E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
damage to the spinal cord |
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E.1.1.2 | Therapeutic area | Diseases [C] - Injuries, poisonings, and occupational diseases [C21] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10041545 |
E.1.2 | Term | Spinal cord and nerve root disorders traumatic |
E.1.2 | System Organ Class | 100000004852 |
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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 |
The primary objective of this study is to determine if treatment of ASCI with SUN13837, when compared with placebo, will result in a greater improvement in measures of overall functional independence by a comparison of the difference in the final mean total Spinal Cord Independence Measure, version III (SCIM III) scores between the 2 treatment groups. |
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E.2.2 | Secondary objectives of the trial |
SECONDARY OBJECTIVES: • To determine if treatment of ASCI with SUN13837, when compared with placebo, will result in: - greater improvement in Total Motor Score at the final SCIM III assessment - greater improvement in self-care and mobility by a comparison of the final mean SCIM III related subscale scores combined - greater improvement in AIS grade • To evaluate the PK of SUN13837 in ASCI subjects and to evaluate exploratory PK/PD relationships between SUN13837 exposure and selected efficacy endpoints • To evaluate the safety of SUN13837 versus placebo using standard measures of safety (physical examinations, vital signs, 12 lead ECGs, clinical laboratory parameters, and AE reporting)
EXPLORATORY OBJECTIVES: To assess differences in: - the mean total SCIM III scores between the 2 treatment groups - the mean SCIM III subscale scores between the 2 treatment groups - the proportion of responders between the 2 treatment groups based on AIS grade and ISNCSCI score |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Acute traumatic injury to the cervical neurological spinal cord as follows: a. AIS grade A with a level of injury at either C4, C5, C6, or C7 (for C4, the subject must have at least 1 point of motor activity within the ZPP inclusive of C5 to T1). In addition, the AIS A subject may be included if ALL of the following are present 1) the most caudal intact sensory segment (both pinprick and light touch) is C3, 2) at least one side (right or left) has both intact pinprick and light touch sensation in the C4 dermatome, AND 3) at least 1 point of motor activity within the zone of partial preservation (ZPP) inclusive of C5 to T1 b. AIS grade B or C with a neurological level of injury at either C3, C4, C5, C6, C7, or C8 2. Closed single traumatic spinal cord injury occurring within 12 hours of first dosing 3. Male or female cervical AIS A subjects ≥16 to ≤80 years and male or female cervical AIS B or C subjects ≥16 to ≤70 years 4. Females of childbearing potential and males must agree to maintain adequate contraception (eg, condoms, intrauterine devices, diaphragm, spermicide, contraceptive patch, oral contraceptive pills, progestin injections, under-skin contraceptive implants, vaginal ring) for the first 35 days of the study |
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E.4 | Principal exclusion criteria |
1. Unable to obtain informed consent (either from the subject or from the subject‘s Legally Authorised Representative) 2. Women who are breastfeeding (if unwilling to stop for the first 35 days of the study) or are pregnant 3. Coma or significant impairment in the level of consciousness that interferes with the performance or interpretation of protocol specified assessments 4. Any disease, concomitant injury, or condition that interferes with the performance or interpretation of the protocol specified assessments 5. Unable, as determined by the investigator, or unwilling to discontinue use of potent P-glycoprotein (P-gp) inhibitors (cyclosporine A, erythromycin, itraconazole, ketoconazole, nelfinavir, quinidine, reserpine, ritonavir, saquinavir, tacrolimus, and verapamil) for the first 35 days of the study 6. Unable, as determined by the investigator, or unwilling to discontinue use of potent cytochrome P450 (CYP) 3A4/5 inducers (eg, phenytoin, carbamazepine, oxcarbazepine, phenobarbital, efavirenz, nevirapine, etravirine, rifampicin, modafinil, hyperforin [constituent of St Johns Wort], and cyproterone) for the first 35 days of the study 7. Renal compromise (serum creatinine greater than 1.5 times the age- and sex-appropriate Upper Limit of Normal (ULN) for the local laboratory) at screening before the first dose of study drug 8. Severe hepatic dysfunction (serum ALT, AST, and GGT ALL greater than 2.5 times the age- and sex-appropriate ULN) OR hepatic impairment (detectable ascites, serum bilirubin greater than 2 mg/dL, serum albumin less than 3.5 g/dL, and prothrombin time prolonged by more than 6 seconds above the ULN for the local laboratory in the absence of anticoagulant therapy) at screening before the first dose of study drug 9. Concomitant spinal cord injury or abnormality as determined by routine imaging: a. Conclusive radiological evidence of complete spinal cord transection b. Multiple injuries to the neurological spinal cord at different levels 10. History of symptomatic cervical spinal stenosis with myelopathy as a factor confounding subject assessment 11. Unlikely to be available for follow-up as specified in the protocol 12. Participated in a previous clinical study and received an investigational product within 30 days of screening 13. Previous exposure to SUN13837 14. Allergy to SUN13837 or any of its excipients 15. Any other issue which, in the opinion of the investigator, will make the subject unsuitable for study participation |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is a comparison of the difference in the mean total SCIM III score between the 2 treatment groups at Day 112 (±7 days). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Total SCIM III score will be recorded at baseline and at Day 112 (±7 days). |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints: • Comparison of TMS from baseline to the final SCIM III assessment for placebo and SUN13837 treated subjects • Comparison of the mean SCIM III Self Care and Mobility subscale scores for placebo and SUN13837 treated subjects at Day 112 (±7 days) • Comparison of AIS grade from baseline to final assessment for placebo and SUN13837 treated subjects
Supportive and Exploratory Endpoints • Mean SCIM III total scores at Day 14 (±2 days); the final dosing day, Day 27 or 28 (±2 days); and Day 56 (±7 days) • Comparison of the mean SCIM III Self Care subscale score for placebo and SUN13837 treated subjects at Day 14 (±2 days); the final dosing day, Day 27 or 28 (±2 days); Day 56 (±7 days); and Day 112 (±7 days) • Comparison of the mean SCIM III Respiration and Sphincter Management and Mobility subscale scores for placebo and SUN13837 treated subjects at Day 112 (±7 days) • Proportion of SUN13837- and placebo-treated subjects who are defined as responders. A responder, based on baseline cervical AIS grade, is defined as a subject who has reached the following outcome at Day 112 (±7 days) as described below. • For cervical AIS A subjects at baseline: an improvement of 2 or more motor levels from baseline on either the right or left side. Motor level is determined from the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) Scale • For cervical AIS B or C subjects at baseline: a total Lower Extremity Motor Score (LEMS) of 40 or more points, as determined from the ISNCSCI Scale • Proportions of placebo and SUN13837 treated subjects who are responders as per the definition on Day 3 (within 12 hours postdose); Day 14 (±2 days); the final dosing day, Day 27 or 28 (±2 days); and Day 56 (±7 days) for assessment of onset of effect • Change in TMS from baseline to Day 3 (within 12 hours postdose); Day 14 (±2 days); the final dosing day, Day 27 or 28 (±2 days); Day 56 (±7 days); and Day 112 (±7 days) • Proportions of placebo and SUN13837 treated subjects who improve 1 or more AIS grades from baseline to Day 3 (within 12 hours postdose); Day 14 (±2 days); the final dosing day, Day 27 or 28 (±2 days); Day 56 (±7 days); and Day 112 (±7 days)
Safety endpoints: -Incidence , severity, seriousness and relatedness of adverse events. -Changes in vital signs. -Changes in ECG parameters. -Changes in laboratory safety results (clinical chemistry, haematology, coagulation, urinalysis) and the incidence of abnormal laboratory test results.
PK/PD: Pharmacokinetics of SUN13837 Injection as well as exploratory PK analysis of its metabolite, 1-benzyl-N-methylpiperidin-4-amine (BMP [ASB15490]) will be evaluated at selected sites. Exploratory PK/PD relationships between SUN13837 exposure and selected efficacy endpoints will be evaluated. Clearance (CL), Volume of distribution in central and peripheral compartments (Vc, Vp) and Intercompartmental clearance (Q) will be assessed. Additional PK parameters may be provided as necessary. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy: Scores will be recorded on the following days: -SCIM III total score: Day 112. -Total Motor Score, motor ZPP and AIS grades: baseline and on Days 3, 14, 27 or 28 (the final dosing day), 56 and 112. -SCIM III subscales scores: Days 14, 27 or 28, 56 and 112.
Safety: - physical examinations: Days 1, 3, 14, 27 or 28, 56, 112 and and 182. - Vital signs, clinical laboratory testing (chemistry, hematology, coagulation, and urinalysis), and ECGs: Days 1, 3, 14, 27 or 28, and 56 -Where applicable, urine pregnancy testing: pre-dose on Days 1 and 27 or 28. -Adverse events will be recorded throughout the duration of the study.
PK/PD: Blood samples will be collected after the following doses: 1st, 3rd (for rich sampling scheme), 14th and (pre-dose) 28th. |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
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 |
Canada |
Czech Republic |
France |
Poland |
Spain |
United Kingdom |
United States |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
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 |
E.8.9.2 | In all countries concerned by the trial days | 0 |