E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Tibial fracture considered at risk of DU/NU (based on the combination of risk factors documented to be associated with increased proportion of DU/NU). |
|
E.1.1.1 | Medical condition in easily understood language |
Tibial fracture considered at risk of delayed union/non union |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10043827 |
E.1.2 | Term | Tibia fracture |
E.1.2 | System Organ Class | 10022117 - Injury, poisoning and procedural complications |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate that treatment with ALLOB leads to a significant improvement in RUST score at Week 12 with respect to placebo in patients with a tibial fracture. |
|
E.2.2 | Secondary objectives of the trial |
Key Secondary objectives:
- To assess the impact of ALLOB on the time of fracture healing,
as assessed by the Investigator up to Month 12
- To assess the impact of ALLOB on time to radiological fracture healing, as assessed by the Independent Radiologists up to Month 12
Other Secondary objectives:
- To assess the overall safety of ALLOB® based on key safety outcomes
(product failure, infection related to implantation, hypersensitivity
reaction, ectopic bone formation)
- To assess the impact of ALLOB® on time to clinical fracture healing, as
assessed by the Investigator up to Month 12
- To assess the impact of ALLOB® on time to radiological fracture union,
as assessed by the Investigator up to Month 12
- To assess the impact of ALLOB® on RUST score up to Month 12
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
All patients must satisfy ALL of the following criteria to be included in the study:
1. Men and women at least 18 years of age
2. Patient diagnosed with a fresh proximal, midshaft or distal tibial fracture with definitive reduction and stabilization performed with nail(s) and wound closure (as required) within 14 days of fracture occurrence. This time window of 14 days allows for potential intermediate stabilization, wound cleaning and closure.
3. Factor(s) with risk of DU/NU:
- Mechanism of injury: High energy impact fracture
OR
- Any 2 of following patient-related factors: current smoker, chronic NSAID use, high BMI (>30), polytrauma
4. Soft-tissue injury pattern including:
- Severe open fracture (Gustilo-Anderson grade IIIa and IIIb)
OR
- Open fracture (Gustilo-Anderson grade I-II) with at least one additional risk (current smoker, chronic NSAID use, high BMI (>30), polytrauma, comminuted fracture or cortical continuity ≤50%)
OR
- Closed fracture (Tscherne grade I-III) with at least one additional risk factor (current smoker, chronic NSAID use, high BMI (>30), polytrauma, comminuted fracture or cortical continuity ≤50%)
The following fracture patterns are included based on the 2018 AO online classification system:
- 41A (Proximal Extraarticular) includes 41A1; 41A2; 41A3
- 42A (Simple Diaphyseal) includes 42A1; 42A2; 42A3
- 42B (Wedge Fracture) includes 42B2; 42B3 (also called butterfly fracture)
- 43A (Distal extra-articular) includes 43A1; 43A2; 43A3 (and all sub-components)
-42C (complex/comminuted): Patients will be included at the discretion
of the Medical Monitor.
5. Ability to provide a written, dated, and signed informed consent prior to any study related procedures and ability to understand and comply with study requirements |
|
E.4 | Principal exclusion criteria |
Current symptoms and/or signs related to the disease under study:
1. Definitive reduction at the fracture site under investigation performed with plate, screw or external fixator (Note: It is acceptable to first stabilize the fracture with an external fixator prior to definitive stabilization with intramedullary nail)
2. Patients who did not receive a standard antibiotic prophylaxis before definitive reduction at the fracture site under investigation
3. Intra-articular tibial pilon and/or plateau fracture at the site under investigation (AO classification 41B; 41C; 43B; 43C)
4. Known osteomyelitis at the fracture site under investigation
5. Residual bone defect post-definitive reduction greater than 1cm at least on 2 cortices at the fracture site under investigation
6. Fracture requiring vascular surgery at the site under investigation
7. Pathological fractures as judged by the Investigator, such as tumor or metabolic bone disease
8. Multi-segmental fracture at the site under investigation (where there are more than 2 separate segments and thus requiring more than a single dose of the investigational product).
Current or previous diagnoses, signs and/or symptoms:
9. Presence of signs/symptoms suggestive of active systemic infection before randomization
10. Severe brain trauma with a Glasgow Coma Scale (GCS) [3 – 8] or severe spinal cord injury with impossibility of weight-bearing
11. Current or history (within 5 years) of any neoplasia (except for basal cell carcinoma of the skin and for carcinoma in situ of the cervix that has been treated with no evidence of recurrence)
12. Known metabolic diseases potentially interfering with bone healing as judged by the Investigator, such as thyroid dysfunction, Paget disease or severe osteoporosis
13. Planned or history of solid organ transplantation or bone marrow transplantation
14. Known disease, including genetic disease, that may possibly need solid organ transplantation
15. Patient with renal impairment requiring dialysis or with clinically significant renal impairment defined as serum creatinine >2.0 x ULN
16. Clinically significant hepatic function impairment defined as ALT/AST levels > 3x ULN or total bilirubin levels > 2 x ULN
17. Known hematologic disease as evidenced by hematocrit < 25%, white blood cell < 2,500/µl or platelet values < 100,000/µl without another explanation
18. Patient with an history of long standing poorly controlled chronic hypertension or diabetes that could put him at risk of needing a kidney transplant later on according to the Investigator
19. History of hypersensitivity to human biological material including blood and blood derived products
20. Known allergy to DMSO, dextran, gentamicin and any other aminoglycosides
Current or previous treatment:
21. Participation in another interventional clinical study within 3 months prior to screening
22. Any chronic or long-term intake of medication within one month that might affect bone metabolism or the quality of bone formation such as but not limited to bisphosphonates, teriparatide, systemic steroids, anticoagulant therapies, methotrexate and other immunosuppressant drugs or related immunotherapy
23. Previous (within 10 years) treatment with bisphosphonates
24. Current treatment with bone morphogenic protein or any other osteo-biologic intervention at the site of the tibial fracture
Safety aspects concerning WOCBP: not applicable to Germany:
25. Actively breast-feeding
26. Pregnancy
27. Woman with positive urine pregnancy test at screening
28. WOCBP not using a highly effective contraceptive method at the time
of enrollment and not willing or able to use a double barrier method
during the 6-month period after IMP administration.
OR
WOCBP using a highly effective contraceptive method (as described in
the CTFG contraception guidance version 1.1) for at least 6 weeks prior
to enrollment and not willing to continue use during the 6 month period
following IMP administration.
Safety aspects concerning female patients: only applicable to Germany
29. WOCBP, defined as being post onset of menarche and not meeting
any of the following conditions:
a. menopausal for at least 2 years,
b. having undergone bilateral tubal ligation at least 1 year previously,
c. having undergone bilateral oophorectomy or hysterectomy.
30. Actively breast-feeding
Other exclusion criteria:
31. Life expectancy less than 12 months at screening
32. Signs of an active drug or alcohol dependence, serious current
illness, mental illness or any other factors which, in the opinion of the
Investigator, may interfere with patient's ability to understand and
comply with study requirements, as judged by the Investigator
33. Prisoner
34. Patient with a fracture resulting from military involvement (war
zone)
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the mean RUST score at Week 12 (Visit #4). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Key efficacy secondary endpoints:
- Time to fracture healing. Fracture healing, defined as full weight
bearing on the treated tibia, a lack of pain at palpation, and radiological
fracture union, will be assessed up to Month 12 by the Investigator
- Time to radiological fracture healing. The presence of radiological
fracture healing will be assessed up to Month 12 by the Independent
Radiologists
Other efficacy secondary endpoints:
- Time to clinical fracture healing. Clinical fracture healing, defined as
full weight bearing on the treated tibia and lack of pain at palpation,
with be assessed up to Month 12 by the Investigator
- Time to radiological fracture union. Radiological fracture union, defined
by bone bridging on at least three of the four cortices and absence of
fracture line, will be assessed up to Month 12 by the Investigator
- RUST score at each visit up to Month 12
Safety endpoints:
- Any Treatment emergent Adverse Event (TEAE)/Serious Adverse Event (SAE)
- Adverse Event of Special Interest (AESI):
o Suspected or confirmed acute or chronic infection related to the medical condition under evaluation
o TEAEs possibly related to product failure
o TEAEs suggesting infection related to implantation procedure
o TEAEs suggesting hypersensitivity reaction
o TEAEs suggesting ectopic bone formation |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
6-12-16-20 weeks
6-9-12 months
|
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 36 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |