SENIOR: SENolytics to Improve Osteoporosis Therapy

Sponsor

Odense University Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT06018467

Collaborator

Odense Patient Data Explorative Network (Other), Novo Nordisk A/S (Industry)

120

Enrollment

Location

Arms

Anticipated Duration (Months)

4.3

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Osteopenia, Osteoporosis	Drug: Dasatinib 100 Mg Oral Tablet Dietary Supplement: Quercetin 1.250 mg (oral) Dietary Supplement: Nicotinamide Riboside 1g (oral)	Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

SENolytics to Improve Osteoporosis Therapy: a Randomised Controlled Clinical Trial The SENIOR Trial

Anticipated Study Start Date :

Sep 1, 2023

Anticipated Primary Completion Date :

Dec 31, 2025

Anticipated Study Completion Date :

Dec 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dasatinib plus Quercetin (DQ) 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)	Drug: Dasatinib 100 Mg Oral Tablet Dasatinib tablets in blister packs of 10 tablets, from either: "Sandoz", "STADA Nordic", "Zentiva" or "Bristol-Myers Squibb" Other Names: Sprycel Dietary Supplement: Quercetin 1.250 mg (oral) five 200mg Quercetin Phytosome capsules, from Thorne Other Names: Quercetin Phytosome
Experimental: Nicotinamide Riboside (NR) The participants will receive treatment with 1g Nicotinamide Riboside (oral) daily for 20 weeks	Dietary Supplement: Nicotinamide Riboside 1g (oral) four 250mg Nicotinamide Riboside Capsules, from Elysium Health Other Names: NR
No Intervention: Control The participants in the Control group, will not receive any treatment for 20 weeks.

Arm

Intervention/Treatment

Experimental: Dasatinib plus Quercetin (DQ)

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)

Drug: Dasatinib 100 Mg Oral Tablet

Dasatinib tablets in blister packs of 10 tablets, from either: "Sandoz", "STADA Nordic", "Zentiva" or "Bristol-Myers Squibb"

Other Names:

Sprycel

Dietary Supplement: Quercetin 1.250 mg (oral)

five 200mg Quercetin Phytosome capsules, from Thorne

Other Names:

Quercetin Phytosome

Experimental: Nicotinamide Riboside (NR)

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

Dietary Supplement: Nicotinamide Riboside 1g (oral)

four 250mg Nicotinamide Riboside Capsules, from Elysium Health

Other Names:

No Intervention: Control

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

Outcome Measures

Primary Outcome Measures

Bone resorption marker CTX [Baseline, week 5, week 13, week 21]
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 [Baseline, week 5, week 13, week 21]
Change in circulating marker of bone resorption Tartrate Resistant Acid Phosphatase (TRAcP) at 21 weeks.
Bone formation markers (PINP, osteocalcin, and bone alkaline phosphatase) [Baseline, week 5, week 13, week 21]
Change in circulating markers of bone formation (PINP, osteocalcin, and bone alkaline phosphatase) at 21 weeks.

Eligibility Criteria

Criteria

Ages Eligible for Study:

60 Years to 90 Years

Sexes Eligible for Study:

All

Accepts 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