E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
Acute cervical spinal cord injury, patients who suffer from spinal cord injury within 4-28 days post-injury are eligible |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10041554 |
E.1.2 | Term | Spinal cord injury cervical |
E.1.2 | System Organ Class | 10022117 - Injury, poisoning and procedural complications |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10041552 |
E.1.2 | Term | Spinal cord injury |
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 evaluate efficacy of acute treatment (initiation of drug treatment within 4 - 28 days post-injury) with
NG-101 by repeated intrathecal (i.t.) bolus injections on day 168. |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the safety of acute treatment (initiation of drug treatment
within 4 - 28 days post--injury) with NG-101 by repeated intrathecal
bolus injections (6 injections of 45 mg each over 4 weeks)
- Adverse Events (Frequency, type, duration and intensity of AEs and
SAEs)
- Relationship of AE/SAE frequency and time and duration of study
medication administration
- Documented reasons for any unplanned study medication
interruptions and/or withdrawal from the study
- Vital signs (blood pressure, heart frequency, body temperature)
-Muscle spasticity measured by the Modified Ashworth Scale
- Effect on pain (neuropathic pain and non-neuropathic pain) assessed by SCI pain data set, allodynia questionnaire and SCIPI |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
3 Sub studies (work packages (WP)) according to the EU application (that are not relevant to laws regulating the use of medicinal products):
-Biostatistics (sub study WP2)
Objective: develop a statistical model for the conditional distribution
of ordinal measurements in two-- armed randomized clinical trials.
Based on this model, minimal clinically important differences shall be
discussed, and methods for sample size estimation, statistical
inference and subgroup analyses shall be developed. We plan to setup
a statistical framework allowing future clinical trials using SCIM self
care & mobility or UEMS as primary endpoints to be planned and
analyzed with procedures taking the specific properties of these
endpoints into account. Results shall be used to improve the power to
discern treatment effects in future studies.
-Proteomics analysis (sub study WP3)
Important part of the current trial is the collection of high quality
biological samples (Serum derived from blood samples and CSF
collected during diagnostic and therapeutic interventions, respectively)
of patients suffering from acute SCI. Serum and CSF samples obtained
in the course of the study will undergo proteomics analyses in order to
identify proteomics based biomarkers to enable or support prognosis
and outcome of the patients. Afterwards, a systematic categorization of
the proteomes will be performed with comprehensive bioinformatic tools.
-Neuroimaging (sub study WP4)
Baseline MRI data acquired at the cervical level and brain will be used
to characterize the extent of the lesion and the subsequent de- and
regenerative processes occuring remote from the cervical cord injury
both treatment groups. For the longitudinal data acquired at three
distinct time points (0, 3, and 6 months), routine postprocessing
pipelines will be applied to assess differences between the rates of
change of neurodegeneration between both groups and explore
possible treatment effects.
Specifically, these quantitative images will provide information on the
spontaneous and potentially treatment altered rates of changes of
atrophy (volumetry), de- and remyelination and iron accumulation in
both groups.
These sub-studies are included in the main protocol. |
|
E.3 | Principal inclusion criteria |
1. Male or female, 18 through 70 years of age
2. Acute cervical spinal cord injury (SCI) (Neurological level of injury
C1 ≤ lesion ≤ C8) with confirmed classification of ASIA impairment
scale (AIS) A-D at screening and predicted upper
extremities motor score (UEMS) recovery of less than 41/50
(according to the URP prediction model)
3. 4-28 days post-injury (i.e. initiation of bolus injection within 4-28
days post-injury)
4. Tetraplegic patients who are allowed to start treatment are those
who either do not require mechanical ventilation or who do not
completely depend on mechanical ventilation but show some
degree of spontaneous ventilation. Only those modes of ventilation
where the patient show active initiation of breathing are allowed
(e.g. continuous positive airway pressure (CPAP))
5. Hemodynamically and clinically stable according to the acute SCI
condition at baseline
6. For patients of childbearing potential , use of reliable means of contraception
7. Written informed consent by patient before any study assessment
is performed. If the patient is only able to consent orally a witness
signs and confirms the patient’s consent,
8. Cooperation and willingness to complete all aspects of the study
9. Ability of subject to understand character and individual
consequences of the study |
|
E.4 | Principal exclusion criteria |
1. Complete anatomical transection confirmed by magnetic resonance imaging (MRI).
2. Trauma caused by ballistic or other injury that directly penetrates the spinal cord including gunshot and knife wounds.
3. Multiple levels of clinically relevant spinal cord lesions.
4. Major brachial or lumbar plexus damage/trauma.
5. Significant head trauma (e.g. cortical damage/lesion), or other injury that was, in the opinion of the investigator, sufficient to interfere with the assessment of the spinal cord function or otherwise compromise the validity of the patient's data.
6. Other significant pre-existing or current severe systemic disease such as lung, liver (exception: history of uncomplicated Hepatitis A), gastrointestinal, cardiac, immunodeficiency (including anamnestic known HIV) or kidney disease; or active malignancy or any other condition as determined by history or laboratory investigation that could cause a neurological deficit including syphilis, myelopathy, clinically relevant polyneuropathy, etc.
7. History of or an acute episode of Guillain-Barre syndrome.
8. History of recent (6 months) meningitis or meningoencephalitis.
9. History of refractory epilepsy.
10. Patients with uncontrolled bleeding diathesis and/or who require uninterrupted concomitant therapeutic anticoagulation (e.g. phenoprocoumon (Marcumar®), heparin/heparinoids and new oral anticoagulants) at a higher dose than for the prophylaxis of venous thromboembolism
11. Presence of any unstable medical or psychiatric condition (defined by the Diagnostic and Statistical Manual of Mental Disorders, Edition 4 (DSM-IV)) that could reasonably have been expected tosubject the patient to unwarranted risk from participation in the study or result in a significant deterioration of the patient's clinical course.
12. Drug dependence (as defined by DSM-IV) any time during the 6 month’s preceding study entry.
13. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test (> 5 mIU/mL).
14. History of a life-threatening allergic or immune mediated reaction.
15. Patients with the presence of infection around the location where the spinal needle insertions are planned for applying the intrathecal injections.
16. Inability to communicate effectively with the neurological examiner such that the validity of the patient's data could be compromised.
17. Participation in any clinical investigation within 4 weeks prior to dosing or longer if required by local regulations, and for any other limitation of participation based on local regulations.
18. Patients who are unconscious, including those patients who are unconscious due to medication causing marked sedation.
19. History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Upper extremity motor scores (UEMS) according to the International
Standards for the Neurological Classification of Spinal Cord Injury
(ISNCSCI) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary efficacy endpoint (UEMS recovery) will be analysed by the comparison of the mean of the
control and treatment groups. Also the secondary efficacy endpoints will be analysed by comparing the
means of outcomes between the control and treatment groups. The primary criterion is the UEMS recovery score at day 168.
No interim analysis is planned. |
|
E.5.2 | Secondary end point(s) |
Effect on motor and sensory function according to the ISNCSCI protocol (ASIA impairment scale,
ASIA lower extremities motor score (LEMS) and sensory scores (light touch (LT), pin prick (PP)).
Effect on autonomic dysfunction (i.e. bladder function as measured by bladder diary, Qualiveen
questionnaire, bladder function questionnaire)
Effect on functioning evaluated by the Spinal Cord Independence Measure (SCIM-III).
Effect on hand/upper limb function as assessed by the Graded and Redefined Assessment of
Strength, Sensibility and Prehension (GRASSP) subscales.
Effect on the Walking Index for Spinal Cord Injury (WISCI), 10 meter walk test (10mWT) and the 6‐
minute walking test (6MWT).
Effect on neurophysiological parameters (nerve conducting velocity, Somatosensory evoked
potentials)
To evaluate the pharmacokinetics (PK) and immunogenicity of NG-101. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
For the exact time points of evaluation refer to assessment schedule. |
|
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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Immunogenicity. One of the secondary outcome measures for this clinical trial is the assessment of the
pharmacokinetic (PK) and immunogenicity of NG-101 based on serial samples. The concentrations
of NG-101 in serum and CSF will be analyzed by validated enzyme-linked immunosorbent assay
(ELISA) methods. Samples for analysis of anti-NG-101 immunogenicity (antibody detection) will be
screened using an immunoassay and possibly go through other characterization assays. |
|
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 | 9 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Czech Republic |
Italy |
Spain |
Switzerland |
|
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |