Clinical Trials Register

Summary
EudraCT Number:	2021-004034-11
Sponsor's Protocol Code Number:	GR-OG-279239-04
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2022-04-05
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

2021-004034-11

A.3

Full title of the trial

A randomized, evaluator-blinded, dose-ranging, proof of concept study of
efficacy, safety and tolerability of Osteogrow-C (rhBMP6 delivered in
autologous blood coagulum [ABC] supplemented with synthetic ceramics
as a compression resistant matrix) compared to bone autograft, after
single local administration on top osteosynthesis for the treatment of post-traumatic non-union of the tibia

Eine randomisierte, Bewerter verblindete, dosisabhängige, proof-of-concept Studie zur Wirksamkeit, Sicherheit und Verträglichkeit von Osteogrow-C (rhBMP6 verabreicht in eigenem blutkoagel, ergänzt mit synthetischer Keramik als kompressionsresistente Matrix) im vergleich zu knochen-autotransplantat, nach einmaliger lokaler Verabreichung zusätzlich zu der Osteosynthese zur Behandlung einer posttraumatischen Tibiapseudarthrose

A.3.1

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

Blinded study on efficacy, safety and tolerability of a single dose of rhBMP6 mixed with patient's own blood and synthetic ceramics in adult patients for the treatment of post-traumatic tibial non-union

A.4.1

Sponsor's protocol code number

GR-OG-279239-04

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	Genera Research Ltd
B.4.2	Country	Croatia
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Clinres Farmacija d.o.o
B.5.2	Functional name of contact point	Clinical Trial Information
B.5.3	Address:
B.5.3.1	Street Address	Slandrova ulica 4B
B.5.3.2	Town/ city	Ljubljana-Črnuče
B.5.3.3	Post code	1231
B.5.3.4	Country	Slovenia
B.5.4	Telephone number	3861426 95 70
B.5.6	E-mail	ana.ivanovska@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-C
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

The treatment of non-union of the tibia

E.1.1.1

Medical condition in easily understood language

Tibial non-union

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	20.0
E.1.2	Level	SOC
E.1.2	Classification code	10042613
E.1.2	Term	Surgical and medical procedures
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	PT
E.1.2	Classification code	10017088
E.1.2	Term	Fracture nonunion
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

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 the efficacy of two strengths of Osteogrow-C (two rhBMP6 dose
levels) in patients with non-union of the tibia, after single local administration on top of osteosynthesis and compared to bone autograft

E.2.2

Secondary objectives of the trial

Evaluate the safety and tolerability of Osteogrow-C when used for the
treatment of non-union of the tibia on top of osteosynthesis and compared to bone autograft.
Evaluate the overall clinical outcome after non-union treatment with
Osteogrow-C, when used on top of osteosynthesis and compared to bone autograft.
Evaluate the effects of study treatments on patient's work ability and
quality of life.

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 and to comply with study requirements. Written informed consent must be obtained 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. Skeletally mature male or female, age ≥18 years. Females of childbearing potential must use a highly effective method of birth control within 1 year following surgery, be willing to extend the use for additional year, if needed, and must have a negative urine pregnancy test prior to randomization.
3. The diagnosis of tibial non-union as a consequence of traumatic,
unilateral, displaced, isolated, closed extra-articular fracture of the tibia
previously treated with osteosynthetic device, confirmed by medical
history and radiographic analyses. A patient is non-responsive to
conservative and/or alternative treatment (e.g., electrical stimulation,
ultrasound, skeletal fixation with or without supplemental bone graft),
and there is a lack of evidence of healing progression over previous 3
months.
4. Otherwise in good general condition in the investigator's opinion, based on vital signs, full physical examination, standard clinical laboratory tests, ECG findings at screening.

E.4

Principal exclusion criteria

Patients meeting ANY of the following criteria at screening will NOT be
eligible for participation in the study:
1. Documented titanium allergy or intolerance.
2. History of bilateral bone graft harvesting from the iliac crest.
3. Previous treatment with bone morphogenetic proteins (e.g.,
INDUCTOS/INFUSE or OSIGRAFT/OPGENRA/OP-1).
4. Active systemic infection.
5. Presence of neuropathy, which in the investigator’s opinion can
interfere with walking or appreciation of pain.
6. Presence or history of pathological fractures or osteomalacia.
7. Known active malignancy, history of malignancy (except for fully
resected basal cell carcinoma of the skin), or ongoing treatment with
antineoplastic agents or radiation therapy.
8. Presence of poorly controlled diabetes mellitus as evident from
hemoglobin A1c >8% at screening.
9. History of autoimmune disease of connective tissue (e.g., rheumatoid
arthritis, systemic lupus erythematosus, Sjögren’s syndrome), or
other chronic disease or condition treated with
immunosuppressants.
10. History of severe symptomatic osteoarthritis or other chronic
disease or condition associated with frequent or prolonged use of
nonsteroidal anti-inflammatory drugs (NSAIDs).
11. History of alcohol or drug dependence, or a positive urine drug
screen at screening which cannot be explained by medication history
and current smokers unless they are willing to quit smoking during
the six months period following surgery.
12. Treatment with platelet aggregation inhibitors within 5 days (for
clopidogrel) or 7 days (for low-dose acetylsalicylic acid) prior to
surgery.
13. Treatment with systemic corticosteroids within 1 week, or with
immunosuppressants (e.g., methotrexate) within 2 weeks prior to
surgery.
14. Treatment with an investigational drug within 6 months or 5 half-lives of the drug (whichever is longer) prior to surgery.
15. Presence of any other disease or condition which in the
investigator’s opinion represents a high safety risk for surgery, or
interferes with patient’s ability to comply with study procedures.

E.5 End points

E.5.1

Primary end point(s)

The incidence of clinical success at 9 months after surgery, where clinical success is defined as:
o Full weight-bearing on the treated leg, or ability to walk using one crutch at most, with
o Less than severe pain on weight-bearing, and
o No additional surgical procedure related to the non-union.
Safety endpoints:
• The incidence and type of treatment-emergent adverse events (TEAEs), where TEAE is defined as any AE occurring after the start of surgery.
• Change from baseline in hematology, clinical chemistry and urinalysis findings on postoperative Day 3 and 1 month after surgery.
• Change from baseline in vital signs on postoperative Day 3, at discharge from the hospital, and at each onsite follow-up visit.
• Change from baseline in physical examination findings at discharge from the hospital and at each onsite follow-up visit.
• Change from baseline in ECG findings on postoperative Day 3.
• The occurrence of anti-rhBMP6 antibodies at baseline and 3, 6, 9 and 12 months after surgery.
• The incidence of heterotopic ossification at 3, 6, 9 and 12 months after surgery.
• The incidence of local signs of inflammation at the non-union site (erythema, oedema, tenderness, wound discharge) over time, based on the blinded evaluator’s assessment using a 4-grade scale ranging from 0 (absent) to 3 (severe).
• Change from baseline in knee and ankle range of motion (ROM) at 1, 3, 6, 9 and 12 months after surgery.
• Intraoperative blood loss, estimated using a modified Lopez-Pikado’s formula.
Tolerability endpoints:
• The incidence of implant-related TEAEs of severe intensity.
• Pain intensity in the area of iliac crests over time, assessed by the patient using a NRS.

E.5.1.1

Timepoint(s) of evaluation of this end point

Patients will be evaluated preoperatively (within 1 months of surgery), intra-operatively, and postoperatively at 1, 2, 3, 6, 9 and 12 months. The incidence of clinical success will be evaluated at month 6, 9 and 12 months after the surgery. 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, 9 and 12 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 12 months of follow-up.

E.5.2

Secondary end point(s)

• The incidence of clinical success at 6 and 12 months after surgery.
• Walking ability at baseline and 2, 3, 6, 9 and 12 months after surgery, based on the patient’s response to Question 6 of the American Academy of Orthopedic Surgeons Lower Limb Outcomes Questionnaire (AAOS-LLQ).
• Weight-bearing at baseline and 1, 3, 6, 9 and 12 months after surgery, expressed as a percentage of body weight.
• Pain intensity in the treated leg over time, at rest and on weight-bearing/walking, assessed by the patient using a numeric rating scale (NRS).
• The incidence of radiographic union of the tibia at 3, 6, 9 and 12 months after surgery, based on each of the following definitions:
o Cortical bridging (continuous bony connection of the non-union gap) on at least 3 out of 4 cortices on anteroposterior (AP) and latero-lateral (LL) projections;
o Cortical bridging on at least 6 out of 8 cortices on AP, LL and two oblique projections;
o Cortical bridging visible on at least 1 out of 4 projections (AP, LL and two oblique).
• AAOS-LLQ score at baseline and 2, 3, 6, 9 and 12 months after surgery.

E.5.2.1

Timepoint(s) of evaluation of this end point

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

Yes

E.8.1.4

Double blind

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

Yes

E.8.4

The trial involves multiple sites in the 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

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

2022-05-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-01-14

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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