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A Gene Therapy Study for Hemophilia B

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ClinicalTrials.gov Identifier: NCT02484092
Recruitment Status : Completed
First Posted : June 29, 2015
Results First Posted : May 19, 2020
Last Update Posted : June 16, 2020
Sponsor:
Information provided by (Responsible Party):
Pfizer

Study Type Interventional
Study Design Intervention Model: Sequential Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Hemophilia B
Intervention Biological: SPK-9001
Enrollment 15
Recruitment Details A total of 22 participants were screened, 15 participants were assigned to treatment and completed study. All 15 participants received the lowest dose in the study (5 x 10^11 vg/kg). No participants were assigned to the 2 higher dose arms. Results presented here are from the lowest dose level.
Pre-assignment Details  
Arm/Group Title SPK-9001 (5 x 10^11 vg/kg) IV Infusion
Hide Arm/Group Description Participants were infused with 100 IU/kg of their usual FIX protein product over 10 minutes at Day 0 visit. Following the bolus infusion of the usual FIX protein product, the participant was infused with SPK-9001 (5 x 10^11 vg/kg) for approximately 60 minutes via infusion pump.
Period Title: Overall Study
Started 15
Completed 15
Not Completed 0
Arm/Group Title SPK-9001 (5 x 10^11 vg/kg) IV Infusion
Hide Arm/Group Description Participants were infused with 100 IU/kg of their usual FIX protein product over 10 minutes at Day 0 visit. Following the bolus infusion of the usual FIX protein product, the participant was infused with SPK-9001 (5 x 10^11 vg/kg) for approximately 60 minutes via infusion pump.
Overall Number of Baseline Participants 15
Hide Baseline Analysis Population Description
Baseline analysis population included all participants who received at least 1 dose of study treatment.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 15 participants
38.6  (14.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 15 participants
Female
0
   0.0%
Male
15
 100.0%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 15 participants
White or Caucasian 12
Black or African American 1
Native Hawaiian or Other Pacific Islander 1
Multiple 1
1.Primary Outcome
Title Number of Participants With Clinically Significant Change From Baseline in Physical Examination Findings
Hide Description Physical examination included examination of the head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The examination assessed the participants for any potential changes in general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms. Findings were considered to be clinically significant based on investigator's decision.
Time Frame Baseline up to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received the infusion of SPK-9001.
Arm/Group Title SPK-9001 (5 x 10^11 vg/kg)
Hide Arm/Group Description:
Participants were infused with 100 IU/kg of their usual FIX protein product over 10 minutes at Day 0 visit. Following the bolus infusion of the usual FIX protein product, the participant was infused with SPK-9001 (5 x 10^11 vg/kg) for approximately 60 minutes via infusion pump.
Overall Number of Participants Analyzed 15
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
2.Primary Outcome
Title Number of Participants With Clinically Significant Change From Baseline in Vital Signs
Hide Description Vital signs (temperature, respiratory rate, pulse rate, height, weight, systolic and diastolic blood pressure) were obtained with participant in the seated position, after having sat calmly for at least 5 minutes. Clinical significance of vital signs was determined at the investigator's discretion.
Time Frame Baseline up to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received the infusion of SPK-9001.
Arm/Group Title SPK-9001 (5 x 10^11 vg/kg)
Hide Arm/Group Description:
Participants were infused with 100 IU/kg of their usual FIX protein product over 10 minutes at Day 0 visit. Following the bolus infusion of the usual FIX protein product, the participant was infused with SPK-9001 (5 x 10^11 vg/kg) for approximately 60 minutes via infusion pump.
Overall Number of Participants Analyzed 15
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
3.Primary Outcome
Title Number of Participants With Clinical Laboratory Abnormalities Reported as TEAE
Hide Description Following parameters were analyzed for laboratory examination: hematology (neutrophils, lymphocytes, monocytes, eosinophils, basophils, red blood cell [RBC] count, hemoglobin, hematocrit, platelet count); liver function (albumin, total bilirubin, total protein, direct bilirubin, indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, GGT); Lipid panel (HDL, VLDL, triglycerides, total cholesterol); clinical chemistry (sodium, potassium, chloride, bicarbonate, glucose, phosphate, serum creatinine, BUN); urinalysis (specific gravity, pH, glucose, protein, blood, ketones; coagulation, immunology, etc. Investigators determined which laboratory abnormalities were reported as treatment-emergent adverse events (TEAEs).
Time Frame Baseline up to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received the infusion of SPK-9001.
Arm/Group Title SPK-9001 (5 x 10^11 vg/kg)
Hide Arm/Group Description:
Participants were infused with 100 IU/kg of their usual FIX protein product over 10 minutes at Day 0 visit. Following the bolus infusion of the usual FIX protein product, the participant was infused with SPK-9001 (5 x 10^11 vg/kg) for approximately 60 minutes via infusion pump.
Overall Number of Participants Analyzed 15
Measure Type: Count of Participants
Unit of Measure: Participants
2
  13.3%
4.Primary Outcome
Title Number of Participants With Drug -Related TEAEs and Serious Adverse Events (SAEs)
Hide Description An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product; the event did not need to have a causal relationship with the treatment. A serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and AEs. An AE was regarded as TEAE if the start date was on or after the infusion of SPK-9001 but before participant's last visit on study (or the date of withdrawal/the date of being lost to follow-up). Severe TEAEs were TEAEs that interfered significantly with participants' usual function. Treatment-related TEAEs were determined by the investigator.
Time Frame Baseline up to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received the infusion of SPK-9001.
Arm/Group Title SPK-9001 (5 x 10^11 vg/kg)
Hide Arm/Group Description:
Participants were infused with 100 IU/kg of their usual FIX protein product over 10 minutes at Day 0 visit. Following the bolus infusion of the usual FIX protein product, the participant was infused with SPK-9001 (5 x 10^11 vg/kg) for approximately 60 minutes via infusion pump.
Overall Number of Participants Analyzed 15
Measure Type: Count of Participants
Unit of Measure: Participants
Drug-related TEAE
2
  13.3%
Drug-related Serious TEAE
0
   0.0%
5.Primary Outcome
Title Number of Participants With Positive Immune Reponses Against Adeno-associated Virus Vector (AAV) Capsid
Hide Description Peripheral blood mononuclear cells (PBMC) results by interferon gamma enzyme-linked immunospot assay (ELISPOT) to assess cellular immune responses to AAV capsid and to FIX were presented. The ELISPOT is a type of assay that focuses on quantitatively measuring the frequency of cytokine secretion for a single cell. The positive ELISPOT results suggested a T-cell reaction to capsid protein.
Time Frame Baseline up to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received the infusion of SPK-9001.
Arm/Group Title SPK-9001 (5 x 10^11 vg/kg)
Hide Arm/Group Description:
Participants were infused with 100 IU/kg of their usual FIX protein product over 10 minutes at Day 0 visit. Following the bolus infusion of the usual FIX protein product, the participant was infused with SPK-9001 (5 x 10^11 vg/kg) for approximately 60 minutes via infusion pump.
Overall Number of Participants Analyzed 15
Measure Type: Count of Participants
Unit of Measure: Participants
2
  13.3%
6.Primary Outcome
Title Number of Participants Who Reached > 150% Vector-derived FIX:C Activity Level After SPK-9001 Infusion
Hide Description Based on non-clinical studies in non-human primates (NHPs), it was not predicted that vector-derived FIX:C activity levels >150% of normal would be achieved in this study. However, thrombin antithrombin (TAT) levels as thrombotic potential were to be measured if vector derived FIX:C activity levels >150% of normal were achieved in any participant during the study. Blood samples for TAT at Day 0 visit (prior to FIX protein product infusion) were used to establish baseline value.
Time Frame Baseline up to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received the infusion of SPK-9001.
Arm/Group Title SPK-9001 (5 x 10^11 vg/kg)
Hide Arm/Group Description:
Participants were infused with 100 IU/kg of their usual FIX protein product over 10 minutes at Day 0 visit. Following the bolus infusion of the usual FIX protein product, the participant was infused with SPK-9001 (5 x 10^11 vg/kg) for approximately 60 minutes via infusion pump.
Overall Number of Participants Analyzed 15
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
7.Primary Outcome
Title Number of Participants With FIX Inhibitor
Hide Description FIX inhibitors were measured using the Bethesda assay from the central and local laboratory. The Bethesda assay measures the amount of factor (FIX) inactivated when the plasma from the patient is incubated with an external source of factor for 2 hours at 37ºC. Inhibitor levels are quantified in Bethesda units (BU). An inhibitor titer of ≥ 0.6 BU/ml is to be taken as clinically significant.
Time Frame Baseline up to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received the infusion of SPK-9001.
Arm/Group Title SPK-9001 (5 x 10^11 vg/kg)
Hide Arm/Group Description:
Participants were infused with 100 IU/kg of their usual FIX protein product over 10 minutes at Day 0 visit. Following the bolus infusion of the usual FIX protein product, the participant was infused with SPK-9001 (5 x 10^11 vg/kg) for approximately 60 minutes via infusion pump.
Overall Number of Participants Analyzed 15
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
8.Primary Outcome
Title Incremental Recovery of FIX Product
Hide Description Incremental recovery was determined as the peak factor level recorded within the first 3 hours after infusion and was reported as (IU/ml)/(IU/kg), using the formula:([Activity IU/mL peak post infusion] - [Activity IU/mL pre-infusion]) / (IU/kg infused).
Time Frame Day 0 and Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had received 100 IU/kg of FIX protein product infusion and completed the blood sample collection within the first 3 hours post infusion for FIX protein product enabling determination of FIX incremental recovery.
Arm/Group Title SPK-9001 (5 x 10^11 vg/kg)
Hide Arm/Group Description:
Participants were infused with 100 IU/kg of their usual FIX protein product over 10 minutes at Day 0 visit. Following the bolus infusion of the usual FIX protein product, the participant was infused with SPK-9001 (5 x 10^11 vg/kg) for approximately 60 minutes via infusion pump.
Overall Number of Participants Analyzed 15
Mean (Standard Deviation)
Unit of Measure: [IU/ml]/[IU/kg]
Day 0 Number Analyzed 15 participants
0.0100  (0.00242)
Week 52 Number Analyzed 6 participants
0.0162  (0.01351)
9.Secondary Outcome
Title FIX:C Activity
Hide Description All samples collected from participants for plasma FIX activity levels were analyzed and used to determine peak and steady-state vector-derived circulating FIX activity levels. The vector-derived endogenous (not affected by intercurrent FIX product infusions) FIX:C activity levels were characterized by post-treatment population mean. Dose escalation and dose level expansion strategies were employed in the study based on vector-derived FIX activity levels as well as any immune responses against AAV capsid. Steady-state levels were based on 2 separate vector-derived FIX:C activity level measurements (at least 2 weeks apart) starting from Week 8-12 with adequate washout.
Time Frame Baseline up to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had received SPK-9001 and had collected vector-derived FIX:C activity levels enabling acceptable determination of the peak and steady-state derived activity level.
Arm/Group Title SPK-9001 (5 x 10^11 vg/kg)
Hide Arm/Group Description:
Participants were infused with 100 IU/kg of their usual FIX protein product over 10 minutes at Day 0 visit. Following the bolus infusion of the usual FIX protein product, the participant was infused with SPK-9001 (5 x 10^11 vg/kg) for approximately 60 minutes via infusion pump.
Overall Number of Participants Analyzed 15
Mean (Standard Deviation)
Unit of Measure: Percentage of Normal
Steady-State Level 22.9  (9.89)
Peak Activity 29.1  (11.63)
10.Secondary Outcome
Title Change From Baseline in FIX:C Antigen Level at Steady State
Hide Description The vector-derived endogenous (not affected by intercurrent FIX product infusions) FIX:C activity antigen levels were characterized by post-treatment population mean.
Time Frame Week 12 up to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had received SPK-9001 and had collected vector-derived FIX:C activity levels enabling acceptable determination of the peak and steady-state derived activity level.
Arm/Group Title SPK-9001 (5 x 10^11 vg/kg)
Hide Arm/Group Description:
Participants were infused with 100 IU/kg of their usual FIX protein product over 10 minutes at Day 0 visit. Following the bolus infusion of the usual FIX protein product, the participant was infused with SPK-9001 (5 x 10^11 vg/kg) for approximately 60 minutes via infusion pump.
Overall Number of Participants Analyzed 15
Mean (Standard Deviation)
Unit of Measure: Percentage of Normal
Week 12 Number Analyzed 15 participants
-4.4  (19.26)
Week 14 Number Analyzed 14 participants
-4.7  (23.11)
Week 16 Number Analyzed 15 participants
-4.7  (19.79)
Week 18 Number Analyzed 15 participants
-5.8  (21.81)
Week 22 Number Analyzed 15 participants
-4.6  (22.06)
Week 26 Number Analyzed 15 participants
-6.6  (20.64)
Week 32 Number Analyzed 14 participants
-7.1  (20.48)
Week 42 Number Analyzed 15 participants
-4.9  (19.87)
Week 52 Number Analyzed 15 participants
-6.9  (19.70)
Time Frame Baseline up to Week 52
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title SPK-9001 (5 x 10^11 vg/kg) IV Infusion
Hide Arm/Group Description Participants were infused with 100 IU/kg of their usual FIX protein product over 10 minutes at Day 0 visit. Following the bolus infusion of the usual FIX protein product, the participant was infused with SPK-9001 (5 x 10^11 vg/kg) for approximately 60 minutes via infusion pump.
All-Cause Mortality
SPK-9001 (5 x 10^11 vg/kg) IV Infusion
Affected / at Risk (%)
Total   0/15 (0.00%) 
Hide Serious Adverse Events
SPK-9001 (5 x 10^11 vg/kg) IV Infusion
Affected / at Risk (%)
Total   0/15 (0.00%) 
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
SPK-9001 (5 x 10^11 vg/kg) IV Infusion
Affected / at Risk (%)
Total   14/15 (93.33%) 
Blood and lymphatic system disorders   
Microcytic anaemia * 1  1/15 (6.67%) 
Normocytic anaemia * 1  1/15 (6.67%) 
Cardiac disorders   
Palpitations * 1  1/15 (6.67%) 
Eye disorders   
Conjunctivitis allergic * 1  1/15 (6.67%) 
Gastrointestinal disorders   
Abdominal discomfort * 1  1/15 (6.67%) 
Abdominal distension * 1  1/15 (6.67%) 
Abdominal pain lower * 1  1/15 (6.67%) 
Aphthous ulcer * 1  1/15 (6.67%) 
Diarrhoea * 1  1/15 (6.67%) 
Dyspepsia * 1  2/15 (13.33%) 
Food poisoning * 1  1/15 (6.67%) 
Gastrooesophageal reflux disease * 1  2/15 (13.33%) 
Nausea * 1  1/15 (6.67%) 
General disorders   
Catheter site bruise * 1  1/15 (6.67%) 
Face oedema * 1  1/15 (6.67%) 
Immune system disorders   
Seasonal allergy * 1  1/15 (6.67%) 
Infections and infestations   
Gastroenteritis * 1  1/15 (6.67%) 
Nasopharyngitis * 1  3/15 (20.00%) 
Otitis media * 1  1/15 (6.67%) 
Pharyngitis * 1  1/15 (6.67%) 
Upper respiratory tract infection * 1  5/15 (33.33%) 
Injury, poisoning and procedural complications   
Ligament sprain * 1  1/15 (6.67%) 
Muscle injury * 1  1/15 (6.67%) 
Muscle strain * 1  3/15 (20.00%) 
Investigations   
Transaminases increased * 1  2/15 (13.33%) 
Musculoskeletal and connective tissue disorders   
Arthralgia * 1  1/15 (6.67%) 
Back pain * 1  3/15 (20.00%) 
Calcification of muscle * 1  1/15 (6.67%) 
Costochondritis * 1  1/15 (6.67%) 
Exostosis * 1  1/15 (6.67%) 
Joint range of motion decreased * 1  1/15 (6.67%) 
Musculoskeletal chest pain * 1  1/15 (6.67%) 
Musculoskeletal pain * 1  1/15 (6.67%) 
Pain in extremity * 1  1/15 (6.67%) 
Tendonitis * 1  2/15 (13.33%) 
Nervous system disorders   
Dizziness * 1  1/15 (6.67%) 
Dysgeusia * 1  1/15 (6.67%) 
Headache * 1  2/15 (13.33%) 
Hypoaesthesia * 1  1/15 (6.67%) 
Sinus headache * 1  1/15 (6.67%) 
Psychiatric disorders   
Insomnia * 1  1/15 (6.67%) 
Irritability * 1  1/15 (6.67%) 
Renal and urinary disorders   
Haematuria * 1  1/15 (6.67%) 
Respiratory, thoracic and mediastinal disorders   
Cough * 1  2/15 (13.33%) 
Epistaxis * 1  1/15 (6.67%) 
Nasal congestion * 1  2/15 (13.33%) 
Oropharyngeal pain * 1  1/15 (6.67%) 
Rhinorrhoea * 1  1/15 (6.67%) 
Sinus congestion * 1  1/15 (6.67%) 
Upper-airway cough syndrome * 1  1/15 (6.67%) 
Skin and subcutaneous tissue disorders   
Rash macular * 1  1/15 (6.67%) 
1
Term from vocabulary, MedDRA 21.1
*
Indicates events were collected by non-systematic assessment
15 participants were treated at the first dose planned for this dose escalation study. Requirements for dose escalation were not met as per protocol and the study completed once all participants completed 52 weeks of follow-up at the initial dose.
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.
Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Pfizer ClinicalTrials.gov Call Center
Organization: Pfizer, Inc.
Phone: 1-800-718-1021
EMail: ClinicalTrials.gov_Inquiries@pfizer.com
Layout table for additonal information
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02484092    
Other Study ID Numbers: C0371005
SPK-9001-101 ( Other Identifier: Alias Study Number )
First Submitted: June 18, 2015
First Posted: June 29, 2015
Results First Submitted: April 4, 2020
Results First Posted: May 19, 2020
Last Update Posted: June 16, 2020