Trial Outcomes & Findings for Safety of Monthly Recombinant Factor XIII Replacement Therapy in Subjects With Congenital Factor XIII Deficiency: An Extension to Trial F13CD-1725 (NCT NCT00978380)

Last Updated: 2018-01-24

Results Overview

An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Trial AEs (serious) included any event such as death, life-threatening experience, in-subject hospitalisation, significant disability/ congential anomaly experienced from the trial product.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

63 participants

Primary outcome timeframe

All AEs were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit.

Results posted on

2018-01-24

Participant Flow

The trial was conducted at 34 sites in 12 countries as follows: Austria: 1 site; Canada: 1 site; Finland: 1 site; France: 4 sites; Germany: 4 sites; Israel: 1 site; Italy: 1 site: Japan: 2 sites; Spain: 2 sites; Switzerland: 1 site; United Kingdom: 4 sites; United States: 12 sites.

Subjects who completed F13CD-1725 (CT.gov identifier: NCT00713648) end of trial visit were eligible to enroll in this trial. Also, new subjects diagnosed with congenital FXIII A-subunit deficiency (confirmed by genotyping at screening visit or documented results from previously performed genotyping) were enrolled to expand the safety population.

Participant milestones

Participant milestones
Measure	Recombinant Factor XIII (rFXIII) Subjects received 35 IU/kg bodyweight of rFXIII slow intravenous (i.v.) injection every 4 weeks (28 days±2 days) for a minimum period of 52 weeks until the end of trial visit. The dose was identical to the dose administered in the F13CD- 1725 trial. A total of 60 unique subjects were enrolled and exposed in the trial, but 3 of these subjects were later withdrawn and subsequently re-enrolled with new subject IDs, giving rise to a total of N=63 subjects. The unique subjects (N=60) were presented as full analysis set (FAS) while summarising adverse events to avoid double-counting.
Overall Study STARTED	63
Overall Study COMPLETED	44
Overall Study NOT COMPLETED	19

Reasons for withdrawal

Reasons for withdrawal
Measure	Recombinant Factor XIII (rFXIII) Subjects received 35 IU/kg bodyweight of rFXIII slow intravenous (i.v.) injection every 4 weeks (28 days±2 days) for a minimum period of 52 weeks until the end of trial visit. The dose was identical to the dose administered in the F13CD- 1725 trial. A total of 60 unique subjects were enrolled and exposed in the trial, but 3 of these subjects were later withdrawn and subsequently re-enrolled with new subject IDs, giving rise to a total of N=63 subjects. The unique subjects (N=60) were presented as full analysis set (FAS) while summarising adverse events to avoid double-counting.
Overall Study Protocol Violation	2
Overall Study Withdrawal criteria	9
Overall Study Unclassified	8

Baseline Characteristics

Safety of Monthly Recombinant Factor XIII Replacement Therapy in Subjects With Congenital Factor XIII Deficiency: An Extension to Trial F13CD-1725

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Recombinant Factor XIII (rFXIII) n=63 Participants Subjects received 35 IU/kg bodyweight of rFXIII slow intravenous (i.v.) injection every 4 weeks (28 days±2 days) for a minimum period of 52 weeks until the end of trial visit. The dose was identical to the dose administered in the F13CD- 1725 trial. A total of 60 unique subjects were enrolled and exposed in the trial, but 3 of these subjects were later withdrawn and subsequently re-enrolled with new subject IDs, giving rise to a total of N=63 subjects. The unique subjects (N=60) were presented as full analysis set (FAS) while summarising adverse events to avoid double-counting.
Age, Continuous	31 Years STANDARD_DEVIATION 16.8 • n=5 Participants
Sex: Female, Male Female	23 Participants n=5 Participants
Sex: Female, Male Male	40 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	7 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	52 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 Participants n=5 Participants
Race/Ethnicity, Customized Asian	9 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	6 Participants n=5 Participants
Race/Ethnicity, Customized White	37 Participants n=5 Participants
Race/Ethnicity, Customized More than one race	0 Participants n=5 Participants
Race/Ethnicity, Customized Unknown or Not Reported	4 Participants n=5 Participants
Race/Ethnicity, Customized Other	6 Participants n=5 Participants

PRIMARY outcome

Timeframe: All AEs were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit.

Population: The FAS included the 60 unique subjects exposed to trial product in this extension trial.

Outcome measures

Outcome measures
Measure	Recombinant Factor XIII (rFXIII) n=60 Participants Subjects received 35 IU/kg bodyweight of rFXIII slow intravenous (i.v.) injection every 4 weeks (28 days±2 days) for a minimum period of 52 weeks until the end of trial visit. The dose was identical to the dose administered in the F13CD- 1725 trial. A total of 60 unique subjects were enrolled and exposed in the trial, but 3 of these subjects were later withdrawn and subsequently re-enrolled with new subject IDs, giving rise to a total of N=63 subjects. The unique subjects (N=60) were presented as full analysis set (FAS) while summarising adverse events to avoid double-counting.
Adverse Events (AEs)(Serious and Non-serious) All adverse events	920 Events
Adverse Events (AEs)(Serious and Non-serious) Serious adverse events	19 Events
Adverse Events (AEs)(Serious and Non-serious) Non-serious adverse events	901 Events

SECONDARY outcome

Timeframe: From week 0 to week 52

Population: The safety analysis set included all subjects exposed to trial product in this extension trial.

All subjects who received rFXIII were monitored for anti-rFXIII antibodies and inhibitor development. Samples passed through 2 tiers of ELISA testing: an initial screen with a specific cut-off point (including \~5% false positives) and a second confirmatory assay for samples yielding a result above the screening cut-off point. If samples were confirmed as antibody positive in the confirmation assay, an inhibitor assay was also carried out to detect functional inhibitors. Percentage of subjects with antibody and inhibitor development were reported.

Outcome measures

Outcome measures
Measure	Recombinant Factor XIII (rFXIII) n=63 Participants Subjects received 35 IU/kg bodyweight of rFXIII slow intravenous (i.v.) injection every 4 weeks (28 days±2 days) for a minimum period of 52 weeks until the end of trial visit. The dose was identical to the dose administered in the F13CD- 1725 trial. A total of 60 unique subjects were enrolled and exposed in the trial, but 3 of these subjects were later withdrawn and subsequently re-enrolled with new subject IDs, giving rise to a total of N=63 subjects. The unique subjects (N=60) were presented as full analysis set (FAS) while summarising adverse events to avoid double-counting.
Antibody and Inhibitor Development	0 Percentage of subjects

Adverse Events

rFXIII Novo Nordisk

Serious events: 12 serious events

Other events: 54 other events

Deaths: 0 deaths

rFXIII Avecia

Serious events: 0 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Global Clinical Registry (GCR, 1452)

Novo Nordisk A/S

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee At the end of the trial, one or more scientific publication will be prepared collaboratively between Investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or communication for up to 60 days to protect intellectual property.
Publication restrictions are in place

Restriction type: OTHER

Measure	rFXIII Novo Nordisk n=59 participants at risk Subjects in this arm received identical dose of 35 IU/kg bodyweight of rFXIII slow intravenous (i.v.) administered every 4 weeks (28 days±2 days) until the end of trial for a minimum period of 52 weeks. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the rFXIII drug substance (rFXIII Avecia) and subsequently, Novo Nordisk took over production of the rFXIII drug substance (rFXIII Novo Nordisk). Characterisation testing between the two products confirmed that rFXIII Novo Nordisk and rFXIII Avecia had identical structures, and similar physico-chemical properties. The AE data are presented seperately for rFXIII Novo Nordisk and rFXIII Avecia. However, subjects in this arm received rFXIII Novo Nordisk drug.	rFXIII Avecia n=26 participants at risk Subjects in this arm received identical dose of 35 IU/kg bodyweight of rFXIII slow intravenous (i.v.) administered every 4 weeks (28 days±2 days) until the end of trial for a minimum period of 52 weeks. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the rFXIII drug substance (rFXIII Avecia) and subsequently, Novo Nordisk took over production of the rFXIII drug substance (rFXIII Novo Nordisk). Characterisation testing between the two products confirmed that rFXIII Novo Nordisk and rFXIII Avecia had identical structures, and similar physico-chemical properties. The AE data are presented seperately for rFXIII Novo Nordisk and rFXIII Avecia. However, subjects in this arm received rFXIII Avecia drug.
Congenital, familial and genetic disorders Atrial septal defect	1.7% 1/59 • Number of events 1 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.	0.00% 0/26 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.
Nervous system disorders Cerebral ischaemia	1.7% 1/59 • Number of events 1 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.	0.00% 0/26 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.
Injury, poisoning and procedural complications Chest injury	1.7% 1/59 • Number of events 1 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.	0.00% 0/26 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.
Infections and infestations Diverticulitis	1.7% 1/59 • Number of events 1 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.	0.00% 0/26 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.
Pregnancy, puerperium and perinatal conditions Ectopic pregnancy	1.7% 1/59 • Number of events 1 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.	0.00% 0/26 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.
Injury, poisoning and procedural complications Fall	3.4% 2/59 • Number of events 2 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.	0.00% 0/26 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.
Injury, poisoning and procedural complications Head injury	3.4% 2/59 • Number of events 2 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.	0.00% 0/26 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.
Nervous system disorders Headache	1.7% 1/59 • Number of events 1 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.	0.00% 0/26 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.
Gastrointestinal disorders Inguinal hernia	1.7% 1/59 • Number of events 1 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.	0.00% 0/26 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.
Injury, poisoning and procedural complications Laceration	1.7% 1/59 • Number of events 1 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.	0.00% 0/26 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.
Injury, poisoning and procedural complications Multiple fractures	1.7% 1/59 • Number of events 1 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.	0.00% 0/26 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.
Infections and infestations Otitis media chronic	1.7% 1/59 • Number of events 1 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.	0.00% 0/26 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.
Congenital, familial and genetic disorders Patent ductus arteriosus	1.7% 1/59 • Number of events 1 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.	0.00% 0/26 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.
Injury, poisoning and procedural complications Road traffic accident	3.4% 2/59 • Number of events 2 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.	0.00% 0/26 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.
Injury, poisoning and procedural complications Spinal cord injury	1.7% 1/59 • Number of events 1 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.	0.00% 0/26 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.
Psychiatric disorders Suicide attempt	1.7% 1/59 • Number of events 1 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.	0.00% 0/26 • All adverse events (AEs) were collected and reported from screening (week 0) for a minimum period of 52 weeks or until the end of trial visit. The FAS was used for AEs. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the drug. Later, Novo Nordisk took over production of the drug. Hence, AE data are presented seperately who received both rFXIII Avecia and Novo Nordisk. Subsequently, subjects were counted under both groups.