Safety and Efficacy of NNC-0156-0000-0009 in Haemophilia B Patients (paradigm™ 2)

• ClinicalTrials.gov Identifier: NCT01333111
• Recruitment Status: Completed
• First Posted: April 11, 2011
• Results First Posted: July 28, 2017
• Last Update Posted: July 28, 2017
• Sponsor: Novo Nordisk A/S
• Information provided by (Responsible Party): Novo Nordisk A/S

Study Description

Brief Summary:

This trial is conducted in Africa, Asia, Europe, Japan and North America. The aim of this trial is to evaluate the safety and efficacy, including pharmacokinetics (the rate at which the body eliminates the trial drug), of NNC-0156-0000-0009 (nonacog beta pegol) when used for treatment and prophylaxis of bleeding episodes in patients with haemophilia B.

Condition or disease	Intervention/treatment	Phase
Congenital Bleeding Disorder; Haemophilia B	Drug: nonacog beta pegol	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 74 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: A Multi-centre, Single-blind Trial Evaluating Safety and Efficacy, Including Pharmacokinetics, of NNC-0156-0000-0009 When Used for Treatment and Prophylaxis of Bleeding Episodes in Patients With Haemophilia B
• Actual Study Start Date: April 27, 2011
• Actual Primary Completion Date: March 31, 2013
• Actual Study Completion Date: March 31, 2013

Arms and Interventions

Arm	Intervention/treatment
Experimental: Prophylaxis, high dose (trial duration 52 weeks)	Drug: nonacog beta pegol; One single dose administered intravenously (into the vein) once weekly. Patients will receive instruction on how to treat any bleeding episode they may experience; Other Name: NNC-0156-0000-0009
Experimental: Prophylaxis, low dose (trial duration 52 weeks)	Drug: nonacog beta pegol; One single dose administered intravenously (into the vein) once weekly. Patients will receive instruction on how to treat any bleeding episode they may experience; Other Name: NNC-0156-0000-0009
Experimental: On-demand (trial duration 28 weeks)	Drug: nonacog beta pegol; Patients will treat themselves with either a low or a high dose dependent on the severity of the bleeding episode; Other Name: NNC-0156-0000-0009

Outcome Measures

Primary Outcome Measures :

1. Incidence of Inhibitory Antibodies Against Factor IX Defined as Titre Equal to or Above 0.6 BU (Bethesda Units) [ Time Frame: 52 weeks after treatment start for patients on prophylaxis ]
   Inhibitors were analysed with either the Nijmegen modified factor IX Bethesda assay or a heat/cold Nijmegen modified factor IX Bethesda assay. Number of subjects who developed inhibitory antibodies against factor IX are reported.
2. Incidence of Inhibitory Antibodies Against Factor IX Defined as Titre Equal to or Above 0.6 BU (Bethesda Units) [ Time Frame: 28 weeks after treatment start on on-demand treatment ]
   Inhibitors were analysed with either the Nijmegen modified factor IX Bethesda assay or a heat/cold Nijmegen modified factor IX Bethesda assay. Number of subjects who developed inhibitory antibodies against factor IX are reported.

Secondary Outcome Measures :

1. Haemostatic Effect of NNC-0156-0000-0009 When Used for Prophylaxis of Bleeding Episodes, Assessed as Success/Failure Based on a Four-point Scale for Haemostatic Response [ Time Frame: 52 weeks after treatment start for patients on prophylaxis ]

   Haemostatic response after treatment of a bleed with nonacog beta pegol was evaluated on a 4 point scale as excellent, good, moderate or poor. A success rate was calculated based on counting good or excellent as successes and poor and moderate as failures.

   • Excellent - abrupt pain relief and/or clear improvement in objective signs of bleeding within 8 hours after a single injection
   • Good - noticeable pain relief and/or improvement in signs of bleeding within 8 hours after a single injection
   • Moderate - probable or slight beneficial effect within the first 8 hours after the first injection but requiring more than one injection within 8 hours
   • Poor - no improvement, or worsening of symptoms within 8 hours after two injections.

   The success rate and 95% confidence interval (CI) are reported here.

2. Haemostatic Effect of NNC-0156-0000-0009 When Used for Treatment of Bleeding Episodes, Assessed as Success/Failure Based on a Four-point Scale for Haemostatic Response [ Time Frame: 28 weeks after treatment start on on-demand treatment ]

   Haemostatic response after treatment of a bleed with nonacog beta pegol was evaluated on a 4 point scale as excellent, good, moderate or poor. A success rate was calculated based on counting good or excellent as successes and poor and moderate as failures.

   • Excellent - abrupt pain relief and/or clear improvement in objective signs of bleeding within 8 hours after a single injection
   • Good - noticeable pain relief and/or improvement in signs of bleeding within 8 hours after a single injection
   • Moderate - probable or slight beneficial effect within the first 8 hours after the first injection but requiring more than one injection within 8 hours
   • Poor - no improvement, or worsening of symptoms within 8 hours after two injections.

   The success rate and 95% confidence interval (CI) are reported here.

3. Number of Bleeding Episodes Per Patient During Routine Prophylaxis [ Time Frame: 52 weeks after treatment start for patients on prophylaxis ]
   The number of bleeding episodes per patient during routine prophylaxis was assessed using the individual annualised bleeding rates (spontaneous and traumatic bleeding episodes per patient per year).
4. Factor IX Trough Levels [ Time Frame: 52 weeks after treatment start for patients on prophylaxis ]
   The mean pre-dose factor IX levels was measured with the one-stage clotting assay during the trial. Lowest factor IX activity recorded during single-dose and steady state, immediately before next dose was given. The analysis was based on a mixed model on the log-transformed plasma factor IX activity with subject as a random effect. The estimated mean factor IX trough level was presented back-transformed to the natural scale.
5. Incidence of Adverse Events (AEs) [ Time Frame: at 56 weeks ±2 weeks for patients on prophylaxis ]
   The incidence of adverse events were summarised by the rate of AEs (number of AEs per patient years of exposure [PYE]). Number of adverse events per PYE is number of adverse events /total time in trial. All adverse events reported are treatment emergent (any adverse events which occurred after trial product administration).
6. Incidence of Adverse Events (AEs) [ Time Frame: at 32 weeks ±2 weeks for patients on on-demand treatment ]
   The incidence of adverse events were summarised by the rate of AEs (number of AEs per PYE). Number of adverse events per PYE is number of adverse events /total time in trial. All adverse events reported are treatment emergent (any adverse events which occurred after trial product administration).
7. Incidence of Serious Adverse Events (SAEs) [ Time Frame: at 56 weeks ±2 weeks for patients on prophylaxis ]
   SAE was defined as an AE that resulted in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect. The incidence of SAEs were summarised by the rate of SAEs (number of SAEs per PYE). Number of SAEs per PYE is number of SAEs/total time in trial. All SAEs reported are treatment emergent (any serious adverse events which occurred after trial product administration).
8. Incidence of Serious Adverse Events (SAEs) [ Time Frame: at 32 weeks ±2 weeks for patients on on-demand treatment ]
   SAE was defined as an AE that resulted in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect. The incidence of SAEs were summarised by the rate of SAEs (number of SAEs per PYE). Number of SAEs per PYE is number of SAEs/total time in trial. All SAEs reported are treatment emergent (any serious adverse events which occurred after trial product administration).
9. Host Cell Proteins (HCP) Antibodies [ Time Frame: 52 weeks after treatment start for patients on prophylaxis ]
   Subjects who were positive for anti-Host Cell Protein (HCP) antibodies.
10. Host Cell Proteins (HCP) Antibodies [ Time Frame: 28 weeks after treatment start on on-demand treatment ]
    Subjects who were positive for anti-HCP antibodies.

Eligibility Criteria

• Ages Eligible for Study: 13 Years to 70 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Male patients with moderately severe or severe congenital haemophilia B with a factor IX activity of 2% or below according to medical records
• History of at least 150 exposure days to other factor IX products
• Patients currently treated on-demand with at least 6 bleeding episodes during the last 12 months or at least 3 bleeding episodes during the last 6 months, or patients currently on prophylaxis

Exclusion Criteria:

• Known history of factor IX inhibitors based on existing medical records, laboratory report reviews and patient and legally acceptable representative (LAR) interviews
• HIV (Human immunodeficiency virus) positive, with a viral load equal to or above 400,000 copies/mL and/or CD4+ lymphocyte count equal to or below 200/microL
• Congenital or acquired coagulation disorders other than haemophilia B
• Previous arterial thrombotic events (e.g. myocardial infarction and intracranial thrombosis) or previous deep venous thrombosis or pulmonary embolism (as defined by available medical records)
• Immune modulating or chemotherapeutic medication

Contacts and Locations

Locations

United States, California

Novo Nordisk Investigational Site

Los Angeles, California, United States, 90027-6016

United States, Florida

Novo Nordisk Investigational Site

Jacksonville, Florida, United States, 32207

United States, Georgia

Novo Nordisk Investigational Site

Augusta, Georgia, United States, 30912

United States, Iowa

Novo Nordisk Investigational Site

Iowa City, Iowa, United States, 52242

United States, Maryland

Novo Nordisk Investigational Site

Baltimore, Maryland, United States, 21287

United States, Minnesota

Novo Nordisk Investigational Site

Minneapolis, Minnesota, United States, 55404

United States, Nebraska

Novo Nordisk Investigational Site

Omaha, Nebraska, United States, 68198-5456

United States, New Jersey

Novo Nordisk Investigational Site

Newark, New Jersey, United States, 07102

United States, New York

Novo Nordisk Investigational Site

New York, New York, United States, 10029

Novo Nordisk Investigational Site

Syracuse, New York, United States, 13210

United States, Pennsylvania

Novo Nordisk Investigational Site

Hershey, Pennsylvania, United States, 17033

United States, Texas

Novo Nordisk Investigational Site

Houston, Texas, United States, 77030

Canada, Alberta

Novo Nordisk Investigational Site

Edmonton, Alberta, Canada, T6G 2B7

France

Novo Nordisk Investigational Site

Kremlin-Bicêtre, France, 94270

Novo Nordisk Investigational Site

Lyon, France, 69003

Germany

Novo Nordisk Investigational Site

Bonn, Germany, 53127

Novo Nordisk Investigational Site

Duisburg, Germany, 47051

Novo Nordisk Investigational Site

Giessen, Germany, 35392

Novo Nordisk Investigational Site

Hannover, Germany, 30625

Hungary

Novo Nordisk Investigational Site

Budapest, Hungary, H-1134

Italy

Novo Nordisk Investigational Site

Firenze, Italy, 50134

Novo Nordisk Investigational Site

Milano, Italy, 20124

Japan

Novo Nordisk Investigational Site

Kawasaki-shi, Kanagawa, Japan, 216-8511

Novo Nordisk Investigational Site

Nagoya-shi, Aichi, Japan, 466 8560

Novo Nordisk Investigational Site

Nishinomiya-shi, Japan, 663 8051

Novo Nordisk Investigational Site

Shinjuku-ku, Tokyo, Japan, 160 0023

Novo Nordisk Investigational Site

Suginami-ku, Tokyo, Japan, 167 0035

Macedonia, The Former Yugoslav Republic of

Novo Nordisk Investigational Site

Skopje, Macedonia, The Former Yugoslav Republic of, 1000

Malaysia

Novo Nordisk Investigational Site

Kuala Lumpur, Malaysia, 50400

Netherlands

Novo Nordisk Investigational Site

Utrecht, Netherlands, 3584 CX

Russian Federation

Novo Nordisk Investigational Site

Moscow, Russian Federation, 105077

Novo Nordisk Investigational Site

Saint-Petersburg, Russian Federation, 191119

South Africa

Novo Nordisk Investigational Site

Parktown Johannesburg, Gauteng, South Africa, 2193

Thailand

Novo Nordisk Investigational Site

Bangkok, Thailand, 10400

Turkey

Novo Nordisk Investigational Site

Ankara, Turkey, 06500

Novo Nordisk Investigational Site

Kayseri, Turkey, 38010

Novo Nordisk Investigational Site

Konya, Turkey, 42090

United Kingdom

Novo Nordisk Investigational Site

Basingstoke, United Kingdom, RG24 9NA

Novo Nordisk Investigational Site

Cardiff, United Kingdom, CF14 4XW

Novo Nordisk Investigational Site

London, United Kingdom, NW3 2QG

Novo Nordisk Investigational Site

London, United Kingdom, SE1 7EH

Novo Nordisk Investigational Site

Manchester, United Kingdom, M13 9WL

Novo Nordisk Investigational Site

Oxford, United Kingdom, OX3 7LJ

Sponsors and Collaborators

Novo Nordisk A/S

Investigators

• Study Director: Global Clinical Registry (GCR, 1452); Novo Nordisk A/S

More Information

Additional Information:

Clinical Trials at Novo Nordisk 

Publications:

Collins PW, Young G, Knobe K, Karim FA, Angchaisuksiri P, Banner C, Gursel T, Mahlangu J, Matsushita T, Mauser-Bunschoten EP, Oldenburg J, Walsh CE, Negrier C; paradigm 2 Investigators. Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood. 2014 Dec 18;124(26):3880-6. doi: 10.1182/blood-2014-05-573055. Epub 2014 Sep 26.

• Responsible Party: Novo Nordisk A/S
• ClinicalTrials.gov Identifier: NCT01333111
• Other Study ID Numbers: NN7999-3747; 2010-023069-24 ( EudraCT Number ); U1111-1119-6415 ( Other Identifier: WHO ); JapicCTI-111644 ( Other Identifier: Japic )
• First Posted: April 11, 2011
• Results First Posted: July 28, 2017
• Last Update Posted: July 28, 2017
• Last Verified: June 2017

Additional relevant MeSH terms:

Hemostatic Disorders; Hemophilia A; Hemophilia B; Blood Coagulation Disorders; Hemorrhage; Pathologic Processes; Blood Coagulation Disorders, Inherited; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Vascular Diseases; Cardiovascular Diseases