Clinical trial NCT04718844: A Study Investigate the Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Response of SLN124 in Adults With Alpha/Beta-thalassaemia and Very Low- and Low-risk Myelodysplastic Syndrome
Official title: A Randomised, Single-blind, Placebo-controlled, Phase 1, Single-ascending and Multiple-dose Study in Adult Subjects With Alpha/Beta-thalassaemia and Very Low- and Low-risk Myelodysplastic Syndrome to Investigate the Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Response of SLN124.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Non-transfusion-dependent Thalassemia
Low Risk Myelodysplastic Syndrome
Very-Low Risk Myelodysplastic Syndrome
Lead sponsor: Silence Therapeutics plc
Sponsor class: INDUSTRY
First posted: 2021-01-22
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will investigate the safety and tolerability of SLN124 in patients with Thalassaemia or patients with Very Low- and Low-risk Myelodysplastic Syndrome (MDS) after single ascending s.c. doses and multiple doses in healthy male and female subjects. Up to 7 cohorts of 56 patients with Thalassaemia and up to 7 cohorts of 56 patients with MDS will be enrolled. Each subject will receive single or multiple doses of SLN124 or placebo given by subcutaneous (s.c) injection.


Eligibility criteria: Inclusion Criteria:

* Adult with alpha- or beta-thalassaemia or compound heterozygous haemoglobin E/beta-thalassaemia or adult with very low- or low-risk MDS according to the 2016 revision to the World Health Organisation classification.
* All subjects must agree to adhere to appropriate contraception requirements.
* Subjects must provide written informed consent and be able to comply with all study requirements.
* Body mass index ≥18 kg/m2 and ≤35 kg/m2 at screening.
* At least one of: a) Mean ferritin \>250 μg/L based on a minimum of 2 measurements ≥1 week apart within 20 days before the planned dosing day, in the absence of active significant infection; b) Mean TSAT \>40% measured on a minimum of 2 occasions ≥1 week apart within 20 days before the planned dosing day; c) Liver iron \>3 mg Fe/g dry weight, measured according to local procedures.
* Mean baseline haemoglobin concentration ≥5 g/dL and ≤11 g/dL, based on a minimum of 2 measurements ≥1 week apart, within 20 days before the planned dosing day.

Exclusion criteria

* Adult with haemoglobin S/alpha-thalassaemia or haemoglobin S/beta-thalassaemia or adult with secondary MDS, i.e., MDS that is known to have arisen because of chemical injury or treatment with chemotherapy and/or radiation for another disease.
* History of multiple drug allergies or history of allergic reaction to an oligonucleotide or GalNAc, or intolerance to s.c. injections.
* Known infection with HIV, or active infectious hepatitis A, B, or C virus.
* Any conditions which, in the opinion of the Investigator, would make the subject unsuitable for enrolment in the study or could interfere with the subject's participation in, or completion of the study.
* History or clinical evidence of alcohol or illegal drug misuse within 2 years before screening.
* Currently using ESA, or plan to use ESA at any point during the study.
* Require daily treatment with 1 or more non-steroidal anti-inflammatory drugs during the study period. Paracetamol will be permitted for use as an antipyretic and/or analgesic.
* Treatment, or change in treatment with prohibited medications as specified in the protocol
* Treatment with ICT where the subject has not been on a stable dose for at least 8 weeks before screening or it is planned to initiate ICT therapy during the study.
* Clinically significant cardiac disease
* Clinically significant pulmonary disease

For subjects with thalassaemia:

* Treatment, or change in treatment with prohibited medications as specified in the protocol
* currently and anticipated to receiving more than 5 units of RBCs during the 24 weeks to 6 weeks period before first dose of study drug.

For subjects with very low / low-risk MDS:

* Previous allogeneic or autologous stem cell transplantation.
* Currently or planned to receive treatment with a corticosteroid for MDS within 8 weeks before screening.
* Currently or planned to receive treatment with haematopoietic growth factors (e.g., eltrombopag, romiplostim) within 8 weeks before screening.

Primary outcomes:
measure: Incidence of treatment-emergent adverse events
timeFrame: Day 84
measure: Incidence of treatment-emergent adverse events
timeFrame: Day 140
Secondary outcomes:
measure: Pharmacokinetic: peak plasma concentration (Cmax)
timeFrame: Day 84 and Day 140
measure: Pharmacokinetic: area under the plasma concentration (AUC)
timeFrame: Day 84 and Day 140
measure: Pharmacokinetic: apparent total clearance from plasma after s.c injection (CL/F)
timeFrame: Day 84 and Day 140
measure: Pharmacodynamic biomarkers: Change in TSAT after s.c injection.
timeFrame: Day 84 and Day 140
measure: Pharmacodynamic biomarkers: Change in hepcidin after s.c injection.
timeFrame: Day 84 and Day 140
measure: Pharmacodynamic biomarkers: Change in serum iron after s.c injection.
timeFrame: Day 84 and Day 140
measure: Pharmacodynamic biomarkers: Change in haemoglobin after s.c injection.
timeFrame: Day 84 and Day 140
Other outcomes:
Locations:
city: Düsseldorf
country: Germany
facility: Universitaetsklinikum Duesseldorf
city: Leipzig
country: Germany
facility: Universitat Leipzig
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Ramat Gan
country: Israel
facility: Sheba Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Zefat
country: Israel
facility: Bar-Ilan University - Faculty of Medicine
city: Ravenna
country: Italy
facility: AUSL della Romagna - Ospedale di Ravenna
city: Reggio Emilia
country: Italy
facility: Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia
city: Amman
country: Jordan
facility: Jordan University Hospital
city: Amman
country: Jordan
facility: King Hussein Cancer Center
city: Irbid
country: Jordan
facility: Irbid Speciality Hospital
city: Kampung Sarawak
country: Malaysia
facility: Sarawak General Hospital
city: Kampung Selangor
country: Malaysia
facility: Hospital Ampang
city: Bangkok
country: Thailand
facility: King Chulalongkorn Memorial Hospital
city: Bangkok
country: Thailand
facility: Mahidol University - Faculty of Medicine - Ramathibodi Hospital
city: Bangkok
country: Thailand
facility: Mahidol University - Siriraj Hospital
city: Chiang Mai
country: Thailand
facility: Faculty of Medicine, Chiang Mai University
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
city: Leeds
country: United Kingdom
facility: The Leeds Teaching Hospitals NHS Trust - Saint James's University Hospital
city: London
country: United Kingdom
facility: Hammersmith Medicines Research Ltd (HMR)
Study officials:
References: