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Senolytics to Improve Osteoporosis Therapy (SENIOR)

Primary Purpose

Osteopenia, Osteoporosis

Status
Recruiting
Phase
Phase 2
Locations
Denmark
Study Type
Interventional
Intervention
Dasatinib 100 Mg Oral Tablet
Quercetin 1.250 mg (oral)
Nicotinamide Riboside 1g (oral)
Sponsored by
Odense University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Osteopenia, Osteoporosis focused on measuring Age related bone loss, Cellular senescence

Eligibility Criteria

60 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Men and women (menopause > 5 years and FSH and LH in the postmenopausal range) aged 60-90 years with increased fracture risk according to WHO 10 years absolute Fracture Risk Assessment Tool (FRAX) osteopenia (ICD10 DM858A) based on a T-score ≤ -2 to -2.5 at the total hip/femoral neck, or lumbar spine (FRAX score ranging from 10-70) osteopenia (ICD10 DM858A) based on a T-score < -1 to -2.5 and a fragility fracture at any time (excluding hip and vertebral fractures within the last 2 years) (FRAX ranging from 11-68) osteoporosis (ICD10 DM819) based on a T-score between >-3 and ≤ -2.5, which includes candidates suitable for conventional osteoporosis therapies, but who prefer to participate in the trial, despite being candidates for conventional osteoporosis therapy, or candidates which cannot be treated with conventional therapies due to contraindications. Ability to provide informed consent Exclusion Criteria: DXA of hip or spine not possible e.g., due to a prosthesis Inability to provide fasting blood samples Primary hyperparathyroidism Vitamin D deficiency (<50 nM) (re-test after substitution acceptable) Known disorders affecting bone metabolism, e.g., uncontrolled thyrotoxicosis, chronic kidney disease defined as eGFR <30 or liver dysfunction, rheumatism, celiac disease/malabsorption, hypogonadism, severe COPD, hypopituitarism, Cushing's disease, uncontrolled diabetes (HbA1c > 58 mmol/mol). Antiresorptive or bone anabolic drugs for the last 2 years (5 years if treated with zoledronic acid) Concomitant treatments known to influence bone metabolism e.g., glucocorticoids (systemic treatments), anabolic steroids, etc. Subjects taking the following other drugs if they cannot be held for at least 2 days before and during administration of D+Q: digoxin, lithium, all statins, repaglidine, bosentan, gemfibrozil, olmesartan, enalapril, valsartan, methotrexate, corticosteroids, eluxadoline, eltrombopag, nitroglycerin, pioglitazone, glyburide, enzalutamide, ezetimibe, colchicine, imatinib, cyclosporine, tacrolimus, sirolimus, carbamazepine, flecainide, phenytoin, phenobarbital, rifampicin, theophylline, warfarin, heparin, clopidogrel, celecoxib, desipramine, thioridazine, venlafaxine, tizanidine, atomoxetine, voriconazole, citalopram, diazepam, escitalopram, propranolol, clozapine, cyclobenzaprine, mexiletine, olanzapine, ondansetron Subjects taking medications that are sensitive to substrates or substrates with a narrow therapeutic range for CYP3A4, CYP2C8, CYP2C9, or CYP2D6 or strong inhibitors or inducers of CYP3A4 (e.g., cyclosporine, tacrolimus or sirolimus). If antifungals are necessary from an infectious disease perspective, then they will be allowed only if the levels are therapeutic. Subjects taking proton pump inhibitors and unwilling to discontinue therapy for two days before and during the study drug dosing periods. Anti-arrhythmic medications known to cause QTc prolongation Tyrosine kinase inhibitor therapy Subjects with an abnormal Complete Blood Count (clinically insignificant changes would be acceptable based on the judgement of the investigators) Subjects on antiplatelet agents (Clopidogrel; Dipyridamole + ASA; ASA, Ticagrelor; Prasugrel; Ticlopidine or other) who are unable or unwilling to reduce or hold therapy prior to and during the study drug dosing periods and collection of bone biopsies. Subjects may continue their previous regimen between study drug dosing periods. Known allergy to dasatinib, quercetin, or nicotinamide riboside Subjects taking the following antimicrobial agents: Aminoglycosides, Azole antifungals (fluconazole, miconazole, voriconazole, itraconazole), Macrolides (clarithromycin, erythromycin), antivirals (nelfinavir, indinavir, saquinavir, ritonavir, elbasvir/grazoprevir) Presence of any condition the Investigator believes would place the subject at risk or would preclude the subject from successfully completing all aspects of the trial e.g., heart failure, malignancy etc. QTc >470 msec Inability to take oral medication The study will exclude subjects with inability to speak and understand Danish and with inability to cooperate

Sites / Locations

  • Odense University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

No Intervention

Arm Label

Dasatinib plus Quercetin (DQ)

Nicotinamide Riboside (NR)

Control

Arm Description

Study participants will receive a combination of 100 mg/d dasatinib (oral) for two consecutive days and 1.250 mg/d quercetin (oral) for three consecutive days followed by 25 days without treatment, with treatment being repeated every 4 weeks for a total of 20 weeks (i.e., 5 times)

The participants will receive treatment with 1g Nicotinamide Riboside (oral) daily for 20 weeks

The participants in the Control group, will not receive any treatment for 20 weeks.

Outcomes

Primary Outcome Measures

Bone resorption marker CTX
Change in circulating marker of bone resorption C-terminal telopeptide of type I collagen (CTX) at 21 weeks.

Secondary Outcome Measures

Bone resorption marker TRAcP
Change in circulating marker of bone resorption Tartrate Resistant Acid Phosphatase (TRAcP) at 21 weeks.
Bone formation markers (PINP, osteocalcin, and bone alkaline phosphatase)
Change in circulating markers of bone formation (PINP, osteocalcin, and bone alkaline phosphatase) at 21 weeks.

Full Information

First Posted
August 23, 2023
Last Updated
September 28, 2023
Sponsor
Odense University Hospital
Collaborators
Odense Patient Data Explorative Network, Novo Nordisk A/S
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1. Study Identification

Unique Protocol Identification Number
NCT06018467
Brief Title
Senolytics to Improve Osteoporosis Therapy
Acronym
SENIOR
Official Title
SENolytics to Improve Osteoporosis Therapy: a Randomised Controlled Clinical Trial The SENIOR Trial
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 6, 2023 (Actual)
Primary Completion Date
December 31, 2025 (Anticipated)
Study Completion Date
December 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Odense University Hospital
Collaborators
Odense Patient Data Explorative Network, Novo Nordisk A/S

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This randomised clinical trial aims to study osteoporosis as a disease of accelerated skeletal aging caused by the accumulation of senescent cells within the skeleton and investigate the effects and safety of senolytics and antioxidant therapy on bone.
Detailed Description
Background, hypothesis, and aim: Evidence suggests that it is feasible to alleviate chronic age-related disorders by targeting the biology of aging. Recent studies implicate cellular senescence at the nexus of skeletal aging, suggesting that selectively eliminating senescent cells may emerge as a conceptually novel approach to manage the enormous problem of age-related bone loss. In addition, previous studies have demonstrated that antioxidants inhibit cellular senescence. The aim of this randomised clinical trial is to study osteoporosis as a disease of accelerated skeletal aging caused by accumulation of senescent cells within the skeleton and investigate the effects and safety of senolytics and antioxidant therapy on bone. The main trial endpoint is the percent change in circulating marker of bone resorption (CTX) measured at baseline and at week 21. Secondary endpoints are the changes in bone resorption marker tartrate resistant acid phosphatase (TRAcP) and bone formation markers (PINP, osteocalcin, and bone alkaline phosphatase) measured at baseline and at 21 weeks. Trial design: The study design is a randomised controlled open-label clinical trial. Study participants will be randomised 1:1:1 to one of three treatment groups, that will include either, a combination of 100 mg/d dasatinib (oral) for two consecutive days and 1.250 mg/d quercetin (oral) for three consecutive days followed by 25 days without treatment, with treatment being repeated every 4 weeks for a total of 20 weeks (i.e., 5 times), or treatment with 1 g nicotinamide riboside (NR) (oral) daily for 20 weeks, or no treatment for 20 weeks. Each participant will have a total of 7 to 10 visits at the clinical site. Blood samples will be obtained at all but one visit (2x20 ml each time). ECG will be performed at 6 visits for group 1 and at 2 visits for group 2 and 3. Scans will be performed at the first two and the last visit. Muscle-function tests will be performed at 2nd and last visit. Bone biopsies for RNA-sequencing (a technique indicating which of the genes encoded in our DNA that are active) will be collected in those that provide a separate consent and in up to 20 participants in each group (using block randomisation to ensure balanced distribution of sex and age, equaling a maximum of 60 biopsies.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Osteopenia, Osteoporosis
Keywords
Age related bone loss, Cellular senescence

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Dasatinib plus Quercetin (DQ)
Arm Type
Experimental
Arm Description
Study participants will receive a combination of 100 mg/d dasatinib (oral) for two consecutive days and 1.250 mg/d quercetin (oral) for three consecutive days followed by 25 days without treatment, with treatment being repeated every 4 weeks for a total of 20 weeks (i.e., 5 times)
Arm Title
Nicotinamide Riboside (NR)
Arm Type
Experimental
Arm Description
The participants will receive treatment with 1g Nicotinamide Riboside (oral) daily for 20 weeks
Arm Title
Control
Arm Type
No Intervention
Arm Description
The participants in the Control group, will not receive any treatment for 20 weeks.
Intervention Type
Drug
Intervention Name(s)
Dasatinib 100 Mg Oral Tablet
Other Intervention Name(s)
Sprycel
Intervention Description
Dasatinib tablets in blister packs of 10 tablets, from either: "Sandoz", "STADA Nordic", "Zentiva" or "Bristol-Myers Squibb"
Intervention Type
Dietary Supplement
Intervention Name(s)
Quercetin 1.250 mg (oral)
Other Intervention Name(s)
Quercetin Phytosome
Intervention Description
five 200mg Quercetin Phytosome capsules, from Thorne
Intervention Type
Dietary Supplement
Intervention Name(s)
Nicotinamide Riboside 1g (oral)
Other Intervention Name(s)
NR
Intervention Description
four 250mg Nicotinamide Riboside Capsules, from Elysium Health
Primary Outcome Measure Information:
Title
Bone resorption marker CTX
Description
Change in circulating marker of bone resorption C-terminal telopeptide of type I collagen (CTX) at 21 weeks.
Time Frame
Baseline, week 5, week 13, week 21
Secondary Outcome Measure Information:
Title
Bone resorption marker TRAcP
Description
Change in circulating marker of bone resorption Tartrate Resistant Acid Phosphatase (TRAcP) at 21 weeks.
Time Frame
Baseline, week 5, week 13, week 21
Title
Bone formation markers (PINP, osteocalcin, and bone alkaline phosphatase)
Description
Change in circulating markers of bone formation (PINP, osteocalcin, and bone alkaline phosphatase) at 21 weeks.
Time Frame
Baseline, week 5, week 13, week 21

10. Eligibility

Sex
All
Minimum Age & Unit of Time
60 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Men and women (menopause > 5 years and FSH and LH in the postmenopausal range) aged 60-90 years with increased fracture risk according to WHO 10 years absolute Fracture Risk Assessment Tool (FRAX) osteopenia (ICD10 DM858A) based on a T-score ≤ -2 to -2.5 at the total hip/femoral neck, or lumbar spine (FRAX score ranging from 10-70) osteopenia (ICD10 DM858A) based on a T-score < -1 to -2.5 and a fragility fracture at any time (excluding hip and vertebral fractures within the last 2 years) (FRAX ranging from 11-68) osteoporosis (ICD10 DM819) based on a T-score between >-3 and ≤ -2.5, which includes candidates suitable for conventional osteoporosis therapies, but who prefer to participate in the trial, despite being candidates for conventional osteoporosis therapy, or candidates which cannot be treated with conventional therapies due to contraindications. Ability to provide informed consent Exclusion Criteria: DXA of hip or spine not possible e.g., due to a prosthesis Inability to provide fasting blood samples Primary hyperparathyroidism Vitamin D deficiency (<50 nM) (re-test after substitution acceptable) Known disorders affecting bone metabolism, e.g., uncontrolled thyrotoxicosis, chronic kidney disease defined as eGFR <30 or liver dysfunction, rheumatism, celiac disease/malabsorption, hypogonadism, severe COPD, hypopituitarism, Cushing's disease, uncontrolled diabetes (HbA1c > 58 mmol/mol). Antiresorptive or bone anabolic drugs for the last 2 years (5 years if treated with zoledronic acid) Concomitant treatments known to influence bone metabolism e.g., glucocorticoids (systemic treatments), anabolic steroids, etc. Subjects taking the following other drugs if they cannot be held for at least 2 days before and during administration of D+Q: digoxin, lithium, all statins, repaglidine, bosentan, gemfibrozil, olmesartan, enalapril, valsartan, methotrexate, corticosteroids, eluxadoline, eltrombopag, nitroglycerin, pioglitazone, glyburide, enzalutamide, ezetimibe, colchicine, imatinib, cyclosporine, tacrolimus, sirolimus, carbamazepine, flecainide, phenytoin, phenobarbital, rifampicin, theophylline, warfarin, heparin, clopidogrel, celecoxib, desipramine, thioridazine, venlafaxine, tizanidine, atomoxetine, voriconazole, citalopram, diazepam, escitalopram, propranolol, clozapine, cyclobenzaprine, mexiletine, olanzapine, ondansetron Subjects taking medications that are sensitive to substrates or substrates with a narrow therapeutic range for CYP3A4, CYP2C8, CYP2C9, or CYP2D6 or strong inhibitors or inducers of CYP3A4 (e.g., cyclosporine, tacrolimus or sirolimus). If antifungals are necessary from an infectious disease perspective, then they will be allowed only if the levels are therapeutic. Subjects taking proton pump inhibitors and unwilling to discontinue therapy for two days before and during the study drug dosing periods. Anti-arrhythmic medications known to cause QTc prolongation Tyrosine kinase inhibitor therapy Subjects with an abnormal Complete Blood Count (clinically insignificant changes would be acceptable based on the judgement of the investigators) Subjects on antiplatelet agents (Clopidogrel; Dipyridamole + ASA; ASA, Ticagrelor; Prasugrel; Ticlopidine or other) who are unable or unwilling to reduce or hold therapy prior to and during the study drug dosing periods and collection of bone biopsies. Subjects may continue their previous regimen between study drug dosing periods. Known allergy to dasatinib, quercetin, or nicotinamide riboside Subjects taking the following antimicrobial agents: Aminoglycosides, Azole antifungals (fluconazole, miconazole, voriconazole, itraconazole), Macrolides (clarithromycin, erythromycin), antivirals (nelfinavir, indinavir, saquinavir, ritonavir, elbasvir/grazoprevir) Presence of any condition the Investigator believes would place the subject at risk or would preclude the subject from successfully completing all aspects of the trial e.g., heart failure, malignancy etc. QTc >470 msec Inability to take oral medication The study will exclude subjects with inability to speak and understand Danish and with inability to cooperate
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Shakespeare Jeromdesella, MD
Phone
+4521351927
Email
shakespeare.jeromdesella@rsyd.dk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Moustapha Kassem, DMSc, PhD
Organizational Affiliation
Head of Research, Department of Endocrinology, Odense University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Odense University Hospital
City
Odense
ZIP/Postal Code
5000
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Shakespeare Jeromdesella, MD
Phone
+4521351927
Email
shakespeare.jeromdesella@rsyd.dk
First Name & Middle Initial & Last Name & Degree
Moustapha Kassem, DMSc, PhD
First Name & Middle Initial & Last Name & Degree
Morten F Nielsen, MD, PhD

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
After completion of the project and irrespective of the outcomes, de-identified trial results will be published in peer-reviewed journals and www.clinicaltrials.gov. A summary of the clinical trial results will be presented in a language understandable to the layperson and made available in the EU database.

Learn more about this trial

Senolytics to Improve Osteoporosis Therapy

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