TM-105

TikoMed AB

Box 81, Viken, Sweden, 26303

Lars Bruce, TikoMed AB, +46 707238414, florence.lange@tikomed.com

Lars Bruce, TikoMed AB, +46 707238414, florence.lange@tikomed.com

No

No

No

Final

16 Oct 2019

Yes

20 Aug 2019

Yes

20 Aug 2019

Yes

To study safety and tolerability of subcutaneously administered ILB in patients diagnosed with ALS.

The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki that are consistent with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)/Good Clinical Practice (GCP) and applicable regulatory requirements. Informed consent was obtained from all patients prior to initiation of the study. Protocol deviations related to GCP that were reported during the study are discussed further in the section "More information".

17 Sep 2018

No

No

Sweden: 13

13

13

0

0

0

0

0

0

9

4

0

Overall trial (overall period)

Not applicable

Not applicable (open-label study)

ILB

The active pharmaceutical ingredient is a low molecular weight dextran sulfate (LMW-DS, approx. 20 % sulfate, mean MW 5 kDa)

Solution for injection

Subcutaneous use

There was only 1 treatment group in the study (ILB treatment group). The dose administered (1 mg/kg) depended on the patient’s body weight at Visit 2, prior to the first ILB administration. The ILB was administered in single short term subcutaneous injections on alternative sides of the abdomen, thigh or buttock, in that order of priority. The maximum volume injected at each injection site was approximately 2 mL and the number of injections per patient could range between 1 and 3 sites depending on the volume to be injected. Each administration occurred within ±3 days from the pre-defined dosing days (Days 1, 8, 15, 22 and 29) with at least 4 days between 2 IMP administrations. ILB administration was performed by the study personnel and patients were observed for at least 3 hours after the injection.

Overall trial

Safety analysis set

The safety analysis set was defined as patients who received any dose of the test product (ILB)

Full analysis set

Defined as all patients who received at least 1 dose of the test product (ILB) and with at least 1 efficacy measurement

Per protocol analysis set

Defined as all patients who received at least 1 dose of the test product (ILB) and with at least 1 efficacy measurement. This analysis set was the same as the full analysis set.

Results at baseline

This sub-group consists of the same subjects as the safety analysis set and the full analysis set. The sub-group was created to present the statistical analysis of changes from baseline in this single-arm study. The total number of subjects in the analysis is 13.

Results at post-treatment visits

This sub-group consists of the same subjects as the safety analysis set and the full analysis set. The sub-group was created to present the statistical analysis of changes from baseline in this single-arm study. The total number of subjects in the analysis is 13.

TEAEs during the treatment period

TEAEs that occurred during the treatment period are reported using this group. This group consisted of the same subjects as in the Safety analysis set (N=13).

TEAEs during the follow-up period

TEAEs that occurred during the follow-up period are reported using this group. This group consisted of the same subjects as in the Safety analysis set (N=13).

Safety analysis set - copy

This is not a separate subgroup of subjects but contains data for the same 13 subjects as in the safety analysis set.

ILB treatment group

Safety analysis set

The safety analysis set was defined as patients who received any dose of the test product (ILB)

Full analysis set

Defined as all patients who received at least 1 dose of the test product (ILB) and with at least 1 efficacy measurement

Per protocol analysis set

Defined as all patients who received at least 1 dose of the test product (ILB) and with at least 1 efficacy measurement. This analysis set was the same as the full analysis set.

Results at baseline

This sub-group consists of the same subjects as the safety analysis set and the full analysis set. The sub-group was created to present the statistical analysis of changes from baseline in this single-arm study. The total number of subjects in the analysis is 13.

Results at post-treatment visits

This sub-group consists of the same subjects as the safety analysis set and the full analysis set. The sub-group was created to present the statistical analysis of changes from baseline in this single-arm study. The total number of subjects in the analysis is 13.

TEAEs during the treatment period

TEAEs that occurred during the treatment period are reported using this group. This group consisted of the same subjects as in the Safety analysis set (N=13).

TEAEs during the follow-up period

TEAEs that occurred during the follow-up period are reported using this group. This group consisted of the same subjects as in the Safety analysis set (N=13).

Safety analysis set - copy

This is not a separate subgroup of subjects but contains data for the same 13 subjects as in the safety analysis set.

A Treatment-emergent Adverse Event (TEAE) was defined as any AE not present prior to the initiation of IMP administration or any event already present that worsened in either intensity or frequency following exposure to the IMP. A serious AE (SAE) was defined as any untoward medical occurrence that at any dose: • Resulted in death • Was life-threatening • Required inpatient hospitalization or prolongation of existing hospitalization • Resulted in persistent or significant disability/incapacity, or • Was a congenital anomaly/birth defect All AEs and SAEs were recorded from start of IMP administration until the end of follow-up (Visit 9). Adverse events that occurred before first IMP treatment were reported separately as baseline events.

Primary

Total study: Visit 1a (Screening), pre-dose at Visits 2-5 (days 1, 8, 15, 22 and 29, treatment) and Visits 7-9 (days 36, 50 and 99, follow-up)

A complete physical examination included assessments of the head, eyes, ears, nose, throat, cardiac, peripheral vascular, pulmonary, musculoskeletal, neurologic, abdominal, lymphatic and dermatologic functions. Abnormal findings were specified and presented by patient and summarised in frequency tables. No statistical analysis was performed.

Primary

Total study: Visit 1a (Screening), pre-dose at Visits 2-5 (days 1, 8, 15, 22 and 29, treatment) and Visits 7-9 (days 36, 50 and 99, follow-up)

Diastolic and systolic blood pressure was measured in supine position after 5 minutes of rest using the same method each time. Data were presented by visit for each parameter and patient and summarised using summary statistics, including absolute and percent change from baseline. The baseline was defined as the last measurement prior to first dose of the test product (i.e. measurement at Visit 2).

Primary

Total study: Visit 1a (Screening), pre-dose at Visits 2-5 (days 1, 8, 15, 22 and 29, treatment) and Visits 7-9 (days 36, 50 and 99, follow-up)

The subgroups "Results at baseline" and "Results at post-treatment visits" were only defined in this report in order to describe the statistical analysis. No such analysis sets were used in the study. The statistical analysis was performed within the safety analysis set to assess the statistical significance of changes from baseline.

Results at baseline v Results at post-treatment visits

26

Pre-specified

Heart rate was measured in supine position after 5 minutes of rest using the same method each time. Data were presented by visit for each parameter and patient and summarised using summary statistics, including absolute and percent change from baseline. The baseline was defined as the last measurement prior to first dose of the test product (i.e. measurement at Visit 2).

Primary

Total study: Visit 1a (Screening), pre-dose at Visits 2-5 (days 1, 8, 15, 22 and 29, treatment) and Visits 7-9 (days 36, 50 and 99, follow-up)

The subgroups "Results at baseline" and "Results at post-treatment visits" were only defined in this report in order to describe the statistical analysis. No such analysis sets were used in the study. The statistical analysis was performed within the safety analysis set to assess the statistical significance of changes from baseline.

Results at post-treatment visits v Results at baseline

26

Pre-specified

Single 12-lead electrocardiogram (ECG)was recorded after 10 minutes of supine rest using an ECG machine. PQ/PR, QRS, QT and QTcH intervals were recorded. All ECG data were listed for each patient and summarised as vital signs parameters. The baseline was defined as the last measurement prior to first dose of the test product (i.e. measurement at Visit 1a).

Primary

Visit 1a (screening) and Visit 7( day 36, follow-up)

The subgroups "Results at baseline" and "Results at post-treatment visits" were only defined in this report in order to describe the statistical analysis. No such analysis sets were used in the study. The statistical analysis was performed within the safety analysis set to assess the statistical significance of changes from baseline.

Results at baseline v Results at post-treatment visits

26

Pre-specified

Body temperature was measured in supine position after 5 minutes of rest using the same method each time. The baseline was defined as the last measurement prior to first dose of the test product (i.e. measurement at Visit 2). Data were presented by visit for each parameter and patient and summarised using summary statistics, including absolute and percent change from baseline (Visit 2).

Primary

Total study: Visit 1a (Screening), pre-dose at Visits 2-5 (days 1, 8, 15, 22 and 29, treatment) and Visits 7-9 (days 36, 50 and 99, follow-up)

The subgroups "Results at baseline" and "Results at post-treatment visits" were only defined in this report in order to describe the statistical analysis. No such analysis sets were used in the study. The statistical analysis was performed within the safety analysis set to assess the statistical significance of changes from baseline.

Results at baseline v Results at post-treatment visits

26

Pre-specified

Clinical chemistry parameters assessed: Sodium Potassium Chloride Calcium Albumin Aspartate aminotransferase (AST) Alkaline Phosphatase Alanine aminotransferase (ALT) Creatinine Creatinine kinase Myoglobin C-reactive protein (CRP) Total bilirubin Glucose (non-fasting) Data were presented by visit for each parameter and patient and summarised using summary statistics, including absolute and percent change from baseline (Visit 2). The overall significance level was 5%.

Primary

Total study: Visit 1a (Screening), pre-dose at Visits 2-5 (days 1, 8, 15, 22 and 29, treatment) and Visits 7-9 (days 36, 50 and 99, follow-up)

The subgroups "Results at baseline" and "Results at post-treatment visits" were only defined in this report in order to describe the statistical analysis. No such analysis sets were used in the study. The statistical analysis was performed within the safety analysis set to assess the statistical significance of changes from baseline.

Results at baseline v Results at post-treatment visits

26

Pre-specified

Haematological parameters assessed: Haemoglobin (Hb) Haemoglobin S (only at screening) Haemoglobin A1c (only at screening) Red blood cells (RBC) White blood cells (WBC) Differential cell count Platelets (thrombocytes) Data were presented by visit for each parameter and patient and summarised using summary statistics, including absolute and percent change from baseline (Visit 2). The overall significance level was 5%.

Primary

Total study: Visit 1a (Screening), pre-dose at Visits 2-5 (days 1, 8, 15, 22 and 29, treatment) and Visits 7-9 (days 36, 50 and 99, follow-up)

The subgroups "Results at baseline" and "Results at post-treatment visits" were only defined in this report in order to describe the statistical analysis. No such analysis sets were used in the study. The statistical analysis was performed within the safety analysis set to assess the statistical significance of changes from baseline.

Results at baseline v Results at post-treatment visits

26

Pre-specified

Haemostatic parameters assessed: Effect activated partial thromboplastin time (APTT): Visit 1a, Visit 2 and Visit 6 (15 min pre-dose, 30 min post-dose, 1 hour post-dose, 2 hours post-dose, 2.5 hours post-dose, 3 hours post-dose, 4 hours post-dose and 6 hours post-dose) Fibrinogen: Total study: Visit 1a (Screening), pre-dose at Visits 2-5 (days 1, 8, 15, 22 and 29, treatment) and Visits 7-9 (days 36, 50 and 99, follow-up) Von Willebrand factor (vW antigen, vW activity + factor VIII): Visit 1a (screening) Prothrombin intl. normalized ratio (PK-INR): Total study: Visit 1a (Screening), pre-dose at Visits 2-5 (days 1, 8, 15, 22 and 29, treatment) and Visits 7-9 (days 36, 50 and 99, follow-up) Data were presented by patient and assessment time as changes from baseline, using summary statistics. The overall significance level was 5%. Statistics were presented for all factors except APTT.

Primary

APTT: Visit 1a (screening), Visit 2 (day 1 of treatment) and Visit 6 (day 29 of treatment) Fibrinogen and PK-INR: total study Von Willebrand factor :Visit 1a (screening)

The subgroups "Results at baseline" and "Results at post-treatment visits" were only defined in this report in order to describe the statistical analysis. No such analysis sets were used in the study. The statistical analysis was performed within the safety analysis set to assess the statistical significance of changes from baseline.

Results at baseline v Results at post-treatment visits

26

Pre-specified

Disease severity was evaluated by the Investigator using the ALSFRS-R rating scale in an interview with the patient at Visit 1a (Screening), pre-dose at Visits 2-5 (treatment) and Visits 7-9 (follow-up). ALSFR-S measured 12 different functions (speech, salivation, swallowing, handwriting, cut food and use utensils, dressing and hygiene, turning in bed and adjusting the bedding, walking, climbing stairs, dyspnea, orthopnea and respiratory insufficiency). For each function, 0 to 4 points were assigned, where 0= worst and 4= best. The total ALSFR-S score was the sum of all points collected. The baseline was defined as the last measurement prior to first dose of the test product (i.e. measurement at Visit 2). The parameters were presented as changes from baseline using summary statistics. The overall significance level was 5%. The statistical test used was non-parametric Wilcoxon signed rank sum test, for within patient changes over time.

Secondary

Total study: Visit 1a (Screening), pre-dose at Visits 2-5 (days 1, 8, 15, 22 and 29, treatment) and Visits 7-9 (days 36, 50 and 99, follow-up)

The subgroups "Results at baseline" and "Results at post-treatment visits" were only defined in this report in order to describe the statistical analysis. No such analysis sets were used in the study. The statistical analysis was performed within the full analysis set to assess the statistical significance of changes from baseline.

Results at baseline v Results at post-treatment visits

26

Pre-specified

Disease severity was evaluated by the Investigator using the Norris rating scale in an interview with the patient at Visit 1a (Screening), pre-dose at Visits 2-5 (treatment) and Visits 7-9 (follow-up). Norris measured 34 different functions. For each function, 0 to 3 points were assigned, where 0= missing, 1= weak, 2= reduced and 3= normal. The total Norris score was the sum of all points collected. The baseline was defined as the last measurement prior to first dose of the test product (i.e. measurement at Visit 2). The parameters were presented as changes from baseline using summary statistics. The overall significance level was 5%. The statistical test used was non-parametric Wilcoxon signed rank sum test, for within patient changes over time.

Secondary

Total study: Visit 1a (Screening), pre-dose at Visits 2-5 (days 1, 8, 15, 22 and 29, treatment) and Visits 7-9 (days 36, 50 and 99, follow-up)

The subgroups "Results at baseline" and "Results at post-treatment visits" were only defined in this report in order to describe the statistical analysis. No such analysis sets were used in the study. The statistical analysis was performed within the full analysis set to assess the statistical significance of changes from baseline.

Results at baseline v Results at post-treatment visits

26

Pre-specified

Extent of presence of biomarkers for neurological diseases was evaluated in serum, plasma and CSF sampled at Visit 1b and Visit 7. Biomarkers assessed: In CSF: Albumin, Immunoglobulin G and M (IgG and IgM), IgG index, IgM index, Tau, Phosphorylated Tau, NFL, Beta-amyloid, glial fibrillary acidic protein (GFAP) and Compleasome In serum: Albumin, IgG and IgM In plasma: NFL and Compleasome All biomarkers were presented, using summary statistics, as changes from baseline(Visit 1b) to Visit 7. The overall significance level was 5%. The statistical test used was non-parametric Wilcoxon signed rank sum test, for within patient changes over time.

Secondary

Visit 1b (screening) and Visit 7 (Day 36, follow-up)

The subgroups "Results at baseline" and "Results at post-treatment visits" were only defined in this report in order to describe the statistical analysis. No such analysis sets were used in the study. The statistical analysis was performed within the full analysis set to assess the statistical significance of changes from baseline.

Results at baseline v Results at post-treatment visits

26

Pre-specified

Pulmonary function was measured as percentage of Forced Vital Capacity (FVC) at Visit 1a (Screening), pre-dose at Visits 2-5 (treatment) and Visits 7-9 (follow-up). The baseline was defined as the last measurement prior to first dose of the test product (i.e. measurement at Visit 2). The overall significance level was 5%. The statistical test used was non-parametric Wilcoxon signed rank sum test, for within patient changes over time. The mean FVC at baseline (Visit 2) was 84.60% (SD 13.74). Statistically significant changes from this baseline are presented below.

Secondary

Total study: Visit 1a (Screening), pre-dose at Visits 2-5 (days 1, 8, 15, 22 and 29, treatment) and Visits 7-9 (days 36, 50 and 99, follow-up)

The subgroups "Results at baseline" and "Results at post-treatment visits" were only defined in this report in order to describe the statistical analysis. No such analysis sets were used in the study. The statistical analysis was performed within the full analysis set to assess the statistical significance of changes from baseline.

Results at baseline v Results at post-treatment visits

26

Pre-specified

The patient’s quality of life (QoL) was evaluated using a visual analogue scale (VAS)-based questionnaire on a scale of 0 to 100, where 0= very bad and 100= very good) which was filled out by the patient and, if applicable, a next of kin. The same next of kin was used throughout the study. The baseline was defined as the last measurement prior to first dose of the test product (i.e. measurement at Visit 2). QoL was reported as changes from baseline using summary statistics.

Secondary

Total study: Visit 1a (Screening), pre-dose at Visits 2, 4 and 6 (days 1, 15 and 29, treatment period) and Visit 8 (days 50, follow-up)

The subgroups "Results at baseline" and "Results at post-treatment visits" were only defined in this report in order to describe the statistical analysis. No such analysis sets were used in the study. The statistical analysis was performed within the full analysis set to assess the statistical significance of changes from baseline.

Results at baseline v Results at post-treatment visits

26

Pre-specified

Prevalence and extent of 16 sensory and autonomous symptoms were recorded by the Investigator in an interview with the patient . The measuring scale was the following: 0= no symptoms, 1= some symptoms, 2= moderate number of symptoms and 3= many symptoms. These parameters were presented as changes from baseline using summary statistics. The overall significance level was 5%. The statistical test used was non-parametric Wilcoxon signed rank sum test, for within patient changes over time. The total score mean value was 6.2 (SD= 3.5) at baseline (Visit 2) and it was significantly decreased throughout the study (p<0.05). Changes from baseline to Visit 6 (last treatment day) and to Visit 9 (last follow-up) are presented below.

Secondary

Total study: Visit 1a (Screening), pre-dose at Visits 2-5 (days 1, 8, 15, 22 and 29, treatment) and Visits 7-9 (days 36, 50 and 99, follow-up)

The subgroups "Results at baseline" and "Results at post-treatment visits" were only defined in this report in order to describe the statistical analysis. No such analysis sets were used in the study. The statistical analysis was performed within the full analysis set to assess the statistical significance of changes from baseline.

Results at baseline v Results at post-treatment visits

26

Pre-specified

Blood samples for Hepatocyte Growth Factor (HGF) measurement were collected through venepuncture or through an indwelling venous catheter into a vacutainer tube with citrate. The HGF levels were presented by patient and assessment time as changes from baseline, using summary statistics. The baseline was defined as the last measurement prior to first dose of the test product (i.e. measurement at Visit 2 ,15 min pre-dose).

Secondary

Visit 2 (Day 1, treatment) and Visit 6 (day 29, treatment): 15 min pre-dose, 30 min post-dose, 1 hour post-dose, 2 hours post-dose, 2.5 hours post-dose, 3 hours post-dose, 4 hours post-dose and 6 hours post-dose

Descriptive statistics for time to maximum concentration (tmax) were presented after first and last ILB administration (Visit 2 and Visit 6), as well as pooled data over the dosing days (if appropriate).

Secondary

Visit 2 (treatment day 1) to Visit 6 (treatment day 29)

Descriptive statistics for maximum concentration (Cmax) were presented after first and last ILB administration (Visit 2 and Visit 6), as well as pooled data over the dosing days (if appropriate).

Secondary

Visit 2 (treatment day 1) to Visit 6 (treatment day 29)

Descriptive statistics for the terminal elimination (t½ )were presented after first and last ILB administration (Visit 2 and Visit 6), as well as pooled data over the dosing days (if appropriate).

Secondary

Visit 2 (treatment day 1) to Visit 6 (treatment day 29)

Total study: Visit 1a (Screening), pre-dose at Visits 2-5 (treatment) and Visits 7-9 (follow-up)

All adverse events (AEs) and SAEs were recorded from start of IMP administration until the end of follow-up (Visit 9). Adverse events that occurred before first IMP treatment were reported separately as baseline events. All AEs presented are treatment-emergent AEs (TEAEs).

20.1

Overall trial