Events (SAEs)	From the start of study treatment up to 28 days after the last dose of the study treatment (up to 56 days)	An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that did not necessarily have a causal relationship with this treatment. An AE was considered to be a TEAE in a specific treatment period of the study if the date and time of onset were after investigational product administration in that period and if it occurred less than equals to (\<=) Day 28 and was both not present at the start of that period and was not a chronic condition that was part of the participant's medical history, or it was present at the start of that period or as part of the participant's medical history but the severity or frequency increased during that period \<= Day 28. An SAE was defined as any untoward medical occurrence (whether considered to be related to investigational product or not) that at any dose.

Secondary

Measure	Time frame	Description
Time of Maximum Plasma Concentration (Tmax) of SHP623 Sampled During a Dosing Interval	Pre-dose, 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, 216, 312, 648 hours post-dose.	Tmax of SHP623 (rC1 INH) antigen was calculated based on observed concentration-versus-time data. Tmax of SHP623 for both treatment period 1 (IV) and treatment period 2 (SC) was presented in the categories for each dosing group.
Terminal Half-life (t1/2) of SHP623	Pre-dose, 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, 216, 312, 648 hours post-dose.	t1/2 is the time required for the concentration of the drug to reach half of its original value. t1/2 of SHP623 (rC1 INH) antigen for both treatment period 1 (IV) and treatment period 2 (SC) was presented in the categories for each dosing group.
Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC 0-inf) of SHP623	Pre-dose, 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, 216, 312, 648 hours post-dose.	AUC 0-inf is the area under the curve extrapolated to infinity, calculated using the observed value of the last non-zero concentration. AUC 0-inf of SHP623 (rC1 INH) antigen was calculated from observed concentration-versus-time data. AUC 0-inf of SHP623 for both treatment period 1 (IV) and treatment period 2 (SC) was presented in the categories for each dosing group. The unit of measure is hour\microgram per milliliter (hr\mcg/ml).
Area Under the Plasma Concentration Curve From Time Zero to 168 Hours Postdose (AUC 0-168) of SHP623	Pre-dose, 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, 216, 312, 648 hours post-dose.	AUC 0-168 is the area under the concentration curve over the interval from 0 to 168 hours after dosing of SHP623. AUC 0-168 of SHP623 (rC1 INH) was calculated based on observed concentration-versus-time data. AUC 0-168 of SHP623 for both treatment period 1 (IV) and treatment period 2 (SC) was presented in the categories for each dosing group. The unit of measure is hour\microgram per milliliter (hr\mcg/ml).
Maximum Observed Plasma Concentration (Cmax) of SHP623 Occurring at Time of Maximum Observed Concentration During a Dosing Interval (Tmax)	Pre-dose, 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, 216, 312, 648 hours post-dose.	Cmax of SHP623 recombinant human C1 esterase inhibitor (rC1 INH) antigen at Tmax was calculated based on observed concentration-versus-time data. Cmax at Tmax of SHP623 for both treatment period 1 (IV) and treatment period 2 (SC) was presented in the categories for each dosing group.
Total Body Clearance (CL) for Intravascular (IV) Administration of SHP623	Pre-dose, 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, 216, 312, 648 hours post-dose.	CL is the total body clearance of SHP623 for IV administration. The unit of measurement is unit per hour\microgram per milliliter \[U/(hr\mcg/ml)\].
Volume of Distribution Associated With the Terminal Slope (Vz) Following Intravenous (IV) Administration of SHP623	Pre-dose, 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, 216, 312, 648 hours post-dose.	Vz is the volume of distribution associated with the terminal slope following IV administration. Vz was calculated for SHP 623 (rC1 INH) antigen from observed concentration-versus-time data. The unit of measure is unit per microgram per milliliter \[U/(mcg/ml)\].
Total Body Clearance for Extravascular Administration (CL/F) of SHP623 for Subcutaneous (SC) Administration	Pre-dose, 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, 216, 312, 648 hours post-dose.	CL/F is the total body clearance for extravascular administration of SHP623 for SC administration divided by the fraction of dose absorbed. CL/F of SHP623 (rC1 INH) was calculated based on observed concentration-versus-time data. The unit of measure is unit per hour\microgram per milliliter \[U/(hr\mcg/ml)\].
Volume of Distribution Influenced by Fraction of Dose Absorbed (Vz/F) Following Extravascular Administration of SHP623	Pre-dose, 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, 216, 312, 648 hours post-dose.	Vz/F is the volume of distribution associated with the terminal slope following extravascular administration divided by the fraction of dose absorbed for subcutaneous (SC) administration. Vz/F of SHP623 (rC1 INH) were calculated from observed concentration-versus-time data. The unit of measure is unit per microgram per milliliter \[U/(mcg/ml)\].
Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of SHP623	Pre-dose, 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, 216, 312, 648 hours post-dose.	AUClast is the area under the curve from the time 0 to the last measurable concentration of SHP623 (rC1 INH), which was calculated from observed concentration-versus-time data. AUClast of SHP623 for both treatment period 1 (IV) and treatment period 2 (SC) was presented in the categories for each dosing group. The unit of measure is hour\microgram per milliliter (hr\mcg/ml).

Countries

United States

Participant flow

Recruitment details

The study was conducted at a single center in the United States between 19 February 2016 (first participant first visit) and 05 December 2016 (last participant last visit).

Pre-assignment details

A total of 48 participants were screened, randomized and received at least one dose of treatment.

Participants by arm

Arm	Count
Placebo Participants received placebo matched to SHP623 intravenous and subcutaneous administration in 1:3 ratio for each cohort during treatment period 1 and 2 for 28 days respectively with 28 days interval between intravenous (IV) and subcutaneous (SC) dosing in the following order: once as an IV dose and once as an SC dose.	12
1000 U SHP623 Participants received 1000 unit (U) of SHP623 in each cohort during treatment period 1 and 2 for 28 days respectively with 28 days interval between IV and SC dosing in the following order: once as an IV dose and once as an SC dose.	9
2000 U SHP623 Participants received 2000 unit (U) of SHP623 in each cohort during treatment period 1 and 2 for 28 days respectively with 28 days interval between IV and SC dosing in the following order: once as an IV dose and once as an SC dose.	9
3000 U SHP623 Participants received 3000 unit (U) of SHP623 in each cohort during treatment period 1 and 2 for 28 days respectively with 28 days interval between IV and SC dosing in the following order: once as an IV dose and once as an SC dose.	9
5000 U SHP623 Participants received 5000 unit (U) of SHP623 in each cohort during treatment period 1 and 2 for 28 days respectively with 28 days interval between IV and SC dosing in the following order: once as an IV dose and once as an SC dose.	9
Total	48

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004
Overall Study	Adverse Event	1	0	0	0	0
Overall Study	Other	1	0	1	0	0

Baseline characteristics

Characteristic	Placebo	1000 U SHP623	2000 U SHP623	3000 U SHP623	5000 U SHP623	Total
Age, Continuous	36.3 Years STANDARD_DEVIATION 7.93	40.7 Years STANDARD_DEVIATION 7.25	36.8 Years STANDARD_DEVIATION 7.08	38.0 Years STANDARD_DEVIATION 10.49	35.7 Years STANDARD_DEVIATION 8.63	37.4 Years STANDARD_DEVIATION 8.17
Sex: Female, Male Female	5 Participants	2 Participants	5 Participants	4 Participants	4 Participants	20 Participants
Sex: Female, Male Male	7 Participants	7 Participants	4 Participants	5 Participants	5 Participants	28 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	0 / 12	0 / 9	0 / 9	0 / 9	0 / 9
other Total, other adverse events	8 / 12	4 / 9	3 / 9	8 / 9	4 / 9
serious Total, serious adverse events	0 / 12	0 / 9	0 / 9	0 / 9	0 / 9

Outcome results

Primary

Number of Participants With Treatment-emergent Adverse Events (TEAEs ) Including Serious Adverse Events (SAEs)

An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that did not necessarily have a causal relationship with this treatment. An AE was considered to be a TEAE in a specific treatment period of the study if the date and time of onset were after investigational product administration in that period and if it occurred less than equals to (\<=) Day 28 and was both not present at the start of that period and was not a chronic condition that was part of the participant's medical history, or it was present at the start of that period or as part of the participant's medical history but the severity or frequency increased during that period \<= Day 28. An SAE was defined as any untoward medical occurrence (whether considered to be related to investigational product or not) that at any dose.

Time frame: From the start of study treatment up to 28 days after the last dose of the study treatment (up to 56 days)

Population: Safety analysis set consisted of all participants who were administered at least 1 dose of investigational product.

Arm	Measure	Group	Value (NUMBER)
Placebo	Number of Participants With Treatment-emergent Adverse Events (TEAEs ) Including Serious Adverse Events (SAEs)	Any TEAE	8 Participants
Placebo	Number of Participants With Treatment-emergent Adverse Events (TEAEs ) Including Serious Adverse Events (SAEs)	Serious TEAE	0 Participants
1000 U SHP623	Number of Participants With Treatment-emergent Adverse Events (TEAEs ) Including Serious Adverse Events (SAEs)	Any TEAE	4 Participants
1000 U SHP623	Number of Participants With Treatment-emergent Adverse Events (TEAEs ) Including Serious Adverse Events (SAEs)	Serious TEAE	0 Participants
2000 U SHP623	Number of Participants With Treatment-emergent Adverse Events (TEAEs ) Including Serious Adverse Events (SAEs)	Any TEAE	3 Participants
2000 U SHP623	Number of Participants With Treatment-emergent Adverse Events (TEAEs ) Including Serious Adverse Events (SAEs)	Serious TEAE	0 Participants
3000 U SHP623	Number of Participants With Treatment-emergent Adverse Events (TEAEs ) Including Serious Adverse Events (SAEs)	Serious TEAE	0 Participants
3000 U SHP623	Number of Participants With Treatment-emergent Adverse Events (TEAEs ) Including Serious Adverse Events (SAEs)	Any TEAE	8 Participants
5000 U SHP623	Number of Participants With Treatment-emergent Adverse Events (TEAEs ) Including Serious Adverse Events (SAEs)	Any TEAE	4 Participants
5000 U SHP623	Number of Participants With Treatment-emergent Adverse Events (TEAEs ) Including Serious Adverse Events (SAEs)	Serious TEAE	0 Participants

Secondary

Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of SHP623

AUClast is the area under the curve from the time 0 to the last measurable concentration of SHP623 (rC1 INH), which was calculated from observed concentration-versus-time data. AUClast of SHP623 for both treatment period 1 (IV) and treatment period 2 (SC) was presented in the categories for each dosing group. The unit of measure is hour\*microgram per milliliter (hr\*mcg/ml).