Clinical Trials Register

Summary
EudraCT Number:	2017-000860-14
Sponsor's Protocol Code Number:	GR-OG-279239-03
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-01-17
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Austria - BASG

A.2

EudraCT number

2017-000860-14

A.3

Full title of the trial

Patient and evaluator blinded non-inferiority study on safety, tolerability and lumbar fusion efficacy of a single administration of Osteogrow (rhBMP6 in autologous blood coagulum (ABC) carrier) in adult patients treated by posterolateral lumbar interbody fusion (PLIF) for degenerative disc disease

Patienten und Gutachter verblindete non-inferiority Studie zur Sicherheit,
Verträglichkeit und Auswirkung auf die knöcherne Fusion der lumbalen Wirbelsäule einer Einzeldosis von Osteogrow (rhBMP6 – rekombinantes humanes bone morphogenetic protein - in einem autologen Vollblutkoagel) bei erwachsenen Patienten, die mit einer postero-lateralen interkorporellen Fusion (PLIF) bei degenerativen Bandscheibenerkrankungen behandelt werden

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Blinded study on safety, tolerability and lumbar fusion efficacy of a single dose of Osteogrow (which comprises a protein called BMP6 mixed with the patients own blood to form a clot) in adult patients treated by spinal fusion (posterolateral lumbar interbody fusion, PLIF) for degenerative disc disease

A.4.1

Sponsor's protocol code number

GR-OG-279239-03

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Genera Research Ltd
B.1.3.4	Country	Croatia
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	EU Commision, H2020 work programme
B.4.2	Country	European Union
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Clinres farmacija
B.5.2	Functional name of contact point	Clinical Trial Information
B.5.3	Address:
B.5.3.1	Street Address	Vilharjeva cesta 29
B.5.3.2	Town/ city	Ljubljana
B.5.3.3	Post code	1000
B.5.3.4	Country	Slovenia
B.5.4	Telephone number	3861426 95 70
B.5.6	E-mail	robert.ivanec@clinres.si

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Osteogrow
D.3.2	Product code	rhBMP6
D.3.4	Pharmaceutical form	Powder and solvent for implantation paste
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Implantation
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not yet available
D.3.9.2	Current sponsor code	rhBMP6
D.3.9.3	Other descriptive name	RECOMBINANT HUMAN BONE MORPHOGENETIC PROTEIN 6
D.3.9.4	EV Substance Code	SUB176170
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Lumbar spine single segment destabilization caused by degenerative disc disease

E.1.1.1

Medical condition in easily understood language

Chronic lower back pain

E.1.1.2

Therapeutic area

Body processes [G] - Bones and nerves physological processes [G11]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10050505
E.1.2	Term	Spinal fusion surgery
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluate safety and composite endpoint non-inferiority of one of the two doses of Osteogrow+Allograft delivered bilaterally between transverse processes of a single lumbar spine segment in comparison to autologous iliac crest bone graft (with a non-inferiority absolute margin of 10% as patient success at 20 months after surgery)

E.2.2

Secondary objectives of the trial

Demonstrate the fusion success superiority of a single administration of Osteogrow+Allograft delivered bilaterally between transverse processes of a single lumbar spine segment.
Explore improvement and show superiority in ODI, pelvic pain (autologous bone donor site), general health status and patient satisfaction
Explore the rhBMP6 antibody level in plasma.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients meeting ALL of the following criteria at screening will be eligible for participation in the study:
1. Willing and able to provide informed consent. A signed informed consent form must be provided before any study assessments are done. Patients must be fluent in the language that is spoken by the investigator and the trial staff and in which the informed consent is written.
2. Male or female, age ≥18 years. Females of childbearing potential must be using a highly effective method of birth control within 2 years following surgery and must have a negative urine pregnancy test prior to the randomization.
3. Degenerative disc disease (DDD) of L3-S1 segment accompanied by back pain of corresponding segment, with or without leg pain, with degeneration of the disc confirmed by patient history and radiographic analyses. Patients are non-responsive to conservative treatment (e.g., bed rest, physical therapy, medications, spinal injections, manipulation, and/or TENS) for a period of 6 months.
DDD is defined as presence of one or more of the following:
a. instability (defined as angulation 5° and/or translation 4 mm, based on flexion/extension radiographs
b. osteophyte formation
c. decreased disc height
d. thickening of ligamentous tissue
e. disc degeneration or herniation and/or facet joint degeneration
f. required fusion of a single level disc space from L3 to S1
g. preoperative Oswestry Disability Index score of 30
h. no greater than Grade 1 spondylolisthesis utilizing Meyerding's Classification
4. Patients not receiving platelet aggregation inhibitors at least 5 days prior to surgery.
5. Patients should be otherwise in good general condition as defined by absence of clinically relevant abnormalities identified at screening by a detailed medical history, full physical examination (including blood pressure and heart rate measurement), 12-lead ECG, and clinical laboratory tests.
6. Willing and able to be confined to the hospital/inpatient unit for at least 5 days (at least 10 days for the first 15 patients) postoperatively and to comply with all other follow-up procedures according to the protocol.

E.4

Principal exclusion criteria

Patients meeting ANY of the following criteria at screening will NOT be eligible for participation in the study:
1. Previous lumbar spinal fusion procedure at the involved level
2. Required spinal fusion at more than one lumbar level
3. Previous treatment with bone morphogenetic proteins (e.g. Infuse or Ossigraft).
4. Primary diagnosis of a spinal disorder other than degenerative disc disease with Grade 1 or less spondylolisthesis at the involved level
5. Inflammatory and neoplastic diseases of the spine.
6. Presence of active malignancy or prior history of malignancy (except for basal cell carcinoma of the skin)
7. Conditions that might have been associated with diagnosis of osteoporosis including:
a. Postmenopausal Non-Black female over 60 years of age and weighing less than 140 pounds (63.5 kg).
b. Postmenopausal female that had sustained a nontraumatic hip, spine, or wrist fracture.
c. Male over the age of 70.
d. Male over the age of 60 that had sustained a non-traumatic hip or spine fracture.
If the level of BMD is a T score of -3.5 or a T score of -2.5 with vertebral crush fracture, the patient will be excluded from the study
8. Previous diagnosis of osteomalacia
9. Evidence or history of clinically significant hepatic disease (>3 x ULN for AST/ALT and total bilirubin) or other abnormalities in screening laboratory tests, which in the judgment of the investigator, would interfere with the patient’s participation in the study.
10. Presence or history of an uncontrolled, unstable, clinically significant medical condition (bone metabolic, renal, endocrine, hepatic, respiratory, cardiovascular, hematologic, immunologic or cerebrovascular disease, and malignancy) that in the judgment of the investigator may interfere with the interpretation of safety.
11. History of symptomatic nephro- or urolithiasis within two years.
12. Medically evident and confirmed diabetes mellitus, if treated with insulin, or in case of inadequate glycemic control, as evident from hemoglobin A1c ≥8% and/or medical history indicative of recurring episodes of hypoglycemia.
13. Treatment with an investigational drug within 6 months or 5 half-lives (whichever is longer) preceding the first dose of study medication.
14. Screening 12-lead ECG findings like sinus tachycardia, left ventricular hypertrophy, pathological Q waves or ST segment shift, atrial fibrillation, frequent premature ventricular complexes, pacemaker rhythm, or other, which in the investigator’s opinion represent a safety risk for spinal surgery.
15. Conditions that require postoperative medications that interfere with fusion, such as steroids or prolonged use of non-steroidal anti-inflammatory drugs, including routine perioperative non-steroidal anti-inflammatory drugs (except Metamizole which is allowed). This does not include low dose aspirin for prophylactic anticoagulation.
16. Overt or active bacterial infection, either local or systemic.
17. Documented titanium allergy or intolerance
18. Positive urine pregnancy test.
19. Breastfeeding a child.
20. Use within 7 days prior to surgery and postoperatively for 6 months of systemic corticosteroids except for dexamethasone for the first 2 days postoperatively.
21. Received drugs that may interfere with bone metabolism within two weeks prior to the planned date of spinal surgery (e.g., systemic steroids or methotrexate);
22. Known serological evidence of human immunodeficiency virus (HIV) antibody
23. History of hepatitis B infection within the past year or history of non-adequately treated hepatitis C infection.
24. Patient is a known drug or alcohol abuser, or has a positive urine drug screen which cannot be explained by medication history.
25. Donation of blood in excess of 500 mL within 56 days prior to surgery.
26. Mentally impaired
27. Prisoner

E.5 End points

E.5.1

Primary end point(s)

Composite endpoint for safety and clinical success in fusion, ODI, and neurological status. Overall success is considered if all of the following conditions are met:
1. Safety, based on: neurological maintenance or improvement compared to baseline, no additional surgical procedure related to the treated spine level; and no serious implant associated or implant/surgical procedure associated adverse events; and
2. Effectiveness based on: fusion and function, i.e., pain/disability (Oswestry) improvement.

E.5.1.1

Timepoint(s) of evaluation of this end point

Patients will be evaluated preoperatively (within 1 months before surgery), intra-operatively, and postoperatively at 3 and 6 weeks, 3, 6, 12, and 20 months. Fusion will be evaluated at 6, 12, and 20 months. Complications and adverse events will be evaluated over the course of the clinical trial. The protocol also includes plasma measurements of antibodies to rhBMP6 screening in both investigational and control patients pre-operatively and at 3, 6, 12 and 20 months. At each evaluation time-point, the primary and secondary clinical and radiographic outcome parameters will be assessed. Success will be determined from data collected during the initial 20 months of follow-up.

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

Overall clinical success at 6 and 12 months
Radiographic fusion at 6, 12 and 20 months (bone size generated between the transverse processes)
Function evaluated as ODI and neurological status at 6, 12 and 20 months
Back pain (ODI pain intensity subscore) and leg pain (Lower leg questionnaire score) over time; pelvic/hip pain (Hip dysfunction and Osteoarthritis Outcome Score) from discharge day onwards
Adverse events, including serious implant-associated or implant/surgical procedure-associated adverse events
Number of additional surgical procedures related to treated spinal level
Quality of life (general health status and patient satisfaction) as assessed by SF-36 questionnaire
Antibodies to rhBMP6 at 3, 6, 12 and 20 months
Operative time
Blood loss
Number of hospital days

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Standard of care

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

134

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-02-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-11-02

P. End of Trial
P.	End of Trial Status	Ongoing

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