A Study Evaluating the Safety and Tolerability of QRL-201 in ALS

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to determine the safety and tolerability of multiple doses of QRL-201 in people living with ALS

Detailed Description
-----------------
This first-in-human, Phase 1 study will evaluate safety, tolerability, and pharmacokinetics (PK) of QRL-201 administered intrathecal (IT) to participants with Amyotrophic Lateral Sclerosis. 8 cohorts of 8 participants each, in a 6:2 ratio of QRL-201 to placebo will be tested.

Official Title
-----------------
A Multi-Center, Randomized, Double-Blind Placebo Controlled Multiple-Ascending Dose Study to Evaluate the Safety and Tolerability of QRL-201 in Amyotrophic Lateral Sclerosis

Conditions
-----------------
Amyotrophic Lateral Sclerosis

Intervention / Treatment
-----------------
* Drug: QRL-201 - Dose 1
* Drug: QRL-201 - Dose 2
* Drug: QRL-201 - Dose 3
* Drug: QRL-201 - Dose 4
* Drug: QRL-201 - Dose 5
* Drug: QRL-201 - Dose 6
* Drug: QRL-201 - Dose 7
* Drug: QRL-201- Dose 8


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female participants aged 18 to 80 years diagnosed with ALS ALS symptom onset within 24 months of Screening Slow vital capacity >50% Clinical evidence of lower motor neuron involvement Not pregnant and not nursing Willing and able to practice effective contraception Able to tolerate lumbar puncture If on approved therapies for the treatment of ALS during the course of the study, must be on a stable dose (at the Sponsor's discretion) Exclusion Criteria: Pathogenic variant, likely pathogenic variant, or variant of uncertain significance in the superoxide dismutase 1 (SOD1) and/or fused in sarcoma (FUS) genes Currently enrolled in any other clinical study involving either an investigational product (IP) or off-label use of a drug or device Prior exposure to stem cell or gene therapy products Any contraindication to intrathecal drug administration Abnormal laboratory values deemed clinically significant by the Investigator Significant infection, or known inflammatory process

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: QRL-201 - Arm 1<br>Placebo Comparator: Placebo consists of the same components as the formulation buffer for QRL-201 | Drug: QRL-201 - Dose 1<br>* Drug: Dose 1 of QRL-201 administered via intrathecal injection Diluent: artificial cerebrospinal fluid (aCSF) Placebo: consists of the same components as the formulation buffer for QRL-201 administered via intrathecal injection. Calculated volume to match active comparator Diluent: artificial cerebrospinal fluid (aCSF)<br>|
| Experimental: QRL-201 - Arm 2<br>Placebo Comparator: Placebo consists of the same components as the formulation buffer for QRL-201 | Drug: QRL-201 - Dose 2<br>* Drug: Dose 2 of QRL-201 administered via intrathecal injection Diluent: artificial cerebrospinal fluid (aCSF) Placebo: consists of the same components as the formulation buffer for QRL-201 administered via intrathecal injection. Calculated volume to match active comparator Diluent: artificial cerebrospinal fluid (aCSF) Diluent: artificial cerebrospinal fluid (aCSF)<br>|
| Experimental: QRL-201 - Arm 3<br>Placebo Comparator: Placebo consists of the same components as the formulation buffer for QRL-201 | Drug: QRL-201 - Dose 3<br>* Drug: Dose 3 of QRL-201 administered via intrathecal injection Diluent: artificial cerebrospinal fluid (aCSF) Placebo: consists of the same components as the formulation buffer for QRL-201 administered via intrathecal injection. Calculated volume to match active comparator Diluent: artificial cerebrospinal fluid (aCSF)<br>|
| Experimental: QRL-201 - Arm 4<br>Placebo Comparator: Placebo consists of the same components as the formulation buffer for QRL-201 | Drug: QRL-201 - Dose 4<br>* Drug: Dose 4 of QRL-201 administered via intrathecal injection Diluent: artificial cerebrospinal fluid (aCSF) Placebo: consists of the same components as the formulation buffer for QRL-201 administered via intrathecal injection. Calculated volume to match active comparator Diluent: artificial cerebrospinal fluid (aCSF)<br>|
| Experimental: QRL-201 - Arm 5<br>Placebo Comparator: Placebo consists of the same components as the formulation buffer for QRL-201 | Drug: QRL-201 - Dose 5<br>* Drug: Dose 5 of QRL-201 administered via intrathecal injection Diluent: artificial cerebrospinal fluid (aCSF) Placebo: consists of the same components as the formulation buffer for QRL-201 administered via intrathecal injection. Calculated volume to match active comparator Diluent: artificial cerebrospinal fluid (aCSF)<br>|
| Experimental: QRL-201 - Arm 6<br>Placebo Comparator: Placebo consists of the same components as the formulation buffer for QRL-201 | Drug: QRL-201 - Dose 6<br>* Drug: Dose 6 of QRL-201 administered via intrathecal injection Diluent: artificial cerebrospinal fluid (aCSF) Placebo: consists of the same components as the formulation buffer for QRL-201 administered via intrathecal injection. Calculated volume to match active comparator Diluent: artificial cerebrospinal fluid (aCSF)<br>|
| Experimental: QRL-201 - Arm 7<br>Placebo Comparator: Placebo consists of the same components as the formulation buffer for QRL-201 | Drug: QRL-201 - Dose 7<br>* Drug: Dose 7 of QRL-201 administered via intrathecal injection Diluent: artificial cerebrospinal fluid (aCSF) Placebo: consists of the same components as the formulation buffer for QRL-201 administered via intrathecal injection. Calculated volume to match active comparator Diluent: artificial cerebrospinal fluid (aCSF)<br>|
| Experimental: QRL-201 - Arm 8<br>Placebo Comparator: Placebo consists of the same components as the formulation buffer for QRL-201 | Drug: QRL-201- Dose 8<br>* Drug: Dose 8 of QRL-201 administered via intrathecal injection Diluent: artificial cerebrospinal fluid (aCSF) Placebo: consists of the same components as the formulation buffer for QRL-201 administered via intrathecal injection. Calculated volume to match active comparator Diluent: artificial cerebrospinal fluid (aCSF)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with one or more treatment emergent adverse events and serious adverse events | Endpoints: A summary of treatment emergent adverse events, serious adverse events, and other non-serious adverse events, regardless of causality, will be reported in the Reported Adverse Events module. | Baseline through 253 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (plasma): Maximum observed concentration of QRL-201 (Cmax) | Endpoints: PK: Cmax of QRL-201 | Predose up to 24 hours postdose | 
| Pharmacokinetics (plasma): Area under the concentration time curve from zero to infinity (AUCinf) of QRL-201 | Endpoints: PK: AUC (0-inf) of QRL-201 | Predose up to 24 hours postdose | 
| Pharmacokinetics (plasma): Time of maximum concentration (Tmax) of QRL-201 | Endpoints: PK: Tmax of QRL-201 | Predose up to 24 hours postdose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ALS, Stathmin-2, STMN2, ASO, Antisense Oligonucleotide