Human Cell Line-derived Recombinant Factor VIII (Human-cl-rhFVIII) in Previously Untreated Patients

• ClinicalTrials.gov Identifier: NCT01712438
• Recruitment Status: Completed
• First Posted: October 23, 2012
• Results First Posted: October 21, 2019
• Last Update Posted: January 19, 2021
• Sponsor: Octapharma
• Information provided by (Responsible Party): Octapharma

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Severe Hemophilia A
• Intervention: Biological: Human cl rhFVIII
• Enrollment: 110

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Human-cl rhFVIII
Arm/Group Description	Of the total number of patients that started in the study, the safety (SAF) and intent-to-treat (ITT) population received at least one treatment with Human-cl rhFVIII. Prophylactic treatment dose given to all patients in the PROPH population (all patients who received at least one administration of Human cI rhFVIII with prophylaxis documented as the reason for treatment): 20-50 IU/FVIII/kg body weight (BW)). On-demand treatment of bleeding episodes (BEs) dose given to the BLEED population (all patients with bleeding episodes treated with Human cI rhFVIII): 20-30 IU FVIII/kg BW (minor haemorrhage), 30-40 IU FVIII/kg BW (moderate to major haemorrhage) or 40-60 IU FVIII/kg BW (major to life-threatening haemorrhage). Surgical prophylaxis dose given to the SURG population (all patients with surgeries performed under Human cI rhFVIII treatment): 25-30 IU FVIII/kg BW (minor surgeries) or 40-60 IU FVIII/kg BW (major surgeries).
Period Title: Overall Study
Started	110
SAF Population [1]	108
ITT Population [2]	108
PP Population [3]	95
PROPH Population [4]	103
BLEED Population [5]	94
SURG Population [6]	24
Completed	73
Not Completed	37
Reason Not Completed
Not treated with Human-cl rhFVIII	2
Ongoing ITI treatment	6
Violated inclusion & exclusion criteria	4
Prematurely Discontinued	25
[1] SAF population = study population of patients in safety analysis; [2] ITT population = intent-to-treat population; [3] PP Population = per-protocol population; [4] PROPH population = study population of patients receiving prophylaxis; [5] BLEED population = study population of Bleeding Events (BEs); [6] SURG population = study population of patients undergoing surgery treated with Human-cl rhFVIII

Baseline Characteristics

Arm/Group Title		Human-cl rhFVIII
Arm/Group Description		The safety (SAF) and intent-to-treat (ITT) population consists all patients who had data collected post-treatment with Human-cl rhFVIII (n=108).
Overall Number of Baseline Participants		108
Baseline Analysis Population Description		The safety (SAF) and intent-to-treat (ITT) population consist of all patients who had data collected post-treatment with Human-cl rhFVIII (n=108).
Age, Continuous [1]; Mean (Full Range); Unit of measure: Months
	Number Analyzed	108 participants
		19.0; (0 to 146)
		[1] Measure Description: Age at screening in months
Age, Continuous [1]; Mean (Full Range); Unit of measure: Months
	Number Analyzed	108 participants
		21.6; (0 to 146)
		[1] Measure Description: Age at exposure day 1 in months
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	108 participants
	Female	0 0.0%
	Male	108 100.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	108 participants
	Hispanic or Latino	2 1.9%
	Not Hispanic or Latino	105 97.2%
	Unknown or Not Reported	1 0.9%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	108 participants
	American Indian or Alaska Native	1 0.9%
	Asian	14 13.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%
	Black or African American	0 0.0%
	White	89 82.4%
	More than one race	0 0.0%
	Unknown or Not Reported	4 3.7%
Body Mass Index (BMI) at Exposure Day 1 (ED1); Mean (Full Range); Unit of measure: Kg/m2
	Number Analyzed	108 participants
		17.2; (9 to 43)
Height at Exposure Day 1 (ED1) [1]; Mean (Full Range); Unit of measure: Centimeters (cm)
	Number Analyzed	108 participants
		82.0; (45 to 144)
		[1] Measure Description: Height at exposure day 1 in centimeters
Weight at Exposure Day 1 (ED1) [1]; Mean (Full Range); Unit of measure: Kilograms (kg)
	Number Analyzed	108 participants
		11.7; (3 to 31)
		[1] Measure Description: Weight at exposure day 1 in kilograms
Family history of inhibitors; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	108 participants
	Yes	13 12.0%
	No	95 88.0%

Outcome Measures

1. Primary Outcome

Title	Immunogenicity of Human-cl rhFVIII: Incidence of Inhibitors
Description	The number of patients developing FVIII inhibitors was observed during the observation period by assessing inhibitor development using the modified Bethesda assay (Nijmegen modification). The definitions for thresholds were ≥0.6 to <5 BU/mL for a "low titre" inhibitor and ≥5 BU/mL for a "high-titre" inhibitor.
Time Frame	maximum 5 years (100 exposure days)

Outcome Measure Data

Analysis Population Description

The analysis was performed for the SAF/ITT population which includes all patients who had data collected post-treatment with Human-cl rhFVIII (n=108). Of the 108 patients, 105 patients had at least one inhibitor test after exposure day (ED) 1.

Arm/Group Title	SAF/ITT Population
Arm/Group Description:	All patients who had data collected post-treatment with Human-cl rhFVIII (n=108).
Overall Number of Participants Analyzed	105
Measure Type: Count of Participants; Unit of Measure: Participants
High titre inhibitor (>5 BU/mL)	17 16.2%
Low titre inhibitor (<5 BU/mL)	11 10.5%
Any inhibitor (>0.6 BU/mL)	28 26.7%

2. Secondary Outcome

Title	Frequency of Spontaneous Break-through Bleeds
Description	The annualized bleeding rate (ABR) was calculated during inhibitor-free periods for spontaneous bleeding events (BEs) during prophylactic treatment with Human cl rhFVIII
Time Frame	Maximum 5 years (100 exposure days)

Outcome Measure Data

Analysis Population Description

The analysis population includes all patients who received at least one prophylactic treatment with Human-cl rhFVIII (PROPH population; n=103). Of all patients in the PROPH population, data was available on spontaneous break-through bleeds for 102 patients.

Arm/Group Title	PROPH Population
Arm/Group Description:	All patients who received at least one prophylactic treatment with Human-cl rhFVIII (n=103).
Overall Number of Participants Analyzed	102
Mean (95% Confidence Interval); Unit of Measure: No. BEs per duration (year) (ABR)
	0.976; (0.431 to 1.521)

3. Secondary Outcome

Title	Efficacy of Human-cl rhFVIII for the Treatment of Bleeds
Description	A personal efficacy assessment to assess the efficacy of Human-cl rhFVIII for the on-demand treatment of bleeding episodes. Efficacy was assessed using a four-point scale (excellent, good, moderate, none).
Time Frame	Maximum 5 years (100 exposure days)

Outcome Measure Data

Analysis Population Description

The analysis population includes patients (n=94) who received Human-cl rhFVIII for on-demand treatment of BEs (BLEED population).

Arm/Group Title	BLEED Population
Arm/Group Description:	All patients that experienced at least one bleeding episode that was treated with Human-cl rhFVIII (n=94).
Overall Number of Participants Analyzed	94
Overall Number of Units Analyzed; Type of Units Analyzed: Number of Bleeding Events	804
Count of Units; Unit of Measure: Number of Bleeding Events
Excellent	510 63.4%
Good	237 29.5%
Moderate	51 6.3%
None	6 0.7%

4. Secondary Outcome

Title	Efficacy of Human-cl rhFVIII for Surgical Prophylaxis
Description	An overall efficacy assessment to assess the efficacy of human-cl rhFVIII in surgical prophylaxis of minor and major surgeries. The efficacy assessment was analyzed using a four-point scale (excellent, good, moderate, none).
Time Frame	Maximum 5 years (100 exposure days)

Outcome Measure Data

Analysis Population Description

The analysis population includes 24 patients that received Human-cl rhFVIII for surgical prophylaxis during a total of 26 surgeries (SURG population). Of these, 13 patients had minor surgeries and 11 patients had major surgeries. Of the total 26 surgeries, 21 had an overall efficacy assessment (an assessment was not performed for 5 surgeries).

Arm/Group Title	Minor Surgeries	Major Surgeries	All Surgeries
Arm/Group Description:	All patients that had minor surgeries performed under Human-cl rhFVIII treatment (n=13)	All patients that had major surgeries performed under Human-cl rhFVIII treatment (n=11)	All patients that had surgeries performed under Human-cl rhFVIII treatment (n=24)
Overall Number of Participants Analyzed	13	11	24
Overall Number of Units Analyzed; Type of Units Analyzed: Number of surgeries	10	11	21
Count of Units; Unit of Measure: Number of surgeries
Excellent	7 70.0%	8 72.7%	15 71.4%
Good	1 10.0%	2 18.2%	3 14.3%
Moderate	1 10.0%	1 9.1%	2 9.5%
None	1 10.0%	0 0.0%	1 4.8%

5. Other Pre-specified Outcome

Title	The Occurrence of Any Adverse Event (AE)
Description	The frequency of AEs, as monitored throughout the whole study by the number of patients with at least one adverse event occurrence.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

Of the 110 patients enrolled in the study, 2 were excluded because they had no treatment with Human-cl rhFVIII leaving 108 patients in the safety (SAF) and intent-to-treat (ITT) population.

Arm/Group Title	SAF/ITT Population
Arm/Group Description:	All patients who had data collected post-treatment with Human-cl rhFVIII (n=108).
Overall Number of Participants Analyzed	108
Measure Type: Count of Participants; Unit of Measure: Participants
Adverse Event (AE)	101 93.5%
Serious adverse event (SAE)	48 44.4%
Severe AE	27 25.0%
Temporally related adverse event	78 72.2%
Death	0 0.0%
Death due to probably/possibly related AE	0 0.0%
AE leading to permanent study discontinuation	2 1.9%

Adverse Events

Time Frame	Maximum 5 years (100 exposure days)
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	SAF/ITT Population
Arm/Group Description	All patients who had data collected post-treatment with Human-cl rhFVIII (n=108).
All-Cause Mortality
	SAF/ITT Population
	Affected / at Risk (%)
Total	0/108 (0.00%)
Serious Adverse Events
	SAF/ITT Population
	Affected / at Risk (%)	# Events
Total	48/108 (44.44%)
Blood and lymphatic system disorders
Factor VIII inhibition †	28/108 (25.93%)	29
Factor IX inhibition †	1/108 (0.93%)	1
Haemorrhagic anaemia †	2/108 (1.85%)	2
Anaemia †	1/108 (0.93%)	1
Gastrointestinal disorders
Ileus †	1/108 (0.93%)	1
Mouth haemorrhage †	1/108 (0.93%)	1
General disorders
Pyrexia †	5/108 (4.63%)	8
Infections and infestations
Tonsillitis †	1/108 (0.93%)	1
Pneumonia †	2/108 (1.85%)	2
Bronchitis †	1/108 (0.93%)	1
Staphylococcal infection †	1/108 (0.93%)	1
Gastroenteritis †	2/108 (1.85%)	2
Nasopharyngitis †	1/108 (0.93%)	1
Device related sepsis †	2/108 (1.85%)	3
Device related infection †	2/108 (1.85%)	2
Ear infection †	1/108 (0.93%)	1
Influenza †	1/108 (0.93%)	1
Septic shock †	1/108 (0.93%)	1
Fungal skin infection †	1/108 (0.93%)	1
Lower respiratory tract infection †	1/108 (0.93%)	1
Gastrointestinal infection †	1/108 (0.93%)	1
Periodontitis †	1/108 (0.93%)	1
Injury, poisoning and procedural complications
Injury †	1/108 (0.93%)	1
Head injury †	1/108 (0.93%)	1
Skin injury †	1/108 (0.93%)	1
Traumatic haematoma †	1/108 (0.93%)	1
Limb injury †	1/108 (0.93%)	1
Fall †	1/108 (0.93%)	1
Contusion †	1/108 (0.93%)	1
Scrotal haematoma †	1/108 (0.93%)	1
Subdural haemorrhage †	1/108 (0.93%)	1
Subdural haematoma †	1/108 (0.93%)	2
Metabolism and nutrition disorders
Type 1 diabetes mellitus †	1/108 (0.93%)	1
Musculoskeletal and connective tissue disorders
Haemarthrosis †	2/108 (1.85%)	2
Joint swelling †	1/108 (0.93%)	1
Nervous system disorders
Haemorrhage intracranial †	1/108 (0.93%)	1
Product Issues
Device Issue †	1/108 (0.93%)	1
Respiratory, thoracic and mediastinal disorders
Apnoea †	1/108 (0.93%)	1
Skin and subcutaneous tissue disorders
Rash †	1/108 (0.93%)	1
Vascular disorders
Haematoma †	4/108 (3.70%)	4
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	2%
	SAF/ITT Population
	Affected / at Risk (%)	# Events
Total	101/108 (93.52%)
Blood and lymphatic system disorders
Factor VIII inhibition †	28/108 (25.93%)
Anaemia †	21/108 (19.44%)
Haemorrhagic anaemia †	3/108 (2.78%)
Gastrointestinal disorders
Diarrhoea †	14/108 (12.96%)
Teething †	10/108 (9.26%)
Vomiting †	10/108 (9.26%)
Constipation †	5/108 (4.63%)
Toothache †	4/108 (3.70%)
Stomatitis †	3/108 (2.78%)
General disorders
Pyrexia †	61/108 (56.48%)
Immune system disorders
Hypersensitivity †	3/108 (2.78%)
Infections and infestations
Nasopharyngitis †	35/108 (32.41%)
Rhinitis †	20/108 (18.52%)
Upper respiratory tract infection †	12/108 (11.11%)
Ear infection †	11/108 (10.19%)
Bronchitis †	10/108 (9.26%)
Conjunctivitis †	9/108 (8.33%)
Gastroenteritis †	9/108 (8.33%)
Varicella †	8/108 (7.41%)
Respiratory tract infection †	7/108 (6.48%)
Laryngitis †	6/108 (5.56%)
Pharyngitis †	5/108 (4.63%)
Tonsillitis †	5/108 (4.63%)
Lower respiratory tract infection †	4/108 (3.70%)
Pneumonia †	4/108 (3.70%)
Device related information †	3/108 (2.78%)
Erythema infectiosum †	3/108 (2.78%)
Influenza †	3/108 (2.78%)
Viral infection †	3/108 (2.78%)
Injury, poisoning and procedural complications
Head injury †	6/108 (5.56%)
Mouth injury †	3/108 (2.78%)
Investigations
Haemoglobin decreased †	4/108 (3.70%)
Metabolism and nutrition disorders
Iron deficiency †	4/108 (3.70%)
Musculoskeletal and connective tissue disorders
Pain in extremity †	4/108 (3.70%)
Arthralgia †	3/108 (2.78%)
Respiratory, thoracic and mediastinal disorders
Cough †	15/108 (13.89%)
Productive cough †	3/108 (2.78%)
Rhinorrhea †	3/108 (2.78%)
Wheezing †	3/108 (2.78%)
Skin and subcutaneous tissue disorders
Rash †	12/108 (11.11%)
Dermatitis allergic †	3/108 (2.78%)
Urticaria †	3/108 (2.78%)
Vascular disorders
Haematoma †	5/108 (4.63%)
† Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Octapharma agreements may vary with individual investigators, but will not prohibit any investigator from publishing. Octapharma supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial. Octapharma also reserves the right to review data prior to publishing and provide comments/changes within a certain time period.

Results Point of Contact

• Name/Title: Sylvia Werner
• Organization: Octapharma
• Phone: 415 260-9577
• EMail: sylvia.werner@octapharma.com

• Responsible Party: Octapharma
• ClinicalTrials.gov Identifier: NCT01712438
• Other Study ID Numbers: GENA-05; 2012-002554-23 ( EudraCT Number )
• First Submitted: October 18, 2012
• First Posted: October 23, 2012
• Results First Submitted: September 25, 2019
• Results First Posted: October 21, 2019
• Last Update Posted: January 19, 2021