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

• ClinicalTrials.gov Identifier: NCT02663687
• Recruitment Status: Completed
• First Posted: January 26, 2016
• Results First Posted: September 6, 2018
• Last Update Posted: June 3, 2021
• Sponsor: Shire
• Information provided by (Responsible Party): Takeda ( Shire )

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Hereditary Angioedema (HAE)	Drug: Recombinant human C1 esterase inhibitor; Drug: Placebo; Drug: SHP623	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: February 19, 2016
• Actual Primary Completion Date: December 5, 2016
• Actual Study Completion Date: December 5, 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment 1- 4; Treatment A: 9 Subjects will receive dose level I of SHP623 intravenously (IV). B: 9 Subjects will receive dose level I of SHP623 subcutaneously(SC).	Drug: Recombinant human C1 esterase inhibitor; Subjects will receive escalating doses I-IV as both IV and SC injections; Other Name: SHP623; Drug: SHP623; SHP623
Placebo Comparator: Placebo; 3 Subjects will receive placebo for each cohort	Drug: Placebo; Subjects will receive matching placebo; Drug: Placebo; Placebo

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Treatment-emergent Adverse Events (TEAEs ) Including Serious Adverse Events (SAEs) [ Time Frame: 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 Outcome Measures :

1. Maximum Observed Plasma Concentration (Cmax) of SHP623 Occurring at Time of Maximum Observed Concentration During a Dosing Interval (Tmax) [ Time Frame: 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.
2. Time of Maximum Plasma Concentration (Tmax) of SHP623 Sampled During a Dosing Interval [ Time Frame: 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.
3. Terminal Half-life (t1/2) of SHP623 [ Time Frame: 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.
4. Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC 0-inf) of SHP623 [ Time Frame: 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).
5. Area Under the Plasma Concentration Curve From Time Zero to 168 Hours Postdose (AUC 0-168) of SHP623 [ Time Frame: 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).
6. Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of SHP623 [ Time Frame: 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).
7. Total Body Clearance (CL) for Intravascular (IV) Administration of SHP623 [ Time Frame: 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)].
8. Volume of Distribution Associated With the Terminal Slope (Vz) Following Intravenous (IV) Administration of SHP623 [ Time Frame: 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)].
9. Total Body Clearance for Extravascular Administration (CL/F) of SHP623 for Subcutaneous (SC) Administration [ Time Frame: 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)].
10. Volume of Distribution Influenced by Fraction of Dose Absorbed (Vz/F) Following Extravascular Administration of SHP623 [ Time Frame: 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)].

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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.

Contacts and Locations

Locations

United States, Florida

Clinical Pharmacology of Miami

Miami, Florida, United States, 33014

Sponsors and Collaborators

Shire

Investigators

• Study Director: Study Director; Takeda

More Information

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT02663687
• Other Study ID Numbers: SHP623-100
• First Posted: January 26, 2016
• Results First Posted: September 6, 2018
• Last Update Posted: June 3, 2021
• Last Verified: May 2021

Additional relevant MeSH terms:

Angioedema; Angioedemas, Hereditary; Vascular Diseases; Cardiovascular Diseases; Urticaria; Skin Diseases, Vascular; Skin Diseases; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Genetic Diseases, Inborn; Immunologic Deficiency Syndromes; Complement C1s; Complement C1 Inhibitor Protein; Complement C1 Inactivator Proteins; Immunologic Factors; Physiological Effects of Drugs; Complement Inactivating Agents; Immunosuppressive Agents